Olanzapine-fluoxetine Combination Research Articles

Treatment-resistant depression: definition, prevalence, detection, management, and investigational interventions.

Treatment-resistant depression (TRD) is common and associated with multiple serious public health implications. A consensus definition of TRD with demonstrated predictive utility in terms of clinical decision-making and health outcomes does not currently exist. Instead, a plethora of definitions have been proposed, which vary significantly in their conceptual framework. The absence of a consensus definition hampers precise estimates of the prevalence of TRD, and also belies efforts to identify risk factors, prevention opportunities, and effective interventions. In addition, it results in heterogeneity in clinical practice decision-making, adversely affecting quality of care. The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have adopted the most used definition of TRD (i.e., inadequate response to a minimum of two antidepressants despite adequacy of the treatment trial and adherence to treatment). It is currently estimated that at least 30% of persons with depression meet this definition. A significant percentage of persons with TRD are actually pseudo-resistant (e.g., due to inadequacy of treatment trials or non-adherence to treatment). Although multiple sociodemographic, clinical, treatment and contextual factors are known to negatively moderate response in persons with depression, very few factors are regarded as predictive of non-response across multiple modalities of treatment. Intravenous ketamine and intranasal esketamine (co-administered with an antidepressant) are established as efficacious in the management of TRD. Some second-generation antipsychotics (e.g., aripiprazole, brexpiprazole, cariprazine, quetiapine XR) are proven effective as adjunctive treatments to antidepressants in partial responders, but only the olanzapine-fluoxetine combination has been studied in FDA-defined TRD. Repetitive transcranial magnetic stimulation (TMS) is established as effective and FDA-approved for individuals with TRD, with accelerated theta-burst TMS also recently showing efficacy. Electroconvulsive therapy is regarded as an effective acute and maintenance intervention in TRD, with preliminary evidence suggesting non-inferiority to acute intravenous ketamine. Evidence for extending antidepressant trial, medication switching and combining antidepressants is mixed. Manual-based psychotherapies are not established as efficacious on their own in TRD, but offer significant symptomatic relief when added to conventional antidepressants. Digital therapeutics are under study and represent a potential future clinical vista in this population.

Efficacy and safety profiles of mood stabilizers and antipsychotics for bipolar depression: a systematic review.

The whole picture of psychotropics for bipolar depression (BPD) remains unclear. This review compares the differences in efficacy and safety profiles among common psychotropics for BPD. MEDLINE, EMBASE, and PsycINFO were searched for proper studies. The changes in the depressive rating scale, remission/response rates, nervous system adverse events (NSAEs), gastrointestinal adverse events (GIAEs), metabolic parameters, and prolactin were compared between medication and placebo or among medications with the Cohen's d or number needed to treat/harm. The search provided 10 psychotropics for comparison. Atypical antipsychotics (AAPs) were superior to lithium and lamotrigine at alleviating acute depressive symptoms. Lithium was more likely to induce dry mouth and nausea. Cariprazine and aripiprazole seemed to be associated with an increased risk of akathisia and upper GIAEs. Lurasidone was associated with an increased risk of developing akathisia and hyperprolactinemia. Olanzapine, olanzapine-fluoxetine combination (OFC), and quetiapine were associated with an increased risk of NSAEs, metabolic risk, dry mouth, and constipation. Cariprazine, lurasidone, OFC, or quetiapine was optimal monotherapy for BPD. Further studies are needed to assess the efficacy and safety of lamotrigine for treating BPD. Adverse events varied widely across different drug types due to variations in psychopharmacological mechanisms, dosages, titration, and ethnicities.

Pharmacotherapies for Treatment-Resistant Depression: How Antipsychotics Fit in the Rapidly Evolving Therapeutic Landscape.

One in three adults with major depressive disorder (MDD) do not experience clinically significant improvement after multiple sequential courses of antidepressants and have treatment-resistant depression (TRD). The presence of TRD contributes to the morbidity and excess mortality associated with MDD and has been linked to significantly increased health care expenses. In the absence of a consensus definition of TRD, this report takes a broad approach by considering inadequate response to one or more courses of antidepressants and focuses on atypical antipsychotics that are approved by the U.S. Food and Drug Administration for treatment of depression (aripiprazole, brexpiprazole, cariprazine, extended-release quetiapine, and olanzapine-fluoxetine combination). While multiple acute-phase studies have demonstrated the efficacy of these medications in improving depressive symptoms, clinically meaningful improvement (i.e., remission) remains limited, with significant concerns about side effects (including weight gain, metabolic dysfunction, extrapyramidal symptoms, and tardive dyskinesia), especially with long-term use. With the rapidly evolving landscape of antidepressant treatments over the past few years, which has witnessed approval of rapid-acting antidepressants (e.g., esketamine nasal spray and dextromethorphan-bupropion combination) and several more in the late-stage pipeline (e.g., zuranolone and psilocybin), it remains to be seen whether the use of atypical antipsychotics will go the way of the older and rarely prescribed antidepressants (such as tricyclics and monoamine oxidase inhibitors). Pragmatic clinical trials are needed to compare the effectiveness of atypical antipsychotics with TRD-specific pharmacotherapies and neuromodulation treatments and to identify the optimal sequencing of these varied approaches for patients with MDD. When using atypical antipsychotics, clinicians and patients are encouraged to use a shared decision-making approach by personalizing treatment selection based on anticipated side effects, tolerability, cost, and feasibility.

Psychopharmacological Treatment Algorithms of Manic/Mixed and Depressed Episodes in Pediatric Bipolar Disorder.

Introduction: Pediatric bipolar disorder (PBD) is a severe psychiatric illness diagnosed before the age of 18, which is associated with extreme shifts in mood characterized by manic and depressive episodes. In 2005, AACAP published algorithms to guide pharmacological treatment of manic/mixed episodes associated with PBD. At that time, lithium was the only Food and Drug Administration (FDA)-approved treatment for pediatric bipolar manic/mixed episodes. The goal of this article is to review evidence that has emerged since the AACAP algorithm in 2005. Methods: Literature searches were conducted through PubMed and limited to studies published between 2005 and 2021, using keywords that focused on randomized controlled trials (RCTs) for available psychopharmacological medications. In addition, the authors conducted in-depth searches for articles providing evidence for agents included in the 2005 AACAP algorithm. Results: Since the publication of the AACAP algorithm in 2005, multiple RCTs have been conducted in PBD, leading to FDA approval of five medications (aripiprazole, asenapine, olanzapine, quetiapine, and risperidone) for the treatment of manic/mixed episodes and two medications (lurasidone and olanzapine-fluoxetine combination) for the treatment of depressed episodes. Divalproex sodium and oxcarbazepine were studied in pediatric RCTs and failed to separate from placebo. Conclusions: We offer an update to the 2005 AACAP algorithms for the treatment of pediatric bipolar mixed/manic episodes and added an evidence-based algorithm for the treatment of depression in PBD. In addition to treatment algorithms, we review current evidence for efficacy of agents proposed in the AACAP algorithm and provide tables summarizing medication side effects and efficacy.

Second-Generation Antipsychotics in Management of Acute Pediatric Bipolar Depression: A Systematic Review and Meta-analysis.

Objectives: To evaluate the efficacy in reduction of depressive symptoms, and safety and tolerability of second-generation antipsychotics (SGAs) to manage pediatric bipolar depression (PBD). Methods: We conducted a systematic review for randomized clinical trials (RCTs) for PBD in MEDLINE, Scopus, and EMBASE. Four (quetiapine: 2, lurasidone: 1, olanzapine-fluoxetine combination [OFC]: 1) out of 569 studies met the criteria for inclusion in meta-analysis. RevMan was used for statistical analysis, and the mean difference (MD) between mean children's depression rating scale-revised (CDRS-R) score was used to measure treatment difference between SGA and placebo. Results: Lurasidone displayed a significant reduction in depressive symptoms (MD -5.70, 95% confidence interval [CI] -8.67 to -2.73) in PBD, followed by OFC (MD -5.00, 95% CI -8.64 to -1.36) and quetiapine (MD -2.30, 95% CI -6.80 to 2.20; MD 1.00, 95% CI -9.88 to 11.88). The response was significantly higher for lurasidone (59.5% vs. 36.5%; p < 0.001) and OFC (78.2% vs. 59.2%, p = 0.003) compared with placebo. There was no statistically significant MD in treatment and response rates between quetiapine and placebo in all RCTs. The weighted mean CDRS-R total score difference was -4.58 (95% CI -6.59 to -2.56) and overall effect was significant (p < 0.00001). Importantly, the p value for heterogeneity was 0.46, which indicated that there was no heterogeneity between outcomes of the studies. The number needed to treat (NNT) for lurasidone was 4.3, followed by OFC (NNT = 5.3) and quetiapine (NNT = 12.5; NNT = 25). Conclusion: Our findings showed lurasidone and OFC were more efficacious than placebo for acute depressive episodes in PBD. RCTs of treatments for PBD remain scarce pressing the need for more research.

Systematic Review and Network Meta-analysis: Efficacy and Safety of Second-Generation Antipsychotics in Youths With Bipolar Depression

To assess the relative efficacy and safety of second-generation antipsychotics for treating major depressive episodes in youths with bipolar disorder. A systematic literature review using PRISMA guidelines and network meta-analysis (NMA) of randomized controlled trials (RCTs) of second-generation antipsychotics for bipolar depression in youths 10 to 18 years of age was conducted. Efficacy measures included Children's Depression Rating Scale, Revised (CDRS-R) and Clinical Global Impressions-Bipolar Disorder-Severity Depression (CGI-BP-S-depression) and Overall (CGI-BP-S-overall) scores. Available safety outcomes included discontinuations (all-cause, lack of efficacy, adverse events), metabolic parameters (weight change, cholesterol, triglycerides, glucose), changes in prolactin, and somnolence. Results from the NMA were reported as mean changes from baseline or odds ratios (OR) with 95% credible intervals (CrIs). Four RCTs comparing placebo to lurasidone, quetiapine (1 each for immediate- and extended-release), and the olanzapine-fluoxetine combination (OFC) metall of the inclusion criteria. Lurasidone and OFC demonstrated similar and statistically significant improvements in CDRS-R, but quetiapine did not (lurasidone:-5.70 [-8.66,-2.76]; OFC:-5.01 [-8.63,-1.38]; quetiapine:-1.85 [-5.99, 2.27]). Lurasidone was associated with smaller changes in weight, cholesterol, and triglycerides from baseline compared to OFC and quetiapine. There were no differences in changes in glucose levels among antipsychotics. In addition, lurasidone was associated with smaller change in prolactin levels compared to OFC but not quetiapine. Evidence from 4 studies in this NMA indicated that lurasidone and OFC, but not quetiapine, were efficacious for the treatment of bipolar depression in youths. Lurasidone was associated with less weight gain and smaller impacts on cholesterol and triglycerides compared with quetiapine and OFC.

Assessing the Benefit-Risk Ratio of Approved Treatments for Bipolar Depression Using Likelihood to be Helped or Harmed (LHH) Analyses

Four medications are FDA approved for bipolar depression: lurasidone (LUR), cariprazine (CAR), quetiapine IR & XR (QUE), and olanzapine-fluoxetine combination (OFC). Indirect comparisons for efficacy using Number Needed to Treat (NNT) and for tolerability using Number Needed to Harm (NNH) can be useful clinical benchmarks to aid treatment decisions. Benefit and risk may also be examined using the Likelihood to be Helped or Harmed (LHH). In this post-hoc analysis, we examined the benefit-risk ratio of the four treatments using LHH. Individual and pooled monotherapy data from short-term clinical registration trials of patients with bipolar depression were assessed for LUR, CAR, pooled QUE (300 and 600 mg), and pooled OFC (considered as monotherapy for this study at fixed doses of 6/25, 6/50, 12/50 mg) data. NNT estimates were calculated using the proportions of MADRS responders (defined as ≥ 50% improvement at study endpoint) and MADRS remitters (defined as a score of ≤ 10 [for LUR and CAR] and ≤ 12 [for QUE and OFC]) at study endpoint. NNH data were calculated for the proportions of patients who discontinued due to an adverse event (AE) and for individual AEs commonly associated with each treatment. LHH was calculated as the ratio of NNH/NNT to determine the benefit-risk ratio. The NNT estimates for response vs. placebo were: 5 for both LUR 20-60 mg and 80-120 mg; 10 for both CAR 1.5 mg and 3.0 mg; 6 for QUE; and 4 for OFC. The NNTs for remission vs placebo were: 7 for LUR 20-60 mg and 9 for LUR 80-120 mg; 10 for CAR 1.5 mg and 13 for CAR 3.0 mg; 6 for QUE; and 5 for OFC. The NNH estimates for discontinuations due to AEs were: 642 for LUR 20-60 mg and -151 for LUR 80-120 mg; 298 for CAR 1.5 mg and 31 for CAR 3.0 mg; 10 for QUE; and -37 for OFC. NNH values that were negative were assigned a value of 1000 to permit LHH to be calculated. The LHHs for response vs discontinuation due to an AE were: 128.4 for LUR 20-60 mg and 200 for LUR 80-120 mg; 29.8 for CAR 1.5 mg and 3.1 for CAR 3.0 mg; 1.7 for QUE; and 250 for OFC. The LHHs for response vs akathisia were: 3.6 for LUR 20-60 mg and 2.4 for LUR 80-120 mg; 3.6 for CAR 1.5 mg and 1.3 for CAR 3.0 mg; 34 for QUE; and not available (NA) for OFC. The LHHs for response vs EPS were: 8 for LUR 20-60 mg and 3.2 for LUR 80-120 mg; 5 for CAR 1.5 mg and 2.5 for CAR 3.0 mg; NA for QUE; and NA for OFC. The LHH for response vs weight gain was 5.8 for LUR 20-60 mg and 1110 for LUR 80-120 mg; 5 for both doses of CAR; 2.7 for QUE; and 1.5 for OFC. LHH can illustrate the trade-offs regarding potential benefits versus potential harms. Across a variety of measures, the lower-dose groups for both LUR and CAR generally evidenced a better benefit-risk profile than the higher-dose groups. While quetiapine and OFC demonstrated robust efficacy, their reduced tolerability resulted in a more marginal benefit-risk ratio for some of the outcomes. Sunovion Pharmaceuticals Inc.

A preliminary study of resting brain metabolism in treatment-resistant depression before and after treatment with olanzapine-fluoxetine combination.

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.

The Use of Antidepressants in Bipolar Depression.

Depression remains a significant debilitating and frequent phase of illness for patients with bipolar disorder. There are few FDA-approved medications for its treatment, only one of which includes a traditional antidepressant (olanzapine-fluoxetine combination), despite studies that demonstrate traditional antidepressants are one of the most commonly prescribed class of medications for bipolar patients in a depressive episode. While traditional antidepressants remain the primary option for treatment of unipolar depression, their use in bipolar depression has been controversial due to a limited efficacy evidence and the concern for potential harm. This chapter reviews the current data concerning the use of traditional antidepressants in bipolar disorder, and the current expert treatment guideline recommendations for their use.

Quality of life in children and adolescents with bipolar I depression treated with olanzapine/fluoxetine combination

BackgroundWe 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.MethodsPatients 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.ResultsBaseline 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.ConclusionsPatients 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

Efficacy and safety of olanzapine/fluoxetine combination in the treatment of treatment-resistant depression: a meta-analysis of randomized controlled trials.

BackgroundWhether olanzapine/fluoxetine combination (OFC) is superior to olanzapine or fluoxetine monotherapy in patients with treatment-resistant depression (TRD) remains controversial. Thus, we conducted this meta-analysis of randomized controlled trials (RCTs) to compare the efficacy and safety of OFC with olanzapine or fluoxetine monotherapy for patients with TRD.Materials and methodsRCTs published in PubMed, Embase, Web of Science, and the ClinicalTrials.gov registry were systematically reviewed to assess the efficacy and safety of OFC. Outcomes included mean changes from baseline in Montgomery–Asberg Depression Rating Scale (MADRS), Clinical Global Impression-Severity (CGI-S), Hamilton Rating Scale for Anxiety (HAM-A), Brief Psychiatric Rating Scale (BPRS) scores, response rate, remission rate, and adverse events. Results were expressed with weighted mean difference (WMD) with 95% confidence intervals (CIs) and risk ratio (RR) with 95% CIs.ResultsA total of five RCTs with 3,020 patients met the inclusion criteria and were included in this meta-analysis. Compared with olanzapine or fluoxetine monotherapy, OFC was associated with greater changes from baseline in MADRS (WMD =−3.37, 95% CI: −4.76, −1.99; P<0.001), HAM-A (WMD =−1.82, 95% CI: −2.25, −1.40; P<0.001), CGI-S (WMD =−0.37, 95% CI: −0.45, −0.28; P<0.001), and BPRS scores (WMD =−1.46, 95% CI: −2.16, −0.76; P<0.001). Moreover, OFC had significantly higher response rate (RR =1.35, 95% CI: 1.12, 1.63; P=0.001) and remission rate (RR =1.71, 95% CI: 1.31, 2.23; P<0.001). The incidence of treatment-related adverse events was similar between the OFC and monotherapy groups (RR =1.01, 95% CI: 0.94, 1.08; P=0.834).ConclusionOFC is more effective than olanzapine or fluoxetine monotherapy in the treatment of patients with TRD. Our results provided supporting evidence for the use of OFC in TRD. However, considering the limitations in this study, more large-scale, well-designed RCTs are needed to confirm these findings.

Important clinical features of atypical antipsychotics in acute bipolar depression that inform routine clinical care: a review of pivotal studies with number needed to treat.

English-language literature cited in MEDLINE from January, 1980 to October 30, 2014 was searched by using terms of antipsychotic, generic and brand names of atypical antipsychotics, "bipolar depression/bipolar disorder", "placebo", and "trial". The parameters of response (≥50% improvement on MADRS, Montgomery-Asberg Depression Rating Scale total score), remission (either ≤12 or 8 on MADRS total score at endpoint), discontinuation due to adverse events (DAEs), somnolence, ≥7% weight gain, overall extrapyramidal side-effects (EPSs), and akathisia, were extracted from originally published primary outcome papers. The number needed to treat to benefit (NNT) for response and remission or harm (NNH) for DAEs or other side effects relative to placebo were estimated and presented with the estimate and 95% confidence interval. Olanzapine monotherapy, olanzapine-fluoxetine combination (OFC), quetiapine-IR monotherapy, quetiapine-XR monotherapy, lurasidone monotherapy, and lurasidone adjunctive therapy were superior to placebo with NNTs for responses of 11-12, 4, 7-8, 4, 4-5, and 7, and NNTs for remission of 11-12, 4, 5-11, 7, 6-7, and 6, respectively. There was no significant difference between OFC and lamotrigine, and between aripiprazole or ziprasidone and placebo in response and remission. Olanzapine monotherapy, quetiapine-IR, quetiapine-XR, aripiprazole, and ziprasidone 120-160 mg/day had significantly increased risk for DAEs with NNHs of 24, 8-14, 9, 12, and 10, respectively. For somnolence, quetiapine-XR had the smallest NNH of 4. For ≥7% weight gain, olanzapine monotherapy and OFC had the smallest NNHs with both of 5. For akathisia, aripiprazole had the smallest NNH of 5. These findings suggest that among the FDA-approved agents including OFC, quetiapine-IR and -XR, lurasidone monotherapy and adjunctive therapy to a mood stabilizer, the differences in the NNTs for response and remission are small, but the differences in NNHs for DAEs and common side-effects are large. Therefore, the selection of an FDA-approved atypical antipsychotic for bipolar depression should be based upon safety and tolerability.

Antipsicóticos para la depresión bipolar: la paradoja

Bipolar depression is a frequent but complex psychiatric illness. Despite the high prevalence and relevance of bipolar depression, both clinical and economic, few treatments have shown a high and consistent efficacy. Recommendations from recent guidelines show controversies regarding the role of antidepressants in bipolar disorder, especially in terms of safety. The antidepressant efficacy of mood stabilizers appears to be generally weak. Furthermore, the evidence of specific types of bipolar depression with a high component of excitement and agitation has led to the need to reconsider the classic strategy of treating bipolar depression.In this context, recent research has focused on “no antidepressant” pharmacological alternatives and in particular on the use of atypical antipsychotics. To date, quetiapine, olanzapine-fluoxetine combination and lurasidone represent the only drugs with regulatory approval for bipolar depression in various countries.In this chapter the current available evidence on the role of atypical antipsychotics in bipolar depression will be reviewed.

Olanzapine‐fluoxetine combination has some benefit, but placebo effect and adverse events high

Adolescents and children diagnosed with bipolar disorder (BP) have a significantly reduced quality of life, including greater risk of suicidal behavior. Rapid intervention is critical, but unfortunately pharmacological treatments are challenging, with antidepressants sometimes causing manic symptoms. While there are medications effective in treating mania, the depressive phase is more difficult to treat. Only three medications are approved by the Food and Drug Administration (FDA) for the acute treatment of bipolar depression in adults: quetiapine, lurasidone, and olanzapine/fluoxetine combination (OFC).

Acute pharmacotherapy for anxiety symptoms in patients with depression

Patients with depression often also present symptoms of anxiety. First-line pharmacotherapy of comorbid symptoms of depression and anxiety is often a combination therapy of an antidepressant agent, which is combined with benzodiazepines. However, benzodiazepines pose the drawbacks of being associated with cognitive and motor impairments and hold a significant risk for dependence. For some patients, benzodiazepines are contraindicated or patients refuse to take them. Therefore, alternative therapy strategies for the acute treatment of anxiety symptoms in depressed patients are urgently needed. A selective Medline/Pubmed search with focus on acute pharmacological treatment strategies for anxiety and agitation in depressed patients was undertaken. In the light of the paucity of studies in this field, positive effects could be assumed for quetiapine, olanzapine, olanzapine-fluoxetine combination, pregabaline and silexan.

Olanzapine/Fluoxetine Combination in Children and Adolescents With Bipolar I Depression: A Randomized, Double-Blind, Placebo-Controlled Trial

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.

The pharmacodynamic properties of lurasidone and their role in its antidepressant efficacy in bipolar disorder

The treatment of bipolar depression is one of the most challenging issues in contemporary psychiatry. Currently only quetiapine, the olanzapine–fluoxetine combination and recently lurasidone are officially FDA-approved against this condition. The neurobiology of bipolar depression and the possible targets of bipolar antidepressant therapy remain elusive. The current study investigated whether the pharmacodynamic properties of lurasidone fit to a previously developed model which was the first to be derived on the basis of the strict combination of clinical and preclinical data with no input from theory or opinion. The authors performed a complete and systematic review of the literature to identify the pharmacodynamic properties of lurasidone. The original model suggests that a constellation of effects on different receptors are necessary but the serotonin reuptake inhibition does not seem to play a significant role for bipolar depression. On the contrary norepinephrine activity seems to be very important. Probably the early antidepressant effect can be achieved through an agonistic activity at 5HT-1A and antagonism at alpha1 noradrenergic and 5-HT2A receptors, but the presence of a norepinephrine reuptake inhibition is essential in order to sustain it. Overall the properties of lurasidone fit well the model and add to its validity. A point that needs clarification is norepinephrine reuptake inhibition which is not yet studied for lurasidone.

Pros and cons of approved therapies for bipolar depression and ongoing unmet needs.

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.

Long-Term Augmentation of SSRIs with Atypical Antipsychotics: Is There a Need?

When treating patients whose depression remits when an atypical antipsychotic is added to an antidepressant, clinicians want to know if the antipsychotic can be stopped because the antidepressant alone prevents relapse. A manufacturer-sponsored study tries to answer this question. In the initial phase, 892 patients with major depression who had failed at least two antidepressants were treated with olanzapine-fluoxetine combination (OFC) for 6 to 8 weeks …

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