Effectiveness and Safety of the Combination of Fluoxetine and Olanzapine in Outpatients With Bipolar Depression An Open-Label, Randomized, Flexible-Dose Study in Puerto Rico

CES University, Medellín, Colombia.
Journal of clinical psychopharmacology (Impact Factor: 3.24). 08/2009; 29(4):358-61. DOI: 10.1097/JCP.0b013e3181ad223f
Source: PubMed


We studied the effectiveness of olanzapine/fluoxetine combination (OFC) treatment of bipolar depressive episode (7 weeks, study period 1 [SP1]). Study period 1 responders (mean modal daily OFC dosage, 10.8/27.8 mg) were randomized to OFC continuation treatment or olanzapine (OLZ) monotherapy starting at 10 mg (12 weeks, SP2). Seventy-three percent of the 114 patients who entered into SP2 completed the trial. The Montgomery-Asberg Depression Rating Scale total score changes from baseline in SP1 (primary outcome) were significant (-20 +/- 10, P < 0.001) and, during SP2, worsened for patients in the OLZ group (OFC vs OLZ, -0.4 +/- 7.55 vs +8.2 +/- 14.1, respectively; P < 0.001). During SP1, 69% responded and 59% remitted. During SP2, significantly more patients in the OFC group maintained response (31.3% vs 12.5%) and remission (71.4% vs 39.6%) than patients in the OLZ group. Treatment-emergent adverse events with OFC (SP1 and SP2) included increased appetite, increased weight, somnolence, anxiety, insomnia, and depressed mood. Since visit 1, the mean weight increases (in pounds) were 4.8 +/- 6.8 for SP1 (P < 0.001) and 6.3 +/- 10.3 (OFC) or 10.7 +/- 11.3 (OLZ) for SP2; 50% (OLZ) and 33% (OFC) of the patients had a 7% or higher weight increase. For cholesterol, triglycerides, and low-density lipoprotein levels and some hepatic enzymes, there were statistically and clinically significant changes in both study periods but no differences between the SP2 groups. Study limitations included the open-label design and exclusion of the SP1 nonresponders from SP2. These study results suggest that improvements resulting from 7 weeks of acute OFC treatment of a bipolar depressive episode are maintained in responders for an additional 12 weeks with OFC, but switching to OLZ alone may result in symptom worsening.

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    • "Our results demonstrated that continuing the administration of olanzapine after the acute phase in patients with a good response and tolerability to the agent obtained good efficacy in preventing both manic and depressive episodes. To the best of our knowledge, most previous maintenance studies randomly allocated participants to different regimens from the original treatment after remission from the index episode [25,33,45,47,48]. The process of switching drugs or adjusting dosage may induce exacerbation of the illness and subsequent recurrence. "
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    ABSTRACT: Bipolar disorder is a highly recurrent disease and has great impact on the function of patients. Depressive symptoms consist of more than 50% of life time during the illness and may lead to self harm or suicidal behaviors. Little is known about the antidepressant effects of olanzapine, an atypical antipsychotic, as monotherapy despite its indication for preventing manic episodes. In contrast, lamotrigine, a mood stabilizer, has been proven to be effective in preventing depression in patients with bipolar disorder. However, no studies have compared the efficacy between lamotrigine and olanzapine in the maintenance treatment of bipolar disorder. This enriched naturalistic study was implemented to assess the effectiveness of olanzapine and lamotrigine as monotherapy in the prevention of recurrence of bipolar disorder. Patients with bipolar disorder in a euthymic state (Young’s Mania Rating Scale (YMRS) score <12, and 21-item Hamilton Depression Rating Scale (HAM-D) score <7) for at least two months, having already received either olanzapine or lamotrigine as the maintenance treatment were recruited. The patients maintained with olanzapine (n = 22) were applied to olanzapine group whereas those maintained with lamotrigine (n = 29) were applied to lamotrigine group. They were followed up for 12 months. Differences in the efficacy between olanzapine and lamotrigine in recurrence prevention were analyzed. The Kaplan-Meier method was used to generate time-to-recurrence curves, and differences between the two groups were compared using the log-rank test. Olanzapine had a significantly lower recurrence rate of depressive episodes than lamotrigine (20.0% vs. 57.7%, χ2 = 6.62, p = .010). However, olanzapine and lamotrigine had similar mania (15.0% vs. 0%, χ2 = 4.17, p = .075, Fisher’s exact test) and any mood episode (35.0% vs. 57.7%, χ2 = 2.33, p = .127) recurrence rates. Olanzapine was significantly superior to lamotrigine in the time to recurrence of depressive episodes (χ2 = 4.55, df = 1, p = .033), but there was no difference in the time to recurrence of any mood episode (χ2 = 1.68, df = 1, p = .195). This prospective naturalistic study suggests that olanzapine is more effective than lamotrigine in the prevention of depressive episodes in patients with bipolar disorder. Future large-scale randomized studies are warranted to validate our results. Trial registration ID NCT01864551.
    Full-text · Article · May 2014 · BMC Psychiatry
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    • "Responders were then randomized to either OFC continuation or olanzapine alone for 12 weeks, showing maintenance of response to be significantly higher for the OFC group than the olanzapine group (31.3% versus 12.5%). Metabolic adverse effects were highly prevalent, with 33% of the OFC-treated patients gaining over 7% of their body weight over the 4-month course [46]. "
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    ABSTRACT: While studies in the past have focused more on treatment of the manic phase of bipolar disorder (BD), recent findings demonstrate the depressive phase to be at least as debilitating. However, in contrast to unipolar depression, depression in bipolar patients exhibits a varying response to antidepressants, raising questions regarding their efficacy and tolerability. Methods. We conducted a MEDLINE and Cochrane Collaboration Library search for papers published between 2005 and 2011 on the subject of antidepressant treatment of bipolar depression. Sixty-eight articles were included in the present review. Results. While a few studies did advocate the use of antidepressants, most well-controlled studies failed to show a robust effect of antidepressants in bipolar depression, regardless of antidepressant class or bipolar subtype. There was no significant increase in the rate of manic/hypomanic switch, especially with concurrent use of mood stabilizers. Prescribing guidelines published in recent years rely more on atypical antipsychotics, especially quetiapine, as a first-line therapy. Conclusions. Antidepressants probably have no substantial role in acute bipolar depression. However, in light of conflicting results between studies, more well-designed trials are warranted.
    Full-text · Article · Jan 2012 · Depression research and treatment
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    • "Olanzapine (OLZ) has demonstrated efficacy in the treatment of acute bipolar mania [59,61–63,65] stabilizing effects [11] [60] [62] [65] [66] and has been found to improve depressive symptoms in patients with schizophrenia [58] [64]. In a controlled study of Shelton et al. [53] subjects with treatment-resistant depression received OLZ alone, fluoxetine (FLX) alone, or a combination of both. "
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    ABSTRACT: Evidence is emerging for a role for neurotrophins in the treatment of mood disorders. In this study, we evaluated the effects of chronic administration of fluoxetine, olanzapine and the combination of fluoxetine/olanzapine on the brain-derived-neurotrophic factor (BDNF), nerve growth factor (NGF), and neurotrophin-3 (NT-3) in the rat brain. Wistar rats received daily injections of olanzapine (3 or 6 mg/kg) and/or fluoxetine (12.5 or 25mg/kg) for 28 days, and we evaluated for BDNF, NGF and NT-3 protein levels in the prefrontal cortex, hippocampus and amygdala. Our results showed that treatment with fluoxetine and olanzapine alone or in combination did not alter BDNF in the prefrontal cortex (p=0.37), hippocampus (p=0.98) and amygdala (p=0.57) or NGF protein levels in the prefrontal cortex (p=0.72), hippocampus (p=0.23) and amygdala (p=0.64), but NT-3 protein levels were increased by olanzapine 6 mg/kg/fluoxetine 25mg/kg combination in the prefrontal cortex (p=0.03), in the hippocampus (p=0.83) and amygdala (p=0.88) NT-3 protein levels did not alter. Finally, these findings further support the hypothesis that NT-3 could be involved in the effect of treatment with antipsychotic and antidepressant combination in mood disorders.
    Full-text · Article · Jun 2011 · Neuroscience Letters
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