Tranylcypromine has been found effective in patients hospitalized with endogenous depressions.17 Most clinicians experienced with MAOIs prefer this agent because it triggers weight gain to a much lesser degree than other MAOIs. Tranylcypromine can cause insomnia and a greater increase in tyramine sensitivity than other MAOIs, which therefore brings a greater risk of hypertensive crisis.
Phenelzine has the advantage that the effective dosage for depression is probably now known—more than 1 mg/kg body weight—although in three earlier large negative controlled studies, the effective dosage was not known and too little was given for too short a period. Weight gain and hypotension may be more common with this drug than with other MAOIs.
Isocarboxazid is the least studied but has been shown to be effective, with an average 41% drug-placebo difference in two studies.16 One of us (JOC) preferred it for several years, based on good responses in a handful of treatment-resistant patients.
Selegiline is used in low dosages for parkinsonism. At higher dosages (more than 20 mg/d), selegiline is a good antidepressant but is no longer MAO-B selective—inhibiting both the MAO-B and MAO-A enzymes and thus requiring the usual dietary restrictions. One of us (JAB) routinely maintains bipolar patients with mild baseline depression or lethargy on a mood stabilizer plus a low dosage (5 to 10 mg/d) of selegiline. With this combination, patients are more satisfied and compliant with the mood stabilizer regimen and require no dietary restrictions.
Overall, there may be a special clinical benefit to phenelzine in the more anxious, easily distressed patient and to tranylcypromine or selegiline in the more sluggish, lethargic patient. But probably the soundest way to choose MAOIs is if other, more standard treatments have not worked.
Combinations with other antidepressants
We have found all antidepressants that do not involve significant serotonin reuptake inhibition (e.g., bupropion, trazodone, and tricyclics other than clomipramine) can be safely administered with MAOIs. Combination therapy is worth considering because it may be effective when other approaches have failed.
For a patient switching from an SSRI, a trial of one of these other antidepressants may be appropriate before undertaking MAOI therapy, simply because it avoids the SSRI washout period. Normally, patients should be off fluoxetine for 5 weeks, other SSRIs or clomipramine for 2 weeks, and venlafaxine for 1 week before starting an MAOI.
With the exception of clomipramine, TCAs generally are safe with MAOIs, although the Physician’s Desk Reference warns against adding a TCA to an MAOI. We know of one death and one case of delirium when parenteral imipramine was given to a patient who had been on a MAOI for some time unbeknownst to the MD giving the injection. Both amitriptyline (and by extension, nortriptyline) and trimipramine have been given along with an MAOI in controlled studies with no special adverse effects.18 Both drugs, and probably doxepin, are good hypnotics and seem safe in combination, although one should begin with a low dosage (e.g., 25 mg hs) if the patient is improving on an MAOI but is bothered by insomnia.
Table 1
RECOMMENDED MAOI DOSAGE RANGES
| Drug | Dosage range |
|---|---|
| Isocarboxazid | 20 to 80 mg/d |
| Moclobemide* | 300 to 900 mg/d |
| Phenelzine | 30 to 90 mg/d |
| Selegiline | 15 to 60 mg/d |
| Tranylcypromine | 20 to 100 mg/d |
| * Available in Canada but not in the United States | |
Trazodone is frequently employed as a remedy for MAOI-induced insomnia.19 Mirtazapine can be used safely in combination with MAOIs, and the agent has been reported to acutely treat serotonin syndrome.20
Determining dosage
Failure to understand the required effective dosages of MAOIs led to many early treatment failures and fueled clinicians’ perception that drugs in this class were ineffective. The senior author had to hospitalize a depressed man who had failed to improve on 30 mg/d of phenelzine for 10 days. The author later learned that a dose of more than 1 mg/kg per day for 3 to 4 weeks was necessary for response.
A rule of thumb is to start with one MAOI pill the first day and increase the dosage by one pill every 4 to 7 days until these levels are reached:
- 1 mg/kg/d for phenelzine;
- 40 mg/d for tranylcypromine and isocarboxazid;
- 45 mg/d for selegiline.
Reduce the dosage if side effects occur, or increase it if improvement is not noted in 1 to 2 months. We’ve tried starting patients on the 1 mg/kg dose of phenelzine the first day and elicited rapid and severe insomnia. Other intolerable side effects can also emerge from too-rapid dosage escalation. Clinical experience suggests the dosage ranges shown in Table 1.
Avoiding MAOI-related hypertension
We believe two factors have contributed to disuse of MAOIs by U.S. psychiatrists and slow development of new MAOIs here. These are the fear of severe hypertensive crisis and often vastly inflated MAOI dietary restrictions. In our practice, we provide patients receiving MAOIs with a reasonable list developed at the University of Toronto that explains foods to be avoided and alternatives that are allowed (Table 2).21