Second Generation Antipsychotics

Second generation antipsychotics (clozapine, olanzapine, risperidone, paliperidone, quetiapine, ziprasidone, lurasidone, asenapine, amisulpride, aripiprazole, brexpiprazole, cariprazine) cause fewer extrapyramidal effects than first generation drugs but more metabolic effects. They are first-line in usual practice for schizophrenia and bipolar disorder.

Mechanism. They antagonise D2 and 5-HT2A receptors, with variable activity at histamine, muscarinic and adrenergic receptors. Aripiprazole, brexpiprazole and cariprazine are D2 partial agonists. Clozapine has low D2 affinity and broad receptor activity.

Pharmacokinetics. Mostly hepatic metabolism through CYP3A4, CYP2D6 and CYP1A2. Clozapine and olanzapine are metabolised by CYP1A2, so smoking induces them (smokers need higher doses; stopping smoking raises clozapine levels by about 50%). Amisulpride and paliperidone are renally cleared.

Long-acting injections. Risperidone 25 to 50 mg every 2 weeks; paliperidone palmitate 150 mg on day 1 and 100 mg on day 8 then monthly maintenance 25 to 150 mg; aripiprazole 400 mg monthly with 14 days of oral cover; olanzapine pamoate 150 to 405 mg every 2 to 4 weeks, with post-injection sedation syndrome (observe for 3 hours).

• First-line: choose by side effect profile. Weight and metabolic risk favour aripiprazole, lurasidone or ziprasidone; sedation and agitation favour olanzapine or quetiapine; avoid risperidone and amisulpride when prolactin matters.
• Treatment-resistant schizophrenia: clozapine after two adequate courses. Titrate slowly, restart titration if more than 48 hours of doses are missed, and give prophylactic laxatives.
• Clozapine blood count: baseline and weekly for 18 weeks, every 2 weeks to 1 year, then monthly. Stop for an absolute neutrophil count under 1.5 x 10^9/L (under 1.0 x 10^9/L where a lower baseline is established as benign ethnic neutropenia, common in people of African ancestry and Duffy-null phenotype).
• Clozapine myocarditis: weekly troponin and C-reactive protein for the first 4 weeks; stop for troponin over twice the upper limit or CRP over 100 mg/L, or unexplained fever, tachycardia or chest pain.
• Bipolar disorder: olanzapine, quetiapine (300 mg for bipolar depression), risperidone and aripiprazole.
• Parenteral olanzapine: avoid within 1 hour of a parenteral benzodiazepine, because of cardiorespiratory depression.

Special groups. Pregnancy: olanzapine and quetiapine have the most data; monitor gestational diabetes. Breastfeeding: avoid clozapine. Children: specialist use only. Older adults: lower doses, increased stroke and mortality in dementia. Kidney impairment: reduce amisulpride and paliperidone. Liver impairment: reduce doses. Regional: risperidone is the most available; olanzapine and quetiapine are more costly; clozapine services are limited by blood monitoring, so use point-of-care counts where possible.

Adverse effects. Weight gain and metabolic syndrome (clozapine, olanzapine), hyperprolactinaemia (risperidone, paliperidone, amisulpride), akathisia (aripiprazole, lurasidone, cariprazine), sedation, orthostatic hypotension, QT prolongation (ziprasidone, amisulpride), seizures (clozapine above 600 mg), sialorrhoea, constipation and ileus (clozapine), agranulocytosis (clozapine), and myocarditis (clozapine).

Contraindications. Clozapine with neutropenia, uncontrolled epilepsy, or paralytic ileus; ziprasidone with QT prolongation.

Interactions. Fluvoxamine and ciprofloxacin raise clozapine and olanzapine levels sharply. Carbamazepine, rifampicin and smoking lower levels. Ritonavir raises aripiprazole, quetiapine and risperidone levels.

Monitoring. Weight at 4, 8 and 12 weeks then each year, fasting glucose and lipids at 12 weeks then yearly, blood pressure, prolactin if symptoms, ECG where QT risk exists, and clozapine blood counts (weekly for 18 weeks, every 2 weeks to 1 year, then monthly).

Referral and escalation. All clozapine starts, neutropenia, myocarditis, severe constipation, or treatment resistance.