Schizophrenia: epidemiology, etiological theories, clinical subtypes, course, outcome, and treatment

01Definition and overview

Schizophrenia is a chronic, usually relapsing psychotic disorder that distorts thinking, perception, emotion, will and the sense of self, without an organic cause. Kraepelin described it as dementia praecox in the 1890s, set apart from manic-depressive illness by its deteriorating course; Bleuler named it in 1908 for the split between thought, emotion and behaviour, not a split personality. There is no test: the diagnosis rests on the symptoms, their duration and the exclusion of other causes.

ICD-10 asks for one very clear symptom from groups a to d, or symptoms from two of groups e to h, for most of the time during a month or more:

It is not diagnosed when marked mood symptoms came first, with overt brain disease, or in intoxication or withdrawal.

02Etiology and pathophysiology

Many genes of small effect, a few rare variants of large effect and exposures from before birth to early adulthood together disturb brain development and the dopamine and glutamate systems.

Heritability is about 80 per cent. The lifetime risk is about 1 per cent in the general population, 10 to 15 per cent with an affected parent or sibling, about 40 per cent when both parents are affected and 40 to 50 per cent for an identical twin. The largest genome-wide study found 287 risk loci, many in synaptic genes including the D2 receptor; the strongest signal, in the major histocompatibility complex, involves the complement gene C4, which tags synapses for pruning in adolescence. The 22q11.2 deletion leads to schizophrenia in about one in four carriers.

In a European study across eleven sites, removing high-potency cannabis would have prevented about 12 per cent of first episodes of psychosis overall, 30 per cent in London and half in Amsterdam.

The neurodevelopmental model rests on what comes before the illness: children who later develop it walk and talk slightly late, do less well at school and are more socially awkward, and at the first episode the ventricles are already enlarged, without the gliosis of degeneration. Early insults on a genetic background are thought to leave a vulnerability that shows when synapses are pruned in adolescence, often after a second hit such as cannabis or stress.

1. 1

   Dopamine

   Amphetamine causes psychosis, and antipsychotics block D2 receptors in proportion to their potency. Imaging shows raised dopamine synthesis and release in the associative striatum, thought to give ordinary perceptions abnormal salience from which delusions and hallucinations are built.
2. 2

   Glutamate

   Blocking the NMDA receptor with ketamine reproduces positive, negative and cognitive symptoms, and antibodies against it cause an encephalitis that mimics schizophrenia. Hypofunction on inhibitory interneurons disinhibits the cortex and, downstream, dopamine.
3. 3

   Serotonin and acetylcholine

   LSD acts on 5-HT2A receptors, which most second-generation antipsychotics block. Stimulating central muscarinic receptors lowers striatal dopamine release, the basis of a new drug.

In the stress-vulnerability model, stress, drugs, sleep loss and a family high in criticism and over-involvement (high expressed emotion) bring on episodes in a vulnerable person. Theories that families cause schizophrenia were wrong.

03Clinical features

Positive symptoms respond best to antipsychotics; negative and cognitive symptoms respond poorly and decide, more than voices, whether a person can work and live independently. Insight is impaired in most patients during an episode. Depression, anxiety, smoking (more than half), cannabis and alcohol are common. Violence is commoner than in others, mostly with substance use, but patients are far more often victims than perpetrators.

Schneider's first-rank symptoms suggest schizophrenia but are neither necessary nor specific, as they also occur in mania and organic psychoses: hearing one's thoughts aloud, voices arguing or commenting in the third person, thought insertion, withdrawal and broadcasting, feelings, impulses, actions or sensations made from outside, and delusional perception (a normal perception given a sudden delusional meaning).

1. 1

   Prodrome

   Months to years of withdrawal, falling performance, suspiciousness, odd ideas and poor sleep, with brief or attenuated psychotic symptoms late on.
2. 2

   First episode

   Florid psychosis, often presenting through family, school, police or self-harm rather than as a complaint of voices.
3. 3

   Relapse

   Positive symptoms settle over weeks to months; relapses follow, often heralded by the same warning signs each time.
4. 4

   Later course

   Recovery in some, relapses with residual negative and cognitive symptoms in most, a chronic disabling course in a minority.

04Diagnosis and management

Assessment

The history includes family or friends, drugs and alcohol and a family history; the mental state examination records the psychosis, mood, insight, cognition and risk. A physical and neurological examination and tests look for organic causes and set a baseline: blood tests (full blood count, renal, liver and thyroid function, calcium, HbA1c, lipids, prolactin, HIV and syphilis where at risk), a urine drug screen and an ECG. MRI is done for neurological signs, cognitive decline or an atypical or late onset. NMDA receptor antibodies are sought when psychosis comes with seizures, abnormal movements, autonomic instability, reduced consciousness or a rapid course: anti-NMDA receptor encephalitis is treatable and must not be missed.

Early intervention

People with an at-risk mental state (distress and falling function with attenuated or brief psychotic symptoms) are referred to a specialist service and offered individual CBT and help with anxiety, depression and substance use, with follow-up for up to three years; antipsychotics are not given to prevent psychosis. In the UK, everyone with a first episode is offered care from an early intervention in psychosis team for up to three years: medication, psychological therapy, family work and help with study and work. In England treatment should start within two weeks of referral; a long untreated psychosis predicts a poorer outcome.

The acute episode

Most patients are treated at home by a crisis or early intervention team; admission, under mental health law if necessary, is for high risk to self or others, severe disturbance or failure of community care. No antipsychotic apart from clozapine is clearly more effective than the others, so the choice is made with the patient by side effects:

• One antipsychotic at the lowest effective dose; a first episode often needs less than a relapse.
• Response is judged at two to four weeks; a trial is adequate after at least six weeks at a therapeutic dose, with adherence checked.
• Antipsychotics are combined only while switching or after clozapine has failed.
• A benzodiazepine helps agitation for a short time; catatonia is treated with lorazepam, then ECT.

Treatment resistance and clozapine

About a third of patients keep at least moderate symptoms after two antipsychotics, each given for six weeks or more at an adequate dose with adherence confirmed. Once the diagnosis, adherence (plasma levels help), substance use and interactions have been reviewed, clozapine is offered: the only antipsychotic shown to work better in treatment-resistant schizophrenia, it helps about four in ten and reduces suicide. It is underused and often started years late. It is titrated from 12.5 mg over two to three weeks, aiming for a plasma level of at least 350 µg/L.

• In the UK the full blood count is checked weekly for 18 weeks, fortnightly to a year, then every four weeks, through a monitoring service; the MHRA announced a review of this in 2025. In the EU since 2025 the absolute neutrophil count alone is used, at least 1,500 per mm³ to start (1,000 in benign ethnic neutropenia), weekly for 18 weeks, monthly to the end of the first year, then every 12 weeks, and yearly after two years without neutropenia.
• Stopping smoking can raise clozapine levels by about half over a week or two, into toxicity, as can infection or ciprofloxacin.
• After more than 48 hours of missed doses it is retitrated from 12.5 mg.

Psychological and social care

Cognitive behavioural therapy for psychosis (at least 16 sessions) eases the distress of voices and delusions, and family intervention (at least 10 sessions over 3 to 12 months) reduces relapse. Arts therapies help negative symptoms, and supported employment, education and housing come through psychosocial rehabilitation.

Relapse, adherence and physical health

In trials, about a quarter of patients kept on an antipsychotic relapsed within a year, against nearly two thirds switched to placebo. After a first episode treatment usually continues for one to two years, and after relapses for years, with any reduction slow and watched. About half of patients take medication irregularly; shared decisions, fewer side effects, simple regimens and family support help, and where non-adherence keeps causing relapse, or the patient prefers it, a long-acting injectable antipsychotic is offered.

Weight is checked at baseline, weekly for six weeks, at 12 weeks, at a year and then yearly; blood pressure, HbA1c and lipids at baseline, 12 weeks, a year and yearly; prolactin and an ECG when the drug or symptoms call for it. Diabetes and dyslipidaemia are treated as in anyone else, and everyone who smokes is offered help to stop.

05Epidemiology

new cases, the median incidence, varying several-fold between places

about 15per 100,000 a yearnew cases, the median incidence, varying several-fold between places

live with schizophrenia, about 27 million

1 in 300people worldwidelive with schizophrenia, about 27 million

the incidence in men compared with women

1.4timesthe incidence in men compared with women

The lifetime risk is about 0.7 per cent and the point prevalence 3 to 5 per 1,000. Onset peaks at 18 to 25 in men and 25 to 35 in women, who have a second, smaller peak after 45; onset before 13 is rare. Incidence is higher in cities, in migrants and their children and with high-potency cannabis. It is among the leading causes of disability in young adults, mostly through lost education and work.

06Prognosis

In round figures, 15 to 25 per cent recover fully, most have relapses with some lasting negative and cognitive symptoms, and about one in five stays severely disabled. Four in five relapse within five years of a first episode; stopping medication makes relapse about five times as likely, and cannabis, stress and a critical family add to the risk.

Life expectancy is shorter by roughly 10 to 15 years, depending on the study and the country. About 4 to 5 per cent die by suicide, most often early in the illness, after discharge and in post-psychotic depression (see suicidal behaviour), but most excess deaths are from heart and lung disease. Long-term antipsychotic treatment, clozapine above all, is linked with lower mortality than none. Follow-up reviews the mental state and warning signs, side effects, risk, physical health, substance use, and work, housing and relationships.