quetiapine-fumarate and olanzapine-fluoxetine-combination

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

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-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

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

While the clinical utility of atypical antipsychotics has been established in patients with major depressive disorder (MDD) who are refractory to antidepressant therapy, their cost-effectiveness is unknown.. To examine the cost-effectiveness of aripiprazole, quetiapine, and olanzapine/fluoxetine in adults with MDD who are refractory to antidepressant therapy.. Using techniques of decision analysis, we estimated expected outcomes and costs over 6 weeks in adults with MDD receiving (1) aripiprazole 2-20 mg/day and antidepressant therapy; (2) quetiapine 150 mg/day or 300 mg/day and antidepressant therapy; (3) the fixed-dose combination of olanzapine 6, 12, or 18 mg/day with fluoxetine 50 mg/day; or (4) antidepressant therapy alone. Cost-effectiveness was assessed in terms of the cost per additional responder at 6 weeks, defined as the ratio of the difference in the cost of MDD-related care over 6 weeks versus antidepressant therapy alone to the difference in the number of patients achieving clinical response by 6 weeks. We estimated the model using data from Phase 3 clinical trials of atypical antipsychotics along with other secondary data sources.. With antidepressant therapy alone, the estimated clinical response rate at 6 weeks was 30%. Aripiprazole, quetiapine 150 mg/day, quetiapine 300 mg/day, and olanzapine/fluoxetine were estimated to increase clinical response at 6 weeks to 49%, 34%, 38%, and 45%, respectively. Costs of MDD-related care over 6 weeks were estimated to be $192 for antidepressant therapy, $847 for aripiprazole, $541 for quetiapine 150 mg/day, $672 for quetiapine 300 mg/day plus antidepressant therapy, and $791 for olanzapine/fluoxetine. Costs per additional responder (vs antidepressant therapy) over a 6-week period were estimated to be $3447 for aripiprazole, $8725 for quetiapine 150 mg/day, $6000 for quetiapine 300 mg/day, and $3993 for olanzapine/fluoxetine.. Atypical antipsychotics substantially increase clinical response at 6 weeks. Cost per additional responder is lower for aripiprazole than for quetiapine or olanzapine/fluoxetine.

Topics: Antidepressive Agents; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Cost-Benefit Analysis; Decision Support Techniques; Depressive Disorder, Major; Dibenzothiazepines; Drug Combinations; Drug Costs; Drug Resistance; Fluoxetine; Health Care Costs; Humans; Piperazines; Quetiapine Fumarate; Quinolones