A concise guide to monoamine oxidase inhibitors: How to avoid drug interactions

Desipramine, a potent norepinephrine transporter (NET) inhibitor, blocks the entry of tyramine into cells by NET, thereby preventing hypertensive events in animal models of tyramine overexposure. However, in some assays, the affinity for the serotonin transporter is not insignificant, so at higher doses desipramine may pose the same theoretical risk for SS as seen with other tricyclics.³

Lastly, rasagiline is an MAO-B selective inhibitor that has been available in the United States since 2008 for the treatment of Parkinson’s disease (PD). Although this drug lacks MAO-A antagonism, its package insert carries SS warnings; however, analysis of outcomes from a large multicenter rasagiline trial (N = 1,504) found no SS events in the 471 patients receiving rasagiline plus antidepressants (74.5% on SSRIs).⁸ Because depression is a common comorbidity in PD, clinicians who encounter rasagiline-treated patients who need antidepressant therapy should consult with the patient’s neurologist regarding their experience and comfort level with combining rasagiline and SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs).

Astute clinicians will recognize that antidepressants that lack 5HT reuptake (eg, bupropion, mirtazapine) are not on this list of agents that may increase SS risk when taken with an MAOI. Older papers often list mirtazapine, but as a 5HT2A antagonist, it does not possess a plausible mechanism by which it can induce 5HT toxicity.^9,10 Most atypical antipsychotics have significant 5HT2A antagonism and can be combined with MAOIs, but ziprasidone is an exception: as a moderate SNRI, it has been associated with SS when administered with an MAOI.¹¹

Pressor reactions. The only theoretical sources of concern for pressor effects are medications that act as norepinephrine releasers through interactions at the trace amine-associated receptor 1 (TAAR1) (for more information on TAAR1, see “A concise guide to monoamine inhibitors,” Current Psychiatry. December 2017, p. 14-23,47,A). Amphetamines are one such class, but a 2004 review did not find cases of hypertensive crises when amphetamines were combined with MAOIs,¹² nor did a recent article that described the combined use of lisdexamfetamine and transdermal selegiline.¹³ Presumably, the low level of intracellular exposure mitigates the risk of excessive TAAR1 agonism, but amphetamine derivatives should be approached cautiously and with careful blood pressure monitoring. On the other hand, methylphenidate is an inhibitor of dopamine reuptake with no affinity for TAAR1¹⁴ or the serotonin transporter,¹⁵ and does not induce a pressor response nor increase risk for SS when combined with MAOIs.³ Concerns about the use of α1-adrenergic agonists in patients taking MAOIs are not universal, as the deleterious effects on blood pressure are seen only in certain vulnerable patients, typically those with preexisting hypertension. Nonetheless, all patients should be cautioned about the use of phenylephrine and pseudoephedrine.¹⁶
 

Starting a patient on an MAOI

Contraindicated medications need to be tapered before beginning MAOI treatment. The duration of the washout period depends on the half-life of the medication and any active metabolites. Antidepressants with half-lives of approximately ≤24 hours should be tapered over 7 to 14 days (depending on the dose) to minimize the risk of withdrawal syndromes, while those with long half-lives (eg, fluoxetine, vortioxetine) can be stopped abruptly. After stopping a medication for 5 half-lives, 96.875% of the medication is removed, so adequate time must elapse after the last dose before starting an MAOI. Table 2^17-22 lists the half-lives of commonly used newer antidepressants and any active metabolites or isomers. Clinicians should always err on the side of caution before starting an MAOI, and give their patients a brief overview of SS symptoms; however, be mindful of not extending time the patient is without effective antidepressant levels.