Combined SSRIs and TCAs  The strategy of combining fluoxetine or other SSRIs with a TCA in the treatment of patients with refractory depression has been popular. An early study (Nelson et al. 1991) had shown that this combination may produce a more rapid onset of antidepressant action, whereas a more recent study by the same author (Nelson 1999) has shown that remission rates are significantly higher with desipramine plus fluoxetine than with either drug alone. Some case reports and series had suggested the efficacy in treatment-resistant depression of adding a TCA to an SSRI (e.g., fluoxetine or sertraline) (Eisen 1989; Seth et al. 1992; Zajecka et al. 1995) or of adding fluoxetine or citalopram to a TCA (Baettig et al. 1993; Seth et al. 1992).

In a retrospective study of 30 depressed nonresponders, 26 (87%) were reported to have improved when fluoxetine was added to a non-MAOI antidepressant. When the non-MAOI antidepressant treatment was withdrawn for 12 of the responders, 8 of them relapsed on fluoxetine treatment alone but recovered when treatment with the discontinued agent was restarted (Weilburg et al. 1989).

In another retrospective study, the addition of a TCA to fluoxetine led to significant improvement in 13 (65%) of 20 depressed patients who had not responded adequately to fluoxetine alone (Weilburg et al. 1991). The prospective studies in resistant depression have not shown comparable response rates. In a double-blind study (M. Fava et al. 1994b), desipramine augmentation (up to 50 mg/day) of fluoxetine 20 mg/day was associated with a lower response rate (3 of 12; 25%) than raising the dosage of fluoxetine to 40-60 mg/day (8 of 15; 53%). Similar response rates were reported in an open trial by Levitt et al. (1999), in which 4 (31%) of 13 patients with resistant depression responded to the addition of desipramine or imipramine to fluoxetine, and in an open trial by Amsterdam et al. (1997), which showed improvement in 4 (36%) of 11 patients who received a combination of the TCA clomipramine and fluoxetine. Fluoxetine, like most SSRIs, inhibits the metabolism of the TCAs, and marked elevations in TCA blood levels when a TCA was coadministered with fluoxetine (Ciraulo and Shader 1990), paroxetine (Alderman et al. 1997), and fluvoxamine (Maskall and Lam 1993; Szegedi et al. 1996) have been reported. However, it is possible to safely administer fluoxetine and other SSRIs with TCAs if a low dosage of the latter (25-50 mg/day) is used and plasma TCA levels are monitored. Although reports of SSRI-TCA combinations mostly feature fluoxetine, it is likely that any SSRI could be used.