Metabolic drug interactions with new psychotropic agents

Abstract

New psychotropic drugs introduced in clinical practice in recent years include new antidepressants, such as selective serotonin reuptake inhibitors (SSRI) and 'third generation' antidepressants, and atypical antipsychotics, i.e. clozapine, risperidone, olanzapine, quetiapine, ziprasidone and amisulpride. These agents are extensively metabolized in the liver by cytochrome P450 (CYP) enzymes and are therefore susceptible to metabolically based drug interactions with other psychotropic medications or with compounds used for the treatment of concomitant somatic illnesses. New antidepressants differ in their potential for metabolic drug interactions. Fluoxetine and paroxetine are potent inhibitors of CYP2D6, fluvoxamine markedly inhibits CYP1A2 and CYP2C19, while nefazodone is a potent inhibitor of CYP3A4. These antidepressants may be involved in clinically significant interactions when coadministered with substrates of these isoforms, especially those with a narrow therapeutic index. Other new antidepressants including sertraline, citalopram, venlafaxine, mirtazapine and reboxetine are weak in vitro inhibitors of the different CYP isoforms and appear to have less propensity for important metabolic interactions. The new atypical antipsychotics do not affect significantly the activity of CYP isoenzymes and are not expected to impair the elimination of other medications. Conversely, coadministration of inhibitors or inducers of the CYP isoenzymes involved in metabolism of the various antipsychotic compounds may alter their plasma concentrations, possibly leading to clinically significant effects. The potential for metabolically based drug interactions of any new psychotropic agent may be anticipated on the basis of knowledge about the CYP enzymes responsible for its metabolism and about its effect on the activity of these enzymes. This information is essential for rational prescribing and may guide selection of an appropriate compound which is less likely to interact with already taken medication(s).

Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research

“…Genetic variants in Phase I and II enzymes are known to reduce or increase their activity and subsequently to alter drug metabolic ratios. Excellent papers have been published on the subject 28,29,[33][34][35] and only a summary of key findings relevant to schizophrenia will be covered in this review.…”

“…Additionally, antidepressants and classical antipsychotics are known to inhibit hepatic enzymes which may result in elevated levels of drug metabolites with toxic consequences (newer atypical antipsychotics have a negligible effect). 34,40 CYP-inductor drugs may affect plasma concentrations of antipsychotic compounds with potential clinical implications. In a pharmacogenetic study, CYP inhibitors and inducer significantly predicted risperidone discontinuation due to side effects but did not significantly predict risperidone side effects.…”

Intermediate metabolizer: increased side effects in psychoactive drug therapy. The key to cost-effectiveness of pretreatment CYP2D6 screening?

“…A possible explanation could be that the metabolic pathway mediated by CYP2D6 is easily inhibited or saturated by a multitude of psychoactive or cardiovascular co-medication. 16 The resulting drug-drug interactions may delay response to drug treatment.…”

Effect of fluvoxamine on plasma risperidone concentrations in patients with schizophrenia

“…Fluvoxamine interacts with several CYP isoenzymes in vitro: it is a potent inhibitor of CYP1A2 and CYP2C19 and a moderate inhibitor of CYP2C9 and CYP3A4, while it affects only slightly CYP2D6 activity [15][16][17][18][19]. Due to this nonselective inhibition of various CYP isoenzymes, fluvoxamine has a high potential for metabolic drug interactions in vivo [20].…”