Schizophrenia

Hallucinations, delusions, negative and cognitive symptoms; the dopamine and glutamate hypotheses, genetic and developmental risk, early intervention, and the first new class of antipsychotic in decades.

What it is — and isn't

Schizophrenia affects about 24 million people worldwide (around 1 in 300, WHO). Despite the name, which means "split mind", it does not mean a split or multiple personality. The term was coined in 1908 by the Swiss psychiatrist Eugen Bleuler; earlier, Emil Kraepelin had called it dementia praecox ("premature dementia").

Symptoms

Positive symptoms (added experiences): hallucinations, most often hearing voices; delusions, fixed false beliefs such as being persecuted or controlled; disorganised speech and behaviour. Negative symptoms (losses): reduced motivation, emotional expression, speech and social interest. Cognitive symptoms: problems with attention, working memory and processing speed — often the strongest predictors of everyday functioning. Onset is typically in the late teens to early thirties, often earlier in men.

Brain chemistry

The dopamine hypothesis arose because antipsychotic drugs block dopamine D2 receptors and amphetamines, which boost dopamine, can cause psychosis. PET studies show increased dopamine synthesis and release in the striatum in many people with psychosis. Excess dopamine may cause irrelevant things to seem strangely significant ("aberrant salience"), seeding delusions. The glutamate hypothesis points to reduced NMDA receptor function: NMDA blockers such as ketamine and PCP produce both positive and negative symptoms in healthy people.

Genes and development

Schizophrenia is highly heritable (around 80% in twin studies), but involves hundreds of common genetic variants plus rare ones. The strongest single common signal is in the immune MHC region: variants increasing activity of the complement gene C4, which tags synapses for pruning, raise risk (Sekar et al., 2016). It's seen as a neurodevelopmental disorder, with risk factors including obstetric complications, childhood adversity, migration and urban upbringing, and heavy cannabis use in adolescence, especially of high-potency cannabis.

Treatment

The first antipsychotic, chlorpromazine, was introduced in the early 1950s and transformed care. Antipsychotics reduce positive symptoms for most people but often help negative and cognitive symptoms less, and side effects can be significant. Clozapine is the most effective for treatment-resistant cases. In September 2024 the US FDA approved xanomeline-trospium (Cobenfy), the first antipsychotic in decades that works mainly through muscarinic acetylcholine receptors rather than blocking dopamine directly. Early intervention services, family support, psychological therapies and supported employment improve outcomes.