Combination Therapy for Treatment-Resistant Depression: Should MAOIs Be Included?

Due to the risk of adverse effects and dietary and drug interactions, use of monoamine oxidase inhibitors (MAOIs) for the treatment of depression is fairly low. Risks can include hypertensive crisis with consumption of tyramine-rich food, and serotonin syndrome (in combination with other drugs), which is why is it recommended that MOIs not be used with another antidepressant, certain prescription medications like tramadol, meperidine, dextromethorphan, or methadone, and nonprescription drugs. Because some research has indicated benefits of MAOIs combined with another antidepressant for treatment-resistant depression (TRD), a review in Pharmacotherapy evaluated data from 18 published studies and case reports and the medical records of 29 adult patients from a large Midwestern teaching hospital on the safety and efficacy of combination therapy with MAOIs and other antidepressants or stimulants for TRD. The results are as follows:

MAOI + SSRI/SNRI:

There are few controlled, prospective studies because this combination is considered to be dangerous due to the increased risk of serotonin syndrome. It is recommended that SSRIs and SNRIs be discontinued for at least two weeks before initiating MAOI treatment, except for fluoxetine which requires five weeks. Data from the case studies were uninformative or had no positive outcomes. The authors state that the risks outweigh the benefits with this combination, especially with concomitant trazodone use.

MAOI + Trazodone:

With an open-label case study and a case series, low-dose trazodone was a safe and effective treatment option for insomnia associated with MAOI use. There is limited data on its safety and efficacy in higher doses; doses used to target insomnia are generally not effective as antidepressant doses. Because the risk of serotonin syndrome increased with rising doses, the risks would likely outweigh any potential benefits.

MAOI + TCA

Small studies and case studies have led to mixed findings on MAOIs plus TCAs. While some have demonstrated safety, this combination is usually less well-tolerated than either agent alone. There is evidence that the combination is no more effective than either agent alone. However, in the case studies culled from the patient medical records in this review, sustained tolerability and efficacy was observed with an MAOI + TCA. The exception to this is clomipramine, which should not be used concomitantly with an MAOI.

MAOI + Bupropion:

Only three case studies assessed buproprion and tranylcypromine but had limited positive effects. While this combination may be considered for TRD, the risk of hypertension or other adverse effects should be closely monitored.

MAOI + Stimulants

Although stimulants are not indicated for treatment of depression, they are used as an augmentation strategy and are supported by evidence in the literature as to their safety with MAOIs. Stimulants could help to normalize blood pressure in patients experiencing hypotension due to MAOI.

MAOI + Antidepressants + Stimulants

This combination has demonstrated efficacy in case reports, although the case studies from the hospital showed mixed results. The authors warn that this should be prescribed only as a last resort, including failure of electroconvulsive therapy.

While the literature supports cautious use of combining MAOIs with other antidepressants in patients with TRD who have failed multiple treatment modalities, risks of combination treatment must be considered and addressed. The authors emphasize that close supervision, under the care of an experienced clinician in psychiatry is necessary for considering combination therapy for the management of TRD in patients not responding to monotherapy or other combinations of antidepressants.

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