We searched PubMed and Embase from January, 1966, to June, 2013, and reviewed article bibliographies with the following search terms: “schizophrenia”, “psychosis”, in combination with “dopamine”, “aetiology”, “risk factors”, “cause”, “theory”, “neurodevelopmental”, and “cognitive”. We excluded papers that were not in English or peer-reviewed journals. When possible we have cited meta-analyses and systematic reviews. When these studies were not available, we selected well controlled studies
ReviewSchizophrenia: an integrated sociodevelopmental-cognitive model
Introduction
Schizophrenia affects about 1% of the population, and is one of the leading causes of health burden in the world.1 The clinical presentation is characterised by psychotic (positive) and negative symptoms, and cognitive impairments (panel). People who develop schizophrenia tend to show subtle cognitive, social, and motor impairments in childhood. These signs are followed, in adolescence and early adulthood, by anxiety, low mood, and social withdrawal, and then emergence of prodromal symptoms of psychosis followed by the onset of the first psychotic episode (figure 1). Schizophrenia frequently follows a fluctuating course, with enduring residual positive and negative symptoms interspersed by acute exacerbations of positive symptoms. Antipsychotic drugs, the main pharmacological treatment, effectively treat psychosis and reduce the risk of relapse, but largely do not treat other aspects of the disorder and have troubling side-effects.2 Progress in development of alternative drugs has been slow, and, unfortunately, all present antipsychotics essentially use the same mechanism as that for drugs discovered in the 1950s.3 This lack of progress emphasises the importance of understanding the pathogenesis of the disorder. Fortunately, understanding of schizophrenia has advanced from earlier data-free, stigmatising theories such as the idea that bad parenting caused the disorder (the so-called schizophrenogenic mother4). Dopaminergic and neurodevelopmental alterations, and biases in thinking and in appraising experiences, are now known to underlie the disorder.5, 6, 7, 8 We review how recent advances help with understanding of the onset and course of schizophrenia.
Section snippets
Dopamine dysfunction in schizophrenia
The dopamine hypothesis was built on the findings that antipsychotics work by blocking dopamine D2/3 receptors, and that drugs that activate the dopamine system such as amphetamine can induce psychotic symptoms (table 1).3, 9, 10, 11 However, meta-analysis of more than 50 molecular imaging studies of the dopamine system in schizophrenia shows that the alterations in D2/3 receptor availability are inconsistent and small,12 and that transporter availability does not differ.12, 13 By contrast,
The neurodevelopmental hypothesis
When the neurodevelopmental hypothesis was first articulated, it was based on three main lines of evidence (table 2).6, 7 First, there were the associations between prenatal and perinatal hazards on the one hand, and later schizophrenia on the other. Second, there was an excess of neuromotor, minor physical, and other markers of developmental deviance in children destined to develop schizophrenia. Third, imaging studies showed that structural brain defects were present at onset of
The effect of developmental insults on the dopaminergic system
Early developmental insults to rodents have effects that mirror changes noted in schizophrenia. Thus animals exposed to inflammatory challenges in utero show increased striatal concentrations of dopamine and its metabolites, and increased concentrations of dopamine synthetic enzymes in adulthood.40 They also show increased behavioural responses to amphetamine41—another indicator of increased dopamine release. Perinatal hypoxia models increase brain dopamine synthesis capacity and concentrations,
Social risk factors
Evidence for the effects of social factors on schizophrenia has become well established. Thus, being an immigrant is associated with a relative risk of schizophrenia of 2·9 and a risk of more than 4 if the migrant lives in an area where he or she is readily identifiable as being in the minority.50 Similarly, having grown up in a city is associated with increased risk (pooled odds ratio of 1·9).51 Childhood adversity, such as loss of a parent or abuse, is also associated with an increased risk
The sensitivity, and sensitisation, of the dopamine system
The effects of neurodevelopmental insults on different neurotransmitter systems have been compared. Caesarean section and mild hypoxia both affect the dopaminergic but not the serotonergic system;42 although caesarean section increases dopamine concentrations, it decreases norepinephrine concentrations, at least in male rats.44 Furthermore, although dexamethasone exposure in utero, a prenatal stress model, increases both brain serotonin and dopamine concentrations, the effect is more marked for
Genes, neurodevelopment, and the dopamine system
Much of the variance in schizophrenia is considered genetic. Dopamine-related genes have been much studied in schizophrenia, particularly the genes for dopamine receptors and for catechol-O-methyltransferase (COMT); the most notable finding from recent genome-wide association studies is that the D2 receptor gene is reliably associated with schizophrenia. However, generally, effects in dopamine-related genes have been small and inconsistent.81 This finding is not surprising in view of results
Postsynaptic dopamine signalling
We have focused on presynaptic dopamine, but cannot exclude a role for postsynaptic dopamine signalling. A finding in patients with both schizophrenia and substance dependence draws attention to the potential role of postsynaptic dopamine signal transduction.100 By contrast with previous findings in schizophrenia, this study showed reduced dopamine release to amphetamine; however, dopamine release was still positively associated with the induction of psychotic symptoms.101 This finding suggests
Cognitive theories and their link to dopaminergic dysfunction
Together the dopamine and developmental hypotheses explain much of what is known about the biology of psychosis. However, they do little to help understanding of the symptoms that patients have. The past decade has seen the rise of cognitive models that attempt to elucidate this knowledge gap.8, 113 These models suggest that exposure to social adversities (eg, child abuse, intrusive life events) bias an individual towards development of cognitive schemas that view the world as threatening, and
An integrated sociodevelopmental model
Our model combines aspects of the dopamine, neurodevelopmental, and sociodevelopmental hypotheses with cognitive theories. First, developmental deviance secondary to variant genes, hazards to the brain, and social adversity in childhood disrupt the development of and sensitises the dopamine system (figure 2). At the same time, social adversity also biases the cognitive schema that the individual uses to interpret experiences towards psychotic interpretations. Subsequent stress then results in
Strengths and limitations
Findings from meta-analyses lend support to the evidence linking neurodevelopmental and sociodevelopmental risk factors to schizophrenia, and for presynaptic dopamine dysfunction in the disorder (Table 1, Table 2). Similarly, findings from several preclinical studies support the link between developmental risk factors and altered dopamine function. As such, a substantial amount of new evidence would be needed to refute these aspects of the model. However, the link between the environmental risk
Implications and future directions
This model draws on several previous theories,7, 55, 101, 140, 141, 142 and is likely to be refined with further testing. There are several areas in which more evidence might be particularly informative. One is the developmental trajectory of dopamine function in experimental models of schizophrenia, beginning earlier than previously studied,143 and examining the interactive effects of social risk factors. Another is the interaction between genes affecting the dopamine system and environmental
Search strategy and selection criteria
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