Chapter 16  ·  Module 5  ·  Introduction to Medical Pharmacology

Adverse Effects and Systematic Clinical Management

Extrapyramidal syndromes, tardive dyskinesia, neuroleptic malignant syndrome, metabolic effects, QTc risk, and hyperprolactinemia

Extrapyramidal Syndromes — Quick Reference

Syndrome Onset Key Features Risk Factors Treatment
Acute Dystonia Hours to days Oculogyric crisis, torticollis, opisthotonus; laryngeal dystonia = airway emergency Young males; antipsychotic-naive; high-potency agents Benztropine or diphenhydramine IM or IV — rapid
Akathisia Days to weeks Subjective restlessness, urge to move; danger: mistaken for worsening psychosis All antipsychotics; partial agonists at higher doses Propranolol first-line; dose reduction; benzodiazepines short-term. Anticholinergics NOT first-line
Drug-Induced Parkinsonism Weeks Bradykinesia, rigidity, tremor; identical to Parkinson disease at examination Elderly; high-potency agents; dose-dependent Dose reduction preferred; benztropine or amantadine if needed. Caution: anticholinergics worsen cognition
Tardive Dyskinesia Months to years Repetitive orofacial movements (lip smacking, tongue protrusion); may be irreversible Older age; female; high cumulative dose; first-generation agents Minimize dose or switch agent; valbenazine or deutetrabenazine (vesicular monoamine transporter 2 inhibitors) for established cases

Neuroleptic Malignant Syndrome and Metabolic Monitoring

Neuroleptic Malignant Syndrome

  • Tetrad: Hyperthermia + Lead-pipe rigidity + Autonomic instability + Altered consciousness
  • Lab: Markedly elevated creatine kinase (rhabdomyolysis)
  • Onset: 24–72 hours (slow vs. serotonin syndrome)
  • vs. Serotonin syndrome: Rigidity + bradyreflexia (not hyperreflexia/clonus)
  • Treatment: Stop antipsychotic immediately + dantrolene + bromocriptine + intensive care unit
  • Rechallenge: Wait minimum 2 weeks after full resolution; use lowest-potency agent

Metabolic Syndrome Monitoring

  • Baseline: Weight/body mass index, waist circumference, blood pressure, fasting glucose/hemoglobin A1c, lipid panel
  • Follow-up weight: At 4, 8, and 12 weeks
  • Fasting glucose and lipids: At 12 weeks, then annually
  • Highest risk agents: Clozapine > olanzapine > quetiapine
  • If >5% weight gain: Dietary counseling, exercise referral, consider switch or metformin
  • Best pharmacological adjunct: Metformin — strongest evidence base for antipsychotic-induced weight gain

QTc Prolongation Risk by Agent

Agent(s) QTc Risk Level Clinical Note
Thioridazine, pimozide Highest — last resort hERG channel blockade; risk of torsades de pointes; rarely used
Ziprasidone, haloperidol (intravenous), iloperidone Moderate — monitor Baseline electrocardiogram required; avoid in known QTc prolongation
Clozapine, olanzapine, quetiapine, risperidone Low — nonzero Assess when adding QTc-active comedications
Aripiprazole, brexpiprazole, cariprazine, lurasidone Negligible No meaningful QTc effect at therapeutic doses

Hyperprolactinemia: Highest with risperidone, paliperidone, and high-potency first-generation antipsychotics. Absent with clozapine, quetiapine, and partial agonists. Consequences: amenorrhea, galactorrhea, sexual dysfunction, gynecomastia, reduced bone density. Management: switch to prolactin-sparing agent, or add low-dose aripiprazole to existing regimen.

Tardive dyskinesia treatment: Valbenazine (once daily) and deutetrabenazine (twice daily) — vesicular monoamine transporter 2 inhibitors approved specifically for tardive dyskinesia. Treat without stopping the antipsychotic. Monitor for depression/suicidality — class adverse effect. Contraindicated in untreated depression or active suicidality.