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Tuesday, August 19, 2025

Antipsychotics


Introduction

Antipsychotics, also called neuroleptics or major tranquilizers, are a class of medications primarily used to treat psychotic disorders such as schizophrenia, schizoaffective disorder, and delusional disorders. They are also employed in the management of bipolar disorder, severe depression with psychotic features, agitation, Tourette’s syndrome, and behavioral disturbances in dementia (with caution).

These agents function mainly by modulating dopaminergic and serotonergic neurotransmission in the brain, particularly within the mesolimbic and mesocortical pathways.

They are broadly divided into:

  1. First-generation antipsychotics (FGAs, typical antipsychotics)

  2. Second-generation antipsychotics (SGAs, atypical antipsychotics)

  3. Third-generation antipsychotics (partial dopamine agonists with unique mechanisms)

Classification and Generic Names

1. First-Generation (Typical) Antipsychotics

High-potency FGAs:

  • Haloperidol

  • Fluphenazine

  • Trifluoperazine

  • Thiothixene

Medium-potency FGAs:

  • Perphenazine

  • Loxapine

Low-potency FGAs:

  • Chlorpromazine

  • Thioridazine

  • Mesoridazine

2. Second-Generation (Atypical) Antipsychotics

  • Clozapine

  • Risperidone

  • Olanzapine

  • Quetiapine

  • Ziprasidone

  • Paliperidone

  • Lurasidone

  • Asenapine

  • Iloperidone

  • Sertindole (not widely available in some countries)

3. Third-Generation Antipsychotics

  • Aripiprazole

  • Brexpiprazole

  • Cariprazine

Mechanism of Action

  • FGAs (typical antipsychotics): Potent dopamine D2 receptor antagonists in mesolimbic pathways. This reduces positive symptoms of psychosis (hallucinations, delusions), but high D2 blockade in nigrostriatal and tuberoinfundibular pathways leads to extrapyramidal symptoms (EPS) and hyperprolactinemia.

  • SGAs (atypical antipsychotics): Block both D2 receptors and serotonin 5-HT2A receptors. This dual mechanism reduces EPS risk and improves efficacy against negative and cognitive symptoms of schizophrenia.

  • Third-generation antipsychotics: Partial D2 agonists (rather than full antagonists), providing “dopamine stabilizing” effects with fewer side effects.

Clinical Uses

  • Schizophrenia – mainstay treatment for positive and negative symptoms.

  • Bipolar disorder – management of acute mania, depression, and maintenance therapy (e.g., quetiapine, olanzapine, risperidone).

  • Depression with psychotic features – in combination with antidepressants.

  • Tourette’s syndrome and tics – haloperidol, risperidone.

  • Severe agitation or aggression – haloperidol, olanzapine, or benzodiazepine co-therapy.

  • Treatment-resistant schizophrenia – clozapine remains the gold standard.

Dosage Examples

  • Haloperidol: 2–20 mg/day orally; depot formulation (monthly IM injection).

  • Chlorpromazine: 100–1000 mg/day orally.

  • Clozapine: Start 12.5 mg once or twice daily; titrate to 300–600 mg/day.

  • Risperidone: 2–8 mg/day orally; long-acting injectable (every 2 weeks).

  • Olanzapine: 10–20 mg/day orally; depot formulation available.

  • Quetiapine: 300–800 mg/day orally (divided doses).

  • Ziprasidone: 40–80 mg orally twice daily (with food).

  • Aripiprazole: 10–30 mg/day orally; depot injection every 4 weeks.

  • Brexpiprazole: 1–4 mg/day orally.

  • Cariprazine: 1.5–6 mg/day orally.

Contraindications

  • Absolute contraindications:

    • Known hypersensitivity to the drug

    • Coma, severe CNS depression

    • Bone marrow suppression (especially for clozapine)

  • Relative contraindications:

    • Severe liver or kidney disease

    • Cardiac disease (QT prolongation with ziprasidone, haloperidol, thioridazine)

    • Parkinson’s disease (due to worsening of motor symptoms)

    • Epilepsy (lowered seizure threshold with chlorpromazine, clozapine)

Side Effects

1. Neurological (EPS-related)

  • Acute dystonia (muscle spasms)

  • Parkinsonism (rigidity, tremor)

  • Akathisia (restlessness)

  • Tardive dyskinesia (chronic, often irreversible involuntary movements)

2. Metabolic effects (common with SGAs, especially olanzapine, clozapine)

  • Weight gain

  • Diabetes mellitus (insulin resistance)

  • Dyslipidemia

3. Endocrine effects

  • Hyperprolactinemia (risperidone, FGAs): galactorrhea, amenorrhea, gynecomastia, infertility

4. Cardiovascular

  • Orthostatic hypotension (alpha-1 blockade)

  • QT prolongation (ziprasidone, haloperidol, thioridazine)

5. Hematologic

  • Clozapine: agranulocytosis (requires regular blood monitoring)

6. Other notable adverse effects

  • Neuroleptic malignant syndrome (rare, life-threatening; muscle rigidity, hyperthermia, autonomic instability)

  • Sedation (histamine H1 blockade)

  • Anticholinergic effects (dry mouth, blurred vision, constipation, urinary retention)

Precautions

  • Clozapine: Requires weekly blood counts initially due to agranulocytosis risk.

  • Cardiac monitoring: Patients on ziprasidone, haloperidol, thioridazine require ECG monitoring due to QT prolongation risk.

  • Metabolic monitoring: Weight, fasting glucose, lipids checked regularly in patients on SGAs.

  • Elderly with dementia: Antipsychotics carry an FDA boxed warning for increased risk of mortality.

  • Pregnancy: Most antipsychotics are category C; use only if benefits outweigh risks.

Drug Interactions

  • CNS depressants (benzodiazepines, opioids, alcohol): Increased sedation and respiratory depression.

  • QT-prolonging drugs (antiarrhythmics, macrolide antibiotics): Increased risk of torsades de pointes.

  • Enzyme inducers/inhibitors:

    • Carbamazepine reduces plasma concentrations of antipsychotics.

    • CYP3A4 inhibitors (ketoconazole, erythromycin) increase levels of some antipsychotics (quetiapine, lurasidone).

  • Lithium + antipsychotics: Neurotoxicity risk.

  • Antihypertensives: Additive hypotensive effects.

Comparative Efficacy

  • FGAs: Effective for positive symptoms, but limited for negative/cognitive symptoms; high risk of EPS.

  • SGAs: Broader efficacy (positive, negative, and mood symptoms); better tolerability for EPS but higher metabolic side effects.

  • Third-generation antipsychotics: Balance of efficacy and safety, with lower metabolic and prolactin effects.

Role of Clozapine

Clozapine is considered the most effective antipsychotic for treatment-resistant schizophrenia but is reserved due to risk of agranulocytosis, seizures, myocarditis, and significant metabolic effects. Despite risks, it reduces suicide rates in schizophrenia, making it invaluable in select cases.

Long-Acting Injectables (Depot Antipsychotics)

To improve adherence, several antipsychotics are available as depot injections:

  • Haloperidol decanoate

  • Fluphenazine decanoate

  • Risperidone microspheres (every 2 weeks)

  • Paliperidone palmitate (monthly or every 3 months)

  • Olanzapine pamoate

  • Aripiprazole long-acting injectable

These provide steady plasma concentrations, reduce relapse risk, and are beneficial for patients with poor compliance.

Monitoring

  • CBC: Clozapine (for agranulocytosis).

  • ECG: QT prolonging drugs.

  • Metabolic panel: Glucose, lipid profile, weight for SGAs.

  • Neurological assessment: EPS, tardive dyskinesia (Abnormal Involuntary Movement Scale – AIMS test).



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