Chapter 16  ·  Module 3  ·  Introduction to Medical Pharmacology

Second-Generation Antipsychotics: Core Agents

Clozapine, olanzapine, quetiapine, risperidone, and paliperidone — receptor profiles and clinical trade-offs

Receptor Profile and Adverse Effect Comparison

Agent Key Mechanism Extrapyramidal Symptom Risk Metabolic Risk Prolactin Elevation Distinguishing Feature
Clozapine Multi-receptor (D2, D4, 5-HT2A, H1, M1, alpha-1) None Highest None Only agent for treatment-resistant schizophrenia; agranulocytosis requires Risk Evaluation and Mitigation Strategy monitoring
Olanzapine D2 + 5-HT2A + H1 + M1 + 5-HT2C Low High Low No agranulocytosis; intramuscular form contraindicated with benzodiazepines; cytochrome P450 1A2 substrate (smoking interaction)
Quetiapine D2 (fast-off) + 5-HT2A + H1 + alpha-1 None Moderate None Broadest indication range; strong cytochrome P450 3A4 interactions; low-dose sedation widely used off-label
Risperidone D2 + 5-HT2A (high affinity) Low at ≤6 mg; High above 8 mg Moderate High Dose-dependent extrapyramidal symptom threshold; most prolactin elevation in second-generation class; cytochrome P450 2D6 substrate
Paliperidone D2 + 5-HT2A (active metabolite of risperidone) Low at standard doses Moderate High Renal elimination — unaffected by cytochrome P450 inhibitors; monthly/3-monthly/6-monthly injectable formulations available

Clozapine — Unique Properties and Monitoring

Why Clozapine Is Used

  • Indication: Treatment-resistant schizophrenia — failed 2 adequate trials
  • Response rate: 30–60% in treatment-resistant patients vs. near zero for further standard agents
  • Anti-suicidal: Only antipsychotic with Food and Drug Administration indication for reducing suicidal behavior
  • No extrapyramidal symptoms: Low, fast-dissociating D2 occupancy (40–60%)
  • No prolactin elevation
  • Initiate after 2nd trial failure — not as last resort

Clozapine Adverse Effects and Monitoring

  • Agranulocytosis (0.8–1%): absolute neutrophil count weekly ×6 months → biweekly → monthly via Risk Evaluation and Mitigation Strategy
  • Weight gain: Highest of any antipsychotic; new-onset diabetes and diabetic ketoacidosis possible
  • Seizures: Dose-dependent — up to 5% above 600 mg/day; use valproate (not carbamazepine)
  • Sialorrhea: Paradoxical — muscarinic M4 agonism in salivary glands
  • Myocarditis: First 6–8 weeks — monitor troponin and C-reactive protein
  • Orthostatic hypotension: Slow titration required — start at 12.5 mg

Drug Interactions — Summary: Clozapine and olanzapine: cytochrome P450 1A2 substrates — smoking reduces levels 40–50%; fluvoxamine raises clozapine levels 5–10-fold; carbamazepine contraindicated with clozapine. Quetiapine: cytochrome P450 3A4 substrate — strong inhibitors (azole antifungals) raise levels ×5; strong inducers (carbamazepine) reduce levels up to 90%. Risperidone: cytochrome P450 2D6 substrate — fluoxetine/paroxetine raise levels; paliperidone is renally cleared and avoids these interactions.

Intramuscular olanzapine contraindication: Never combine intramuscular olanzapine with intramuscular or intravenous benzodiazepines — risk of fatal respiratory depression.