Antipsychotic Drug Actions
How typical and atypical antipsychotics differ in receptor binding profiles, efficacy, and side effect patterns.
## Dopamine Hypothesis of Schizophrenia
The dopamine hypothesis posits that positive symptoms (hallucinations, delusions) arise from excessive mesolimbic dopaminergic activity, while negative symptoms (flat affect, avolition) and cognitive deficits relate to mesocortical dopamine hypofunction. All effective antipsychotics block D2 receptors, with therapeutic occupancy of 60-80%.
## Typical (First-Generation) Antipsychotics
High-potency agents (haloperidol, fluphenazine) bind D2 tightly, effectively controlling positive symptoms but causing significant extrapyramidal symptoms (EPS): acute dystonia, akathisia, parkinsonism, and tardive dyskinesia with chronic use. Low-potency agents (chlorpromazine) have more anticholinergic and antihistaminic effects but less EPS.
**Neuroleptic malignant syndrome (NMS)** is a rare, life-threatening reaction characterized by hyperthermia, rigidity, autonomic instability, and elevated CK. Treatment involves dantrolene and bromocriptine.
## Atypical (Second-Generation) Antipsychotics
Atypicals are defined by 5-HT2A antagonism combined with D2 antagonism. The 5-HT2A/D2 binding ratio partly explains their lower EPS risk.
| Drug | Key Features |
|------|-------------|
| Clozapine | Gold standard for treatment-resistant schizophrenia; risk of agranulocytosis (requires monitoring); low D2 affinity, broad receptor profile |
| Risperidone | Potent D2 + 5-HT2A; dose-dependent EPS and hyperprolactinemia |
| Olanzapine | Effective but high metabolic risk (weight gain, diabetes, dyslipidemia) |
| Quetiapine | Low D2 affinity; sedating; used off-label for insomnia and bipolar depression |
| Aripiprazole | D2 partial agonist (functional selectivity); lower metabolic burden; may cause akathisia |
| Cariprazine | D3-preferring partial agonist; efficacy for negative symptoms |
## Third-Generation Concepts
D2 partial agonists (aripiprazole, brexpiprazole, cariprazine) stabilize dopaminergic tone rather than blocking it completely. They reduce activity where dopamine is excessive (mesolimbic) and maintain it where dopamine is deficient (mesocortical).
## Metabolic Monitoring
Atypical antipsychotics, particularly olanzapine and clozapine, require metabolic monitoring: fasting glucose, lipid panel, weight, and waist circumference at baseline and regularly thereafter. Metabolic syndrome is a leading cause of reduced life expectancy in schizophrenia.
## Key Takeaways
- All antipsychotics require D2 receptor blockade for efficacy against positive symptoms
- Atypicals add 5-HT2A antagonism, reducing EPS but introducing metabolic risks
- Clozapine is uniquely effective for treatment-resistant schizophrenia but requires blood monitoring
- D2 partial agonists represent an evolving approach to dopamine stabilization