Double-Blind Study of High-Dose Fluoxetine Versus Lithium or Desipramine Augmentation of Fluoxetine in Partial Responders and Nonresponders to Fluoxetine

Abstract

In a previous study, of 41 depressed patients who had not responded to fluoxetine 20 mg/day, 53% were treated with high-dose fluoxetine (40-60 mg/ day) and responded (i.e., their 17-item Hamilton Rating Scale for Depression [HAM-D-17] score was <7) versus 29% and 25% of patients treated with fluoxetine plus lithium (300-600 mg/day) or fluoxetine plus desipramine (25-50 mg/day), respectively. We wanted to assess whether these findings could be replicated in a larger sample of depressed outpatients. We identified 101 outpatients with major depressive disorder (52 men and 49 women; mean age, 41.6 + 10.6 years) who were either partial responders (n = 49) or nonresponders (n = 52) to 8 weeks of treatment with fluoxetine 20 mg/ day. These patients were randomized to 4 weeks of double-blind treatment with high-dose fluoxetine (40-60 mg/day), fluoxetine plus lithium (300-600 mg/day), or fluoxetine plus desipramine (25-50 mg/day). In the overall group of patients (N = 101), there was no significant difference in response rates across the three treatment groups (high-dose fluoxetine, 42.4%; fluoxetine plus desipramine, 29.4%; fluoxetine plus lithium, 23.5%). Dropout rates were also comparable, ranging from 9.1% (high-dose fluoxetine) to 14.7% (fluoxetine plus desipramine and fluoxetine plus lithium). There were also no significant differences in response rates across the three treatment groups among partial responders (high-dose fluoxetine, 50.0%; fluoxetine plus desipramine, 33.3%; fluoxetine plus lithium, 33.3%) and nonresponders (high-dose fluoxetine, 35.3%; fluoxetine plus desipramine, 26.3%; fluoxetine plus lithium, 12.5%). At the end of the study, the mean lithium level was 0.37 + 0.15 mEq/L (n = 27; range, 0.1-0.8 mEq/L) among lithium-treated patients, and the mean desipramine level was 104.7 + 58.8 ng/mL (n = 22; range, 25-257 ng/mL). There were no significant relationships between lithium or desipramine blood levels and degree of improvement (as measured by the change in HAM-D-17 score). We found no significant differences in efficacy among these three treatment strategies among patients who had failed to respond adequately to 8 weeks of treatment with fluoxetine 20 mg/day, although the high-fluoxetine group was associated with nonsignificantly higher response rates in both partial responders and nonresponders.

Comparative efficacy and acceptability of seven augmentation agents for treatment-resistant depression: A multiple-treatments meta-analysis

“…1). [17][18][19][20][21][22][23][24][25][26][27][28] All 12 of these studies had obtained ethical approval. Altogether, the 12 studies included 1 936 patients and seven kinds of augmentation agents, namely lithium, tricyclic antidepressants (TCAs), atypical antipsychotics (AAPs), antiepileptic drugs (AEDs), buspirone, cognitive behaviour therapy (CBT) and tri-iodothyronine (T3).…”

Pharmacogenomic Testing and Personalized Treatment of Depression

“…Although it may seem counterintuitive, there is no convincing evidence of a dose response or therapeutic window with SSRIs and SNRIs, with the possible exception of venlafaxine [reviewed in (11 ); a small number of studies do support dose increase as a strategy in initial treatment nonresponders (12 )]. At the extremes, blood concentrations likely matter a great deal.…”

Use of Treatment Algorithms for Depression

“…Osser: Dr. Fava, you conducted 2 studies 18,19 in which you augmented fluoxetine with desipramine or lithium or increased the dose of fluoxetine. In both of those studies, the results were relatively unimpressive for the augmentation with lithium.…”