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Pathways to schizophrenia: the impact of …-dopamine pathways in schizophrenia pdf

International Journal of Neuropsychopharmacology (2004), 7 (Supplement 1), S7-S13. Copyright f 2004 CINP
DOI : 10.1017/S1461145704004122
Pathways to schizophrenia: the impact
of environmental factors
Oliver D. Howes, Colm McDonald, Mary Cannon, Louise Arseneault, Jane Boydell
and Robin M. Murray
Department of Psychological Medicine, Institute of Psychiatry, De Crespigny Park, London SE5 8AF, UK
Schizophrenia is an aetiologically complex disorder arising from the interaction of a range of factors acting
at various stages of life. Schizophrenic individuals inherit genes that cause structural brain ` deviations'
which may be compounded by early environmental insults. As a result some pre-schizophrenic children
exhibit subtle developmental delays, cognitive problems, or poor interpersonal relationships. They are
susceptible to dysregulation of dopamine, the final pathway leading to the onset of a psychotic illness.
Dopamine dysregulation may arise through a process of sensitization, which, in animals, can be caused by
repeated administration of dopamine-releasing drugs. It is clear that the same process occurs in humans,
and that some individuals are particularly sensitive to the effects of such drugs for either genetic reasons
or through early environmental damage. Stress has also been shown to induce dopamine release in animal
studies, and epidemiological studies have demonstrated that social stresses can precipitate schizophrenia.
Thus, stresses, such as drug use and social adversity, in adolescence or early adult life may propel the
neurodevelopmentally impaired individual over a threshold into frank psychosis.
Received 17 August 2003 ; Reviewed 1 October 2003 ; Revised 25 November 2003 ; Accepted 27 November 2003
Key words : Aetiology, neurodevelopment, psychosis, schizophrenia, stress.
Introduction Predisposing factors to schizophrenia
Schizophrenia results from the cumulative interaction Inheriting ` deviant' traits
of a number of risk factors, some of which are neuro-
developmental. Susceptible individuals appear to Schizophrenia shows a high degree of heritability but
inherit a number of deviant traits, each of which is no single gene has been found to be responsible, in the
not uncommon in the general population, but which same way that no single gene has been identified as
together render them vulnerable to schizophrenia. being the cause of all coronary artery disease, diabetes
This genetic vulnerability may be compounded by mellitus and many other medical disorders (Harrison
early insults to the developing brain, such as prenatal and Owen, 2003). Rather, these complex disorders are
and perinatal complications. A proportion of pre- thought to arise from the interaction of many different
schizophrenic children show slight developmental genes with each other, as well as with environmental
delays, minor cognitive difficulties and social anxiety, factors. Reviewing genetic factors in schizophrenia is
which supports the hypothesis that the disorder is at beyond the scope of this paper, however, recent in-
least in part neurodevelopmental. But what causes terest has focused on two types of genes that provide
such a child or adolescent to go on to become psy- a plausible pathophysiological mechanism to schizo-
chotic ? This paper provides an overview of current phrenia and are particularly relevant to environmental
evidence on factors influencing the trajectory to factors (Harrison and Owen, 2003). These are neuro-
schizophrenia, highlighting illustrative studies, and is developmental genes, such as neuregulin (Stefansson
not intended to be exhaustive. et al., 2002), and genes associated with dopamine
regulation, such as the catechol-O-methyltransferase
(COMT) gene (Mattay et al., 2003 ; Shifman et al.,
Address for Correspondence : Dr O. D. Howes and Professor 2002). These genes may either operate very early in life
R. M. Murray, Department of Psychological Medicine, Institute
of Psychiatry, De Crespigny Park, London SE5 8AF, UK. or nearer to the onset of psychosis.
Tel. : +44 (0)20 7848 0080 Fax : +44 (0)20 7701 9044 Schizophrenic individuals have consistently been
E-mail : O.Howes@iop.kcl.ac.uk ; robin.murray@iop.kcl.ac.uk reported to have structural brain abnormalities. At
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S8 O. D. Howes et al.
Schizophrenics Controls
Figure 1. MRI scans of schizophrenic and control subjects in the Maudsley Family Study. (Adapted from McDonald et al., 2002.)
least some of the brain abnormalities are inherited. not have a large effect on brain development. However,
McDonald et al. (2002) performed MRI scans on pro- in non-psychotic but predisposed relatives from mul-
bands and unaffected relatives from families multiply tiply affected families, the left hippocampal volume
affected with schizophrenia, which are likely to trans- was decreased in those who had suffered an obstetric
mit an elevated genetic predisposition. Unaffected insult but normal in those who had not. The schizo-
family members displayed similar brain deviations phrenic group was even more sensitive to obstetric
to their schizophrenic relatives, including enlarged insult : there was greater decrease in left hippocampal
lateral ventricles and a reduced cortical volume volume and increase in lateral ventricular volume in
(Figure 1). Furthermore, a gradient of ventricular en- those who had suffered obstetric complications com-
largement was found amongst the unaffected relatives pared to those who had not. This suggests that early
in proportion to their likelihood of carrying schizo- environmental factors may produce a more detrimen-
phrenia genes, with greater enlargement amongst tal effect on the brains of individuals carrying a genetic
relatives who were more closely related to the schizo- predisposition to schizophrenia than those who do not.
phrenic proband. This indicates there is transmission In animal studies, perinatal damage has also been
of genes that subtly alter brain development. shown to lead to a labile dopamine system vulnerable
to sensitization. Moore et al. (1999) suggested that
Environmental insults developmental disruption of the temporal cortex can
Many studies have shown that early environmental result in dysregulation of the dopaminergic inputs to
`insults ', such as prenatal infections and nutrition, the striatum, increasing the response to novelty, mild
maternal substance misuse, early life stressors, and ob- stress or psychotomimetics. In a similar way, early
stetric complications, are more common in people with environmental factors appear to interact with genetic
schizophrenia than the general population (Cannon predisposition to schizophrenia, increasing the risk
et al., 2002a ; Hulshoff Pol et al., 2000 ; Lieberman et al., that an individual will develop dopamine dysregu-
2001). Recent studies investigating the effects of these lation and resultant psychosis in adolescence or later.
factors on brain development provide evidence for the Neurocognitive impairments
interaction between genetic and environmental factors
acting early in life. For example, McDonald and col- Many studies have suggested that children who go
leagues (McDonald et al., 2002 ; Schulze et al., 2003) on to develop schizophrenia may be different from
examined the impact of obstetric complications on their peers and display some developmental devi-
brain development in schizophrenic probands, their ations, such as mild social, motor and cognitive dys-
unaffected relatives, and controls. Obstetric compli- functions (Cornblatt et al., 1999 ; Erlenmeyer-Kimling,
cations of moderate severity in the control subjects did 2001). However, these deviations are not sufficiently
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Schizophrenia and environmental factors S9
specific or sensitive to enable identification of `at risk' `Have you ever thought that people are following you
individuals early in childhood (Lieberman et al., 2001). or spying on you ? '
To find a better predictor of psychosis, the Dunedin `Have you heard voices other people cannot hear ? '
Birth Cohort Study assessed the development of 1037
children every 2 yr from the ages of 3-15 yr, and then The cohort was categorized on the basis of responses
again at ages 18, 21 and 26 yr (Cannon et al., 2002b ; to these questions. The strong-symptom group con-
Moffitt et al., 2001). They were assessed in great detail sisted of children who answered ` yes, likely ' to two
by neurologists, psychologists and social workers, and symptoms or `yes, definitely ' to one symptom, and
a child psychiatrist interviewed the children at age children who answered ` yes, likely' to one symptom
11 yr. Ninety-six per cent of the cohort was again in- were assigned to the weak-symptom group. When the
terviewed at age 26 yr, using a standardized interview 13 children in the strong-symptom group were ex-
schedule to obtain DSM-IV diagnoses (APA, 1994). A amined at age 26 yr, the risk of schizophreniform dis-
total of 3.7 % were found to meet criteria for schizo- order was increased 16 times compared to the rest of
phreniform disorder, which is characterized by the the population. Twenty-five per cent of the strong-
same symptoms as schizophrenia but the criteria for symptom group and 9 % of the weak-symptom group
symptom duration are shorter (1 month vs. 6 months). went on to develop schizophreniform disorder. Of the
Schizophreniform disorder was examined rather than control subjects (those who answered negatively to all
severe schizophrenia partly because of the low base quasi-psychotic symptoms at age 11 yr), less than 2 %
rate of schizophrenia in general population samples, had developed schizophreniform disorder by the age
and because many studies have previously focused on of 26 yr. Thus, the presence of quasi-psychotic symp-
children of schizophrenic parents or on frank schizo- toms at age 11 yr is a more powerful predictor of later
phrenia. psychosis than cognitive or psychomotor problems.
One study focused on whether individuals with As well as exhibiting neurocognitive impairments,
schizophreniform disorder also showed developmen- children who go on to develop schizophrenia tend to
tal impairments (Cannon et al., 2002b). Not surpris- be socially anxious. These children tend to set them-
ingly, obstetric complications (such as neonatal insults, selves apart from their peers and begin to experience
being small for gestational age and, in particular, odd thoughts that may include strange ideas about
hypoxia) were found to increase the risk of psychosis. what other children are doing or of particular mess-
Individuals who developed schizophreniform dis- ages being sent to them. But what triggers the devel-
order had shown early in their life (aged 4-7 yr) opment of psychosis in adolescence or later ?
poorer motor development, poorer receptive language
and a lower IQ (Cannon et al., 2002b). Many of the
symptoms of schizophrenia involve language sys- Precipitants to the development of psychosis
tems : for example, thought disorder is expressed as Drugs that release dopamine, such as cannabis,
disordered language, and auditory hallucinations are amphetamines and cocaine, can increase the risk of
a misinterpretation of inner language. Therefore, it psychosis and exacerbate psychosis in those already
is not surprising that individuals who have difficulty ill. Stress can also induce dopamine release in animals
in understanding language early in life are more prone and epidemiological studies have demonstrated
to the language-based symptoms of schizophrenia. that social stresses can precipitate schizophrenia
However, although motor or cognitive abnormalities (Bebbington et al., 1993).
increased the risk of subsequently developing schizo-
phreniform disorder, they were not powerful pre-
dictors - increasing the risk by only 2- to 3-fold. Drug use
The interview at age 11 yr was the best predictor Psychoactive drug use has become very common
of whether a child would go on to develop schizo- in many countries, and may be a factor in the trend
phreniform disorder in adulthood (Poulton et al., towards a lower age of onset of schizophrenia
2000). Children, interviewed by a child psychi- (Di Maggio et al., 2001). Cannabis is the drug most
atrist, were asked questions about quasi-psychotic commonly used by people with psychoses, and
phenomena, such as : they often report taking the drug as a type of self-
medication - the reasons given include counteracting
`Have other people ever read your mind ? ' the negative effects of their medications or to feel bet-
`Have you ever had messages sent just to you through ter (Hambrecht and Hafner, 1996). Most studies report
the TV or radio ? ' a positive association between cannabis use and
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How does dopamine affect schizophrenia?The positive symptoms of schizophrenia include hallucinations and delusions as a result of increased subcortical release of dopamine, which augments D 2 receptor activation ( 15 ), and are thought to be due to a disturbed cortical pathway through the nucleus accumbens ( 16 ).


Title: Pathways to schizophrenia: the impact of environmental factors
Keywords: Aetiology, neurodevelopment, psychosis, schizophrenia, stress
Author: Oliver D. Howes, Colm McDonald, Mary Cannon, Louise Arseneault, Jane Boydell, Robin M. Murray
Creator: 3B2 Total Publishing System 7.51g/W
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CreationDate: Tue Feb 3 18:50:45 2004
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