Nursing Mental Health , Topic : Schizophrenia

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Schizophrenia Michael J Owen, Akira Sawa, Preben B Mortensen

Schizophrenia is a complex, heterogeneous behavioural and cognitive syndrome that seems to originate from disruption of brain development caused by genetic or environmental factors, or both. Dysfunction of dopaminergic neurotransmission contributes to the genesis of psychotic symptoms, but evidence also points to a widespread and variable involvement of other brain areas and circuits. Disturbances of synaptic function might underlie abnormalities of neuronal connectivity that possibly involves interneurons, but the precise nature, location, and timing of these events are uncertain. At present, treatment mainly consists of antipsychotic drugs combined with psychological therapies, social support, and rehabilitation, but a pressing need for more eff ective treatments and delivery of services exists. Advances in genomics, epidemiology, and neuroscience have led to great progress in understanding the disorder, and the opportunities for further scientifi c breakthrough are numerous—but so are the challenges.

Introduction Schizophrenia is a severe psychiatric disorder that has a profound eff ect on both the individuals aff ected and society. Although outcomes might not be as uniformly negative as is commonly believed, more than 50% of individuals who receive a diagnosis have intermittent but long-term psychiatric problems, and around 20% have chronic symptoms and disability.1 Unemployment is staggeringly high at 80–90%,2,3 and life expectancy is reduced by 10–20 years.4 In England, schizophrenia costs £11·8 billion per year, with around a third of this fi gure accounted for by direct expenditure on health and social care, provided both in hospitals and in the community.5 Two of the most formidable challenges are to understand the causes and pathogenesis of the disorder, and to develop new, eff ective, and acceptable treatments. However, the past decade has seen substantial advances in the application of genomics, epidemiology, and neuroscience to schizophrenia research, and the opportunities for progress have never been greater.

Clinical presentation, signs, and symptoms Schizophrenia is characterised by diverse psychopathology (table); the core features are positive symptoms (delusions and hallucinations; so-called psychotic symptoms in which contact with reality is lost), negative symptoms (particularly impaired motivation, reduction in spontaneous speech, and social withdrawal), and cognitive impairment (patients had poorer performance than controls over a wide range of cognitive functions, although much individual variability was reported).6 The positive symptoms tend to relapse and remit, although some patients have residual long-term psychotic symptoms.

The negative and cognitive symptoms tend to be chronic and are associated with long-term eff ects on social function. The fi rst episode of psychosis usually occurs in late adolescence or early adulthood, but it is frequently preceded by a prodromal phase or a so-called at-risk mental state.7,8 In some instances, premorbid impairments in cognition or social functioning, or both, can manifest many years before the fi rst psychotic episode.9 However, in other instances, onset is sudden in previously well functioning individuals.

Diagnosis and diff erential diagnosis Diagnosis is made clinically on the basis of history and by examination of the mental state; no diagnostic tests or biomarkers are available. Schizophrenia usually presents with psychosis; according to the fi fth edition of Diagnostic and Statistical Manual of Mental Disorders (DSM-5),10 the main diff erential diagnoses are aff ective psychoses (bipolar disorder with psychotic features and major depressive disorder with psychotic features), other closely related non-aff ective psychoses (schizoaff ective disorder, schizophreniform disorder, delusional disorder, brief psychotic disorder, and psychotic disorder not otherwise specifi ed), psychotic disorders induced by alcohol or other substances, and psychotic disorders caused by a general medical illness. Diff erential diagnosis takes into account the duration of illness, the nature and pattern of associated substance abuse, the co-occurrence of depression or mania, and the presence of somatic illness.

Schizophrenia, like most psychiatric diagnoses, remains a syndromic concept. The use of operational criteria, such as those embodied in DSM-510 or the WHO International Classifi cation of Diseases (ICD),11 has provided a reliable approach to psychiatric diagnoses in the clinic. However, the assumption that the clinical syndromes defi ned in this way represent valid disease entities with distinct underlying causes and pathogenesis is increasingly being seen as having impeded research.12–14 Indeed, psychiatric diagnoses have the unusual feature of being simultaneously too broad and too narrow.14 On the one hand, individuals with a diagnosis of schizophrenia vary greatly in predominant symptoms, response to treatment, course, and outcome. However, attempts to

Lancet 2016; 388: 86–97

Published Online January 14, 2016

http://dx.doi.org/10.1016/ S0140-6736(15)01121-6

MRC Centre for Neuropsychiatric Genetics and

Genomics, Cardiff University, Cardiff, UK (Prof M J Owen PhD);

Department of Psychiatry, Johns Hopkins University

School of Medicine, Baltimore, MD, USA (Prof A Sawa MD); and

Department of Economics, School of Business and Social

Science, Aarhus University, Aarhus, Denmark

(Prof P B Mortensen DrMedSc)

Correspondence to: Prof Michael J Owen, MRC Centre

for Neuropsychiatric Genetics and Genomics, Cardiff University,

Cardiff CF24 4HQ, UK [email protected]

Search strategy and selection criteria

We searched publications in PubMed using the search term “schizophrenia” for reviews and meta-analyses published in English between March 1, 2010, and March 1, 2015. The manuscripts were assessed for relevance to the topics selected. Further focused searches on PubMed were then done on the selected topics.

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resolve this heterogeneity into valid subtypes have repeatedly failed. On the other hand, many psychiatric diagnoses have symptoms in common (table), and the boundaries between schizophrenia and other disorders are indistinct, as are the boundaries between disorder and wellness. An increasing realisation is that psychotic symptoms, such as auditory hallucinations and paranoid thinking, occur in attenuated form in 5–8% of the healthy population,15 leading to suggestions that dimensional approaches to diagnosis and classifi cation might replace or enhance existing categorical methods.14,16,17

Genetics Many genetic epidemiological studies have shown, for more than 50 years, that genetic factors contribute substantially, but not exclusively, to the underlying cause of schizophrenia.18,19 What has changed in the past 8 years is that, with large-scale genomic studies, the contribution of specifi c DNA variants and diff erent types of risk alleles to the disorder has begun to emerge. Three lessons of general importance can be drawn from these fi ndings.

First, schizophrenia is highly polygenic, as predicted in the 1960s on the basis of genetic epidemiological fi ndings.20 Genome-wide association studies have identifi ed more than 100 distinct genetic loci containing fairly common alleles of small eff ect and the en-masse eff ects of many hundreds of such loci,21,22 suggesting that single-nucleotide polymorphisms (SNPs) with a range of population frequencies contribute to risk (appendix). Genomic studies have also identifi ed 11 rare, but recurrent, copy number variants (CNVs; large regions of the genome that have been deleted or duplicated) that individually confer a relatively high risk of schizophrenia (appendix),23,24 and also a role for newly occurring (ie, de-novo) CNVs in the disorder.23,25,26 Whole-exome sequencing studies have implicated rare, inherited, and de-novo SNPs, and insertion and deletion variants (indels) in schizophrenia,27,28 although the net contribution of mutations of this type is unknown, and much larger sequencing studies, with tens of thousands of cases and controls, are pending. In view of the fact that

schizophrenia is associated with reduced fecundity,29 the emerging picture is that alleles conferring high individual risk are rare in the population because of the eff ects of natural selection,30 whereas those with small eff ects on individual risk can become common as a result of genetic drift or balancing selection (appendix).

Second, genetic risk seems to be highly pleiotropic (ie, one gene or allele can aff ect multiple seemingly unrelated phenotypic traits) and does not map onto existing defi nitions of disease. Pleiotropy has been reported for common variants at the level of individual risk alleles and en-masse eff ects. A study showed signifi cant sharing of common risk variants between schizophrenia and bipolar disorder, between bipolar disorder and major depressive disorder, between schizophrenia and major depressive disorder, between attention defi cit hyperactivity disorder (ADHD) and major depressive disorder, and, to a lesser extent, between schizophrenia and autism spectrum disorder.31 An overlap in risk variants between schizophrenia and ADHD has also been reported.32 Pleiotropy is also seen in rare variants: CNVs that confer risk to schizophrenia also aff ect generalised epilepsy and a range of childhood neurodevelopmental disorders, such as autism spectrum disorder, intellectual disability, and ADHD.23,33,34 Additionally, some rare SNPs and indels are associated with a similar range of outcomes.27 Risk alleles that are relatively non-specifi c to the diagnostic group will be easier to detect than those that confer risk to particular diagnoses or subgroups; indeed, alleles with fairly specifi c risk profi les are beginning to be identifi ed.12,35,36 However, the pleiotropic eff ects reported so far, along with the absence of clear boundaries between disorders in clinical studies, suggest that overlapping mechanisms are likely to be at work and that existing diagnostic categories might not be best for stratifi cation of cases for research into disease cause and pathogenesis.

Third, despite the fact that much of the genetic risk for schizophrenia remains unaccounted for at the DNA level and the complexity of the picture that has already emerged, there are encouraging signs of convergence

See Online for appendix

Schizophrenia Bipolar disorder Schizoaff ective disorder Autism ADHD

Core features Delusions, hallucinations, impaired motivation, reduction in spontaneous speech, and social withdrawal

Episodes of elated mood and episodes of depressive mood

Delusions, hallucinations, and mood episodes (depressive, manic, or mixed)

Social and communication diffi culties, and restricted repetitive behaviours

Inattention, hyperactivity, and impulsivity

Additional features Cognitive impairment, episodes of elated mood, and episodes of depressive mood

Delusions and hallucinations Cognitive impairment Cognitive impairment, delusions, and hallucinations

Cognitive impairment

Heritability estimate Roughly 80% Roughly 85% Roughly 85% Roughly 58% Roughly 75%

Average age of onset 16–30 years 18–40 years 25–35 years <3 years 7–12 years

Drug treatment Antipsychotics Antidepressants and mood stabilisers

Antipsychotics, antidepressants, and mood stabilisers

No recommended drug treatment; treatment for comorbidities if present

Stimulants

ADHD=attention defi cit hyperactivity disorder.

Table: Clinical features of schizophrenia, bipolar disorder, schizoaff ective disorder, autism, and ADHD

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onto a set of plausible biological processes. Rare mutations, CNVs, SNPs, and indels have been reported in genes encoding a range of synaptic proteins, including components of the post-synaptic density (PSD) protein and members of the voltage-dependent calcium channel family of proteins (fi gure 1).37 A large-scale genome-wide association study22 has also implicated common variation at genes encoding glutamate receptors, the voltage- dependent calcium channel family of proteins, and dopamine receptor D2 (DRD2), which is the principal target of antipsychotic drugs. The relation between glutamatergic dysfunction and abnormalities of dopamine signalling might provide a clue as to how psychosis and cognitive defi cits arise in schizophrenia and related disorders. These are very unlikely to be the only mechanisms involved, and more possible processes are expected to emerge as we move into the next phase of genomic studies. Of note, the most signifi cant association from genome-wide association studies of schizophrenia

is with multiple highly correlated variants in major histocompatibility complex (MHC). This locus contains many genes that are not involved in immune function, but preliminary data suggest that variants associated with schizophrenia are also enriched in genomic regions outside MHC that are potentially involved in acquired immunity.22 These fi ndings are in accord with epidemiological and clinical studies implicating immune and infl ammatory processes occurring at various developmental stages in psychiatric disorders.38,39

Most genetic discoveries in schizophrenia do not yet have direct clinical application. CNV testing with chromosomal microarray analysis is now a routine fi rst- line diagnostic test for autism and intellectual disability, disorders in which 10–20% of aff ected cases have a clinically relevant deletion or duplication. Since the prevalence of clinically relevant CNVs in schizophrenia is around 5%, the use of chromosomal microarray analysis has been suggested as a diagnostic test.40 A positive test would have implications for genetic counselling and medical management because many CNVs are associated with specifi c patterns of physical morbidities. A genetic diagnosis might also have psychological benefi ts for patients and their families by reducing internalised stigma and self-blame.40

Epidemiology and environmental risk factors Schizophrenia occurs worldwide, and for decades it was generally thought to have a uniform lifetime morbid risk of 1% across time, geography, and sex. The implication is either that environmental factors are not important in conferring risk or that the relevant exposures are ubiquitous across all populations studied. This view of uniform risk was effi ciently dismantled only in 2008 in a series of meta-analyses by McGrath and colleagues.41 They provided central estimates of an incidence per 100 000 population per year of roughly 15 in men and 10 in women, a point prevalence of 4·6 per 1000, and a lifetime morbid risk of around 0·7%. These estimates were based on fairly conservative diagnostic criteria; when broad criteria—including other psychotic disorders such as delusional disorder, brief psychotic disorder, and psychosis not otherwise specifi ed—were applied, the rates were higher by 2–3 times.42 However, more importantly, McGrath and colleagues documented a large variation (more than fi ve times) across studies that could not be ascribed to diagnostic or other methodological diff erences, but that pointed to real diff erences in occurrence and exposure to risk factors. These fi ndings have revitalised the epidemiology of schizophrenia, and the resulting new wave of studies, together with advances in genetics, have begun to cast light on how the disorder might arise.

For more than three decades, the dominant paradigm for understanding the environmental contributions to schizophrenia has been the neurodevelopmental hypothesis.43 This hypothesis has directed attention

Figure 1: A representative molecular pathway for schizophrenia—fi ne-tuning of the glutamate synapse Advances in human genetics, from both genome-wide association studies and large-scale sequencing, have lent further support to the importance of fi ne-tuning of glutamatergic neurotransmission in the pathology of schizophrenia. The genes implicated in these studies include GRIN2A (which encodes a subunit of the NMDA receptor), GRIA1 (which encodes a subunit of the AMPA receptor), SRR, CACNA1C, genes encoding the ARC complex, and several genes encoding proteins located in, or associated with, the post-synaptic density of glutamatergic synapses. The NMDA-type glutamate receptors are fi ne-tuned by the co-agonist D-serine, which is synthesised by SRR. VDCCs (eg, the protein encoded by CACNA1C) are also likely to be involved in tuning neural excitability and synaptic transmission via intracellular calcium signalling. In response to activation of glutamate receptors, proteins associated with the post-synaptic scaff old—eg, PSD95, stargazin (also known as CACNG2), several kinases, the RHO, CDC42, and RAC family of small G proteins, and the ARC complex—convey intracellular signalling that underlies cytoskeletal regulation and receptor traffi cking, which are crucial for synaptic plasticity. The dashed oval represents converged intracellular protein networks that underlie synaptic plasticity. AMPA=α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid. NMDA=N-methyl-D-aspartate. PSD=post-synaptic density protein. SRR=serine racemase. VDCC=voltage-dependent calcium channel.

Astrocyte

D-serine

Exocytosis

Presynaptic terminal

Glutamate

Endocytosis

GRIN2A

Newly synthesised

Receptor trafficking and recycling

Kinases

Ca2+ ions RHO, CDC42,

RAC families

ARC complex

Actin

GRIA1

SRR

NMDA receptor

PSD95

AMPA receptor

PSD95 Stargazin VDCC

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towards established risk factors for schizophrenia that aff ect early neurodevelopment during pregnancy, including maternal stress,44 maternal infections,45,46 nutritional defi ciencies,45,47 intrauterine growth re- tardation, and pregnancy and birth complications.48,49 However, socioeconomic factors,50–52 childhood adversity,53 and immigration (both fi rst and second generation)54,55 have also been associated with schizophrenia. Additionally, high rates of schizophrenia have been consistently reported in individuals born in late winter or early spring,56 in individuals born or raised in cities,57 and in individuals with relatively old fathers (aged 40 years or older) or young parents (below age 20 years).58,59 The association with advanced paternal age has been ascribed to the increased rate of de-novo mutations in their off spring,60,61 but alternative or complementary explanations have been proposed—eg, higher paternal age suggests selection of individuals with reduced fertility, including being less likely to fi nd a partner.62 Accumulating evidence has implicated cannabis use in adolescence, particularly misuse of compounds with high tetrahydrocannabinol content.63,64 Moreover, factors such as head injury,65 epilepsy,66 autoimmune diseases,67,68 and severe infections69–71 have been associated with an increased risk.

Several environmental exposures associated with schizophrenia, especially those directly aff ecting early brain development, are also associated with a range of other neurodevelopmental outcomes, such as intellectual disability, autism, ADHD, and epilepsy.34,72 This fi nding is similar to the range of outcomes associated with large, rare CNVs23,33,34 and suggests that schizophrenia might be best conceived as one of a spectrum of clinical outcomes that result from disruption to the developing brain induced by genetic or environmental factors, or both. Therefore, future epidemiological studies need to look carefully at the range of outcomes associated with particular exposures and should not be constrained by existing diagnostic approaches.

Many of the associations with environmental risk factors seem to be robust, and the odds ratios typically range from 1·5 to 3·0. However, observational epidemiology is unable to distinguish true causation from association because of confounding, pleiotropy, or reverse causation. Thus, at present, caution is required when interpreting these associations, and more work is needed before preventive intervention is justifi ed. Animal models can be used to obtain evidence to support a causative role for environmental risk factors, and a rapidly growing literature of such studies is now corroborating epidemiological fi ndings. These include studies of infections, prenatal maternal infl ammation, stressors from postnatal stages onwards, and the eff ect of these stressors on behavioural and neurobiological variables that model aspects of schizophrenia.73,74 In some of these studies, prenatal factors and prepubertal stressors have been found to interact,75 which suggests that the eff ect of

environmental exposures is modifi ed by earlier events and that longitudinal epidemiological studies will need to integrate prenatal and postnatal factors.

Another limitation of observational epidemiological studies is the inability to control effi ciently for confounding as a result of diff erences in genetic liability—ie, are diff erences associated with, say, infections, because of a high rate of infections among those who are genetically predisposed to schizophrenia? Until now, epidemiology has, at best, been able to control for this only by taking psychiatric family history into account; since only a minority of patients have family members with the disease, this measure of liability is highly imprecise. This situation is now changing with advances in the identifi cation of common genetic variants associated with schizophrenia risk. Although of no use as an individual predictor of disease risk, a polygenic risk score summarising associations with around 20 000 variants has been shown to reliably predict risk diff erences of 5–10 times.22 This method is expected to develop and improve rapidly in the next few years, providing researchers with an effi cient approach to separate nature from nurture and to study how genetic and environmental factors interact.76 Such interactions are plausibly of substantial importance in schizophrenia, as in other complex disorders. The concept of gene– environment interactions, in its broadest sense, means that the eff ect of an environmental factor depends on one or more genetic variants, and vice versa. Although such interactions are conceptually simple, their study presents several challenges, and diff erent approaches have been used.76,77 Some studies have focused on one candidate gene interacting with a specifi c environmental exposure. Since these studies have a specifi c prior hypothesis, they can be done with a fairly modest sample size. However, because the choice of candidate genes has to be based on the understanding of the genetic architecture of schizophrenia and the probable mechanisms involved in the interactions between these genes and the environment, this approach, albeit relevant in its own right, cannot discover the majority of relevant gene– environment interactions. However, the search for interactions across the genome in a hypothesis-free manner requires unrealistically large sample sizes. Therefore, several new techniques have been developed for so-called gene–environment wide interaction studies, and these methods have begun to be applied in schizophrenia research.78,79

Another application of genetic data to enhance the causal interpretation of environmental factors is the mendelian randomisation design, in which genes associated with the level of exposure are used as instrumental variables,80 and this method can be used to assess the extent to which risk factors are mediated through measures of genetic liability.81 For example, Agerbo and colleagues82 showed that a large proportion of the association between a family history of psychosis

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and schizophrenia risk was mediated through a polygenic risk score, whereas this was not the case for socioeconomic risk factors.

In summary, a large body of published work suggests that several risk factors, particularly those aff ecting early neurodevelopment, contribute to schizophrenia. Environmental factors, both biological and psychosocial, might have an eff ect at later timepoints (fi gure 2). The eff ects on the developing brain of early environmental exposures and genetic factors might also increase susceptibility to these risk factors. However, caution is needed before inferring causality, and future studies need to combine both prenatal and postnatal factors with measures of genetic liability. The integration of genomics with large-scale epidemiological approaches off ers new and exciting ways to understand the causal role of the environment, hopefully leading to primary prevention.

Pathophysiology Many brain imaging and neuropathological studies have attempted to relate the manifestations of schizophrenia to altered structure or function of particular brain regions and circuits.84,85 Some aspects of the disorder have been associated with specifi c underlying neurobiology, and several lines of evidence implicate the involvement of the prefrontal cortex in specifi c cognitive defi cits (eg, working

memory and executive control).86–88 However, subtle reductions in grey matter and abnormalities of white matter have been reported in many brain regions and circuits of patients.89 The reduction of grey matter, especially in the temporal lobe, progresses with the duration of illness90 and seems to be associated with antipsychotic treatment.91 However, even patients who did not receive any antipsychotics show volume reductions (albeit not as pronounced as treated patients), especially in the caudate nucleus and thalamus.89 Moreover, despite many hundreds of studies, no circumscribed anatomical or functional abnormalities that are specifi c to the disorder have been identifi ed,85 probably because of the complexity and heterogeneity of the psychopathology and associated cognitive impairments, and the absence of clear boundaries separating schizophrenia from other disorders or wellness.

A coherent body of evidence from pharmacological and brain-imaging studies implicates dysfunction of dopaminergic neurotransmission in the genesis of psychotic symptoms such as delusions and hallucinations.92 However, although these symptoms are reported in almost all cases of schizophrenia, they are also present in many other psychiatric disorders.92 Moreover, pharmacological and other studies show that dopaminergic dysfunction is unlikely to explain the full range of clinical features of the disorder. Evidence from clinical pharmacology, brain imaging, and clinical physiology suggests that disturbed glutamatergic function might contribute to the biological processes underlying some clinical features, particularly cognitive dysfunction, in schizophrenia.86,93,94 One theory is that glutamatergic dysfunction in schizophrenia is related to dysfunction of parvalbumin-positive interneurons in the cerebral cortex and hippocampus, which are sensitive to alterations in N-methyl-D-aspartate (NMDA)-type glutamate receptors.87 These fast-spiking neurons synchronise the fi ring of pyramidal neurons and underlie the generation of gamma oscillations, which is critical to proper cognitive function.95 As a result, dysfunction of this population of neurons might lead to the cognitive defi cits in schizophrenia (fi gure 3).95

Advances in human genetics, from both genome-wide association studies and large-scale sequencing, have further lent support to the importance of fi ne-tuning of synaptic transmission, particularly at glutamatergic and dopaminergic synapses, in schizophrenia.22,27,28 Nonetheless, a gap exists between genetic and other molecular knowledge and its application in translational research. Although psychiatric genetics now convincingly implicates specifi c sets of genes involved in synaptic function (eg, genes encoding glutamate and dopamine receptors and signalling proteins),22,27,28,37,96 it does not provide information about the developmental stages, brain regions, and circuitries in which the molecules have roles in pathogenesis. Therefore, further studies of brain imaging, post-mortem brains, clinical physiology, and animal models will need to build on genetic fi ndings.

Figure 2: Interaction of genetic and environmental risk factors in the developmental pathology of schizophrenia Several genetic and environmental risk factors might aff ect long-term neurodevelopmental processes and lead to schizophrenia. The disorder typically presents when the fi rst episode of psychosis occurs in late adolescence or early adulthood, but it is frequently preceded by a prodromal phase; in some instances, premorbid impairments in cognition or social functioning, or both, are seen many years before the fi rst episode of psychosis. Disturbances caused by susceptibility genes and environmental insults during early development and adolescence were proposed to disturb postnatal brain maturation. These factors are likely to impair some of the crucial processes in early development, including progenitor cell proliferation, neuronal migration, and dendritic arborisation and outgrowth. Independent of such initial risks and insults, intrinsic disease-associated factors might also directly aff ect postnatal brain maturation. Accumulation of such deleterious insults results in overall disturbance of proper postnatal brain maturation, including maturation of interneurons and dopaminergic projections, pruning of glutamate synapses, and myelination. Interneuron maturation is plotted as an increase in interneuron response to dopamine D2 agonists in the prefrontal cortex, whereas mesocortical dopaminergic projection is based on levels of tyrosine hydroxylase. The relative levels of glutamatergic synapse density and myelination are depicted. Adapted from Jaaro-Peled and colleagues.83

Birth

Prenatal and perinatal period (early development)

Postnatal brain maturation

Fertilisation

M ax

im um

v al

ue (%

)

Genetic factors

Prodromal phase

Future drugs (disease progression)

Environmental factors

0

25

50

75

100

Adolescence

Glutamatergic synapse density

Myelination

Interneuron maturation

Young adulthood

Existing drugs (neuromodulation)

Onset of schizophrenia

Mesocortical dopaminergic projection

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At least two types of mechanisms might be involved in schizophrenia. First, the development and maintenance of normal synaptic function depends on a large number of molecular pathways (fi gure 1), which will be aff ected by several environmental factors as the brain develops. Second, stress-associated signalling cascades, particularly those involving infl ammatory processes and oxidative stress, are well known to modulate the development and maintenance of synaptic connectivity (fi gure 3). For example, microglia (the glial cells that mediate brain infl ammation) are involved in synaptic maintenance and deterioration, particularly synaptic pruning in adolescence,97–99 and the MHC class I and complement system has been implicated in synaptic plasticity.99–105 Furthermore, the fast-spiking parvalbumin-positive inter- neurons are particularly vulnerable to oxidative stress.106,107 In addition, oxidative stress also causes defi cits in myelination.108,109 Both of these mechanisms have been shown in recent studies of preclinical models of schizophrenia.106–109

In summary, the neurobiology of schizophrenia remains poorly understood. Strong evidence implicates dysfunction of dopaminergic neurotransmission in the genesis of psychotic symptoms, and abnormalities of glutamate signalling might account for the negative and cognitive symptoms. Some brain areas have been linked

to specifi c cognitive dysfunctions (eg, the prefrontal cortex in working memory impairment), but a widespread and variable involvement of other brain areas and circuits is also likely. Disturbances of synaptic function might underlie abnormalities of neuronal connectivity, possibly through eff ects on interneurons, but the nature, location, and timing of these events remain unclear. Progression towards schizophrenia can be triggered by postnatal environmental exposures—which might be modulated by genetic factors and environmental factors in early development—and, in some cases, also by oxidative and infl ammatory mechanisms (fi gure 3).

Management and outcome Since the serendipitous discovery of chlorpromazine more than 50 years ago, almost all antipsychotic drugs available in the clinical setting for schizophrenia work via DRD2 blockade.110,111 A group of antipsychotics, of which clozapine is the most potent, binds and aff ects not only DRD2 but also other neurotransmitter receptors, such as serotonin receptors 2 (5HT-2R).112 In the UK, clozapine is only licensed for use in those who did not respond to other antispsychotics because of the risk of agranulocytosis and neutropenia (1–3%), and therefore a need for continuous blood monitoring. Antipsychotic drugs are relatively eff ective, compared with placebo, in

Figure 3: Neuron–glia interactions in the cerebral cortex—key neural substrates for the pathology of schizophrenia In the cerebral cortex, interneurons (inhibitory neurons) regulate the output of pyramidal neurons (excitatory neurons). Many studies have reported abnormalities of interneurons (particularly parvalbumin-positive interneurons) and defi cits of dendritic spines in the pyramidal neurons in schizophrenia. Imbalance of excitatory and inhibitory neurons might be a key feature that underlies disease pathology. Parvalbumin-positive interneurons are particularly vulnerable to oxidative stress, refl ecting an imbalance between the production of reactive oxygen species and the availability of antioxidants, which leads to cellular damage. Astrocytes and microglia have key roles in the maintenance and pruning of dendritic spines, which involves immune infl ammatory mechanisms. Oligodendrocytes create the myelin sheath, which is crucial for signal transmission inside the axon. Abnormalities of these glial cells have also been reported in schizophrenia.

Oligodendrocyte

Myelin

Myelin

Pyramidal neuron

Interneuron

Parvalbumin- positive

interneuron

Pyramidal neuron

Microglia

Astrocyte

Microglia

Pyramidal neuron

Pyramidal neuron

Oxidative stress

Inflammatory response

Inflammatory response

Oxidative stress

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reducing positive symptoms, such as auditory hallucinations and delusions, and remain the mainstay of both acute and long-term pharmacological treatment. However, they are not eff ective for other important clinical features of schizophrenia, such as negative symptoms and cognitive dysfunction, which are more strongly associated with functional impairment than are positive symptoms. Evidence shows that long-term maintenance treatment with antipsychotic drugs is eff ective in preventing relapse of psychotic symptoms, but troublesome side-eff ects such as weight gain, movement disorders, and sedation are common and contribute to poor adherence.113 Moreover, a substantial number of patients show no, or at best partial, response in positive symptoms with existing antipsychotic drugs.114–116 Individual response is often idiosyncratic and diffi cult to predict. New, so-called second-generation, antipsychotic drugs can be eff ective in treatment of psychotic symptoms, with fewer movement disorders, but they carry a higher risk of cardiometabolic side- eff ects than do fi rst-generation drugs. Choice of the optimum drug is therefore usually pragmatic and balances individual benefi ts with costs and risks. Clozapine is eff ective in around 60% of patients who are previously treatment refractory,116 but evidence shows that it is underprescribed.5

Although antipsychotic drugs remain the main treatment approach, eff ective management requires pharmacotherapy to be embedded within a framework of strong psychological and social support—eg, approaches aimed at improving adherence, vocational and educational support, and rehabilitation. Therefore, a multidisciplinary approach, involving a range of health-care professionals and agencies, delivered in a community-care setting is necessary. Specialist early intervention services, which focus on those who are experiencing their fi rst psychotic episode and the following 3 years, are available in many developed countries, and are popular with service users and carers.5 These services have benefi cial eff ects on outcome in the fi rst few years, but their long-term eff ect remains uncertain.117 Psychological treatments have been mandated by the UK National Institute for Health and Care Excellence (NICE) guidelines, which recommend that all patients with schizophrenia should be off ered cognitive behavioural therapy (CBT) and family intervention in addition to antipsychotic drugs. A role for CBT is justifi ed by evidence that various potentially mutable psychological mechanisms increase the risk of specifi c symptoms.118 However, the treatment and cost eff ectiveness of CBT in schizophrenia is controversial,119 and little evidence shows that CBT can target the underlying psychological mechanisms. One possibility is that the eff ectiveness of CBT depends on non-specifi c factors, such as the quality of the relationship between the therapist and the patient (ie, therapeutic alliance), and evidence supports this in regard to schizophrenia.120 Medical management also focuses on physical

health—particularly preventive measures such as dietary advice, exercise, smoking cessation, and prevention of drug abuse; and monitoring of cardiovascular and metabolic risk factors. In many countries, care is provided by a multidisciplinary team of mental health professionals in primary, secondary, and community settings and focuses on both health and social care.42

In the past 10 years, the perception that outcome is necessarily poor has been challenged by results of prospective studies, which show great heterogeneity with fairly good outcome in 20–50% of cases.42 However, although most patients with schizophrenia live independently outside hospitals, many need continuing support either from services or from their relatives. Moreover, all-cause mortality is substantially increased.121,122 The relative risk for suicide is increased by 12 times, with a lifetime risk of roughly 6·5%,123 but mortality from most natural causes, especially cardiovascular disorders, is the strongest contributor to the 10–20 year reduction in life expectancy. The causes of this increase in mortality are thought to include smoking and other lifestyle factors, suboptimal treatment of physical disorders,121,124 and side- eff ects of pharmacological treatment (especially cardiometabolic outcomes). Several trials to reduce the excess mortality are being done.

Unresolved research questions and opportunities for progress Although progress has been great in the past 5–10 years, much is still to be learnt about what causes schizophrenia and how to treat it eff ectively. Genomic studies have begun to reveal the complex genetic architecture of the disorder and to converge on some tractable areas of biology. The focus for the next few years will be to identify more rare and common risk alleles, and rare variants conferring high individual risk will be of particular importance for the design of cellular and animal models. Somatic de-novo mutations have been shown to contribute to some neurodevelopmental disorders,125 and another important focus is to determine the extent to which these mutations contribute to schizophrenia; to do so, deep sequencing of brain tissue will be necessary. Extensive pleiotropy shown in genetic studies has challenged existing categorical notions of classifi cation, but the large samples needed for robust studies have come at the expense of detailed phenotypic data. Therefore, to deepen our insights into the relations between genetic risk and phenotypic outcome, a major goal will be to include more detailed clinical and endophenotypic data in large-scale genetic studies. These data will be necessary to understand how genetic risk aff ects brain mechanisms that lead to particular clinical outcomes and to develop new approaches to diagnosis and classifi cation with improved representation of the underlying disturbances in brain function.

As genetic studies continue to drive mechanistic studies in patients and model systems, and bioinformatic

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analyses become increasingly informative with large study sizes, a key challenge is to determine how, where, and when genetic risk aff ects brain development and function. Genetically engineered cells obtained directly from patients, such as induced pluripotent stem cells and induced neuronal cells, provide an opportunity to investigate neuronal mechanisms in vitro.126 New genome engineering approaches, such as the clustered regularly interspaced short palindromic repeat (CRISPR) system, can be used to introduce risk alleles, and combinations thereof, into human stem cell lines. Many types of CNS cells, including diff erent subtypes of neurons (eg, glutamatergic and dopaminergic neurons) and glial cells, can be diff erentiated from induced pluripotent stem cells or progenitors derived from such cells in vitro to partially recapitulate neurodevelopmental processes.127 However, whether these diff erentiated cells can capture features of mature neural networks in vivo is still unclear. Nonetheless, such patient-derived neuronal cells will be useful to address cell-autonomous intrinsic susceptibility to the disease. Moreover, if such cellular susceptibility provides valid drug targets, human cell culture could be used for compound screening.128

The study of animal models (particularly rodents), in combination with human brain imaging, will be needed to address mechanisms at the level of neural circuits. The validity of many animal models can be questioned, but advances in genetics allow models of human risk mutations to be developed. The polygenic basis of psychiatric disorders restricts the usefulness of genetic rodent models, which often include one specifi c mutation; at present, rare high-penetrance alleles off er the best approach to generating models with high construct validity. However, the CRISPR system is a useful way to introduce genetic variations at multiple sites.129 Additionally, neural circuits in genetic animal models will need to be examined with respect to behavioural changes, with a particular attention to the pathological trajectory from early development to full onset of disease in adulthood. Such studies will benefi t from new approaches, such as optogenetics, to intervene with specifi c neural cells and circuits.130 Since environmental stressors have key roles in schizophrenia,17 the study of gene–environment interactions in cell and animal models will become increasingly important to answer key questions such as which biological contexts, cells, and mechanisms are the key sites of convergence of genetic and environmental stressors.

Besides the impressive advances in genetics, epidemiological studies have also been highly productive in pinpointing several biological and psychosocial risk factors. However, observational epidemiology has little explanatory power. To understand the relevance of environmental risk exposures to disease causation, the integration of genomics with epidemiological studies will be helpful. Longitudinal epidemiological research will need to address how environmental exposures at

diff erent timepoints interact with each other and with genetic risk to produce clinically relevant outcomes. These studies are likely to benefi t from access to routinely obtained electronic clinical data, although ethical and other challenges remain. Such data should also allow the identifi cation of protective factors and guide the implementation of public health measures.

A clear need is to develop antipsychotic compounds with reduced side-eff ects, particularly those aff ecting metabolic processes that result in adverse cardiovascular outcomes.131 Eff orts are being made to develop compounds that are eff ective not only for positive symptoms but also for negative and cognitive symptoms—eg, by modulation of glutamate and acetylcholine neurotransmission through interfering with glycine transporter 1 and alpha7 nicotinic acetylcholine receptor.132–134 Interest in the use of pharma co genetics is increasing—eg, to identify patients at particular risk of specifi c side-eff ects,135,136 and, in combination with other biomarkers, to identify patients who might respond diff erently to drugs with diff erent modes of action;137 this follows the general trend to investigate the potential of stratifi ed medicine, in which drugs are targeted effi ciently to specifi c subgroups of patients. The road from advances in genetics and biology to the discovery of new treatments is likely to be a long one, and progress will depend on insights from cellular and animal modelling and from clinical trials.138 To achieve this goal, the key issues of cell type and circuit specifi city, and also of the timing of crucial events, will need to be addressed, and improvements in high- throughput methods and in-vitro modelling of cell circuits will be necessary.138

A burgeoning interest lies in the possibility of treating individuals at high risk to prevent the development of full-blown psychosis and to reduce functional impairment. Meta-analyses of randomised controlled trials suggest a positive, if modest, outcome of such treatment, despite the wide range of interventions used (psychological, pharmacological, and nutritional);139,140 however, further well controlled trials will be necessary.141–143 Stress-associated signalling cascades are likely to aff ect synaptic pruning and the maturation of neural networks in adolescence, and compounds that can regulate infl ammation and oxidative stress are being developed. For example, omega-3 fatty acids had benefi cial eff ects in a clinical trial.144 Preclinical studies have shown that application of antioxidants, including N-acetyl cysteine, ameliorate physiological and behavioural defi cits associated with schizophrenia.108 Encouraged by such preclinical studies, increasing numbers of investigator- initiated clinical trials with antioxidants are being done. High research priorities include applications of genetic and other biomarkers, together with early neuro- psychological, developmental, and behavioural risk markers, to identify high-risk groups as relevant recipients of preventive interventions, and controlled studies of the interventions in high-risk children.

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Arguably, the greatest challenge facing future research into disease cause, pathogenesis, and treatment is the failure of existing syndromic defi nitions to delineate a valid disease entity. New approaches to patient stratifi cation will need to recognise the varying degree of overlap between syndromes and use measures that plausibly index the pathophysiology underlying the various clinical features and impairments. This will require a closer dialogue between basic neuroscientists and clinical researchers.14 In view of the complex and variable clinical features and cognitive impairments associated with the disorder, multiple brain systems are likely to be aff ected to varying extents in diff erent individuals, and dysfunction of one brain region or circuit is unlikely to account for the full range of features of schizophrenia and distinguish it from other disorders. Rather, diff erent features probably result from disturbances of diff erent brain functions, crossing existing diagnostic boundaries. These considerations also imply that new treatments should target particular symptoms, or groups of symptoms, that share common underlying mechanisms, making them applicable across diagnostic groups.

Controversies and uncertainties Schizophrenia has long divided opinion: do its origins lie in nature or nurture? Does it have a psychosocial or biological origin? Is it a myth, an illness, or a sane response to an insane society? That controversies are not as polarised at present is perhaps a sign of increased knowledge. However, as should be clear from this Seminar, many debates and uncertainties do remain— eg, how should we diagnose schizophrenia? Should we use categories or dimensions? What clinical features, or combination of features, will map best onto underlying neurobiological disturbances? Which environmental risk factors are truly casual, and which are secondary to illness or genetic confounding? Is it better viewed as a disorder of circumscribed brain regions and circuits, or a disorder of the whole brain? Is a progressive, neurodegenerative component present in addition to a neurodevelopmental one? Is it one disorder, several disorders, or part of a continuous landscape of psychopathology, analogous to, say, metabolic syndrome? What is the relation between schizophrenia and disorders such as autism and ADHD, with which it shares several clinical features and risk factors?

One area that we have not discussed, which is perhaps of greatest immediate concern, is the poor quality of care for schizophrenia even in developed countries. The Schizophrenia Commission reviewed this issue in 2012 and described services in the UK as “broken and demoralized”.5 Not only did the Commission document, in uncompromising terms, the shortcomings of present approaches to clinical management, but it also made many recommendations to improve policy and practice.5 Undoubtedly, the implementation of these changes would greatly improve the lives of those with schizophrenia.

In view of the need for an overhaul in the ways in which care is provided, to point out the inadequate investment in research in mental disorders relative to burden is perhaps inappropriate.145 Some have argued that the low research investment is a result rather than a cause of insuffi cient progress and capacity in this area. However, a counterview is that this is yet another example of the way in which mental disorders fail to achieve parity of esteem with physical illnesses. Whatever the explanation, we hope that the advances and unprecedented opportunities documented in this Seminar will help to redress this imbalance. Contributors All authors developed the structure of the Seminar, did literature searches, wrote the manuscript, constructed the fi gures, and approved the fi nal manuscript.

Declaration of interests MJO receives funding from the UK Medical Research Council, Wellcome Trust, US National Institute of Mental Health, the European Union, and the UK National Institute for Social Care and Health Research. He has received speaker’s fee from Janssen Pharmaceutical Companies. AS receives research funding from the US National Institutes of Health (MH-069853, MH-084018, MH-085226, MH-088753, MH-092443, MH-094268, MH-105660, and DA-040127), Brain & Behavior Research Foundation (formerly the National Alliance for Research on Schizophrenia and Depression), Stanley Foundation, RUSK Foundation, and Maryland Stem Cell Research Funds. PBM receives research funding from the Lundbeck Foundation, the Stanley Medical Research Institute, and the European Research Council. None of the funding bodies had any infl uence on any part of the work on this Seminar. None of the authors received any payment from any pharmaceutical company or other agency to write this Seminar.

Acknowledgments We thank David Linden and Richard Bentall for their valuable suggestions, and Ruth Sellars, Yukiko Lema, Annette Rand Madsen, and Victoria Hirst for their help in preparation of the Seminar.

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