SELECTIVE SEROTONIN REUPTAKE INHIBITORS AND CNS DRUG-INTERACTIONS - ACRITICAL-REVIEW OF THE EVIDENCE

The potential for drug-drug interactions in psychiatric patients is ve ry high as combination psychopharmacotherapy is used to treat comorbid psychiatric disorders, to treat the adverse effects of a medication, to augment a medication effect or to treat concomitant medical illness es. Interactions can be pharmacodynamic or pharmacokinetic in nature. This paper focuses on the metabolic kinetic interactions between selec tive serotonin reuptake inhibitors (SSRIs) and other central nervous s ystem (CNS) drugs. The evidence for and clinical significance of these interactions are reviewed, with special emphasis on antipsychotics, t ricyclic antidepressants and benzodiazepines. Many psychotropic medica tions have an affinity for the cytochrome P450 (CYP) enzymes which pro mote elimination by transforming lipid soluble substances into more po lar compounds. SSRIs serve both as substrates and inhibitors of these enzymes. In vitro, studies provide a screening method for evaluating d rug affinities for substrates, inhibitors or inducers of CYP enzymes. Although in vitro data are important as a starting point for predictin g these metabolic kinetic drug interactions, case reports and controll ed experimental studies in humans are required to fully evaluate their clinical significance. Several factors must be considered when evalua ting the clinical significance of a potential interaction including: ( a) the nature of each drugs' activity at an enzyme site (substrate, in hibitor or inducer); (b) the potency estimations for the inhibitor/ind ucer; Cc) the concentration of the inhibitor/inducer at the enzyme sit e; (d) the saturability of the enzyme; (e) the extent of metabolism of the substrate through this enzyme (versus alternative metabolic route s); (f) the presence of active metabolites of the substrate; (g) the t herapeutic window of the substrate; (h) the inherent enzyme activity o f the individual, phenotyping/genotyping information; (i) the level of risk of the individual experiencing adverse effects (e.g. the elderly ) and (j) from an epidemiological perspective, the probability of conc urrent use. This paper systematically reviews both the in vitro and in vivo evidence for drug interactions between SSRIs and other CNS drugs . As potent inhibitors of CYP2D6, both paroxetine and fluoxetine have the potential to increase the plasma concentrations of antipsychotic m edications metabolised through this enzyme, including perphenazine, ha loperidol, thioridazine and risperidone in patients who are CYP2D6 ext ensive metabolisers. Controlled studies have demonstrated this for per phenazine with paroxetine and haloperidol with fluoxetine. Fluvoxamine , as a potent inhibitor of CYP1A2, can inhibit the metabolism of cloza pine, resulting in higher plasma concentrations. Drug interactions bet ween the SSRIs and tricyclic antidepressants (TCAs) can occur. Fluoxet ine and paroxetine, as potent inhibitors of CYP2D6, can increase the p lasma concentrations of secondary and tertiary tricyclic antidepressan ts. Sertraline and citalopram are less likely to have this effect. Flu voxamine can increase the plasma concentrations of tertiary TCAs. Fluv oxamine inhibits, via CYP3A, CYP2C19 and CYP1A2, the metabolism of sev eral benzodiazepines, including alprazolam, bromazepam and diazepam. F luoxetine increases the plasma concentrations of alprazolam and diazep am by inhibiting CYP3A and CYP2C19, respectively. The clinical importa nce of the interaction with diazepam is attenuated by the presence of its active metabolite. Sertraline inhibits these enzymes only mildly t o moderately at usual therapeutic doses. Therefore the potential for i nteractions is less: however, the in vivo evidence is minimal. Paroxet ine and citalopram are unlikely to cause interactions with benzodiazep ines. The evidence is conflicting for an interaction between carbamaze pine and the SSRIs fluoxetine and fluvoxamine. These combinations shou ld be used cautiously, and be accompanied by monitoring for adverse ev ents and carbamazepine plasma concentrations. A lack of interaction be tween paroxetine or sertraline and carbamazepine has been documented. The SSRIs are not equivalent in their potential for drug interactions when combined with other CNS medications. Each combination must be ass essed individually. Several factors must be considered when predicting the outcome of a potential interaction based on in vitro data (e.g. a ctive metabolites and concentration ranges). In vivo studies are requi red to evaluate their clinical significance. Generally, sertraline and citalopram at the lower therapeutic dosage range appear to have less propensity for interactions. Anticipated pharmacokinetic interactions can usually be managed with careful monitoring and appropriate adjustm ents in dosage and titration.