Most psychotropic drugs show wide intersubject variability in their efficacy and the risk of complications. Potential factors for the variability include gender, age, body weight, drug interactions and genetics. Molecular genetic approaches provide a novel method of dissecting the heterogeneity of psychotropic drug response and the genetic factor seems to be one of the most important determinants of drug response. Many psychotropic agents are known to be involved in drug-drug interactions because they are substrates for cytochrome P450 (CYP450) isoforms, the uridine 5’-diphosphate glucuronosyltransferases (UGTs) as well as ATP-binding cassette (ABC) membrane transporters proteins. P450 inhibitors impair the ability of specific P450 enzymes to metabolize their target substrates, thus producing increased blood levels of those substrates. Conversely, inducers cause an increase in the production of particular P450 enzymes, leading to increased metabolism of substrates of those P450 enzymes.

Antidepressants are metabolized by and are competitive inhibitors of several isoenzymes: CYP1A2, CYP2D6, CYP3A3/4, CYP2C8/9, CYP2C19, and others. Of these, CYP2D6 has been the most thoroughly investigated and is the most extensively characterized, whereas CYP3A3/4 are more abundant and play a major role in the metabolism of many commonly used drugs. Fluoxetine and its active metabolite are together metabolized by P450 CYP2C9, 2C19, 2D6 and 3A4. They potently inhibit 2D6 and mildly to moderately inhibit 1A2, 2B6, 2C9 and P-glycoprotein. The combination of fluoxetine and risperidone or carbamazepine can lead to increase in the blood level of those two drugs because interactions involve substrate-inhibitor pairings, in witch substrate blood levels are increased. Moreover, after administration of fluoxetine, the phenytoin concentration increase by 160%. Conversely, carbamazepine activates CYP1A2 and 3A4 and decreases level of mirtazapine.

Many antipsychotic drugs are metabolized mainly by CYP2D6. Inhibition of P450CYP2D6 and P-glycoprotein by haloperidol triggers the increase levels of tricyclic antidepressant.

Other drug interactions have been reported between psychotropic and other drugs such as warfarin, theophylline, mediated by CYP1A2 and CYP2C9. Ketoconazole is a relatively specific inhibitor of CYP3A4. It can reduce imipramine clearance and prolong its half-life.

The activities of some isoenzymes of CYP (CYP2D6, CYP2C19) are genetically inherited. Individuals with impaired enzyme function resulting from genetic mutation are likely to develop adverse effects from high levels of unmetabolized drugs, where in extensive metabolizers drugs may be ineffective.

It is very useful to genotype some CYP isoenzymes before giving antipsychotic or antidepressant drugs. Genetic tests may contribute to optimalization of drug therapy leading to increased efficacy and reduced rate of side effects.

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