atypical antipsychotic

Atypical antipsychotics (e.g., risperidone, olanzapine, quetiapine, clozapine, aripiprazole, ziprasidone) act primarily via combined antagonism of D2 and 5-HT2A receptors, with some agents (aripiprazole) acting as partial D2 agonists. The serotonin antagonism is thought to reduce extrapyramidal symptoms by increasing dopamine release in the nigrostriatal pathway, which is why these drugs have a lower risk of EPS and tardive dyskinesia compared to first-generation (typical) antipsychotics that block D2 receptors more potently and non-selectively.

Clinical uses include schizophrenia (positive and negative symptoms), bipolar disorder (mania and depression), treatment-resistant depression (adjunct), and autism-related irritability. Clozapine is reserved for treatment-resistant schizophrenia due to risk of agranulocytosis requiring regular ANC monitoring; it's also uniquely effective for reducing suicidality in schizophrenia.

Key adverse effects: metabolic syndrome (weight gain, hyperglycemia, dyslipidemia) - most notably with olanzapine and clozapine; QT prolongation (ziprasidone); hyperprolactinemia (risperidone, paliperidone - the atypical most similar to typicals in this regard); sedation and anticholinergic effects (quetiapine, olanzapine); orthostatic hypotension (due to alpha-1 blockade). Aripiprazole and ziprasidone have more favorable metabolic profiles. All antipsychotics carry a black box warning for increased mortality in elderly patients with dementia-related psychosis.

Monitoring includes baseline and periodic metabolic panels (glucose, lipids), weight/BMI, and for clozapine, weekly to monthly CBC with differential to monitor for agranulocytosis. Neuroleptic malignant syndrome (NMS) remains a risk with atypicals, though less common than with typicals - presents with fever, rigidity, autonomic instability, and elevated CK.