Management of Schizophrenia

1. Classification of Antipsychotics

• First-Generation Antipsychotics (FGAs / "typicals"): e.g. haloperidol, chlorpromazine, fluphenazine, trifluoperazine. High D2 blockade, high extrapyramidal side-effect (EPSE) risk. Piperazine phenothiazines and butyrophenones carry the highest EPS risk.
• Second-Generation Antipsychotics (SGAs / "atypicals"): e.g. olanzapine, risperidone, quetiapine, aripiprazole, amisulpride, paliperidone, lurasidone, ziprasidone. Lower EPSE risk at therapeutic doses; broader receptor profiles.
• Clozapine: The only truly "atypical" SGA with near-zero EPSE liability and superior efficacy in treatment-resistant schizophrenia (TRS). Reserved due to the risk of agranulocytosis.

The real distinction between FGAs and SGAs is the ability to choose a dose within the licensed range that is effective without causing EPSEs. - The Maudsley Prescribing Guidelines in Psychiatry, 15th ed.

2. Treatment Algorithm (First-Episode Schizophrenia)

• Effective → Continue at established dose; switch to depot/LAI before discharge.
• No effect → Change drug and repeat the process. If still not effective → Clozapine.
• Not tolerated / poor adherence → Switch to a drug with a more favourable adverse-effect profile; then convert to LAI once efficacy and tolerability are established.

• FGAs should probably be reserved for 2nd- or 3rd-line use given higher TD and EPS risk and possibly poorer outcomes vs SGAs.
• Choice should be based primarily on the comparative adverse-effect profile.
• Patients given informed choice tend to have better outcomes.
• Where prior treatment failure has occurred (but not confirmed TRS), olanzapine or risperidone are better options than quetiapine.
• Olanzapine, given the wealth of evidence for slight superiority, should generally be tried before clozapine.

3. Multi-Episode Schizophrenia and Maintenance Treatment

• The majority of patients with one episode will have further episodes; with each relapse, baseline function deteriorates - most of this decline occurs in the first decade of illness.
• Suicide risk (10%) is concentrated in the first decade.
• Antipsychotics taken regularly protect against relapse in the short and medium term.
• Targeted treatment (only when symptoms re-emerge) produces a worse outcome than prophylactic treatment.
• Optimal prophylactic dose: 5 mg/day risperidone equivalents. Higher doses offer no benefit and worsen tolerability.
• Doses that are acutely effective should generally be continued as maintenance.

Depot / Long-Acting Injectable (LAI) Antipsychotics

• Meta-analyses show that depot/LAI maintenance treatment reduces relative risk of relapse by 30% and absolute risk by 10% compared with oral treatment.
• LAIs should be offered to:
  • Patients who would prefer them after an acute episode
  • Patients known to be non-adherent to oral treatment

Given low rates of adherence and the near-certainty of relapse if antipsychotics are not taken, the routine use of oral antipsychotics is difficult to justify. - The Maudsley Prescribing Guidelines in Psychiatry, 15th ed.

4. Treatment-Resistant Schizophrenia (TRS)

• Confirm adherence (check plasma drug levels - absolute non-adherence with zero blood levels is surprisingly common)
• Exclude substance use (including alcohol) as a confounding factor
• Review co-prescribed medications and physical illness

Clozapine - The Gold Standard for TRS

• Evidence supporting clozapine in TRS is overwhelming.
• Clozapine should be started at 6.25 mg (effective test dose), then titrated slowly to achieve a target plasma level of ~350 mcg/L over approximately 3 weeks.
• Target doses vary by sex, smoking status, and genetic CYP1A2 activity (e.g. Asian patients metabolise clozapine more slowly and require lower doses).
• Mandatory monitoring: FBC for agranulocytosis (weekly for 18 weeks, then fortnightly, then monthly).

Clozapine-Resistant Schizophrenia

1. Add a second antipsychotic to augment (adequate trial = 8-10 weeks; choose a drug that does not compound clozapine's adverse effects - e.g. avoid metabolically problematic agents)
2. ECT augmentation - meta-analyses suggest benefit; some RCTs show ~50% of patients achieve response with ECT + clozapine vs none with clozapine alone. Evidence quality is moderate and results are mixed; ECT + clozapine is generally well tolerated (transient amnesia, headache, nausea as main adverse effects)

5. Managing Suboptimal Response: Dose Increase, Switch, or Augment?

1. Increase the dose - evidence is limited; higher doses risk more adverse effects
2. Switch antipsychotic - often the most practical step
3. Add an adjunctive medication - limited evidence base
4. Wait and monitor - reasonable if external factors are expected to improve

6. Side Effect Management

Metabolic Effects (Diabetes, Weight Gain)

• Schizophrenia itself carries elevated rates of insulin resistance even before antipsychotic exposure.
• Clozapine and olanzapine carry the highest risk of hyperglycaemia, impaired glucose tolerance, and diabetic ketoacidosis (DKA) - risk from clozapine may reach one-third of patients after 5 years.
• Risperidone / paliperidone / amisulpride cause the most prolactin elevation.
• Lifestyle interventions (diet, weight management, physical activity) should be offered to all patients.
• Monitor: fasting glucose, HbA1c, lipids, weight/BMI, blood pressure.

Extrapyramidal Side Effects (EPSEs)

• Tardive dyskinesia (TD): Switch to clozapine, olanzapine, quetiapine, or a D2 partial agonist. Consider vesicular monoamine transporter 2 (VMAT2) inhibitors (valbenazine, deutetrabenazine) if switch is not possible.
• Parkinsonism: Dose reduction or switch to a weaker D2 antagonist or partial agonist. Adjunctive anticholinergics are not routinely recommended.
• Akathisia: Dose reduction; switch to quetiapine or olanzapine; adjunctive propranolol (10-30 mg bid/tid) or mirtazapine 15 mg daily.

Hyperprolactinaemia

• Most common with risperidone, paliperidone, amisulpride.
• If symptomatic (galactorrhoea, sexual dysfunction): switch to a dopamine partial agonist (aripiprazole, cariprazine) or add adjunctive aripiprazole 5 mg daily.
• Counsel about risks of untreated asymptomatic hyperprolactinaemia (reduced bone density, increased breast cancer risk in women).

7. Psychosocial Interventions

8. Physical Health Monitoring

• Weight, BMI, waist circumference
• Blood pressure
• Fasting glucose / HbA1c
• Fasting lipids
• ECG (particularly for drugs prolonging QTc: haloperidol, ziprasidone, sertindole)
• Prolactin level (if symptomatic)
• FBC (mandatory for clozapine)
• Smoking status and cessation support
• Substance use review

9. Duration of Treatment

Summary - Key Principles

1. Start with an SGA - agree choice with patient; prefer one available as LAI.
2. Use minimum effective dose - equivalent to ~5 mg risperidone/day for maintenance.
3. Convert to LAI early - non-adherence is universal; LAI reduces relapse risk by 30% relative to oral.
4. Two adequate trials failed → clozapine - confirm adherence first; ensure at least one prior drug was olanzapine.
5. Monitor metabolic and physical health at every stage.
6. Always combine with psychosocial treatments - medications alone are insufficient.
7. Clozapine-resistant patients: augment with a second antipsychotic or consider ECT.

Recent Evidence Update

• A 2025 JAMA Psychiatry network meta-analysis (PMID 39412783) found differential effects of antipsychotics on cognitive function - clinically relevant when choosing agents.
• A 2025 Lancet Psychiatry international guideline (INTEGRATE) provides updated algorithmic treatment guidance with akathisia, TD, and hyperprolactinaemia management recommendations largely consistent with the above.