Which antidepressants could be recommended in a patient treated with methylphenidate?/nA 19-year-ol

Fråga: Which antidepressants could be recommended in a patient treated with methylphenidate? A 19-year-old man has been prescribed methylphenidate (Ritalina) 20 mg/d for ADHD (attention deficit hyperactivity disorder). He now requires treatment for an on-going depression.

Sammanfattning: Monoamine oxidase inhibitors are contraindicated in patients taking methylphenidate, due to the risk of hypertensive crises. For the same reason, it seems advisable to avoid antidepressants with noradrenergic properties. Theoretically, methylphenidate could increase the plasma levels of antidepressants by inhibiting their metabolism but the effects on individual substances are difficult to predict.

It appears rational to choose an antidepressant with serotonergic profile and metabolism that does not depend on a single metabolic pathway, e.g. citalopram. We suggest the therapy is aided with therapeutic drug monitoring and close attention to possible side-effects.

Svar: No comparisons of antidepressant therapies in patients treated with methylphenidate were found in Drugline, Medline or standard pharmacological literature.

Methylphenidate is a sympaticomimetic central stimulant thought to influence multiple neurotransmitters, including dopamine and noradrenaline (1). Since most antidepressants act by stimulatory effects on monoaminergic neurotransmission, pharmacodynamic interactions could occur. Coadministration with monoamine oxidase inhibitors has e.g. resulted in hypertensive crises and the combination is therefore contraindicated (2). Theoretically, the risk of sympatic over-stimulation would be less pronounced with selective serotonin reuptake inhibitors (SSRI:s) compared to antidepressants with noradrenergic properties, e.g. tricyclics, mirtazapine, reboxetine and venlafaxine.

Methylphenidate is known to inhibit the elimination of several drugs, including coumarin, phenobarbital, phenytoin, primidone and imipramine (2, 3). Since several of these drugs are metabolised by the cytochrome P450 enzyme system, it seems plausible that the interaction mechanism may involve inhibition of such enzymes. This notion has been confirmed in mice, where supposedly therapeutic levels of methylphenidate reduced the catalytic activity of CYP1A (4). When the dose was increased ten times to simulate methylphenidate abuse, inhibition of CYP2E1 and CYP3A supervened. Considering the metabolic pathways involved in the degradation of the interacting drugs mentioned above, additional inhibition of other cytochrome P450 isoenzymes, e.g. CYP2C9 or CYP2C19, seems likely. Most antidepressants are heavily metabolised by the cytochrome P450 system, although the relative contribution of individual enzymes differ between substances. Hence, methylphenidate could theoretically hamper the metabolism of antidepressants. However, this could easily be controlled for by therapeutic drug monitoring.

No examples of pharmacokinetic interactions causing altered plasma concentrations of methylphenidate were identified. Furthermore, its elimination is independent of CYP2D6, an enzyme involved in the metabolism of several antidepressants (5).