Should moclobemide be used with other antidepressants?

Summary
Moclobemide is a shortacting, specific, reversible inhibitor of monoamine oxidase A (MAOA). Since moclobemide increases the concentrations of serotonin and noradrenaline in the brain, it can have significant interactions with both selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs), even in therapeutic doses. There are very few indications for combining moclobemide and other antidepressants. The efficacy of these combinations is unproven. Sequential use of moclobemide and other antidepressants is acceptable, but adequate time should be allowed between different drugs, especially when moclobemide is used second.

Introduction
Classical monoamine oxidase (MAO) inhibitors have numerous, serious interactions with a range of other drugs including tricyclic antidepressants (TCAs). They also have significant interactions with dietary sympathomimetic amines, such as tyramine.¹

Moclobemide is a new MAO inhibitor antidepressant which differs from previous MAO inhibitors in two ways: its action on MAO is reversible and its inhibitory action is relatively selective for MAOA. The drug is short acting and increases brain concentrations of both noradrenaline and serotonin.² Its interaction with dietary amines causes considerably less increase in blood pressure than occurs with the classical MAO inhibitors.

It is an effective antidepressant which is relatively free of adverse effects. Moclobemide is also less toxic than classical MAO inhibitors when taken in overdose, although its selectivity and safety are less apparent at doses above 2000 mg (14 tablets).³ The combination of moclobemide and other antidepressants has not been well investigated.

Combinations of antidepressants
There is no evidence from clinical trials that combinations of MAO inhibitors and other antidepressants have greater efficacy than either type of drug used alone. Combinations should only be considered for patients who have failed to respond to electroconvulsive therapy and other antidepressants tried alone for adequate periods, in adequate doses, with associated social and psychological interventions. For this reason, the Royal Australian and New Zealand College of Psychiatrists ha s recommended that the concomitant prescription of moclobemide with any other antidepressant should only occur after careful review in selected patients.⁴ However, some psychiatrists believe that there is never an indication for combination treatment because of unproven efficacy and the potential for serious toxicity.

Moclobemide and selective serotonin reuptake inhibitors (SSRIs)
The TCA clomipramine and the newer SSRIs such as fluoxetine, paroxetine and sertraline raise the concentration of serotonin in the brain more than other neurotransmitters. Serotonin is metabolised by MAO-A and its concentration will be increased by both selective and non-selective inhibitors of MAO-A. A combination of a serotonergic antidepressant with a selective or non-selective MAO inhibitor is therefore completely contraindicated. The major risk is the so called 'serotonin syndrome'. This is a complex of agitation, delirium, hypertonicity, seizures, hyperpyrexia and variable elevation of heart and respiratory rates. Blood pressure is not usually elevated, but coma and even death may ensue. There was hope that, because of its reversibility, moclobemide would be safer than non-selective MAO inhibitors in combined regimens, but 5 cases of fatal interactions have been reported after overdoses of moclobemide and SSRIs.5 There is currently insufficient evidence to state that such interactions do not occur at therapeutic doses.

The sequential use of drugs from these different pharmacological groups is acceptable. The actions of moclobemide are almost completely reversed after 24 hours and a SSRI may be started 24-48 hours after ceasing moclobemide. Conversely, the SSRIs mostly have very long half-lives and their effects may last for long periods. A case of non-fatal serotonergic syndrome has occurred when a patient began moclobemide, at a therapeutic dose, a few days after stopping clomipramine. Theoretically, before changing from a SSRI to moclobemide, at least 5 times the longest reported half-life (see Table 1) should be allowed to elapse between stopping the first drug and starting moclobemide. In practice, a lesser time is usually sufficient to allow a safe change-over with careful monitoring, particularly if the dose of SSRI was not high.

Moclobemide and tricyclic antidepressants
The TCAs vary in their relative effects on uptake of serotonin and noradrenaline. Clomipramine predominantly affects serotonin uptake, causing a significant increase in its brain concentrations. In general, the tertiary amines (see Table 1) have relatively greater effects on serotonin than on noradrenaline reuptake. The secondary amines have a relatively greater effect on noradrenaline uptake. Noradrenaline is also a substrate for MAO-A and therefore the TCAs have a potential to interact with moclobemide.

It has been claimed that amitriptyline and desipramine may be used safely with moclobemide. The studies on which this claim is based were performed in very small numbers of patients using sub-therapeutic doses of all drugs. The safety of these combinations is therefore unproven. If this regimen is the only possible course of action in a patient who has failed to respond to any other treatment, then moclobemide and amitriptyline should be started simultaneously, in low doses, and the doses increased gradually over a number of weeks.

Great care must be taken when stopping moclobemide or a TCA to change to the other drug class. As with the SSRIs, a TCA can be introduced 24-48 hours after stopping moclobemide. Theoretically, the TCA must be stopped for at least 5 half-lives before moclobemide can be safely introduced. In practice, a lesser time is usually sufficient to allow a safe change-over with careful monitoring, particularly if the dose of TCA was not high. Particular care should be taken with clomipramine because of its greater inhibition of serotonin uptake.

Conclusion
Moclobemide, a specific, reversible inhibitor of MAO-A, is an advance on the classical MAO inhibitors. It should only be used very rarely (if ever) in combination with other antidepressants. When used sequentially, adequate time should be allowed between different types of drug.

Further reading
Nierenberg DW, Semprebon M. The central nervous system serotonin syndrome [see comments]. Clin Pharmacol Ther 1993;53:84-8. Comment in: Clin Pharmacol Ther 1993;54:230.