olanzapine-fluoxetine-combination and Depressive-Disorder--Treatment-Resistant

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.

Topics: Adult; Antidepressive Agents; Benzodiazepines; Depressive Disorder, Major; Depressive Disorder, Treatment-Resistant; Double-Blind Method; Drug Combinations; Female; Fluoxetine; Hospitalization; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Psychiatric Status Rating Scales; Secondary Prevention; Suicide; Time Factors; Treatment Outcome; Weight Gain

To determine whether single-nucleotide polymorphisms (SNPs) in candidate genes are associated with response to olanzapine-fluoxetine combination.. A post hoc analysis of a priori-selected SNPs used data from a clinical trial (dates: April 2002-July 2005) of olanzapine-fluoxetine combination, fluoxetine, and olanzapine in patients with major depressive disorder (DSM-IV criteria) and with nonresponse to prestudy antidepressant treatment and nonresponse to fluoxetine treatment during the study. Patients received open-label treatment with fluoxetine for 8 weeks (2 weeks, 25 mg/d; then 6 weeks, 50 mg/d), at the end of which nonresponders (< 25% decline in the 17-item Hamilton Depression Rating Scale score) were randomized to receive double-blind, monotherapy treatment with olanzapine-fluoxetine combination (6/50-18/50 mg/d, n = 71), fluoxetine (50 mg/d, n = 78), or olanzapine (6-18 mg/d, n = 56) for 8 weeks. Statistical significance was assessed at P < .05. The primary efficacy measure for within-study treatment was improvement on the Montgomery-Asberg Depression Rating Scale (MADRS).. Rs36024, an intronic SNP in the norepinephrine transporter (SLC6A2), as well as 3 SNPs in melanocortin 3 receptor (MC3R) and 2 SNPs in tryptophan hydroxylase 2 (TPH2), were associated with MADRS-defined response to treatment with olanzapine-fluoxetine combination (adjusted Li-Nyholt P < .05). Except for 1 SNP in TPH2, identified SNPs were not significantly associated with response to continued-fluoxetine or olanzapine treatments.. Our findings further support the hypothesis that the synergistic effect of olanzapine and fluoxetine on prefrontal cortical levels of norepinephrine and dopamine might be an underlying mechanism for the efficacy of olanzapine-fluoxetine combination in the treatment of treatment-resistant depression and, if replicated, may form a basis on which response to olanzapine-fluoxetine combination versus continued fluoxetine can be predicted based on variants in SLC6A2.. Parent study registered at ClinicalTrials.gov identifier: NCT00035321.

Topics: Antidepressive Agents, Second-Generation; Benzodiazepines; Depressive Disorder, Treatment-Resistant; Double-Blind Method; Drug Combinations; Fluoxetine; Genetic Association Studies; Genotype; Humans; Linkage Disequilibrium; Norepinephrine Plasma Membrane Transport Proteins; Olanzapine; Polymorphism, Single Nucleotide; Psychiatric Status Rating Scales; Receptor, Melanocortin, Type 3; Selective Serotonin Reuptake Inhibitors; Tryptophan Hydroxylase

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.

Topics: Adult; Amygdala; Benzodiazepines; Brain; Depressive Disorder, Treatment-Resistant; Drug Combinations; Female; Fluoxetine; Humans; Image Processing, Computer-Assisted; Male; Middle Aged; Positron-Emission Tomography; Prefrontal Cortex; Severity of Illness Index