Pathophysiology

• Antipsychotic agents exert their therapeutic effect largely by antagonizing dopamine receptors in the central nervous system. Newer antipsychotic agents also modulate serotonergic tone.
  • Dopamine antagonism unbalanced by muscarinic antagonism leads to extrapyramidal neuromuscular effects, such as acute dystonia, torticollis, oculogyric crisis, drug-induced Parkinsonism, and tardive dyskinesia.
  • Generally speaking, the atypical or second-generation antipsychotics have significant antimuscarinic effects that mitigate (but do not eliminate) the risk of extrapyramidal symptoms.
  • Dopamine antagonism in the tuberoinfundibular system may lead to gynecomastia and galactorrhea; risperidone is particularly problematic in this regard.
• The antipsychotics also have several well-known “off-target” effects on other receptors and ion channels that are relevant in therapeutic use and overdose.
  • Muscarinic antagonism may produce sedation and an antimuscarinic toxidrome in overdose. Quetiapine is particularly antimuscarinic.
  • Alpha-1 adrenoceptor antagonism may produce orthostasis and reflex tachycardia.
  • Blockade of the cardiac sodium and potassium channels may produce prolongation of the QRS and QT intervals and predispose to dysrhythmias.
• Although each antipsychotic has its own unique pharmacologic profile, in general, first-generation agents (neuroleptics, e.g., haloperidol, droperidol, chlorpromazine) cause more cardiac toxicity and extrapyramidal symptoms than second-generation agents (atypicals, e.g., quetiapine, olanzapine, risperidone).
• Clozapine has unique adverse effects, including profound sialorrhea and agranulocytosis. Its use is closely monitored and restricted.