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.
SeminarSchizophrenia
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
References (145)
- et al.
The early stages of schizophrenia: speculations on pathogenesis, pathophysiology, and therapeutic approaches
Biol Psychiatry
(2001) New approaches to psychiatric diagnostic classification
Neuron
(2014)- et al.
CNVs: harbingers of a rare variant revolution in psychiatric genetics
Cell
(2012) - et al.
De novo rates and selection of schizophrenia-associated copy number variants
Biol Psychiatry
(2011) - et al.
The penetrance of copy number variations for schizophrenia and developmental delay
Biol Psychiatry
(2014) - et al.
Genetic risk for schizophrenia: convergence on synaptic pathways involved in plasticity
Biol Psychiatry
(2015) - et al.
Chromosomal microarray analysis—a routine clinical genetic test for patients with schizophrenia
Lancet Psychiatry
(2014) - et al.
Schizophrenia
Lancet
(2009) The environment and susceptibility to schizophrenia
Prog Neurobiol
(2011)- et al.
Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review
Lancet
(2007)