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Efficacy and safety of olanzapine/fluoxetine combination vs fluoxetine monotherapy following successful combination therapy of treatment-resistant major depressive disorder.

ABSTRACT: This study assessed prevention of relapse in patients with treatment-resistant depression (TRD) taking olanzapine/fluoxetine combination (OFC). Patients with major depressive disorder (MDD) who failed to satisfactorily respond to ≥ 2 different antidepressants for ≥ 6 weeks within the current MDD episode were acutely treated for 6-8 weeks, followed by stabilization (12 weeks) on OFC. Those who remained stable were randomized to OFC or fluoxetine for up to 27 weeks. Time-to-relapse was the primary efficacy outcome defined as 50% increase in Montgomery-Åsberg Depression Rating Scale score with Clinical Global Impressions-Severity of Depression score of ≥ 4; hospitalization for depression or suicidality; or discontinuation for lack of efficacy or worsening of depression or suicidality. A total of 444 patients were randomized 1:1 to OFC (N=221) or fluoxetine (N=223). Time-to-relapse was significantly longer in OFC-treated patients compared with fluoxetine-treated patients (p<0.001). Treatment-emergent weight gain and some mean and categorical fasting metabolic changes were significantly greater in OFC-treated patients. Clinically significant weight gain (≥ 7%) was observed in 55.7% of patients who remained on OFC throughout the study, including the relapse-prevention phase (up to 47 weeks). There were no significant differences between patients treated with OFC and fluoxetine in extrapyramidal symptoms or serious adverse events. We believe this is the first controlled relapse-prevention study in subjects with TRD that supports continued use of a second-generation antipsychotic beyond stabilization. A thorough assessment of benefits and risks (in particular metabolic changes) associated with continuing treatment with OFC or fluoxetine must be done based on individual patient needs.

SUBMITTER: Brunner E

PROVIDER: S-EPMC4207330 | biostudies-other | 2014 Oct

REPOSITORIES: biostudies-other

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Project description:Treatment-resistant depression (TRD) occurs in many patients and causes high morbidity and mortality. Because TRD subjects are particularly difficult to study especially longitudinally, biological data remain very limited. In a preliminary study to judge feasibility and power, 25 TRD patients were referred from specialty psychiatric practices. All were severely and chronically depressed and mostly had comorbid psychiatric disorders as is typical in TRD. Nine patients were able to complete all required components of the protocol that included diagnostic interview; rating scales; clinical magnetic resonance imaging; medication washout; treatment with maximally tolerated olanzapine-fluoxetine combination for 8 weeks; and pre- and post-treatment fluorodeoxyglucose positron emission tomography. This drug combination is an accepted standard of treatment for TRD. Dropouts arose from worsening depression, insomnia, and anxiety. One patient remitted; three responded. A priori regions of interest included the amygdala and subgenual cingulate cortex (sgACC; Brodmann area BA25). Responders showed decreased metabolism with treatment in the right amygdala that correlated with clinical response; no significant changes in BA25; better response to treatment the higher the baseline BA25 metabolism; and decreased right ventromedial prefrontal metabolism (VMPFC; broader than BA25) with treatment which did not correlate with depression scores. The baseline metabolism of all individuals showed heterogeneous patterns when compared to a normative metabolic database. Although preliminary given the sample size, this study highlights several issues important for future work: marked dropout rate in this study design; need for large sample size for adequate power; baseline metabolic heterogeneity of TRD requiring careful subject characterization for future studies of interventions; relationship of amygdala activity decreases with response; and the relationship between baseline sgACC and VMPFC activity with response. Successful treatment of TRD with olanzapine-fluoxetine combination shows changes in cerebral metabolism like those seen in treatment-responsive major depression.

Project description:BackgroundIn the population of postmenopausal patients with major depressive disorder (MDD), the superiority of serotonin-norepinephrine reuptake inhibitors (SNRIs) over selective serotonin reuptake inhibitors (SSRIs) has not yet been definitively proven. Consequently, a direct comparison of the efficacy of SSRIs and SNRIs in the treatment of postmenopausal depression could provide relevant data. The aim of this study was to compare the efficacy and safety of venlafaxine vs. fluoxetine in the treatment of postmenopausal MDD.MethodsThis was an 8-week, multicenter, randomized, single-blind, active-controlled trial conducted at a psychiatric hospital (Beijing Anding Hospital) and a general hospital (Beijing Chaoyang Hospital) between April 2013 and September 2017. The primary outcome measure was improving depressive symptoms (Hamilton Depression Rating Scale (HAMD-24) score). The secondary outcomes included the change of HAMD-24 anxiety/somatization factor score and Clinical Global Impressions-Improvement (CGI-I) response rate. Safety was assessed by treatment-emergent adverse events (TEAEs) and laboratory tests. Efficacy was analyzed by using the full analysis set (FAS) following the modified intention-to-treat (mITT) principle. The primary endpoint measurements were analyzed using a mixed-effect model for repeated measures (MMRM) model with patients as a random-effect factor, treatment group as the independent variable, time as a repeated measure, and baseline covariates, using a first-order ante dependence covariance matrix.ResultsA total of 184 women were randomized. The full analysis set (FAS) included 172 patients (venlafaxine, n = 82; fluoxetine, n = 90). Over the 8-week study period, the reduction in HAMD-24 scores was significant (P < 0.001) in both groups, while a significantly greater decline from baseline was observed in the venlafaxine group compared with the fluoxetine group (least-squares mean difference [95% CI]: - 2.22 [- 7.08, - 0.41]), P = 0.001). The baseline-to-week-8 least-squares mean change of the anxiety/somatization factor scores, CGI-I response rate were greater in the venlafaxine group than in the fluoxetine group (all P < 0.05). The most frequent TEAEs (≥5%) in both groups were nausea, somnolence, dizziness, headache, and dry mouth. There was no significant difference in the incidence of adverse events between the two groups.ConclusionVenlafaxine was well tolerated and compared to fluoxetine, it led to a greater improvement in the treatment of postmenopausal MDD.Trial registrationClinical Trials. gov #NCT01824433 . The trial was registered on April 4, 2013.

Project description:BACKGROUND:We examined the efficacy of olanzapine/fluoxetine combination (OFC) in improving health-related quality of life (QoL) in the treatment of bipolar depression in children and adolescents. METHODS:Patients aged 10-17 years with bipolar I disorder, depressed episode, baseline children's depression rating scale-revised (CDRS-R) total score ?40, Young Mania Rating Scale (YMRS) total score ?15, and YMRS-item 1 ? 2 were randomized to OFC (6/25-12/50 mg/day olanzapine/fluoxetine; n = 170) or placebo (n = 85) for up to 8 weeks of double-blind treatment. Patients and parents completed the revised KINDL questionnaire for measuring health-related QoL in children and adolescents (KINDL-R) at baseline and endpoint. The mean change in CDRS-R total and item scores were used to compare improvement in symptomatology in patients taking OFC and placebo. Tests were 2-sided using a Type I error cutoff of 0.05, and no adjustments for multiple comparisons were made. RESULTS:Baseline QoL as measured by the KINDL-R was substantially impaired relative to published norms for a healthy school-based sample. OFC-treated patients demonstrated an improvement over placebo at endpoint with respect to mean change from baseline in the patient-rated KINDL-R Self-esteem subscale score (p = 0.028), and in the parent KINDL-R ratings of emotional well-being (p = 0.020), Self-esteem (p = 0.030), and Family (p = 0.006). At endpoint, OFC-treated patients still had a lower QoL compared to the normative population. OFC showed significant improvement (p ? 0.05) versus placebo on the CDRS-R total score and on 7 of the 17 CDRS-R items. CONCLUSIONS:Patients aged 10-17 years with an acute episode of bipolar depression and their parents reported greater improvements (parents noticed improvements in more areas than did their offspring) on some aspects of QoL when treated with OFC compared with placebo. However, after 8 weeks of treatment, KINDL-R endpoint scores remained lower than those of the, presumably healthy, control population. Clinical trial registration information A Study for Assessing Treatment of Patients Ages 10-17 with Bipolar Depression; http://www.clinicaltrials.gov; NCT00844857.

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Efficacy and safety of olanzapine/fluoxetine combination vs fluoxetine monotherapy following successful combination therapy of treatment-resistant major depressive disorder.

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