Extrapyramidal side effects
Benperidol
High risk of extrapyramidal side effects due to potent D2 antagonism. Can cause dystonia, akathisia, parkinsonism, and tardive dyskinesia, especially at high doses.
Clozapine
Low risk of extrapyramidal side effects due to weaker D2 antagonism and additional 5-HT2A antagonism. Rarely causes movement disorders even at high doses.
Sedation and drowsiness
Benperidol
Moderate sedation and drowsiness due to antihistamine and anticholinergic effects. Risk is dose-dependent and usually highest at start of treatment or dose increases.
Clozapine
Significant sedation and drowsiness, especially at high doses. Due to strong H1 antihistamine effects. Usually most pronounced during titration period but can persist long-term. Requires slow dose titration.
Orthostatic hypotension
Benperidol
Can cause moderate drop in blood pressure upon standing due to alpha-adrenergic blockade. Usually transient but can lead to dizziness, fainting and falls. Blood pressure monitoring recommended.
Clozapine
High risk of orthostatic hypotension due to potent alpha-adrenergic antagonism. Can cause persistent hypotension throughout treatment. Frequent blood pressure monitoring required, especially during titration. Hospitalization often needed for initial dose titration.
Weight gain
Benperidol
Can cause moderate weight gain, especially long term. Due to effects on serotonin, histamine and dopamine receptors. Weight gain may be dose-dependent.
Clozapine
Significant weight gain occurs in most patients. Due to strong 5-HT2C inverse agonism and H1 antihistamine effects. Weight gain can continue even with long term treatment and stable dosing. Strict diet and exercise often have limited effect. Weight gain contributes to increased morbidity and mortality.
Anticholinergic effects
Benperidol
Anticholinergic side effects such as dry mouth, constipation, blurred vision, and urinary retention. Due to muscarinic M1 antagonism. Higher risk in elderly or at high doses.
Clozapine
Rarely causes significant anticholinergic side effects. Weaker binding to muscarinic receptors compared to benperidol and most other typical antipsychotics. Reduces risk of confusion and cognitive impairment, especially in elderly.
In summary, clozapine has a lower risk of extrapyramidal, anticholinergic and orthostatic side effects compared to benperidol, but causes significant sedation, dizziness and weight gain due to its potent antihistamine effects. The choice of antipsychotic depends on weighing up an individual patient’s risk factors for different side effects and tailoring treatment accordingly. Close monitoring and management of side effects is needed with both agents.