Combined MAOIs and TCAs  Although in the 1960s combined antidepressant therapy with MAOIs and TCAs was more common, involving up to 5% of all antidepressant prescriptions (Tyrer and Murphy 1990), concern over the safety of this combination led to recommendations that these drugs not be used together (Sheperd et al. 1968). The combination of MAOIs and TCAs, however, appears safe if both treatments are initiated in low doses simultaneously and are gradually increased together (Spiker and Pugh 1976; White and Simpson 1981). On the other hand, possibly imipramine and certainly clomipramine pose greater risks of toxicity (Lader 1983).

Some uncontrolled case reports suggest combined MAOI and TCA treatment to be effective in treatment-refractory depression. In a retrospective study on 94 inpatients with treatment-resistant depression, 64 (68%) of the patients responded to a combination of MAOIs, TCAs, and tetracyclic antidepressants (Schmauss et al. 1988). Furthermore, in a survey of 27 patients with treatment-resistant depression treated with the combination of the MAOI isocarboxazid and mianserin, 20 (74%) of 27 patients responded (Riise and Holm 1984). In a controlled study on the efficacy of MAOI and TCA combinations in patients with treatment-refractory depression, electroconvulsive therapy (ECT) proved to be more effective than amitriptyline and phenelzine together in 17 patients (Davidson et al. 1978); however, the small sample size, the presence of psychotic depression in some of the patients, and the use of relatively low average dosages of amitriptyline (71 mg/day) and phenelzine (34 mg/day) might have accounted for the results.

Overall, it appears from the literature that the combination of MAOIs and TCAs can be relatively safe and effective in the treatment of patients whose depression is treatment-resistant. On the other hand, the risks associated with MAOI and TCA treatment have made this strategy relatively unpopular since the introduction of the newer agents.

Finally, the combination of MAOIs and SSRIs (or clomipramine) is generally contraindicated, because it can cause potentially fatal reactions such as serotonin syndrome (Feighner et al. 1990). One exception is a report of 11 patients with refractory depression who were treated with a combination of a reversible inhibitor of monoamine oxidase A (RIMA), moclobemide, and either sertraline or fluvoxamine (Joffe and Bakish 1994). The investigators found that 8 (73%) of 11 patients responded. This number is too small to determine with confidence that the combination of an SSRI and a RIMA is safe.