Schizophrenia

Diagnosis (DSM-5)

A. Two or more of the following, each present for a significant portion of a 1-month period (or less if successfully treated) — at least one must be (1), (2), or (3):

1. Delusions
2. Hallucinations
3. Disorganised speech (frequent derailment or incoherence)
4. Grossly disorganised or catatonic behaviour
5. Negative symptoms (diminished emotional expression or avolition)

B. Functioning in one or more major areas (work, relationships, self-care) is markedly below the level before onset — or, for childhood/adolescent onset, the expected level of functioning is never achieved.

C. Continuous signs of disturbance persist for at least 6 months, including at least 1 month of active-phase (criterion A) symptoms; this period may include prodromal or residual phases, during which only negative symptoms or attenuated positive symptoms (odd beliefs, unusual perceptual experiences) may be present.

D. Schizoaffective disorder and mood disorder with psychotic features have been excluded.

E. Not attributable to a substance or another medical condition.

F. If there’s a history of autism spectrum disorder or a childhood-onset communication disorder, only diagnose schizophrenia additionally if prominent delusions or hallucinations are also present for at least a month.

Differentials: major depressive or bipolar disorder with psychotic/catatonic features; schizoaffective disorder; schizophreniform disorder (<6 months) or brief psychotic disorder (<1 month); delusional disorder; schizotypal personality disorder; OCD and body dysmorphic disorder; PTSD; autism spectrum/communication disorders; and organic causes (drug-induced, or another medical illness — e.g. MS, SLE, Wilson’s, Huntington’s disease).

Symptom domains

Domain	Features
Positive	Hallucinations, delusions, disorganised thinking, impaired insight
Negative	Lack of motivation, poor self-care, blunted affect, reduced speech output, social withdrawal
Cognitive	Impaired planning, reduced mental flexibility, impaired memory and social cognition
Excitement	Disorganised behaviour, aggression, hostility
Mood	Anxiety, depression

Epidemiology and course

• Incidence is roughly 4× higher in men than women; estimated lifetime morbid risk ~2.4 per 1,000.
• Higher rates of admission (and the effects of pervasive social disadvantage) suggest higher prevalence among Aboriginal and Torres Strait Islander people.
• Course: schizophrenia has recognisable clinical stages, including a pre-psychotic or prodromal stage before the first psychotic episode. Of those diagnosed, roughly 6% have a single episode with good recovery, ~55% have multiple episodes with good or partial recovery between them, and ~39% follow an unremitting, continuous course with deterioration.
• Early-adult-life onset of psychosis can cause lifelong socioeconomic disadvantage and prevent people reaching their full potential; particular difficulty is seen with complex demands and social interaction.

Comorbidity and mortality: life expectancy is reduced by roughly 20%. Suicide accounts for around 28% of the excess mortality; cardiometabolic disease and accidents are the other leading causes of premature death.

Legal/forensic: people with schizophrenia face higher incarceration rates than the general population — sometimes for violent offences, but also for trivial ones.

Physical health and comorbidity monitoring

People with schizophrenia have reduced life expectancy compared to the general population — 18.7 years shorter in men, 16.3 years shorter in women. This is largely attributable to physical conditions such as cardiovascular disease, respiratory disease and cancer, rather than to external causes like suicide or accidents. Over half of Australians with a psychotic disorder meet the criteria for metabolic syndrome, and approximately one-quarter already have cardiovascular disease or are at high risk of it. For people living with severe mental illness, consider reclassifying their estimated cardiovascular disease risk to a higher risk category on the standard Australian risk calculator, particularly if their estimated risk is close to a higher risk threshold.

People with schizophrenia have a greater predisposition to the WHO’s top six modifiable global mortality (cardiometabolic) risk factors: hypertension, smoking, hyperglycaemia, physical inactivity, obesity and dyslipidaemia. Approximately two-thirds of people with schizophrenia still smoke, compared with approximately 11% of the general population. A specific ‘Quitline’ intervention for people with mental illness may be more effective than the usual Quitline resources. The requirements for nicotine replacement are often higher in this population because they tend to be heavier smokers. Smoking cessation itself needs monitoring, since it reduces the metabolism — and so raises the serum concentration — of clozapine and olanzapine specifically; a dose adjustment may be needed after a patient quits. Approximately three-quarters of people with schizophrenia are classified as overweight or obese. Clozapine and olanzapine have been shown to cause the largest weight gains from baseline in patients starting antipsychotics. The risk of type 2 diabetes is 2 to 5 times higher than in the general population. There is a high prevalence of hypertension and dyslipidaemia in people with schizophrenia. However, patient awareness of their diagnoses is low, which suggests screening for cardiometabolic risk factors may be insufficient. One study reported a 0.37-fold decrease in antihypertensive use, and a 0.47-fold decrease in lipid-lowering drug use, among people with schizophrenia compared with the general population. This suggests that only about half of people with schizophrenia and known hypertension or dyslipidaemia are actually receiving treatment for these manageable conditions. Obstructive sleep apnoea is an under-recognised and significant comorbidity in people with schizophrenia. Its symptoms may be misidentified as negative symptoms of schizophrenia or antipsychotic adverse effects. People with suspected OSA should have a home-based sleep study or be referred to a sleep physician. Hyperprolactinaemia is a well-recognised adverse effect of some antipsychotics, particularly risperidone, paliperidone and amisulpride. It can manifest with galactorrhoea, sexual dysfunction, osteoporosis and amenorrhoea. RANZCP recommends assessing prolactin concentration and switching to a prolactin-sparing antipsychotic if necessary, in conjunction with specialist psychiatric and endocrinology input, if it’s raised.

Monitoring schedule: start monitoring cardiometabolic risk factors immediately after an antipsychotic is started, then every three months during the first year, then every six months after that.

Lifestyle interventions are the first-line response to rising cardiometabolic risk. A package of care comprising aerobic exercise, weight loss, smoking cessation, a high soluble fibre diet, reducing alcohol intake and potentially adding omega-3 fish oils may lead to significant improvements in cardiovascular risk. The response of patients with psychosis to structured lifestyle programs may be more vigorous than anticipated. Behavioural interventions for weight loss have been shown to reduce weight gain in patients starting antipsychotics. They also lead to weight loss and improved lipid and glucose profiles in those already receiving treatment — work with families and carers when devising the plan, since they often play an extensive role in day-to-day support. If considering switching the patient’s antipsychotic because of emerging metabolic risk, consult the treating psychiatrist beforehand. Patients taking clozapine have probably not responded to other antipsychotics, and switching is not usually advisable. Review the weight-gain potential of co-prescribed drugs too — valproate, lithium, mirtazapine, tricyclic antidepressants and some SSRIs can all add to weight gain. Standard pharmacotherapy (e.g. statins) can be used for dyslipidaemia as it would for any other patient, but people with mental illness are significantly less likely to actually receive appropriate pharmaceutical therapies than those without.

Exercise specifically has evidence as an add-on treatment in its own right, not just a cardiometabolic risk-reduction measure. Numerous studies confirm that exercise, as an add-on to pharmacological therapy, can significantly attenuate the psychiatric symptoms of schizophrenia and improve quality of life, general cognition and global functioning. Aerobic, but not non-aerobic, exercise interventions have been shown to reduce both negative and positive symptoms of schizophrenia. Better results are generally reported with higher-intensity exercise, but dropout rates and the potential for adverse events in high-risk individuals may increase. Significantly better results are generally reported with supervision by exercise professionals. The European Psychiatric Association suggests aerobic exercise of moderate-to-vigorous intensity at a frequency of 2–3 times a week, achieving 90–150 minutes of moderate-to-vigorous physical activity per week. This should be tailored to the individual rather than prescribed uniformly. The GP can develop appropriate individualised protocols taking into consideration the patient’s age, gender, general health status, physical fitness level and barriers to exercise. The GP can also provide ongoing motivation and encouragement, and where necessary involve the services of exercise professionals. And the GP can regularly monitor patients and provide feedback and, where appropriate, revise the physical activity regimen.

Management

Pre-psychotic / prodromal (ultra-high-risk) phase

Ultra-high risk of psychosis = subthreshold psychotic symptoms combined with functional decline.

• Monitor mental state every 2–4 weeks.
• Don’t use antipsychotics unless frank positive psychotic symptoms are present.
• Consider omega-3 fatty acids and CBT — both may reduce progression to a first psychotic episode.

Acute psychotic phase

Assess risk of harm to self, others, and reputation, and the need for involuntary admission — reducing the duration of untreated psychosis is a key evidence-based priority for outcomes.

Start an antipsychotic low and go slow, after a psychiatric and physical assessment (and, where possible, an antipsychotic-free assessment window). Adjunctive diazepam can help acute anxiety and temazepam can help sleep disturbance while the antipsychotic takes effect. First consider other diagnoses that can present with psychosis if mood symptoms are prominent — bipolar disorder with psychotic features, schizoaffective disorder, major depressive disorder with psychotic features.

Typical starting/target/maximum doses for first-episode non-affective psychosis (start low, titrate to response and tolerability):

Drug	Starting dose	Initial target	Highest dose
Amisulpride	50–100 mg/day	300–400 mg/day	up to 800 mg/day
Aripiprazole	5–10 mg/day	15–20 mg/day	up to 30 mg/day
Quetiapine	25–50 mg/day	300–400 mg/day	up to 750 mg/day
Risperidone	0.5–1 mg/day	2–3 mg/day	up to 6 mg/day
Ziprasidone	20–40 mg/day	80–120 mg/day	up to 160 mg/day

If there’s an insufficient response after 3 weeks, increase the dose over the next 2–3 weeks and optimise psychosocial interventions. If there’s still no response after 6–8 weeks, cross over to a different second-generation antipsychotic. If there’s non-response to a second antipsychotic trial, review for adherence, substance use, and family stressors, then consider:

Drug	Starting dose	Initial target	Highest dose
Olanzapine (caution — see metabolic monitoring)	2.5–5 mg/day	10 mg/day	up to 20 mg/day
Clozapine	25 mg/day	300 mg/day	up to 900 mg/day

If clozapine isn’t possible, consider add-on or a trial of a low-dose typical antipsychotic, a mood stabiliser, or combination antipsychotic therapy.

For non-adherence specifically: discuss with the patient and carers, analyse the reasons, and optimise compliance therapy. If non-adherence is due to side effects, try a different antipsychotic. Consider a depot formulation (atypical depot agent, or low-dose typical depot) — long-acting injectables can also be offered as first-line treatment within a shared decision-making framework, not just as a fallback for non-adherence.

Continuing treatment: once response is achieved, continue for at least 2–5 years. If remission is incomplete or there’s treatment resistance, consider long-term treatment. If discontinuing, taper gradually over at least several months with close follow-up.

Switching antipsychotics

Reasons to switch include inadequate efficacy after an adequate trial, intolerable side effects, non-adherence linked to side effects, or a change in clinical priority (e.g. moving to a lower-metabolic-risk agent, or to a depot). Switching is a skilled process — done abruptly or carelessly, it risks rebound psychosis, agitation, insomnia, and cholinergic/anticholinergic rebound (nausea, sweating, diarrhoea, restlessness) as receptor occupancy shifts.

General principles:

• Cross-titrate wherever possible — taper the first antipsychotic down while building the second up, over days to a few weeks depending on the drugs and clinical urgency. Brief overlap of two antipsychotics during this window is expected and appropriate; it isn’t the same as intending long-term combination therapy.
• Don’t stop the first drug abruptly and start the second at full dose — this is the pattern most likely to cause withdrawal/rebound symptoms. Reserve an abrupt switch for genuine emergencies (e.g. a severe adverse reaction requiring immediate cessation), and be prepared to manage rebound symptoms actively if this is unavoidable.
• Commit to completing the switch. It’s common for a patient to improve part-way through cross-titration and for the taper to then stall, leaving the patient on two antipsychotics indefinitely — unplanned combination therapy like this is poorly evidence-based, adds side-effect and cost burden, and should prompt a deliberate decision to either complete the switch or explicitly justify ongoing combination treatment, not just drift into it.
• Switching between two pharmacologically similar agents (e.g. two drugs with comparable anticholinergic/antihistaminic burden) is generally the fastest and best-tolerated switch, sometimes achievable over about a week.
• Switching from a more sedating/anticholinergic agent to a less sedating one (e.g. from olanzapine, quetiapine, or clozapine towards aripiprazole or a higher-potency agent) needs a slower taper of the first drug — stopping too fast risks a cholinergic/histaminic “rebound” (agitation, insomnia, GI upset) as those blocked receptors are suddenly unblocked.
• Aripiprazole, as a partial D2 agonist, can cause transient activation, agitation, or akathisia when cross-titrated with a full D2 antagonist — go slower and warn the patient this may occur early in the switch.
• Clozapine needs special handling in both directions: starting it requires its own mandatory monitoring program (baseline and ongoing FBC for agranulocytosis risk) and a slow up-titration regardless of what’s being switched from; stopping or switching away from clozapine carries a disproportionately high relapse risk and should generally be specialist-led, with a slow taper and close monitoring.
• Depot/long-acting injectable switches need the oral-equivalent dose and the injection interval factored in — typically continue oral cover (or the outgoing agent) until the depot has reached steady-state levels, per the specific product’s switching guidance.
• Watch for supersensitivity psychosis — a relapse driven by dopamine-receptor upregulation from prolonged D2 blockade, which can present as a rebound psychotic episode weeks after stopping or substantially reducing a high-potency antagonist, distinct from the underlying illness simply re-emerging.

Because individual drug potency, receptor-binding profile, and half-life all affect how a given switch should be paced, get current specific-agent switching advice from eTG/AMH (subscription — cite by name only) or specialist/pharmacist input for anything outside a straightforward same-class switch.