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Aum Gung Ganapathaye Namah
Namo tassa bhagavato arahato samma-sambuddhassa
Homage to The Blessed One, Accomplished and Fully Enlightened
In the name of Allah, Most Gracious, Most Merciful
Schizophrenia
A Collection of Articles, Notes and References
References
(Revised: Sunday, October 29, 2006)
References Edited by
A Mad Schizophrenic
What’s in a name? That which we call a rose
By any other name would smell as sweet.
- William Shakespeare
Copyright © 2006-2010 A Mad Schizophrenic
The following educational writings are STRICTLY for academic research purposes ONLY.
Should NOT be used for commercial, political or any other purposes.
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8 "... Freely you received, freely give”.
- Matthew 10:8 :: New American Standard Bible (NASB)

The attempt to make God just in the eyes of sinful men will always lead to error.
- Pastor William L. Brown.

1 “But mark this: There will be terrible times in the last days.
2 People will be lovers of themselves, lovers of money, boastful, proud, abusive, disobedient to their parents, ungrateful, unholy,
3 without love, unforgiving, slanderous, without self-control, brutal, not lovers of the good,
4 treacherous, rash, conceited, lovers of pleasure rather than lovers of God—
5 having a form of godliness but denying its power. Have nothing to do with them.
6 They are the kind who worm their way into homes and gain control over weak-willed women, who are loaded down with sins and are swayed by all kinds of evil desires,
7 always learning but never able to acknowledge the truth.
8 Just as Jannes and Jambres opposed Moses, so also these men oppose the truth--men of depraved minds, who, as far as the faith is concerned, are rejected.
9 But they will not get very far because, as in the case of those men, their folly will be clear to everyone.”
- 2 Timothy 3:1-9 :: New International Version (NIV)

The right to be left alone – the most comprehensive of rights, and the right most valued by a free people
- Justice Louis Brandeis, Olmstead v. U.S., 1928.

15 I know thy works, that thou art neither cold nor hot: I would thou wert cold or hot.
16 So then because thou art lukewarm, and neither cold nor hot, I will spue thee out of my mouth.
- Revelation 3:15-16 :: King James Version (KJV)

6 As he saith also in another place, Thou art a priest for ever after the order of Melchisedec.
- Hebrews 5:6 :: King James Version (KJV)

3 Without father, without mother, without descent, having neither beginning of days, nor end of life; but made like unto the Son of God; abideth a priest continually.
- Hebrews 7:3 :: King James Version (KJV)

Therefore, I say:
Know your enemy and know yourself;
in a hundred battles, you will never be defeated.
When you are ignorant of the enemy but know yourself,
your chances of winning or losing are equal.
If ignorant both of your enemy and of yourself,
you are sure to be defeated in every battle.
-- Sun Tzu, The Art of War, c. 500bc

There are two ends not to be served by a wanderer. What are these two? The pursuit of desires and of the pleasure which springs from desire, which is base, common, leading to rebirth, ignoble, and unprofitable; and the pursuit of pain and hardship, which is grievous, ignoble, and unprofitable.
- The Blessed One, Lord Buddha

3 Neither let the son of the stranger, that hath joined himself to the LORD, speak, saying, The LORD hath utterly separated me from his people: neither let the eunuch say, Behold, I am a dry tree.
- Isaiah 56:3 :: King James Version (KJV)

21 But this kind does not go out except by prayer and fasting.
- Matthew 17:21 :: Amplified Bible (AMP)

Contents
Color Code
A Brief Word on Copyright
References
Educational Copy of Some of the References

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A Brief Word on Copyright
Many of the articles whose educational copies are given below are copyrighted by their respective authors as well as the respective publishers. Some contain messages of warning, as follows:
Republication or redissemination of the contents of this screen are expressly prohibited
without the written consent of “so and so”.
According to the concept of “fair use” in US copyright Law,
The reproduction, redistribution and/or exploitation of any materials and/or content (data, text, images, marks or logos) for personal or commercial gain is not permitted. Provided the source is cited, personal, educational and non-commercial use (as defined by fair use in US copyright law) is permitted.
Moreover,
• This is a religious educational website.
o In the name of the Lord, with the invisible Lord as the witness.
• No commercial/business/political use of the following material.
• Just like student notes for research purposes, the writings of the other children of the Lord, are given as it is, with student highlights and coloring. Proper respects and due referencing are attributed to the relevant authors/publishers.
I believe that satisfies the conditions for copyright and non-plagiarism.
• Also, from observation, any material published on the internet naturally gets read/copied even if conditions are maintained. If somebody is too strict with copyright and hold on to knowledge, then it is better not to publish “openly” onto the internet or put the article under “pay to refer” scheme.
• I came across the articles “freely”. So I publish them freely with added student notes and review with due referencing to the parent link, without any personal monetary gain. My purpose is only to educate other children of the Lord on certain concepts, which I believe are beneficial for “Oneness”.

References
Some of the links may not be active (de-activated) due to various reasons, like removal of the concerned information from the source database. So an educational copy is also provided, along with the link.
If the link is active, do cross-check/validate/confirm the educational copy of the article provided along.
1. If the link is not active, then try to procure a hard copy of the article, if possible, based on the reference citation provided, from a nearest library or where-ever, for cross-checking/validation/confirmation.

Notes

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Reference
Energy The Invisible Living Lord
http://www.geocities.com/praisethebuddha/lordenergy/chap.html

Concentration

Even if the body gets destroyed, all are in the hands of the Lord. A new vehicle (body is only a vehicle) will be given to continue, from where one left off. So nothing to worry about.

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Wealth as a simile (from the Anguttara Nikaya):
Sakya Sutta (AN X.47) -- Sakya. Money can't buy you happiness, but practicing the Dhamma can.
(Reference: 188)

Anguttara Nikaya X.47
Sakka Sutta
To the Sakyans (on the Uposatha)


Translated from the Pali by Thanissaro Bhikkhu.
For free distribution only.

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On one occasion the Blessed One was staying near Kapilavatthu at the Banyan Park. Then many Sakyan lay followers, it being the Uposatha day, went to the Blessed One. On arrival, having bowed down to him, they sat to one side. As they were sitting there, the Blessed One said to them, "Sakyans, do you observe the eight-factored uposatha?"
"Sometimes we do, lord, and sometimes we don't."

"It's no gain for you, Sakyans. It's ill-gotten, that in this life so endangered by grief, in this life so endangered by death, you sometimes observe the eight-factored uposatha and sometimes don't.

"What do you think, Sakyans. Suppose a man, by some profession or other, without encountering an unskillful day, were to earn a half-kahapana. Would he deserve to be called a capable man, full of initiative?"

"Yes, lord."

"Suppose a man, by some profession or other, without encountering an unskillful day, were to earn a kahapana... two kahapanas... three... four... five... six... seven... eight... nine... ten... twenty... thirty... forty... fifty... one hundred kahapanas. Would he deserve to be called a capable man, full of initiative?"

"Yes, lord."

"Now what do you think: earning one hundred, one thousand kahapanas a day; saving up his gains, living for one hundred years, would a man arrive at a great mass of wealth?"

"Yes, lord."

"Now what do you think: would that man, because of that wealth, on account of that wealth, with that wealth as the cause, live sensitive to unalloyed bliss for a day, a night, half a day, or half a night?"

"No, lord. And why is that? Sensual pleasures are inconstant, hollow, false, deceptive by nature."

"Now, Sakyans, there is the case where a disciple of mine, spending ten years practicing as I have instructed, would live sensitive to unalloyed bliss for a hundred years, a hundred centuries, a hundred millenia. And he would be a once-returner, a non-returner, or at the very least a stream-winner.

"Let alone ten years, there is the case where a disciple of mine, spending nine years... eight years... seven... six... five... four... three... two years... one year practicing as I have instructed, would live sensitive to unalloyed bliss for a hundred years, a hundred centuries, a hundred millenia. And he would be a once-returner, a non-returner, or at the very least a stream-winner.

"Let alone one year, there is the case where a disciple of mine, spending ten months... nine months... eight months... seven... six... five... four... three... two months... one month... half a month practicing as I have instructed, would live sensitive to unalloyed bliss for a hundred years, a hundred centuries, a hundred millenia. And he would be a once-returner, a non-returner, or at the very least a stream-winner.

"Let alone half a month, there is the case where a disciple of mine, spending ten days & nights... nine days & nights... eight... seven... six... five... four... three... two days & nights... one day & night practicing as I have instructed, would live sensitive to unalloyed bliss for a hundred years, a hundred centuries, a hundred millenia. And he would be a once-returner, a non-returner, or at the very least a stream-winner.

"It's no gain for you, Sakyans. It's ill-gotten, that in this life so endangered by grief, in this life so endangered by death, you sometimes observe the eight-factored uposatha and sometimes don't."

"Then from this day forward, lord, we will observe the eight-factored uposatha."


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See also: AN III.70; AN VIII.43; Ud II.10; "Uposatha Observance Days" in the Path to Freedom Pages.
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Revised: Fri 17 May 2002
http://www.accesstoinsight.org/canon/anguttara/an10-047.html

192. Bhikkhu, Thanissaro. (Translated from the Pali) Anguttara Nikaya X.47. Sakka Sutta. To the Sakyans (on the Uposatha).
http://www.accesstoinsight.org/canon/anguttara/an10-047.html

(Reference: Bhikkhu, Thanissaro. (Translated from the Pali)
Anguttara Nikaya X.47. Sakka Sutta. To the Sakyans (on the Uposatha))

(Reference: 192)
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Thus an adept who “dies” and returns/reborn in human form need to train a lesser time than a non-adept to “awaken” to his previous state, the state of spiritual achievement just before “death” in previous life.

Since all energy, a higher level achievement never goes away. Never disappear. It is similar to an ever-lasting bank-account. The more work you do, the payment for the work goes into the account. You die and come back in a new body. But you are the same energy. The account you left in the previous life is still open with the bank balance you left. You again start accumulating from where you left off. You never start all from the beginning. You can’t. No one can. The accumulated karma, action, reaction remains.
There are many adepts who left their body after reaching a certain stage of development. When re-born, they may be asleep as the ordinary masses. But the invisible Lord creates scenarios for them to access their account from past lives. For example, the person may be very interested in spiritual things from a very young age. Certain environments may force warfare on such a trainee. The “sleepy” trainee stumbles to meditation practices. Intense meditation over a short period opens up his account from previous lives. The trainee slowly wakes up to a new level of understanding and way of life. Concepts like “siddhis” fall under this category. Such power require long duration of intense training, austerities and meditation. Not at all possible for a modern man to achieve with a few days or months of “intense” practice.
Such spiritual concepts itself act as an armour on the trainee.
The ancient legends mention the above concept by means of a strange story, with heavy inner meaning. The birth of Karna, the son of the Sun-God, born with in-built armour for protection. As long as such an armour exist, the warrior can never ever be defeated in a battle.

An Imaginary Chat 4

“ I used to emphasize intense meditation over a long duration. The Lord created a scenario where I was taken to a Zen master. A very different form of ideology was put forward by the master. Actual sitting meditation need not be for long hours. Anything a person do in his daily life is meditation. It incorporates concentration.”

Let’s try to quantify concentration in numbers, in a fictitious manner. Instead of money account, let it be concentration account. The amount of concentration in seconds, minutes, hours, days, months etc.
Achieving a certain level, say siddhis, require a certain level of concentration in the account. Anyone who achieves the required account gets the siddhi.

Consider two people at the same level of spirituality. One person did intense meditation, thereby fast-tracking the amount of concentration. The concentration account increases by hours, random jumps. He builds up his account in one life time to the required level of siddhi and achieves that stage.
The other person did not fast track. He lived a normal day-to-day life like the ordinary masses. He used to sleep as everyone. He works. He drives vehicle. He does his prayers and so on. BUT in all these activities, concentration account is slowly increasing in seconds, minutes. For any job or work or activity, be it mental or manual require concentration. He died and again came back in human form and lived normally. Again the concentration began to accumulate from the previous left-off level. After a certain number of births, his account equalized with that amount required for reaching that specific spiritual stage. He also achieves the “siddhi”.
If we look from such an angle, all human beings, man or woman are actually monks and nuns in training on a daily basis. But living in an ignorant state of who and what they are.
Yes, on the battle field, Lord Krishna advises the four stage of life – brahmacharya etc for the ordinary masses. The ones who sleep. He also mentions the exceptional case of those who slowly wake up. Such exceptions do not follow the four stages, for they are already in the true state of monk-hood – the only state or way of life of a human being.

6 As he saith also in another place, Thou art a priest for ever after the order of Melchisedec.
- Hebrews 5:6 :: King James Version (KJV)

So, is concentration, the true activity going on everywhere? Any part of the planet. By one way or other? Be it “good” or “evil”. Any job. Any work. Any activity.
What else?
Energy concentration. Concentration of energy.
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Sri Sankara writes in the commentary on Chhandogya Upanishad (VII-xx-1) that a man's duty consists in the control of the senses and concentration of mind. So long as the thoughts of one are not thoroughly destroyed through persistent practice, he should ever be concentrating his mind on one truth at a time. Through such unremitting practice, one-pointedness will accrue to the mind and instantly, all the hosts of thoughts will vanish. Concentration is opposed to sensuous desires, bliss to flurry and worry, sustained thinking to perplexity, applied thinking to sloth to torpor, rapture to ill-will.

You are born to concentrate the mind on God after collecting the mental rays that are dissipated on various objects. That is your important duty. You forget the duty on account of Moha for family, children, money, power, position, respect, name and fame.

Concentration of the mind on God after purification can give you real happiness and knowledge. You are born for this purpose only. You are carried away to external objects through Raga and Moha (attachment and infatuated love).

Fix the mind on Atman. Fix the mind on the all-pervading, pure Intelligence and self-luminous effulgence (Svayamjyotis). Stand firm in Brahman. Then will you become 'Brahma-samstha,' established in Brahman.
(Reference: Swami Sivananda. (1998) Mind--Its Mysteries and Control. (WWW Edition) Himalayas, India: The Divine Life Society. Chapter 31. Concentration. Concentration, Man's Foremost Duty.)

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Reference
Narada Mahathera. (1982) Buddhism in a Nutshell. Kandy, Sri Lanka: Buddhist Publication Society.
http://www.accesstoinsight.org/lib/bps/misc/nutshell.html

Chapter XI
The Path to Nibbana
How is Nibbana to be attained?

It is by following the Noble Eight-fold Path which consists of Right Understanding (Samma-ditthi), Right Thoughts (samma-sankappa), Right Speech (samma-vaca), Right Actions (samma-kammanta), Right Livelihood (samma-ajiva), Right Effort (samma-vayama), Right Mindfulness (samma-sati), and Right Concentration (samma-samadhi).

1. Right Understanding, which is the key-note of Buddhism, is explained as the knowledge of the four Noble Truths. To understand rightly means to understand things as they really are and not as they appear to be. This refers primarily to a correct understanding of oneself, because, as the Rohitassa Sutta states, "Dependent on this one-fathom long body with its consciousness" are all the four Truths. In the practice of the Noble Eightfold Path, Right Understanding stands at the beginning as well as at its end. A minimum degree of Right Understanding is necessary at the very beginning because it gives the right motivations to the other seven factors of the Path and gives to them correct direction. At the culmination of the practice, Right Understanding has matured into perfect Insight Wisdom (vipassana-pañña), leading directly to the Stages of Sainthood.

2. Clear vision of right understanding leads to clear thinking. The second factor of the Noble Eight-fold Path is therefore, Right Thoughts (samma-sankappa), which serves the double purpose of eliminating evil thoughts and developing pure thoughts. Right Thoughts, in this particular connection, are three fold. They consist of:

i. Nekkhamma -- Renunciation of worldly pleasures or the virtue of selflessness, which is opposed to attachment, selfishness, and possessiveness;
ii. Avyapada -- Loving-kindness, goodwill, or benevolence, which is opposed to hatred, ill-will, or aversion; and
iii. Avihimsa -- Harmlessness or compassion, which is opposed to cruelty and callousness.

3. Right Thoughts lead to Right Speech, the third factor. This includes abstinence from falsehood, slandering, harsh words, and frivolous talk.

4. Right Speech must be followed by Right Action which comprises abstinence from killing, stealing and sexual misconduct.

5. Purifying his thoughts, words and deeds at the outset, the spiritual pilgrim tries to purify his livelihood by refraining from the five kinds of trade which are forbidden to a lay-disciple. They are trading in arms, human beings, animals for slaughter, intoxicating drinks and drugs, and poisons.

For monks, wrong livelihood consists of hypocritical conduct and wrong means of obtaining the requisites of monk-life.

6. Right Effort is fourfold, namely:

i. the endeavor to discard evil that has already arisen;
ii. the endeavor to prevent the arising of unarisen evil;
iii. the endeavor to develop unarisen good;
iv. the endeavor to promote the good which has already arisen.

7. Right Mindfulness is constant mindfulness with regard to body, feelings, thoughts, and mind-objects.

8. Right Effort and Right Mindfulness lead to Right Concentration. It is the one-pointedness of mind, culminating in the Jhanas or meditative absorptions.

Of these eight factors of the Noble Eightfold Path the first two are grouped under the heading of Wisdom (pañña), the following three under Morality (sila), and the last three under Concentration (samadhi). But according to the order of development the sequence is as follows:

I. Morality (sila)
Right Speech
Right Action
Right Livelihood

II. Concentration (samadhi)
Right Effort
Right Mindfulness
Right Concentration

III. Wisdom (pañña)
Right Understanding
Right Thoughts

Morality (sila) is the first stage on this path to Nibbana.

Without killing or causing injury to any living creature, man should be kind and compassionate towards all, even to the tiniest creature that crawls at his feet. Refraining from stealing, he should be upright and honest in all his dealings. Abstaining from sexual misconduct which debases the exalted nature of man, he should be pure. Shunning false speech, he should be truthful. Avoiding pernicious drinks that promote heedlessness, he should be sober and diligent.

These elementary principles of regulated behavior are essential to one who treads the path to Nibbana. Violation of them means the introduction of obstacles on the path which will obstruct his moral progress. Observance of them means steady and smooth progress along the path.

The spiritual pilgrim, disciplining thus his words and deeds, may advance a step further and try to control his senses.

While he progresses slowly and steadily with regulated word and deed and restrained senses, the Kammic force of this striving aspirant may compel him to renounce worldly pleasures and adopt the ascetic life. To him then comes the idea that,

"A den of strife is household life,
And filled with toil and need;
But free and high as the open sky
Is the life the homeless lead."

It should not be understood that everyone is expected to lead the life of a Bhikkhu or a celibate life to achieve one's goal. One's spiritual progress is expedited by being a Bhikkhu although as a lay follower one can become an Arahat. After attaining the third state of Sainthood, one leads a life of celibacy.

Securing a firm footing on the ground of morality, the progressing pilgrim then embarks upon the higher practice of Samadhi, the control and culture of the mind -- the second stage on this Path.

Samadhi -- is the "one-pointedness of the mind." It is the concentration of the mind on one object to the entire exclusion of all irrelevant matter.

There are different subjects for meditation according to the temperaments of the individuals. Concentration on respiration is the easiest to gain the one-pointedness of the mind. Meditation on loving-kindness is very beneficial as it is conducive to mental peace and happiness.

Cultivation of the four sublime states -- loving-kindness (Metta), compassion (Karuna), sympathetic joy (Mudita), and equanimity (Upekkha) -- is highly commendable.

After giving careful consideration to the subject for contemplation, he should choose the one most suited to his temperament. This being satisfactorily settled, he makes a persistent effort to focus his mind until he becomes so wholly absorbed and interested in it, that all other thoughts get ipso facto excluded from the mind. The five hindrances to progress -- namely, sense-desire, hatred, sloth and torpor, restlessness and brooding and doubts are then temporarily inhibited. Eventually he gains ecstatic concentration and, to his indescribable joy, becomes enwrapt in Jhana, enjoying the calmness and serenity of a one-pointed mind.

When one gains this perfect one-pointedness of the mind it is possible for one to develop the five Supernormal Powers (Abhiñña): Divine Eye (Dibbacakkhu), Divine Ear (Dibhasota), Reminiscence of past births (Pubbenivasanussati-ñana). Thought Reading (Paracitta vijañana) and different Psychic Powers (Iddhividha). It must not be understood that those supernormal powers are essential for Sainthood.

Though the mind is now purified there still lies dormant in him the tendency to give vent to his passions, for by concentration, passions are lulled to sleep temporarily. They may rise to the surface at unexpected moments.

Both Discipline and Concentration are helpful to clear the Path of its obstacles but it is Insight (Vipassana Pañña) alone which enables one to see things as they truly are, and consequently reach the ultimate goal by completely annihilating the passions inhibited by Samadhi. This is the third and the final stage on the Path of Nibbana.

With his one-pointed mind which now resembles a polished mirror he looks at the world to get a correct view of life. Wherever he turns his eyes he sees nought but the Three Characteristics -- Anicca (transiency), Dukkha (sorrow) and anatta (soul-lessness) standing out in bold relief. He comprehends that life is constantly changing and all conditioned things are transient. Neither in heaven nor on earth does he find any genuine happiness, for every form of pleasure is a prelude to pain. What is transient is therefore painful, and where change and sorrow prevail there cannot be a permanent immortal soul.

Whereupon, of these three characteristics, he chooses one that appeals to him most and intently keeps on developing Insight in that particular direction until that glorious day comes to him when he would realize Nibbana for the first time in his life, having destroyed the three Fetters -- self-illusion (Sakkaya-ditthi), doubts (Vvicikiccha), indulgence in (wrongful) rites and ceremonies (Silabbataparamasa).

At this stage he is called a Sotapanna (Stream-Winner) -- one who has entered the stream that leads to Nibbana. As he has not eradicated all Fetters he is reborn seven times at the most.

Summoning up fresh courage, as a result of this glimpse of Nibbana, the Pilgrim makes rapid progress and cultivating deeper Insight becomes a Sakadagami (Once Returner) by weakening two more Fetters -- namely Sense-desire (Kamaraga) and ill-will (Patigha). He is called a Sakadagami because he is reborn on earth only once in case he does not attain Arhatship.

It is in the third state of Sainthood -- Anagama (Never-Returner) that he completely discards the aforesaid two Fetters. Thereafter, he neither returns to this world nor does he seek birth in the celestial realms, since he has no more desire for sensual pleasures. After death he is reborn in the "Pure Abodes" (Suddhavasa) a congenial Brahma plane, till he attains Arhatship.

Now the saintly pilgrim, encouraged by the unprecedented success of his endeavors, makes his final advance and, destroying the remaining Fetters -- namely, lust after life in Realms of Forms (Ruparaga) and Formless Realms (Aruparaga), conceit (Mana), restlessness (Uddhacca), and ignorance (Avijja) -- becomes a perfect Saint: an Arahant, a Worthy One.

Instantly he realizes that what was to be accomplished has been done, that a heavy burden of sorrow has been relinquished, that all forms of attachment have been totally annihilated, and that the Path to Nibbana has been trodden. The Worthy One now stands on heights more than celestial, far removed from the rebellious passions and defilements of the world, realizing the unutterable bliss of Nibbana and like many an Arahat of old, uttering that paean of joy:

"Goodwill and wisdom, mind by method trained,
The highest conduct on good morals based,
This maketh mortals pure, not rank or wealth."

As T.H. Huxley states -- "Buddhism is a system which knows no God in the Western sense, which denies a soul to man, which counts the belief in immortality a blunder, which refuses any efficacy to prayer and sacrifice, which bids men to look to nothing but their own efforts for salvation, which in its original purity knew nothing of vows of obedience and never sought the aid of the secular arm: yet spread over a considerable moiety of the world with marvelous rapidity -- and is still the dominant creed of a large fraction of mankind."
(Reference: Narada Mahathera. (1982) Buddhism in a Nutshell. Kandy, Sri Lanka: Buddhist Publication Society.)
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To ponder…
If you believe the above Buddhist concept on spiritual evolution, then ponder on what happens to these

At this stage he is called a Sotapanna (Stream-Winner) -- one who has entered the stream that leads to Nibbana. As he has not eradicated all Fetters he is reborn seven times at the most.

Where are they??
If you take the planet as whole, these people have to be amongst us…
And they need not necessarily be monks…just ordinary men and women like you or me…
By their past spiritual practices, they have reached a certain level where in celibacy in form or another is inculcated into their life…is part and parcel of their life…have to be…and that celibacy or prevention of sexual indulgence can take various forms – the specific man or woman may be ailing with some mental or bodily ailment which prevents the person from indulgence – a protective cover, say. The ailment can even take the form of deformation or accidents which just put a full stop to any form of bodily sexual indulgence. Or maybe the person by virtue of intelligence and cross questioning may have reached a personal decision to abstain or even to become a monk or nun.
Written around 02:35 pm Wednesday, February 04, 2004

An offshoot of such a reasoning or interpretation:
The modern concept that sexual indulgence is a requirement for man or woman is wrong. There are various factors – external environment, past lives, previous spiritual practices etc which play a vital part in one’s life. For no matter who you are, the following concept is always valid, and it includes celibacy and ascetic practices in your day to day life…
Written around 02:40 pm Wednesday, February 04, 2004

6 As he saith also in another place, Thou art a priest for ever after the order of Melchisedec.
- Hebrews 5:6 :: King James Version (KJV)

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References
Kaplan & Sadock's Comprehensive Textbook of Psychiatry Seventh Edition

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Educational Copy of Some of the References
FOR EDUCATIONAL PURPOSES ONLY
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Reference
Kaplan & Sadock's Comprehensive Textbook of Psychiatry Seventh Edition

12.1 Schizophrenia: Introduction and Overview

ROBERT W. BUCHANAN, M.D., and WILLIAM T. CARPENTER, JR., M.D.
Schizophrenia is the paradigmatic illness of psychiatry. It is a clinical syndrome of variable but profoundly disruptive psychopathology, which involves thought, perception, emotion, movement, and behavior. The expression of these symptoms varies across patients and over time, but the cumulative effect of the illness is always severe and usually long lasting.
HISTORY
Written descriptions of symptoms commonly observed today in patients with schizophrenia are found throughout recorded history. Early Greek physicians described delusions of grandeur, paranoia, and deterioration in cognitive functions and personality. These behaviors were generally considered to merit social sanction. However, since these symptoms are not necessarily unique to schizophrenia, one cannot be certain whether these behaviors were actually associated with what today would be called schizophrenia. Indeed, several scholars have argued that schizophrenia is of relatively recent origin.
Schizophrenia did not emerge as a medical condition worthy of study and treatment until the eighteenth century. By the nineteenth century the various psychotic disorders were generally viewed as insanity or madness, and the movement to conceptualize the condition as a regrettable affliction replaced the view of insanity as a reprehensible behavior. During the middle to late nineteenth century many clinical categories were described, but a general approach capable of integrating the widely diverse manifestations of mental illness into distinguishable clinical syndromes was lacking.
A major impediment to distinguishing schizophrenia from other forms of psychoses was the existence of another common type of insanity, general paresis. The symptom manifestations of general paresis were quite diverse and overlapped extensively with those of schizophrenia. The cause of syphilitic insanity was subsequently traced to a spirochetal infestation, and antibiotics were eventually found to be effective in treatment and prevention. The identification of syphilitic insanity enabled Emil Kraepelin to delineate the two other major patterns of insanity: manic-depressive psychosis and dementia praecox (or dementia of the young), and to group together under the diagnostic category of dementia precox the previously disparate categories of insanity, such as hebephrenia, paranoia, and catatonia. In differentiating dementia precox from manic-depressive disorder, Kraepelin emphasized what he believed to be the characteristic poor long-term prognosis of dementia precox, as compared to the relatively nondeteriorating course of manic-depressive illness. In Dementia Praecox and Pathophysiology (1919) Kraepelin went on to describe what he believed to be the two principal pathophysiological or disease processes occurring in dementia precox:
On the one hand we observe a weakening of those emotional activities which permanently form the mainsprings of volition. In connection with this, mental activity and instinct for occupation become mute. The result of this part of the process is emotional dullness, failure of mental activities, loss of mastery over volition, of endeavor, and of ability for independent action. The essence of personality is thereby destroyed, the best and most precious part of its being, as Griesinger once expressed it, torn from her ¼ . The second group of disorders, which gives dementia praecox its peculiar stamp ¼ consists in the loss of the inner unity of the activities of intellect, emotion, and volition in themselves and among one another. Stransky speaks of an annihilation of the "intrapsychic co-ordination" ¼ [T]his annihilation presents itself to us in the disorders of association described by Bleuler, in incoherence of the train of thought, in the sharp change of moods as well as in desultoriness and derailments in practical work. But further, the near connections between thinking and feeling, between deliberation and emotional activity on the one hand, and practical work on the other is more or less lost. Emotions do not correspond to ideas.
The description of the former process provides the conceptual framework for the avolitional or negative symptom component of the illness, and the description of the latter process provides the conceptual framework for the positive symptoms of schizophrenia.
In 1911 Eugen Bleuler, recognizing that dementia was not a usual characteristic of dementia precox, suggested the term schizophrenia (splitting of the mind) for the disorder. Bleuler introduced the concept of primary and secondary schizophrenic symptoms; his four primary symptoms (the four As) were abnormal associations, autistic behavior and thinking, abnormal affect, and ambivalence. Of these four symptoms Bleuler viewed as central to the illness the loss of association between thought processes and among thought, emotion, and behavior. Typical examples of these losses of associations are silly giggling on receiving news of the death of a loved one, the introduction of magical thinking and peculiar concepts into an ordinary discussion, and the sudden display of angry behavior without experiencing anger (or an understandable provocation).
Bleuler's view that a dissociative process is fundamental to schizophrenia and that this process underlies a wide variety of the symptom manifestations of schizophrenia has supported a major paradigm for conceptualizing the illness, namely, that in spite of its various manifestations, schizophrenia is a single disease entity in which there is extensive similarity in cause (etiology) and mechanism (pathophysiology) across all patients with the disorder. In this view, a neurophysiological disturbance of indeterminate origin and nature occurs that is manifest as dissociative processes adversely influencing the development of mental capacities in the areas of thought, emotion, and behavior. Depending on the individual's adaptive capacity and environmental circumstances, this fundamental process could lead to secondary disease manifestations such as hallucinations, delusions, social withdrawal, and diminished drive.
There are many parallels in medicine for this single-disease model. Diabetic patients share an impairment in glucose metabolism, but the secondary manifestations vary considerably depending on which organ systems are involved. Similarly, seizure disorders may share a common pathophysiological mechanism, but different lesion locations lead to marked variability in signs and symptoms. One patient may have full-body convulsions, while another may experience strange sexual sensations and excessive religiosity. The diverse manifestations of syphilitic insanity best illustrate the utility of this disease-entity approach for schizophrenia.
The major alternative etiopathophysiological model conceptualizes schizophrenia as a clinical syndrome rather than a single disease entity. This view holds that although patients with schizophrenia share a sufficient commonality of signs and symptoms to validly differentiate them from patients with other forms of psychosis (e.g., mood disorder with psychotic features, substance-induced psychotic disorder), more than one disease entity will eventually be found within this syndrome. This view is supported by the existence of multiple risk factors and heterogeneity in clinical presentation, treatment response, and clinical course. The emergence over the past 50 years of proof that mental retardation is a clinical syndrome comprised of multiple disease entities rather than a single disease entity best illustrates this construct. Schizophrenia currently maintains the status of a clinical syndrome in the absence of evidence for the existence of a single disease entity.
There are other competing models for conceptualizing schizophrenia, which, although seriously debated in the past, are presently dismissed as demonstrably invalid or so seriously reductionistic as to not account for major observations associated with the illness. Nondisease models, such as the societal reaction theory ("a sane reaction to an insane world") or Thomas Szasz's theory that schizophrenia is a myth enabling society to manage deviant behavior, cannot adequately account for the distribution of schizophrenia among biological relatives, the myriad of associated brain abnormalities, the normalizing effects of drug treatment, and the extensive similarity and lifetime prevalence and clinical manifestations of schizophrenia across widely divergent cultures. Narrow framework disease models that attempt to account for the illness solely at the level of psychological mechanisms are also demonstrably inadequate in accommodating the known facts of the illness. Genetic or immunovirological causal factors cannot be addressed by reductionistic theories operating at the psychological or social levels. The many biological, psychological, and social factors relevant to the understanding and treatment of the person with schizophrenia require a broad medical model and eschew reduction to any single level of the functioning organism.
In summary, schizophrenia is appropriately and accurately conceptualized as a disease process. Although it is possible that a unifying etiology or pathophysiology will eventually be uncovered that will account for all or almost all cases, it seems more likely that more than one disease entity exists within the clinical syndrome of schizophrenia, with each having a distinguishable etiology and pathophysiology. Any reductionistic approach to the description or explanation of the disorder cannot adequately account for the range of relevant information and facts. A broad medical model that integrates factors ranging from the molecular to the psychosocial level of organization is necessary to describe schizophrenia, to account for the range of pathogenic influences, and to provide for treatment and rehabilitation.
EPIDEMIOLOGY
Schizophrenia is a leading public health problem that exacts enormous personal and economic costs worldwide. Schizophrenia affects just under 1 percent of the world's population (approximately 0.85 percent). The number of affected individuals increases if schizophrenia spectrum disorders are included in prevalence estimates. The concept of schizophrenia spectrum disorders is derived from observations of psychopathological manifestations in the biological relatives of patients with schizophrenia. Diagnoses and approximate lifetime prevalence rates (percentage of population) for spectrum disorders are: schizoid personality disorder (fractional), schizotypal personality disorder (1 to 4 percent), schizoaffective psychosis (0.7 percent), and atypical psychoses and delusional disorder (0.7 percent). The relation of these disorders to schizophrenia in the general population is unclear, but in family pedigree studies the presence of a proband with schizophrenia significantly increases the prevalence of these disorders among biological relatives.
Schizophrenia is found in all societies and geographical areas. Although comparable data are difficult to obtain, incidence and lifetime prevalence rates are roughly equal worldwide. The positive symptom component of the disorder usually becomes manifest during late adolescence and early adulthood, although there is a difference in onset associated with gender. In males, the incidence of the onset of positive symptoms peaks during years 17 to 27, whereas in females the peak incidence is a lengthy plateau between the years 17 to 37. Rural and urban incidence figures are probably similar, but there is a greater prevalence of schizophrenia among urban and lower socioeconomic populations. This is generally attributed to the "social drift" phenomenon in which afflicted or vulnerable individuals tend to lose their occupation and social niche and drift toward pockets of poverty and inner-city areas. Occasional geographical areas of increased prevalence of schizophrenia are interesting in terms of illness etiology. For example, a Northern Scandinavian isolated population appears to have a gene pool enriched for schizophrenia vulnerability, probably brought to the region generations ago by two immigrating families.
Because schizophrenia begins early in life; causes significant and long-lasting impairments; makes heavy demands for hospital care; and requires ongoing clinical care, rehabilitation, and support services, the financial cost of the illness in the United States is estimated to exceed that of all cancers combined. In 1990 the direct and indirect costs of schizophrenia were estimated at $33 billion. The locus of care has shifted dramatically over the last 40 years from long-term hospital-based care to acute hospital care and community-based services. In 1955 about 500,000 hospital beds in the United States were occupied by the mentally ill, the majority of whom had a diagnosis of schizophrenia; that figure is now under 250,000.
Deinstitutionalization has dramatically reduced the number of beds in custodial facilities, but an overall evaluation of the consequences of deinstitutionalization is disheartening. Many patients have simply been transferred to alternative forms of custodial care (instead of to treatment or rehabilitative services), including nursing home care and poorly supervised shelter arrangements. Others have been released to communities often unable or unwilling to provide the minimal requirements for clinical care or humane support. For the more fortunate patients the burden of care has shifted to the family, creating an extreme hardship for large numbers of families in this country. The estimated overall financial burden to these families ranges from $2 to 2.5 billion. The less fortunate patient may either have no place to live, be forced to live in circumstances of isolation and hopelessness, or end up in jail. Patients with a diagnosis of schizophrenia are reported to account for 33 to 50 percent of homeless Americans. Managed care places further pressure to reduce bed utilization while communities remain marginally prepared and a relative dearth of alternative care systems exists. Continuity-of-care systems, which include assertive outreach programs and supervised housing and emergency care, provide an effective alternative to hospital-based care for many patients, but costs are substantial, and simply shifting cost from impoverished public hospital sectors has not proved feasible.
ETIOLOGY
The etiological process or processes by which a causal agent creates the pathophysiology of schizophrenia is not yet known. However, a good deal is known about risk factors for developing schizophrenia, which leads to direct inferences regarding possible etiopathophysiologies. Family, twin, and adoptive studies have long since documented a robust contribution of genetic factors to the etiology of schizophrenia, with genetic factors established as relevant to some, perhaps all, cases. However, it is not yet known which genes are involved or how the proteins they produce contribute to the pathophysiology of schizophrenia. Recent linkage analyses have made substantial progress towards identifying a potential location on chromosome 6, and have also provided preliminary indications of additional genetic contributions associated with chromosomes 4, 8, 15, and 22. Other markers of early influences, including gestational and birth complications, exposure to influenza epidemics, Rhesus (Rh) incompatibility, starvation, and an excess of winter births, further suggest a neurodevelopmental pathological process in schizophrenia; however, here, too, the exact pathophysiological mechanisms associated with these risk factors are not known. There are interesting reports that a subgroup of patients with the avolitional component of the illness, as assessed by the deficit syndrome, do not share in the winter birth excess, but rather show a summer birth excess, suggesting the possibility of a separate disease entity within the schizophrenia syndrome. A number of speculations regarding viral and immune mechanisms, sometimes posited as an explanation of the season of birth risk factor, are plausible, but no virus or immune mechanism has yet been established as an etiological factor in schizophrenia. Finally, substance abuse has been identified as a risk factor for developing schizophrenia.
A central conceptual issue in the investigation of the etiology of schizophrenia is whether schizophrenia is a neurodevelopmental or a neurodegenerative disorder. Is the cause of schizophrenia to be found in the failure of the normal development of the brain, or is it to be found in a disease process that alters a normally developed brain? Both these options, or a combination of these options, may be true because the schizophrenia syndrome probably represents more than one disease process, or a developmental abnormality may increase the risk for the subsequent occurrence of the disorder. Although Kraepelin believed that schizophrenia had an early onset and was a chronic deteriorating disorder, the examination of the clinical course of the illness has not been helpful in clarifying this issue. Subtle neurological manifestations, cognitive dysfunction, and disturbances in affect are often present early in the course of illness, usually prior to the onset of hallucinations and delusions, and perhaps from birth. However, it is not clear whether these abnormalities reflect abnormal brain development or are the consequences of an early lesion to a normal brain. Nor is it clear whether the early morbid picture progresses into the full manifestation of psychosis or whether early morbidity represents a vulnerability state susceptible to expressing psychosis in the context of a later lesion, or stressful new demands on cognition and interpersonal skills later in adolescence and early adulthood. It is clear that the illness process usually plateaus within the first 5 to 10 years of psychosis and does not manifest progressive deterioration throughout its course. Late-life improvement, perhaps based on a decrease in the intensity of the psychotic component of the illness, is more typical than continued progression.
An alternative perspective, which has produced somewhat less ambiguous results, is the neuropathological investigation of schizophrenia. Although there are sporadic reports of gliosis in schizophrenic brains, which may indicate the presence of a neurodegenerative disease process and subsequent neuropathological response, the preponderance of current evidence is consistent with the hypothesis that schizophrenia is a neurodevelopmental disorder. Of particular relevance in this regard are the neuropsychological, cognitive psychological, and neuroimaging findings in first-episode cases, which tend to be similar to findings in more chronic cases and, in the few longitudinal studies, tend not to progress. Perhaps even more decisive are abnormalities in morphological features, which are believed to be developmental in nature and are associated with at least some forms of schizophrenia. Such findings range from abnormalities in peripheral development such as finger ridge formation to abnormal cell migration to landmarks of abnormal brain development such as asymmetry of the planum temporale. The consistency with which the known data point to early deviations in the development of the central nervous system has been useful in focusing theory and investigative work.
The explosion of information on the neurobiology of brain development has led to considerable new knowledge on the potential mechanisms of pathogenic influences. It is now clear that subtle deviations in the development of the brain could create dysfunctions associated with specific behaviors. Postmortem findings of abnormalities in neural plate formation, which suggest a deviation in programmed cell migration or reduced cell density, provide intriguing support for the proposition that the developmental process that establishes normal brain cytoarchitecture may have gone awry in schizophrenia. Another view is that the brain has established extensive redundancy during the developing years, and that the fine-tuning necessary for efficient functioning involves eliminating certain nerve cells and many of the synapses connecting cells. A failure to adequately prune nerve cells and synapses, or to err in selection for pruning could, in theory, underlie dysfunctions that later lead to schizophrenia symptoms. Altered nerve cell migration or pruning are speculative, but illustrate plausible mechanisms by which risk factors could alter normal brain development in schizophrenia.
Principal hypotheses regarding causation include altered expression of genes, neuroimmunovirology factors, and birth and pregnancy complications such as hypoxic or neurotoxic damage.
Altered Expression of Genes
Schizophrenia and schizophrenia-related disorders (i.e., schizotypal, schizoid, and paranoid personality disorders; schizophreniform disorder; and other nonaffective psychotic disorders) occur at an increased rate among the biological relatives of patients with schizophrenia. This increased rate is most dramatically illustrated in the case of monozygotic twins, who have an identical genetic endowment and a concordance rate for schizophrenia between 40 to 50 percent. This rate is four to five times the concordance rate in dizygotic twins or the rate of occurrence found in other first-degree relatives (i.e., siblings, parents, or offspring). The role of genetic factors is further reflected in the drop off in occurrence of schizophrenia among second- and third-degree relatives, in whom one would hypothesize a decreased genetic loading. The finding of a higher rate of schizophrenia among the biological relatives of an adopted-away person who develops schizophrenia, as compared to the adoptive, nonbiological relatives who rear the patient has added further support to the overwhelming pedigree and twin study evidence suggesting a significant genetic contribution to the etiology of schizophrenia. However, the data on monozygotic twins clearly demonstrate the fact that individuals who are genetically vulnerable to schizophrenia do not inevitably become schizophrenic; environmental factors must be involved in determining a schizophrenia outcome. If a vulnerability and liability model of schizophrenia is correct in its postulation of an environmental influence, then other biological or psychosocial environmental factors may prevent or cause schizophrenia in the genetically vulnerable individual. Possible environmental factors include the risk factors described, as well as psychosocial factors.
A major obstacle to delineating which genes are involved in schizophrenia is the fact that the mode of genetic transmission in schizophrenia is unknown. No current model (e.g., single gene dominant or recessive, polygenetic, multifactorial, or latent trait) satisfactorily accounts for the data. Determining the mode of transmission in a putative genetic disorder requires a known phenotype and genetic homogeneity across the pedigrees. Neither of these conditions is met in schizophrenia. To understand the etiology of schizophrenia, it will eventually be necessary to identify the actual genes and their products, and to evaluate their expression in the brain. The delineation of the different phenotypic manifestations of the schizophrenic genes or markers of the phenotypes is crucial, both for case ascertainment and in moving genetic inquiry closer to the neuronal effects of schizophrenia-related genes. Measures of smooth pursuit eye movements (SPEM), information processing (e.g., the continuous performance task and forced span of attention test), and sensory gating are the most prominent candidate markers. These measures have been found to distinguish schizophrenic probands and their biological relatives from control groups. Similarly, patients and their biological relatives are more likely than comparison groups to fail to inhibit neuronal response to a repeated stimuli (measured by a peak amplitude in electrical signal at about 50 milliseconds). The P50 sensory gating phenomena marker is of particular interest because it captures a basic neuronal property whose dysfunction could explain schizophrenic pathophysiology. In a recent application a defect in a neuronal mechanism that regulates response to auditory stimuli was used to define a schizophrenia phenotype, and positive linkage was found on an area of chromosome 15 with markers near the site of the a 7 nicotinic receptor. This receptor is thought to mediate normal inhibition of the auditory evoked response to the second of paired stimuli.
It has proven exceedingly difficult to progress from evidence confirming a genetic contribution to the etiology of schizophrenia to evidence implicating specific genes in the disease. Nonetheless, the area of genetic investigation is highly promising because there is unequivocal evidence for a genetic contribution to some, perhaps all, forms of the illness. There is presently an explosion of knowledge and techniques relevant to discovering the genetic basis for human disease. Linkage analysis has quickly moved from a few marker probes to banks of hundreds, and the entire genome will soon be examined with probes spaced along all chromosomes. Analytic techniques have been developed to evaluate polygenetic disorders, and gene substructure techniques now enable investigators to focus on candidate genes found to distinguish schizophrenic brains.
Neuroimmunovirology
Immune and viral hypotheses of schizophrenia are as old as scientific knowledge in these areas. That a virus could cause a neuropsychiatric disease was confirmed when Pasteur isolated the rabies virus in 1881. But schizophrenia is not an acute encephalitis or a fulminating infection; it involves more subtle pathophysiological mechanisms, which make it more difficult to establish etiology. Furthermore, the epidemiological data supporting an infectious theory, although interesting, is weak. Schizophrenia may have a north to south prevalence gradient in the Northern hemisphere (south to north in the Southern hemisphere), may be endemic to a few areas (e.g., northern Sweden), has a winter birth excess, and, similar to multiple sclerosis, has monozygotic twin discordance. However, it has been difficult to conduct definitive studies of immunovirological hypotheses because any potential marker of an immune or viral process associated with schizophrenia is applicable to only some cases of schizophrenia and is subject to interpretation as being due to conditions associated with the disease (e.g., crowding of chronically hospitalized patients, exposure of chronic patients living in low socioeconomic circumstances, and poor health habits).
Viral theories remain popular despite the difficulty of validating any particular version. Their popularity stems from the fact that several specific viral theories have the power to explain the particular localization of pathology necessary to account for a range of manifestations in schizophrenia without overt febrile encephalitis. The six general pathogenic models of viral and immune pathophysiology relevant to schizophrenia are described next.
Retroviral Infection A retrovirus can insert itself into the genome and thereby alter it which could initiate a genetic contribution to schizophrenia. It is postulated that the retrovirus inserts itself into the genome and alters the expression of the host's own genes and the genes of the host's offspring toward the development of schizophrenia (the virogene hypothesis). There is no evidence at present to support the retrovirus theory of schizophrenia, and at least one study has failed to find retrovirus-associated enzymes that would be present in an active infection but not in a virogene scenario.
Current or Active Viral Infection Many researchers postulate that viruses with an affinity for the central nervous system are involved in the etiology of schizophrenia. It is hypothesized that either a neurotropic virus infects nerve cells in discrete parts of the brain and causes sustained alterations in the functioning of the involved neural systems, or that byproducts of a viral infection have direct toxic effects on nerve cell functioning. Abnormal immune indices have been reported in schizophrenia and could be indicative of an active infectious process; however, most investigators consider the viral factor to be an early event that results in ensuing brain damage, which in twins has a long-lasting effect.
An alternative formulation of this hypothesis is based on the observation that viruses can infect the brain, with substantive disease manifestations only showing up many years later. In theory, this could account for the subtle early manifestations frequently observed in schizophrenic patients, which are followed by more intense symptom manifestations 10 to 30 years later.
A substantial challenge to either formulation of the current or active viral infection hypothesis is the absence of direct evidence substantiating a viral etiology, including the lack of physical signs of encephalitis (e.g., lymphocytic infiltrate) in postmortem tissue and the failure to recover or isolate a putative agent.
Past Viral Infection This hypothesis posits a virus infecting certain brain tissues either early in life to create a vulnerability to schizophrenia or as a causal mechanism for the initial illness processes that later lead to the picture of classic schizophrenia. The resulting tissue damage produces long-lasting alterations in neural systems, leading to schizophrenia manifestations without persistent viral infection. Gliosis, sometimes observed in postmortem tissue, would support the proposition of an earlier viral infection, and would also help account for the fact that signs of encephalitis are not ordinarily observed in the postmortem brain tissue of schizophrenia patients. A limited number of experiments have been unsuccessful in using brain material from schizophrenic patients as a source for transmitting central nervous system (CNS) viral infection into the brain tissue of other species. Although many viruses do not easily cross species, these studies lend some support to the proposition that even if a virus is relevant to the etiology of schizophrenia, it is not causing an active infection at the time of patient death.
Virally Activated Immunopathology One of two general mechanisms is proposed in this category. The first is based on the observation that viruses are normally endogenous to the human brain and are discontinuously or focally distributed in the brain. Periodic viral reactivation of these foci normally does not result in psychotic symptoms. However, in an individual with a genetically or environmentally determined abnormal immune response to viruses, it is hypothesized that viral reactivation could result in an induction of schizophrenic psychopathology. This theory regards the products of immunoreactivity, such as alpha interferon, as the mediators of the pathogenic influence. There is little direct evidence to support this hypothesis, but it receives indirect support from findings of abnormalities in alpha interferon responsiveness in schizophrenic patients as compared to normal controls.
The second mechanism in this category is that the virus may induce the host to fail to recognize its own tissues as "self" and, as a consequence, mount a destructive immune response against them. The virus may do this by altering some cellular component, such as normally cryptic neural cell surface proteins, causing it to stimulate a host response. A cytotoxic or antibody response would cause direct interference of nerve-cell function by either destruction of the cells or, in the case of receptor proteins, altered neurotransmission.
Autoimmune Pathology The aforementioned viral induction of an autoimmune pathology is an example of this pathogenic model. Schizophrenia has also been hypothesized to be an idiopathic autoimmune disease, such as rheumatoid arthritis or systemic lupus erythematosus; wherein, for reasons that are not entirely clear but probably involve genetics, some tissues are not recognized as self and become the target of immune response.
Secondary Influences: In Utero Exposure to Maternal Infection A number of epidemiological studies have reported that women who are exposed to influenza epidemics during the second trimester of pregnancy are more likely to give birth to offspring who are at increased risk for schizophrenia. This observation raises the possibility that some attribute of maternal infection such as fever or cytokine activation perturbates normal brain development during the period of active neural cell migration. This interesting etiological angle has recently been challenged by studies attempting to assess whether the mother was actually infected, rather than simply being exposed to an epidemic. Such case ascertainment might strengthen the finding, but at present this type of study can only be validly conducted using a prospective design and contemporaneous serological and molecular diagnostic techniques.
Birth and Pregnancy Complications
Infants born with a history of pregnancy or birth complications are at increased risk for developing schizophrenia as adults. The reason for this has not been established. The following plausible explanations, which are not mutually exclusive, guide present-day research.
1. The genes that create vulnerability for schizophrenia may also alter early embryonic development in a manner that leads to increased likelihood of gestational and birth complications.
2. Adverse influences on the developing brain during early gestation create a risk for both birth complications and schizophrenia. The potential role of Rh incompatibility as a risk factor for schizophrenia is an interesting example of this proposition.
3. Gestational or birth complications may cause hypoxic damage. Brain regions most frequently implicated as deviant in schizophrenia (e.g., hippocampus) are among the areas in the developing brain that are most sensitive to hypoxia.
PATHOPHYSIOLOGY
Schizophrenia is a disease of the brain. However, it is easier to make this assertion than to document any actual deviations in brain physiology. Since the illness represents a disturbance in some, but not all, brain functions, it is reasonable to suppose that specific areas or neural circuits of the brain are involved and that the manifestations of schizophrenia must necessarily involve altered processing of physiological information; this altered processing would, in turn, be dependent on disturbances of cytoarchitectural, biochemical, or electrophysiological properties of the neural systems.
Throughout most of this century examination of postmortem brain tissue has been the principal source of data with relevance to the neuroanatomy of schizophrenia. Early reference to schizophrenia as "the graveyard of neuropathology" was not because of a lack of neuropathological findings, but rather because of the lack of a discernible pattern in the frequently observed pathological findings and the possibility that deviations were either artifactual in nature or were a consequence, rather than a cause, of the disease. For example, head trauma and viral infections affecting the brain would be more common in crowded custodial hospitals than in typical comparison groups. Moreover, the widespread use of neuroleptic drugs in the treatment of schizophrenia introduced additional artifacts in the investigation of brain pathophysiology. Finally, knowledge of brain-behavioral relations was not sufficiently detailed to guide neuropathological inquiry during much of this century.
Scientists have long been keenly aware of the necessity for the development of noninvasive techniques to study the functioning brain of living patients. This is particularly important in the absence of valid animal models. During the middle third of this century, pneumoencephalography (PEG) provided substantial evidence for enlarged brain ventricles, suggesting diminished tissue in schizophrenia compared to controls. Electroencephalography (EEG) provided information on cortical surface electrical activity, but neither PEG nor EEG techniques could provide a comprehensive evaluation of the functioning human brain.
The development of structural (e.g., computerized axial tomography [CT] and magnetic resonance imaging [MRI]) and functional (e.g., positron emission tomography [PET], single photon emission computerized tomography [SPECT], functional MRI, magnetoencephalography, and MR spectroscopy) in vivo imaging techniques have made a more detailed view of brain structure and physiology possible. These techniques have become available at a time when a better understanding of the interconnections between cortical and subcortical structures and their implications for brain-behavior relations is emerging from preclinical studies of the brain. CT studies have replicated the PEG observation of enlarged ventricles and have further shown that a substantial proportion of schizophrenic patients, in comparison to normal controls, exhibit increased sulcal widening. These results suggest that schizophrenic patients may have relatively less brain tissue, a condition that could represent either a failure to develop or a subsequent loss of tissue. With its enhanced gray and white matter resolution, MRI is able to provide a far more detailed assessment of specific brain structures. Studies employing MRI have found evidence in schizophrenic patients for decreased cortical gray matter, especially in the temporal cortex, decreased volume of limbic system structures, (e.g., the amygdala, hippocampus, and parahippocampus), and increased volume of basal ganglia nuclei. These findings are consistent with the findings of neuropathological examinations of postmortem tissue, including ultrastructural examination, which in some cases indicates cell loss, misalignment of cells, altered intracellular structure and protein expression, or gliosis.
Structural findings may help clarify the meaning of altered patterns of function. Functional imaging studies have documented abnormal patterns of glucose metabolism or blood flow during the performance of specific cognitive tasks. These techniques are also able to provide insights into the functional neuroanatomy of the various symptom complexes that characterize patients with schizophrenia, with preliminary evidence suggesting a differential association of functional indexes with the positive psychotic symptoms and primary, enduring negative symptoms (Figs. 12.1–1 and 12.1–2).
FIGURE 12.1–1 Axial sections demonstrating brain areas with significantly increased activity during auditory verbal hallucinations in the group study. Functional PET results (threshold at Z > 3.09, P < 0.001, by reference to the unit normal distribution) are displayed in color, superimposed upon a single structural T1-weighted magnetic resonance imaging (MRI) scan that has been transformed into the Talairach space for anatomical reference. Section numbers refer to the distance from the anterior commissure-posterior commissure line, with positive numbers being superior to the line. The areas of activation extend into the amygdala bilaterally, and into the right orbitofrontal cortex. Although these regions of extension are consistent with the limbic paralimbic component of activity during hallucinations, and may contribute to drive and affect in this context, definitive statements cannot be made in the absence of discrete maxima. (Reprinted with permission from Silbersweig DA, Stern E, Frith C, Cahill C, Holmes A, Grootoonk S, Seaward J, McKenna P, Chua SE, Schnorr L, et al: A functional neuroanatomy of hallucinations in schizophrenia. Nature 378:1769, 1995.) (See Color Plate 7.)
FIGURE 12.1–2 There is a significant difference in O15 activity in the prefrontal and parietal cortex during the performance of an auditory discrimination task in deficit and nondeficit patients, with deficit patients having decreased activity in these regions. (Courtesy of A. Lahti, Maryland Psychiatric Research Center, Baltimore, MD.) (See Color Plate 7.)
Present-day knowledge of the pathophysiology of schizophrenia is acquired from the study of living subjects by using structural and functional imaging, and anatomically relevant symptom assessment and neuropsychological techniques. These technologies are supplemented by advances in postmortem biochemical, molecular, and structural evaluations to test increasingly sophisticated neuroanatomical and biochemical theories of schizophrenia.
Major Neuroanatomical Theories
Over the last 20 years there has been a gradual evolution from conceptualizing schizophrenia as a disorder that involves discrete areas of the brain to a perspective that views schizophrenia as a disorder of brain neural circuits. These neural circuit models of the pathophysiology of schizophrenia posit that either a structural or a functional lesion disrupts the functional integrity of the entire circuit. There are several factors that have contributed to this change in perspective. First, the delineation of the neuroanatomy of the different neurotransmitter pathways has led to an increased appreciation of how different brain regions are connected with each other and how cortical and subcortical structures are able to reciprocally regulate the function of each other. For example, the identification of the mesolimbic and mesocortical dopaminergic pathways contributed to the development of neuroanatomical hypotheses implicating the prefrontal cortex and limbic system in the pathophysiology of schizophrenia. The further delineation of the reciprocal regulatory pathways between the prefrontal cortex and the limbic system, particularly the hippocampus, led to more recent formulations of these hypotheses, in which limbic and prefrontal neuroanatomical models of schizophrenia have been integrated into a single unifying neurodevelopmental theory of schizophrenia. These hypotheses propose that an early developmental lesion of the dopaminergic tracts to the prefrontal cortex results in the disturbance of both prefrontal and limbic system function, and leads to the positive and negative symptoms and cognitive impairments observed in patients with schizophrenia.
Prefrontal cortex and limbic system hypotheses are the predominant neuroanatomical hypotheses of schizophrenia. The demonstration of decreased volumes of prefrontal gray or white matter, prefrontal cortical interneuron abnormalities, disturbed prefrontal metabolism and blood flow, decreased volumes of hippocampal and entorhinal cortex, and disarray or abnormal migration of hippocampal and entorhinal neurons provide strong support for the involvement of these brain regions in the pathophysiology of schizophrenia. In the context of neural circuit hypotheses linking the prefrontal cortex and limbic system, studies demonstrating a relation between hippocampal morphological abnormalities and disturbances in prefrontal cortex metabolism or function are particularly interesting.
A second contributing factor to the adoption of a neural circuit conceptual framework has been the increased understanding of how the brain is organized into local microcircuits, which consist of the connections among afferent and efferent neurons and interneurons, and macrocircuits. An example of the latter are the segregated parallel basal ganglia-thalamocortical neural circuits, which connect the cerebral cortex with the thalamus through the basal ganglia. Each of these circuits is hypothesized to subserve a discrete range of functions. Several investigators have used these circuits as a starting point for their hypotheses of schizophrenic pathophysiology. These hypotheses differ from each other primarily on their point of emphasis. For example, integrating data from animal studies, and neurobehavioral, functional, and structural imaging studies in humans, it has been hypothesized that dysfunction of the anterior cingulate basal ganglia-thalamocortical circuit underlies the production of psychotic symptoms (Fig. 12.1–1) and dysfunction of the dorsolateral prefrontal circuit underlies the production of primary enduring negative or deficit symptoms (Fig. 12.1–2). Dysfunction in one of these circuits may be independent from dysfunction in the other.
A third factor has been the elucidation of the neural basis of cognitive functions observed to be impaired in patients with schizophrenia. The observation of the relationship among impaired Wisconsin Card Sort Test (WCST) performance and diminished prefrontal cortex blood flow and diminished hippocampal volume provides strong support for the validity of prefrontal cortex or limbic system neuroanatomical models. Similarly, the delineation of the neural circuits for language and attention or information processing have influenced the conceptualization of schizophrenia pathophysiology. The classic language circuit, which includes Wernicke's and Broca's areas and associated cortical and subcortical structures, has been hypothesized to be involved in the production of hallucinations, delusions, and positive formal thought disorder. This hypothesis is the most important alternative to the anterior cingulate hypothesis for positive symptoms. The involvement of this circuit, at least for auditory hallucinations, has been documented in a number of functional imaging studies contrasting hallucinating versus nonhallucinating patients.
Attention and information processing abnormalities are routinely observed in patients with schizophrenia. The type of abnormalities range from disturbances in sensory gating to disturbances in visual information processing. The latter impairments have been argued to be selectively related to negative symptoms. The overlap between brain regions that have been implicated in the production of negative symptoms and the visual information processing neural circuit, which includes inferior and superior parietal and prefrontal cortices, caudate and thalamic nuclei, and the reticular activating system, provides a neuroanatomical rationale for the relationship between these two dimensions of schizophrenia and a conceptual framework for future studies of the neuroanatomy of negative symptoms.
The development of neural circuit hypotheses offers tremendous advantages to the investigation of the neuroanatomy of schizophrenia. First, these hypotheses more accurately reflect the actual organization of the brain. Second, models of neural circuit hypotheses can be developed to investigate how perturbations of circuit function can lead to schizophrenia signs and symptoms. Neural circuit models have been created for both the cognitive and symptom manifestations of schizophrenia. Third, neural circuit hypotheses provide a conceptual framework for hypothesis-testing studies and optimize the interpretation of information derived from current brain imaging and postmortem studies. Finally, the use of neural circuit models implicates brain regions, such as the thalamus and the cerebellum, that are not typically conceptualized as being central to the neuroanatomy of schizophrenia.
Major Biochemical Theories
Information is processed in neuronal networks through the transmission of an electrical signal from a nerve cell through its axon and across synapses to postsynaptic receptors on other nerve cell components. Nerve cells generally receive, process, and send signals to and from thousands of other cells. The transmission of the signal across the synapse and the processing of the signal within a cell involve a complex series of biochemical events that require large amounts of energy and include gene expression and the synthesis and degradation of protein. It is evident that physiological function in any brain system involves the chemistry of that system, and that dysfunction can emanate from these biochemical processes. It is therefore natural to assume that the biochemistry of the brain plays a fundamental role in the disruptions of brain function involved in schizophrenia. The move from a general concept of the biochemistry of schizophrenia to specific theories is based on two principal sources of knowledge. The first is an ever-increasing understanding of intracellular communication from the cell membrane to the nucleus and the cell's genetic material and of intercellular communication through the various neurotransmitter systems of the brain. The second source is knowledge of the mechanism of action of drugs that can induce schizophrenia-like behaviors or that alter symptom expression in patients with schizophrenia. Our knowledge of cellular communication and the pharmacological actions of antipsychotic drugs have led to biochemical hypotheses involving dopamine, noradrenalin, serotonin, acetylcholine, glutamate, and several neuromodulatory peptides and their receptors. Because there are many possibilities, it is important to understand the general development of a biochemical hypothesis of schizophrenia, of which the dopamine hypothesis is the most prominent and enduring.
Dopamine and Schizophrenia The hyperdopamineric hypothesis of schizophrenia arose from two sets of observations of drug action relating to the dopaminergic system. Drugs that increase dopamine system activity, such as d-amphetamine, cocaine, levodopa (Larodopa), and methylphenidate (Ritalin), can induce a paranoid psychosis that is similar to some aspects of schizophrenia. When administered to schizophrenic patients, these compounds may produce a transitory worsening of symptoms, especially in the area of hallucinations, delusions, and thought disturbance. In contrast, drugs that share the capacity to block postsynaptic dopamine receptors reduce the symptoms of schizophrenia. Substantial evidence supports the role of postsynaptic dopamine blockade as an initiating factor in a cascade of events responsible for the mode of therapeutic action of antipsychotic drugs. Other mechanisms, such as depolarization blockade, have been implicated as plausible explanations for long-term antipsychotic effects. That these actions are actually corrective for the pathophysiological disturbance in schizophrenia is suggested by the fact that dopamine-stimulating drugs can worsen schizophrenic symptoms or induce psychosis. This rationale for the role of dopamine excess, particularly for the cognitive and positive symptom aspects of schizophrenia, is compelling.
However, despite the compelling evidence for the role of dopamine in schizophrenia, testing the hypothesis has proven problematic. Clinical studies across a broad range of indices of dopamine metabolism have been characterized by marked variability in results. The most decisive clinical testing of the hypothesis has been at the level of observed drug action and symptom manipulation. Studies aimed at measuring abnormal concentrations of dopamine or its metabolites in blood, urine, and spinal fluid are confronted by problems that are almost insurmountable. In large fluid compartments, alterations in dopamine metabolism associated with schizophrenia will represent only a minor contribution to the particular index of dopamine metabolism; spinal fluid necessarily provides a summation of total brain activity, most of which is not considered germane to schizophrenia, and blood and urine provide even more indirect indices.
Functional imaging studies provide indirect evidence of dopamine involvement through the examination of metabolic rates in brain regions where dopamine is an important neurotransmitter. For example, data confirming metabolic alterations in limbic anatomy are consistent with a disturbance in dopamine metabolism, but it is not possible to determine the extent to which this reflects an alteration of dopamine biochemistry versus an alteration of any one of a number of interacting neurotransmitter and neuromodulatory systems. A more informative approach for assessing abnormal dopamine metabolism in patients with schizophrenia is to infuse subjects with an indirect dopamine agonist and then determine the extent to which radioligand occupancy of postsynaptic dopamine receptors is reduced by competition with the increased endogenous dopamine. The comparison of preinfusion and postinfusion radioligand occupancy provides an index of dopamine release and reuptake rates. PET studies of dopamine receptor distribution and the density of receptor expression may offer an alternative approach for documenting the dopamine hypothesis. The observation of an increased quantity of dopamine type 2 (D2) receptors in the caudate nucleus of drug-free schizophrenic patients is an example of this approach, but replication has been difficult. The extension of this approach to other dopamine receptor types is an important new direction of research.
Finally, there is the potential for the relatively precise biochemical study of dopamine in postmortem tissue, but here, as with the use of body fluids, sources of artifact and imprecision have been difficult to manage. The concentration of a neurotransmitter in any tissue will be altered as cellular components break down following death and as small differences in dissection from brain to brain take place. The administration of neuroleptic drugs during life almost always confounds the biochemistry of postmortem tissue, and one can rarely be sure of the extent to which any biochemical finding is secondary, rather than primary, to the schizophrenic disease process. In addition, there are a large number of candidate areas for brain dysfunction, so that one may easily examine the wrong location. It is also quite possible that areas of biochemical dysfunction earlier in life are no longer dysfunctional at the time of death or that the biochemistry of death may obscure the biochemistry of life.
Despite these methodological limitations, postmortem studies have reported differences between schizophrenic and control brains. For example, increased concentration of dopamine has been found in the left amygdala (a limbic system structure) in the postmortem brains of patients with schizophrenia. This finding has been replicated and, since it is lateralized, is not likely to be an artifact. There has also been a report of an increase in D2 postsynaptic receptors in postmortem tissue of schizophrenic patients whose medical records provided a diagnosis of schizophrenia but did not reveal neuroleptic drug use. These results suggest that the increase in binding (receptor) number is not secondary to neuroleptic drugs. The investigation of receptor abnormalities has been extended to other dopamine receptor types, and an increase of D4 receptors in entorhinal cortex, independent of antipsychotic use, has been reported.
Although conclusive evidence for the dopamine excess theory has been elusive, the hypothesis remains a viable explanation for the positive symptoms of schizophrenia. It is a particularly robust proposition for explaining the antipsychotic effect of neuroleptic drugs. Interestingly, recent studies have suggested the possibility that a dopamine deficiency may also occur in schizophrenic patients. For example, an inverse correlation between cerebrospinal fluid (CSF) and homovanillic acid (HVA) concentrations and negative symptoms has been reported. Also, patients with influenza encephalitis, who were mistaken for being schizophrenic, tended to have emotional dullness and low drive. Similarities in these cases with aspects of Parkinson's disease (which is known to involve loss of dopamine neurons) and the fact that some of these postencephalitic patients developed Parkinson's disease, lends support to a dopamine deficiency hypothesis for the negative symptom aspect of schizophrenia. In addition, neuroleptic drugs, which are dopamine-blocking agents, produce behaviors suggestive of the negative symptoms of schizophrenia in animals and humans free of mental illness. A modification of the dopamine hypothesis, incorporating the possibility of concomitant dopamine excess and deficiency, would restrict dopamine excess to the dopaminergic pathways projecting to the basal ganglia and limbic system and dopamine deficiency to the mesocortical pathways. Hypofunction of the mesocortical neurons would account for the negative symptoms of schizophrenia.
Glutamate and Schizophrenia Glutamate is the major excitatory neurotransmitter in the brain. Interest in the possible role of glutamate in the pathophysiology of schizophrenia has emerged from an increased understanding of the N-methyl-D-aspartate (NMDA) receptor complex, a major glutamate system receptor; an increased understanding of the interactions between glutamatergic and dopaminergic and GABAergic systems; and observations of the acute and chronic effects of phencyclidine (PCP). The consequences of PCP use provide a compelling model of schizophrenia symptomatology. Short-term administration of PCP produces symptoms that have been argued to mimic both the positive and negative symptoms of schizophrenia. Chronic administration produces a hypodopaminergic state in the prefrontal cortex, a state that has been argued to result in negative symptoms. PCP occupies receptors within the open calcium channels of the NMDA receptor complex, thereby blocking ion flow. PCP and the analogue ketamine (Ketalar) interfere with glutamatergic transmission. In addition to the observation of schizophrenia-like symptomatology in humans abusing PCP or ketamine has been used in the laboratory and has been observed to produce transitory mild manifestations of positive and negative symptoms in normal volunteers and a transitory and mild worsening of positive symptoms in patients with schizophrenia. Activation of dopamine receptors inhibiting glutamatergic neurons or decreased NMDA-mediated inhibition of dopamine neurons, either directly or through the actions of GABAergic interneurons, could be associated with a dopamine-excess psychosis (Fig. 12.1–3). These considerations support a hypoglutamatergic hypothesis for schizophrenia pathophysiology and predict a therapeutic effect for compounds activating the NMDA receptor complex. This is a difficult strategy to implement because excessive glutamatergic activity is neurotoxic; however, activation of the NMDA receptor complex via the glycine site with either glycine or d-cycloserine has been reported to alleviate negative symptoms in patients with schizophrenia.
FIGURE 12.1–3 A tentative scheme of interactions between glutamate and dopamine in the basal ganglia. The cholinergic interneurone in the striatum is a large, aspiny cell with a rich collateral network that can be assumed to make synaptic contacts with a large number of other striatal cells. The cholinergic interneurone receives a cortical glutamatergic input on its soma, while its axon terminals are in synaptic contact with medium-sized, spiny GABAergic output neurones. Only two such GABA neurons are shown but in reality it is reasonable to assume that one cholinergic neurone innervates many GABAergic neurones. The cholinergic interneurone also makes contact (although maybe not forming a real synapse) with dopaminergic nerve terminals. From the way the synapses are drawn here, the cortex would be able to control the activity in the GABAergic output neurones projecting to the thalamus via the medial segment of the globus pallidus (partly via the subthalamic nucleus and substantia nigra pars reticulata. In this manner the cortex can selectively suppress impulse flow in one subpopulation of GABAergic projection neurones while facilitating impulse flow in another, thus presumably enabling a meaningful behavior by suppressing irrelevant locomotor programs. The importance of glutamatergic pathways for maintaining a purposeful behavior is revealed by the primitive locomotor pattern that results from treatment with the NMDA antagonist MK-801.
The glutamatergic hypothesis exemplifies a major transition that has occurred recently in the biochemistry of schizophrenia. Prior to this transition, observations of drug actions in schizophrenia first led to clinical treatment and then to the advancement of the pathophysiological theory of schizophrenia. With the ever-increasing knowledge of the neural organization of the brain and of the various properties and receptor sites of neurotransmitters, it is now possible to postulate pathophysiological theory first and then attempt to derive new clinical treatment from theory. New treatment approaches will be developed more rapidly in the future, based on a broader range of pathophysiological hypotheses and the availability of animal models for aspects of the illness that are not therapeutically responsive to dopamine blockade-based medications.
Other Neurotransmitters and Neuromodulators Any neurotransmitter involved in neural systems subserving behaviors whose disruption could result in symptoms of schizophrenia is naturally of interest in schizophrenia theory and research. The rich innervation of the frontal cortex and limbic system with serotonergic neurons, the modulatory effect of these neurons on dopaminergic neurons, and the involvement of these pathways in the regulation of a broad range of complex functions has led several investigators to posit a pathophysiological role for serotonin in schizophrenia. These hypotheses have taken various forms over the course of the last four decades. In the early 1950s a serotonergic deficiency hypothesis was proposed for schizophrenia. Observations of hallucinations in subjects who had ingested lysergic acid diethylamide (LSD), a compound that is chemically similar to serotonin and blocks serotonin receptor sites, furthered the hyposerotonin hypothesis. However, drugs that decrease serotonin activity tend to reduce schizophrenic symptoms (e.g., reserpine [Serpasil], some antipsychotics, clozapine [Clozaril]), and have diminished interest in the deficiency hypothesis.
Of greater current interest are hypotheses positing that a serotonin excess causes positive and negative symptomatology. The robust serotonergic antagonist activity of clozapine and other new-generation antipsychotics, coupled with clozapine's demonstrated effectiveness for positive symptoms in chronic, treatment-resistant patients have contributed to the current emphasis on this proposition. However, several studies have raised questions about the efficacy of serotonin antagonists for either negative symptoms broadly defined or deficit symptoms. Moreover, pharmacological modification of serotonin systems with specific serotonergic agents has not produced impressive clinical results.
As with the dopamine hypothesis, the strength of the support for the serotonin hypothesis is derived from reasoning based on knowledge of brain and behavior relationships, the anatomy of neural transmitter systems, and drug mechanism of actions, and the same weaknesses in the clinical and postmortem studies on dopamine apply to serotonin also.
A similar rationale can be applied to construct hypotheses implicating norepinephrine in the psychopathology of schizophrenia. Anhedonia, (i.e., the impaired capacity for emotional gratification and the decreased ability to experience pleasure), has long been noted to be a prominent feature of schizophrenia. A selective neuronal degeneration within the norepinephrine reward neural system could account for this symptom. However, biochemical and pharmacological data bearing on this proposal are inconclusive. As with dopamine and serotonin, there have been both noradrenergic excess and deficiency pathophysiological hypotheses.
Neuromodulatory hypotheses focus on the fact that neuropeptides, such as substance P and neurotensin, are co-localized with the catecholamine and indolamine neurotransmitters, and influence the action of these neurotransmitters. Alterations in neuromodulatory mechanisms could facilitate, inhibit, or otherwise alter the pattern of firing in these neuronal systems. Explorations of neuromodulator hypotheses are preliminary and inconclusive at this time.
Integrative Hypotheses
The natural evolution of pathophysiological hypotheses of schizophrenia is the development of comprehensive models that integrate both neuroanatomical and biochemical hypotheses. The superimposition of the neurotransmitters involved in the connections among cortical, basal ganglia, and thalamic structures that comprise the basal ganglia-thalamocortical neural circuits is a prime example of this approach. Through glutamate projections from the cortex to the basal ganglia, the cerebral cortex facilitates the performance of selected behaviors while inhibiting others. The excitatory glutamatergic neurons terminate on GABAergic and cholinergic neurons, which in turn suppress or excite dopaminergic and other neurons. This regulatory activity can enable the cortex to protect itself from overstimulation from thalamocortical neurons. The elucidation of the neuroanatomy and biochemistry of cortical microcircuits has also served as a starting point for the articulation of pathophysiological hypotheses of schizophrenia. These integrative models provide a framework for identifying potential neurotransmitter targets for drug development, as well as providing explanatory models for the observed effects of pharmacological agents in patients with schizophrenia (e.g., PCP-induced psychotic symptoms mediated through the interactions of glutamate and other neurotransmitter systems in the neocortex, basal ganglia, or limbic system structures).
DIAGNOSIS
The history of the diagnosis of schizophrenia is often misunderstood, which has led to erroneous conclusions about the validity of the diagnostic process. Throughout most of the twentienth century there has been substantial agreement among diagnosticians throughout the world, using seemingly divergent diagnostic approaches, in the recognition of typical cases of schizophrenia. There has also been no difficulty in distinguishing schizophrenia from normality. Although useful refinements have evolved, diagnostic systems in place when effective drug treatment was introduced in 1952 were capable of identifying suitable subjects for therapy.
The major areas of disagreement among diagnostic approaches were how broad the definition of schizophrenia should be; whether positive symptoms, including hallucinations, delusions, and positive formal thought disorder, were required; and whether positive symptoms in the absence of known organic causes always signified schizophrenia. In general, the broader the definition the greater the likelihood that more subtle cases would be included and the greater the likelihood that disagreement would arise regarding the diagnosis of such cases. Even in such cases, there was little disagreement regarding the presence of psychopathology; rather, when present, the disagreement focused on whether the psychopathology observed was part of schizophrenia. This difference in viewpoint did create problems, which became important as different types of drugs were found to be effective for different classes of illness.
The success of the scientific search for more effective drugs for specific disease classes created the urgency to establish an agreed-upon diagnostic approach to schizophrenia and the major affective disorders in order to maximize appropriateness of treatment. The need for such agreement was also highlighted by the results of an influential study comparing diagnostic approaches in the United Kingdom with those in New York City, in which it was convincingly demonstrated that American diagnosticians employed a much broader and less defined construct of schizophrenia than their British counterparts. For a time in North America, especially in the northeastern United States, a broad definition of schizophrenia tended to include two categories of patients ill suited for the standard pharmacological treatment of schizophrenia. The first category was patients with bipolar or major depressive disorders with psychotic features, who, if erroneously considered to have schizophrenia, were administered antipsychotic medication rather than the more specific and effective treatments available for patients with these disorders (i.e., antidepressants, lithium, and electroconvulsive therapy). The second category included patients with schizophrenia spectrum personality disorders, (i.e., schizoid, schizotypal, and borderline personality disorders). These patients were sometimes misdiagnosed as having schizophrenia and were thus likely to be administered drugs designed for the positive symptoms of schizophrenia, which provided them little benefit and subjected them to substantial risk.
A considerable body of research during the 1960s and 1970s clarified many diagnostic issues and set the stage for the development of a diagnostic system implemented in the third edition of the American Psychiatric Association's Diagnostic and Statistical Manual of the Mental Disorders (DSM-III). The DSM-III approach, with specified symptom-based diagnostic criteria and demonstrated reliability, is now the accepted diagnostic system in North America and throughout the international research community. The use of this approach has led to the reliable and consistent differential diagnosis of schizophrenia, which has enhanced scientific and clinical communication and substantially increased the likelihood of the effective use of diagnostically specific treatments. The DSM-III approach has been retained in the revised third edition of DSM (DSM-III-R) and the fourth edition of DSM (DSM-IV) and has been incorporated in the International Classification of Diseases (ICD) diagnostic system. The ultimate goal is to standardize the diagnosis of schizophrenia across all diagnostic systems. Substantial progress has been made in this area, with extensive integration between DSM-IV and the 10th revision of International Statistical Classification of Diseases and Related Health Problems (ICD-10).
Beyond Diagnosis
A valid diagnostic system for schizophrenia has considerable utility for clinical and epidemiological purposes. It is now possible to estimate the occurrence of schizophrenia accurately, to identify individuals suffering from the illness process, to guide treatment and rehabilitation considerations, and to differentiate schizophrenia from other illnesses with similar manifestations but with importantly different treatment requirements. However, diagnosis at the syndrome level has not been an adequate guide to the scientific study of either the etiology or pathophysiology of schizophrenia nor to the development of treatments for all key features of the illness.
The traditional approach to reducing the heterogeneity of the schizophrenia syndrome has been to delineate subtypes and attempt to confirm or disprove their validity. The classic subtypes, disorganized (DSM-IV) or hebephrenic (ICD-10), paranoid (DSM-IV and ICD-10), catatonic (DSM-IV and ICD-10) and simple schizophrenia (ICD-10) or simple deteriorative disorder (DSM-IV) represent the most frequently used subtype approach for reducing heterogeneity. Although important differences such as age of onset and pattern of symptom development validate these subtypes, the classical subtypes have not provided a strong heuristic framework for the study of differential etiology and pathophysiology.
In light of the limitations of the classic subtypes, alternative approaches have been sought to reduce syndromal heterogeneity. One approach that has received considerable attention is the proposition that specific symptom complexes define pathological entities that differ from one another in neuroanatomical pathophysiology, in course and onset, in treatment requirements, and possibly in etiology. Interest in the proposition that symptom complexes, or domains of psychopathology, represent unique disease processes has emerged from the extensive study of the longitudinal patterns of symptom manifestations in patients with schizophrenia. A large number of studies have documented that the symptoms of schizophrenia usually segregate into three semi-independent symptom complexes: (1) hallucinations and delusions; (2) disorganized behavior, including positive formal thought disorder, bizarre behavior, and inappropriate affect; and (3) primary, enduring negative or deficit symptoms, including restricted affective experience and expression, diminished drive, and poverty of thought. Longitudinal studies provide support for the long-term independence and stability of these domains. These results suggest a modification of the central paradigm for the study of the etiopathophysiology and neuroanatomy of schizophrenia: the study of the etiopathophysiology and neuroanatomy of schizophrenia becomes the study of the etiopathophysiology and neuroanatomy of hallucinations and delusions, of disorganized behavior, and of negative symptoms. This approach is also germane for treatment and rehabilitation studies.
The domains approach has been extensively applied to the investigation of deficit symptoms. These symptoms differ from the other symptom complexes in their familial heritability, neuroanatomy as evidenced in both structural and functional neuroimaging studies, and response to antipsychotic treatment. Long-term outcome, season of birth, and age of onset are also distinctive. These results provide strong support for the heuristic value of this approach and raise the hope that this approach to heterogeneity reduction will yield more decisive data in studies of etiopathophysiology and neuroanatomy and will provide explicit information regarding the efficacy profile of pharmacological treatments.
Cognitive Impairment
In addition to the three symptom complexes, patients with schizophrenia also manifest a broad array of cognitive impairments, including impaired performance on measures reflecting attention, information processing, executive function, memory, and language capabilities. These manifestations are not used in the diagnosis of schizophrenia, but are a critical component of the disorder. On a theoretical level, attentional and verbal memory impairments are conceptualized as vulnerability markers, which may be useful in defining schizophrenia phenotypes, may be applicable to early detection, and may provide a basis for creating new models for treatment development. Cognitive impairments are also hypothesized to meaningfully determine many aspects of quality of life and functional capacity and adjustment. Moreover, the neuropsychological assessment of cognitive impairments permits probablistic anatomical inferences, and the use of cognitive tasks that assess these impairments has become increasingly important in guiding functional neuroimaging studies.
The relations among cognitive impairments and the symptoms of schizophrenia are unclear. For many years, cognitive impairments were conceptualized as the psychological foundations of symptom manifestations. However, there is a large body of evidence that has documented the relative independence of cognitive impairments and symptoms. For example, clinical trials have repeatedly demonstrated that large changes in symptom status can occur without a corresponding improvement in cognitive function as reflected in cognitive or neuropsychological test performance. Parenthetically, these trials have also revealed the lack of effective pharmacological treatment for these fundamental manifestations of the illness. The use of the three-symptom complex model and less complex cognitive paradigms may lead to the elucidation of possible relationships between the various cognitive impairments and the symptom complexes.
In summary, the manifestations of schizophrenia have been consistently described since the turn of the century. The conceptualization of schizophrenia as a clinical syndrome, importantly distinguished from manic-depressive and other psychoses, has been validated. Research on diagnostic systems has produced modest modifications in classification and has demonstrated the adequacy of the reliability and validity of current approaches. It has also produced a reasonable degree of uniformity in international usage that serves both clinical and scientific purposes. Because the clinical syndrome of schizophrenia probably represents more than one pathological process, specifically addressing the etiology, pathophysiology, and treatment of specific symptom complexes offers important new power to research designs.
COURSE, PROGNOSIS, AND OUTCOME
In his pioneering description of schizophrenia Emil Kraepelin argued that schizophrenia was characterized by an early onset, which was followed by a chronic deteriorating course. Eugen Bleueler suggested that a chronic deteriorating course was a frequent but not a necessary outcome. However, neither of these early workers took into account the extent to which their observations were based on chronic, institutionalized populations. Extensive longitudinal-outcome data on patients who were treated prior to and after the introduction of antipsychotics support a more optimistic prognostic picture. Whereas schizophrenia is always a serious disease, it is now clear that patients suffering from it may follow a variety of courses over the long term, including some that are relatively benign. It remains true that although schizophrenia does not always progress to a deteriorated end state, there are substantial and enduring adverse consequences for most patients.
The course of the illness can be divided into four major epochs: premorbid adjustment, onset of illness, middle course, and late course.
Premorbid Adjustment
Premorbid adjustment refers to symptoms that appear prior to the onset of positive symptoms. Twenty-five to fifty percent of patients with schizophrenia have abnormal premorbid adjustment, which may be manifested as poor social and scholastic adjustment or diminished social drive; decreased emotional responsivity; withdrawn, introverted, suspicious, or impulsive behavior; idiosyncratic responses to ordinary events or circumstances; short attention span; and delayed developmental milestones or poor motor and sensorimotor coordination. Childhood asociality, a trait that has been referred to in the past as a poor prognostic indicator, is probably more appropriately conceptualized as the early morbid manifestation of deficit symptomatology. Disturbances in social behavior have been picked up as early as infancy by workers who have noticed a lack of responsiveness and emotional expression in infants who later developed schizophrenia. It is also evident, however, that deficit symptoms may have their onset following psychosis and become part of the progression of the illness during the initial years of psychosis. Subtle forms of positive formal thought disorder may also be manifest before overt hallucinations and delusions occur. Studies that have evaluated the development of the offspring of mothers with schizophrenia have observed cognitive difficulties during the pre-teen and teenage years in these high-risk children.
Onset of Illness
The second epoch, onset of illness, typically refers to the onset of positive symptoms (i.e., hallucinations, delusions, and positive formal thought disorder). The onset of positive symptoms is insidious in about half of the patients, with the earliest signs of involvement occurring many years before the appearance of the more blatant manifestations of psychosis. In other cases, onset is relatively sudden or acute, with the onset of positive symptoms marking a sharp deviation in development. Patients with the insidious type of onset are very likely to have a poor intermediate course and a poor long-term outcome. In contrast, patients with normal development and ordinary personality attributes who experience a relatively sudden appearance of hallucinations, delusions, and disorganized thought vary widely in their intermediate and long-term outcomes.
Although the rate of schizophrenia is relatively similar in women and men, there are gender differences in age of onset. In males, the peak age of onset ranges from 17 to 27, whereas females tend to have a wider and flatter window of vulnerability, with age of onset generally between ages 17 and 37.
Middle Course
The middle epoch or course of illness may be subdivided into two subepochs. The first 5 to 10 years of illness are frequently characterized by multiple exacerbations of positive symptoms, during which a patient may return to an asymptomatic baseline between episodes, or remain actively psychotic without achieving full recovery. This subepoch is followed by a plateau phase, in which patients experience a stabilization of their symptoms and a decrease in the number of exacerbations. Recent studies have made it evident that the underlying deterioration associated with schizophrenia principally occurs during the onset of illness and the first half of the middle phase, rather than over the remaining course of illness. However, complications caused by the illness lead to ever-increasing impediments to normal existence, so that secondary effects may be progressive even though the primary pathology has plateaued. For example, patients who live in understimulating environments will lose social skills and work capabilities even if their symptoms improve. Effective treatment late in the course of a chronic disease will diminish morbidity, but it will not restore lost experience and opportunity—nor will it overcome stigma. A history of disabling schizophrenia is a serious social and occupational burden regardless of the degree of recovery.
Late Course
In the late epoch there is a tendency for the intensity of positive symptoms to diminish, and many patients with long-term impairments regain some degree of social and occupational competence. Although the illness becomes less disruptive and easier to manage, the effects of years of dysfunction are rarely overcome. It would be highly unusual for an individual with a chronic form of the illness to gain the niche in society and the quality of personal life that would have been possible had the illness not been present. More typically, patients continue to manifest direct signs of the illness process throughout their lives. Twenty- to forty-year follow-up studies provide a basis for estimating that approximately 55 percent of patients with schizophrenia have moderately good outcomes and 45 percent have more severe outcomes. These figures are more optimistic than earlier views for at least two reasons. First, sample selection was broader and more representative. Second, effective treatments, which make a considerable difference in the short-term course, also have a modest impact on the long-term course of the illness.
Although no present treatment approach can prevent or cure schizophrenia, some approaches have had remarkable remedial effects on course. Despite not being scientifically verified, there is considerable evidence from a large body of clinical experience that a form of schizophrenia referred to as devastating schizophrenia, which represented about 15 percent of the cases before the introduction of antipsychotic medication, now represents only about 5 percent of the cases. This form of the illness had an acute rather than insidious onset, but, paradoxically, had an unrelenting deteriorating course. Another line of evidence suggests that outcome may be related to the time interval between the initial detection of schizophrenia and the initiation of antipsychotic treatment. The more rapidly patients are treated, the more benign is the course of illness. This observation has led to an increased interest in establishing a methodology for early detection and the development of intensive therapeutic interventions, which combine pharmacological and psychosocial treatments, in order to ascertain whether future course can be substantially affected by treatment. There is also considerable evidence suggesting that the prophylactic use of antipsychotic medication reduces the relapse rate by more than one-half. This fact is largely responsible for making it possible to substantially reduce inpatient care in favor of brief hospital stay, crisis intervention, and community-based treatment. The level of success associated with this major shift in primary treatment setting as well as the serious shortcomings associated with shifting care to unprepared communities are noted in the discussion on treatment and rehabilitation.
Predictors of outcome have been principally found to be related to the already-established pattern of illness, the early developmental pattern, and the emotional qualities of the patient. Patients with limited emotional expression, who demonstrate a lack of social drive and social affiliation during childhood, and who display poor social and occupational functioning in recent years, are quite likely to run a chronic course of the illness. On the other hand, patients who have a normal developmental history with an abrupt onset of psychosis, and who have not established a pattern of social and occupational failure, have a much better prognosis. There is also evidence that prognosis is better in females than males. However, some patients in the good prognosis group will progress to a devastating form of the illness. In general, there are more reliable predictors of poor than good prognosis, with prognosis uncertain until the pattern of illness has been established.
There are interesting results from the World Health Organization study of the social determinants of outcome in different cultures. This work has documented that the course of schizophrenia tends to be more benign in developing countries than in developed countries. This difference in course is generally understood as representing a psychosocial influence on course rather than cultural differences in the causes of schizophrenia. The incidence and lifetime prevalence of the disease appear to be relatively comparable across cultures and societies. One compelling explanation for the observed difference is that the sociocentric structures of developing countries place less demand on individual performance and provide a more broadly supportive interpersonal environment than do the egocentric cultures of more developed nations. With their marked emphasis on individual accomplishment and productivity, the latter nations are more demanding and stressful for those with impaired drive or impaired mental functioning. Rather than finding an appropriate, usually reduced level of functioning, the patient with schizophrenia in Western industrialized societies tends to be isolated, with greatly reduced opportunities for work and meaningful social contacts. Indicative of this lack of involvement, unemployment rates for patients with schizophrenia are over 70 percent in the United States.
TREATMENT AND REHABILITATION
The history of the care and treatment of patients with schizophrenia is replete with instances of both humane and inhumane approaches. From a practical and moral standpoint, the value of humane care is intrinsic and does not rest on scientific evaluation of efficacy. There is a large body of literature and scientific data regarding the pharmacological and psychosocial interventions and the rehabilitation of patients with schizophrenia. The general conclusions of this accumulated information are presented below.
Pharmacological Interventions
Prior to 1952, there were no generally applicable, effective pharmacological treatments of schizophrenia. Reserpine had been used with some limited success, and electroconvulsive treatment (ECT) was important in reducing symptoms in the most acutely disturbed cases. This situation changed abruptly with the introduction of chlorpromazine (Thorazine) in France in 1952 and in North America in 1954, which ushered in the modern era of effective pharmacological therapy for schizophrenia.
The antipsychotic drugs used to treat schizophrenia have a wide variety of mechanisms of action, but all share the capacity to occupy postsynaptic dopamine receptors in the brain. Conventional antipsychotics or dopamine-receptor antagonists are often referred to as neuroleptics because of their neurological adverse effects. The new antipsychotics are less likely to exhibit these effects and have been referred to as atypical antipsychotics or serotonin-dopamine antagonists. The generally recognized clinical effect of antipsychotic drugs is to diminish symptom expression and reduce relapse rates. Although sedation may be a side effect and diminished anxiety a clinical effect, the primary value of these drugs is their remedial effect on positive symptoms, and not their sedating or tranquilizing properties. In contrast to positive symptoms, conventional antipsychotics have not been shown to be effective for either primary, enduring negative or deficit symptoms or the cognitive impairments observed in patients with schizophrenia.
Antipsychotic drugs are used throughout the world for four primary clinical purposes: (1) to manage acute positive symptomatic disturbances; (2) to induce remission from positive symptom exacerbations; (3) to maintain the achieved clinical effect over prolonged periods of time (maintenance therapy); and (4) to prevent relapses or new episodes of positive symptom expression (prophylactic therapy). A recent emphasis with regard to the use of conventional antipsychotic drugs has been on dose reduction, in the hope of diminishing adverse effects without losing clinical benefit. The intent is to administer the drugs in a manner that will increase patient compliance and avoid illness exacerbations caused by patients' discontinuing their medication.
The first atypical antipsychotic to be available for clinical use was clozapine. Clozapine has a unique mechanism of action, and was shown in the 1970s to have a superior effect on patients resistant to the therapeutic effects of conventional antipsychotics. However, patients on clozapine run an approximately 1 percent risk of agranulocytosis. This potentially lethal cessation in the production of white blood cells was associated with a series of deaths in Finland during the mid-1970s and led to a decreased use of clozapine in Europe and a failure to market the drug in the United States. Interest in clozapine in the United States was rekindled by the results of a large-scale multicenter study in chronic, treatment-resistant patients with schizophrenia. The study yielded convincing evidence of clozapine's effectiveness in ameliorating positive symptoms in approximately one-third of these patients. In addition, the study also showed that clozapine could be used with relative safety within the context of careful monitoring for agranulocytosis. Clozapine represents the first incremental gain in the effectiveness of the pharmacological agents used to treat schizophrenia since the original introduction of chlorpromazine.
The demonstration of clozapine's efficacy for treatment-resistant patients has spawned considerable interest in the development of new pharmacological treatments for schizophrenia. Risperidone (Risperdal), olanzapine (Zyprexa), quetiapine (Serlect), ziprasidone and other compounds have quickly followed. Since the specific mode of clozapine's superior therapeutic efficacy is not known, it is not possible to design new compounds with confidence that they will have superior efficacy. However, each of the new medications appears to be as effective an antipsychotic drug as the conventional antipsychotics, but with a substantially decreased adverse effect burden. This decreased adverse effect burden may result in greater effectiveness based on better patient compliance, and may reduce the incidence of long-lasting adverse effects (e.g., tardive dyskinesia). As each new drug is introduced, it will be important to examine whether the drug shares with clozapine a superior efficacy for positive symptoms. In addition, it will be important to examine if there are any meaningful advantages to using atypical antipsychotic medications in first-episode patients. Finally, future drug development must also recognize the absence of significant therapeutic efficacy of currently available medications for the primary avolitional component of the disease and the fundamental cognitive impairments detected by various psychological performance tasks. The rapidly advancing knowledge of brain biochemistry and brain-behavior relationships has set the stage for the development of new models for psychopathological processes other than positive symptoms. These new models may prove useful for screening potential novel treatments, which would enable a more comprehensive treatment of the varied manifestations of schizophrenia.
Lithium and antiepileptic, antidepressant, and antianxiety drugs have also been used to treat the positive symptoms of schizophrenia. However, these drugs have not proved to be effective alternatives to antipsychotic therapy, nor has there been a consistent demonstration of substantially enhanced benefits when they are used in combination with antipsychotics. A small subgroup of patients may be differentially responsive to a class of drugs other than antipsychotics, but in the absence of the capacity to identify in advance which patients will respond favorably, it is difficult to prove or disprove this proposition. In contrast, these drugs and a series of medications that counteract the side effects of conventional antipsychotics have been effective for co-occurring anxiety and depressive, manic, and aggressive symptoms.
Augmentation strategies have also been used for persistent negative symptoms, including deficit symptoms. These strategies have included the use of dopamine and serotonergic and noradrenergic agents. Perhaps the most promising development is the attempt to treat these symptoms by activating the NMDA receptor at the glycine site. Glycine and d-cycloserine have produced encouraging results in preliminary controlled clinical trials.
ECT was frequently used to treat patients with schizophrenia prior to the introduction of antipsychotic drugs. ECT is particularly effective in the treatment of catatonic stupor and excitement, but generally produces results similar to those obtained with antipsychotics, (i.e., a reduction of positive symptoms rather than a reversal of long-term functional impairments). Although ECT is safe and painless, its use is restricted, in part by litigation and societal attitudes, but also because any therapeutic advantage gained in an initial series of treatments is not easily maintained. Also, there is no indication that ECT is effective in patients who are resistant to conventional antipsychotics. For all of these reasons, drug treatment approaches are generally preferred.
Psychosocial Interventions
The debate over whether patients should be administered pharmacological agents or psychosocial treatments has given way to the search for how these treatments should be optimally integrated. Controlled clinical trials have conclusively demonstrated that intensive psychotherapy is less effective than drug treatment; that it is not superior to less expensive, less ambitious psychosocial forms of psychotherapy; and that it should no longer be considered an alternative to the use of antipsychotic drugs. In addition, studies have repeatedly demonstrated that supportive forms of psychosocial treatment are entirely compatible with drug treatment and can increase the effectiveness of overall treatment, reduce the amount of medication necessary, enhance patient participation in the full range of treatment, and optimize social and occupational functioning. Especially impressive are studies documenting the considerable additional benefit achieved in reducing relapse and hospitalization rates when family therapy and education programs are added to maintenance pharmacological treatment. These studies make it clear that psychosocial and rehabilitative interventions have become essential components of the comprehensive treatment of patients with schizophrenia.
Psychosocial and rehabilitation interventions include supportive, problem-solving, educationally oriented psychotherapy; family therapy and education programs aimed at helping patients and their families understand the patient's illness, reduce stress, and enhance coping capabilities; social and living skills training; vocational training, including job coaching; and the provision of supervised residential living arrangements. The development and increased utilization of psychosocial services have been complemented by the evolution of services designed to decrease the utilization of inpatient hospital services and to maintain the patient in the community. Assertive community treatment teams are designed to provide intensive outreach services to patients who are unable to be maintained in the community with traditional outpatient clinical treatment. Crisis management services, including 24-hour crisis beds and partial hospitalization programs, represent alternatives to hospitalization during periods of symptom exacerbation.
The development of these services reflects the ongoing shift in the treatment of the patient with schizophrenia from a hospital-based to a community-based system of care. When optimal treatment with these services is provided, the rewards of therapeutic accomplishment, reduction in morbidity, and economic cost benefits are profound and rival therapeutic accomplishments found anywhere in medicine. The demonstrated benefits of these services challenge the field to establish an adequate community-based treatment approach prepared to meet the challenge and demands of broad-based integrated treatment.
FUTURE DIRECTIONS
The care and study of the person afflicted with schizophrenia are extraordinarily interesting and promising. Basic brain science has matured, and technological advances permit increasingly sophisticated questions to be addressed regarding the anatomy, ultrastructure, and function of the brain. The field is closer to understanding risk factors at the level of causal mechanism, and new treatments are being developed at an increasing rate. The cadre of schizophrenologists capable of integrating basic and clinical sciences has grown substantially, and new paradigms providing heuristic advantage in the classification of psychopathological phenomena provide and address the problem of heterogeneity, which has undermined so much of the investigative work in schizophrenia. Physiological markers have been validated, and investigators are able to articulate, with ever-increasing specificity, the what and where of brain dysfunction in patients with schizophrenia.
The twenty-first century promises to be a time of fundamental discovery regarding the etiology and pathophysiology of what may be the world's most vexing public health problem. These developments have emerged at a time of decreasing stigma, increasing partnership in clinical care and research with citizen advocacy groups, and the initiation of nationwide private fundraising for research on this disease.
SUGGESTED CROSS-REFERENCES
More detailed discussions of etiology, brain structure and function, clinical features, and somatic and psychosocial treatments are presented in the other sections of Chapter 12. A detailed introduction to areas of neuroscience and cognitive science relevant to schizophrenia is provided in Section 1.2 on functional neuroanatomy, Section 1.3 on neuronal development and plasticity, Sections 1.15 and 1.16 on brain imaging, and Section 3.1 on perception and cognition.
REFERENCES
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Andreasen NC, O'Leary DS, Cizadlo T, Arndt S, Rezai K, Boles Ponto LL, Watkins G ll, Hichwa RD: Schizophrenia and cognitive dysmetria: A positron-emission tomography study of dysfunctional prefrontal-thalamic-cerebellar circuitry. Proc Natl Acad Sci 93:9985, 1996.
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Buchanan RW, Brandes M, Breier A: Treating negative symptoms: Pharmacological strategies. In The New Pharmacotherapy of Schizophrenia, vol 36, A Breier, editor. American Psychiatric Press, Washington, DC, 1996.
Carlsson A: Neurocircuitries and neurotransmitter interactions in schizophrenia. Int Clin Psychopharmacol 3:21, 1995.
Carpenter WT, Buchanan RW: Schizophrenia. N Engl J Med 330:681, 1994.
Carpenter WT, Buchanan RW, Kirkpatrick B, Tamminga C, Wood F: Strong inference, theory testing, and the neuroanatomy of schizophrenia. Arch Gen Psychiatry 50:825, 1993.
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Mortensen PB, Pedersen CB, Westergaard T, Wohlfahrt J, Ewald H, Mors O, Andersen PK, Melbye M: Effects of family history and place and season of birth on the risk of schizophrenia. N Engl J Med 340:603, 1999.
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For the sake of simplification, the different thalamic nuclei are not shown. Conceivably, striatopallido-thalamic neurones can influence the entire thalamus via, for example, the reticular nucleus, which communicates with all other thalamic nuclei. Apart from the corticostriatal glutamatergic pathway, there are at least three other corticifugal systems that the cortex can use to protect itself from overstimulation: (1) the corticonigral projection; (2) the corticothalamic projection, which terminates in the thalamic intralaminar nuclei, from which a thalamostriatal projection originates; and (3) the corticosubthalamic projection.
Abbreviations: DA, dopamine; Glu, glutamate; Snc, Substantia nigra pars compacta; Snr, substantia nigra pars reticulata; STN, subthalamic nucleus; VTA, ventral tegmental area. (Reprinted with permission from Carlsson M, Carlsson A: Interactions between glutamatergic and monoaminergic systems within the basal ganglia-implications for schizophrenia and Parkinson's disease. Trends Neurosci 13:896, 1990.)
12.2 Schizophrenia: Epidemiology

GRAYSON S. NORQUIST, M.D., M.S.P.H., and WILLIAM E. NARROW, M.D., M.P.H.
An etiologically puzzling and clinically severe disorder, schizophrenia has long held the attention of psychiatric epidemiologists. Until fairly recently, however, efforts to elucidate the epidemiology of schizophrenia were hindered by two critical deficiencies: the lack of reliable case definition and limited generalizability of findings because of reliance on treated samples. Two lines of scientific development have converged since the late 1970s to help resolve these issues and advance epidemiological studies of schizophrenia. First was the development of Diagnostic and Statistical Manual of Mental Disorders (DSM), culminating in the publication of operationalized criteria for schizophrenia in the third edition of DSM (DSM-III). Second, modern epidemiological methods, particularly those of chronic disease and genetic epidemiology, have been applied to the study of schizophrenia. These methods have increased the robustness of epidemiological research findings because of their emphasis on precise study designs, representative sampling, and sophisticated techniques of data analysis.
Psychiatric epidemiology is traditionally concerned with patterns of psychopathology in human population groups and the factors that influence these patterns. It examines the occurrence of pathology in terms of time, place, and individual characteristics, in order to elucidate the etiology of illness and its population burden. In terms of schizophrenia, such research includes studies of prevalence and incidence, natural history of illness including risk and protective factors for onset, remission, and relapse; longitudinal followup of populations at high risk for schizophrenia, including children of parents with schizophrenia or relatives of a proband with schizophrenia; and genetic epidemiology, including twin, family, association, and linkage studies in samples that are representative of the persons with schizophrenia, an associated marker of interest, or a population isolate with a high prevalence of the disorder.
In epidemiology, a population is a collection of individuals defined by time, place, and characteristics such as age, sex, and race. Although general community populations are often studied, epidemiological study populations may be defined in other ways, including treatment status or exposure to a risk factor. For rare disorders such as schizophrenia, it is often easier to sample study cases from treated populations. However, by excluding untreated cases, the findings are not generalizable to all individuals with schizophrenia. Point prevalence is defined as the number of persons in a population who are affected with a disorder at a given point in time. Incidence is defined as the number of persons without a disorder at the beginning of a given time period who subsequently develop the disorder in that time period. A "first" or "true" incident case has never had a previous episode of disorder; a recurrent case has had a previous episode. Period prevalence includes existing cases at the beginning of a given time period (point prevalence), plus all incident cases developing in the time period, both first incidence and recurrence. An important concept in epidemiology is that prevalence is proportional to incidence and duration (P~I ´ d). Thus, in a chronic condition such as schizophrenia, a steady prevalence is maintained by a long duration of illness despite a relatively low incidence rate; cutting short the duration of illness would decrease the prevalence of the condition if incidence remained unchanged.
EVOLUTION OF NOMENCLATURE AND DIAGNOSTIC CRITERIA
The value of operationalized diagnostic criteria as a commonly accepted language for clinicians and researchers cannot be overemphasized. In the United States the DSM system of classification has become the diagnostic standard for both clinical and research purposes.
DSM
In 1952 the first edition of DSM (DSM-I) was published by the Mental Hospital Service of the American Psychiatric Association. DSM-I was derived largely from the section on mental disorders in the Standard Classified Nomenclature of Disease developed by the National Conference on Nomenclature of Disease in 1933. In DSM-I, "Schizophrenic Reactions" were classified under "Disorders of Psychogenic Origin or without Clearly Defined Physical Cause or Structural Change in the Brain." and were described as "synonymous with formerly used term dementia praecox."
It represents a group of psychotic reactions characterized by fundamental disturbances in reality relationships and concept formations, with affective, behavioral, and intellectual disturbances in varying degrees and mixtures. The disorders are marked by strong tendency to retreat from reality, by emotional disharmony, unpredictable disturbances in stream of thought, regressive behavior, and in some, by a tendency to "deterioration." The predominant symptomatology will be the determining factor in classifying such patients into types.
The types of schizophrenic reactions were simple, hebephrenic, catatonic, paranoid, acute undifferentiated, chronic undifferentiated, schizo-affective, childhood, and residual.
DSM-II
The second edition of DSM (DSM-II) was published in 1968 and was an attempt to achieve uniformity of diagnostic classification at an international level. The nomenclature used in DSM-II was based, with a few exceptions, on the terms used in the eighth revision of the World Health Organization's (WHO's) International Statistical Classification of Diseases, Injuries, and Causes of Death (ICD-8). DSM-II had initial attempts to remove from the diagnostic nomenclature implications about the nature or cause of a disorder. Thus, the "schizophrenic reaction" of DSM-I became "schizophrenia" in DSM-II. Attempts were also made to distinguish schizophrenia from the psychotic mood disorders. The term schizophrenia was defined as:
¼ a group of disorders manifested by characteristic disturbances in thinking, mood, and behavior. Disturbances in thinking are marked by alterations of concept formation which may lead to misinterpretation of reality and sometimes to delusions and hallucinations, which frequently appear psychologically self-protective. Corollary mood changes include ambivalent, constricted, and inappropriate emotional responsiveness and loss of empathy with others. Behavior may be withdrawn, regressive and bizarre. The schizophrenias, in which the mental status is attributable primarily to a thought disorder, are to be distinguished from the Major affective illnesses which are dominated by a mood disorder. The paranoid states are distinguished from schizophrenia by the narrowness of their distortions of reality and by the absence of other psychotic symptoms.
Several subtypes remained unchanged in DSM-II: simple, hebephrenic, paranoid, childhood, and residual. Catatonic type was divided into excited and withdrawn subtypes, and schizoaffective type was divided into excited and depressed subtypes. Acute undifferentiated type was renamed acute schizophrenic episode. Latent type was distinguished from the DSM-I chronic undifferentiated type in order to cover patients unofficially diagnosed as having incipient, prepsychotic, pseudoneurotic, pseudopsychopathic, or borderline schizophrenia.
DSM-III and DSM-III-R
The publication of the third edition of DSM (DSM-III) in 1980 represented a revolutionary advance in the development of a common diagnostic language for clinicians and researchers. It offered explicit criteria for diagnosing disorders based on observable signs and symptoms, rather than the earlier prose definitions that had a rather wide latitude of clinical interpretation. Beginning with DSM-III and continuing through the revised third edition of DSM (DSM-III-R) and the fourth edition (DSM-IV), the criteria for schizophrenia have followed a general pattern. These are: (1) a listing of the psychotic symptoms, of which one or two are required to be present; (2) a requirement for decline in social functioning and self-care; (3) "exclusion criteria" in which other disorders must be ruled out before assigning a diagnosis of schizophrenia; and (4) a duration and course criterion. Thus, in DSM-III, schizophrenic disorder was defined by the presence of six criteria: Criterion A required the presence of one of a list of six psychotic symptoms: three having to do with delusions; two with auditory hallucinations; and one with thought disorder associated with affective disturbance, delusions, hallucinations, or catatonic or grossly disorganized behavior. Criterion B required a deterioration in functioning from a previous level. Criterion C required a 6-month duration of illness with an active phase that included criterion A, and additional prodromal and residual symptoms, which were listed. Criterion D excluded persons for whom psychotic symptoms were preceded by a manic or depressive syndrome or for whom the mood syndrome was not "brief" in relation to the duration of the psychotic syndrome. Criterion E restricted age of onset to under 45 years. Criterion F ruled out syndromes that were "due to" any organic mental disorder or mental retardation. In DSM-III, catatonic, paranoid, and residual types were maintained. Hebephrenic type was renamed disorganized type. The term chronic was removed from chronic undifferentiated type. Schizoaffective type was removed from the schizophrenic disorders, renamed schizoaffective disorder and placed in the "Psychotic Disorders not Elsewhere Classified" category; unlike schizophrenia, no criteria were provided for the diagnosis of schizoaffective disorder in DSM-III. Another innovation in DSM-III was its classification of course of illness into categories of subchronic, chronic, subchronic with acute exacerbation, chronic with acute exacerbation, and in remission.
DSM-III-R, published in 1987, contained several changes in criteria for schizophrenia (no longer "schizophrenic disorder"). The various types of delusions specified in DSM-III criterion A were simplified—DSM-III-R distinguished only bizarre and nonbizarre delusions. In addition criterion A symptoms were expanded to allow nonauditory hallucinations. A minimum duration requirement of 1 week for criterion A symptoms was set. Criterion B was clarified, with a comparison point of the person's highest-ever level of functioning. Criterion C in DSM-III became criterion D in DSM-III-R; little was changed in this criterion except for the addition of "marked lack of initiative, interests, or energy" as a prodromal or residual symptom. Criterion D, the mood disorder exclusion, became criterion C in DSM-III-R; now if a mood syndrome was ever present during an active phase of the illness, schizophrenia was not diagnosed. Significantly, criterion E, the age requirement, was dropped in DSM-III-R. The organic mental disorder exclusion remained in DSM-III-R, and a new criterion was added that dealt with the comorbidity of autistic disorder and schizophrenia.
DSM-IV
Few changes were made to the diagnosis of schizophrenia in DSM-IV. Most significantly for case identification, the duration requirement for criterion A symptoms was increased to 1 month. In Criterion A, the concept of negative symptoms was added and the concept of loosening of associations was dropped and replaced with "disorganized speech." Specific criteria for prodromal and residual phases were dropped. Modifications were made to the organic disorder exclusion to include direct physiological effects of a substance, and the autistic disorder relationship was expanded to include all pervasive developmental disorders. No additional schizophrenia types were added in DSM-IV.
DIAGNOSTIC ASSESSMENT INSTRUMENTS
Identification of persons with mental disorders in the community, regardless of treatment status or severity of disorder, is the ultimate test of a diagnostic classification system. In order to be useful for service planning and research needs, a credible diagnostic classification system must be able to detect and correctly classify untreated cases and cases on the threshold of diagnosis. Unfortunately, for many years the lack of reliably operationalized diagnostic criteria hindered the ability of epidemiologists to identify cases in the community, and prevalence rates were usually based on treated cases only.
Diagnostic Interview Schedule
In the 1970s several psychiatric interviews were developed: the Schedule for Affective Disorders and Schizophrenia (SADS), a clinical interview based on Research Diagnostic Criteria (RDC); the Present State Examination (PSE), a nondiagnostic clinical interview that covered present symptoms only; the Psychiatric Epidemiological Research Interview (PERI), another nondiagnostic interview; and the Renard Diagnostic Interview, a diagnostic interview based on Feighner diagnostic criteria. The development of DSM-III in 1980 spurred renewed interest in gathering community epidemiological data based on the new criteria, but none of these interviews were entirely suitable for the purpose. To respond to this need, the Diagnostic Interview Schedule (DIS) was developed for use in the National Institute of Mental Health (NIMH) Epidemiologic Catchment Area (ECA) Program. The DIS covered DSM-III criteria for schizophrenia and schizophreniform disorder; Research Diagnostic Criteria for schizophrenia and schizoaffective disorder, manic and depressed types; and Feighner criteria for schizophrenia. It was a highly structured interview, based on respondent self-report only, which did not allow interviewer discretion in the administration of questions or recording of responses and did not rely on other clinical information to make diagnoses. Diagnoses were generated by computer algorithm, not by the interviewer. Because of these factors, the DIS was suitable for administration by nonclinician interviewers and could be administered in large surveys for relatively low cost. The DIS has undergone subsequent revisions to incorporate DSM-III-R and DSM-IV diagnostic criteria and it has been translated into over twenty other languages. Various reliability and validity studies performed on the DIS have demonstrated inconsistent results for schizophrenia; in such studies, results are often within an acceptable range if corrected for the low prevalence of schizophrenia in the population.
CIDI
With the evolution of the DSM and the International Classification of Diseases (ICD) diagnostic systems, the need for a comprehensive diagnostic instrument for use in cross-cultural and comparative studies worldwide became apparent. To address this need, the Composite International Diagnostic Instrument (CIDI) was developed as a joint venture of WHO and the U.S. Alcohol, Drug Abuse, and Mental Health Administration. The structured question-and-probe structure of the DIS served as the template for the construction of the CIDI. Questions from the PSE, an interview widely used in epidemiological studies outside the United States were then added. Updates of the CIDI added criteria from the 10th revision of International Statistical Classification of Diseases and Related Health Problems (ICD-10), and then DSM-III-R and DSM-IV criteria. The CIDI, like the DIS, remains a highly structured diagnostic interview with diagnoses made via computer algorithm. Throughout its development, efforts were made to ensure its cross-cultural appropriateness.
COMMUNITY SURVEYS
Three community surveys are most frequently cited for data on the prevalence and incidence of schizophrenia.
ECA NIMH Epidemiologic Catchment Area Program
The ECA NIMH Program is the largest community survey of mental disorders ever undertaken in the United States. A total of 18,571 household residents and 2290 institutional residents (of nursing homes, jails, psychiatric hospitals) age 18 and over were sampled and interviewed in five areas: New Haven, Baltimore, Durham, St. Louis, and Los Angeles. Two face-to-face interviews were done 12 months apart (Wave I and Wave II). A telephone interview (face-to-face in New Haven) of the household respondents was conducted 6 months after Wave I. The institutional residents were interviewed in Waves I and II only; no telephone interview was conducted for these respondents. DSM-III diagnostic data were obtained at Waves I and II using the DIS. Respondents were asked about their use of health services at each wave. Questions to ECA respondents pertaining to use of mental health services covered use of ambulatory specialty mental and addictive, general medical, and human services, and admissions to hospitals and residential treatment centers for reasons related to mental health or addictions.
National Comorbidity Survey
Following the success of the ECA Program, the National Comorbidity Survey (NCS) was conducted in the early 1990s to obtain more detailed information about mental disorders in the community, particularly the relation between co-occurring mental disorders and co-occurring mental and substance use disorders. Conducted by the Institute for Social Research at the University of Michigan, the study used a nationally representative household sample of 15- to 54-year-olds. A modified version of the CIDI (the UM CIDI) for DSM-III-R was used in the NCS. For psychotic disorders, in addition to a CIDI computerized diagnosis, a clinical reinterview was conducted with individuals who screened positive for psychosis on the CIDI. Results pertaining to the schizophrenia and related disorders are usually presented in a summary category called nonaffective psychosis, which is made up of schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, and atypical psychosis. Comparisons of the results of the ECA to the NCS are not straightforward because of the differences in the diagnostic instrument, differences in age range of respondents, and temporal differences, among other factors.
WHO Collaborative Study on the Determinants of Outcome of Severe Mental Disorders (DOS)
This study was conducted at 12 field centers in 10 countries across the world. At each of the 12 centers, all persons in a catchment area making first contact with a psychiatric, medical, or other agency for symptoms of possible schizophrenia were identified, assessed, and followed for 2 years. Like the NCS, the study selected only individuals between the ages of 15 and 54. The assessment instrument was the PSE. The final cohort size was 1379. Incidence of schizophrenia was obtained in 7 sites and clinical information on diagnosis and course was obtained at all 12 sites.
PREVALENCE
A 1987 review of over 70 prevalence studies of schizophrenia published since 1948 identified point prevalence in various population groups ranging from 0.06 percent to 1.7 percent, with lower rates in developing countries. It was suggested that this difference was not entirely caused by differences in diagnostic procedures and study methods. Rather, it was posited that higher recovery rates in developing countries and etiological heterogeneity, among other factors, could account for at least a tenfold difference in prevalence.
The prevalence of schizophrenia in the ECA is presented in Table 12.2–1. According to convention in the presentation of ECA results, these figures represent the combined prevalence of schizophrenia and schizophreniform disorders. One-month prevalence is conventionally viewed as "current" prevalence, so based on the ECA results, 0.7 percent of the adult population currently has a diagnosis of schizophrenia. The 1-year prevalence is similar, whether measured retrospectively or prospectively. The prospective period prevalence illustrates the chronicity of schizophrenia: more than twice as many persons had the disorder at the start of the year (0.7 percent) as developed the disorder or had a relapse during the following year (0.3 percent).
Table 12.2-1. Prevalence of Schizophrenia Disorders in the NIMH Epidemiologic Catchment Area Program
Length of Time Prevalence (%) (SE)
1-month 0.7 (0.1)
1-year 1.0 (0.1)
Lifetime 1.5 (0.1)
Prospective
1-month 0.7 (0.1)
1-year new 0.3 (0.1)
1-year total 1.1 (0.1)
SE, standard error

Based on the UM CIDI DSM-III-R computer diagnosis, the lifetime prevalence of "narrowly defined psychotic illness" (schizophrenia or schizophreniform disorder) in the National Comorbidity Survey was 1.3 ± 0.2 percent, very close to the ECA lifetime prevalence. Based on clinician diagnoses, the lifetime prevalence of narrowly defined psychotic illness in the NCS dropped to 0.16 ± 0.06 percent.
In examining the sociodemographic correlates in Table 12.2–2, it is helpful to keep in mind that an unadjusted prevalence represents the prevalence of schizophrenia as it actually appears in the community. The odds ratio tells us whether this rate is different when corrected for differences in age, sex, race, marital status, and socioeconomic status among the groups. For example, the prevalence of schizophrenia among blacks is 1.2 ± 0.2 percent, twice as high as for non-black, non-Hispanic persons. However, when correcting for differences in age, sex, race, and socioeconomic status between the ethnic groups, the odds of having schizophrenia among blacks (0.86) is actually no different than the odds for non-black, non-Hispanic persons (whose odds ratio as the comparison for this group is set at 1.00). It should also be noted that despite the size of the ECA survey, relatively few cases of schizophrenia were detected so there is limited power to detect significant differences in prevalence.
Table 12.2-2. Sociodemographic Correlates of 1-Month Prevalence of Schizophrenia in the NIMH ECA Program
Correlates Unadjusted Rate, % (SE) Odds Ratio †
Age
18–24 0.8 (0.2) —
25–44 1.1 (0.2) 2.31
45–64 0.5 (0.1) 0.76
³65 0.1 (0.1) 0.10*
Sex
Male 0.7 (0.1) —
Female 0.7 (0.1) 0.80
Race or ethnicity
Black 1.2 (0.2) 0.86
Hispanic 0.4 (0.2) 0.57
Non-Black and non-Hispanic 0.6 (0.1) —
Marital status
Married 0.5 (0.1) —
Single 1.1 (0.2) 2.55
Separated or divorced 1.5 (0.3) 2.61*
Widowed 0.4 (0.2) 2.27
Socioeconomic status
1 (high) 0.3 (0.1) —
2 0.6 (0.2) 2.28
3 0.9 (0.1) 3.96
4 (low) 1.2 (0.2) 8.14*
†  Odds ratios adjust for age, sex, race or ethnicity, marital status, socioeconomic status, and ECA site.
* P < 0.0031 (Bonferroni-corrected P value of < 0.05)
SE, standard error

Persons over age 65 were significantly less likely than persons between 18 to 24 years of age to have a diagnosis of schizophrenia. Persons aged 25 to 44 were twice as likely to have the diagnosis, although this difference did not reach statistical significance. The sex ratio was relatively even. Although blacks had twice the rate of schizophrenia in the community compared to other ethnic groups, when adjusted for socioeconomic status, age, and other factors, this difference disappeared. Being unmarried, particularly separated or divorced, was associated with a diagnosis of schizophrenia. There was an eightfold increase in odds of having schizophrenia in the lowest socioeconomic quartile compared to the highest quartile.
Comorbidity of schizophrenic disorders with substance use disorders in the ECA Program is shown in Table 12.2–3. Both the ECA and the NCS have demonstrated extremely high lifetime comorbidity of the psychotic disorders and substance use disorders; 50 to 60 percent of persons with schizophrenia or nonaffective psychosis had a comorbid alcohol or drug use diagnosis. Comorbidity in the NCS was higher, which may be due to methodological differences as well as secular changes in drug and alcohol use in the United States.
Table 12.2-3. Comorbidity of Schizophrenia With Substance Use Disorders in the ECA Program
Comorbid Disorder Rate (%) (SE)
Alcohol dependence 24.0
Any alcohol use disorder 33.7
Drug dependence 12.9
Any drug use disorder 27.5
Any drug or alcohol use disorder 47.0
SE, standard error

Table 12.2-4. Service Use by Persons With Schizophrenia
Average Number
of Visits Per
Using Service Total Ambulatory Treated Person
(%) Visits (%) Per Year
Specialty—mental and 46.0 58.2 13.4
addictive
General medical 29.0 10.5 3.7
health system
Subtotal 60.0 68.7 11.8
Human services 13.7 10.6 7.7
professional
Subtotal 62.9 79.3 13.0
Voluntary support networks 7.0 20.7 29.3
Any service 64.3 100.0 16.0

INCIDENCE
In the WHO DOS, incidence (based on service contacts) ranged between 0.016 and 0.042 percent per year across the sites for broadly defined schizophrenia. For narrowly defined schizophrenia, incidence showed less variation, ranging from 0.007 to 0.014 percent, which was not a statistically significant difference. Age- and sex-specific incidence showed a tendency toward earlier onset in males, a consistent finding in both developing and developed countries. Overall disease expectancy was virtually the same for males and females across the overall age range of 15 to 54 years. Because the DOS minimized methods variance through standardized case ascertainment and assessment methods, the consistency in the incidence of narrowly defined schizophrenia across several international sites is a noteworthy finding. The study's investigators raised fundamental questions in the study of risk factors for schizophrenia such as the possibility of a widely distributed genetic liability, the roles of ubiquitous and culturally specific environmental factors in interacting with that liability, and alternatively, the possibility of multiple genetic liabilities with remarkably similar phenotypic expression in various population groups.
Several studies report that the incidence of schizophrenia is on the decline. Interpretation of these findings is not easy, requiring as it does an accounting of the rapid changes in psychiatry that have occurred in the past 30 years, as well as in social policy and in population demographics. For example, incidence based on inpatient admissions, once widely accepted, is no longer a valid indicator of illness onset because of the shift of treatment away from institutionalization. Diagnostic systems have changed dramatically and these changes are likely to be reflected in different estimates. As the populations of developed countries continue to get older, fewer citizens will be at risk for developing schizophrenia. The issue of declining incidence has not yet been satisfactorily resolved and controversy remains as to what degree the findings represent a true decline in new cases versus a methodological artifact.
USE OF SERVICES
In the ECA Program about 64 percent of persons with a current diagnosis of schizophrenia used some form of mental health service in a 1-year period, a relatively high treated percentage compared to the other disorders surveyed and similar to bipolar I and II disorder and somatization disorder. About 17 percent received inpatient treatment at some point in the year. Consistent with the clinical picture of schizophrenia, most treated individuals had contact in a specialty or general medical setting. Among all ECA disorders, individuals with schizophrenia had the highest proportion (46 percent) treated in the specialty sector, and the bulk of treatment visits were made to this sector as well. Despite the large number of people who had visited the general medical sector, relatively few visits were made there. About 14 percent of persons with schizophrenia were seen only in the general medical sector.
RISK FACTORS
The term risk refers to the likelihood that a person who does not currently have schizophrenia will develop the disorder after exposure to certain factors. Thus, a risk factor for schizophrenia is an inherent or acquired characteristic or an external condition associated with an increased probability of developing schizophrenia. Epidemiological studies in schizophrenia seek to determine the most important risk factors for this disorder.
The concept of risk can be expressed in several ways. The most common is a report of the absolute number of new schizophrenia cases detected in a population exposed to a postulated risk factor. The terms relative risk (risk ratio) and risk difference (attributable risk)—expressions of the relationship of the incidence in those exposed to the risk factor to that of those not exposed—are also often used. In case control studies, if the disorder is rare, the risk ratio is approximated by an odds ratio.
Significant risk factors are identified through the use of several different study designs. One type, cross-sectional studies, reports descriptive data at a defined point in time, such as the increased presence of a particular factor in a population with a higher prevalence of schizophrenia. Case control studies compare schizophrenia cases with unaffected controls and determine whether those who express the disease were exposed to a given risk factor. The most informative (and expensive) study design is the prospective cohort study, which follows a group over time to determine whether those exposed to certain risk factors have a higher incidence of schizophrenia.
Risk factors are categorized in several different ways: demographic and concomitant factors (such as age, sex, race, social class), precipitating factors that operate immediately before the onset of schizophrenia (such as life events, migration), and predisposing factors that act for a long period of time or during an earlier part of life (such as genes, perinatal complications, infections). Another schema describes risk factors as either familial influences or sociodemographic factors. The latter can be further subdivided into mutable factors (such as social class, marital status, immigration) and immutable ones (such as ethnic group, sex, birthplace); mutable sociodemographic factors could be a result and not a cause of the disease. This latter distinction is particularly difficult to disentangle in cross-sectional studies.
Several cautions are necessary before reports from studies of risk factors for schizophrenia are evaluated. First, a high prevalence of schizophrenia in a particular area may be the result of protracted illness rather than an increased incidence of schizophrenia (i.e., prevalence is roughly equal to incidence ´ duration). Second, studies that report only the prevalence of schizophrenia may have failed to control other confounding factors, such as socioeconomic status, that might increase prevalence. Third, designating something as a risk factor does not imply that everyone exposed to it is at personal risk of developing schizophrenia. It means that the group of people exposed to the risk factor at some time are likely to show a higher incidence of schizophrenia than a similar group who were not exposed. Risk does not prove causation but rather an association between that risk factor and the development of schizophrenia. Fourth, schizophrenia may be an etiologically heterogeneous disorder involving many risk factors and many protective factors. Earlier studies or risk factors have many methodological problems, the most important being the failure to standardize diagnostic criteria for selection of schizophrenia cases. However, those studies have helped in the continued search to understand this complicated disorder.
Genetic Factors
Identification of a genetic influence is a major challenge in the understanding of schizophrenia. The search for a genetic risk factor has been examined through studies of twins, of families, and of adopted-away children of parents with schizophrenia. Twin studies have shown a concordance of 33 to 78 percent among monozygotic twins, but of only 8 to 28 percent in dizygotic twins. Those results may be affected by selection bias if monozygotic twins are more likely to come to the attention of researchers than are dizygotic twins. Also, monozygotic twins may have greater environmental similarity. Family studies reveal that first-degree relatives of a person with schizophrenia have approximately a fivefold to tenfold chance of developing schizophrenia than nonrelatives. Children have about a 35 percent greater chance of schizophrenia if both parents have schizophrenia compared with about a 1 percent lifetime risk if neither parent has schizophrenia. Although the results from family studies are thought to indicate genetic influences, similar environmental factors among relatives cannot be discounted. Adoption studies are conducted in an effort to control environmental influences. Those studies show that the adopted-away offspring of persons with schizophrenia are at increased risk for schizophrenia and schizophrenia-spectrum disorders. More recent studies using narrower, criterion-based definitions of schizophrenia have reported risk figures that are lower than those reported in earlier studies.
Although there are methodological problems with all three study approaches, findings from them suggest some type of genetic influence in schizophrenia, the significance of which has yet to be delineated. Likewise, the mode of transmission has not been found. Recent efforts have focused on linkage analyses and attempts to locate specific genes. Genetic and environmental factors play a role in the development of schizophrenia, and further refinement in methodology should help to identify the environmental and genetic components of schizophrenia.
Ethnicity and Racial Factors
Several studies have discovered differences in the prevalence and number of new cases of schizophrenia among various ethnic and racial groups. The findings are not consistent and may result from failure to control for confounding factors such as social class, age, sex, and immigration status. Data from the NIMH ECA study confirm that if potential confounding factors such as socioeconomic status are controlled, the difference in prevalence across races disappears.
Previous studies of different geographical areas have found a higher prevalence and a larger number of new cases in different countries (e.g., Ireland) and within countries (e.g., the Istrian peninsula of Yugoslavia). Most studies comparing geographical areas are usually flawed because they fail to validate diagnostic methods in different ethnic groups and localities. The WHO Determinants of Outcome study reported that the incidence of schizophrenia is similar in various cultures, especially when a restricted definition is used. If true differences in incidence can be shown, perhaps differences in environmental characteristics, genetic characteristics, or both, can be found in these areas.
Age
Early studies showed mean ages of onset for schizophrenia well below 45 in men and women. However, recent data indicate that onset after age 45 is not as rare as was previously assumed. Data from the ECA study reveal that schizophrenia may remain undiagnosed in the elderly because the disease has a different presentation in this age group. When compared with younger persons, most elderly people with delusions or hallucinations may not have the typical pattern of chronic progressive schizophrenia and are less likely to be significantly impaired or to be under the care of a mental health specialist.
Sex
Studies that do not separate groups by age of onset show a male-to-female ratio of close to 1, but this changes when various age cohorts are examined. Men are most likely to have the onset of symptoms between ages 15 and 25; women are at highest risk at ages 25 to 35; the reasons for this difference are not clear. The disease may manifest differently in the two sexes, hormonal factors may be involved or sociocultural factors may predispose men to earlier case findings.
As data from the WHO DOS show, when different cultures are examined the findings (earlier date for first treatment and first hospitalizations for men) are the same. More asocial premorbid characteristics, birth complications, and cerebral structural changes (especially in the left or dominant hemisphere) have been reported in men than in women, and schizophrenia in men may have a more chronic and disabling course. The findings are not conclusive and are limited by methodological problems such as failure to control for sociocultural factors.
Season and Birth Order
Studies have shown that a disproportionate number of persons with schizophrenia are born during winter months (seasonal excess of approximately 10 percent); which, together with a birth pattern in their nonschizophrenic siblings that is similar to that seen in the general population, suggests the presence of a seasonal factor. Proposed explanations for this seasonal effect include deleterious environmental factors in the winter (such as temperature, nutritional deficiencies, infectious agents); a genetic factor in those with a propensity for schizophrenia that protects against infection and other insults and thus increases the likelihood of survival; and more frequent conception in the spring and summer by the parents of persons with schizophrenia.
Although no experimental testing has been conducted, studies appear to favor the harmful-effects hypothesis that schizophrenia involves infectious agents, but the other hypotheses have not been ruled out conclusively. Although some studies in the southern hemisphere confirm a higher birth rate for schizophrenic persons in winter than in other seasons, further study of that hypothesis is needed. There are a number of methodological problems with previous studies. If there are statistically significant increases of schizophrenic births during the southern hemisphere winter, environmental factors should be favored over sociocultural ones. Whether winter- and summer-born persons with schizophrenia differ is not clear, but that would not necessarily be expected if the causative agent is active all year but more active in the colder months.
Early studies also reported a characteristic birth order pattern for persons with schizophrenia, but the results have not been consistent and family size can affect the findings. For example, some have found schizophrenia to be unusually common in the youngest children of large families and in the first-born sons of small families. Again, methodological problems limit the value of the studies.
Birth and Fetal Complications
When compared with controls, persons with schizophrenia as a group, and especially male infants, experience a greater number of birth complications. Some studies have also reported a relationship between perinatal complications and early onset of disease, negative symptoms, and poorer prognosis. The crucial factor appears to be transient perinatal hypoxia, although not all infants so affected later develop a psychiatric disorder. There is, however, a general trend toward psychopathology in persons who have suffered obstetrical complications; such events appear to increase the vulnerability to development of schizophrenia and probably are not a specific cause. Some have proposed that complications at birth may be the result of preexisting fetal neurodevelopmental abnormalities or a vulnerability to such abnormalities. No prospective studies have been done, and retrospective case control studies may be biased if informants interviewed about a relative with schizophrenia try harder to remember birth complications than do informants reporting on healthy controls. Obstetrical records often refer only to severe complications.
Social Class
Social class can be specified in various ways using some combinations of income, occupation, education, and place of residence. In previous studies the prevalence and number of newly identified cases of schizophrenia have been reported to be higher among members of the lower than the upper social classes. Two different explanations have been proposed. One explanation is that socioenvironmental factors found at lower socioeconomic levels are a cause of schizophrenia (social causation theory). Those factors include more life event stressors, increased exposure to environmental and occupational hazards and infectious agents, poorer prenatal care, and fewer support resources if stress does occur.
The other explanation is that lower socioeconomic status is a consequence of the disorder (social selection or drift theory). The insidious onset of inherited schizophrenia is believed to preclude elevating one's status or to cause a downward drift in status. Prospective studies have shown that persons with schizophrenia have less upward mobility from generation to generation than do the general population and that there is downward drift after the onset of symptoms. Many continue to argue this unsettled question, but a recent study strongly suggests that social drift processes are more important than social causation.
Marital Status
Reports based on first hospital admissions have shown higher rates of schizophrenia for unmarried than for married patients, and some have inferred that single status contributes to the development of schizophrenia. However, the phenomenon may be similar to that described under social class; that is, the disease lessens the chance of marriage and increases the chance of divorce. Studies have not shown marriage to have a protective effect against schizophrenia and have not shown an excess of schizophrenia in widowed persons. Previous research using subjects hospitalized for the first time may have been flawed because unmarried and married men appear to have different hospital utilization patterns.
Immigration
A higher risk for schizophrenia among recent immigrants than in native populations has been reported, but no study to date has confirmed that immigration stress leads to schizophrenia. Indeed, the ECA study found a low prevalence of schizophrenia among Mexican-Americans studied in Los Angeles, most of whom were immigrants. The generally reported increased prevalence of schizophrenia among immigrants could result from selection (i.e., persons with schizophrenia may be more likely to leave their families); from the failure to control for such other factors as social class, age, and sex; or from the failure to compare immigrant patients to nonimmigrant controls from the same homeland. These methodological issues limit any conclusions that can be drawn from existing reports.
Urbanization and Industrialization
The prevalence of schizophrenia has been reported to be higher in urban environments than in rural areas. This is consistent with widely held beliefs that cities are places of rapid change and social disorganization, whereas rural areas are more socially stable and the inhabitants more integrated. However, data from the ECA study show no difference in the prevalence of schizophrenia between urban and rural areas when such factors as race, sex, and age are controlled.
The assertion that the prevalence and incidence of schizophrenia have increased in the twentieth century has been tested by comparing developing countries with industrialized nations, but such studies are fraught with methodological problems. For example, because infant mortality is lower in industrialized countries, those likely to develop schizophrenia may survive more frequently. Families are smaller and more insular, and ill members may be more obvious. The question of whether schizophrenia is more prevalent in modern times has also been studied by analyzing the reported number of new cases over time. However, it is difficult to control for probable diagnostic or recognition bias across centuries, especially for a disease that was first defined only in the late 1800s.
Life Stressors
The association between stressful life events (such as loss of job, divorce) and the etiology and course of schizophrenia has been much studied. Schizophrenia or relapse of a preexisting disorder often follows extraordinary stress, so it has been suggested that such stress might provoke acute schizophrenia in a healthy person. Others argue that stress plays only a marginal role in the pathogenesis of the disorder or simply triggers schizophrenia in vulnerable persons. The few studies that have considered the issue have suffered the usual methodological problems of retrospective case-control studies and have had difficulty in outlining predispositional factors in schizophrenia. The stressor might have triggered the onset of a disorder that would have occurred without the stressor. The issue is not settled and will require further studies, especially prospective ones in which the role and severity of stressors in individual cases can be considered.
Infections
Anatomical changes suggestive of viral infection of the central nervous system have been reported in some people with schizophrenia. A viral hypothesis is consistent with seasonal excesses and geographical differences. Viruses could also interact with a genetic predisposition, familial transmission, or both, in complex ways in the development of the disease. Recent studies have reported that exposure to viral infections during the second trimester may increase the risk for development of schizophrenia. As yet no study has conclusively shown an association between viral infection and the onset of schizophrenia. Further studies, especially those that can show evidence of viral transmission, are needed.
Suicide Risk
Suicide is a leading cause of mortality in people suffering from schizophrenia. Estimates vary, but as many as 10 percent of people with schizophrenia may die because of a suicide attempt. Although the risk for suicide is greater in people with schizophrenia than in the general population, some risk factors—such as being male, white, and socially isolated—are similar in both groups. Factors such as depressive illness, a history of suicide attempts, unemployment, and recent rejection also increase the risk for suicide in both populations. Previous studies have revealed other risk factors that are unique to this disorder. Among these are being young and male and having a chronic illness with numerous exacerbations. A postdischarge course involving high levels of psychopathology and functional impairment increases the risk for suicide. In addition, people who have a realistic awareness of the deteriorative effects of the illness and a nondelusional assessment of their future are at increased risk for suicide. Other factors such as fear of further mental deterioration, hopelessness, excessive dependence on treatment, or loss of faith in treatment increase the risk of suicide in people with schizophrenia. The risk of mortality is especially high in the young, during the early postdischarge period, and early in the course of illness, although the risk persists across the person's life span. Risk factors identified in previous studies may be helpful in assessing acute suicidal risk in a specific individual. Further research is needed to better understand what risk factors are most predictive of future suicide in people with schizophrenia and what interventions are most helpful in preventing suicide.
Childhood Schizophrenia
As with adult-onset schizophrenia, different diagnostic criteria can affect the interpretation of results from studies of childhood-onset schizophrenia. Early definitions of childhood-onset schizophrenia tended to be broad and often included patients with autistic disorder. Recent diagnostic systems have departed from these earlier definitions by using the more restrictive criteria applied to adults that emphasize hallucinations and formal thought disorder. This restrictive definition, however, fails to consider developmental issues, such as the nature of delusions in childhood, and how a formal thought disorder can be diagnosed in a child under 8 years of age whose formal cognitive processes are not fully developed. Others have considered developmental stages in diagnosing childhood-onset schizophrenia, but no consensus has been reached. The accuracy of any reported epidemiological data on childhood-onset schizophrenia is compromised by differences in diagnostic criteria. Therefore, the prevalence of childhood-onset schizophrenia is not clear, but it is probably less than that of early infantile autism and is estimated to be less than that of adult-onset schizophrenia. There does not appear to be a greater incidence in boys than girls, as there is in infantile autism.
The risk factors of childhood-onset schizophrenia are not well known, and many investigators have simply extrapolated from adult findings. However, environmental stressors, perinatal complications, and central nervous system dysfunction have all been reported to occur more frequently in children who are diagnosed with schizophrenia.
FUTURE DIRECTIONS
Future epidemiological work in schizophrenia should use multisite, prospective, long-term studies. The WHO studies provide some of the foundations for such proposed efforts. However, longitudinal prospective studies of people at risk should be carried out, from near birth, and extending through the ages of major risk (early adult years). Such studies, with appropriate controls, should incorporate opportunities for genetic mapping of families at risk; chromosomal studies; and current laboratory measures of potential psychophysiological vulnerability such as continuous performance and sensory discrimination testing, neuroimaging, and other measures evolving with methodological advances. The expense of such studies would not be greater than that of comparable multisite, long-term studies of risk factors for cardiovascular and other diseases and would be small compared to the extraordinary direct and indirect costs of this most devastating of mental disorders.
SUGGESTED CROSS-REFERENCES
Some of the methods and concepts applicable to this section are discussed in Section 5.2 on statistics and experimental design. The genetics of schizophrenia is discussed in Section 12.5. Other aspects of schizophrenia are presented throughout the other sections of Chapter 12. Other psychotic disorders are reviewed in Chapter 13. Section 11.3 discusses amphetamine-related disorders, Section 11.7 discusses hallucinogen-related disorders, and section 11.11 discusses phencyclidine-related disorders.
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12.3 Schizophrenia: Brain Structure and Function

RAQUEL E. GUR, M.D., PH.D., and RUBEN C. GUR, PH.D.
The past decade has seen a transformation in psychiatric thinking about schizophrenia. Its conception as a complex behavioral disorder that reflects an interplay between biological and psychosocial factors has been changing as developments in the neurosciences have yielded tools for probing neural substrates of behavior. In particular, advances in neuroimaging methods have enabled translational research in which schizophrenia can be studied from the molecular to the behavioral levels using complementary top-down and bottom-up strategies. Such work has identified some consistent aberration in brain structure and function that may help formulate our new conception of schizophrenia as a brain disorder. This is not to dismiss environmental stressors, but rather to put these in the perspective of a brain disorder in evolution.
Two major aspects of brain integrity can be assessed through neuroimaging: structural anatomy and functional activity. In view of the complexity and course of schizophrenia, these measures need to be taken across the life span and longitudinally to document the association between brain changes and behavior. Furthermore, the disorder-related effects are superimposed on healthy individual differences—for example, sex differences and maturational changes—that have to be established in healthy people before we can understand pathological changes. However, despite the complexity of such an approach, its implementation can yield new opportunities for elucidating the neural substrate of schizophrenia in a way that will lead to improved diagnosis and treatment.
Accordingly, the section first describes studies of structural imaging in schizophrenia, which have been linked to neuropathological findings in postmortem research. This is followed by findings obtained by functional imaging studies.
NEUROANATOMICAL STUDIES IN SCHIZOPHRENIA
Neuroanatomical correlates of dysfunctional performance have provided the foundation for current thinking about brain regulation of behavior. The behavioral aberrations manifested in schizophrenia implicate a diffuse abnormality likely to involve several brain systems. Defining the neuroanatomical differences and possible changes associated with schizophrenia is arguably a prerequisite for understanding its neural substrates and for interpreting functional studies of brain physiology and neurochemistry. Structural studies have progressed from reliance on ratings to planimetric measures and, more recently, reliable computerized segmentation methods for obtaining volumetric measures. The improvement in precision of neuroanatomical parameters has yielded some consistency in effects and correlations with clinical and neurobehavioral measures.
Structural Neuroimaging
Earlier neuroimaging studies with computerized tomography (CT) applied nonvolumetric measures and suggested enlarged ventricles, implying reduced brain parenchyma. Magnetic resonance imaging (MRI) has advanced the study of the neuroanatomy of schizophrenia. It offers improved sensitivity for examining sulcal changes, better contrast resolution, direct multiplanar imaging, lack of bone artifacts, and no ionizing radiation. The field has progressed from initial studies of small samples, examining multiple regions with low-field scanners, using linear and area measurements, to the application of computerized image analysis in large samples. This has enabled linking neuroanatomical measures to two behavioral dimensions: clinical features of the disorder and neurocognitive deficits.
Whole Brain and CSF Volumes Studies with MRI have replicated earlier findings with CT indicating smaller brain volume and more cerebrospinal fluid in patients with schizophrenia than in healthy people. As can be seen in Figure 12.3–1, a person with schizophrenia shows evidence for widening of CSF spaces in both the ventricles and the sulci. Image segmentation methods have permitted increasingly precise quantitation of brain and CSF volume, and although these studies generally support the notion of increased CSF relative to brain volume in schizophrenia, they also indicate considerable overlap with healthy people (Fig. 12.3–2). This suggests that abnormalities at the level of whole brain may characterize only subtypes of patients with schizophrenia. Some patients exhibit a concomitant decrease in brain and increase in CSF volume, consistent with atrophy, whereas other patients show concomitant decreases in brain and CSF volume (hence cranial volume) which is more consistent with dystrophy. A third group shows neither abnormality.
FIGURE 12.3–1 MRI of a young healthy adult (A) and a same-aged adult with schizophrenia (B). Radiological examination showed evidence of the patient's increased cerebrospinal fluid in ventricles and sulci.
FIGURE 12.3–2 Scatterplot of brain volume of adults with schizophrenia relative to that of healthy adults matched sociodemographically.
These measures have been related to phenomenological and other clinical variables such as premorbid functioning, symptom severity, and outcome. The results suggest that whole brain measures are related to clinical features. Abnormalities in these measures are likely to be more pronounced in patients with poorer premorbid functioning, more severe symptoms, and worse outcome. The concept of brain reserve that has been suggested in other disorders, such as Alzheimer's disease, may apply to schizophrenia as well. Thus, normal brain and CSF volumes are preliminary indicators of protective capacity. As our understanding of how brain systems regulate behavior in health and disease improves, we can take advantage of neuroimaging to examine specific brain regions implicated in the pathophysiology of schizophrenia.
Regional Volumes Examination of brain regions implicated in schizophrenia has required methodological developments to enable testing specific hypotheses regarding the neuroanatomical basis of the aberrant behavior. Studies have evolved beyond comparing patients with controls, and current work linking regional measures to specific symptoms and subtypes requires large samples and systematic data acquisition. Furthermore, given the subtle changes evident in schizophrenia, findings must be evaluated relative to well-characterized healthy people. For example, the effects of normal aging appear to be sexually dimorphic. Cross-sectional studies reported age-related reduction in frontal and temporal lobe volumes in healthy men but not women (Fig. 12.3–3).
FIGURE 12.3–3 Frontal and temporal lobe volume in younger and older healthy adult men and women. (Reprinted with permission from Cowell PE, Turetsky BT, Gur RC, Grossman RI, Shtasel DL, Gur RE: Sex differences in aging of the human frontal and temporal lobe. J Neurosci 14:4748, 1994.)
The main regions showing consistent abnormalities in schizophrenia have been frontal and temporal lobe structures. Lower frontal and temporal lobe volume has been observed in patients than in healthy controls matched demographically (Fig. 12.3–4). Reduced temporal lobe volume correlated with both memory impairment and severity of negative symptoms. These findings were observed in first-episode patients, indicating that structural changes are evident at the first clinical presentation, which supports a neurodevelopmental origin. The differences are more pronounced in men than in women with schizophrenia.
FIGURE 12.3–4 Frontal and temporal lobe volume in adults with schizophrenia compared with that of healthy adults matched sociodemographically.
Reduced volume was reported in multiple regions including the superior temporal gyrus, hippocampus, and thalamus. These structures are critical for maintaining the integrity of the complex behaviors that are impaired in schizophrenia. Figure 12.3–5 illustrates some of the regions that show abnormal volume in schizophrenia, as well as an example of an image that has been segmented into gray and white matter and CSF. Most regions show volume decrease; the exception is basal ganglia regions reported to show increased volume in schizophrenia. This increase seems to be related to the effects of dopamine receptor antagonists.
FIGURE 12.3–5 Illustration of regions that have shown volume abnormalities in schizophrenia: A, frontal lobe; B, temporal lobe; C, basal ganglia.
Gray Matter and White Matter Segmentation MRI can yield detailed anatomical information apart from the demarcation of brain and CSF. With sequences that are T1-weighted it is possible to segment gray from white matter (Fig. 12.3–5A, upper right image). Several lines of investigation have demonstrated advantages of applying such methods. Gray matter changes have been found during adolescence and in the course of the normal aging process. Gray-white segmentation is critical in developmental studies in which age-related decreases in gray matter may be obscured by simultaneous increases in total brain and cranial volumes. These improvements in image processing methodology have helped determine whether tissue loss and disorganization in schizophrenia is primarily a gray matter deficit or whether abnormalities in white matter are also involved.
Reduced cortical gray matter was noted in a number of studies that evaluated chronic patients with schizophrenia. More recently, one study of first-episode patients also reported a gray matter deficit in individuals with a recent onset of illness.
Longitudinal Studies Efforts to elucidate the pathophysiology of schizophrenia have focused on the role of the neurodevelopmental relative to progressive neurodegenerative processes. Documenting neuroanatomical aberrations with structural neuroimaging and evaluating their course in relation to clinical and neurobehavioral manifestations can help test such hypotheses. CT and MRI studies have been primarily cross-sectional, and a longitudinal design is necessary to examine the possibility of progressive deterioration suggested by the neurodegenerative hypothesis. The few longitudinal evaluations of structural abnormalities have not been integrated with clinical and neurobehavioral measures.
Results from CT follow-up studies, with planimetric methods and ratings of sulcal enlargement, have varied. Some studies found no significant changes in ventricle-brain ratio (VBR) in relatively small samples rescanned after a number of years, commonly ranging from 2 to 5. Other studies reported that some patients do show an increased VBR over similar time spans. The investigators noted that these initial studies have limitations related to sample size, patient characteristics, and scanning and measurement procedures.
While most follow-up CT studies evaluated chronic patients with schizophrenia, MRI longitudinal studies have examined first-episode patients. This is an informative population because the design enables prospective follow-up starting early in the course of illness. One group of investigators found no ventricular changes in a follow-up (1–2 years) study of 13 patients and 8 controls. Lyn DeLisi and her colleagues initially evaluated 16 patients and 5 controls, studied 2 years after a first psychotic episode. Patients showed no consistent change in ventricular size with time, although there were individual increases or decreases. With a larger group of 24 patients and 6 controls no significant changes were observed in ventricular or temporal lobe volume at follow-up. Recently, a report on 20 of these patients and 5 controls rescanned over 4 years noted greater decreases in whole-brain volume and enlargement in left ventricular volume in patients and concluded that subtle cortical changes may occur after the onset of illness.
These authors have described a reliable and validated method for obtaining MRI measures of brain volume. In healthy adults, these parameters have been related to sex differences and the effects of aging, and in schizophrenia, they were related to clinical features. This method was applied in a longitudinal study of 40 patients (20 first-episode, 20 previously treated) and 17 healthy controls, rescanned an average of 2.5 years later. Volumes of whole brain, CSF, and frontal and temporal lobes were measured. Severity of negative and positive symptoms was assessed, medications were monitored, and neurobehavioral functioning in eight domains was evaluated. First-episode and previously treated patients had smaller whole-brain and frontal and temporal lobe volumes than controls at intake. Longitudinally, reduced frontal lobe volume was found only in patients, whereas temporal lobe reduction was also seen in controls. The association between volume reduction and symptom change differed between patient groups, but in both first-episode and previously treated patients, volume reduction was associated with decline in some neurobehavioral functions. The existence of neuroanatomical and neurobehavioral abnormalities in first-episode patients indicates that brain dysfunction occurred before clinical presentation. However, the longitudinal studies suggest progression in which anatomical changes may affect some clinical and neurobehavioral features of the illness in some patients.
The limited number of longitudinal MRI studies and small sample sizes leaves the question of progression unresolved and precludes confident distinction of disease-related changes from those associated with normal aging. Furthermore, standard therapeutic interventions need to be included in such longitudinal studies.
FUNCTIONAL NEUROIMAGING
Application of Functional Brain Imaging Methods
Evolving technology provides an increasing array of measures of brain function. Some of these measures overlap and others are complementary. For example, the functional integrity of the brain can be examined through measures related to energy metabolism, such as rates of glucose and oxygen utilization and cerebral blood flow. Neuroreceptor function can be assessed through methods for measuring receptor density and affinity at presynaptic and postsynaptic sites. Methods that have been applied in schizophrenia included the Xenon-133 (133Xe) clearance technique for measuring cortical cerebral blood flow; positron emission tomography (PET) for assessing glucose metabolism, cerebral blood flow, and neuroreceptor functioning; single photon emission computerized tomography (SPECT) for studying cerebral blood flow and neuroreceptors; and, more recently, functional MRI (fMRI) for measuring changes attributable to cerebral blood flow. Figure 12.3–6 illustrates the application of such methods in healthy people.
FIGURE 12.3–6 Illustration of functional imaging data obtained in healthy people: A, sex differences in local glucose metabolism; B, activation with verbal and spatial tasks as seen by functional MRI. Abbreviations: SF, superior frontal; DL, dorsal prefrontal-lateral; DM, dorsal prefrontal-medial; MF, midfrontal; IF, inferior frontal; SM, sensorimotor; SP, superior parietal; SG, supramarginal gyrus; OL, occipital cortex, lateral; OM, occipital cortex, medial; LI, lingual gyrus; FG, fusiform gyrus; OT, occipital temporal; ST, superior temporal; MT, midtemporal; IT, inferior temporal; TP, temporal pole; PH, parahippocampal gyrus; HI, hippocampus; AM, amygdala; IN, insula; OF, orbital frontal; RG, rectal gyrus; CA, cingulate gyrus-anterior; CG, cingulate gyrus; CP, cingulate gyrus-posterior; C1, corpus callosum-anterior; C2, corpus callosum-posterior; CN, caudate nucleus; LM, lenticular-medial (globus pallidus); LL, lenticular-lateral (putamen); MB, mammillary body; TH, thalamus; MI, midbrain; PO, pons; CE, cerebellum. Cortical regions are grouped by lobe in a rostral-caudal order, followed by corpus callosum and subcortical regions. This order heuristically also reflects ontogenic and evolutionary development. Top graph shows means + SEM of region to whole brain (R/WB) ratios, and bottom graph shows laterality differences in percentage, i.e., 100*(LR)/mean(L,R). (See Color Plate 7.)
Links between clinical features of schizophrenia and brain function have been guided by hypotheses relating behavior to specific brain regions and systems implicated in schizophrenia. These links are based on preclinical research and the emergence of symptoms commonly seen in schizophrenia that also occur following brain lesions. Persistent negative symptoms have been observed as a neurobehavioral sequela of frontal lobe damage. Other frontal lobe functions such as abstraction, attention, verbal fluency, mental flexibility, and concept formation are also impaired. Productive positive symptoms of hallucinations and delusions have been related to the temporolimbic system, and this region is also implicated by evidence of impaired learning and memory. The greater impairment in verbal functions, the similarity of some symptoms to those observed in patients with left temporal lobe epilepsy, and the increased frequency of left-handedness (or, rather, "left-sidedness" as measured by a combined index of strength of right-handedness, footedness, and sighting dominance) in schizophrenia have led to the laterality hypothesis stipulating left hemispheric dysfunction. Thus the laterality gradient has been examined in several studies. Subcortical regions have been studied with special emphasis on the basal ganglia (implicated by the dopamine hypothesis) and the thalamus (related to sensory gating).
These early efforts, focusing on brain systems that are likely to modulate normal and pathological psychotic behavior, have generated hypotheses that can be examined with functional brain imaging. In addition to obtaining baseline measures of the resting topography of glucose metabolism and cerebral blood flow, functional imaging is an especially powerful methodology for the probe paradigm. There are two complementary approaches: neurobehavioral probes and neuropharmacological probes. The application of neurobehavioral probes has enhanced our ability to evaluate brain systems that regulate specific processes in healthy people and in those affected by schizophrenia, including attention, learning, memory, and executive functions. Neuropharmacological probe paradigms include examination of neuroreceptor function as well as the effects of pharmacological intervention on cerebral blood flow and metabolism.
CEREBRAL METABOLISM AND BLOOD FLOW STUDIES
Semour Kety and his colleagues have pioneered the measurements of whole-brain metabolism and blood flow in healthy people and reported normal values for patients with schizophrenia. Subsequent studies of regional cerebral metabolism and blood flow can be divided into those that measure the physiological parameters at a resting state and those that introduce a perturbation, or challenge, in the form of a neurobehavioral probe or a pharmacological intervention. Initially, investigators have aimed at assessing whether resting cerebral blood flow and glucose metabolism differ between patients with schizophrenia and healthy controls. The topography of physiological activity was examined along the anterior-posterior, subcortical-cortical, and lateral dimensions.
Resting Baseline The frontal lobes were implicated when early physiological studies of cerebral blood flow, reported that patients did not show the normal pattern of more anterior than posterior flow. This "hypofrontal" disturbance in the anterior-posterior gradient has been supported by some, but not all, studies of resting cerebral blood flow (by 133Xe and SPECT) and glucose metabolism (with PET). The relation between this pattern of metabolic activity and clinical variables has also been examined. Decreased frontal metabolic activity has been associated with duration of illness and negative symptoms. Longer duration of illness and more severe negative symptoms are related to a relative decrease in frontal lobe metabolism.
Differences in resting values between patients and controls were also found in laterality indexes, suggesting relatively higher left hemispheric values in more severely ill patients. Furthermore, improvement in clinical status correlated with a shift toward lower left hemispheric metabolism relative to that in the right hemisphere. This supports hypotheses derived from behavioral data concerning lateralized abnormalities in schizophrenia.
After assessing global, anterior-posterior, and lateral dimensions, investigators have begun the study of functional changes in brain systems linked to other impaired behavior in schizophrenia. Dysfunction in temporolimbic structures, including the hippocampus as well as temporal cortex, is supported by neuroanatomical and neuropsychological studies. Lateralized abnormalities in these regions, with greater left than right hemispheric dysfunction, are implicated by characteristic clinical features of schizophrenia, such as thought disorder, auditory hallucinations, and language disturbances. PET studies of temporal lobe metabolism show both increased and decreased glucose utilization. Decreased metabolism was also noted in hippocampus and anterior cingulate cortex. Studies in this region have been limited in part by instrument resolution.
Metabolism and flow pattern in temporolimbic regions have also been related to symptoms. An oxygen-15 (15O)-labeled water study with PET described abnormal cerebral blood flow in the parahippocampal gyrus, associated with positive symptoms. Hallucinations were associated with SPECT blood flow changes in the hippocampus, parahippocampus, and amygdala. There are conflicting reports of superior temporal gyrus functional changes in schizophrenia during active auditory hallucinations. While one study suggested that patients with hallucinations have lower relative metabolism in Wernicke's region, another study showed asymmetrical temporal lobe perfusion (lower in the left than the right) in patients with auditory hallucinations. In one PET study the rate of glucose metabolism was greater in the left anterior temporal lobe and was related to the severity of symptoms. This is consistent with another reported association between severity of symptoms and a relative increase in left hemispheric metabolism.
These reports varied in the method used and definition of regional parameters. Most studies used ratios such as region to whole brain or anterior to posterior rather than absolute values of activity. Inconsistencies in findings could also be related to sample size, heterogeneity, analytical approaches, and individual techniques. Most studies included relatively small samples of patients, which varied in important clinical factors such as chronicity, symptom subtypes and severity, level of functioning, and history of treatment. Furthermore, inclusion criteria varied, and some laboratories applied more stringent criteria (e.g., related to history of comorbidity of substance abuse or head trauma with loss of consciousness). Another potential source of variability in results is the definition of resting state. Investigators have been reluctant to include an unstructured resting state because of concern that such measures will be uncontrolled and therefore produce unreliable results. Some studies used reduced sensory input, and others used sensory stimulation to standardize this condition. However, several studies examined the reproducibility of resting baseline measures with relatively unstructured conditions (i.e., eyes open and ears unoccluded, with ambient noise kept to a minimum). These studies found high reproducibility among healthy subjects and patients with schizophrenia.
Given the demonstrated reliability of the standardized resting baseline condition, these authors believe such a condition should be included in physiological neuroimaging studies. This will serve three main purposes. First, it will permit comparison across studies within a center as technology evolves and patient characteristics change. Without a common resting baseline condition it would be impossible to interpret differences in results. Second, it will enable comparability across centers. Imagine the need to explain why two centers using the same or similar tasks find evidence for different regional abnormalities in schizophrenia. If resting baseline values are available and are comparable in the two samples, different task effects could be legitimately attributed to theoretically meaningful sources such as task condition or symptomatic variability. Third, a standardized resting baseline provides a reference point for determining whether a given task or condition has increased neural activity. In studies that have included such a condition, cognitive activation was consistently shown to increase cortical activity in both patients and controls. Using a resting baseline condition enables the investigator to make much stronger statements in interpreting regional effects. Rather than being restricted to statements that a given region has changed in its activation relative to the remainder of the brain, resting baseline data can be used to determine whether the task has induced increased neural activity.
Functional changes in the basal ganglia have been examined with PET and SPECT. Several PET studies implicate basal ganglia dysfunction in schizophrenia. The withdrawal-retardation factor (emotional withdrawal, blunted affect, and motor retardation) of the Brief Psychiatric Rating Scale has been negatively correlated with PET basal ganglia metabolic activity. Neuroleptic-naive patients with schizophrenia were reported to have relatively increased blood flow in the left globus pallidus. Other PET studies report decreased basal ganglia metabolism in schizophrenia, while yet others found increased basal ganglia metabolic rates following administration of neuroleptic medication.
Thus, while the contribution of PET metabolic and blood flow studies so far has been to add to the growing evidence implicating basal ganglia involvement in schizophrenia, the exact nature of the dysfunction remains unclear. In particular, the relation between basal ganglia and frontal lobe activity in schizophrenia needs further scrutiny. Emerging evidence from structural and functional imaging indicates a dynamic interrelationship between the various key regions. One study showed that patients with schizophrenia not only fail to activate dorsolateral prefrontal cortex in response to the Wisconsin Card Sorting Test, but they also fail to inhibit caudate activation. Hence, in schizophrenia, basal ganglia continue to show relatively increased flow in the caudate during performance of the task, while healthy controls seem to demonstrate a reciprocal relationship in which relative blood flow decrease in the basal ganglia is associated with increased perfusion to the frontal region.
Activation Studies Regardless of the debate over the value of obtaining resting baseline measures, measures of cerebral blood flow and metabolism during the performance of cognitive tasks clearly tend to accentuate differences between patients and controls. Perhaps even more importantly, such measures are critical for establishing the link between behavioral deficits and the ability of brain regions to become activated in response to task demands. This expectation has been supported in studies that used neurobehavioral probes.
The general approach in the field has been to work from hypotheses, derived from neurobehavioral data, which associate behavioral measures with regional brain function. Task selection can be made to include a target task (for which patients are expected to have a differential deficit) and control tasks. Patients are then compared with healthy controls in the pattern of task-induced changes in regional brain activity. This has now become the established research paradigm and significant progress has been made since the early studies with 133Xe.
The authors, Daniel Weinberger, and their colleagues applied the 133Xe method during resting measures and while subjects were performing specific tasks. Both groups found no differences in overall or hemispheric cerebral blood flow between patients and controls at resting baseline. However, distinct abnormalities were seen when physiological activity was measured in response to cognitive probes. Pursuing the laterality hypothesis, the first author of this section and coworkers administered tasks with a demonstrated link to left (verbal analogies) and right (spatial line orientation) hemispheric functioning. Healthy controls showed the expected greater left hemispheric increase for the verbal task and greater right hemispheric increase for the spatial task. However, patients with schizophrenia had a bilaterally symmetrical activation for the verbal task and greater left hemispheric activation for the spatial task. Thus, patients failed to show the normal left hemispheric dominance for the verbal task and instead showed left hemispheric overactivation for the spatial task.
Similarly, Weinberger and coworkers found no regional abnormalities in the resting cerebral blood flow of patients with schizophrenia. However, distinct abnormalities were reported in the dorsolateral prefrontal region during activation with the Wisconsin Card Sorting Test of abstraction and mental flexibility, which is sensitive to frontal lobe damage. Application of this paradigm to the study of monozygotic twins discordant for schizophrenia revealed that all affected twins had lower dorsolateral prefrontal cortex cerebral blood flow response than discordant cotwins. Furthermore, negative symptoms, which have been related to frontal lobe dysfunction, showed a negative correlation with frontal blood flow during performance of executive tasks but not control tasks. Probing brain systems with specific tasks has also been advanced in SPECT and in cerebral blood flow studies with PET. These methods have also indicated abnormalities in patients with schizophrenia with a range of tasks including memory, executive, and attentional measures. The consistent finding is a lack of normal regional activation in response to task, and activation in some regions not seen in healthy subjects.
These results suggest that brain systems recruited for the performance of specific tasks in healthy people are not similarly engaged in patients with schizophrenia. What may account for such aberrations? Genetic liability, neurodevelopmental abnormalities in which brain systems fail to achieve maturity, or the impact of a psychotic process that interrupts normally developed structures and processes? Does therapeutic intervention ameliorate the abnormal signature? How specific are the results to schizophrenia? These are some of the questions yet to be answered that can certainly be addressed with neuroimaging.
Functional MRI The introduction of MRI is an exciting, more recent development in functional imaging research. Functional MRI methods offer several potential advantages over PET for imaging brain function, including higher spatial resolution, higher temporal resolution, noninvasiveness, lack of ionizing radiation, direct correlation with anatomical imaging, greater reproducibility, and economy. Disadvantages include the loud background noise generated by the gradients, difficulties in presenting stimuli and performing tasks in the magnet bore, claustrophobia, low signal-to-noise ratio for most methods, and lack of quantitation in physiological units for most methods. Many of these disadvantages can be overcome by using specialized equipment compatible with the MRI environment. These methods are described briefly because they are recent and hold potential for functional imaging in schizophrenia.
Currently, three main techniques exist for MRI of the brain. Gadolinium bolus-tracking was the first technique to be applied to mapping task-specific regional brain function in animals and humans by use of MRI. In normal brain, gadolinium diethylenetriaminepentaacetic acid (DPTA) is an intravascular tracer, allowing semiquantitative transit time and blood volume images to be calculated with rapid imaging techniques. Because of the accumulation of the intravascular tracer, the number of determinations is limited to two to three per day. Because gadolinium DPTA is an intravascular tracer, dynamic measurements of its passage through brain yield measurements of cerebral blood volume and mean transit time rather than cerebral blood flow, but changes in cerebral blood flow are generally reflected by changes in these other indexes.
Blood oxygenation–sensitive imaging has been most widely applied to fMRI, replicating previous PET studies. The technique relies on magnetic susceptibility effects of deoxyhemoglobin that cause regional signal decreases in imaging sequences that are sensitive to susceptibility (e.g., echoplanar or routine gradient echo sequences). With regional brain activation studies a net increase in signal intensity is observed in regions known to be activated by the task. The increase in image intensity corresponds to a local decrease in deoxyhemoglobin. This finding is attributed to a greater increase in regional blood flow than in regional oxygen consumption, a notion supported by PET measurements of blood flow and oxygen consumption with regional brain activation. A wide variety of pulse sequences can be used to obtain blood oxygenation–sensitive imaging measures. Many simple activation paradigms have been tested, and activation has been observed with both fast and slow imaging. A typical response is a 1 to 25 percent change in regional image intensity, which develops over 3 to 8 seconds following task initiation. Susceptibility effects of deoxyhemoglobin are field dependent. Thus, a scanner with 1.5 tesla field strength would typically record signal changes with functional activation of about 0.25 to 5 percent, while at 4 telsa changes up to 25 percent have been observed. The main advantage of ultrafast imaging is that the time course of signal change can be observed and multislice imaging can be carried out in a reasonable time period.
The third technique, arterial spin tagging (quantitative perfusion imaging) uses magnetization tagging of endogenous arterial water to determine the perfusion of brain parenchyma by comparing images obtained with and without a labeled arterial supply. The method is analogous to steady-state techniques used in PET, since the regional signal intensity depends upon the arterial blood flow (which delivers labeled spins) and the T1 relaxation rate (which causes the labeling to decay). This technique has the important advantage of providing quantitative cerebral blood flow parameters. Furthermore, perfusion is measured in brain parenchyma directly and is thus better localized than measurements obtained by use of an intravascular tracer, which is most sensitive to venous outflow effects. There may also be less motion sensitivity than with blood oxygenation–sensitive imaging.
Application of this technology to the study of schizophrenia is quite new. Perry Renshaw and colleagues measured the relative change in image signal intensity caused by photic stimulation in eight patients and nine controls. The mean signal intensity change in the primary visual cortex was significantly greater in patients than in controls. A subsequent study examined a sample of 12 subjects with schizophrenia and 11 healthy controls performing a word fluency task, associated with left frontal lobe function. Patients showed less left frontal activation and greater left temporal activation than controls. Sensorimotor cortex and supplementary motor area activation were examined in right-handed patients (8) and controls (9) during finger-to-thumb opposition. All subjects showed a significant activation of the supplementary motor area and both ipsilateral and contralateral sensorimotor cortices. Compared with controls, patients showed a decreased activation of both sensorimotor cortices and supplementary motor area as well as a reversed lateralization effect. Increased understanding of the technology and elucidation of neural systems involved in the processing of tasks in healthy people should enhance our ability to apply this methodology to schizophrenia.
Effects of Medication The pharmacological status of patients undergoing metabolic and blood flow studies has varied. Research has ranged from investigations in which antipsychotic agents were considered a variable that needed to be controlled to those in which pharmacological intervention was introduced in a standardized fashion to examine treatment effects on the regional metabolic landscape. The washout period in studies that attempted to control the effects of antipsychotic drugs on cerebral blood flow and metabolism has commonly been short, ranging from 2 to 4 weeks. This period is a compromise between what is feasible and desirable. Monte Buchsbaum and colleagues examined cerebral glucose metabolism in cortical-striatal-thalamic circuits in a large sample of unmedicated men with schizophrenia. They found that patients had low metabolic activity in the medial frontal cortical regions and the basal ganglia, as well as an impaired lateralization pattern in the frontal and temporal regions. More recently in schizophrenia research, antipsychotic drug-naive first-episode patients have been studied. This population is particularly informative when the study is focused on the effects of pharmacological intervention. The study of neuroleptic-naive patients before pharmacological intervention separates the disease state from its treatment. The pattern of abnormalities summarized above is evident in first-episode patients across studies that examined differences between their first episode and episodes of previously treated patients. This suggests that disruption in normal brain processes is apparent at the presentation of illness and cannot be attributed to treatment or chronicity. While this is an informative approach, further progress can be made in metabolic studies using complementary methods to integrate pharmacological probes with metabolic studies.
A repeated-measures longitudinal design has been applied in a limited number of PET studies. In addition to examining symptom severity over time, this paradigm is singularly useful when pharmacological intervention is standardized. One study compared the effects of thiothixene (Navane) and haloperidol (Haldol) in chronic patients who were scanned off medication and after 4 to 6 weeks on medication. A different pattern of global and regional glucose metabolism was seen in the two groups. In another study PET scans were obtained at weeks 5 and 10 of a double-blind crossover trial of haloperidol and placebo in 25 patients with schizophrenia. Low relative metabolism in the striatum on placebo was associated with improved symptomatology. Responders to treatment had increased metabolism in the striatum after treatment. Nonresponders failed to show such a change and had more marked hypofrontality on medication. In a subsequent study, 12 patients were scanned before and 4 to 6 weeks after treatment with clozapine (Clozaril) or thiothixene. The drugs had a differential effect, with clozapine increasing and thiothixene decreasing metabolism in the basal ganglia, right more than left. Henry Holcomb and coworkers used a repeated-measures design to study glucose metabolism in 12 patients on a fixed dose of haloperidol and 5 and 30 days after drug withdrawal. No differences were observed between metabolism on medication and after 5 days of discontinuation. However, at 30 days, metabolism decreased in the caudate, putamen, and anterior thalamus and increased in the frontal cortex and anterior cingulate. The authors concluded that the basal ganglia are the site of the primary antidopaminergic action of haloperidol and that other changes observed are mediated through the cortical-striatal-thalamic pathways. The integration of pharmacological and neurobehavioral probes is a potentially powerful approach. For example, patients exhibited enhanced activation of the anterior cingulate after administration of apomorphine, suggesting a modulating role for dopamine.
Methodological Considerations and Potential Limitations
Anxiety has complex effects on regional cerebral blood flow and metabolism, which investigators in a few laboratories have reported. It would seem desirable to measure anxiety carefully by use of complementary behavioral and psychophysiological procedures and to examine the relation of these measures to the regional metabolic and cerebral blood flow values and performance.
Motivation is an important factor in cognitive studies of schizophrenia. Whether poor performance can be improved by providing instructions and monetary reinforcement has been addressed in studies with the Wisconsin Card Sorting Test. One approach to this issue is the calculation of "mental effort" scores by subtracting basal cognitive abilities (e.g., I.Q. measures) from current performance. This difference between current and basal performance provides a measure of how well subjects perform in relation to their inherent ability, which may provide a parameter of motivation that can be related to cognitive and physiological data. This approach has been taken in 133Xe and PET cerebral blood flow studies.
Task selection and choice of stimuli raise several questions. There are reasons to prefer elemental tasks that have been used extensively in cognitive psychology and are applicable across physiological measurements. A continuous presentation format of the tasks provides flexibility and ensures that subjects receive continuous stimulation during the measurement epoch. The importance of examining the issue of epoch has been recently demonstrated in a study by the Iowa group.
In many studies, self-paced task presentation was used with the hope of engaging the subject's utmost mental resources and efforts. This was considered essential for the 133Xe and the PET flurodeoxyglucose studies, which integrate data across long periods of clearance (15 and 40 minutes, respectively). The disadvantage of self-paced administration for the PET cerebral blood flow and functional MRI measurements may, however, outweigh their advantage because of the brief measurement epoch. For brief duration, there could be considerable variability in the number of stimuli processed by subjects, and because patients with schizophrenia have slower initiation and response times, the differences in cerebral blood flow activation between patients and controls could be hard to interpret.
Central to the goal of relating regional cerebral blood flow change to task performance and clinical state variables is the problem of correlating behavioral data with physiologic data that are themselves intercorrelated. Innovative statistical approaches (e.g., Statistical Probability Mapping [SPM]) are used to address the global scaling factors inherent in this area of investigation.
NEURORECEPTOR STUDIES
Study of Neuroreceptors Another critical window for assessing brain function, the study of neuroreceptors, can give insight into the nature of neurochemical abnormalities in schizophrenia. Because advances in elucidating the pathophysiology of schizophrenia require understanding neurotransmitter function, the application of PET and SPECT to the study of receptor occupancy is likely to have an impact in the near future. These efforts are guided both by an extensive psychopharmacological literature and by advances in basic neuroscience on neuroreceptor subtyping. Functional neuroimaging is the meeting ground of preclinical and clinical neuropharmacology. Human neuroreceptor PET studies have built on progress with in vitro binding measurements of receptor density and affinity and neuroreceptor autoradiography. Psychotic symptoms seen in schizophrenia have been associated with dysfunction of dopamine, and the dopamine hypothesis has undergone revisions on the basis of these data.
PET Studies of D2 Ligands The development of radioligands for PET studies first focused on the dopamine type 2 (D2) receptor because of its clinical significance in relation to treatment with a neuroleptic agent. The study of antipsychotic drug-naive patients could potentially differentiate effects of the psychotic state before antipsychotic-drug intervention. Two major methodologies for quantitative measurement were developed and applied in the study of schizophrenia. Investigators at Johns Hopkins University applied [11C]N-methylspiperone and reported that patients have higher D2 Bmax values than controls. Studies at the Karolinska Institute, using [11C]raclopride, reported similar Bmax and Kd values in patients and controls.
These apparent differences have been discussed and summarized extensively and are likely related to multiple factors including patient variables, ligand properties, and PET modeling methods. Because the ligands differ in binding properties and sensitivity to endogenous dopamine, studies permitting a more direct comparison will be particularly helpful. In such an effort, Anna-Lena Nordstrom and coworkers evaluated the reproducibility of the [11C]N-methylspiperone finding in a study of seven neuroleptic-naive patients and seven controls, before and after administration of 7.5 mg of haloperidol. Consistent with previous quantitative PET study of [11C]raclopride binding, there were no differences between patients and controls pretreatment, and after haloperidol the specific binding of [11C]N-methylspiperone was reduced by 80 to 90 percent. More recently, investigators at Johns Hopkins replicated the initial report in a new sample of drug-naive patients with schizophrenia. Other data reveal D2 receptor density increases in psychotic, but not in nonpsychotic, patients with bipolar I disorder. The increase is comparable to that reported in schizophrenia. This raises questions regarding the specificity of the dopamine hypothesis to schizophrenia versus other psychotic syndromes.
Jean-Luc Martinot and coworkers measured D2 striatal dopamine receptors using [76Br]-bromospiperone in a PET study of 12 untreated patients with schizophrenia and found no increase in receptors in patients relative to controls. In a subsequent study, [76Br]bromolisuride was applied to the measurement of striatal D2 receptors in 19 untreated patients and 14 controls. Again, no differences in striatum-to-cerebellum ratios emerged, and no relation to symptoms or subtypes was evident in either study.
Receptor Function and Clinical Response The study of neuroreceptors can also address issues related to the relationship between receptor function and signs such as akathisia, commonly seen in patients treated with neuroleptic agents. Farde and colleagues determined in four control subjects the activity of [11C]SCH 23390, a selective D1 receptor antagonist. Two PET studies, at low and high doses of the radioligand, were conducted per subject. Transient akathisia occurred only when binding in the basal ganglia was at a high level with 45 to 59 percent occupancy. The D2 receptor antagonist [11C]raclopride was measured in 20 controls and 13 patients. Akathisia was associated with maximal ligand binding in the basal ganglia in patients and controls. Adam Wolkin and colleagues found that neuroleptic-resistant patients with schizophrenia did not differ from neuroleptic responders in degree of D2 receptor occupancy by the antipsychotic agents. The regional distribution and kinetics of haloperidol binding were studied with [18F]haloperidol in a PET study of five patients with schizophrenia examined while on haloperidol and after a drug washout and nine controls. Wide regional distribution of the ligand was evident in the cerebellum, basal ganglia, and thalamus, in contrast to the specific binding to the basal ganglia of [18F]N-methylspiroperidol. Thus, small structural differences among butyrophenones are associated with changes in kinetics and distribution.
Typical and Atypical Antipsychotics PET neuroreceptor methods have also been applied in studies comparing atypical (serotonin–dopamine antagonists) and typical (dopamine receptor antagonists) antipsychotic drugs. The properties of clozapine binding to D1 and D2 receptors were examined in an open study of 5 patients, relative to 22 patients treated with dopamine receptor antagonists. Clozapine induced lower D2 occupancy (38 to 63 percent), whereas D2 receptor occupancy with dopamine receptor antagonists at conventional doses was 70 to 89 percent. Neuroleptic-induced extrapyramidal syndromes were associated with higher D2 occupancy. In a follow-up study, Nordstrom and coworkers examined the relation between D2 receptor occupancy and antipsychotic drug effect in a double-blind PET study using [11C]raclopride. Seventeen patients with schizophrenia were randomly assigned to three groups treated with varied dosages of raclopride. A PET study was conducted at steady-state on 13 patients during the third to fourth week of treatment. A curvilinear relation between plasma concentration of raclopride and D2 receptor occupancy was obtained. A significant relationship was noted between D2 receptor occupancy and Brief Psychiatric Rating Scale percentage change as a measure of outcome. The D2 receptor occupancy in patients who had extrapyramidal adverse effects was higher than in patients without. Nordstrom and coworkers examined D1, D2, and 5-hydroxytryptamine type 2 (5-HT2) receptor occupancy in 17 patients treated with clozapine (125 to 600 mg a day) applying [11C]SCH23390, [11C]raclopride, and [11C]N-methylspiperone. D2 receptor occupancy (20 to 67 percent) was lower than for dopamine receptor antagonists (70 to 90 percent); D1 receptor occupancy (36 to 59 percent) was higher than that reported for dopamine receptor antagonists (0 to 44 percent); and 5-HT2 receptor occupancy was high (84 to 94 percent). Thus clozapine shows a combination of relatively high D1, low D2, and quite high 5-HT2 receptor occupancy values, and serum concentrations are not predictive of receptor occupancy. In a PET study of [11C]raclopride, Shitis Kapur and coworkers determined D2 receptor occupancy induced by 2 mg a day of haloperidol for 2 weeks in seven patients. High levels of D2 occupancy (53 to 74 percent) were noted with substantial clinical improvement. A similar investigation in nine patients receiving 2 to 6 mg a day of risperidone (Risperdal) showed receptor occupancy (66 to 79 percent) similar to that of dopamine receptor antagonists and higher than that of clozapine. When 10 patients with psychoses treated with loxapine were evaluated for D2 and 5-HT2 receptor occupancy, the agent differed from serotonin-dopamine antagonists. It has high 5-HT2 receptor occupancy, which is not higher than D2 occupancy. These research paradigms illustrate the integration of functional neuroimaging with pharmacological research. Incorporation of these strategies to psychopharmacological studies of schizophrenia with available therapeutic agents can advance the field and guide treatment intervention.
SPECT Studies The D2 receptor SPECT ligand iodine-benzamide 123I-iodobenzamide (IBZM) has been applied in studying dopamine D2 receptors in patients with schizophrenia. Fifty-six patients were evaluated and a semiquantitative analysis of D2 receptor binding was calculated (basal ganglia to frontal cortex ratio of activity). These ratios in patients taking typical neuroleptic agents were significantly lower than those in the neuroleptic-free subjects but not lower than those in the patients taking serotonin-dopamine antagonists (clozapine, remoxipride). No overall elevation of D2 receptor binding was observed comparing 20 patients off medications and 20 controls, but a left lateralized asymmetry was found in male patients.
METABOLITE STUDIES: MAGNETIC RESONANCE SPECTROSCOPY (MRS)
MRS provides analytical qualitative and quantitative data on cellular metabolism and molecular structure. It has been used to study metabolism in vitro and in vivo in animals and humans. Spectral localization methods permit the measurement of 1H and 31P nuclear magnetic resonance (NMR) spectra from precisely localized volumes of interest, and this provides the basis for applying these techniques to study brain diseases. Because the technology is fundamentally similar to that used in MRI, several groups have begun to develop an approach that integrates these two modalities into a single examination. There are few reports that use this approach to investigate the underlying metabolism of neuropsychiatric disorders. Jay Pettegrew and colleagues pioneered applying phosphorus-31 (31P) methods to the study of several neuropsychiatric diseases, including schizophrenia. They reported hypofunction in the dorsolateral prefrontal cortex in a sample of antipsychotic drug-naive patients with schizophrenia. The patients had significantly lower levels of phosphorus monoesters (PME) and higher levels of phosphorus diesters (PDE) than normal controls. Inorganic phosphate concentration was decreased and ATP concentration was increased in the patients. These latter results were interpreted as reflecting hypofunction of the dorsal prefrontal cortex in the patients. This interpretation is consistent with reports of decreased blood flow and decreased utilization of glucose in this region, as summarized above. A follow-up case report described a patient who exhibited in the 31P MRS spectra PME and PDE levels similar to those reported for schizophrenia, well before the onset of psychotic symptoms. This finding led the authors to suggest that MRS may be of value in examining high-risk subjects such as family members of patients with schizophrenia for the presence of spectral abnormalities. Another group reported 31P MRS results on patients with schizophrenia that support the findings of Jay Pettegrew and coworkers. Thus, a growing body of evidence from several laboratories shows converging findings.
This suggests the possibility of dysfunction in the normal process of programed synaptic pruning. Abnormal pruning could result in neuronal loss as well as upregulation of the postsynaptic dopaminergic receptors. These changes observed with 31P clearly suggest that there should be alterations in the levels of the compounds routinely detectable by localized proton MRS.
Considerable interest exists in obtaining solvent-suppressed proton spectra in humans. As the technical issues involved in obtaining spectra are being solved, it is important to begin to relate MRS measurements to the underlying biochemistry in the tissue being sampled. The role of N-acetylaspartate was reviewed by D.L. Birken and W.H. Oldendorf. This compound was found by NMR in glia and neurons but not on astrocytes. For this reason N-acetylaspartate concentration has been proposed as an index of neuronal integrity. The roles of the amino acids present in the brain have been examined. There is about 12 mM glutamate present in the brain, making it by far the most abundant amino acid. The rates of glutamate synthesis and oxidation differ in astrocytes and neurons. Two important products of glutamate are glutamine which is formed from glutamate by glutamate synthetase located in astrocytes and g-aminobutyric acid (GABA), an inhibitory neurotransmitter. Aspects of the metabolism of these compounds and the influence of this metabolism on MRS spectral appearance has received increased attention. Glutamate is largely confined to the tissue in which it is formed by barriers in permeability. Glutamine can be converted to glutamate at the site of neurotransmitter activity by glutaminase, which is present in neurons. The combination of two enzymes, glutamine synthetase (which converts glutamate to glutamine) and glutaminase, acts as a sort of cycle to maintain the concentrations of glutamate and glutamine. GABA and glutamate concentrations were determined by MRS in cultured preparations of cortical neurons and cerebellar granule cells, and colleagues granule cells contained large amounts of glutamate, while the neuronal cells contained large amounts of GABA.
Detection of these compounds in vivo in clinical studies showed increased glutamine concentrations in patients with chronic hepatic encephalopathy. Douglas Rothman and coworkers showed that it is possible to determine the glutamine concentration in human brain by spectral editing methods. The glutamine concentrations reported were in excellent agreement with literature values. These workers referenced their measurement of glutamate to the concentration of total creatine present (9.6 mM) in the brain. The key feature in their methodology was the use of short echo delays (12 milliseconds) to estimate the glutamate present. It seems therefore that MRS can be used to measure the concentrations of these amino acids, which may provide some insights into the activity of the excitatory glutamate and inhibitory (GABA) neurotransmitters present in the tissue being sampled. The studies so far are preliminary, since larger samples and a comprehensive and systematic approach to behavioral assessment are needed to link behavioral dimensions to both neuroanatomy and metabolism.
FUTURE DIRECTIONS
Structural and functional neuroimaging research in schizophrenia has made progress in advancing the understanding of neuroanatomical and neurophysiological substrates of this disorder. Structural imaging studies have identified subtypes of patients with reduced brain volume, and lower regional volumes have also been reported in structures that are key to healthy processing of complex behavior. While it is too early to outline with any precision the network of regions most affected, some consistent evidence has emerged implicating frontotemporal and corticostriatal thalamic regions. By and large, these structural abnormalities are present early in the course of illness and are related to disease features. These research methods can be applied to informative populations such as high-risk individuals and in genetic paradigms. Furthermore, recent evidence for progressive changes in some patients encourages longitudinal studies.
Two areas have been examined in functional imaging studies: energy metabolism and neuroreceptor studies. In a review of this field Goran Sedvall concluded that the major future contribution for understanding the pathophysiology of schizophrenia will be achieved through advanced resolution and development of new ligands for neurotransmitter systems. While the authors agree on the potential of these developments, they believe that metabolic studies can make unique contributions that will prove essential for finding the neural basis of schizophrenia and ultimately for improved treatment. In the context of the overall effort in neurobiological research in schizophrenia, functional neuroimaging studies have advanced the understanding of brain dysfunction related to neurobehavior and neuropharmacology. The field has reached some maturity in developing appropriate paradigms, and there is now a need for adequate sample size in patient and healthy populations, with attention to clinical heterogeneity and variability in brain function in relation to gender and age.
One of the major challenges in this research is the integration of neuroimaging data across anatomical and functional measures with clinical and neurobehavioral variables. A potential strength of functional neuroimaging is the integration of data on neuroreceptor function, metabolites, and metabolic activity. Ultimately, dysfunctional neurotransmitter systems translate to aberrant metabolism. Since cerebral blood flow and metabolism reflect neuronal activity, relating these domains is prerequisite to understanding the neurobiology of schizophrenia. As new receptor subtypes are cloned and radioligands are developed and available for human studies, it will be necessary to know which neuroreceptor measures result in increased neuronal activity and in turn how regional activation relates to behavior.
Thus, while new receptor ligands and improved resolution are welcome and exciting, as is the development of methods for MRS and flow measures, it is unlikely that the neural basis of schizophrenia will simply result from applying the right method with sufficient resolution. Rather, the harder and longer route of understanding the interaction among the brain's structural integrity, regional activity, and neuroreceptors as they affect the clinical and neurobehavioral manifestations of schizophrenia will probably be needed. On the positive side, this examination may yield partial answers of immediate benefit for treatment, and the evolution of this work will systematically improve our ability to articulate a neuropsychiatric perspective of this devastating disorder.
SUGGESTED CROSS-REFERENCES
The neural basis of schizophrenia psychopathology is further discussed in Section 1.1 an introduction and overview of neural sciences, in Section 1.2 on functional neuroanatomy, in Section 1.4 on monoamine neurotransmitters, in Section 1.10 on basic molecular neurobiology, and in Section 3.5 on brain models of mind. Neuroimaging is presented in Sections 1.15 and 1.16. Typical antipsychotics drugs are presented in Section 31.17 on dopamine receptor antagonists. Atypical antipsychotics are covered in Section 31.26 on serotonin-dopamine antagonists. Other aspects of schizophrenia are discussed throughout Chapter 12.
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12.4 Schizophrenia: Neurobiology

MICHAEL F. EGAN, M.D., and THOMAS M. HYDE, M.D., PH.D.
Schizophrenia is a chronic mental illness affecting approximately 1 percent of the population. Beginning in early adulthood, schizophrenia typically causes a dramatic, lifelong impairment in social and occupational functioning. From a public health standpoint, the costs of treatment and lost productivity make this illness one of the most expensive disorders in medicine. Despite the tremendous economic and emotional costs, research on schizophrenia lags far behind that on other major medical disorders. A primary impediment to developing more effective treatment is the limited understanding of the etiology and neurobiology of this disorder. New technologies, such as neuroimaging and molecular genetics, are removing the obstacles that once blocked major progress in the field. Although the stigma associated with the illness has not yet been eliminated, these new techniques have markedly altered the conception of the nature of schizophrenia.
One of the most rapidly changing fields is genetics. Family, twin, and adoption studies have clearly shown that genes play a prominent role in the development of schizophrenia. Estimates of heritability typically range from 50 to 85 percent. Initial attempts to isolate major genes using linkage studies were unsuccessful, but more recent approaches using increasingly sophisticated methods have uncovered several chromosomal regions that may harbor genes of minor effect. It seems likely that schizophrenia is the result of the interaction of many genes, some of which also interact with environmental factors. Investigations of environmental factors have looked at the role of stress, viruses, obstetrical complications, and in utero insults, among others. None of these have been definitively shown to be causative. It is possible that different combinations of genetic and environmental factors affect specific neurobiological systems, leading to a final common pathway of neural dysfunction.
Several neurobiological abnormalities have been found to have major implications for understanding the pathophysiology of schizophrenia. The first are structural brain abnormalities. Initially seen decades ago using pneumoencephalography, structural changes have been more clearly delineated using computerized tomography (CT) and magnetic resonance imaging (MRI). The most commonly reported alterations include enlarged lateral ventricles, enlarged third ventricle, and reduced volume of a number of structures, including hippocampus, amygdala, and frontal and temporal cortices. These abnormalities may predate the onset of illness. Second, functional cortical deficits have been seen with a variety of techniques, such as neuroimaging and neuropsychological testing. Prefrontal and temporal lobe dysfunction is most prominent, and is possibly related to structural abnormalities. Third, neuropathological studies have consistently failed to find any evidence of gliosis to account for the structural deficits. If anything, they tend to find subtle cytoarchitectural alterations. The recurring theme of this research suggests some type of failure in neuronal migration, orientation, or connectivity. Finally, several neurotransmitter systems appear to play a role, particularly in the expression of positive as well as negative psychotic symptoms. Evidence for alterations in the dopamine system is the most compelling. Other neurotransmitters have also been implicated, including glutamate, serotonin, and g-aminobutyric acid (GABA).
Neurochemical, structural, and functional imaging abnormalities can be understood in the context of the neural circuits involved and models of the illness. Cortico-striato-thalamic, limbic, and dopamine systems all appear to play a role. These three interconnected pathways mediate different aspects of higher-level information processing, such as judgment, memory, planning, and motivation. Their involvement could arise in several ways. One model suggests that neurodevelopmental abnormalities occur in utero. The clinical manifestations of schizophrenia appear only after brain development is largely completed, in late adolescence. Although this hypothesis has come to dominate thinking about schizophrenia, the neurodevelopmental model has several weaknesses.
ROLE OF GENES AND ENVIRONMENT
Genetic Factors
Family, twin, and adoption studies indicate that there is a major heritable component to schizophrenia. Whereas the incidence in the normal population is approximately 0.5 to 1 percent, the lifetime risk in first-degree relatives is roughly 10 percent, indicating that the risk to first-degree relatives is 10 times that of the general population. This strongly implicates a familial factor in the etiology of the illness. Twin and adoption studies have shown that this is mostly, if not entirely, due to genetic factors. For example, the concordance rate in monozygotic twins is approximately 50 percent, as compared to 10 to 14 percent for dizygotic twins, suggesting that heritability may be as high as 80 percent. Of seven adoption studies, all found an increased incidence of schizophrenia in biological relatives, but not in adoptive relatives. This data convincingly demonstrates that genetic factors rather than shared, familial environmental factors are at work.
Although such epidemiological data implicate a major heritable component, the genetic architecture appears complex. Early attempts at modeling genetic transmission in families (using segregation analysis) suggested that heritability could not be explained by a single, dominant gene. In the early 1990s, increasingly sophisticated modeling indicated that at least several genes were involved, each with incomplete penetrance. One very real possibility is that there are many genes of minor effect. Such genes are difficult to detect using traditional linkage approaches. A triggering role for the environment in those with a genetic predisposition has also been hypothesized. While genetic modeling has been heuristically useful, the lack of a clear genetic mechanism complicates attempts to find the causative genes.
Early linkage studies were based on traditional assumptions that a single dominant gene produced the illness. These were, in general, unsuccessful. The first published study to use restriction fragment length polymorphisms (RFLP) reported linkage between two markers on the long arm of chromosome 5 (5q11–13) and schizophrenia. Subsequently, a number of other groups using separate cohorts were unable to replicate this, and several were able to clearly reject linkage to loci from 5q. While this failure dampened enthusiasm for genetic studies of schizophrenia, the relentless advances in statistical genetics and the molecular biology of the human genome have provided powerful new tools for detecting genes of minor effect. For example, some of the problems with specifying the unknown parameters needed for linkage analysis can be circumvented by using nonparametric approaches. These approaches use large collections of sibling pairs, both affected with the illness. As investigators have begun to use such tools, positive linkage reports for schizophrenia susceptibility genes of minor effect have been reported. Recent examples of putative schizophrenia susceptibility loci yielding some evidence of confirmation include loci on chromosomes 6, 8, and 22.
Despite real advances, several statistical issues continue to complicate interpretation of linkage studies. First, ambiguities persist about what diagnoses should be included. Family and adoption studies have suggested that diagnoses such as schizoaffective disorder, schizotypal personality disorder, and atypical psychosis are genetically related. To hedge their bets, investigators looking for linkage typically test several definitions of "schizophrenia spectrum," ranging from narrow to very broad inclusion criteria. This means that more family members are included in the analysis as diagnostic criteria broaden. Second, the issue of which genetic model to use continues to plague parametric approaches. Typically, linkage studies include dominant, recessive, and mixed models. Here again, investigators hedge their bets by testing three or four genetic models. Since both problems lead to multiple testing, correction for multiple comparisons is indicated. Unfortunately, it is not entirely clear how to correct for this multiple testing. Currently, the commonly accepted significance level (p values) for initial linkage reports is ~10-4 to 10-5 or a logarithm of the odds (LOD) score of 3.3 and 0.01 for confirmation. Several groups have published putative replications of linkage findings based on these statistical criteria.
The first linkage study with some independent confirmation came from a study of a large Irish cohort. Using microsatellite markers and 186 multiplex schizophrenia families, evidence was found for linkage to the short arm of chromosome 6 (6p22). However, when adjusting for multiple comparisons, a genome-wide significance was estimated at .05 to .08 percent. When the original cohort was extended to 265 pedigrees, an LOD score of 3.51 was obtained, again using a moderately broad definition of illness. The LOD score was highest with a model of intermediate penetrance; of note, only 15 to 30 percent of pedigrees were linked. Supportive evidence for linkage to 6p22 was found in three independent studies. Interestingly, the three replications were different from the original in several ways; one used a recessive model and a narrow definition. In contrast to the original findings, a dominant model and broad disease definition yielded an LOD score of 0.06. A second replication study found suggestive linkage at a marker very close to the one in the original report. Not unexpectedly, a number of studies have failed to replicate the D6p22 linkage. These results illustrate some of the complexities of linkage studies of schizophrenia, but also provide some hope that these methods will uncover the genes involved in schizophrenia.
In addition to 6p22–24, at least two other regions have yielded evidence of linkage to schizophrenia. Ann Pulver and colleagues first described evidence for suggestive linkage to chromosome 8 at 8p22-p21 using 57 multiplex families. Soon after, another group, using a very broad definition of illness, reported confirmatory evidence for linkage using the Irish cohort; again, only 10 to 25 percent appeared to be affected by this putative susceptibility gene. A second attempt at replication by a multicenter collaborative group also found support for linkage. Suggestive evidence for a third potential vulnerability locus was reported for chromosome 22 at q12-q13.1.
Although the evidence for susceptibility loci in these reports does not overlap completely, the differences in location are not large. In other heritable complex diseases, for example, susceptibility genes have been cloned that are 20 centimorgans (about 20 million base pairs) away from the sites initially linked to the illness. As with 6p22–24, the strength of evidence for linkage to both 8p22-p21 and 22q12-q13.1 depends in part on what is acceptable as a significant replication. This in turn is related to how multiple tests are corrected for using a variety of phenotypes and model parameters. It is possible that there are schizophrenia susceptibility genes in a roughly 10 to 20 cM area in these regions that may each affect a small percentage of families. Several other regions have received attention but the evidence is less compelling. These regions include, at present, 5q, 6q, 9p, 18p, and 22q.
Using the candidate gene approach, weak support for involvement of the dopamine type 3 (D3) receptor gene has emerged. In 1992, an excess of homozygosity was noted in schizophrenia patients compared to controls for a polymorphism in the first exon of the D3 receptor gene. A few subsequent studies have supported a modest association between schizophrenia and homozygosity of the Ser-9-Gly polymorphism, but a large number of other studies failed to replicate this association. Linkage studies with D3 receptor gene polymorphisms have not found significant LOD scores. As more functional variants in candidate genes are discovered, focused association studies of these genes will become increasingly common.
It is crucial to determine exactly what is inherited. One possibility is that genes determine susceptibility to certain environmental factors. Another possibility is that specific neurobiological abnormalities are produced by specific genes. Family studies have shown that relatives have an increased incidence of several neurobiological traits associated with schizophrenia. These include structural brain abnormalities, changes in evoked potentials, eye-tracking dysfunction, negative symptoms, and subtle cognitive deficts. These parameters could be more basic phenotypes that are closer to the molecular manifestations of the genes that cause schizophrenia. If so, they may improve the ability to detect these genes.
Environmental Factors
Family-based epidemiological studies clearly demonstrate that environmental factors play a role in the pathophysiology of schizophrenia. The contributions of environmental factors have been estimated to be as much as 30 to 50 percent. Genetic modeling indicates that genes could set the threshold for liability to environmental factors. It is sobering to realize that environment can play a crucial role even in disorders that appear to be autosomal dominant. For example, phenylketonuria is an autosomal-dominant disorder that causes mental retardation. The illness is expressed, however, only if individuals with the abnormal gene ingest phenylalanine. Without this critical environmental exposure, the illness does not develop. Environmental factors hypothesized to play a role in schizophrenia range from problems with maternal bonding and early rearing to poverty, immigration status, stress, and viruses. The neurodevelopmental hypothesis has shifted the research focus somewhat from psychosocial variables to those that affect brain development. Several specific insults have been implicated, including pregnancy and birth complications, in utero viral infections (such as influenza), season of birth, and prenatal starvation.
Research into pregnancy, obstetric, and neonatal complications has had a particularly significant impact on the field. These complications include events such as prolonged labor, prematurity, preeclampsia, toxemia, fetal distress, and hypoxia. The majority of studies examining the incidence of such complications find increases in patients with schizophrenia. Positive studies include those that compare patients with matched controls, with their own well siblings, and even with a monozygotic twin discordant for schizophrenia. On the other hand, several impressive negative reports, including prospective, epidemiological surveys have failed to find a significant increase in such complications. However, these studies have been criticized on methodological grounds, thereby leaving the issue in doubt. Some authors have suggested that perinatal complications may increase risk only in persons with a genetic predisposition whereas others assert just the opposite. Although these conflicting findings make definite conclusions tentative, the bulk of the data suggests that perinatal complications are increased somewhat in patients with schizophrenia.
One possibility for how such complications lead to schizophrenia is that they produce some type of brain damage. The hippocampus, for example, is particularly susceptible to perinatal hypoxia and this limbic structure is thought to play an important role in schizophrenia. A number of studies have found that patients with a history of obstetric complications have increased likelihood of structural brain abnormalities, such as enlarged ventricles. A similar relationship has been seen in nonschizophrenic controls with a history of obstetric complications. However, many studies have failed to find any relationship between structural abnormalities and obstetric complications. Some authors have suggested that only nongenetic forms of the illness (sporadic cases) are more likely to have structural problems and obstetric complications, but data on this are very mixed. More problematic, obstetric complications are thought to mediate increased risk by transient hypoxia but hypoxia typically produces gliosis, a finding notably absent from the postmortem literature on schizophrenia. An alternative explanation is that obstetric complications are themselves secondary to abnormal fetal brain development. In any event, if obstetric complications increase the risk of schizophrenia, they are likely to be a minor factor; most persons with these complications do not develop schizophrenia and most patients with schizophrenia do not have an obvious history of obstetric complications.
A second risk factor that has been extensively studied is season of birth. There appears to be an increased incidence of schizophrenia associated with winter and spring birth dates. This finding is controversial, and has been attributed by detractors to a statistical artifact. If there is such a relationship, it could implicate an infectious process, such as a virus; viral infections are more common during winter months. Viral hypotheses have taken several forms, and candidates include slow viruses, retroviruses, or virally activated autoimmune reactions. In a related vein, several large-scale epidemiological studies have reported that the frequency of schizophrenia is increased following exposure to influenza during the second trimester. The effect is slight, however, and some studies have not observed this relationship. Another intriguing risk factor is starvation or poor nutrition. In studies of the effects of starvation during World War II in Holland, researchers found that starvation at the time of conception and in the first trimester increased the risk of developing schizophrenia by a factor of 2. Other factors recently reported to increase the risk of schizophrenia include Rh incompatibility and low intelligence quotient (I.Q.).
At this point, no single major factor has been unambiguously identified as an environmental cause of schizophrenia, and it is likely that none exists. As with genetic loci, environmental effects probably consist of a variety of factors, each having a minor effect at best. These will be difficult to detect, as will their hypothesized interaction with genes of minor effect, without large-scale studies.
STRUCTURAL AND FUNCTIONAL NEUROIMAGING
Neuroimaging studies of schizophrenia have demonstrated alterations in both structural and functional measures. Structural abnormalities include increased volume of the third and lateral ventricles, sulcal widening, and reduced volume of gray matter regions. Functional abnormalities include alterations in blood flow and measures of chemical moieties using MRI spectroscopy. Neuroimaging has also been used to assay receptor density and dynamic parameters related to dopamine release. Neurochemical studies are discussed separately in sections on specific neurotransmitters.
Neuroimaging has had a major impact on the conceptualization of schizophrenia. The notion that patients with schizophrenia have an actual deficit in the volume of brain tissue clearly established that this was a brain disease rather than a purely psychological or biochemical disorder. Functional neuroimaging has implicated the prefrontal and temporal lobes in particular, and has begun to relate activity in these regions to the clinical manifestation of schizophrenia. As critical as these findings have been, important controversies remain.
Structural Abnormalities
One of the most widely replicated neurobiological findings in schizophrenia research is that of altered volume of cerebral structures. Increased size of the cerebral ventricles and reduced brain volume were observed early in the twentieth century using pneumoencephalography and postmortem material. These early findings, however, had little enduring impact on the field. The advent of CT technology renewed interest in cerebral volumetric parameters. The earliest CT studies found enlargement of the lateral and third ventricles and cortical sulci. Although these findings were initially viewed with skepticism, over 100 subsequent studies have been published with lateral ventricular enlargement reported in 75 percent, third ventricular enlargement in 83 percent, and cortical changes in 67 percent. Concerns that ventricular enlargement could be secondary to factors such as antipsychotic medications, institutionalization, and diet have generally been ruled out. Furthermore, studies using MRI, with its markedly enhanced resolution, have confirmed the presence of lateral and third ventricular enlargement and provided estimates of tissue loss to be roughly 3 to 10 percent.
The finding of ventricular enlargement dramatically shifted the focus of research on schizophrenia. Subsequently, several critical questions have dominated this landscape. First, is ventricular enlargement caused by focal areas of tissue loss or a more generalized process? Second, do the structural abnormalities predate the onset of the illness, implicating a neurodevelopmental process, or do they arise concomitantly with the illness, suggesting a neurodegenerative process? Third, are all patients affected or only a subgroup? Finally, what are the functional implications of these abnormalities?
To localize brain abnormalities, researchers have looked at a variety of measures, including cortical sulcal enlargement, ventricular enlargement, and quantitative measures of individual brain structures. Regarding cortical sulcal enlargement the data are split, with some reporting sulcal enlargement in the frontal and temporal lobes whereas others have found more diffuse enlargement. More specific measures of cortical volume typically show reductions of temporal and, less consistently, frontal lobe volume. These reductions involve gray rather than white matter, although some studies have found reductions in white matter as well. Regional volumetric studies of specific brain structures have generally focused on the temporal lobes. Bilateral volume reductions in amygdala-hippocampus, parahippocampal gyrus, entorhinal cortex, and superior temporal gyrus have been reported. In the ventricular system, increased volume in the temporal poles of the lateral ventricles has been found most often; increased volume of the frontal horns and third ventricle is also commonly found. In quantitative studies of subcortical regions, findings have been mixed. Some researchers find no changes in areas such as caudate, putamen, nucleus accumbens, and external segment of the globus pallidus; others have reported increased striatal volume and reduced globus pallidus (internal segment) volume. Increased striatal volume is thought to be an effect of treatment with antipsychotic medications. Reduced volume of the thalamus has also been observed.
The notion that the temporal and frontal lobes may play a particularly important role in schizophrenia has been supported by findings from other areas. For example, neurological damage to the temporal lobes sometimes produces positive psychotic symptoms, such as hallucinations, while damage to the frontal lobes is associated with negative symptoms such as apathy, social withdrawal, and blunted affect. On neuropsychological testing, patients with schizophrenia typically show impaired frontal and temporal lobe function. More recently, magnetic resonance spectroscopy has been used to examine these regions. This new technology can measure in vivo concentrations of a variety of neurochemical moieties. These include N-acetyl aspartate (NAA), an intraneuronal amino acid sensitive to mitochondrial energy metabolism and to pathological processes affecting neuronal integrity, choline-containing compounds, creatine plus phosphocreatine, glutamate, glutamine, and high-energy phosphate-containing compounds. Several intriguing findings have emerged. First, specific reductions of NAA have been observed in the dorsolateral prefrontal cortex and hippocampal area, probably reflecting neuronal pathology in these locations. Other areas are, for the most part, unaffected. Second, an imbalance between phosphomonoesters and phosphodiesters has been described in the frontal cortex. These studies, combined with volumetric data, lend support to the theory that there may be selective deficits in frontal and temporal regions.
Attempts to pinpoint when volumetric alterations occur have led to studies of patients at the onset of their illness. This issue is crucial to understanding what neurobiological processes could possibly account for structural abnormalities. In general, first-break studies have found the same alterations seen in prior studies of patients with chronic schizophrenia. These results are supported by the lack of relation between volumetric alterations and duration of illness or age of onset seen in studies of such patients. If an active process produced tissue loss, the loss would be correlated with illness duration, which it is not in most studies. On the other hand, cognitive deficits associated with schizophrenia do not progress but probably develop very early in the illness. Although portions of these deficits may be present even in childhood, a significant component probably develops sometime around the onset of the illness. It is not inconceivable that structural abnormalities could develop at the same time. Such changes would not necessarily be detected by first-break studies. Another approach has been to scan first-break patients when they initially present for treatment and then again several years later. The results have been mixed: some find no changes whereas others have suggested that a subgroup of patients do show slight, but progressive tissue loss. The latter approach has been criticized on methodological grounds and certainly more studies are needed. At present, it seems fairly certain that structural abnormalities are present from very early on in the illness.
A third issue is whether structural alterations are present in all patients or only a subgroup. Several early studies had found associations between ventricular enlargement and a variety of clinical characteristics, including poor premorbid adjustment, age of onset, cognitive impairment, negative symptoms, poor response to antipsychotic medications, and greater incidence of tardive dyskinesia. Such observations have led to suggestions that there are two forms of schizophrenia, one involving a hyperdopaminergic state and the other involving structural abnormalities. Since then, many CT and MRI studies have examined this issue but have generally failed to confirm this schema. Structural abnormalities do appear to be correlated to some degree with cognitive impairment and negative symptoms, but these correlations are not particularly robust. Another approach to subtyping has been to look at the distribution of these deficits. In a meta-analysis of studies that have used CT scans to evaluate ventricular enlargement, the lack of a bimodal distribution in over 1000 patients suggests that a clear subgroup with these abnormalities does not exist.
An elegant attempt to assess the frequency of structural abnormalities was provided by a study of discordant monozygotic twin pairs. Unaffected monozygotic twins serve as an ideal control for assessing illness-related changes. In an MRI study of 15 such pairs, the ill twin had more pronounced deficits for most structural measures in over 85 percent of cases. These findings are similar to those of a prior twin study using CT scans. The data suggest that volumetric abnormalities in schizophrenia are very common, if not ubiquitous; detecting the abnormality may depend on having a perfectly matched genetic control (Fig. 12.4–1) because patients with normal ventricular volume were often seen to have significantly larger ventricles than their unaffected twin. However, when this MRI study of twins was expanded to 27 discordant pairs, lateral ventricular enlargement was only seen in about 63 percent of the affected twins relative to the unaffected twins. This is only somewhat higher than 50 percent, which is what would be expected by chance. In this expanded sample, it appears that ventricular enlargement may not be universal. In contrast, hippocampal measures continued to predict the affected twin in roughly 80 percent of cases, which is significantly higher than the 50 percent chance level; this suggests that hippocampal pathology is common. Although the exact percent of patients having structural abnormalities is not known, it is probably fairly high. An alternative view is that structural abnormalities represent a quantitative trait that is commonly associated with schizophrenia but neither necessary nor sufficient to produce the illness.
FIGURE 12.4–1 MRI scans (coronal sections) of two sets of discordant monozygotic twins (A and B = set 1; C and D = set 2). For each pair, one has schizophrenia (A and C) while the other does not (B and D). For both pairs, the affected twin has larger ventricles than the unaffected twin, even though ventricular size appears to be within the normal range for the affected twin (C). (Courtesy of D. Weinberger and E. F. Torrey.)
In summary, structural abnormalities, such as enlarged ventricles and reduced cortical volume, are a prominent feature of schizophrenia. It is unclear whether cortical involvement is multifocal or diffuse. Temporal and frontal lobe regions are certainly involved. These abnormalities are present very early in the illness. It is too early to say, however, whether they are present from birth or develop at a later stage. Structural abnormalities may be present in a majority of patients, although the exact percentage is unknown. The prevalence is most apparent when compared to ideally matched genetic controls. Structural abnormalities are correlated to some degree with clinical aspects of the illness, such as cognitive deficits. A key issue remains unresolved: what neurobiological processes account for these enigmatic changes?
Functional Neuroimaging
Functional neuroimaging refers to a group of methods that look at changes in regional neural activity by measuring regional cerebral blood flow (rCBF) or glucose utilization. These two parameters can be measured with several techniques, including positron emission tomography (PET),* (SPECT), and more recently functional MRI (fMRI), each having its own particular advantages and disadvantages. These techniques have been used to explore brain regions that may be dysfunctional in schizophrenia. Several designs have been employed: (1) patients and controls are compared at rest; (2) they are compared during cognitive testing that normally increases activity in a particular brain region; and (3) brain activity is correlated with psychiatric symptoms, either cross-sectionally among patients or within a patient over time. The most consistent finding is reduced activation of the prefrontal cortex (hypofrontality), but other regions, such as the temporal lobes, have also been implicated. Also, correlations have been found between specific symptom clusters and regional activity in both frontal and temporal areas (Fig. 12.4–2).
FIGURE 12.4–2 PET scans using H2O15 of two monozygotic twins, one with (right) and one without (left) schizophrenia. Top and bottom scans show two levels through the dorsolateral prefrontal cortex. At the time of scanning, subjects are performing a cognitive task that typically requires prefrontal cortical function. The affected twin blood flow to the dorsolateral prefrontal cortex is markedly reduced compared to the unaffected twin. (Courtesy of R. Berman and D. Weinberger.) (See Color Plate 8.)
Frontal lobe function has been studied most intensively. Initially reported in 1974, the finding of reduced frontal blood flow has been controversial. Many studies, particularly those looking at the resting state, have not found evidence of hypofrontality. Such studies have been criticized, however, because the resting state is an uncontrolled feature and may introduce unnecessary variability. Using cognitive tasks that appear to require prefrontal activation in controls, a number of studies have consistently found that patients with schizophrenia fail to increase blood flow to this region. Although many resting studies have reported hypofrontality, most, if not all, studies using activation tasks have found hypofrontality; this suggests that the use of activation tasks can increase the sensitivity of these procedures to detecting abnormalities by assessing function of regions involved in the illness (Fig. 12.4–2).
The finding of hypofrontality in schizophrenia has often been interpreted as an artifact of poor performance, motivation, clinical state, medications, or other factors. However, studies have not shown that these factors account for differences between patients and controls. For example, poor performance on working memory tasks is not necessarily associated with reduced prefrontal blood flow. Patients with Huntington's disease and groups with low I.Q. who do equally poorly on prefrontal cognitive tasks, are able to activate the dorsolateral prefrontal cortex. Interestingly, hypofrontality appears to be correlated with several structural and neurochemical indices. Prefrontal activation is highly correlated with homovanillic acid (HVA) concentrations in cerebrospinal fluid, possibly reflecting prefrontal dopamine activity. Hypofrontality has also been correlated with hippocampal volume in one study of discordant monozygotic twins, suggesting a dysfunctional circuit. Finally, preliminary reports suggest that reduced prefrontal NAA concentrations, markers of neuronal integrity, are correlated with reduced frontal activation. These data imply that hypofrontality could result from a process that affects neuronal viability in both frontal and hippocampal regions and that these have downstream effects on the regulation of prefrontal dopamine.
The temporal lobe has also been examined with functional neuroimaging techniques. Both elevated and reduced blood flow has been reported. The most common finding is an association between resting blood flow and positive psychotic symptoms. For example, one report found a correlation between increased psychopathology and blood flow to the left parahippocampal gyrus; a second found a similar correlation between positive symptoms and left temporal lobe blood flow. More specific correlations have been seen for auditory hallucinations and activation of Broca's area and medial temporal regions. A potential criticism of this finding is that patients may have simply been responding to auditory hallucinations with their own vocalizations. Activation of Broca's area, in this case, would be expected and trivial. Research into the relation between symptom clusters and blood flow revealed that positive symptoms were associated with increased medial temporal flow, negative symptoms with decreased prefrontal (dorsolateral) blood flow, and disorganization with increased cingulate flow. This parcelation of symptoms with neuroanatomy suggests that separate but related neurophysiological processes may underlie specific types of symptoms. The few studies that examine several regions simultaneously tend to find changes in the coordinated activity between regions, particularly between prefrontal and temporal areas. Typically, increased activation in temporal areas is found in functional connectivity of the two regions.
One report on other brain regions found increased left globus pallidus activity at rest; others have reported both decreased and increased glucose utilization in the striatum (Fig. 12.4–3). Antipsychotic medications appear to increase striatal metabolism, suggesting that medications are an important confound. Reduced cingulate activation has also been described. As newer techniques that do not depend on radioactivity, such as fMRI, are more commonly used, further characterization of these and other brain regions can be expected.
FIGURE 12.4–3 A, Schematic diagram of the mesial temporal lobe at the level of the body of the hippocampus and posterior entorhinal cortex, in coronal section. B, The illustrated connections of the coronal section are described in this table. (Drawn by Kyle Christensen.)
In summary, blood flow to several brain regions, including prefrontal and temporal areas, is altered in schizophrenia. These changes may be related to or may underlie positive and negative symptoms as well as some cognitive deficits. Regional abnormalities may also be related to each other, indicating a more global problem with the function of the larger systems or neural networks. Many questions remain. How closely are the changes in temporal and prefrontal activity associated with the clinical features of schizophrenia? Is the activation of other brain regions affected? Can functional brain imaging pinpoint which brain areas cause specific symptoms? What neurobiological processes account for differences in brain function? Correlations with structural abnormalities, dopamine metabolites, and regional NAA levels suggest that these variables could play a role.
NEUROPATHOLOGY
The neuropathological basis of schizophrenia remains obscure despite an increased number of techniques applied to the investigation of this subject. The future appears bright, however, as more laboratories across the world become engaged in this research. Regions that have become the focus of postmortem studies include temporal and limbic structures (hippocampus, amygdala, hypothalamus, nucleus accumbens, and cingulate cortex), and prefrontal and orbitofrontal cortices. Other paralimbic structures recently have been added to the neural network thought to be dysfunctional in schizophrenia, including the ventral tegmental area, substantia nigra, anterior thalamic nuclei, and entorhinal cortex. With this focused approach a number of intriguing findings have emerged; almost all still need independent replication, and the confounds of antemortem exposure to antipsychotic drugs must be considered when reviewing these studies.
Temporal Lobes
Mesial Structures Perhaps the one region that has received the greatest attention in postmortem schizophrenia research is the mesial temporal lobe, which contains the entorhinal cortex, amygdala, and hippocampal formation (Fig. 12.4–3). These structures have been examined in both morphological and neurochemical studies. The entorhinal cortex, which relays cortical input into the hippocampus and distributes output from the hippocampus to a diverse group of brain structures, has been carefully scrutinized. The laminar distribution of neurons in the superficial layers of the rostral entorhinal cortex has been reported to be abnormal and disorganized by several independent groups of investigators. One study in particular has suggested that the subtle changes in neuronal aggregation may be restricted to layers II and III. Taken together, these data suggest a mild disruption of normal cytoarchitectural features. Although it may not be impossible for this to occur later in life, the findings would strongly support the notion that abnormal neuronal migration may occur during brain development in patients with schizophrenia.
The finding that cytoarchitectural abnormalities are present in the entorhinal cortex have recently been contested by two carefully controlled, anatomically precise studies. Both studies failed to find the abnormal cytoarchitectural features described previously and suggested that earlier reports may have been confounded by incomplete matching of sections from normal controls and individuals with schizophrenia. The normal cytoarchitecture of the entorhinal cortex markedly changes along its rostrocaudal extent, making the issue of appropriate matching critical. However, the entorhinal cortex may not be entirely normal in schizophrenia; one study found a limited reduction in neuronal number and density. This is consistent with other reports of smaller volume, a reduction in the number of neurons, and volumetric measures using MRI.
Neurochemical elements that subserve the anatomic integrity of a given brain region have also been measured, as an indirect assessment of the cytoarchitecture. Microtubule-associated proteins (MAPs) are important elements of the neuronal cytoskeleton. One recent study found a marked loss of MAPS immunoreactivity in the subiculum and the entorhinal cortex in schizophrenia. This finding was interpreted as support for and evidence of cytoarchitectural abnormalities in this mesial temporal lobe. However, given the qualitative nature of most immunostaining techniques, direct replication and additional investigations with more quantifiable strategies are needed.
Synaptophysin is a synaptic vesicle protein, and as such is widely distributed throughout the central nervous system. Levels of synaptophysin or its mRNA on both can be used as indices of synaptic density. Decreased synapsin I, but not synapsin IIb or synaptophysin, has been found in the hippocampus of patients with schizophrenia. A more recent report noted a reduction in synaptophysin messenger ribonuclei acid (mRNA) in CA4, CA3, subiculum, and the parahippocampal gyrus. There were no changes in synaptophysin in these regions, however, suggesting that the loss of synapses may occur at extra-hippocampal sites. Alternatively, local circuits within the hippocampus may be compromised but the ability to detect these changes is limited by the volume of extra-hippocampal input to this brain region. In any event, this finding is another element in the emerging picture of structural alterations in the mesial temporal lobe.
Hippocampus The hippocampus, the predominant structure within the mesial temporal lobe, also may have anatomic abnormalities. Postmortem studies of the hippocampus have proliferated since the mid-1980s. One group found a volume reduction in the whole hippocampal formation in schizophrenia. Others, however, have reported that decreased volume is restricted to the white matter of the left hippocampus, or in the volume of the CA4 subfield. A number of other postmortem studies have found subtle structural abnormalities in the hippocampal formation in schizophrenia, providing a relatively robust body of evidence implicating alterations of the hippocampal formation in schizophrenia.
Within the pyramidal cell layer of the hippocampus, the most recognizable microscopic feature is the orientation of pyramidal cells. While cellular disarray in the CA1-prosubiculum and CA1-CA2 interface has been observed by one group, at least three other groups were unable to replicate this finding. Decreased numbers of pyramidal cells in hippocampal subfields and reduced neuronal size (in left CA1 and CA2, and right CA3) have also been found. These are both consistent with prior MRI findings. Alteration in the density of staining of the mossy fibers in the hilus of the dentate gyrus, and several hippocampal subfields have been seen as well. However, this finding is surprising because cell loss in the adjacent entorhinal complex should lead to an increase in the staining density of the mossy fibers. Finally, decreased polysialic acid-neural cell adhesion molecule (PSA-NCAM) immunoreactivity has been reported in the CA4 subfield of the hippocampus in schizophrenia. PSA-NCAM, a cell adhesion molecule, is thought to be important in synaptic rearrangements in adulthood. Although no clear consensus has emerged on the nature of pathological change within the hippocampus proper, there is abundant evidence of structural abnormalities.
Amgydala The amygdala, located within the mesial temporal lobe, has major interconnections with the entorhinal cortex and hippocampus, as well as many other structures. The amygdala appears to have a smaller volume in schizophrenia patients; this finding is in accordance with postmortem reports.
Prefrontal Cortex
Postmortem studies of the prefrontal cortex have been stimulated by the deficits observed with in vivo neuroimaging. One recent study found increased neuronal density in prefrontal area 9; a change of similar magnitude was observed in occipital area 17 as well, suggesting a widespread pathological process. This finding was interpreted as representing a loss of neuropil throughout the cortex in schizophrenia without accompanying gliosis. Area 9 has also been shown to have a smaller average neuronal size and an increased density of smaller neurons, with unchanged glial size and density. The absence of gliosis again suggests that the pathological change in schizophrenia is probably not an active inflammatory process. Area 17, visual cortex, did not show any of these abnormalities, suggesting some anatomic specificity of this finding. In addition to smaller neuronal size, layer 3 pyramidal cells may have diminished dendritic spine density, which in part may explain the abnormalities in neuropil noted by others. Finally, area 46, prefrontal cortex adjacent to area 9, also has increased neuronal density in layers 2, 3, 4, and 6, and a thinning of layer 2. Taken together, these studies suggest a loss of neuropil in the prefrontal cortex, and abnormalities in the cellular constituency of this region.
A somewhat murky picture has emerged from studies of the distribution of neurons in the subcortical white matter underlying the prefrontal cortex. Such neurons are thought to represent a vestige of neuronal migration during early brain development. One group found an increased density of nicotinamide-adenine dinucleotide phosphate diaphorase-positive neurons in the deep white matter and a lower density in the superficial white matter underlying the superior and middle frontal gyri. This is consistent with a developmental arrest in the migration of cortical neurons from deeper white matter areas to superficial cortical layers. A second, similar study looked at MAP2-immunoreactive neuron distribution in the subcortical white matter underlying area 46 and the transition zone between areas 46 and 9 in the prefrontal region. Patients with schizophrenia had a greater density of MAP2-immunoreactive neurons in the superficial white matter compared to controls. In contrast to the first study, no differences are seen in deeper white matter. This was interpreted as either abnormal expression of MAP2, a defect in neuronal migration, a failure of programmed cell death, or a decrease in white matter volume in schizophrenia patients. Although these two studies looked at different neuronal subpopulations, the different findings are contradictory and must be interpreted with caution.
Orbitofrontal Cortex The orbitofrontal cortex has also come under scrutiny, at least in part because of interconnections with a variety of limbic system structures and the efficacy of leukotomy in the treatment of some clinical aspects of schizophrenia. In area 10, orbitofrontal cortex, a decrease in neuronal number, maximal in layers 4 and 5, and in cortical thickness has been observed in a small sample of schizophrenia subjects. A similar reduction in areas 4 (frontal), 24 (cingulate), and 17 (occipital), has also been seen, suggesting a pancortical process. A more recent study found a significant reduction in neuronal density in layer 6 of area 10, but also in layer 5 of area 24 (cingulate cortex) and layer 3 of area 4 (primary motor cortex). The meaning of changes in such disparate layers cannot be easily explained, especially in light of the findings in areas 9 and 17.
Neurochemical analyses also have been performed on the prefrontal cortex as an index of structural integrity. One group examined the concentrations of synaptic vesicle associated protein-25 (SNAP-25) a synaptosomal associated protein involved in neurotransmitter release. Using quantitative Western blots, they found an elevation in SNAP-25 concentrations in area 9, reductions in areas 10 and 20 (temporal cortex), and no change in area 17. Such findings could be due to either a change in synaptic density or to an abnormality in neurotransmitter release; the former interpretation may account at least in part for the decreased neuropil in area 9.
Cingulate Cortex The anterior cingulate cortex (area 24) is part of the neural network subserving the cortical regulation of emotion and attention, both of which appear to be deficient in schizophrenia. In a series of postmortem studies, one group demonstrated an increase in vertical axon number in the cingulate cortex of schizophrenia patients. These researchers have also reported abnormalities in neuronal aggregation in layer 2 of area 24 and a decrease in the number of interneurons in layers 2–6 of this region. Others have seen an abnormality in the usual asymmetry of weight and surface area for the anterior cingulate cortex; independent replication of these findings will be important.
Other Regions
Subcortical structures also may have an abnormal anatomy in schizophrenia. Consistent with MRI studies, the mediodorsal nucleus of the thalamus may have fewer neurons in schizophrenia patients in comparison to controls. Studies of the basal ganglia are somewhat limited. Whereas one study did not find any absolute volume differences in the striatum as a whole or individually in the caudate, putamen, or nucleus accumbens, a second group reported an increase in left striatal volume in schizophrenia patients. A third report on the ultrastructure of the caudate nucleus using electron microscopy found abnormalities in synaptic morphology and dystrophic and reactive changes in astrocytes. Regarding midbrain dopaminergic nuclei, decreased volume of the lateral substantia nigra, and a decrease in the average volume of the nerve cell bodies in the medial segment have been observed. Several other studies have found no significant brainstem pathology or relatively nonspecific findings. Clearly, more research needs to be devoted to the brainstem, given the importance of ascending catecholamine and serotonin systems in regulating the activity of forebrain structures, and the clinical data implicating these neurochemical systems in schizophrenia.
Gliosis Of all these subtle yet potentially important cytoarchitectural findings, one of the most critical observations is the apparent absence of gliosis. The importance of this stems from theoretical implication that reduced volume of brain regions and other abnormalities are not the result of an active pathological process: instead, they are likely to be secondary to very early developmental processes. The issue of whether gliosis is present has been addressed by many postmortem studies over the past century. Of these, at least a dozen recent studies have used methodologically superior quantitative techniques. While several have noted increased gliosis, the large majority has found no differences between brains from patients with schizophrenia and those from normal controls. These include studies using several different techniques for counting glial cell number, such as the Holzer stain, Nissl stain, and immunoreactivity for glial fibrillary acidic protein. Some methodological questions about the ability of some techniques to detect the effects of chronic gliosis persist; it seems unlikely, however, that clinically relevant gliosis would be obscured.
The wide variety of potentially important findings must be approached with a healthy skepticism. Several common problems plague almost all postmortem volumetric and cell counting studies in schizophrenia. First, standard stereological techniques, using serial sections at regular intervals through the rostrocaudal extent of the mesial temporal lobe, are infrequently applied. Fortunately, more recent studies are employing stereology with greater frequency. Moreover, rarely, if ever, is the time of fixation carefully controlled, so that there is a wide variation within and across studies. Tissue shrinkage, which affects tissue volume and cell density, and maybe quality of cell staining, varies with the duration of fixation. Nevertheless, postmortem studies point to subtle volume reductions in the hippocampal formation in schizophrenia. The precise neuropathological changes that underlie this volume reduction remain controversial.
NEUROCHEMISTRY
Dopamine
One of the most important observations in twentieth-century psychiatry is that dopamine antagonists ameliorate symptoms of schizophrenia. The implication that too much dopamine causes psychosis has dominated research for well over two generations and continues to exert a profound impact. In its most basic form, the dopamine hypothesis states that an excess of subcortical dopamine neurotransmission leads to psychotic symptoms. Observations that the prefrontal cortex modulates subcortical dopamine release have established a compelling link between cortical abnormalities and changes in the dopamine system. A current version of the dopamine hypothesis is that dopamine is dysregulated; levels may be reduced in the prefrontal cortex and altered in complex ways in subcortical and limbic regions. Reduced cortical dopamine could explain hypofrontality, impaired cognition, and negative symptoms (such as anhedonia and lack of motivation). Altered subcortical and limbic dopamine, on the other hand, could cause positive symptoms (such as hallucinations and delusions). Theories about the role of dopamine in schizophrenia have advanced in tandem with the increased understanding of the neurobiology of dopamine.
Neurobiology of Dopamine Dopamine (Fig. 12.4–4) is synthesized from tyrosine through dopa. The first step, the conversion of tyrosine to dopa by tyrosine hydroxylase, is the rate-limiting step, and is subject to feedback regulation. The major metabolic product of dopamine catabolism in humans is homovanillic acid, and, to a lesser extent dihydroxyphenylacetic acid and 3-methoxytyramine. Concentrations of these metabolites have been examined in the brain, cerebral spinal fluid (CSF), plasma, and urine of patients with schizophrenia to look for evidence of increased or decreased dopamine neurotransmission.
FIGURE 12.4–4 Dopamine metabolism and synaptic structure. In this schematic synapse, dopamine is released into the synaptic cleft where it can act on D1 or D2 postsynaptic receptors. Synaptic dopamine is inactivated by reuptake pumps or by catabolism via COMT and MAO. Presynaptic D2 autoreceptors modulate dopamine synthesis and release in the striatum. (Drawn by Kyle Christensen.)
Dopamine cell bodies are primarily located in two midbrain nuclei: the substantia nigra (pars compacta) and ventral tegmental area. Projections from these nuclei have three primary target regions, and are named accordingly. The nigrostriatal tract carries nigral dopaminergic projections to subcortical motor control areas of the striatum (caudate and putamen in humans). The nigrostriatal projections come primarily from the substantia nigra but also, to a lesser extent, from the ventral tegmental area. Mesolimbic dopamine projections from this area target a number of limbic regions, such as the nucleus accumbens and temporal lobes. The mesocortical dopamine pathway projects primarily from the ventral tegmental area to the prefrontal cortex. A fourth dopamine tract is found entirely within the hypothalamus. In addition to different target regions, these separate projection systems function independently to some degree and are regulated by different mechanisms.
Dopamine exerts its effects through at least five receptor types, D1 through D5, identified on the basis of their deoxyribonucleic acid (DNA) sequence. Most pharmacological functions of dopamine receptors characterized so far are attributed to D1 and D2 receptors. Much less is known about the actions of D3, D4, and D5 receptors. The D1 family includes D1 and D5, while the D2 family includes D2, D3, and D4 receptors. Genes for the D2 family have a number of introns, leading to alternative splicing and several isoforms. For example, the D2 receptor has two common splice variants, a long and short form, usually both expressed in the same cell. The D4 receptor has numerous polymorphisms, including longer and shorter forms, although these do not arise through alternative splicing. Different isoforms of the D2 family may have different affinities for second messenger systems, presumably leading to variations in biological effects. Introns or alternative splicing variants for the D1 family of receptors have not yet been identified.
D1 and D2 receptors are found predominantly on the primary efferent neurons of the striatum, and limbic system (e.g., the nucleus accumbens), prefrontal cortex, and other cortical regions. D2 receptors are also located on the presynaptic dopamine terminals in target regions and dopamine cell bodies in the midbrain. These autoreceptors regulate dopamine synthesis, neuronal firing, and release. The latter two autoreceptors are not on mesocortical nerve terminals in the prefrontal cortex. D3 receptors are expressed predominantly in subcortical limbic regions, such as the islands of Calleja and nucleus accumbens in the rodent, but are also seen in the hippocampus. D4 receptors are thought to be presynaptic regulators of glutamate release on projections from cortical areas to the striatum and some limbic regions. D5 receptors are found in limited distribution in the thalamus, hippocampus, and hypothalamus.
The role of the dopamine system in the overall economy of the brain is not well understood. The relation between dopamine cell loss and Parkinson's disease established its role in regulating motor activity. The link between dopamine and drugs of abuse suggest a critical role in motivation and reward. Increasingly sophisticated electrophysiological studies have shown that activation of subcortical dopamine pathways alert the organism to changes associated with the prediction of future salient and rewarding events. This function is essential for predicting future events, which allows an organism the ability to plan and control interactions with the environment. Furthermore, prefrontal cortical dopamine is critically involved with working memory, a key component for higher-level information processing tasks. Thus, dopamine is involved in motor behavior, motivation, reward, and a variety of higher cognitive tasks, all of which have been implicated in schizophrenia. Clearly, the dopamine system has a complex molecular, cellular, and physiological neurobiology, and this underlies an equally complex functional role in normal brain and behavioral function.
Dopamine and Schizophrenia Evidence for the dopamine hypothesis of schizophrenia comes from a variety of sources. One approach has been to examine the effects of different medications on schizophrenic symptoms. Drugs that block D2 receptors reduce psychotic symptoms; dopamine agonists worsen symptoms. These observations form the cornerstone of the dopamine hypothesis. A second approach has been to look at various indices of dopaminergic neurotransmission in patients with schizophrenia. Such indices include measures of presynaptic activity, such as the major dopamine metabolites, dihydroxyphenylacetic acid and homovanillic acid, as well as postsynaptic markers, primarily dopamine receptors. Metabolite studies have examined homovanillic acid in urine, plasma, CSF, and autopsied brain. Receptor studies have been performed on postmortem brain tissue and in living patients using PET and SPECT. More recent methods have been used to assess in vivo presynaptic dopamine levels and dopamine release using both PET and SPECT. Dopamine neurotransmission could be altered by changes in any one of a number of neuronal functions, including synthesis, degradation, release, uptake, receptor binding, or effects on second and third messenger systems. Although several decades of research have not provided definitive affirmation of the dopamine hypothesis, increasingly sophisticated methods to assess in vivo dopamine activity are beginning to yield important clues.
The notion that dopamine neurotransmission is increased in schizophrenia derives its most compelling support from clinical observations on the effects of drugs that impact psychotic symptoms. The introduction of antipsychotic medications in 1954 was a dramatic breakthrough in psychiatry and initiated an intense search for their mechanism of action. In 1963 antipsychotic medications were found to increase the concentrations of dopamine metabolites. It was suggested that increased metabolite concentrations were a compensatory response to the blockade of dopamine receptors by antipsychotic agents and a subsequent reduction in dopamine neurotransmission. The idea that these drugs reduced dopamine neurotransmission was further supported by the observation that they also induced parkinsonian adverse effects, symptoms that had recently been linked to the loss of midbrain dopamine neurons. In 1977, following pharmacological characterization of the D2 receptor, a striking correlation was reported between the relative clinical potencies of all clinically available antipsychotic medications and their ability to block D2 receptors. This landmark finding convincingly demonstrated that antipsychotic effects were mediated by D2 receptor blockade.
While the correlation between clinical potency and D2 blockade for antipsychotic medications was compelling, several problems emerged. D2 blockade occurs within hours of administration, but the antipsychotic effects can take days or weeks to develop; this suggests that a secondary process is required. Studies of the chronic effects of neuroleptics then led to the observation that, after several weeks, dopamine neurons themselves stopped firing. After short-term administration of antipsychotic medications there is an initial increase in dopamine neuronal firing as neurons attempt to overcome D2 blockade; eventually this overexcitation leads to the phenomenon of depolarization block, where depolarized neurons simply stop firing. Reduced neuronal firing was thought to markedly reduce dopamine release, leading to reduced dopamine neurotransmission. For some time, the depolarization block theory was crucial in supporting the view that antipsychotic drugs exert their therapeutic effects by reducing dopamine neurotransmission. Subsequently, a number of studies have not found reduced dopamine release after long-term treatment with antipsychotic medication. While methodological issues are still debated, this suggests that some process other than a simple reduction in dopamine release may underlie the therapeutic effects of these medications.
Other observations have been difficult to reconcile with the dopamine hypothesis. For example, many symptoms such as cognitive deficits, anhedonia, and alogia typically fail to respond to treatment with antipsychotic medications, suggesting that other processes are involved. A second problem relates to the unique clinical effects of clozapine (Clozaril). Clozapine has been shown to benefit patients who do not respond to dopamine receptor antagonists. The dopamine hypothesis, on the other hand, implies that D2 blockers should be equally efficacious. The unique clinical effects of clozapine suggest that it may have a different mechanism of action. Clozapine's effects have been attributed to several properties, such as its antagonism of serotonin receptors or its combination of D1, D2, and D4 blockade. Drugs developed to mimic different aspects of clozapine's receptor-binding profile, such as risperidone (Risperdal), olanzapine (Zyprexa), and quetiapine (Seroquel), share some of clozapine's "atypical" characteristics.
A second line of evidence supporting the dopamine hypothesis comes from observing the effects of dopamine agonists. Chronic amphetamine abuse, for example, increases dopamine release and can lead to a psychosis similar to paranoid schizophrenia. Amphetamine-induced psychotic disorder, however, lacks other features associated with schizophrenia, such as negative symptoms and cognitive impairment. Furthermore, psychotic symptoms only develop after prolonged use (and typically at high doses), whereas dopamine neurotransmission is increased shortly after a single dose of amphetamine. This suggests that repeated increases in dopamine release produce secondary changes that are more directly responsible for the psychosis.
METABOLITE STUDIES The search for more direct evidence of altered dopamine release in schizophrenia led to investigations of dopamine and its metabolites in urine, plasma, CSF, and postmortem brain tissue. Consistent with the basic dopamine hypothesis, several studies of plasma homovanillic acid have found increases in unmedicated schizophrenia patients compared with controls. These studies sometimes report correlations between concentrations of homovanillic acid and severity of psychosis. Furthermore, antipsychotic medications appear to reduce plasma homovanillic acid over time, correlating with patients' improvement. Methodological problems, however, cloud the interpretation of studies using plasma homovanillic acid. It is unclear whether plasma homovanillic acid correlates with its concentrations in limbic brain regions, areas most likely to underlie the production of psychotic symptoms.
Investigators have also looked at dopamine metabolite levels in CSF. While most studies have failed to find significant changes, several have reported a correlation between concentration of homovanillic acid and severity of psychotic symptoms. Studies of medication-free patients have tended to show a reduction in dopamine metabolites. Negative correlations have been found between concentrations of homovanillic acid in CSF and ventricular enlargement and severity of negative symptoms (e.g., anhedonia and flat affect). Prefrontal cognitive deficits have also been associated with reduced CSF homovanillic acid, perhaps consistent with a model of subcortical dopaminergic overactivity and prefrontal cortical hypoactivity; methodological issues make the interpretation of CSF studies problematic. First, dopamine and metabolite concentrations in the CSF are affected by a number of variables that are not commonly controlled. These include diet, time of day, height, and motor activity. Second, increased ventricular volume itself could affect the concentration of homovanillic acid. Third, CSF monoamine concentrations appear to have little relation to either regional brain levels of dopamine or, more importantly, to more direct measures of dopamine neurotransmission. Certainly if dopamine transmission in the prefrontal cortex is reduced and subcortical transmission is increased, it is difficult to predict what would happen to CSF concentration. Nevertheless, CSF data is often interpreted as supporting the notion that too much dopamine is related to positive symptoms whereas too little underlies negative symptoms.
More direct assessments of dopamine neurotransmission have come from postmortem studies of dopamine metabolites. Increased dopamine or homovanillic acid or both have been reported in a number of brain regions, although reports are often inconsistent. For example, one study found increased dopamine in the left amygdala, a second reported increases in the nucleus accumbens, and a third found increases in the caudate but not the accumbens. Increased homovanillic acid has been found in the cortex, accumbens, and caudate. The latter finding has been attributed to the effects of previous treatment with antipsychotic medications. At this point no clear consensus can be derived from studies of dopamine metabolites.
DOPAMINE RECEPTOR STUDIES A number of studies using postmortem brain tissue have shown increased numbers of D2 dopamine binding sites in the brains of schizophrenia patients. A major confounding issue is whether this increase is a primary alteration in schizophrenia or secondary to long-term treatment with antipsychotic agents, known to cause rapid D2 upregulation in animals. Studies in nonmedicated and medication-naive patients are conflicting. A number of studies of patients off medication for at least 1 month have found increased D2 receptors, although several have not. It has been suggested that treatment with antipsychotic medications cannot account for the marked increase and bimodal distribution of D2 receptors seen in patients who had been treated. Imbalances between D1 and D2 receptors have also been reported. Recent studies of D3 receptors have suggested that D3 mRNA may be processed abnormally in cortical neurons of patients with schizophrenia, resulting in reductions in the normal D3 mRNA transcript. On the other hand, a postmortem study of striatal D3 receptor binding found a significant increase in patients who were medication free for 1 month. D4 receptors have been harder to assay because of the lack of specific ligands. While two reports using an indirect method have found evidence of increased D4 receptor density, assays of mRNA for D4 using highly specific antisense probes have not found increased levels.
Neuroimaging techniques have been used to measure indices of dopamine neurotransmission in living human patients. Striatal D2 receptors have been assayed in medication-free patients by several groups using PET; the results, however, have been conflicting. One study found increased receptor numbers while two others did not. These studies used different PET ligands to measure D2 receptor density, perhaps accounting for the conflicting results. One of the PET ligands binds only to D2 and D3 receptors; the second also binds to D4 receptors. The discrepant PET findings have been attributed to an increase in D4 receptors, consistent with postmortem studies. More recently, in vivo neuroimaging methods have been refined to assay presynaptic indices of dopamine storage and release. In this paradigm, radioactive D2 ligand binding is examined at baseline and following a pharmacological challenge with amphetamine. The dramatic increase in dopamine release caused by amphetamine displaces the postsynaptic binding of the D2 ligand. The washoff of the D2 ligand can thus be used as an index of dopamine release. Unmedicated patients with schizophrenia show reduced ligand binding after amphetamine, but not at baseline. This suggests that patients with schizophrenia have increased synaptic dopamine following amphetamine. One explanation for this is that presynaptic stores may be increased; another possibility is that synaptic reuptake is reduced. Although methodological issues continue to be refined, this promising lead implies that subtle aspects of dopamine neurotransmission may be altered.
ANIMAL MODELS Animal studies have been invaluable in efforts to understand normal and abnormal function of the dopamine system. Of particular relevance for schizophrenia research are studies that attempt to model dysfunctional dopamine systems in a way that may shed light on the neurobiology of psychosis.
Initial attempts to develop relevant animal models began with repeated, high doses of stimulants (such as amphetamine), based on the association between stimulant abuse and psychosis in humans. Repeated stimulant treatment was also thought to model repeated stress, an apparent trigger of psychotic relapse. Remarkably, stimulants increase the sensitivity of the mesolimbic dopamine system to stress, a process referred to as sensitization. Furthermore, in some paradigms stimulants can reduce presynaptic indices of dopamine activity, which has led to speculations that repeated increases in dopaminergic transmission (e.g., from stress) could lead to sensitization in limbic regions and long-term dopamine depletion in prefrontal regions. Thus, long-term administration of stimulant may provide a model to explore the interactions between known triggers of psychosis and dysfunctional dopamine systems.
Another promising line of animal research suggests that alterations in dopamine neurotransmission in one region may be secondary to primary deficits in another. For example, depletion of dopamine from prefrontal regions can increase dopamine metabolism in the striatum of rats. This suggests that a primary reduction of prefrontal dopamine in humans could theoretically lead to secondary alterations in subcortical dopamine. Reduced prefrontal dopamine could certainly explain the hypofrontality and negative symptoms that characterize schizophrenia. Although no direct evidence has shown that there are dopamine abnormalities in these regions, the indirect evidence reviewed above is suggestive. In a related line of research, structural damage to cortical and limbic regions has been shown to change subcortical dopamine neurotransmission. For example, within the limbic system lesions of the hippocampus or amygdala alter dopamine neurotransmission in the nucleus accumbens and prefrontal cortex. Such observations have been critical in attempts to relate structural and functional changes in frontal, temporal, and hippocampal regions with abnormalities in the dopamine system. They suggest that information-processing deficits in frontal and limbic regions have marked effects on subcortical processes, including dopamine neurotransmission.
The dopamine hypothesis continues to exert a profound effect on research in schizophrenia. The discovery of new subtypes of dopamine receptors along with new neuroimaging approaches offer improved methods to study the function and pathophysiology of this system in humans. Particularly important for schizophrenia research is the finding that dopamine subsystems are interconnected and that damage to different brain regions previously implicated in schizophrenia can have marked effects of dopamine neurotransmission. At present, a variety of indirect data suggest that prefrontal dopamine neurotransmission may be reduced whereas subcortical dopamine is dysregulated in schizophrenia. Whether these changes are real and whether they are secondary to cortical or limbic dysfunction remains to be seen.
Glutamate
Interest in glutamate's role in the pathophysiology of schizophrenia has developed relatively recently. This interest was spurred primarily by two observations. First, acute ingestion of phencyclidine (PCP), a glutamate antagonist, produces a syndrome similar to schizophrenia. Second, glutamate is an essential neurotransmitter in those neural networks that may be involved in schizophrenia. Subsequently, a variety of postmortem and clinical data have been garnered in support of a glutamatergic abnormality.
Neurobiology of Glutamate Glutamate is one of the most prevalent neurotransmitters in the brain. Virtually all neurons in the brain are affected when glutamate is applied. A nonessential amino acid that does not cross the blood-brain barrier, it can be synthesized in the brain from glutamine. The dominant mode of inactivation of synaptic glutamate is via reuptake by specific, high-affinity uptake sites.
The four classes of glutamate receptors have been identified and named after their affinity for specific ligands: N-methyl-D-aspartate (NMDA), a-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid (AMPA), kainic acid (KA), and L-aminophosphono-butyric acid (AP4). The first three are ionotropic receptors; their effects are mediated by changes in ionic conductance through neuronal membranes, including sodium, potassium, and calcium. The ionotopic receptors have been implicated in neurotoxicity following ischemia, mediated in part by increased intracellular calcium influx and apoptosis. The NMDA receptor is functionally different from the others and has been implicated in long-term potentiation (a process related to memory) in the hippocampus. Paradoxically, NMDA blockade can also result in neurotoxicity, apparently modulated by interneurons and activation of non-NMDA glutamate receptors. The last type of glutamate receptor, labeled by AP4, is a metabotropic receptor, a member of the family of G-protein–linked receptors. The metabotropic receptors modulate activation of second messengers, such as phospoinositide and cyclic adenosine monophosphate (cAMP), which can produce long-term, modulatory effects. Major advances in understanding the molecular biology of these receptors is increasing the understanding of their function.
The NMDA receptor is a complex protein that has particular relevance for schizophrenia research. Blockade of the NMDA receptor by phencyclidine (PCP), a noncompetitive antagonist, produces symptoms similar to those seen in schizophrenia. NMDA receptor activation is excitatory, reducing postsynaptic membrane potential. PCP binds to a site within the open NMDA ion channel, thus blocking ionic flux. The mechanism by which NMDA antagonism produces psychotic symptoms is unclear; one theory is that NMDA antagonists exert their psychotomimetic effects via NMDA receptors' role in regulating striatal and limbic dopamine neurotransmission. Of note, NMDA receptor density is highest in the hippocampus and prefrontal cortex, two areas already implicated in the pathophysiology of schizophrenia. Altered neurotransmission in these regions could also play a role in PCP's effects.
The NMDA receptor has a number of modulatory sites that regulate ionic conductance. Endogenous modulators include glycine, zinc, magnesium, and the polyamine spermidine. The glycine modulatory site has become a target for drug development. Increasing NMDA neurotransmission by increased glycine binding has been hypothesized to reduce symptoms of schizophrenia. Several studies have attempted to do so using glycine agonists such as milacemide or cylcoserine, and the results have been mixed. Another potential pharmacological target is the high-affinity glycine uptake pump. Antagonists of this site should increase synaptic glycine concentrations, enhancing NMDA neurotransmission. Similarly, antagonists of the glutamate reuptake pump could boost NMDA receptor activation. It is unclear whether ongoing efforts to develop antagonists at these sites will lead to therapeutic agents for patients with schizophrenia. A major difficulty with increasing NMDA neurotransmission is its narrow range of physiological responsivity. If NMDA stimulation is too high, seizures or neurotoxicity can result.
Glutamate is relevant to the neurochemistry of schizophrenia because of its role in key neural networks. Projections to and from cortical and hippocampal pyramidal neurons use glutamate as a primary neurotransmitter. These include projections to subcortical structures such as the striatum, nucleus accumbens, and ventral tegmental area; output from these areas is strongly modulated by glutamate. Thalamic projections to the cortex also employ glutamate as the major neurotransmitter. Glutamate neurotransmission is important not only for rapid synaptic transmission between these regions, but also for experience-dependent cortical plasticity and memory. This is particularly true for the voltage-sensitive NMDA receptor, a likely candidate for modulating memory traces at Hebbian synapses. Glutamate's essential role in key neural networks, memory and cortical plasticity, thus make it a likely candidate for involvement in altered information processing in schizophrenia.
Glutamate in Schizophrenia Acute intoxication with the NMDA antagonist, PCP, produces hallucinations, thought disorder, negative symptoms, and cognitive deficits. In comparison, dopamine agonists, such as amphetamine, primarily induce paranoid delusions, and only after long-term use. The differences in these drug-induced psychoses suggest that glutamatergic neurotransmission could be more proximal to the pathological processes mediating psychosis. The search for more direct evidence has focused on CSF and postmortem studies of brain tissue.
Studies of glutamate levels in CSF and brain have been mixed. An initial, pioneering study of CSF found low levels of glutamate in patients compared with controls. Possible methodological problems make this data difficult to interpret, however, and three subsequent studies have been unable to replicate the finding. Two studies have looked at glutamate levels in postmortem brain tissue. One found no differences whereas the other found specific reductions in the hippocampus and prefrontal cortex in patients with schizophrenia. The latter study also looked at a neuropeptide co-localized with glutamate N-acetylaspartylglutamate [NAAG]. The NAAG pathway has recently been identified as an important comodulator of glutamate neurotransmission. The reported changes in NAAG and its metabolism in brains of patients with schizophrenia open up a provocative new area to explore possible alterations in glutamate neurotransmission.
Postmortem receptor studies have been more promising. In general, these studies have tended to find increased receptor binding in prefrontal regions and reductions in temporal areas. Two reports have found increased kainate binding in the medial frontal cortex; a third found increases in orbitofrontal NMDA receptors. An increase of prefrontal cortical glutamate uptake sites has also been described. A recent molecular study using in situ hybridization and probes for all five NMDA receptor subunits, while not finding an overall increase in receptor mRNA did find a 53 percent increase in the expression of a subunit (NR2D), suggesting a change in the functional properties of prefrontal NMDA receptors.
In the temporal lobe, several abnormalities of the glutamate system have been published. Autoradiographic studies have reported that KA receptor binding is reduced, particularly in the hippocampus. Consistent with this finding, reduced expression of mRNA for receptor subunits has been found in temporal lobe areas. Reduced density of temporal lobe AMPA receptors has been seen, but less consistently. In a recent extension of this work, mRNA transcripts for GluR1 and GluR2 were assayed; these transcripts code for AMPA receptor subunits. Consistent with receptor studies, reductions were seen in the hippocampus and other temporal lobe areas. Finally, the glutamate reuptake site has been assayed in the temporal lobe as an index of presynaptic glutamate terminal number. Reduced levels of mRNA for the reuptake site suggest a possible reduction in terminal number and thus in axonal projections. Regarding other brain regions, some receptor studies have performed on material from the basal ganglia. Increases in AMPA receptors and reduced NMDA receptors have been reported; some, studies, but not all, have found reduced glutamate uptake sites.
Taken together, the postmortem literature is notable for a myriad of findings implicating alterations in glutamatergic neurotransmission. However, given the typical small number of brains studied and large number of variables, replication of specific findings is critical. Some have theorized that there is a loss of glutamatergic neurons in temporal areas, consistent with structural neuroimaging findings of reduced volume. In this schema, increased glutamate receptors in the cortex and putamen are hypothesized to be secondary to reduced glutamatergic inputs or neurotransmission. The increased focus on glutamate in postmortem studies will bring increasingly sophisticated assessment of this neural system.
Serotonin
The idea that serotonin may play a role in schizophrenia was first postulated when the hallucinogen lysergic acid diethylamide (LSD) was found to block serotonin receptors. Since then, basic studies have begun to unravel the surprising complexity of this system and have provided new targets for investigation. Studies of schizophrenia have looked at a variety of parameters, including plasma serotonin levels, brain receptor levels, and clinical response to serotonergic drugs. Two findings are particularly promising: first, data from postmortem studies have found changes in frontal cortical receptor number; second, new "atypical" antipsychotic medications that are both serotonergic and dopaminergic antagonists appear to have clinical advantages over pure D2 antagonists. These developments have increased the focus on serotonin in schizophrenia.
Basic Neurobiology Serotonin (5-hydroxytryptamine) is synthesized from tryptophan and is broken down into 5-hydroxyindolic acetic acid (5-HIAA) by monoamine oxidase (MAO). Tryptophan is an essential amino acid; dietary intake of tryptophan can affect CNS synthesis of serotonin. Serotonin synthesis is also modulated by autoreceptors on nerve terminals. Synaptic serotonin is inactivated primarily by reuptake pumps on presynaptic neurons and glia; following uptake, serotonin is repackaged into vesicles or broken down to 5-HIAA. Both serotonin itself and its uptake pumps are found in blood platelets, where they play a role in clotting. In the CNS, serotonin neuronal cell bodies are located in the brainstem in nine separate nuclei. Axons from these cells project through the median forebrain bundle to virtually all regions of the CNS, including the cortex, limbic regions, and the striatum.
The effects of serotonin are mediated by an ever-increasing number of receptor subtypes. Currently, seven classes of serotonin receptors have been characterized: serotonin (5-hydroxytryptamine [5-HT])-type 1 (5-HT1) through 5-HT7. Ten subtypes have been described in the 5-HT1 family (5-HT1a through 5-HT1e), three in the 5-HT2 family (5-HT2a through 5-HT2c) and one for 5-HT3. Most relevant for schizophrenia are the 5-HT2 and 5-HT3 subtypes. 5HT2 receptors are found in the prefrontal cortex, striatum, and nucleus accumbens; 5-HT3 receptors are found in cortical, limbic, and subcortical areas, such as the amygdala and hippocampus.
The serotonin system subserves a bewildering array of physiological and behavioral functions. For example, somatodendritic 5-HT2 receptors regulate dopaminergic neuronal firing. Striatal nerve terminal serotonin receptors inhibit dopamine release. Behaviorally, serotonin has effects on cardiovascular, respiratory and motor activity, emesis, sexual behavior, aggression, anxiety, mood, and pain. Frontal serotonin, in concert with dopamine, may play an important role in the modulation of attention and arousal. Recently, basic research using aplysia has shown that serotonin plays a critical role in synaptic mechanisms associated with learning and memory; it may also have important neurotrophic effects during development and in the adult organism.
Serotonin in Schizophrenia The earliest studies to examine serotonin in schizophrenia looked at peripheral measures, such as serotonin concentrations in plasma and uptake in platelets. These studies found increased concentrations in plasma and, less consistently, reduced uptake in platelets. Studies of CSF metabolites have been mixed and suffer from the same methodological confounds described for dopamine. More direct measures of CNS neurotransmission include postmortem assays of serotonin activity, including concentrations in brain tissue; receptor-binding density; reuptake site binding; and levels of mRNA for receptor subtypes, reuptake sites, and synthetic enzymes for serotonin itself.
Although there have been multiple reports of abnormal serotonin levels in a variety of neural structures, only two findings have been replicated: increased levels in the putamen and increased levels in the globus pallidus. One difficulty with this approach is that measurement of neurotransmitters and their metabolites is notoriously unreliable because of their instability in postmortem tissue. In comparison, receptors, reuptake sites, and the mRNA for receptors, reuptake sites, and synthetic enzymes are more stable. Of studies looking at these parameters, the 5-HT2 subclass has received the most attention. Following an initial report of a reduction in prefrontal cortex in the density of this receptor, two other research groups replicated this finding although a third did not. Whereas this abnormality may be intrinsic to schizophrenia, it is also possible that reduced 5-HT2 receptor density is a consequence of therapy with antipsychotic drugs. The density of reuptake sites for serotonin also appear to be reduced in schizophrenia, particularly in frontal and anterior cingulate cortices.
Studies looking at the mechanism of action of atypical antipsychotic drugs, such as clozapine, have fueled much of the recent interest in serotonin's role in schizophrenia. Clozapine has a variety of therapeutic properties different from the dopamine receptor antagonists. These could be due to clozapine's ability to block 5-HT2a, 5-HT2c, 5-HT3, 5-HT6, or 5-HT7 receptors, or to increased serotonin release in the prefrontal cortex. When one compares serotonin-dopamine antagonists, which share some of clozapine's properties, such as the reduced liability to produce parkinsonian symptoms, two impressive similarities are their 5-HT2-binding affinity and the ratio of 5-HT2 to D2 binding. This suggests that serotonergic antagonist properties may account for the improved adverse effects profile and perhaps also the enhanced therapeutic efficacy often attributed to the serotonin dopamine antagonists.
In summary, both postmortem studies and drug trials using 5-HT2–D2 antagonists suggest that serotonin may play an important role in schizophrenia. Data implicating frontal and anterior cingulate cortices are particularly striking. It is unclear, however, whether alterations in serotonin neurotransmission are primary or secondary and how they may relate to the other neurobiological processes described. Some preliminary investigations suggest that maternal exposure to toxins can produce long-term changes in serotonin neurotransmission. This raises the possibility that neurodevelopmental insults could alter serotonin neurotransmission in adults. Researchers interested in the mechanisms of amphetamine-induced behavioral sensitization have also begun to suspect that serotonin may play a significant role. If sensitization were to be involved in schizophrenia, as has been suggested, serotonin could be a factor. Although research in serotonin has typically taken a backseat to research on dopamine, its relevance for schizophrenia continues to increase as more is revealed about its many neurobiological properties.
Other Neurotransmitters
A wide variety of additional neurochemical systems have been studied in schizophrenia, several of which are noteworthy because of potentially interesting findings or because of how extensively they have been studied. These include GABA, norepinephrine, neurotensin, and cholecystokinin. As with other neurotransmitters, studies of these systems have typically looked at transmitter and metabolite levels in brain, CSF, or plasma, as well as receptor protein and mRNA expression in specific brain regions.
GABA
Particularly intriguing is research into the role of GABA, which is the major inhibitory neurotransmitter in the brain. Virtually all neurons are inhibited by GABA, and up to 40 percent of neurons use GABA as their major neurotransmitter. Many GABA neurons are local inhibitory interneurons, but GABA neurons in some regions (such as the striatum) are also primary efferent neurons. GABA is synthesized from glutamate via the enzyme glutamic acid decarboxylase (GAD). GABA acts at two receptor subtypes, GABAA and GABAB, the former being the more important in the CNS. A variety of drugs act at GABA receptors, including alcohol, benzodiazepines, and barbiturates. Findings implicating GABA in schizophrenia include reduced number of GABAergic cortical interneurons, increased GABAA receptor density in the prefrontal cortex, and reduced GABA uptake sites in the hippocampus. All three findings are consistent with reduced GABA cell number or GABA neurotransmission. Studies of mRNA have found reduction in prefrontal GAD mRNA but not in prefrontal GABAA receptor mRNA. The former is consistent with reduced GABA neuronal activity; the latter is not. This preliminary effort suggests that GABA cell number or activity is reduced in schizophrenia. As with other postmortem findings, however, further replication is necessary before they can be accepted with confidence.
Norepinephrine Norepinephrine, another monoamine neurotransmitter, has been intensively studied in schizophrenia, although interest has waned recently. Similar to dopamine and serotonin, norepinphrine neurons are located in the brainstem in a group of nuclei (including the locus ceruleus) that project to a variety of cortical and subcortical regions. Norepinephrine acts at two receptor families, adrenergic and b-adrenergic receptors; at least seven a and three b subtypes have been cloned. Both receptor families exert their effects via changes in G-protein–mediated second messenger systems, including cAMP and phosphoinositol. Two neuropeptide transmitters, galanin and neuropeptide Y, are colocalized in noradrenergic neurons. Norepinephrine and its co-transmitters are involved in a number of physiological and behavioral processes including the sleep-wake cycle, arousal, stress, and memory. Both basic and clinical studies support a role for this system in psychiatric disorders such as anorexia nervosa, bulimia nervosa, anxiety disorders, post-traumatic stress disorder, depressive disorders, substance dependence, and substance withdrawal. Many of the behavioral states mediated by the noradrenergic system are markedly altered in schizophrenia, suggesting a role here as well. However, more direct evidence is lacking and any changes in noradrenergic function in schizophrenia may be secondary to the agitation that frequently accompanies psychosis.
Initial studies of norepinephrine examined concentrations in plasma, CSF, and brain tissue. Both plasma and CSF concentrations of norepinephrine and its metabolite appear to be increased in patients with schizophrenia, although this has not been a consistent finding. Concentrations are reduced with treatment with antipsychotic agents and are correlated with clinical improvement. Recently, increased plasma concentrations have been associated with deficit symptoms whereas reduced plasma levels have been associated with depressive symptoms. These two findings seem contradictory and cast doubt on the usefulness of this approach. Furthermore, conclusions from such studies are limited by the same methodological pitfalls described above for other neurotransmitters, including the confounds of treatment with antipsychotic agents and the meaning of peripheral measures. Studies of brain norephinephrine and its receptors have been mixed, with some finding elevations and others finding no changes. The clinical effects of adrenergic agents have generally not been impressive. At least one report found that the presynaptic a2-adrenergic receptor agonist clonidine (Catapres) reduces psychotic symptoms, presumably by reducing norepinephrine release. On the other hand, several other studies did not find this effect, and at least one group has reported therapeutic effects for an a2-adrenergic receptor antagonist, idazoxane. Finally, a number of genetic association studies have looked at the incidence of polymorphisms for genes related to norepinephrine neurotransmission, including dopamine beta hydroxylase and the norepinephrine transporter. Although relatively common polymorphisms have been reported for both, no association with schizophrenia has been reported.
Neuropeptides Two other interesting candidate molecules that have been studied in schizophrenia are the neuropeptides cholecystokinin and neurotensin. Both are found in a number of brain regions implicated in schizophrenia, such as the substantia nigra, nucleus accumbens, hippocampus, and various cortical regions. Both are colocalized with dopamine, GABA, glutamate, and other neurotransmitters. Several studies have reported changes in the levels of the peptides themselves, mRNA, or receptors. For example, the following findings have had some degree of replication: reduced temporal lobe cholecystokinin peptide concentrations, reduced cholecystokinin receptor density in both temporal and frontal regions, and reduced cholecystokinin mRNA in the temporal lobe. In general, further replication is required. Drug trials with the cholecystokinin agonist ceruletide have been mixed. Several open trials were promising, but double-blind trials were not. Unfortunately, it is not certain that ceruletide crosses the blood-brain barrier.
Neurotensin's appeal is due in part to its endogenous antipsychotic-like properties. Not only is it colocalized in dopaminergic neurons, but infusions of neurotensin into the nucleus accumbens block the excitatory effects of stimulants and reduce behavioral activation. Neurotensin levels in the nucleus accumbens are markedly increased by treatment with antipsychotic medication. CSF studies have shown reduced neurotensin concentrations and correlations between reduced concentrations and increased psychopathology in drug-free patients with schizophrenia. However, postmortem studies have not shown differences between patients and controls in concentrations of the peptide itself. Such studies are confounded by the pronounced effects of antipsychotic drugs on central nervous system (CNS) neurotensin. One recent report found a 40 percent reduction of neurotensin receptors in the entorhinal cortex in patients with schizophrenia. Further replication and exclusion of effects of treatment with antipsychotic agents will clarify the significance of this finding.
NEURAL CIRCUITS
The variety of structural, functional, and neurochemical abnormalities described implicate disordered information processing in several interconnected neural pathways in patients with schizophrenia. A description of the anatomical components of these pathways and their possible function will provide a basis for integrating the many abnormalities noted in schizophrenia (Figs. 12.4–5).
FIGURE 12.4–5 A, Neural networks implicated in the neurobiology of schizophrenia. Cortico-striatal-thalamic pathway. Prefrontal glutamatergic projections synapse on GABAergic striatal neurons that express either D1 or D2 receptors. The independent D1 and D2 pathways are referred to as the direct and indirect pathways respectively. They have separate efferent pathways projecting to either the globus pallidus, pars externa = E, or pars interna = I. Both pathways ultimately project back to the anterior thalamus. B, Ascending dopamine projection pathways modulate circuits in A. Dopamine neurons (DA) from the substantia nigra tend to project mainly to the striatum, while the adjacent ventral tegmental area DA neurons projects primarily to the prefrontal cortex, ventral striatum, and limbic regions. C, Limbic projections to circuits from A and B. The hippocampal formation and amygdala project to the prefrontal cortex and ventral striatum. They receive glutamatergic cortical input and dopamine projections from the VTA. (Drawn by Kyle Christensen.)
As cortical abnormalities have played a dominant role in theories of schizophrenia, understanding the functional connectivity of these areas is important. One of the most intensively studied pathways is the cortico-striato-thalamic loop. The prefrontal cortex, the most highly and recently evolved part of the primate brain, sends a massive glutamatergic projection to subcortical regions, most notably the striatum (putamen and caudate in humans). The striatum in turn sends GABAergic projections through a number of downstream basal ganglia nuclei that ultimately feed into the anterior thalamus. Completing the loop, the anterior thalamus sends a massive glutamatergic projection back to the prefrontal cortex. Several salient features are noteworthy. First, this loop appears to consist of at least five separate but parallel channels processing different types of information (such as cognitive, emotional, and motoric information). Second, output from the striatum is split into two opposing, counterbalancing pathways. The so-called direct and indirect loops are modulated by D1 and D2 receptors, respectively. Their coordinated output modulates information returned to the cortex via the anterior thalamus. Third, within the striatum itself, the ventral portion (commonly referred to as the nucleus accumbens) receives predominantly limbic inputs, while dorsal regions receive inputs more relevant for motor function. This functional segregation is maintained in downstream projection regions.
A second important system that modulates activity of the cortico-striato-thalamic pathway is the dopamine system. Dopamine neurons in the substantia nigra and ventral tegmental area project to the striatum, nucleus accumbens, and prefrontal cortex. Dopamine modulates cortical output to the striatum via input to glutamatergic pyramidal neurons. In the striatum, dopamine axons synapse on the primary output neurons, the medium-sized, spiny, GABAergic neurons. Coordinated cortical and subcortical dopamine neurotransmission may be important for normal information processing through this loop. Furthermore, dysfunction in one area may produce changes in another. For example, lesions of the prefrontal cortex can induce alterations in subcortical dopamine neurotransmission.
A third neural system interacting with the first two is the limbic system. This complex system involves hippocampus, amygdala, thalamus, hypothalamus, and cingulate gyrus, among others. This immense circuit, subserving functions related to memory and emotional experience, among many others, has direct projections to both prefrontal cortex and ventral striatum. The prefrontal cortex has reciprocal projections back to the mesial temporal lobe and hippocampus. The hippocampus, amygdala, and cingulate have important projections to the ventral (or limbic) aspect of the striatum. This area, in turn, projects to the thalamus via the ventral aspect of the globus pallidus, the pars interna. In this way, three major brain regions—the cortex, limbic system, and basal ganglia—communicate and interact. Information-processing abnormalities in one area, such as in the hippocampus, would have significant downstream effects on other regions, such as prefrontal cortex and striatum.
Structural and functional measures have implicated some abnormality in all three components of these interacting systems. It is uncertain which are primary and which are secondary. It seems very possible that different types of lesions could alter the function of individual components, which could then produce secondary downstream changes in connected circuits.
NEUROBIOLOGICAL MODELS
The essential neurobiological features of schizophrenia may place some constraints on plausible pathophysiological processes. First, there is a major genetic contribution. Many genes are likely to be involved and these may function in part by increasing vulnerability to the deleterious effects of environmental factors. Several environmental factors have been hypothesized to increase the risk of schizophrenia, perhaps by producing subtle brain damage. Structural abnormalities have played an important role in placing theoretical constraints on mechanisms. Since they are present from early in the illness and do not appear to progress, they may predate the onset of illness. Neuropathological data and studies of obstetric and perinatal complications support the idea that an early lesion may account for structural changes. The apparent lack of gliosis in postmortem studies is particularly critical and implicates in utero factors. Structural and functional neuroimaging, as well as neuropsychological data and animal studies present converging evidence for the importance of frontal and temporal regions. Finally, altered dopamine and glutamate neurotransmission are likely to play a part in the expression of psychotic symptoms.
The neurodevelopmental model can account for many of these findings. In short, some process (genetic or environmental) produces damage to selected brain areas early in life. Temporal lobe regions such as the hippocampus may be particularly vulnerable. Secondary functional abnormalities develop later. As the prefrontal cortex matures in late adolescence, the behavioral and cognitive sequelae of subtle structural deficits become manifest. One result is hypofrontality and cognitive impairment. Alterations in limbic and prefrontal function then produce downstream, secondary alterations in subcortical dopamine, glutamate, and other neurotransmitter systems. Dopamine dysfunction, in particular, may lead to positive psychotic symptoms. The feasibility of this model has received substantial validation from animal studies showing the delayed behavioral and neurobiological effects of minor damage to the hippocampus in neonatal rats. Observations that children at risk for schizophrenia have a number of subtle neuropsychiatric abnormalities, such as deficits in attention, motor control, and social interactions, also support the neurodevelopmental model.
Although the neurodevelopmental hypothesis has been an important organizing heuristic since the mid-1980s several critical issues remain unresolved. First, it remains unclear when structural abnormalities actually develop. Finding such abnormalities in young children who go on to develop schizophrenia would offer strong support for this hypothesis. Alternatively, if these abnormalities develop later in life (e.g., in mid-adolescence), other mechanisms would be implicated. For example, it is unclear whether dendritic "pruning" or an apoptotic mechanism could account for volumetric reductions in areas such as the hippocampus. Observations of reduced neuronal size suggest that factors regulating this parameter could play a role. Second, despite the myriad of findings, the lack of any consistently replicable neurodevelopmental lesion in postmortem studies continues to leave the issue in doubt. It is entirely possible that no single lesion exists. Third, the issue of heterogeneity remains unresolved. Although patients with schizophrenia have structural and functional alterations as a group as compared to controls, it remains unclear whether these are necessary features of the illness. Certainly many patients are in the normal range in some or many of these measures. The same is true for most neurodevelopmental parameters. Many patients have completely normal or even above-average function in childhood and adolescence. Most patients with schizophrenia have no known history of pregnancy, obstetric, or neonatal insults. Is it possible that different patients have abnormalities restricted to differing prefrontal, temporal, or subcortical areas? Such primary lesions could induce secondary dysfunction in connected regions. Fourth, the delayed onset of psychosis presents some problems for the neurodevelopmental model. Although onset is typically in the early 20s, some patients do not develop symptoms until the fourth or even fifth decade of life. It seems most likely that such cases involve mechanisms other than or in addition to neurodevelopmental processes.
Several alternative models have been put forward to deal with some of these problems. For example, structural abnormalities could develop in adolescence, very early in the illness. It is unclear what could account for this, but candidate mechanisms might include reduction in neuronal size or excessive dendritic pruning. Neurotransmitter abnormalities, such as in the dopamine and glutamate systems, may follow. Another possibility is that some cases of schizophrenia are due to increased stress associated with entry into adulthood. This could trigger dopamine abnormalities in genetically vulnerable individuals. Structural abnormalities, in these cases, could be nonspecific vulnerability factors or could be secondary to psychosis itself. A third possibility is that schizophrenia is a heterogeneous illness with several dimensions, none of which is necessary or sufficient. Different domains could involve neurodevelopmental cortical dysfunction, dopamine and glutamate function, cortical regulation of dopamine, and interdependent functioning of a myriad of heteromodal cortical neural networks. In this model, a complex web of genetic and environmental factors could impact on these many neural networks.
One approach toward settling this issue is to examine neurobiological traits associated with schizophrenia. Such traits may be closer to the underlying physiological deficits induced by genes associated with the illness. As such, these traits may have a simpler genetic architecture, making it easier to detect their genes in linkage studies. A number of potential phenotypes have been identified that are clearly familial and thus may have a significant genetic basis. These include impaired sensory gating, eye-tracking dysfunction, perceptual aberrations, schizotypal symptoms, attentional impairment, deficit symptoms, structural brain abnormalities, and cognitive deficits. The feasibility of this approach has been validated by a recent report of linkage using a measure of impaired sensory gating. Suppression of the auditory p50 wave in a sensory gating paradigm has been linked to 15q13–14. This is very close to the a7 nicotinic cholinergic receptor, previously implicated in impaired p50 suppression. Several other preliminary reports have used eye tracking and positive psychotic symptoms. The use of such intermediate phenotypes may also reveal genes that are more important to functional outcome. Unfortunately, the heritability and genetic architecture of most intermediate phenotypes are uncertain, despite a wealth of data showing that many such traits are familial. Studies to assess these parameters and attempt linkage will require phenotyping large numbers of patients.
The underlying neurobiology of schizophrenia remains a mystery. Genetically, the disorder is complex, confounding efforts to locate causative genes. Similarly, the effects of environment are subtle, with no clear major factor emerging. Pregnancy, labor, and delivery complications may play a limited role. Increasingly sophisticated techniques, guided by greater understanding of basic neurobiology, are being used to uncover alterations in a number of brain parameters. Neurobiological abnormalities include reduced volume of several brain structures, sulcal widening, and increased ventricular size. Cortical abnormalities, particularly in the prefrontal and temporal cortices, have also been implicated by cognitive testing and functional neuroimaging. Postmortem studies have failed to find a major lesion or gliosis that could account for structural abnormalities. They have, however, detected a variety of subtle cytoarchitectural changes, perhaps caused by abnormal neurodevelopment. Several neurotransmitters, including dopamine, glutamate, and serotonin, have been implicated. The putative structural, functional, and neurochemical abnormalities can be understood in the context of the neural systems they comprise. These include cortical-striatal-thalamic loops, ascending dopamine projection pathways, and the limbic system. Interconnections between these systems make it difficult to determine which lesions are primary and which are secondary.
The neurodevelopmental model has been a critical organizing heuristic that synthesizes these seemingly disparate observations. This theory suggests that nonspecific lesions in early life, perhaps in utero, produce subtle behavioral manifestations in childhood. The onset of psychosis is delayed until brain maturation reaches later stages in late adolescence. Many questions remain unanswered, however, leaving some aspects of this theory in doubt. Combining techniques such as neuroimaging with molecular genetics provide fertile areas for future research to separate the strands that make up the tangled web of schizophrenia.
SUGGESTED CROSS-REFERENCES
Section 1.2 reviews functional neuroanatomy in greater detail. Sections 1.3, 1.4, and 1.5 contain additional information on dopamine, glutamate, and other neurotransmitters. Section 1.18 describes the basic principles of genetic linkage analysis and Sections 1.15 and 1.16 provide a more thorough discussion of the principles of neuroimaging.
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12.5 Schizophrenia: Genetics

KENNETH S. KENDLER, M.D.
The goal of this section is to provide an overview of the current state of knowledge of the genetics of schizophrenia. The following key questions are relevant. Is schizophrenia a familial disorder? To what extent is any familial aggregation of schizophrenia the result of genetic versus environmental factors? What kinds of psychiatric disorders are transmitted within families? The author believes that genetic factors play an important role in the familial transmission of schizophrenia, thus the following additional questions are pertinent: What are the most likely kinds of genetic transmission mechanisms? and What is the current status of and future prospects for identifying the chromosomal location of specific genes that predispose to schizophrenia?
IS SCHIZOPHRENIA FAMILIAL?
The most basic question in the genetics of schizophrenia is whether the disorder aggregates (or runs) in families. Technically, familial aggregation means that a close relative of an individual with a disorder is at increased risk for that disorder compared to a matched individual chosen at random from the general population. This chapter reviews family studies of schizophrenia examining primarily first-degree relatives (parents, full siblings, and offspring) because little systematic information on more distant relationships has been gathered in recent years.
In a 1967 review paper Edith Zerbin-Rudin Zerbin-Rüdin listed 17 major family studies of schizophrenia involving first-degree relatives. By 1980 at least 9 other major studies had been reported. All these studies consistently showed a substantially greater risk for schizophrenia in the close relatives of persons with schizophrenia than would be expected in the general population.
However, nearly all these studies suffered from three methodological limitations. First, because no control groups were used, the rates of schizophrenia in the general population required for comparison had to be derived from the literature. Second, diagnoses were made nonblind, with the research team always knowing that the individual being evaluated was a relative of a schizophrenic individual. Third, neither structured personal interviews nor operationalized diagnostic criteria were used. In fact in many of the early studies it is unclear how many individuals were personally examined and how many were evaluated from indirect information such as reports of relatives or doctors, or from hospital notes.
In the early 1980s several research groups questioned the validity of earlier family studies of schizophrenia. These researchers suggested that the evidence for the familial aggregation of schizophrenia may result from consistent biases in the previous studies. In addition, they were concerned that the diagnostic approach to schizophrenia in these earlier studies might have been overly broad. They argued that the familial aggregation of schizophrenia might be weak or absent when narrowly diagnosed. Since 1980, 11 major family studies of schizophrenia have been reported that used blind diagnoses, control groups, personal interviews, and operationalized diagnostic criteria. These studies permit a more rigorous evaluation than has hitherto been possible of the degree to which schizophrenia aggregates in families.
The key results from these studies are summarized in Table 12.5–1, which contains the diagnostic criteria used in the study, the nature of the control proband group, and the p value (i.e., the probability of observing such a difference in the rates of schizophrenia in the two groups by chance, if the true rates were identical). The term proband refers to the individual through whom the family was identified for study. A typical family study of schizophrenia would then begin with two types of probands: those with schizophrenia and a matched group of control probands. Relatives of these probands would then be systematically assessed. Table 1 also presents the lifetimes at risk in the assessed relatives of schizophrenia and control probands, and the morbid risk for schizophrenia in the two groups. Lifetimes at risk is the sum for all assessed relatives of the proportion of their lifetime risk for schizophrenia they have completed thus far. Morbid risk (MR) is a statistic commonly used in genetics and equals the total proportion of individuals who would be expected to be affected with a disorder in a given population if all members of that population have completed their age at risk. Finally, the table includes the correlation of liability. If schizophrenia is caused by several genetic and environmental factors that act approximately additively in influencing an individual's liability or predisposition to schizophrenia, then this figure represents the degree of correlation between first-degree relatives in overall risk of the disease. This is a very useful figure because it combines into a single, easily understood statistic the risk figures for schizophrenia in relatives of schizophrenic and control probands. The higher the correlation of liability, the stronger is the degree of familial aggregation of schizophrenia.
Scroll right to see more columns.
Table 12.5-1. Summary Results of Major Recent Family Studies of Schizophrenia
That Included a Normal Control Group, Personal Interviews With Relatives, and
Blind Diagnosis of Relatives*
First-Degree Relatives of
Schizophrenic Probands First-Degree Relatives of Control Probands
Senior Author Schizophrenia Schizophrenia Correlation in
and Year Diagnostic Criteria Controls BZ N MR (%) BZ N MR (%) p Liability (r) ± SE
Tsuang, 1980†   Consensus Senior Screened surgical 362 20 5.5 475 3 0.6 .00002 0.36 ± 0.04
Iowa Clinicians patients
Baron, 1985 RDC, DSM-III Screened 329 19 5.8 337 2 0.6 .0001 0.37 ± 0.04
acquaintances
Kendler, 1985  DSM-III Screened surgical 703 26 3.7 931 2 0.2 8 ´ 10-8 0.38 ± 0.03
patients
Frangos, 1985 DSM-III Controls 478 26 5.4 536 6 1.1 .0001 0.28 ± 0.04
Coryell, 1988 RDC Screened volunteers 72 1 1.4 160 #0 0 NS 0.23 ± 0.12
Gershon, 1988 RDC Chronic Schiz Volunteers 97 3 3.1 349 2 0.6 .038 0.25 ± 0.09
Kendler, 1992 DSM-III-R Unscreened general 276 18 6.5 428 2 0.5 .000004 0.41 ± 0.04
population controls
Maier, 1993‡ RDC Unscreened general 435 17 3.9 320 1 0.3 .001 0.36 ± 0.04
population controls
Taylor, 1993 DSM-III Screened medical 335 9 2.7 264 #0 0 .000003 0.33 ± 0.04
patients
Parnas, 1993°‡ DSM-III-R Screened controls 192 31 16.2 101 2 1.9 .0001 0.41 ± 0.04
Erlenmeyer- DSM-III-R Screened controls 54 6 11.1 93 #0 0 .002 0.53 ± 0.08
Kimling, 1995°‡
* BZ indicates bezugsziffer (total lifetime equivalents of risk); MR, morbid risk; SE, standard error;
ICD-9, ninth revision of International Statistical Classification of Diseases; DSM-III, third edition of
Diagnostic and Statistical Manual of Mental Disorders; RDC, Research Diagnostic Criteria; schiz,
schizophrenia; NS, nonsignificant.
† Studies on partially overlapping data sets; results include relatives with only hospital records.
‡ Prevalence rather than MR reported.
° Offspring only
# For the purpose of calculating a correlation in liability, a half a case of illness in controls is
assumed.

Before turning to the major results summarized in this table, two preliminary comments are in order. First, the sample of relatives studied varies very widely in the different investigations. For example, the lifetimes at risk in relatives of schizophrenic patients range over tenfold, from over 700 to 54. On average, the larger studies will provide more stable statistical estimates for the true risk of schizophrenia in relatives of schizophrenia and control probands. Second, various diagnostic criteria were utilized in the different studies. However, eight studies used criteria from either the third edition of Diagnostic and Statistical Manual of Mental Disorders (DSM-III), Research Diagnostic Criteria (RDC) (for chronic schizophrenia), or revised third edition of DSM (DSM-III-R) criteria, all of which require at least 6 months of illness, usually with functional impairment, in addition to specified psychotic symptoms. Third, while nine of the studies examined all available first-degree relatives (parents, full-siblings, and offspring), two studies examined only offspring.
There are five major conclusions that can be drawn from the large body of work summarized in the table. First, the risk for schizophrenia in relatives of schizophrenic probands varies widely across studies, from a low of 1.4 percent to a high of 16.2 percent. Much of this fluctuation may probably be attributable to differences in diagnostic criteria or statistical fluctuations in small samples (the lowest risk is found in the smallest study). However, it remains possible that there are true population differences in the risk for schizophrenia in relatives of schizophrenic probands.
Second, the risk for schizophrenia in the relatives of nonpsychiatric control probands is relatively similar across studies, ranging—with the exception of the study of Parnas et al—from only 0.2 to 1.1 percent, corresponding closely to the range of risks for schizophrenia found in general population studies.
Third, in every study the risk for schizophrenia was higher in the relatives of schizophrenic probands than in relatives of control probands. Across these studies the risk of schizophrenia was, on average, 11 times greater in relatives of schizophrenic probands than in relatives of matched control probands. Fourth, in all but one study, the difference in risk for schizophrenia in the relatives of schizophrenic and control probands was quite unlikely to be attributable to chance (p-value < 0.05). In a number of studies, the p-values were very low (less than 0.001), indicating that such differences in risk would be extremely unlikely to occur by chance.
Finally, although there was some variation, the correlation in liability for all studies fell in the range from +0.23 to +0.53, with a weighted mean across the 11 studies of +0.35. Most of the largest studies that used relatively narrow diagnostic criteria for schizophrenia obtained correlations of liability in the narrow range of +0.32 to +0.41 because the highest and lowest correlations in the table come from the smallest and next to smallest studies, respectively. These results suggest that most of these studies can be seen as replications of one another because they provide similar results on the observed degree of familial aggregation of schizophrenia. The correlation of liability between first-degree relatives in the range of +0.30 to +0.40 indicates a relatively strong degree of familial aggregation.
In conclusion, the questions raised in the early 1980s about the degree of familial aggregation of schizophrenia can now be addressed satisfactorily. The results of a large number of recent, carefully performed family studies support the conclusions of earlier and less methodologically rigorous investigations in finding that schizophrenia strongly aggregates in families. The familial aggregation of schizophrenia appears to be quite substantial when it is defined using modern, relatively narrow diagnostic criteria such as those found in DSM-III-R and DSM-IV. On average, the risk for schizophrenia in the relatives of controls is between 0.5 and 1.0 percent, compared to between 3 and 7 percent in relatives of schizophrenic probands in most studies. The best estimate of the correlation in liability to schizophrenia in first-degree relatives is probably between +0.3 and +0.4.
FAMILIAL AGGREGATION: GENETIC VERSUS ENVIRONMENTAL FACTORS
Twin Studies
Resemblance among relatives can be ascribed to shared environment (nurture) or shared genes (nature). A major goal in psychiatric genetics is to determine the degree to which familial aggregation for a disorder like schizophrenia results from environmental versus genetic mechanisms. Although sophisticated analyses of family data can begin to make this discrimination, nearly all that is known about this problem in schizophrenia comes from twin and adoption studies.
Twin studies are based on the assumption that monozygotic (MZ) and dizygotic (DZ) twins share a common environment to approximately the same degree. However, MZ twins are genetically identical, whereas DZ twins (like full siblings) have on average only half of their genes in common. Although the validity of the second assumption is beyond question, the first (equal environment) assumption has been a focus of considerable controversy.
Several studies have shown that measures of the social environment (for example, common friends, attitudes of parents and teachers) are more highly correlated among young MZ twins than among young same-sex DZ twins. These results at first appear to suggest that the equal environment assumption is false. However, there is another possible interpretation. Similarity in environment might make MZ twins more similar, but it is also plausible that by behaving alike, MZ twins seek out or create more similar environments for themselves. These two alternative hypotheses have been empirically evaluated in a number of studies, nearly all of which suggest that the environmental similarity of MZ twins is the result and not the cause of their behavioral similarity. Current evidence from an increasingly wide range of studies supports the general validity of the equal environment assumption of twin studies.
Results are available from 13 major twin studies of schizophrenia (Table 12.5–2). None of these, however, meets all the methodological criteria outlined above for family studies and the additional criterion that zygosity assignment be made blind with respect to psychiatric diagnosis. Some studies come closer to this model than others. For example, a variety of different clinicians made diagnoses from blind case abstracts in the original report from the Maudsley twin series of Irving Gottesman and James Shields. These case records have more recently been examined using modern operationalized criteria with similar overall results. In the study by Kenneth Kendler and Dennis Robinette from the National Academy of Sciences-National Research Council (NAS-NRC) Registry, psychiatric diagnoses were collected from a wide variety of clinical settings in which clinicians could not possibly have been aware of any research hypotheses. Furthermore, it could be shown that zygosity assignment was not biased with respect to psychiatric diagnosis. The new Norwegian and Finnish studies used the high-quality twin and psychiatric registries in Norway and Finland and thus should be representative of all treated cases of illness. Whereas the Norwegian study was based on personal psychiatric assessments and performed with structured instruments and DSM-III-R operationalized criteria, the Finnish study used previously recorded hospital and disability diagnoses. The sample size of the Finnish study was relatively large (253 pairs) while the Norwegian sample was much more modest in size (52 pairs). Unfortunately, both studies relied on self-report zygosity measures and the interviews and diagnoses in the Norwegian study were performed nonblind.
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Table 12.5-2. Concordance With Respect to Probands and the Heritability of Liability to
Schizophrenia in the Major Twin Studies Reported to Date
Probandwise
Concordance* MZ Same-Sex DZ Heritability of
Author Country Year N % N % Liability (± SE)
Luxenburger Germany 1928 14/22 64 0/13 0  †
Rosanoff et al United States 1934 24/41 to 50/66 61 7/53 to 14/60 13 0.84 ± 0.26 to
76 23 0.63 ± 0.26
Essen-Moller Essen-Möller Sweden 1941 7/11 64 4/27 15 0.87 ± 0.36
Kallmann United States 1946 191/245 78 59/318 19 0.90 ± 0.13
Slater England 1953 28/41 68 11/61 18 0.73 ± 0.21
Inouye Japan 1963 33/55 60 2/11 18 0.66 ± 0.35
Kringlen Norway 1967 31/69 45 14/96 15 0.61 ± 0.20
Fischer Denmark 1973 14/23 61 12/43 28 0.41 ± 0.29
Gottesman and Shields England 1972 15/26 58 4/34 12 0.86 ± 0.32
Tienari Finland 1975 7/21 33 6/42 14 0.53 ± 0.33
Kendler and Robinette United States 1983 60/194 31 18/277 6 0.71 ± 0.04‡
Onstad et al Norway 1991 15/31 48 1/28 4 0.87 ± 0.08‡
Cannon et al Finland 1998 40/87 46 18/195 9 0.83 ± 0.09
* Concordance rates are not age-corrected. Estimates of the heritability of liability are based on
population risks for schizophrenia either provided in the study or estimated by the reviewer. For
further details regarding figures in this table, see the Kendler et al. (1983) studies with multiple
reports; the latest or most complete report was chosen for analysis.
† Cannot be calculated because none of the DZ pairs were concordant.
‡ Correlation in liability in MZ twins is reported rather than the standard heritability of liability, so
standard error is substantially lower.

All these studies agree that proband-wise concordance for schizophrenia (the risk for schizophrenia in the cotwins of a schizophrenic proband twin) is much higher in MZ than in DZ twins, but the absolute rates of concordance vary widely. Two factors are probably responsible for most of this variation. First, some studies defined schizophrenia more broadly than others. Second, some studies obtained most of their proband twins from chronically hospitalized populations; others used population-based registries where milder cases would commonly occur. Twin studies have often but not always found a positive relationship between concordance and severity of illness.
Heritability of Liability The diagnostic approach to schizophrenia and the method of ascertaining probands should equally affect concordance rates in MZ and DZ twins. Therefore, a better method of comparing results across studies would be a summary statistic based on concordance in both MZ and DZ twins. One of the best of these is the heritability of liability as calculated from the correlations in liability in MZ and DZ twins. This statistic ranges from 0.0 if genetic factors play no role in susceptibility to a disorder to a maximum of 1.0 if genes entirely determine disease risk. Because this statistic is based on the polygenic multifactorial threshold model, which may or may not be appropriate for schizophrenia, these results should be regarded as only one plausible way of approximating reality. Nonetheless, the major twin studies of schizophrenia agree in estimating the heritability of liability of schizophrenia at between 0.6 and 0.9 (Table 12.5–2). These results suggest that genetic factors play a major role in the familial transmission of schizophrenia.
Genetic theory predicts that if all the familial aggregation of schizophrenia were due to genetic factors, then the heritability of liability should be approximately double the correlation in liability found in first-degree relatives (because, on average, first-degree relatives have half of their genes in common). Comparing the results of Tables 12.5–1 and 12.5–2 indicates that, at least as a rough approximation, this hypothesis is supported. The range of the heritability of liability to schizophrenia calculated from twin studies is approximately twice the range of the correlation in liability to schizophrenia found in first-degree relatives in most family studies.
Nongenetic Familial Transmission Twin studies also provide two powerful tests for the role of nongenetic familial transmission in the liability to schizophrenia. First, one can ask whether the correlation in liability in DZ twins is more than half that which would be predicted in MZ twins if only additive genetic factors were operating. A review of all major twin studies to date suggests that nongenetic factors may play at most a modest role in the transmission of schizophrenia. Second, the risk for schizophrenia in DZ co-twins can be compared with that in siblings of schizophrenic probands. Although having the same degree of genetic relationship to the affected proband, DZ co-twins certainly share more of the familial environment that do ordinary siblings. Several twin studies have suggested that a difference in risk does exist between these two groups. However, such a difference has not been consistently found across all studies and was not found in the recent Norwegian small-sample twin family study of schizophrenia.
Adoption Studies
Adoption studies can clarify the role of genetic and environmental factors in the transmission of schizophrenia by studying two kinds of rare but informative relationships: (1) individuals who are genetically related but do not share familial-environmental factors, and (2) individuals who share familial-environmental factors but are not genetically related. Table 12.5–3 summarizes, in the order discussed, the major adoption studies of schizophrenia, reporting raw data and statistical tests. Our summary here will be organized by the kind of adoption design utilized.
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Table 12.5-3. Summary Results of Major Adoption Studies of Schizophrenia*
Relationship
of Index
Diagnosis Group to
in Schizophrenic Affected Affected
Study and Year Location Relatives Proband N % Control Group N % P Comments
Heston, 1966 Oregon Schiz AAO 5/47 10.6 AAO of normals 0/50 0 0.01† 
Rosenthal et Denmark Schiz spect AAO 14/52 26.9 AAO of controls 12/67 17.9 0.12 † Including only parents where judges agreed on a schiz
al., 1971 spect dx
Lowing et al, Denmark Schiz spect AAO 11/39 28.2 AAO of controls 4/39 10.3 0.02 † Independent analysis of the study by Rosenthal et al;
1983‡ biological parents restricted to DSM-II schiz; spectrum in
offspring defined by DSM-III as schizophrenia and as
schizotypal and schizoid personality disorders
Tienari, 1997 Finland Schiz spect AAO 24/184 13.0 AAO of controls 5/203 2.5

Does increased dopamine cause schizophrenia? There is compelling evidence that presynaptic dopamine dysfunction results in increased availability and release of dopamine and this has been shown to be associated with prodromal symptoms of schizophrenia. Furthermore, dopamine synthesis capacity has also been shown to steadily increase with the onset of severe psychotic symptoms. [3]