A randomized, double-blind comparison of olanzapine/fluoxetine combination, olanzapine, fluoxetine, and venlafaxine in treatment-resistant depression

Abstract

Based on preliminary evidence of its usefulness in treatment-resistant depression (TRD), an olanzapine/fluoxetine combination (OFC) was examined in comparison with olanzapine, fluoxetine, and venlafaxine in a TRD population. In this 12-week double-blind study, 483 subjects with unipolar, nonpsychotic TRD, with historic failure on a selective serotonin reuptake inhibitor (SSRI) and prospective failure on open-label venlafaxine, were randomized to an OFC or to an olanzapine, fluoxetine, or venlafaxine monotherapy group. Venlafaxine was continued randomly in the double-blind acute phase to explore the benefits of continuation versus switching therapy. The Montgomery-Asberg Depression Rating Scale (MADRS) total change score at end point was the primary outcome measure. The OFC group had significantly greater improvement in depressive symptoms by week 1 of treatment (MADRS mean change =-7.2, baseline =29.6), in comparison to olanzapine (-4.8, P=.03), fluoxetine (-4.7, P=.03), or venlafaxine (-3.7, P=.002) groups and maintained its statistical separation from all three monotherapy groups through week 6. At end point, the OFC group was significantly different only from the olanzapine group (-14.1 vs. -7.7, P<.001). Analysis of a subgroup of subjects who had an SSRI failure in their current depressive episode (n=334) revealed statistical separation from both olanzapine and fluoxetine (but not venlafaxine) at end point: OFC (-14.6) versus olanzapine (-9.4, P<.001) versus fluoxetine (-10.7, P=.006) versus venlafaxine (-14.7, P=.98). The OFC had a safety profile comparable to its component monotherapies (i.e., olanzapine and fluoxetine), showed a rapid onset of antidepressant effect, and was effective in this TRD sample. At the study end point, OFC, fluoxetine, venlafaxine, and low-dose OFC all appeared to be similarly effective.

A randomized, placebo-controlled trial of risperidone augmentation for patients with difficult-to-treat unipolar, non-psychotic major depression

“…The fact that 21% of the placebo group dropped from the study (vs. 12.9% of the risperidone group) may be due to inadequate response to medication. Rapid response to an adjunctive atypical followed by convergence with a control group was found in the recent study by Berman et al (2007) and the combination studies also reported a quick response followed by a leveling off after a few weeks (Shelton et al, 2005;Corya et al, 2006).…”

“…Finally, the small to moderate treatment effect may indicate that the study was underpowered. That other studies testing atypical antipsychotics as augmenting agents (Berman et al, 2007;Ostroff and Nelson, 1999;Shelton et al, 2001) and those with larger samples (Corya et al, 2006;Shelton, 2006) report a similar pattern (i.e., rapid response followed by convergence of treatment groups), suggests otherwise. In fact, a compelling reason to initiate an atypical antipsychotic augmenting agent sooner rather than later may be because several studies, including this one, have reported a significant response as early as 1 week into treatment (Barbee et al, 2004;Bouhours et al, 2004;Ostroff and Nelson, 1999;Shelton et al, 2001).…”

“…In a double-blind, randomized risperidone augmentation trial, patients improved after 4 weeks and maintained the improvement at the 6-week endpoint (Gharabawi et al, 2006). In two large double-blind studies using a combination of medications (i.e., not augmentation trials per se), patients reported a rapid response to the combined use of olanzapine and an antidepressant, though the treatment effect was not sustained at the study endpoints of 8 and 12 weeks (Corya et al, 2006;Shelton et al, 2005). A more recent report of parallel studies of patients with Treatment Resistant Depression (TRD) found that one study showed no treatment differences using an olanzapine/fluoxetine combination while the second study, and the pooled data, did find significant improvement in patients who received the combination therapy (Thase et al, 2007).…”

“…Of interest, study designs often differ in the lack of a standard definition of the study population (e.g., differences between difficult-to-treat and treatment resistant depressions, Thase, 2002;Kupfer and Charney, 2003;Shelton et al, 2005), the variation in lead-in trial time (4-8 weeks, Appelberg et al, 2001;Licht and Qvitzau, 2002;Bouhours et al, 2004;Papakostas et al, 2005;Corya et al, 2006;Berman et al, 2007;Alexopoulos et al, 2008), differences in study length and the range of cut-offs and instruments defining remission (e.g., ≤8-10 on MADRS) (Nemeroff, 2005;Shelton et al, 2005;Berman et al, 2007;Papakostas et al, 2007;Thase et al, 2007).…”

Augmentation Treatments with Second-generation Antipsychotics to Antidepressants in Treatment-resistant Depression

“…Thase et al [18] includes two trials (study 1 and study 2). Response was defined as an improvement of C50% from baseline to endpoint on the HAM-D or the MADRS, and remission was defined as a MADRS total score of B10 and C50% reduction in MADRS total score in the trials except trials by Shelton et al [15] and Corya et al [17] (two subsequent MADRS total score B8), McIntyre and Gendron [22] and Mahmoud et al [24] (HAM-D-17 score B7), Bauer et al [20], El-Khalili et al [21] and Keitner et al [26] (MADRS total score B8), trial by Reeves et al [25] aripiprazole than receiving placebo (0.6 %) had a weight gain of 7 % or more [13]. The difference in weight gain with SGA adjunctive therapy was small, and no other adverse event related to metabolic function, such as changes in mean waist circumference, total cholesterol, high or low-density lipoprotein cholesterol, triglycerides, fasting plasma glucose, or haemoglobin A1C, was associated with aripiprazole augmentation in short-term trials.…”