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COMBINATION

The ability to proceed quickly, with no "down" time during treatment of the depressed patient provides a strong rationale for combination therapy. Indeed, combination strategies have superseded substitution in some specialty practices today. The underlying principle of combination therapy involves using the pharmacokinetics of each agent in such a way as to arrive at a different and potentially more effective therapy than might be possible with either drug alone. While several combination strategies involve standard doses of both antidepressants, often lower doses of both drugs must be given.

Potentially, any number of antidepressant medications might be considered for combination therapy; however, some are clearly more attractive and potentially more effective than others. Two TCAs, given in full dose combination, for example, is not a prudent approach, largely because of the side effect burden such a combination would entail, without evidence of improved efficacy.

Similarly, while theoretically possible to combine a TCA with a MAOI, studies now show that the combination is no more effective than substitution, and it is more logical to stop the TCA altogether, and initiate the MAOI than to use both of them together. (That said, a small percentage of resistant patients may benefit from this combination).

In contrast, evidence suggests that the combination of a TCA and a SSRI, both initiated together or added following a complete trial of one agent, appears to bring about a more rapid onset of action and a more profound response than TCAs alone. There's also some evidence - largely for the combination of desipramine and fluoxetine - to suggest that a certain percentage of patients who fail both a TCA and a SSRI may respond to the combined use of both agents.

Because the SSRIs are generally better tolerated than the TCAs, combination therapy in which a SSRI is used initially, followed by an additional TCA if response to the single agent should prove inadequate, is a particularly attractive approach.

The same SSRI-TCA combination also allows clinicians to go immediately to full-dose TCA therapy, used as a single agent, should the patient fail to respond to the SSRI/TCA combination. (Of note: when using the SSRI/TCA combination approach, it is important to manipulate the dose of the TCA and not the SSRI, if the dosage of one agent needs to be reduced. It should also be noted that doses of the TCA used are lower than normal - in the range of l mg/kg/day - when used in combination with most SSRIs; normal dosage being in the range of 2.5 mg/kg/day).

Preliminary work also suggests a role for combined SSRI / RIMA (moclobmide) therapy, consisting of the usual recommended dose of the SSRI combined with up to 600 mg of moclobemide. Although side effects can be pronounced during the first 24 hours following introduction of this particular combination, early results suggest up to 60 percent of previously refractory patients respond to this combination. (This has to be confirmed in double-blind, controlled trials.) High dose combination SSRI therapy has also been used by a few investigators with some success.

Recent reports on the combined use of bupropion and an SSRI suggests that bupropion, given in relatively low doses, may be able to reverse some of the sexual side effects associated with certain SSRIs. However, data on the antidepressant efficacy and side effect profile of this particular combination is unavailable.

For SSRI-induced insomnia, trazodone has been recommended as an appropriate treatment. Nevertheless, there is little empirical data to support the recommendation, and this particular combination should not be confused with true "combination" therapy, whose purpose is to improve the overall antidepressant effect.

It is important to stress that caution is needed in certain circumstances when using combination therapy. Moreover, before recommendations can be made for wholesale adoption of this particular strategy, results from appropriate, double-blind, placebo-controlled trials are clearly needed. Until clinicians gain more experience with managing patients on combination therapy, it is currently recommended that patients who may potentially benefit from combination therapy be referred to a psychiatrist with an interest in this area. It is also important not to combine any of the conventional, older MAOIs without consulting a specialist.

Finally, although many combinations are possible, the SSRIs, in general, are safe in combination with a wide variety of other antidepressants and they may be a more appropriate choice in the absence of specialist consultation.

Conclusion

For patients who fail to respond to an initial course of antidepressant medication, a number of options exist which serve to enhance therapeutic outcome. The first and most important is optimization.

However, with the development of newer and better tolerated antidepressant medications, many now feel that the combined use of two active antidepressant agents is a more rapid and potentially more effective response than substituting one active antidepressant drug for another. Independent of the strategy chosen, the goal of the practitioner is to successfully treat depression, with the least amount of discomfort for the patient.

For patients who may be severely depressed, more aggressive combination therapy may be justified in order to prevent prolonged disability and self-harm.

This paper was developed and written by Dr. Russell Joffe, Dr. Anthony Levitt, Dr. Stephen Sokolov, and Dr. L. Trevor Young while they were on staff at the Mood Disorders Program, Department of Psychiatry and Behavioural Neurosciences, McMaster University.The paper was supported by an educational grant from Eli Lilly Canada Inc.

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Reviewed: 05/2006