Antipsychotics: Typical vs Atypical
Antipsychotics treat schizophrenia and other psychotic disorders by modulating dopamine pathways. First-generation agents primarily block D2 receptors, while second-generation agents have broader receptor profiles with different side effect trade-offs.
## Dopamine Hypothesis of Schizophrenia
The dopamine hypothesis proposes that positive symptoms (hallucinations, delusions) result from excessive dopamine activity in the mesolimbic pathway, while negative symptoms (flat affect, social withdrawal) and cognitive deficits involve dopamine hypofunction in the mesocortical pathway. All effective antipsychotics block dopamine D2 receptors, but their receptor selectivity and additional binding profiles determine their side effect spectrum.
## First-Generation (Typical) Antipsychotics
These agents primarily antagonize D2 receptors with relatively little activity at other receptor types.
**High-potency:** Haloperidol, fluphenazine. Strong D2 blockade produces reliable antipsychotic effect but high extrapyramidal symptom (EPS) risk. Available in long-acting injectable (LAI) formulations for adherence.
**Low-potency:** Chlorpromazine, thioridazine. Weaker D2 binding but significant blockade of muscarinic (M1), histamine (H1), and alpha-1 adrenergic receptors, causing anticholinergic effects, sedation, and orthostatic hypotension respectively.
## Second-Generation (Atypical) Antipsychotics
These agents combine D2 antagonism with serotonin 5-HT2A antagonism (the defining pharmacological feature), plus variable binding at other receptors.
- **Clozapine** -- Most effective antipsychotic, reserved for treatment-resistant schizophrenia. Unique side effect: agranulocytosis (1-2%), requiring mandatory blood monitoring. Also causes metabolic syndrome, myocarditis, and seizures at high doses. Only agent proven to reduce suicidality in schizophrenia.
- **Risperidone** -- Potent D2 blocker among atypicals; higher EPS risk at higher doses. Significant prolactin elevation.
- **Olanzapine** -- Effective but causes the most weight gain and metabolic derangement among atypicals.
- **Quetiapine** -- Sedating, used off-label for insomnia and anxiety. Low EPS risk. Dose-dependent receptor profile.
- **Aripiprazole** -- Partial D2 agonist (dopamine system stabilizer). Low metabolic and EPS risk. Can cause akathisia.
- **Lurasidone** -- Favorable metabolic profile. Must be taken with food (350+ calories) for absorption.
## Extrapyramidal Symptoms
EPS are movement disorders caused by D2 blockade in the nigrostriatal pathway:
- **Acute dystonia** -- Involuntary muscle contractions (hours to days). Treat with anticholinergics (benztropine).
- **Akathisia** -- Subjective restlessness. Most distressing to patients. Beta-blockers (propranolol) or benzodiazepines help.
- **Parkinsonism** -- Bradykinesia, rigidity, tremor. Reduce dose or switch agents.
- **Tardive dyskinesia** -- Late-onset involuntary movements (lip smacking, tongue protrusion). May be irreversible. Treat with VMAT2 inhibitors (valbenazine, deutetrabenazine).
## Metabolic Side Effects
Second-generation antipsychotics, particularly clozapine and olanzapine, cause significant weight gain, hyperglycemia, dyslipidemia, and increased cardiovascular risk. Metabolic monitoring (weight, glucose, lipids) should occur at baseline, 3 months, and annually. Metformin can attenuate weight gain.
## Key Takeaways
- All antipsychotics block D2 receptors; the difference lies in receptor selectivity and side effect profiles.
- Clozapine is the gold standard for treatment-resistant schizophrenia but requires blood monitoring.
- Typical antipsychotics have higher EPS risk; atypicals have higher metabolic risk -- neither class is clearly "better."
- Tardive dyskinesia risk exists with all antipsychotics -- use the lowest effective dose.