References are located at the bottom of the full toolkit PDF.
Recommended MAOI dosing, according to manufacturer labeling is shown in Table 10.
Moclobemide is usually dosed twice daily. However the manufacturer’s labeling states that single daily doses were equally effective to divided daily doses, although there was a significant increase in dizziness and a tendency toward increased nausea, insomnia, and headache with single daily doses (21). Moclobemide exhibits dose- and time-dependent changes in its pharmacokinetics. Oral bioavailability increases with dose size; it also increases with multiple daily doses versus single daily doses. In addition, oral bioavailability increases from 50 -60% at initiation with 150 mg twice daily to almost 100% after 10 – 14 days. This is believed to result from either saturation or autoinhibition of first-pass metabolism (5). Therefore, it is recommended that the initial dose not be increased for at least 2 weeks to allow completion of this process.
Manufacturer-recommended titration for other MAOIs varies (16-19).
Some clinicians may titrate phenelzine more gradually by starting at 15 mg/day and increasing by 15 mg/day every 2 – 4 days. This approach may reduce the risk of side effects, although there is little evidence for this.
As phenelzine and, possibly, isocarboxazid are more likely to cause sedation, a larger portion of their daily dose can be given at bedtime; this can be based on individual patient response. Tranylcypromine is more likely to be stimulating; if needed, a smaller portion of its daily dose can be given at bedtime.
|Isocarboxazid||10 mg BID||
(BID – QID)
|60 mg/day||Caution with renal impairment; contraindicated with severe renal impairment. Avoid with hepatic impairment.|
|Moclobemide||150 mg BID||
(BID – TID; can be given as single daily dose)
|600 mg/day||No dose adjustment needed with renal impairment. With severe hepatic impairment (cirrhosis), reduce dose to 1/2 or 1/3 of usual|
|Phenelzine||15 mg TID||
(BID – TID)
|90 mg/day||Avoid with severe renal impairment. Avoid with hepatic impairment|
|Transdermal Selegiline||6 mg/24 hours||
6 – 9 mg/24 hours
|12 mg/24 hours||No dose adjustment needed with mild to moderate renal or hepatic impairment. Not studied with severe renal or hepatic impairment|
|Tranylcypromine||10 mg TID||
30 – 60 mg/day
|60 mg/day||Use cautiously with renal impairment. Avoid with hepatic impairment.|
Before initiating MAOI therapy, consideration should be given to the patient’s other illnesses and conditions.
When a patient is switched from another antidepressant to an MAOI, the standard recommendation has been that the prior medication should be discontinued for 2 weeks (5 weeks for fluoxetine and 3 weeks for vortioxetine) before the MAOI is started. This is especially important for serotonergic antidepressants (see Table 6); it is not clear that other antidepressants present a large risk of interaction if they are not completely discontinued before the MAOI is started. This time period may be unnecessarily long for most antidepressants with shorter half-lives. Waiting for 4 – 5 half-lives of the discontinued drug (or any active metabolites) should be sufficient; this usually amounts to five to seven days (2).
In patients who don’t adequately respond to or tolerate their first therapeutic trial of a MAOI, a trial of a second MAOI may be considered. In this situation, FDA labeling recommends that a 7 – 14 day washout of the first MAOI occur before the second is initiated (16-19). There are case reports describing adverse events such as acute central nervous system toxicity, hypertensive crisis, stroke and death following switches between MAOIs with no or short washout periods (140-144). It has been suggested that switches from another MAOI to tranylcypromine may carry a greater risk of adverse outcome; this is possibly based on tranylcypromine’s amphetamine-like actions (140). There are also, however, a number of case reports describing rapid switches and even cross-titration between phenelzine and tranylcypromine (in either direction) without significant adverse effects (140,145). At least one expert suggests that, if a rapid switch is necessary on clinical grounds (e.g., severe depression that would otherwise require lengthy hospitalization or marked, intolerable side effects to the first MAOI), rapid switching is likely to be safe and should be considered (146).
Education of patients about MAOIs should begin during the process of deciding whether or not to use one of these medications. Patients should be given enough information to make an informed decision about electing to take an MAOI. Education should be reinforced at the point of initiation of the MAOI. The education provided should be specific to the MAOI to be used; since there are differences between these agents, a “generic” education approach is not likely to be helpful. The following education points should be helpful.
Drug shortages of MAOIs may occur; these agents are not widely used, and few companies manufacture or market them. Historically, shortages of isocarboxazid seem to have been common. Shortages may also vary depending on the country in which the patient lives
There is little if any information available to recommend strategies in the event that a patient’s MAOI becomes unavailable. Allowing a patient to run out of their MAOI carries a risk of potentially serious withdrawal symptoms and possible rapid, return of severe depression. In shortage situations, a cross-titration to another MAOI may be a possible solution if the shortage can be identified early enough (140); however, there may not be an equivalent antidepressant response to the new MAOI. Pharmacists involved in the management of patients taking MAOIs can help anticipate and recommend management strategies by monitoring shortages of the MAOIs they are using.
There has been debate about the safety of MAOI use during surgical anesthesia. There are no evidence-based guidelines regarding this issue, and there has not been agreement among experts about the necessity for discontinuation of MAOIs before elective surgery. The European Society of Anaesthesiology recommends discontinuation of irreversible MAOIs before surgery (147), and some textbooks also recommend discontinuing MAOIs prior to surgery (2). This recommendation apparently stems from the potential for drug interactions with sympathomimetic pressor agents and opioids (147). There have also been concerns that, when spinal anesthesia is used in a patient taking a MAOI, there may be “combined hypotensive effects” (88).
These recommendations raise concerns, because the MAOI (although not moclobemide) would need to be discontinued for approximately two weeks before surgery to allow re-synthesis of functional MAO. Patients would be placed at risk for return of depressive symptoms as well as significant withdrawal symptoms; slow tapering of the MAOI would expose the patient to several weeks of possibly sub-therapeutic doses. An observational retrospective cohort study from the Netherlands compared cardiovascular outcomes (tachycardia or bradycardia and hypotension or hypertension) and the possible occurrence of serotonin syndrome in 42 patients who underwent 51 elective surgeries while taking either tranylcypromine or moclobemide versus 149 matched surgical patients not taking MAOIs. Most (84%) of patients received general anesthesia (some of these patients also received regional anesthesia); the others received regional anesthesia only: epidural or spinal anesthesia or nerve blocks. Intraoperative hypotension was significantly less common in patients taking tranylcypromine compared to those not taking MAOIs. Rates of tachycardia, bradycardia, or hypertension in patients taking either moclobemide or tranylcypromine were not significantly different in the two groups. Interestingly, the use of sympathomimetic drugs (ephedrine or phenylephrine) was quite common: 46% of tranylcypromine patients; 48% of moclobemide patients; and 65% & 56% of matched patients not taking MAOIs. In MAOI users who were treated with ephedrine versus phenylephrine there was no difference in rates of intraoperative hypertension. No cases of serotonin syndrome occurred, although one patient who was given meperidine in the recovery room became agitated. The authors concluded that there is little justification for discontinuation of MAOIs before surgery – especially in light of the risk of compromised psychiatric status (147). A case report and extensive review of the literature describing regional and general anesthesia in patients taking MAOIs, pointed out that the majority of reported cases did not result in negative outcomes. Reported cases of poor outcome involved patients with cardiac comorbidity and administration of fentanyl. The authors concluded that “…general or regional anesthesia for non-cardiac surgery without discontinuation of MAO inhibitor treatment may be a safe intervention after careful evaluation of an individual’s perioperative and psychiatric risk” (148).
When local anesthesia is needed in patients taking MAOIs, it is recommended that anesthetics without vasoconstrictor (epinephrine or levonordefrin) be used to avoid possible changes in blood pressure (2). FDA labeling for local anesthetics containing epinephrine (149) or levonordefrin (150) contain warnings regarding the risk of severe prolonged hypertension if these agents are given with MAOIs. An animal study (151) found that the pressor effects of epinephrine, NE, and levonordefrin were not potentiated by administration of phenelzine. A human study (152) found that the pressor effects of epinephrine and NE were not increased in patients premedicated with either tranylcypromine or phenelzine. Apparently, this lack of interaction is a result of preferential metabolism of peripherally-administered epinephrine, levonordefrin, and, possibly, NE by catechol-O-methyltransferase (153). Therefore, it appears that concerns about vasoconstrictor-containing local anesthetics in patients receiving MAOIs are based on theoretical concerns alone. There don’t appear to be published examples of severe hypertensive reactions to these agents.
There have been concerns about the safety of ECT administration in patients taking MAOIs. These are primarily based on concerns about administration of general anesthesia in these patients. A literature review (154) found over 100 reported cases of ECT administration in patients taking MAOIs. Very few significant complications were reported; there were a small number of isolated respiratory complications. The authors reported four additional patients who had no complications from ECT combined with MAOI therapy. It was recommended that, if a patient has not responded to a MAOI, it could be discontinued before ECT was started, but that no washout period is necessary. In patients with a partial response to a MAOI, it may be desirable to continue the medication during ECT, and, in patients with severe depression, a MAOI may be a safe and effective augmentation agent during maintenance ECT (154).
Drug overdose is always a potential risk in the treatment of depression. Overdose with an irreversible MAOI (especially tranylcypromine, phenelzine , or isocarboxazid) causes severe, life-threatening manifestations. It is estimated that 5mg/kg or more may lead to a potentially fatal outcome. After overdose, patients may be asymptomatic for up to 24 hours. When symptoms develop they occur in a biphasic pattern. There is initial peripheral sympathetic stimulation with hypertension and CNS excitation; later hypotension occurs. Over a period of days there is a potential end result of coma and death. Manifestations seen in MAOI overdose are summarized in Table 11 (155).
Overdoses of oral selegiline are apparently uncommon. A single reported complex case involved ingestion of 195 mg of selegiline, 8,600 mg of carbamazepine, 16,000 mg of sustained-release valproate, 2,250 mg of trazodone, and 70 mg of nitrazepam. There were symptoms suggestive of serotonin syndrome after 5 days of intubation for aspiration pneumonia. After recovery from pneumonia, on day 12, the patient developed visual hallucinations, high blood pressure, and generalized seizures resistant to drug therapy. These symptoms persisted for 6 days. Too few details about the patient’s drug therapy (e.g., continuation of pre-overdose antiepileptic agents) are provided to allow conclusions about the role of selegiline in the reactions (156).
Moclobemide appears to be safe in even extremely large overdoses when it is ingested alone. Doses as high as 20.55 grams were not associated with fatality. Doses of up to 2 grams are only associated with mild gastrointestinal symptoms; 3 – 8 gram doses were associated with CNS depression, agitation, tachycardia, and hypertension. Co-ingestion of serotonergic drugs (clomipramine, citalopram, fluoxetine) and moclobemide in overdoses has resulted in fatal serotonin syndrome (30,59).
|Body Temperature||Severe hyperthermia (> 106° F)|
|Neuropsychiatric||Agitation, akathisia, hallucinations, headache, seizures, confusion, coma|
|Neuromuscular||Myoclonus, hypertonia, hyperreflexia, muscular rigidity potentially resulting in hyperthermia and rhabdomyolysis|
Early: Hypertension, tachycardia, palpitations
Late: Hypotension, bradycardia, reflex tachycardia
Ischemic ECG changes, peaked T waves
|Gastrointestinal||Nausea, vomiting, diarrhea|
|Dermatologic||Flushing, piloerection, diaphoresis|
|Ophthalmologic||Ocular clonus, mydriasis, nystagmus|
Adapted from Manini (155)