Higher-Dose Antidepressants
What clinical trial evidence for the use of higher-dose antidepressants in treatment-refractory depression is available?  An alternative approach to switching is the use of relatively high doses of antidepressant monotherapy. In an open-label study of higher-dose tranylcypromine (dosage range = 90-170 mg/day), 4 (57%) of 7 subjects who had previously undergone multiple failed trials with antidepressants responded (Amsterdam and Berwish 1989). Similarly, in one retrospective study the relative safety and efficacy of high-dose TCAs in treatment-resistant depression were asserted (Schuckit and Feighner 1972), and in another it was found that 14 (63%) of 22 patients with treatment-resistant depression responded to an open trial with trazodone up to 800 mg/day (Cole et al. 1981). In addition, an open study of 15 patients who had not responded to 8-12 weeks of treatment with a standard 20-mg dose of the SSRI fluoxetine showed a significant improvement in depressive symptoms after an increase in dosage up to 80 mg/day (M. Fava et al. 1992). A subsequent double-blind study (M. Fava et al. 1994b) showed that raising the dosage of fluoxetine to 40-60 mg/day was significantly more effective than adding desipramine 25-50 mg/day or lithium 300-600 mg/day to fluoxetine 20 mg/day among patients who had not responded to 8 weeks of fluoxetine 20 mg/day. Therefore, it would appear that the use of high-dose SSRIs—which are safer than high-dose TCAs—may serve in managing depressions that are resistant to lower doses. Results from the clinical studies of higher-dosage strategies for patients with treatment-resistant unipolar depression are compiled in

Table 45-2.

This approach seems to challenge the assumption of the lack of a dose-response relationship with the SSRIs. However, although a meta-analysis of the placebo-controlled studies with citalopram demonstrated that the dose-response curves based on log odds ratios showed a very flat curve across the 20- to 60-mg range, similar to other SSRIs such as fluoxetine and sertraline, there was evidence for a better response with a higher dosage (60 mg/day) in some subgroups of depressed patients, such as those with severe depression (Montgomery 1995). Similarly, a 7- to 8-week multicenter randomized, double-blind, placebo-controlled study involving 600 patients with major depressive disorder showed that fluvoxamine (50-150 mg/day) was therapeutically effective and well tolerated during 6 weeks of therapy, but based on the HAM-D depressed mood item, efficacy was dose-dependent, with the minimum effective dosage being 50 mg/day (Walczak et al. 1996). Therefore, even though fixed-dose trials do generally suggest the lack of a dose-response relationship with the SSRIs, it seems plausible that some patients may benefit from a dose increase. Perhaps this is why raising the dose is a commonly selected strategy for patients who have not responded to an adequate trial with an SSRI (Fredman et al. 2000).

How should higher-dose antidepressants be used and for how long?  Of patients who do not respond to treatment with a standard dose of a TCA, some will improve when the dosage of the TCA is titrated, if tolerated, up to 400 or 500 mg/day. Clinicians should carefully monitor electrocardiograms (ECGs) and blood levels to minimize the risk of toxicity. Some patients who do not respond to a standard dose of an SSRI have been successfully treated with dosages up to 80-100 mg/day of fluoxetine or paroxetine and up to 400 mg/day of sertraline without significant tolerability problems. No guidelines exist as to the adequate duration of a higher-dose antidepressant therapy trial, but 6 weeks is likely to be a sufficient duration. If tolerated, treatment following response can be maintained for 6-9 months, followed by a decrease by tapering. If the patient has a history of highly recurrent or chronic depression, discontinuation should be deferred.