Psychotic Disorders & Antipsychotic Drugs — Study Pack Study Guide

🧠 Introduction

Psychotropic drugs are agents that primarily affect the psyche and are used to treat psychiatric disorders. Since the 1950s (notably with chlorpromazine), drug treatments shifted psychiatry from custodial care toward rehabilitation and community reintegration.

🧾 Diagnostic Categories

Psychiatric syndromes are imprecise but are grouped to guide drug choice. Major divisions include psychoses (e.g., schizophrenia, organic brain syndromes, paranoid states, mood disorders with psychosis) and neuroses (e.g., anxiety, phobias, obsessive-compulsive disorder, PTSD). Treatment is often symptom-oriented rather than disease-specific.

⚖️ Antipsychotic Classes

Antipsychotics are broadly classified as typical (first-generation) and atypical (second-generation). Typical examples: chlorpromazine (CPZ), haloperidol, phenothiazines, butyrophenones. Atypicals include clozapine, risperidone, olanzapine, quetiapine, aripiprazole, amisulpride. They differ in receptor profiles, side-effect risks, and metabolic effects.

🔬 Mechanism of Action

Typical antipsychotics primarily block dopamine D2 receptors, particularly in mesolimbic pathways, reducing positive symptoms (hallucinations, delusions). Atypical agents often combine weaker D2 antagonism with potent 5-HT2A antagonism, and actions on other receptors (D4, α1, H1, muscarinic), which may improve negative symptoms and reduce extrapyramidal side effects (EPS).

🧩 Clinical Effects

Antipsychotics are most effective for positive symptoms of schizophrenia. Negative symptoms (apathy, social withdrawal) are less responsive to typical agents; some atypicals show better efficacy. Antipsychotics are also used in mania, severe agitation, behavior disturbances, Tourette's syndrome, and in some adjunctive situations for children and elderly with caution.

⚠️ Major Adverse Effects

• Extrapyramidal symptoms (EPS): parkinsonism, acute dystonia, akathisia, tardive dyskinesia. High-potency typicals (haloperidol, fluphenazine) carry higher EPS risk; atypicals lower risk overall.
• Malignant neuroleptic syndrome: rare but life-threatening—rigidity, hyperthermia, autonomic instability; requires immediate drug withdrawal and supportive care.
• Tardive dyskinesia: often late-onset, sometimes irreversible; risk increases with long-term typical antipsychotics and in elderly women.
• Metabolic effects: weight gain, hyperglycemia, dyslipidemia—notably with clozapine and olanzapine.
• Hematologic risks: clozapine has a known risk of agranulocytosis requiring regular WBC monitoring.
• Cardiac risks: QT prolongation possible with several agents (e.g., amisulpride, high-dose quetiapine), caution in predisposed patients.

🧪 Pharmacokinetics & Interactions

Many antipsychotics are extensively metabolized by hepatic CYP enzymes (CYP1A2, CYP2D6, CYP3A4). Interactions include enzyme inducers (phenobarbital, carbamazepine) lowering antipsychotic levels and inhibitors (ketoconazole, fluoxetine) raising levels. Clozapine and olanzapine are metabolized by CYP1A2; quetiapine and aripiprazole by CYP3A4 with CYP2D6 involvement for aripiprazole.

🩺 Drug-Specific Highlights

• Chlorpromazine (CPZ): first major antipsychotic; sedative, hypotensive, anticholinergic effects; variable pharmacokinetics and many active metabolites.
• Haloperidol: potent D2 blocker, high EPS risk, less sedation and anticholinergic effects than CPZ; widely used for acute control.
• Clozapine: most effective for treatment-resistant schizophrenia; low EPS and tardive dyskinesia risk but significant agranulocytosis and metabolic risks; requires strict hematologic monitoring.
• Risperidone: stronger D2 blockade among atypicals; can elevate prolactin and cause some EPS at higher doses; metabolic risk moderate.
• Olanzapine: potent metabolic side effects (weight, glucose, lipids); antimuscarinic and sedating.
• Quetiapine: sedating, modest metabolic risk, useful in bipolar disorder; metabolized by CYP3A4.
• Aripiprazole: partial D2 and 5-HT1A agonist and 5-HT2 antagonist; lower metabolic/EPS liability, long half-life, CYP3A4/CYP2D6 metabolism.
• Amisulpride: D2/D3 selective atypical profile, useful for negative symptoms; hyperprolactinemia and QT prolongation risks.

🧾 Monitoring & Practical Points

• Start with lowest effective dose and titrate; once stable, reduce to maintenance minimum.
• For clozapine, monitor WBC/ANC weekly for first 18 weeks, then fortnightly to monthly as per protocol. Stop if WBC/ANC drops below safety thresholds.
• Monitor metabolic parameters (weight, fasting glucose, lipids) for all atypicals, especially clozapine and olanzapine.
• Screen for cardiac risk factors and check QT when using agents known to prolong QT or in polypharmacy.
• Use caution in elderly, pediatric, pregnant, and medically compromised patients; adjust doses and observe for orthostatic hypotension, anticholinergic effects, and sedation.

🧭 Management of EPS and Emergencies

• Acute dystonia: treat promptly with IM/IV anticholinergic (e.g., biperiden) or antihistamine (promethazine).
• Akathisia: reduce dose, consider benzodiazepines or propranolol.
• Parkinsonism: anticholinergic antiparkinson drugs may help, or switch to atypical antipsychotic.
• Malignant neuroleptic syndrome: stop antipsychotic, provide supportive care, consider dantrolene and bromocriptine.
• Tardive dyskinesia: minimize exposure to offending agents; clozapine and some atypicals have lower risk.

✅ Summary

Antipsychotics are cornerstone treatments for psychosis and acute behavioral disturbances. Choice depends on symptom profile, side-effect risks (EPS vs metabolic), drug interactions, and patient-specific factors. Close monitoring and individualized dosing maximize benefit while minimizing harm.