Selective Serotonin Reuptake Inhibitors and CNS Drug Interactions

Abstract

The potential for drug-drug interactions in psychiatric patients is very high as combination psychopharmacotherapy 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 antidepressants 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 eff...

Carbamazepine toxicity following Oxybutynin and Dantrolene administration: a case report

“…There is no evidence that Baclofen or Atenolol can increase Carbamazepine blood concentration. Fluvoxamine can do it, 16 but it did not cause Carbamazepine toxicity in this patient during the previous 2 years, and signs of Carbamazepine overdose were evident after Fluvoxamine was stopped. Therefore, Fluvoxamine is unlikely to have participated in the intoxication.…”

“…It is eliminated through the hepatic pathway and catalyzed by cytochrome P450 (CYP3A subfamily), 13 so drugs that inhibit the activity of this cytochrome may elevate Carbamazepine blood level and cause toxicity. 11 These drugs include itriconazole, ketokonazole, clarythromycin, erythromycin, nefazodone, ritonavir, 14 isoniazide, propoxyphene, cimetidine, 15 fluvoxamine, fluoxetine, 16 and acetazolamide. 17 Here we present a case of Carbamazepine toxicity related to a pharmacokinetic interaction with either Oxybutynin or Dantrolene.…”

Effects of Cigarette Smoking and Cytochrome P450 2D6 Genotype on Fluvoxamine Concentration in Plasma of Japanese Patients

“…Fluvoxamine is a well-known to be a potent inhibitor of CYP1A2, 2C19 and 3A4. 20) Recently, Sugahara et al have recently reported that the concentration of alprazolam in non-smokers was increased by fluvoxamine, while that in smorkers was unchanged. 21) Thus, it is plausible that the extent of drug interactions by fluvoxamine may be affected by smoking.…”

Serotonin Toxicity and Cytochrome p450 Poor Metaboliser Genotype Patient Case

“…Fluoxetine's metabolism involves the Cytochrome P450 system (Figure 1), and a combination of drugs which are also metabolised by CYPs may lead to drug interactions, even if fluoxetine has been discontinued for 4-5 weeks [55,[57][58][59][60][61].…”