Seminar

Schizophrenia
Jim van Os, Shitij Kapur

Schizophrenia is still one of the most mysterious and costliest mental disorders in terms of human suering and societal expenditure. Here, we focus on the key developments in biology, epidemiology, and pharmacology of schizophrenia and provide a syndromal framework in which these aspects can be understood together. Symptoms typically emerge in adolescence and early adulthood. The incidence of the disorder varies greatly across places and migrant groups, as do symptoms, course, and treatment response across individuals. Genetic vulnerability is shared in part with bipolar disorder and recent molecular genetic ndings also indicate an overlap with developmental disorders such as autism. The diagnosis of schizophrenia is associated with demonstrable alterations in brain structure and changes in dopamine neurotransmission, the latter being directly related to hallucinations and delusions. Pharmacological treatments, which block the dopamine system, are eective for delusions and hallucinations but less so for disabling cognitive and motivational impairments. Specic vocational and psychological interventions, in combination with antipsychotic medication in a context of community-case management, can improve functional outcome but are not widely available. 100 years after being so named, research is beginning to understand the biological mechanisms underlying the symptoms of schizophrenia and the psychosocial factors that moderate their expression. Although current treatments provide control rather than cure, long-term hospitalisation is not required and prognosis is better than traditionally assumed.

Lancet 2009; 374: 63545 See Comment page 590 Department of Psychiatry and Psychology, South Limburg Mental Health Research and Teaching Network, EURON, Maastricht University Medical Centre, Maastricht, Netherlands (Prof J van Os PhD); and Division of Psychological Medicine, Institute of Psychiatry, Kings College London, De Crespigny Park, Denmark Hill, London, UK (Prof J van Os, Prof S Kapur PhD) Correspondence to: Prof Jim van Os, Department of Psychiatry and Psychology, Maastricht University Medical Centre, PO Box 616, 6200 MD Maastricht, Netherlands [email protected]

Introduction
Although the precise societal burden of schizophrenia is dicult to estimate, because of the wide diversity of accumulated data and methods employed, cost-of-illness indications uniformly point to disquieting human and nancial costs.1 Schizophrenia does not just aect mental health; patients with a diagnosis of schizophrenia die 1215 years before the average population, with this mortality dierence increasing in recent decades.2 Thus, schizophrenia causes more loss of lives than do most cancers and physical illnesses. Although some deaths are suicides, the main reason for increased mortality is related to physical causes, resulting from decreased access to medical care and increased frequency of routine risk factors (poor diet, little exercise, obesity, and smoking).2

Diagnosis
Identication of delusions and hallucinations in psychosis is not dicult, but their classication has not been simple. Psychosis is not exclusive to schizophrenia and occurs in various diagnostic categories of psychotic disorder (panel). The criteria used to distinguish between these dierent categories of psychotic disorder are based on duration, dysfunction, associated substance use, bizarreness of delusions, and presence of depression or mania. However, the resulting diagnostic categories show overlap in genetic liability among themselves3 and with bipolar disorder,46 suggesting common underlying aetiology. Analysis of the psychopathological features in the various psychotic disorders suggests that symptoms can be clustered into ve main categories: (i) psychosis (encompassing delusions and hallucinationsalso called the positive-symptom dimension); (ii) alterations in drive and volition (lack of motivation, reduction in spontaneous speech, and social withdrawalthe negative-symptom
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dimension); (iii) alterations in neurocognition (diculties in memory, attention, and executive functioningthe cognitive-symptom dimension); and (iv and v) aective dysregulation giving rise to depressive and manic (bipolar) symptoms. The negative dimension is associated with neurocognitive alterations, but the positive and aective dimensions of psychopathological changes are not,7 and the positive and negative symptoms seem to follow independent courses over time.8 Within the cluster of diagnostic categories, the term schizophrenia is applied to a syndrome characterised by long duration, bizarre delusions, negative symptoms, and few aective symptoms (non-aective psychosis). Patients who present with a psychotic disorder with fewer negative symptoms, but whose psychosis is preceded by a high level of aective (depression and mania) symptoms, are usually diagnosed with psychotic depression or bipolar disorder (aective psychosis; gure 1). The US-based 4th Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV) and the 10th International Classication of Diseases (ICD-10) are currently used to diagnose schizophrenia. However, the various work groups who are developing the next generation of DSM and ICD (DSM-V and ICD-11; expected after 2012) have to nd solutions for several

Search strategy and selection criteria We searched publications in PubMed using the search terms schizophr*[ti] or psychosis[ti] or psychotic[ti]. We used 1558 English language reviews and meta-analyses published in the past 5 years. These reports were downloaded into an Endnote library le and scanned for relevance with regard to the topics selected for this review. Further focused searches on PubMed were then done on the selected topics.

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Panel: DSM-IV main diagnostic categories of psychotic disorders Based on current principles of diagnosis taking into account duration, dysfunction, associated substance use, bizarreness of delusions, co-presence of depression or mania, presence of a somatic disorder, and other criteria. Non-aective psychotic disorders: Schizophrenia Schizoaective disorder Schizophreniform disorder Delusional disorder Brief psychotic disorder Psychotic disorder not otherwise specied Aective psychoses: Bipolar disorder with psychotic features Major depressive disorder with psychotic features Substance-induced psychotic disorder: Alcohol-induced Other substance-induced Psychotic disorder due to a general medical condition

Research suggests that the use of a combination of dimensional and categorical representations of psychopathology for the purpose of diagnosis in psychotic disorders conveys more information about treatment needs and prognosis.11 A debate exists as to whether the term schizophrenia, which refers to a state of so-called split mind, should be retained in DSM-V and ICD-11.1215 Japan was the rst country to abandon the term schizophrenia, and modied the name of the illness from Seishin Bunretsu Byo (mind-split disease) into Togo Shitcho Sho (integration-dysregulation syndrome). The change of name had an instant response. Most psychiatrists started using it in the rst year, bringing about an improved communication of diagnosis to patients and better perception of the disorder.16 Thus, the term schizophrenia will continue to evolve; however, the underlying mechanisms and the eect on the person will not change.

Epidemiology
A systematic review of epidemiological data indicates that, if the diagnostic category of schizophrenia is considered in isolation, the lifetime prevalence and incidence are 030066% and 102220 per 100 000 person-years, respectively.17 Rates vary three-fold depending on the diagnostic denition of schizophrenia that is used: a narrow denition, including patients with illness duration of at least 6 months, age below 45 years, and negative symptoms has lower rates than a broad denition with less specic criteria.18 A recent landmark studyallowing for a broad denition of psychotic disorder, including diagnostic categories such as delusional disorder, brief psychotic disorder, and the catch-all diagnostic category of psychotic disorder not otherwise speciedrevealed a lifetime rate of schizophrenia and related categories of 23%,19 rising to 35% if other psychotic disorders, such as bipolar disorder and substance-induced psychotic disorder, were included. Diagnostic categories that are biased towards negative symptoms and long duration of illness (both associated with poor outcome) produce diagnostic categories with higher incidence rates for men than for women,20 whereas those including more aective symptoms and brief presentations (associated with better outcome) show similar rates in men and women.18,21 These data suggest that the symptomatic expression of schizophrenia and related diagnoses is more severe in men than in women. The nding of an earlier onset in men than in women supports this notion.17,18

dicult diagnostic issues. First, how many disorders ought to be carved out of the current cluster of categories (panel)? And how should a specic category of schizophrenia be dened among them? Second, does diagnosis of schizophrenia refer to a categorical illness (such as Huntingtons disease that one either has or has not) or is it a continuous or dimensional concept (such as the regularly reviewed boundaries of arterial blood pressure above which hypertension is diagnosed)? Finally, is the 19th-century expression referring to a state of so-called split mind a suitable term to diagnose patients in the 21st century? The current diagnoses (panel) are unlikely to represent discrete nosological entities.9 For example, schizophrenia-like psychopathological changes are also expressed, in an attenuated form, in individuals with schizotypal or schizoid personality traits. A systematic review of general-population surveys indicated that the experiences associated with schizophrenia and related categoriessuch as paranoid delusional thinking and auditory hallucinationsare observed in an attenuated form in 58% of healthy people.10 These attenuated expressions could be regarded as the behavioural marker of the underlying liability for schizophrenia and related disorders, just as high blood pressure indicates high susceptibility for cardiovascular disease in a doseresponse fashion. Because of evidence for shared genetic causes underlying diagnoses of psychotic disorders, including bipolar disorder, and evidence for continuity with mental activity in healthy individuals, a major probable change in DSM-V and ICD-11 is the addition of dimensional indicators that can be applied across diagnostic categories of aective and non-aective psychotic disorder (gure 2).
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Perinatal and early childhood factors

Prospective studies have shown that some factors in fetal lifeincluding hypoxia, maternal infection, maternal stress, and maternal malnutritionmight account for a small proportion of incidence of schizophrenia.2225 Birth
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cohort and high-risk studies have yielded consistent evidence that, as a group, children who as adults will be diagnosed with schizophrenia have, compared with their peers, a higher incidence of non-specic emotional and behavioural disturbances and psychopathological changes, intellectual and language alterations, and subtle motor delays.2628 Some of these developmental indicators could be relevant for dierential diagnosis within the cluster of diagnostic categories because motor and cognitive alterations seem to be specic for the diagnosis of schizophrenia (ie, have not been observed in bipolar disorder).2931

More acute onset, better outcome

More insidious onset, poorer outcome

Psychosis: delusions, hallucinations

Mania

Negative symptoms

Environmental factors
Systematic reviews of epidemiological studies have indicated that the rate of schizophrenia and related disorders is aected by some environmental factors.17,32 First, the risk of schizophrenia and related categories increases linearly with the extent to which the environment in which children grow up is urbanised (odds ratio [OR] ~2).33 Second, evidence exists that some immigrant ethnic groups have a higher risk of developing psychotic disorders than have native-born individuals,34 particularly if they live in a low ethnic density area, or an area where there are fewer people of the same migrant group (OR 25).35,36 Third, randomised experimental studies have shown that exposure to dronabinol, the main psychotropic component of cannabis, causes mild and transient psychotic states37,38 to which individuals with pre-existing liability to psychosis are more susceptible than are healthy controls.39,40 Systematic reviews of prospective studies have suggested that cannabis use is associated with increased risk for psychotic disorder and symptoms (OR 1520).41 Although establishment of causality on the basis of epidemiological data is dicult,42 the acute psychotic states induced by dronabinol provide an important model of psychotic symptoms, especially as national register follow-up studies have suggested that cannabis-induced acute psychotic states treated in psychiatric services are the early signs of schizophrenia and related disorders.43,44 The large eect sizes, in terms of relative risk (5) and high fraction (30%) of overall incidence attributable to environmental factors in urbanised areas, migrant and ethnic group, and cannabis, assuming causality, raise a number of important issues. First, the association with urbanisation and migration might indicate a common environmental inuence linked to chronic experience of social disadvantage and isolation,45 suggesting that public health policies targeting these factors might also aect rates of schizophrenia. Further work is needed focusing on the identication of specic environmental inuences and mechanisms underlying the proxy risk factors of migration and extent of urbanisation. Some studies are attempting this aim using virtual reality46 or momentary assessment designs.47
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Depression Cognitive impairment

Aective dysregulation

Developmental impairment

Figure 1: Principles underlying the main distinction between aective psychosis (eg, bipolar disorder and psychotic depression) and non-aective psychosis (eg, schizophrenia and schizophreniform disorder)

Schizophrenia Psychosis

Bipolar disorder

Psychosis

Mania

Negative symptoms

Mania

Negative symptoms

Depression

Cognitive impairment Psychosis

Depression

Cognitive impairment

Mania Schizoaective disorder

Negative symptoms

Depression

Cognitive impairment

Figure 2: Three hypothetical typical patients diagnosed with a combination of categorical and dimensional representations of psychopathology Categorical diagnoses of schizophrenia (blue), bipolar disorder (green), and schizoaective disorder (violet) are accompanied by a patients quantitative scores (connected by red lines) on ve main dimensions of psychopathology.

Second, since the incidence and expression of schizophrenia varies in dierent social contexts, a level of explanation focusing on the eect of the environment on cognitive schemata as well as on brain neurobiological mechanisms is necessary. For example, exposure to trauma during childhood could predispose to a paranoid way of thinking48,49 and, when this is paired with a sensitised dopamine system,50 it could predispose the individual to psychotic disorder.
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18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0% Good outcome 50% Poor outcome 100%

Figure 3: Outcome heterogeneity in schizophrenia Summary of 18 prospectively designed outcome studies of rst admission and rst diagnosis of schizophrenia with follow-up of more than 1 year with variably dened good and poor outcomes, showing balanced proportions of good and poor outcomes across studies. Studies 1 to 18 are references 7693. Examples of good outcomes: symptomatic recovery with no social or intellectual decit throughout follow-up (study 2, reference 77); full recovery over follow-up (study 12, reference 87); complete remission and never readmitted (study 16, reference 91). Examples of poor outcome denition: severe chronic social or intellectual decit (study 2, reference 77); moderate-to-severe symptoms at time of follow-up (study 12, reference 87); chronic continuous psychotic symptoms over full follow up time (study 16, reference 91). For full description of all outcome denitions see reference 94.

Third, although migration and cannabis use do not seem to be specic for a particular diagnostic category among the dierent psychotic disorders, urbanisation exposure is associated with the diagnostic category of schizophrenia and not with bipolar disorder,51 suggesting that some environmental exposures aect dierent causal pathways resulting in specic psychopathological outcomes. Finally, the fact that only a minority of those exposed to urban environments, migration, and cannabis develop schizophrenia indicates that some are resilient to these risk factors. The basis for this resilience could help devise public health strategies.

structural variations (copy number variants occasioned by small duplications or deletions, or inversions). These genomic variants are usually rare individually, but have now been observed at a higher rate in autism52 and schizophrenia compared with controls,5358 suggesting a possible shared neurodevelopmental pathway for these disorders.59 Similarly, new genome-wide association studies have yielded the rst genome-wide results replicated across multiple samples for bipolar disorder and schizophrenia on the one hand, and evidence suggestive for association across disorders on the other hand.60,61 The high heritability (80%) of schizophrenia is not only due to genetic inuences but also due to environmental eects that are moderated by genes (geneenvironment interaction). Epigenetic factors susceptible to environmental inuence might also aect twin heritability estimates.62 Meta-analytic work suggests that paternal age above 40 years is associated with schizophrenia, indicating that epigenetic mechanisms might have a role.63 Genetic epidemiological studies have proposed that geneenvironment interaction in schizophrenia and related diagnostic categories is common.64 Therefore, the worldwide challenge is to bring together the various disciplines that are needed to examine models of disease causation based on various aspects of geneenvironment interplay.65 Research in twins and rst-degree relatives of patients has shown that the genes predisposing to schizophrenia and related disorders aect some heritable traits6668 that underlie the illness: neurocognitive functioning, structural MRI brain volume measures, neurophysiological information processing traits and sensitivity to stress.6972 These so-called intermediary phenotypes (because they are between the predisposing genes and the disease phenotype) might be closer to alterations in gene function than the diagnostic category of schizophrenia and related disorders, and for this reason could be useful targets for molecular genetic studies. Some of these intermediary phenotypes could be diagnostically relevant; for example, the intermediary phenotype of cognitive impairment could have high specicity for the diagnostic category of schizophrenia. Indeed, meta-analytic work has indicated that relatives of patients with bipolar disorder have only minimal cognitive alterations.73

Gene and environment interplay

Vulnerability for schizophrenia is partly genetic. Twin studies suggest that the syndrome has heritability estimates of around 80% (compared with ~60% for osteoarthritis of the hip and 3050% for hypertension). Despite this genetic association, the identication of specic molecular genetic variation has not been easy. Modication of diagnostic criteria and uncertainty about the natural phenotype of psychosis are likely to have hampered progress in this regard. Recent ndings have suggested that a small proportion of schizophrenia incidence could be explained by rare
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Prognosis
The traditional clinical and societal view of schizophrenia is of a debilitating and deteriorating disorder with poor outcome. However, most patients now live independently outside the hospital and the typical duration of admission is short (a few weeks). Although most patients need some degree of formal or informal nancial and daily-living support, the perspective now is one of recovery, where the patient takes an active role in the development of new meaning and purpose while growing beyond the misfortune of mental illness.74,75
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Prospectively designed outcome studies of rst admission and rst diagnosis of schizophrenia with follow-up time of more than 1 year have suggested that heterogeneity is common with poor outcome in less than 50% of patients and, similarly, with good outcome in less than 50% of patients (gure 3). Therefore, the course and outcome of schizophrenia is characterised by mainly unexplained94 heterogeneity rather than uniform poor outcome.95 Understanding of these data and communication to patients and their families at the time of diagnosis are crucial steps, because patients and families often suer for the common assumption of a negative outcome.

Pathophysiology
Since the advent of modern neuroimaging techniques, the number of studies of the pathophysiological changes of schizophrenia has dramatically increased, with more than 1000 reports published in the past 10 years. Structural brain imaging studies have shown a subtle, almost universal, decrease in grey matter, enlargement of ventricles, and focal alteration of white matter tracts.9698 Neurochemical imaging studies to test the dopamine hypothesis of schizophrenia with 18F-dopa and 11 C-raclopride are consistent in showing that schizophrenia, in its acute psychotic state, is associated with an increase in dopamine synthesis, dopamine release, and resting-state synaptic dopamine concentrations.99,100 These neurochemical ndings provide a logical link to the fact that all current pharmacological treatments of schizophrenia block dopamine receptors.101 Abnormal brain structure and neurochemical composition lead to abnormal function that is shown by functional MRI (fMRI) and electrophysiological techniques. fMRI studies show abnormalities in the brain response to cognitive tasks, with an abnormal network response characterised by both hyperactivity and hypoactivity in dierent brain regions (compared with the response in healthy volunteers), depending on the specic tasks.102 Event-related potential studies have looked at the response of patients to novel stimuli (P300) and to repeated stimuli (P50), showing that patients have a diminished brain response to new stimuli and a decreased ability to suppress brain activation in response to repeated stimuli.70,103 In conclusion, diagnosis of schizophrenia is associated with altered brain function; however, these results raise the question of why a change in dopamine concentrations leads a person to become convinced that their colleagues are conspiring and the police are out to get them. Several recent theories attempt to ll the gap between biological alterations and actual experiences reported by patients.104,105 One such theory is based on the fact that neurons in the dopamine system re in response to novel rewards in the environment, and that the released dopamine leads to a switch in attention and behaviour
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towards the rewarding situation, thus imbuing the stimulus with motivational salience.106,107 Aberrant ring of the dopamine system might lead to the aberrant assignment of motivational salience to objects, people, and actions.105,108,109 The patient then makes an eort to interpret these aberrant experiences and constructs a seemingly plausible (to them) account to understand the changing situation. Thus, a mixture of dopamine dysregulation and aberrant assignment of salience to stimuli, together with a cognitive scheme that attempts to grapple with these experiences to give them meaning, might lead to the development of psychotic symptoms.110 Alterations in aective state (depression or mania) and some ways of thinking, such as a tendency to jump to conclusions, might combine with the dopamine dysfunction to increase the risk of delusion formation.111

Clinical management
Diagnosis of schizophrenia is made by reference to the criteria in DSM-IV and ICD-10. Even though these are clinical criteria, diagnosis can be achieved with acceptably high inter-rater reliability and compares well with diagnostic reliability in the rest of medicine. Unfortunately, no objective test exists for this diagnosis. Although several biological abnormalities have been reproduced (eg, abnormally large ventricles, abnormal dopamine concentration, and altered P300), they are not sensitive enough (usually seen only in 4050% of patients) or not specic enough (seen in 30% of rst degree relatives and 10% of otherwise normal controls) to be of diagnostic usefulness.112 Thus, diagnosis is based on conrmation of the key symptoms and elimination of the most probable dierentials (drug abuse, contributory neurological conditions, or metabolic illness). Once the diagnosis is made, antipsychotic drugs, which block dopamine D2 receptors,113 are the main treatment of schizophrenia. First-generation agentsdiscovered in the 1950s, also called rst-generation antipsychotics (eg, haloperidol and chlorpromazine)are eective in the treatment of psychotic symptoms, but often lead to motor side-eects. In the past 10 years, new agents, known as the secondgeneration antipsychoticsrisperidone, olanzapine, quetiapine, ziprasidone, and aripiprazolethat less frequently cause motor side-eects have been introduced for treatment. Initially, there was optimism that they would improve not only the positive psychotic symptoms but also the negative and cognitive aspects of the syndrome. Although the new second-generation antipsychotic drugs are eective in treating positive symptoms with a reduced burden of motor side-eects, the promise of ecacy against negative and cognitive symptoms has not been borne out.114,115 Additionally, the new antipsychotics tend to induce a high incidence of metabolic side-eects (weight gain, increased triglycerides and cholesterol).
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Future of treatmentn

Delusions Hallucinations

Current focus of treatmentn

Aberrant neurodevelopment and cognitive decits

Aberrant salience Aective dysregulation

De

vel op me nta l ge net ic r isk

Dopamine dysregulation

sk c ri eti n e g ive ect A

Urbanisationn

GEn

Migration

Fetal risksn

Cannabisn

Figure 4: A model of schizophrenia and related psychotic disorders The model brings together aective and non-aective dimensions of psychopathological changes and their overlapping genetic liabilities. Aberrant neurodevelopment contributes to biological alterations, whereas aective dysregulation contributes to cognitive explanations of aberrant salience. GxE=geneenvironment interaction.

A recent study of rst-episode patients reported that more than 50% of the patients gained signicant (ie, >7%) weight, with an average weight gain of 47 kg, leading one in ten patients to develop a treatment-emergent metabolic syndrome.116 Thus, the choice between antipsychotic drugs requires an analysis of the potential benets, risks, and costs.114 However, medications alone are not the solution. Antipsychotic drugs are best administered in the context of other psychological and social supports, as indicated by case-management models of treatment delivery.117,118 Community-case management (ie, a multidisciplinary team of mental health professionals, who engage with the patient and their carers inside and outside the hospital, and ensure a combination of health and social care119,120) is available in some countries (eg, the UK) but often remains the exception for most patients worldwide. The low availability of these services is lamentable, because teams and personnel can be easily trained, the model can be adapted to dierent settings, and, when properly implemented, it reduces hospital stay and hospital cost, increases patient retention in treatment, and improves satisfaction of patients and carers.121 With a combination of new medications and community-case management, remission of about 80% of patients can be achieved, especially if treatment is initiated early during the rst episode of the illness.122 The main challenges are to make sure that patients continue to take medication when required and to improve functional outcomes. Many patients with a
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diagnosis of schizophrenia stop their medication, increasing the risk of relapse.122 The reasons for patients discontinuing antipsychotic treatment are not dissimilar from those in other chronic illnesses, although two issues may be specic to schizophrenia: the stigma123,124 of being labelled as psychotic and the fact that dopamine-blocking medications dampen motivational drives.125,126 Although some experimental approaches to improve treatment adherence have been attempted (special pill bottles, reminders, economic incentives, and individual, family, and group therapy) and show some ecacy in experimental situations,127 none is widely available or used. Even in patients with good control of positive symptoms, return to function could remain a challenge. Few patients currently resume employment, the major challenges being lack of eective interventions such as supported employment,128 as well as neurocognitive alterations and impaired motivational drive. Although some pharmacological approaches to improve negative symptoms have been tried (eg, antidepressants and glutamate modication), none have been successful.129 Thus, the emphasis has been on vocational and occupational rehabilitation techniques to restore function. These interventions show good ecacy in increasing the chances of functional improvement in small experimental studies,130,131 but, although some specialised centres oer these interventions, they are neither standardised nor available in routine care. Despite some advancesnew medications, and better psychological and vocational interventionsa substantial proportion of people with schizophrenia, about a third, remain symptomatic. With these patients, doctors often attempt dierent antipsychotic drugs or increase therapy with anxiolytic, antidepressant, and anticonvulsant medications, or experimental agents. A number of systematic reviews show that these additions are of low proven value and might result in unnecessary polypharmacy.132 One intervention that most reliably improves symptoms is the use of clozapine, a unique antipsychotic drug that often works in patients in whom other antipsychotics have failed. It is used only in those who are refractory to other treatments and only given in combination with weekly blood monitoring because of the risk (14%) of agranulocytosis.114 For patients with drug-resistant symptoms, cognitive-behavioural therapy can improve coping and reduce distress and negative aect associated with psychotic symptoms;133 however, such specialised psychological therapies are not routinely available. Comorbid substance misuse is common: more than half of patients with schizophrenia smoke (34 times the local population average) and a signicantly higher number (than the local population) abuse cannabis and alcohol. Comorbid substance abuse is often undetected; even when noted, few therapeutic options exist, with scarce
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evidence of benet for pharmacological134 or psychosocial interventions.135

Prevention
Because psychotic disorders occur in young people and disrupt educational and social development, early intervention is crucial and could favourably aect long-term prognosis. A few studies have assessed the use of specialised early interventions for rst-episode psychotic disorder patients with encouraging results in the rst year;136 follow-up, however, suggests that the benets of early intervention might be lost after 5 years.137 Whether early intervention can be extended to at-risk mental states before the onset of full-blown psychotic illness is not clear.138 Evidence exists from two birth cohorts,139,140 three representative general population cohorts,141143 and other longitudinal studies144 that mild psychotic experiences, such as delusional thinking and mild hallucinations, might precede the diagnosis of a psychotic disorder and hospital admission for schizophrenia by many years. Unfortunately, positive predictive values of such precursors are too low to be useful for ethical and cost-eective preventive interventions.145 Nevertheless, dedicated early intervention clinics might be able to select groups of help-seeking individuals at high risk of making a transition to a clinical psychotic disorder.146 Several small trials have suggested that cognitive-behavioural therapy or pharmacological interventions could reduce rate of transition from an at-risk mental state to full-blown psychotic disorder. More denitive conclusions about ecacy, and whether and how these programmes should be available for help-seeking individuals with an at-risk mental state, require more evidence.136

these symptoms have received not much clinical attention, they are important contributors to the patients inability to regain function and vocation,150 possibly by aecting an area of cognition called social cognition, or the ability to understand and interact with the social world around. Consequently, development of new medications and cognitive remediation approaches131 as add-ons to ongoing antipsychotic treatment is becoming increasingly topical. Several mechanisms are being exploited for new medication development (nicotinic drugs, glutamate system potentiation, treatments that increase dopamine D1 receptor stimulation, and drugs normalising GABA interneuron function151), new scales to measure and document cognitive impairments are being standardised,152 and hope exists that use of these medications, with or without cognitive remediation, might provide the next major advance in the treatment of patients with schizophrenia.

Conclusions
In the 100 years that we have known the diagnosis of schizophrenia, its denition has swung between a biological illness, a psychological dysfunction, and a social construct. The advances of genetics, epidemiology, imaging, and pharmacology now allow us to put these perspectives together (gure 4). A clear genetic susceptibility exists in schizophrenia; however, what one inherits is not the illness, but altered brain development, shared partly with developmental disorders, such as autism, and partly with aective disorders such as bipolar disorder. The behavioural expression of this vulnerability usually remains restricted to subtle alterations in cognition, some suspiciousness, or aective dysregulation, which generally leads only to subtle functional eect. In a minority of those who inherit these vulnerabilities, perhaps when genetic vulnerability is combined with environmental insults, a state of abnormal dopamine release might result, which gives rise to an aberrant assignment of salience, which in turn causes psychotic symptoms, bringing the patients to medical attention. The main treatments for psychosis are antipsychotic drugs, which do not address the vulnerability or the environmental insult but merely block the eects of an abnormal dopamine system. As long as the patient takes the antipsychotic medication, symptoms usually are dampened. However, if the medication is discontinued, the primary vulnerability might re-express itself, leading to relapse. During the past 50 years, advances have helped to deal with the symptomatic expression of the syndrome. In the next few decades, treatments that address the underlying neurobiological vulnerability and protect against environmental risks might be developed. Until then, we hope that society will treat those who suer with psychosis with respect, hope, and dignityrather than stigma, pessimism, and exclusion.
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Cognition
Almost 100 years ago when schizophrenia was rst dened in its current form, it was called dementia praecox, the focus being on the intellectual deterioration that accompanied the syndrome. In the following years, the focus shifted to the psychosis, the delusions, and the hallucinations as the cardinal features of the illness, perhaps because they are easy to identify and greatly aect functioning and society. However, during the past 10 years, there has been a resurgence of interest in the cognitive alterations of schizophrenia and it is now accepted that patients with a diagnosis of schizophrenia have a broad-based cognitive impairment of, on average, about 1 SD below the norm across a range of cognitive abilities (attention, speed of processing, working and long-term memory, executive function, and social cognition).147 These alterations are well established by the time of the rst episode, show scarce relation to psychotic symptoms,7 are not much inuenced by the currently available medications, and often show no improvement despite complete resolution of psychotic symptoms.148,149 Although
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Contributors JvO conceived the idea. Both JvO and SK were involved in the development of the structure of the review, literature search, summary of the results, writing of the article and constructing the graphics; and in responding to the referees suggestions. Conicts of interest JvO is or has been an unrestricted research grant holder with, or has received nancial compensation as an independent symposium speaker from, Eli Lilly, BMS, Lundbeck, Organon, Janssen-Cilag, GlaxoSmithKline, AstraZeneca, Pzer, and Servier. SK has been a research grant holder or has received nancial compensation as an independent symposium speaker from AstraZeneca, Bristol Meyers Squibb, Eli Lilly, Janssen (Johnson and Johnson), Lundbeck, Otsuka, Organon, Pzer , Sano-Synthelabo, Servier, Solvay Wyeth, and Theragenetics, which have an interest in the treatment of psychosis. Acknowledgments We thank Judith Allardyce for sharing data on course and outcome studies in schizophrenia. References 1 Mueser KT, McGurk SR. Schizophrenia. Lancet 2004; 363: 206372. 2 Saha S, Chant D, McGrath J. A systematic review of mortality in schizophrenia: is the dierential mortality gap worsening over time? Arch Gen Psychiatry 2007; 64: 112331. 3 Kendler KS, McGuire M, Gruenberg AM, Spellman M, OHare A, Walsh D. The Roscommon Family Study. II. The risk of nonschizophrenic nonaective psychoses in relatives. Arch Gen Psychiatry 1993; 50: 64552. 4 Lichtenstein P, Yip BH, Bjork C, et al. Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study. Lancet 2009; 373: 23439. 5 Cardno AG, Rijsdijk FV, Sham PC, Murray RM, McGun P. A twin study of genetic relationships between psychotic symptoms. Am J Psychiatry 2002; 159: 53945. 6 Craddock N, Owen MJ. Rethinking psychosis: the disadvantages of a dichotomous classication now outweigh the advantages. World Psychiatry 2007; 6: 8491. 7 Dominguez M, Viechtbauer W, Simons CJ, van Os J, Krabbendam L. Are psychotic psychopathology and neurocognition orthogonal? A systematic review of their associations. Psychol Bull 2009; 135: 15771. 8 Eaton WW, Thara R, Federman B, Melton B, Liang KY. Structure and course of positive and negative symptoms in schizophrenia. Arch Gen Psychiatry 1995; 52: 12734. 9 Linscott RJ, Allardyce J, van Os J. Seeking verisimilitude in a class: a systematic review of evidence that the criterial clinical symptoms of schizophrenia are taxonic. Schizophr Bull 2009; published online Jan 27. DOI:10.1093/schbul/sbn181. 10 Van Os J, Linscott RJ, Myin-Germeys I, Delespaul P, Krabbendam L. A systematic review and meta-analysis of the psychosis continuum: evidence for a psychosis proneness-persistence-impairment model of psychotic disorder. Psychol Med 2009; 39: 17995. 11 Allardyce J, Suppes T, van Os J. Dimensions and the psychosis phenotype. In: Helzer J, Kraemer H, Krueger R, Wittchen HU, Sirovatka P, Regeir D, eds. Dimensional approaches in diagnostic classication. Washington, DC: APA, 2008: 5364. 12 Bentall R. Madness explained: why we must reject the Kraepelinian paradigm and replace it with a complaint-orientated approach to understanding mental illness. Med Hypotheses 2006; 66: 22033. 13 van Os J. A salience dysregulation syndrome. Br J Psychiatry 2009; 194: 10103. 14 Brockington I. Schizophrenia: yesterdays concept. Eur Psychiatry 1992; 7: 20307. 15 Kingdon D, Gibson A, Kinoshita Y, Turkington D, Rathod S, Morrison A. Acceptable terminology and subgroups in schizophrenia: an exploratory study. Soc Psychiatry Psychiatr Epidemiol 2008; 43: 23943. 16 Sato M. Renaming schizophrenia: a Japanese perspective. World Psychiatry 2006; 5: 5355. 17 McGrath J, Saha S, Chant D, Welham J. Schizophrenia: a concise overview of incidence, prevalence, and mortality. Epidemiol Rev 2008; 30: 6776.

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