Drug interactions with antipsychotic agents: Incidence and therapeutic implications

Antipsychotics are the mainstay of treatment for psychotic disorders. Both the newer atypical antipsychotics and their more traditional counterparts are subject to drug-drug interactions amongst themselves, with other psychotropics and with agents used in the treatment of various physical ailments. Furthermore, drug interactions have been documented to occur with many agents commonly used in conjunction with antipsychotics such as anticholinergics, anticonvulsants, antidepressants, anxiolytics and lithium. Different types of drug interaction can occur, including pharmacodynamic, pharmacokinetic and pharmaceutic interactions. Pharmacodynamic interactions occur between agents that have similar receptor site activity. Pharmacokinetic interactions occur when the combination of drugs results in alterations in the absorption, distribution, metabolism or excretion of either agent. As a group, the antipsychotics are highly protein bound (>90%) and distribute widely into tissues. As a consequence, interactions can arise from combining antipsychotics with other agents that are also highly protein bound. Antipsychotics undergo phase I and II metabolism to more water-soluble compounds to aid in excretion from the body. Research has dramatically expanded in the area of metabolism by the cytochrome P450 (CYP) system. Most antipsychotics are metabolised by the CYP system and potential drug interactions could occur when they are administered with other agents that affect or are metabolised by the same isozymes. Persons who lack specific CYP isozymes (CYP2D6 or CYP2C19) can be at an increased risk for the development of adverse effects when administered antipsychotics, due to higher than expected plasma concentrations of these drugs. The anticonvulsants carbamazepine and phenobarbital (phenobarbitone) are enzyme inducers. When these drugs are given concurrently with antipsychotics, decreased plasma concentrations and therapeutic effectiveness of antipsychotics can occur. Tricyclic antidepressants can compete for similar metabolic enzymes with antipsychotics. This can result in an increase in plasma concentrations and a risk of adverse effects of either agent. All clinically available serotonin (5-hydroxytryptamine; 5- HT) reuptake inhibitors have inhibitory activity at various CYP isozymes and potentially cause increases in plasma concentrations of antipsychotics. Smoking is relatively common in schizophrenic populations and can induce metabolic enzymes, resulting in lower