SSRI-nefazodone combination  To date, only anecdotal reports have suggested the efficacy of combining SSRIs with nefazodone—typically at 100 or 200 mg bid. There is one report of this combination resulting in serotonin syndrome (John et al. 1997), although it was not particularly severe, due to the fact that nefazodone is a mildly potent blocker of serotonin uptake. In theory, accumulation of the nefazodone active metabolite m-chlorophenylpiperazine (mCPP) could occur when nefazodone is coadministered with SSRIs that inhibit CYP2D6, since mCPP is a substrate of CYP2D6. This increase in mCPP could cause some anxiety and irritability. Other advantages of adding nefazodone to SSRIs in the event of nonresponse are that nefazodone may help sexual dysfunction related to SSRIs (Reynolds 1997) and improve sleep.

SSRI-bupropion combination  The addition of bupropion (100-150 mg sustained release [SR] once or twice a day) to an ongoing failed SSRI trial was the first augmentation/combination strategy chosen by the psychiatrists that we surveyed (Fredman et al. 2000). Supporting this strategy are mostly anecdotal reports, case series, or small open trials suggesting the usefulness of this approach (Bodkin et al. 1997; Marshall and Liebowitz 1996; Marshall et al. 1995; Spier 1998). Potential disadvantages are that the combination of bupropion and SSRIs may lead to tremor (Bodkin et al. 1997) or anxiety (S. J. Young 1996). However, the positive effects of bupropion augmentation on SSRI-induced sexual dysfunction reported in some studies (Ashton and Rosen 1998; Labbate et al. 1997) may be a significant advantage for this strategy.

SSRI-SSRI combination  SSRIs have been anecdotally reported to be useful in augmenting other SSRIs (Bondolfi et al. 1996). The main disadvantages of this approach are an increase in the intensity of serotonergic side effects and a theoretical risk of serotonin syndrome (Gillman 1998). Although this is not a very widely used approach, a report by Bondolfi and colleagues (1996) suggested that an interesting drug-drug interaction may occur when one combines certain SSRIs. For example, the authors argue that fluvoxamine augmentation of citalopram increases the ratio of S-citalopram to R-citalopram. Because S-citalopram is a more potent inhibitor of serotonin uptake, this drug interaction increases the more active form of citalopram.

Conclusion  The strategy of combining different classes of antidepressants is a promising one. Results from the clinical trials of combination strategies of MAOIs and TCAs or SSRIs and TCAs for patients with treatment-resistant unipolar depression are compiled in

Table 45-3. During the next decade, clinical researchers need to provide clinicians with controlled data on the efficacy of these combination strategies to facilitate the development of more accurate algorithms in the treatment of depressed patients who have undergone failed trials with monotherapy.