Elsevier

The Lancet

Volume 388, Issue 10039, 2–8 July 2016, Pages 86-97
The Lancet

Seminar
Schizophrenia

https://doi.org/10.1016/S0140-6736(15)01121-6Get rights and content

Summary

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 effective 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 scientific breakthrough are numerous—but so are the challenges.

Introduction

Schizophrenia is a severe psychiatric disorder that has a profound effect on both the individuals affected 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 figure 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, effective, 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.

Section snippets

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

Diagnosis and differential 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 fifth edition of Diagnostic and Statistical Manual of Mental Disorders (DSM-5),10 the main differential diagnoses are affective psychoses (bipolar disorder with psychotic features and major depressive disorder with psychotic features), other closely related non-affective psychoses

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 specific DNA variants and different types of risk alleles to the disorder has begun to emerge. Three lessons of general importance can be drawn from these findings.

First, schizophrenia is highly polygenic, as

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 efficiently dismantled only in 2008 in a series of meta-analyses by McGrath and colleagues.41 They provided central estimates of an incidence per

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 specific underlying neurobiology, and several lines of evidence implicate the involvement of the prefrontal cortex in specific cognitive deficits (eg, working memory and executive control).86, 87, 88 However, subtle reductions in grey matter and

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 affects 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

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 effectively. 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

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

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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