SECOND OF 2 PARTS A concise guide to monoamine oxidase inhibitors: How to avoid drug interactions Use these strategies to maximize efficacy and minimize adverse effects when prescribing an MAOI onoamine oxidase inhibitors (MAOIs) have well- established efficacy for treating depression, panic Mdisorder, and social phobia. However, a lack of familiarity with these agents and misconceptions about the risks associated with their use have led to MAOIs being substantially underutilized. The goal of this 2-part guide to MAOIs is to educate clinicians about this often-overlooked class of medications. Part 1 (“A concise guide to mono- amine inhibitors,” Current Psychiatry. December 2017, p. 14-23,47,A) described the pharmacology of MAOIs, the mechanism by which tyramine induces hypertension in patients taking MAOIs, and what to tell patients about dietary restrictions associated with these medications. Part ALEX NABAUM 2 covers how to avoid potential drug interactions, including Jonathan M. Meyer, MD serotonin syndrome (SS) and pressor effects, that could affect Psychopharmacology Consultant patients receiving an MAOI; other factors to consider when California Department of State Hospitals starting a patient on an MAOI; and augmentation strategies Sacramento, California Clinical Professor of Psychiatry for depressed patients who do not achieve remission from University of California, San Diego MAOI monotherapy. San Diego, California Deputy Editor, CURRENT PSYCHIATRY MAOIs and potential drug interactions One source of concern in patients receiving irreversible nonselective MAOIs is the development of excessive sero- tonergic neurotransmission resulting in SS. In the 1960s, researchers noted that administering large doses of tryp- tophan to MAOI-treated patients resulted in clonus and Disclosure Dr. Meyer is a consultant to Acadia Pharmaceuticals, Neurocrine Biosciences, Inc., and Teva Current Psychiatry Pharmaceutical Industries; and is a speaker for Acadia Pharmaceuticals, Alkermes, Allergan, Merck, 22 January 2018 Otsuka America, Inc., and Sunovion Pharmaceuticals. Table 1 Medications with known risk for serotonin syndrome when coadministered with nonselective MAOIs Class Examples Tricyclic antidepressants Imipramine, desipramine, amitriptyline, nortriptyline, clomipramine SSRI antidepressants Citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, trazodone, vilazodone, vortioxetine SNRI antidepressants Duloxetine, levomilnacipran, milnacipran, desvenlafaxine, venlafaxine Antipsychotics Ziprasidone Specific cold products Dextromethorphan, chlorpheniramine Synthetic analgesics Fentanyl, meperidine, tramadol Antibiotics Linezolid Drugs of abuse MDMA, LSD Other Methylene blue LSD: lysergic acid diethylamide; MDMA: 3,4-methylenedioxy-methamphetamine; SNRI: serotonin-norepinephrine reuptake Clinical Point inhibitor; SSRI: selective serotonin reuptake inhibitor Source: Reference 3 The clinical hallmark of serotonin syndrome is clonus, hyperactive reflexes without hyperten- Risk for SS. Most medications that pro- which becomes sive events.1 In 1991, Sternbach2 provided mote serotonergic activity are well known spontaneous and an extensive case series and described for their use as antidepressants, but other sustained as the the first set of criteria for SS. Features of agents that have 5HT reuptake properties SS include: (eg, the antihistamine chlorpheniramine) severity increases • mild symptoms: tremor, akathisia, must be avoided. Although older literature inducible clonus suggests that the use of lower doses of cer- • moderate symptoms: spontaneous or tain tricyclic antidepressants concurrently sustained clonus, muscular hypertonicity with MAOIs may not be as dangerous as • severe symptoms: hyperthermia, once believed,6 there are sufficient reports diaphoresis.2 of serious outcomes that tricyclics should be Although SS can be induced by signifi- avoided in patients taking MAOIs because cant exposure to individual agents that of the risk of SS, and also because, in gen- promote excess synaptic serotonin (eg, eral, tricyclics are poorly tolerated.7 overdose of selective serotonin reuptake Desipramine, a potent norepineph- inhibitors [SSRIs]), the majority of fatal rine transporter (NET) inhibitor, blocks cases have occurred among patients tak- the entry of tyramine into cells by NET, ing MAOIs who were coadministered an thereby preventing hypertensive events in agent that inhibited serotonin reuptake animal models of tyramine overexposure. (Table 13). Animal studies have determined However, in some assays, the affinity for that excessive stimulation of the 5HT2A the serotonin transporter is not insignifi- receptor is primarily responsible for SS,4 cant, so at higher doses desipramine may and that 5HT2A antagonists, such as mir- pose the same theoretical risk for SS as seen tazapine, can block the development of SS with other tricyclics.3 in a mouse coadministered fluoxetine and Lastly, rasagiline is an MAO-B selec- Discuss this article at tranylcypromine.5 In addition to a patient’s tive inhibitor that has been available in the www.facebook.com/ CurrentPsychiatry medication history, the clinical hallmark of United States since 2008 for the treatment SS that helps distinguish it from neuro- of Parkinson’s disease (PD). Although this leptic malignant syndrome, delirium, and drug lacks MAO-A antagonism, its package other acute syndromes is clonus, which insert carries SS warnings; however, anal- becomes spontaneous and sustained as the ysis of outcomes from a large multicenter Current Psychiatry severity increases. rasagiline trial (N = 1,504) found no SS Vol. 17, No. 1 23 Table 2 Pressor reactions. The only theoretical Half-lives of newer sources of concern for pressor effects are antidepressants with potent medications that act as norepinephrine releasers through interactions at the trace serotonin reuptake amine-associated receptor 1 (TAAR1) Medication Half-life (for more information on TAAR1, see “A Selective serotonin reuptake inhibitors concise guide to monoamine inhibitors,” MAOIs and drug Citalopram 33 hours Current Psychiatry. December 2017, interactions Escitalopram 30 hours p. 14-23,47,A). Amphetamines are one such Fluoxetine 87 hours class, but a 2004 review did not find cases of hypertensive crises when amphetamines Norfluoxetine 1 to 2 weeks were combined with MAOIs,12 nor did a Fluvoxamine 22 hours recent article that described the combined Paroxetine 21 hours use of lisdexamfetamine and transdermal Sertraline 26 hours selegiline.13 Presumably, the low level of Trazodone 7 to 10 hours intracellular exposure mitigates the risk of Clinical Point Vilazodone 25 hours excessive TAAR1 agonism, but amphet- Orthostasis is the Vortioxetine 66 hours amine derivatives should be approached Serotonin-norepinephrine reuptake inhibitors cautiously and with careful blood pressure primary dose-limiting monitoring. On the other hand, methylphe- Desvenlafaxine 11 hours adverse effect nidate is an inhibitor of dopamine reuptake Duloxetine 15 hours associated with rapid with no affinity for TAAR114 or the sero- Levomilnacipran 12 hours tritration or higher tonin transporter,15 and does not induce a Milnacipran 6 to 10 hours pressor response nor increase risk for SS dosages of MAOIs Venlafaxine 5 hours when combined with MAOIs.3 Concerns Source: References 17-22 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, events in the 471 patients receiving rasagi- typically those with preexisting hyperten- line plus antidepressants (74.5% on SSRIs).8 sion. Nonetheless, all patients should be Because depression is a common comor- cautioned about the use of phenylephrine bidity in PD, clinicians who encounter and pseudoephedrine.16 rasagiline-treated patients who need anti- depressant therapy should consult with the patient’s neurologist regarding their expe- Starting a patient on an MAOI rience and comfort level with combining Contraindicated medications need to be rasagiline and SSRIs or serotonin and nor- tapered before beginning MAOI treatment. epinephrine reuptake inhibitors (SNRIs). The duration of the washout period depends Astute clinicians will recognize that anti- on the half-life of the medication and any depressants that lack 5HT reuptake (eg, active metabolites. Antidepressants with bupropion, mirtazapine) are not on this list half-lives of approximately ≤24 hours should of agents that may increase SS risk when be tapered over 7 to 14 days (depending on taken with an MAOI. Older papers often the dose) to minimize the risk of withdrawal list mirtazapine, but as a 5HT2A antagonist, syndromes, while those with long half-lives it does not possess a plausible mechanism (eg, fluoxetine, vortioxetine) can be stopped by which it can induce 5HT toxicity.9,10 Most abruptly. After stopping a medication for atypical antipsychotics have significant 5 half-lives, 96.875% of the medication is 5HT2A antagonism and can be combined removed, so adequate time must elapse with MAOIs, but ziprasidone is an excep- after the last dose before starting an MAOI. tion: as a moderate SNRI, it has been asso- Table 217-22 lists the half-lives of commonly ciated with SS when administered with an used newer antidepressants and any active Current Psychiatry 24 January 2018 MAOI.11 metabolites or isomers. Clinicians should continued on page 28 continued from page 24 true in older patients with poor vasomotor Related Resource tone,