Selective Serotonin Reuptake Inhibitors and CNS Drug Interactions
The potential for drug-drug interactions in psychiatric patients is very 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 illnesses. Interactions can be pharmacodynamic or pharmacokinetic in nature. This paper focuses on the metabolic kinetic interactions between selective serotonin reuptake inhibitors (SSRIs) and other central nervous system (CNS) drugs. The evidence for and clinical significance of these interactions are reviewed, with special emphasis on antipsychotics, tricyclic anti-depressants and benzodiazepines.
Many psychotropic medications have an affinity for the cytochrome P450 (CYP) enzymes which promote elimination by transforming lipid soluble substances into more polar compounds. SSRIs serve both as substrates and inhibitors of these enzymes. In vitro studies provide a screening method for evaluating drug affinities for substrates, inhibitors or inducers of CYP enzymes. Although in vitro data are important as a starting point for predicting these metabolic kinetic drug interactions, case reports and controlled experimental studies in humans are required to fully evaluate their clinical significance. Several factors must be considered when evaluating the clinical significance of a potential interaction including: (a) the nature of each drugs’ activity at an enzyme site (substrate, inhibitor or inducer); (b) the potency estimations for the inhibitor/inducer; (c) the concentration of the inhibitor/inducer at the enzyme site; (d) the saturability of the enzyme; (e) the extent of metabolism of the substrate through this enzyme (versus alternative metabolic routes); (f) the presence of active metabolites of the substrate; (g) the therapeutic window of the substrate; (h) the inherent enzyme activity of 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 concurrent 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 medications metabolised through this enzyme, including perphenazine, haloperidol, thioridazine and risperidone in patients who are CYP2D6 extensive metabolisers. Controlled studies have demonstrated this for perphenazine with paroxetine and haloperidol with fluoxetine. Fluvoxamine, as a potent inhibitor of CYP1A2, can inhibit the metabolism of clozapine, resulting in higher plasma concentrations.
Drug interactions between the SSRIs and tricyclic antidepressants (TCAs) can occur. Fluoxetine and paroxetine, as potent inhibitors of CYP2D6, can increase the plasma concentrations of secondary and tertiary tricyclic antidepressants. Sertraline and citalopram are less likely to have this effect. Fluvoxamine can increase the plasma concentrations of tertiary TCAs.
Fluvoxamine inhibits, via CYP3A, CYP2C19 and CYP1A2, the metabolism of several benzodiazepines, including alprazolam, bromazepam and diazepam. Fluoxetine increases the plasma concentrations of alprazolam and diazepam by inhibiting CYP3A and CYP2C19, respectively. The clinical importance of the interaction with diazepam is attenuated by the presence of its active metabolite. Sertraline inhibits these enzymes only mildly to moderately at usual therapeutic doses. Therefore the potential for interactions is less; however, the in vivo evidence is minimal. Paroxetine and citalopram are unlikely to cause interactions with benzodiazepines.
The evidence is conflicting for an interaction between carbamazepine and the SSRIs fluoxetine and fluvoxamine. These combinations should be used cautiously, and be accompanied by monitoring for adverse events and carbamazepine plasma concentrations. A lack of interaction between 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 assessed individually. Several factors must be considered when predicting the outcome of a potential interaction based on in vitro data (e.g. active metabolites and concentration ranges). In vivo studies are required 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 adjustments in dosage and titration.
KeywordsAdis International Limited Carbamazepine Haloperidol Clozapine Fluoxetine
Unable to display preview. Download preview PDF.
- 4.Kasper S, Heiden A. Do SSRIs differ in their antidepressant efficacy. Hum Psychopharmacol Clin Exp Ther 1995; 10 Suppl. 3: S163–72Google Scholar
- 5.den Boer JA, Westenberg HGM. Serotonergic compounds in panic disorder, obsessive-compulsive disorder and anxious depression: a concise review. Hum Psychopharmacol Clin Exp Ther 1995; 10 Suppl. 3: S173–83Google Scholar
- 12.De Vane CL. Pharmacogenetics and drug metabolism of newer antidepressant agents. J Clin Psychiatry 1994; 55 Suppl. 12: 38–45Google Scholar
- 15.Chen ZR, Somogyi AA, Bochner F. Polymorphic O-demethylation of codeine. Lancet 1988; II: 914–5Google Scholar
- 17.von Moltke LL, Greenblatt DJ, Cotreau-Bibbo MM, et al. Inhibitors of alprazolam metabolism in vitro: effect of serotonin-reuptake-inhibitor antidepressants, ketoconazole and quinidine. Br J Clin Pharmacol 1994; 38: 23–31Google Scholar
- 19.Preskorn SH. Clinical pharmacology of selective serotonin reuptake inhibitors. 1st ed. Caddo (OK): Professional Communications Inc., 1996Google Scholar
- 26.Fluvoxamine in perspective: a decade of experience. Chester (UK): Adis International, 1995Google Scholar
- 31.von Moltke LL, Greenblatt DJ, Cotreau-Bibbo MM, et al. Inhibition of desipramine hydroxylation in vitro by serotonin-reuptake-inhibitor antidepressants, and by quinidine and ketoconazole: a model system to predict drug interactions in vivo. J Pharmacol Exp Ther 1994; 268(3): 1278–83Google Scholar
- 36.von Moltke LL, Greenblatt DJ, Court MH, et al. Inhibition of alprazolam and desipramine hydroxylation in vitro by paroxetine and fluvoxamine: comparison with other selective serotonin reuptake inhibitor antidepressants. J Clin Psychopharmacol 1995; 15: 125–31Google Scholar
- 41.von Bahr C, Movin G, Nordin C, et al. Plasma levels of thioridazine and metabolites are influenced by the debrisoquine hydroxylation phenotype. Clin Pharmacol Ther 1991; 49: 234–40Google Scholar
- 49.Øyehaug E. Effect of phenothiazines on citalopram steady-state kinetics in psychiatric patients. Nor Pharm Acta 1982; 46: 37–46Google Scholar
- 54.Nelson MR, Dunner DL. Treatment resistance in unipolar depression and other disorders: diagnostic concerns and treatment possibilities. Psychiatr Clin North Am 1993; 16(3): 541–66Google Scholar
- 56.Bouchard RH, Pourcher E, Vincent P. Fluoxetine and extrapyramidal side effects [letter]. Am J Psychiatry 1989; 146: 1352–3Google Scholar
- 57.Brod TM. Fluoxetine and extrapyramidal side effects [letter]. Am J Psychiatry 1989; 146: 1353Google Scholar
- 62.Özdemir V, Naranjo CA, Herrmann N, et al. Paroxetine potentiates CNS side effects of perphenazine: contribution of cytochrome P450 2D6 inhibition in vivo. Clin Pharmacol Ther. In pressGoogle Scholar
- 63.Cooper SM, Jackson D, Loudon JM, et al. The psychomotor effects of paroxetine alone and in combination with haloperidol, amylobarbitone, oxazepam or alcohol. Acta Psychiatr Scand 1989; 80 Suppl. 350: 53–5Google Scholar
- 65.Weilberg JB, Rosenbaum JF, Meltzer-Brody S. Tricyclic augmentation of fluoxetine. Ann Clin Psychiatry 1991; 3: 209–14Google Scholar
- 84.Zussmann BD, Davie CC, Fowles SE, et al. Sertraline, like other SSRIs, is a significant inhibitor of desipramine metabolism in vivo [abstract]. Br J Clin Pharmacol 1995; 39: 550–1Google Scholar
- 85.Kurtz DL, Bergstrom RF, Goldberg MJ, et al. The effect of sertaline on the pharmacokinetics of desipramine and imipramine. Clin Pharmacol Ther 1998; 62: 145–56Google Scholar
- 90.van Harten J, Holland RL, Wesnes K. Influence of multiple-dose administration of fluvoxamine on the pharmacokinetics of the benzodiazepine bromazepam and lorazepam: a randomized, cross-over study [abstract]. Eur Neuropsychopharmacol 1992; 2: 381Google Scholar
- 92.Andersson T, Miners JO, Birkett DJ, et al. Diazepam metabolism by human liver microsomes is mediated by both S-mephenytion hydroxylase and CYP3A isoforms [abstract]. Clin Pharmacol Ther 1994; 55: 138Google Scholar
- 97.Bannister SJ, Houser VP, Hulse JD, et al. Evaluation of the potential for interactions of paroxetine with diazepam, cimetidine, warfarin, and digoxin. Acta Psychiatr Scand 1989; 80 Suppl. 350: 102–6Google Scholar