olanzapine-fluoxetine-combination and Bipolar-Disorder

Topics: Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Brief Psychiatric Rating Scale; Child; Drug Combinations; Fluoxetine; Humans; Lurasidone Hydrochloride; Pediatrics; Psychopharmacology; Quetiapine Fumarate

To meta-analytically summarize lamotrigine's effectiveness and safety in unipolar and bipolar depression.. We conducted systematic PubMed and SCOPUS reviews (last search =10/01/2015) of randomized controlled trials comparing lamotrigine to placebo or other agents with antidepressant activity in unipolar or bipolar depression. We performed a random-effects meta-analysis of depression ratings, response, remission, and adverse effects calculating standardized mean difference (SMD) and risk ratio (RR) ±95% confidence intervals (CIs).. Eighteen studies (n=2152, duration=9.83 weeks) in patients with unipolar depression (studies=4, n=187; monotherapy vs lithium=1, augmentation of antidepressants vs placebo=3) or bipolar depression (studies=14, n=1965; monotherapy vs placebo=5, monotherapy vs lithium or olanzapine+fluoxetine=2, augmentation of antidepressants vs placebo=1, augmentation of mood stabilizers vs placebo=3, augmentation of mood stabilizers vs trancylpromine, citalopram, or inositol=3) were meta-analyzed. Lamotrigine's efficacy for depressive symptoms did not differ significantly in monotherapy vs augmentation studies (vs. placebo: p=0.98, I2=0%; vs active agents: p=0.48, I2=0%) or in unipolar vs bipolar patients (vs placebo: p=0.60, I2=0%), allowing pooling of each placebo-controlled and active-controlled trials. Lamotrigine outperformed placebo regarding depressive symptoms (studies=11, n=713 vs n=696; SMD=-0.15, 95% CI=-0.27, -0.02, p=0.02, heterogeneity: p=0.24) and response (after removing one extreme outlier; RR=1.42, 95% CI=1.13-1.78; p=0.003, heterogeneity: p=0.08). Conversely, lamotrigine did not differ regarding efficacy on depressive symptoms, response, or remission from lithium, olanzapine+fluoxetine, citalopram, or inositol (studies=6, n=306 vs n=318, p-values=0.85-0.92). Adverse effects and all-cause/specific-cause discontinuation were similar across all comparisons.. Lamotrigine was superior to placebo in improving unipolar and bipolar depressive symptoms, without causing more frequent adverse effects/discontinuations. Lamotrigine did not differ from lithium, olanzapine+fluoxetine, citalopram, or inositol.

Topics: Anticonvulsants; Antidepressive Agents; Antimanic Agents; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Citalopram; Depression; Depressive Disorder, Major; Drug Combinations; Fluoxetine; Humans; Inositol; Lamotrigine; Lithium; Triazines; Vitamin B Complex

Bipolar disorder and treatment-resistant depression (TRD) are common and recurrent conditions associated with significant disability, morbidity and mortality. Despite the clear need for effective treatments, only a few medications have been approved in the US for these indications. The combined formulation of olanzapine-fluoxetine (OFC) has been available for a decade now, thus a review on its safety profile and comparative efficacy is timely and can help clinicians to determine the benefit/risk profile of OFC within the context of other treatment alternatives.. This paper summarizes the rationale and evidence supporting the use of OFC for both bipolar I depressive episodes and TRD with a focus on safety and tolerability. Product labels and the search engine PubMed was used to obtain relevant information on this subject.. Although further comparative studies are needed, the literature confirms that the OFC is an effective treatment for bipolar I depressive episodes, as well as major depressive episodes that have not responded to several adequate courses of antidepressant therapy. Its use as a first-line treatment for bipolar I depressive episodes and at a higher rung of algorithms for patients with TRD is limited by its propensity to cause weight gain and associated metabolic symptoms.

Topics: Animals; Antidepressive Agents, Second-Generation; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Depressive Disorder, Major; Drug Combinations; Fluoxetine; Humans; Treatment Outcome

A major challenge in the treatment of major depressive episodes associated with bipolar disorder is differentiating this illness from major depressive episodes associated with major depressive disorder. Mistaking the former for the latter will lead to incorrect treatment and poor outcomes. None of the classic antidepressants, serotonin specific reuptake inhibitors, or serotonin-norepinephrine reuptake inhibitors have ever received regulatory approval as monotherapies for the treatment of bipolar depression. At present, there are only 3 approved medication treatments for bipolar depression: olanzapine/fluoxetine combination, quetiapine (immediate or extended release), and lurasidone (monotherapy or adjunctive to lithium or valproate). All 3 have similar efficacy profiles, but they differ in terms of tolerability. Number needed to treat (NNT) and number needed to harm (NNH) can be used to quantify these similarities and differences. The NNTs for response and remission for each of these interventions vs placebo range from 4 to 7, and 5 to 7, respectively, with overlap in terms of their 95% confidence intervals. NNH values less than 10 (vs placebo) were observed for the spontaneously reported adverse events of weight gain and diarrhea for olanzapine/fluoxetine combination (7 and 9, respectively) and somnolence and dry mouth for quetiapine (3 and 4, respectively). There were no NNH values less than 10 (vs placebo) observed with lurasidone treatment. NNH values vs placebo for weight gain of at least 7% from baseline were 6, 16, 58, and 36, for olanzapine/fluoxetine combination, quetiapine, lurasidone monotherapy, and lurasidone combined with lithium or valproate, respectively. Individualizing treatment decisions will require consideration of the different potential adverse events that are more likely to occur with each medication. The metric of the likelihood to be helped or harmed (LHH) is the ratio of NNH to NNT and can illustrate the tradeoffs inherent in selecting medications. A more favorable LHH was noted for treatment with lurasidone. However, OFC and quetiapine monotherapy may still have utility in high urgency situations, particularly in persons who have demonstrated good outcomes with these interventions in the past, and where a pressing clinical need for efficacy mitigates their potential tolerability shortcomings. In terms of maintenance therapy, adjunctive quetiapine is the only agent where the NNT vs lithium or valproate alone is less than 10 for

Topics: Antidepressive Agents; Antimanic Agents; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Depressive Disorder, Major; Dibenzothiazepines; Drug Combinations; Drug Therapy, Combination; Fluoxetine; Humans; Isoindoles; Lithium Compounds; Lurasidone Hydrochloride; Quetiapine Fumarate; Thiazoles; Valproic Acid

Depression is the predominant pole of illness disability in bipolar disorder and, compared with acute mania, has less systematic research guiding treatment development. The aim of this review is to present the therapeutic options currently available for managing bipolar depression and to highlight areas of unmet need and future research.. Literature search of PubMed, PsycINFO, and Cochrane databases and bibliographies from 2000 to August 2013 for treatments that have regulatory approval for bipolar depression or early controlled preliminary data on efficacy.. Treatment options for bipolar depression have increased over the last decade, most notably with regulatory approval for olanzapine/fluoxetine combination, quetiapine, and lurasidone. Conventional mood stabilizers lamotrigine and divalproex have meta-analyses suggesting acute antidepressant response. Manual-based psychotherapies also appear to be effective in treating bipolar depression. The therapeutic utility of unimodal antidepressants, as a class, for the treatment of patients with bipolar depression, as a group, remains to be confirmed. There is a substantially unmet need to develop new interventions that are efficacious, effective, and have low side effect burden.. Additional compounds are currently being developed that may ultimately be applicable to the treatment of bipolar depression and early open-trial data encourage further studies, but both of these topics are beyond the scope of this review.. Future registrational trials will need to establish initial efficacy, but increasing interest for personalized or individualized medicine will encourage further studies on individual predictors or biomarkers of response.

Topics: Anticonvulsants; Antidepressive Agents; Benzodiazepines; Bipolar Disorder; Dibenzothiazepines; Drug Combinations; Fluoxetine; Forecasting; Health Services Needs and Demand; Humans; Isoindoles; Lamotrigine; Lurasidone Hydrochloride; Psychotherapy; Quetiapine Fumarate; Thiazoles; Triazines

Bipolar depression is more pervasive than mania, but has fewer evidence-based treatments.. Using data from multicenter, randomized, double-blind, placebo-controlled trials and meta-analyses, we assessed the number needed to treat (NNT) for response and the number needed to harm (NNH) for selected side effects for older and newer acute bipolar depression treatments.. The 2 older FDA-approved treatments for bipolar depression, olanzapine-fluoxetine combination (OFC) and quetiapine (QTP) monotherapy, were efficacious (response NNT=4 for OFC, NNT=6 for QTP), but similarly likely to yield harms (OFC weight gain NNH=6; QTP sedation/somnolence NNH=5). Commonly used unapproved agents (lamotrigine monotherapy and adjunctive antidepressants) tended to be well-tolerated (with double-digit NNHs), although this advantage was at the cost of inadequate efficacy (response NNT=12 for lamotrigine, NNT=29 for antidepressants). In contrast, the newly approved agent lurasidone was not only efficacious (response NNT=5 for monotherapy, NNT=7 as adjunctive therapy), but also had enhanced tolerability (NNH=15 for akathisia [monotherapy], NNH=16 for nausea [adjunctive]). Although adjunctive armodafinil appeared well tolerated, its efficacy in bipolar depression has not been consistently demonstrated in randomized controlled trials.. NNT and NNH are categorical metrics; only selected NNHs were assessed; limited generalizability of efficacy (versus effectiveness) studies.. For acute bipolar depression, older approved treatments may have utility in high-urgency situations, whereas lamotrigine and antidepressants may have utility in low-urgency situations. Newly approved lurasidone may ultimately prove useful in diverse situations. New drug development needs to focus on not only efficacy but also on tolerability.

Topics: Acute Disease; Antidepressive Agents; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Dibenzothiazepines; Drug Combinations; Fluoxetine; Humans; Isoindoles; Lamotrigine; Lurasidone Hydrochloride; Multicenter Studies as Topic; Quetiapine Fumarate; Randomized Controlled Trials as Topic; Thiazoles; Triazines; Weight Gain

Herein we review the evidence supporting Food and Drug Administration (FDA) approved and emerging treatments for bipolar depression.. A PubMed search of all English-language articles published up to July 2013 was conducted. The search terms were quetiapine, olanzapine-fluoxetine, olanzapine, lurasidone, ketamine, modafinil/armodafinil, and lamotrigine. The search was augmented with a manual review of relevant article reference lists, as well as posters presented at national and international meetings. Articles selected for review were based on the adequacy of sample size, the use of standardized diagnostic instruments, validated assessment measures, and overall manuscript quality.. Olanzapine-fluoxetine combination (OFC), quetiapine, and lurasidone are FDA-approved for the acute treatment of bipolar depression. Lurasidone is the most recently approved agent for bipolar depression. Olanzapine-fluoxetine combination and quetiapine are approved as single modality therapies while lurasidone is approved as a monotherapy and as an adjunct to lithium or divalproex. The overall effect size of the 3 treatments in mitigating depressive symptoms is similar. Clinically significant weight gain and metabolic disruption as well as sedation are significant limitations of OFC and quetiapine. The minimal propensity for weight gain as well as the metabolic neutrality of lurasidone in the bipolar population is a clinically significant advantage. Evidence also supports lamotrigine with compelling evidence as an adjunct to lithium and in recurrence prevention paradigm; suggested evidence also exists for ketamine and modafinil/armodafinil; notwithstanding, these treatments remain investigational.. Relatively few agents are FDA-approved for bipolar depression. The selection and sequencing of agents in bipolar depression should give primacy to those agents that are FDA-approved. Further refinement of the selection process will need to pay careful attention to the relative hazards of weight gain and metabolic disruption in this highly susceptible population. Other agents with differential mechanisms (eg, ketamine) offer a promising alternative in bipolar depression.

Topics: Antidepressive Agents; Antidepressive Agents, Second-Generation; Antipsychotic Agents; Benzhydryl Compounds; Benzodiazepines; Bipolar Disorder; Central Nervous System Stimulants; Depressive Disorder; Dibenzothiazepines; Drug Approval; Drug Combinations; Excitatory Amino Acid Antagonists; Fluoxetine; Humans; Isoindoles; Ketamine; Lamotrigine; Lurasidone Hydrochloride; Modafinil; Quetiapine Fumarate; Selective Serotonin Reuptake Inhibitors; Thiazoles; Triazines; United States; United States Food and Drug Administration

Olanzapine plus fluoxetine combination (OFC) is one of the current approaches for treating the depressive phase of bipolar disorder. Our objective was to synthesize the evidence on the efficacy of OFC therapy in bipolar depressed patients.. We searched for randomized controlled trials (RCTs) on MEDLINE, Embase and other databases. Independent researchers selected the studies and extracted the data. The GRADE approach was used to assess the quality of the evidence. The Mantel-Haenszel random effect model was used to perform the meta-analyses.. From 627 unique records retrieved, four RCTs were included (1330 patients). OFC improved the response compared to olanzapine (relative risk [RR]=1.58; 95% confidence interval [95% CI]: 1.27, 1.97) and to placebo (RR=1.99; 95% CI: 1.49, 2.65) but not to lamotrigine (low-quality evidence). Similar results were found for remission and relapse rates. No differences were identified for levels of depression and mania symptoms (low-quality evidence) and incidence of mania (moderate-quality evidence). Adverse effects were more common in patients treated with OFC than in those treated with lamotrigine (RR=1.13; 95% CI: 1.04, 1.23), but no difference was found relative to the patients treated with olanzapine (low-quality evidence).. Despite the totality of the evidence included, there are few RCTs available regarding the efficacy of OFC therapy for bipolar depression. The risk of attrition and reporting bias is also a concern.. OFC therapy improved the response, remission, and relapse rates among other outcomes. However, a worse profile of adverse reactions was observed in some comparisons. These data clarify the therapeutic use of OFC as an option to olanzapine in bipolar depression. The quality of the evidence could be improved by additional comparisons and higher rates of treatment adherence.

Topics: Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Drug Combinations; Fluoxetine; Humans; Randomized Controlled Trials as Topic; Treatment Outcome

Olanzapine-fluoxetine combination is one of only two products currently approved by the US FDA for the acute treatment of depressive episodes associated with bipolar disorder.. This treatment evaluation reviews double-blind randomized controlled trials of olanzapine-fluoxetine combination for bipolar depression. A total of three primary study reports are found in the peer-reviewed literature. Additional data regarding the trials are obtained from study synopses disclosed on the internet by the manufacturer and from product labeling.. Number needed to treat for antidepressant response for olanzapine-fluoxetine combination versus placebo in the 8-week trials was 4 (95% CI 3 - 8), and that for remission was 5 (95% CI 3 - 8). Single-digit numbers needed to harm (NNH) values were observed for the treatment-emergent adverse events of weight gain (NNH 7, 95% CI 5 - 16) and diarrhea (NNH 9, 95% CI 5 - 30). NNH versus placebo for weight gain ≥ 7% from baseline was 6 (95% CI 4 - 10). When contrasted with lamotrigine, olanzapine-fluoxetine combination demonstrates statistically significantly greater improvement in depressive and manic symptoms but there is a higher incidence of treatment-emergent adverse events, weight gain and elevation in metabolic factors. Studies that directly compare quetiapine monotherapy with olanzapine-fluoxetine combination, the only two approved products for the treatment of bipolar depression, are not available. Nonetheless, indirect comparisons indicate similar efficacy outcomes but different tolerability profiles, with quetiapine principally being associated with sedation. Additional approved treatment options would be welcome.

Topics: Animals; Antidepressive Agents, Second-Generation; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Dibenzothiazepines; Drug Combinations; Fluoxetine; Humans; Quetiapine Fumarate

Randomized, controlled trials have demonstrated efficacy for second-generation antipsychotics in the treatment of acute mania in bipolar disorder. Despite depression being considered the hallmark of bipolar disorder, there are no published systematic reviews or meta-analyses to evaluate the efficacy of modern atypical antipsychotics in bipolar depression. We systematically reviewed published or registered randomized, double-blind, placebo-controlled trials (RCTs) of modern antipsychotics in adult bipolar I and/or II depressive patients (DSM-IV criteria). Efficacy outcomes were assessed based on changes in the Montgomery-Asberg Depression Rating Scale (MADRS) during an 8-wk period. Data were combined through meta-analysis using risk ratio as an effect size with a 95% confidence interval (95% CI) and with a level of statistical significance of 5% (p<0.05). We identified five RCTs; four involved antipsychotic monotherapy and one addressed both monotherapy and combination with an antidepressant. The two quetiapine trials analysed the safety and efficacy of two doses: 300 and 600 mg/d. The only olanzapine trial assessed olanzapine monotherapy within a range of 5-20 mg/d and olanzapine-fluoxetine combination within a range of 5-20 mg/d and 6-12 mg/d, respectively. The two aripiprazole placebo-controlled trials assessed doses of 5-30 mg/d. Quetiapine and olanzapine trials (3/5, 60%) demonstrated superiority over placebo (p<0.001). Only 2/5 (40%) (both aripiprazole trials) failed in the primary efficacy measure after the first 6 wk. Some modern antipsychotics (quetiapine and olanzapine) have demonstrated efficacy in bipolar depressive patients from week 1 onwards. Rapid onset of action seems to be a common feature of atypical antipsychotics in bipolar depression.

Topics: Antidepressive Agents; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Bipolar Disorder; Dibenzothiazepines; Drug Combinations; Drug Therapy, Combination; Fluoxetine; Humans; Olanzapine; Piperazines; Placebos; Quetiapine Fumarate; Quinolones; Randomized Controlled Trials as Topic; Treatment Outcome

Although depression accounts for a large part of the burden associated with bipolar disorder, its drug treatment has been under-studied.. To provide the best available evidence supporting the pharmacotherapy of bipolar depression.. A systematic review was conducted, focusing on randomized, controlled trials (RCTs) and meta-analyses.. Despite FDA approval of both the olanzapine-fluoxetine combination and quetiapine for the treatment of acute bipolar depression, independent RCTs (i.e., not trials conducted 'under the umbrella' of a drug company) have not found any drug to have antidepressant effects similar to those seen in unipolar depression. A practice-based suggestion, valuable for both short- and long-term treatment, might be to have a background of mood stabilizers and to add drugs, following one of several treatment options, trusting to find a drug with a degree of effectiveness by trial and error. The list of drugs that could be used would include all the current antidepressants, the olanzapine-fluoxetine combination and probably quetiapine too. Special features and situations might also influence treatment options.

Topics: Antidepressive Agents; Antimanic Agents; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Dibenzothiazepines; Drug Administration Schedule; Drug Combinations; Fluoxetine; Humans; Meta-Analysis as Topic; Quetiapine Fumarate; Randomized Controlled Trials as Topic

Olanzapine/fluoxetine (Symbyax) is an oral once-daily fixed-dose combination of the atypical antipsychotic olanzapine and the SSRI fluoxetine that is approved in the US for the treatment of depressive episodes associated with bipolar disorder in adults. Combination therapy with olanzapine plus fluoxetine is effective in the treatment of patients with acute bipolar depression. The combination improves depressive symptoms and symptom severity in this patient population, with an efficacy greater than that of olanzapine alone or lamotrigine. Furthermore, olanzapine plus fluoxetine is generally well tolerated. Although associated with weight gain and potential elevations in glucose, lipid and prolactin levels, the combination does not increase the risk of treatment-emergent mania. Additional placebo- and active comparator-controlled studies are required in order to confirm the efficacy of olanzapine/fluoxetine in the treatment of bipolar depression and to definitively position olanzapine/fluoxetine with respect to other agents. In the meantime, fixed-dose olanzapine/fluoxetine offers an effective and generally well tolerated first-line option for the treatment of acute bipolar depression.

Topics: Antidepressive Agents; Benzodiazepines; Bipolar Disorder; Drug Combinations; Fluoxetine; Humans

Olanzapine/fluoxetine (Symbyax) is an oral once-daily fixed-dose combination of the atypical antipsychotic olanzapine and the selective serotonin reuptake inhibitor (SSRI) fluoxetine that is approved in the US for the treatment of depressive episodes associated with bipolar disorder in adults. Combination therapy with olanzapine plus fluoxetine is effective in the treatment of patients with acute bipolar depression. The combination improves depressive symptoms and symptom severity in this patient population, with an efficacy greater than that of olanzapine alone or lamotrigine. Furthermore, olanzapine plus fluoxetine is generally well tolerated. Although associated with weight gain and potential elevations in glucose, lipid and prolactin levels, the combination does not increase the risk of treatment-emergent mania. Additional placebo- and active comparator-controlled studies are required in order to confirm the efficacy of olanzapine/fluoxetine in the treatment of bipolar depression and to definitively position olanzapine/fluoxetine with respect to other agents. In the meantime, fixed-dose olanzapine/fluoxetine offers an effective and generally well tolerated first-line option for the treatment of acute bipolar depression.

Topics: Acute Disease; Benzodiazepines; Bipolar Disorder; Clinical Trials as Topic; Drug Combinations; Drug Interactions; Fluoxetine; Humans; Quality of Life

To assess the efficacy and safety of olanzapine/fluoxetine combination (OFC) for the acute treatment of bipolar depression in children and adolescents.. Patients 10 to 17 years of age with bipolar I disorder (BP-I), 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. The primary efficacy measure was mean change in CDRS-R using mixed-model repeated-measures methodology.. Baseline-to-week-8 least-squares mean change in CDRS-R total score was greater for OFC-treated patients than for placebo-treated patients (-28.4 versus -23.4, p = .003; effect size = .46), with between-group differences statistically significant at week 1 (p = .02) and all subsequent visits (all p < .01). Rates of and times to response and remission were statistically significantly greater for OFC- than for placebo-treated patients. The most frequent treatment-emergent adverse events in the OFC group were weight gain, increased appetite, and somnolence. Mean weight gain at patient's endpoint was significantly greater for OFC- than for placebo-treated patients (4.4 kg versus 0.5 kg, p < .001). Treatment-emergent hyperlipidemia was very common among OFC-treated patients. Abnormal increases in hepatic analytes, prolactin, and corrected QT interval (QTc) were also common or very common but generally not clinically significant.. In this study, OFC was superior to placebo, and has been approved by the US Food and Drug Administration (FDA) for the acute treatment of bipolar I depression in patients 10 to 17 years of age. Benefits should be weighed against the risk of adverse events, particularly weight gain and hyperlipidemia. Clinical trial registration information-A Study for Assessing Treatment of Patients Ages 10-17 with Bipolar Depression; http://clinicaltrials.gov; NCT00844857.

Topics: Adolescent; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Child; Double-Blind Method; Drug Combinations; Female; Fluoxetine; Humans; Male; Psychiatric Status Rating Scales; Severity of Illness Index; Suicide, Attempted; Treatment Outcome; United States

To evaluate common genetic variations for association with symptomatic improvement in bipolar I depression following treatment with olanzapine/fluoxetine combination (OFC) or lamotrigine.. Symptom improvement was assessed in 88 OFC-treated and 85 lamotrigine-treated white patients with bipolar I depression in the 7-week acute period of a randomized, double-blind study comparing OFC (6/25, 6/50, 12/25, or 12/50 mg/d [olanzapine/fluoxetine]) with lamotrigine (titrated to 200 mg/d). The original study was conducted from November 2003 to August 2004. Single nucleotide polymorphisms (SNPs) were genotyped in a set of 19 candidate genes corresponding to known sites of activity for olanzapine and fluoxetine or previously associated with antidepressant or antipsychotic response. Primary outcome was the reduction in Montgomery-Asberg Depression Rating Scale (MADRS) total score as assessed by the difference by genotype from baseline to week 7 from a mixed-effects repeated measures analysis with terms for visit, genotype, genotype-by-visit interaction, and baseline MADRS score as a covariate.. SNPs within the dopamine D(3) receptor and histamine H(1) receptor (HRH1) genes were significantly associated with response to OFC. SNPs within the dopamine D(2) receptor, HRH1, dopamine beta-hydroxylase, glucocorticoid receptor, and melanocortin 2 receptor genes were significantly associated with response to lamotrigine.. SNPs in specific candidate genes were associated with symptomatic improvement in a treatment-specific fashion. These results suggest the importance of dopaminergic effects in the treatment of patients with bipolar I depression and the potential utility of genotyping in selection of pharmacologic treatments for bipolar depression.

Topics: Adult; Antidepressive Agents, Second-Generation; Benzodiazepines; Bipolar Disorder; Dopamine beta-Hydroxylase; Double-Blind Method; Drug Combinations; Drug Therapy, Combination; Female; Fluoxetine; Genetic Association Studies; Genotype; Humans; Lamotrigine; Male; Olanzapine; Polymorphism, Single Nucleotide; Psychiatric Status Rating Scales; Receptor, Melanocortin, Type 2; Receptors, Dopamine D2; Receptors, Dopamine D3; Receptors, Glucocorticoid; Receptors, Histamine H1; Treatment Outcome; Triazines

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.

Topics: Adult; Antidepressive Agents; Benzodiazepines; Bipolar Disorder; Drug Combinations; Female; Fluoxetine; Hispanic or Latino; Humans; Male; Middle Aged; Outpatients; Psychiatric Status Rating Scales; Puerto Rico; Remission Induction; Secondary Prevention; Selective Serotonin Reuptake Inhibitors; Severity of Illness Index; Time Factors; Treatment Outcome

Depression in bipolar disorder is a major therapeutic challenge associated with disability and excess mortality.. We reviewed findings from randomized placebo-controlled trials concerning efficacy and adverse effects of treatments for acute bipolar depression, including anticonvulsants, antidepressants, lithium, and modern antipsychotics, to compare numbers-needed-to-treat (NNT) versus -to-harm (NNH).. Included were data from 22 reports involving 33 drug-placebo pairs. Antidepressants (especially modern drugs) had the most favorable (highest) risk/benefit ratio (pooled NNH/NNT=18.1). Anticonvulsants were effective agents (pooled NNT=5.06), but carbamazepine and valproate were not as well tolerated (NNH<10) as lamotrigine, and they had an unfavorable pooled NNH/NNT (3.75). Some antipsychotics (lurasidone, olanzapine+fluoxetine, and quetiapine (NNT all < 10) were effective though aripiprazole and ziprasidone were not (NNT≥45); olanzapine alone was weakly effective (NNT=11.3), and all but lurasidone (NNH=20.2) were not well tolerated (NNH≤4.18). Lithium appeared to be poorly effective but well tolerated in only one trial.. Some anticonvulsants and antipsychotics seemed effective for acute bipolar depression, but most antipsychotics were not well tolerated. Antidepressants were effective and well-tolerated; lithium remains inadequately tested.. There are remarkably few short-term treatment trials (2.75/12 treatments), and fewer long-term trials for bipolar depression, possibly arising from exaggerated concerns about inducing mania.

Topics: Anticonvulsants; Antidepressive Agents; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Drug Combinations; Drug Therapy, Combination; Fluoxetine; Humans; Lurasidone Hydrochloride; Quetiapine Fumarate; Randomized Controlled Trials as Topic

Patients with bipolar disorder spend more time depressed than manic, but fewer clinical trials have been conducted investigating treatments for bipolar depression than for bipolar mania. Olanzapine-fluoxetine combination, quetiapine, and lurasidone are the only FDA-approved treatments for bipolar depression. Clinical trials of these drugs show similar efficacy but different side effect profiles. Clinicians, therefore, should consider possible adverse events and individual patient characteristics when selecting treatments.

Topics: Antidepressive Agents, Second-Generation; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Dibenzothiazepines; Drug Combinations; Fluoxetine; Humans; Isoindoles; Lurasidone Hydrochloride; Quetiapine Fumarate; Thiazoles

Topics: Adult; Benzodiazepines; Bipolar Disorder; Drug Combinations; Female; Fluoxetine; Humans; Patient Compliance; Risk Factors

Topics: Adult; Benzodiazepines; Bipolar Disorder; Drug Combinations; Fluoxetine; Humans; Olanzapine; Selective Serotonin Reuptake Inhibitors

Topics: Antidepressive Agents; Benzodiazepines; Bipolar Disorder; Drug Combinations; Fluoxetine; Humans