Acute Treatment Of Bipolar Depression Research Articles

Lamotrigine: A Safe and Effective Mood Stabilizer for Bipolar Disorder in Reproductive-Age Adults.

Lamotrigine belongs to the group of antiepileptic drugs and mood stabilizers, and its action is based on the selective blocking of voltage-deficient sodium channels. The effect of this mechanism is the stabilization of the presynaptic part of the neuronal membrane and subsequent inhibition of the secretion of the neurotransmitters glutamate and aspartate into the postsynaptic part of the neuron. Lamotrigine has been approved by the Food and Drug Administration for the maintenance treatment of adults with bipolar disorder since 1994. In the field of psychiatry, this medicine is also used off-label in the treatment of acute bipolar depression. Studies show promising effects of the use of lamotrigine in bipolar disorder type II with rapid phase change. Bipolar disorder is a common psychiatric problem that most often affects young adults. Lamotrigine is most effective in bipolar disorder in preventing depressive episodes, which dominate the clinical picture of this disease. The latest research focuses on extending its action, to include manic episodes. Lamotrigine, through an unexplained mechanism, can affect the immune system, causing Stevens-Johnson syndrome, hemophagocytic lymphohistiocytosis, and drug reaction with eosinophilia and systemic symptoms syndrome. These are rare, life-threatening adverse effects that require urgent intervention in the form of drug discontinuation and immunosuppressive treatment. Strict contraindications to the use of lamotrigine include sensitivity reactions accompanied by systemic symptoms. Phenotype testing enables screening of patients predisposed to serious hypersensitivity reactions. The aim of the article is to review the indications, contraindications, and adverse effects of lamotrigine in the treatment of bipolar disorder and depression.

Short-term ketamine use in bipolar depression: a review of the evidence for short-term treatment management.

Bipolar depression constitutes a major problem in psychiatry. It correlates with high suicidality, treatment resistance, chronicity, and poor quality of life. Registered treatment for bipolar depression is limited and insufficient. There is an urgent need for implementing new therapeutic strategies. Intranasal ketamine's enantiomer-esketamine is a novel rapid-acting antidepressant with proven efficacy in treatment-resistant depression. Research on bipolar depression, although not as comprehensive, indicates that it may be a viable and safe substitute with minimal risk for mood polarity changes. Reports suggest that ketamine treatment in bipolar depression may reduce suicidal tendencies, decrease anhedonia, and alleviate anxiety. Ketamine's mood-stabilizing properties are also hypothesized. In this narrative review, we focus on ketamine use as an add-on to standard medication for the acute treatment of bipolar depression.

Lithium in bipolar depression: A review of the evidence.

Lithium is widely used as treatment of acute mania and as prophylactic therapy for bipolar disorder. International and national guidelines also consider lithium as a possible treatment of acute bipolar depression. Research on the use of lithium in bipolar depression, however, seems to be limited compared to the data available for its efficacy in the other phases of bipolar disorder. To provide a systematic review of the evidence for lithium in the treatment of acute bipolar depression and provide directions for further research. A systematic review of clinical studies investigating the use of lithium in bipolar depression was performed using preferred reporting items for systematic reviews and meta-analyses guidelines in Pubmed, Embase and Psychinfo using the medical subjects headings and free text terms "lithium," "bipolar depression," "dosage," "serum concentration" and "bipolar disorders." This review included 15 studies with a total of 1222 patients, between the age of 18 and 65, suffering from bipolar depression of which 464 were treated with lithium. There are currently only limited and low-quality data on the efficacy of lithium as a treatment of bipolar depression. It appears that there have been no placebo controlled randomized controlled trials with lithium concentrations that are considered to be therapeutic. The older studies suffered from limitations such as small sample sizes, insufficient treatment lengths, and insufficient monitoring of serum concentrations. In contrast to data for the treatment of mania and prophylaxis, robust data on the efficacy of lithium in bipolar depression is currently lacking, making it impossible to make conclusions regardingefficacy or inefficacy, for which further research is needed.

Efficacy of Active vs Sham Intermittent Theta Burst Transcranial Magnetic Stimulation for Patients With Bipolar Depression

Major depressive episodes in bipolar disorder are common and debilitating. Repetitive transcranial magnetic stimulation is well established in the treatment of major depressive disorder, and the intermittent theta burst stimulation (iTBS) protocol is replacing conventional protocols because of noninferiority and reduced delivery time. However, iTBS has not been adequately studied in bipolar disorder and, therefore, its efficacy is uncertain. To determine whether iTBS to the left dorsolateral prefrontal cortex (LDLPFC) is safe and efficacious in the treatment of acute bipolar depression. This study was a double-blind, 4-week, randomized clinical trial of iTBS targeting the LDLPFC. Two Canadian academic centers recruited patients between 2016 and 2020. Adults with bipolar disorder type I or type II experiencing an acute major depressive episode were eligible if they had not benefited from a first-line treatment for acute bipolar depression recommended by the Canadian Network for Mood and Anxiety Treatments and were currently treated with a mood stabilizer, an atypical antipsychotic, or their combination. Seventy-one participants were assessed for eligibility, and 37 were randomized to daily sham iTBS or active iTBS using a random number sequence, stratified according to current pharmacotherapy. Data analysis was performed from April to September 2020. Four weeks of daily active iTBS (120% resting motor threshold) or sham iTBS to the LDLPFC. Nonresponders were eligible for 4 weeks of open-label iTBS. The primary outcome was the change in score on the Montgomery-Asberg Depression Rating Scale from baseline to study end. Secondary outcomes included clinical response, remission, and treatment-emergent mania or hypomania. The trial was terminated for futility after 37 participants (23 women [62%]; mean [SD] age, 43.86 [13.87] years; age range, 20-68 years) were randomized, 19 to sham iTBS and 18 to active iTBS. There were no significant differences in Montgomery-Asberg Depression Rating Scale score changes (least squares mean difference between groups, -1.36 [95% CI, -8.92 to 6.19; P = .91] in favor of sham iTBS), and rates of clinical response were low in both the double-blind phase (3 of 19 participants [15.8%] in the sham iTBS group and 3 of 18 participants [16.7%] in the active iTBS group) and open-label phase (5 of 21 participants [23.8%]). One active iTBS participant had a treatment emergent hypomania, and a second episode occurred during open-label treatment. iTBS targeting the LDLPFC is not efficacious in the treatment of acute bipolar depression in patients receiving antimanic or mood stabilizing agents. Additional research is required to understand how transcranial magnetic stimulation treatment protocols differ in efficacy between unipolar and bipolar depression. ClinicalTrials.gov Identifier: NCT02749006.

Meta-analysis of sleep deprivation in the acute treatment of bipolar depression.

Sleep deprivation (SD) is an antidepressant intervention with multiple administration formats that has been investigated primarily with uncontrolled clinical trials and qualitative reviews of the literature. The validity and applicability of these findings to the treatment of bipolar depression (BPD) is uncertain. A PRISMA-based systematic review of the literature and meta-analysis were conducted to determine the efficacy of SD in the treatment of BPD and to identify moderator variables that influence response rate. From a sample of 15 studies covering 384 patients, the overall, mean response rate to SD was 47.6% (CI 36.0%, 59.5%). This response rate compared post-SD to pre-SD depression scores, and not to a placebo control condition. Of several potential moderating variables examined, the use of adjunctive pharmacotherapy achieved statistical significance with response rates of 59.4% [CI 48.5, 69.5] for patients using adjunctive medication vs 27.4% [CI 17.8, 39.8] for patients not using adjunctive medication. This meta-analysis of SD in the treatment of BPD found an overall, response rate of almost 50%, reinforcing earlier estimates of efficacy. The use of adjunctive pharmacotherapy had a statistically significant moderating effect on SD response suggesting that clinical practice should routinely pair these interventions. These findings provide a higher level of evidence supporting the use of SD, especially when used with medication, and should inform future management guidelines for the treatment of BPD.

Possibility of a New Indication for Amantadine in the Treatment of Bipolar Depression-Case Series Study.

Bipolar disorder is a chronic and remitting mental illness. Antidepressants are not effective in treating acute bipolar depression, and antipsychotic drugs used in the treatment of bipolar depression cause frequent side effects. This situation justifies the search for new drugs as well as the repurposing of drugs used in other indications. In an open and naturalistic serious case study, 4 patients diagnosed with bipolar I disorder, chronically treated with a mood stabilizer, in whom at least two antidepressants were ineffective in the depressive phase, were treated with amantadine. The woman received 100 mg/day and 3 men received the target dose of 200 mg/day. All patients treated with amantadine improved their depressive symptoms after 1 week of treatment. None of them experienced side effects or manic switch. To reduce the risk of a manic switch, the treatment with amantadine was discontinued 2 weeks after the improvement of depressive symptoms, and no recurrence of depressive symptoms was observed. Amantadine may be a further therapeutic option for the treatment of acute bipolar depression. The drug in this indication may act quickly and be well tolerated. Confirmation of the antidepressant efficacy of amantadine in this indication requires replication of the results and conducting clinical trials.

Advances toward precision medicine for bipolar disorder: mechanisms & molecules.

Given its chronicity, contribution to disability and morbidity, and prevalence of more than 2%, the effective treatment, and prevention of bipolar disorder represents an area of significant unmet medical need. While more than half a century has passed since the introduction of lithium into widespread use at the birth of modern psychopharmacology, that medication remains a mainstay for the acute treatment and prevention of recurrent mania/hypomania and depression that characterize bipolar disorder. However, the continued limited understanding of how lithium modulates affective behavior and lack of validated cellular and animal models have resulted in obstacles to discovering more effective mood stabilizers with fewer adverse side effects. In particular, while there has been progress in developing new pharmacotherapy for mania, developing effective treatments for acute bipolar depression remain inadequate. Recent large-scale human genetic studies have confirmed the complex, polygenic nature of the risk architecture of bipolar disorder, and its overlap with other major neuropsychiatric disorders. Such discoveries have begun to shed light on the pathophysiology of bipolar disorder. Coupled with broader advances in human neurobiology, neuropharmacology, noninvasive neuromodulation, and clinical trial design, we can envision novel therapeutic strategies informed by defined molecular mechanisms and neural circuits and targeted to the root cause of the pathophysiology. Here, we review recent advances toward the goal of better treatments for bipolar disorder, and we outline major challenges for the field of translational neuroscience that necessitate continued focus on fundamental research and discovery.

PMH5 EFFICACY AND SAFETY OF LURASIDONE AND OTHER ATYPICAL ANTIPSYCHOTIC AGENTS FOR BIPOLAR DEPRESSION: UPDATED SYSTEMATIC REVIEW AND META-ANALYSES

Since publication of a systematic literature review (SLR) and network meta-analysis (NMA) comparing the efficacy and safety of lurasidone with atypical antipsychotic monotherapies for the treatment of acute bipolar depression among adults, new clinical trial data have been released. The purpose of this study was to update an NMA comparing the efficacy and safety of lurasidone with all other atypical antipsychotic monotherapies in adult patients with bipolar depression. A SLR and NMA of randomized controlled trials (RCTs) was updated as of August 2018 using Embase, MEDLINE, PsycINFO, Cochrane library, clinicaltrials.gov, recent abstracts, and press releases. Outcomes included the Montgomery–Åsberg Depression Rating Scale (MADRS), Clinical Global Impressions–Bipolar Disorder–Severity (CGI-BP-S) scale, weight gain, somnolence, akathisia, extrapyramidal symptoms (EPS), and all-cause discontinuation. Mean differences in change from baseline and mean odds ratios (OR) with 95% credible intervals were calculated. Seventeen RCTs of lurasidone, quetiapine (IR or XR), aripiprazole, olanzapine, ziprasidone and cariprazine for the treatment of bipolar depression were included. Lurasidone was significantly more efficacious than cariprazine (MADRS: -2.91 [-5.57, -0.20], CGI-BP-S: -0.44 [-0.74, -0.14]), aripiprazole (MADRS: -3.62 [-6.89, -0.36], CGI-BP-S: -0.42 [-0.77, -0.07]), and ziprasidone (MADRS: -3.37 [-6.49, -0.23], CGI-BP-S: -0.59 [-0.93, -0.24]). Lurasidone had similar efficacy vs olanzapine and quetiapine. Lurasidone had less weight gain than olanzapine (-2.54kg [-3.36, -1.72]), quetiapine (-0.83kg [-1.55, -0.12]), and cariprazine (-0.40kg [-1.30, 0.49]), and less somnolence than ziprasidone (OR: 0.28 [0.09, 0.66]) and quetiapine (OR: 0.32 [0.11, 0.68]). Rates of akathisia, EPS, and all-cause discontinuation were similar. Consistent with the previous NMA, lurasidone was efficacious and well-tolerated. The updated NMA showed lurasidone was more efficacious than cariprazine, aripiprazole, and ziprasidone among adults with acute bipolar depression. Lurasidone also had less weight gain than olanzapine and quetiapine, and less somnolence than quetiapine and ziprasidone.

Stepwise treatment of acute bipolar depression.

Stepwise treatment of acute bipolar depression.

Targeting the immune system in the treatment of bipolar disorder.

Immune dysfunction has been strongly implicated in the pathophysiology of bipolar disorder (BD). As such, numerous clinical trials have investigated the effects of anti-inflammatory agents in the treatment of BD. Review clinical studies evaluating the effects of anti-inflammatory agents in the treatment of BD during all illness phases (e.g., depression, mania, and euthymia). Relevant databases were searched from inception to August 27, 2018 for clinical studies evaluating the effects of anti-inflammatory agents in BD. The majority of identified clinical trials evaluated adjunctive anti-inflammatory agents in the acute treatment of bipolar depression, demonstrating antidepressant effects with N-acetylcysteine (NAC), pioglitazone, minocycline, and coenzyme Q10, along with mixed evidence for omega-3s, and non-steroidal anti-inflammatory drugs (NSAIDs). The anti-manic effects of adjunctive anti-inflammatory agents have been minimally studied, with some promising preliminary results supporting potential anti-manic effects of adjunctive celecoxib and NAC. Maintenance studies are also limited, with inadequate evidence to support mood stabilizing effects of anti-inflammatories while euthymic. Regardless of illness phase, early results suggest that anti-inflammatory agents are likely most beneficial in the subgroup of BD with immune dysregulation. Several proof-of-concept clinical trials have shown promising results for anti-inflammatory agents in the treatment of bipolar depression with moderate effect sizes and good tolerability. The effects of anti-inflammatory agents during manic and euthymic periods remains uncertain. Future larger studies, using stratified samples, enriched for participants with immune dysfunction, are required to determine the role of immune modulating agents in the treatment of BD.

The efficacy of adjunctive N-acetylcysteine in acute bipolar depression: A randomized placebo-controlled study

ObjectiveTo investigate the efficacy of adjunctive N-acetylcysteine (NAC) for the treatment of acute bipolar depression. MethodA randomized, double-blind, multicentre, placebo-controlled trial including adult subjects diagnosed with bipolar disorder, currently experiencing a depressive episode. Participants were treated with 3 g/day NAC or placebo as an adjunctive to standard treatment for 20 weeks, followed by a 4-week washout where the blinding was maintained. The primary outcome was the mean change in the Montgomery Asberg Depression Rating Scale (MADRS) score over the 20-week treatment phase. Linear Mixed Effects Repeated Measures (LMERM) was used for analysing the primary outcome. ResultsA total of 80 subjects were included. The mean MADRS score at baseline was 30.1 and 28.8 in participants randomized to NAC and placebo, respectively. Regarding the primary outcome measure, the between-group difference (NAC vs. placebo) was 0.5, which was statistically non-significant (95% CI: -7.0-5.9;p = 0.88). All findings regarding secondary outcomes were statistically or clinically insignificant. LimitationsThe study had a placebo response rate of 55.6% - high placebo response rates are associated with failure to separate from placebo. ConclusionsBased on our primary outcome measure, we could not confirm previous studies showing a therapeutic effect of adjunctive NAC treatment on acute bipolar depression. Further studies with larger samples are needed to elucidate if specific subgroups could benefit from adjunctive NAC treatment.

Treatment of acute bipolar depression.

Depression is the predominant pole of disability in bipolar disorder and compared with mania/hypomania, has less systematic research guiding the development of treatment especially in its acute phase (acute bipolar depression). The deficiency in the management of the acute bipolar depression largely reflects the natural divergence of opinion resulting from significant knowledge gaps. At present, there are only 3 approved drug treatments for acute bipolar depression: olanzapine/fluoxetine combination, quetiapine (immediate or extended release), and lurasidone (monotherapy or adjunctive to lithium or valproate). Nonapproved agents and nonpharmacologic treatment such as lamotrigine, antidepressants, modafinil, pramipexole, ketamine, and electroconvulsive therapy are often prescribed to treat acute bipolar depression. This article discusses the challenges of diagnosing bipolar depression, and reviews above treatment options for acute bipolar depression.

Lurasidone in combination with lithium or valproate for the maintenance treatment of bipolar I disorder

Lurasidone (DS-RAn) has demonstrated efficacy in the acute treatment of bipolar depression, both as monotherapy, and as combination therapy with lithium or valproate. To evaluate the recurrence prevention efficacy of lurasidone for the maintenance treatment of bipolar I disorder, patients received up to 20 weeks of open-label lurasidone (20–80mg/d) combined with lithium or valproate during an initial stabilization phase. A total of 496 patients met stabilization criteria and were randomized to 28 weeks of double-blind treatment with lurasidone (20–80mg/d) or placebo, in combination with lithium or valproate. Based on a Cox proportional hazard model, treatment with lurasidone reduced the probability of recurrence of any mood episode by 29% (primary endpoint), however, the reduction did not achieve statistical significance. Probability of recurrence on lurasidone was significantly lower in patients with an index episode of depression (HR, 0.57; P=0.039), in patients with any index episode who were not rapid-cycling (HR, 0.69; P=0.046), and when recurrence was based on MADRS, YMRS, or CGI-BP-S severity criteria (HR, 0.53; P=0.025; sensitivity analysis). Long-term treatment with lurasidone combined with lithium or valproate was found to be safe and well-tolerated, with minimal effects on weight or metabolic parameters.

Lurasidone adjunctive to lithium or valproate for prevention of recurrence in patients with bipolar I disorder

IntroductionInformation is not available on the maintenance efficacy of lurasidone in bipolar disorder.Objectives/aimsTo evaluate the recurrence prevention efficacy of lurasidone plus lithium (Li) or valproate (VPA) for the maintenance treatment of bipolar disorder.MethodsPatients with bipolar I disorder received up to 20 weeks of open-label lurasidone (20–80 mg/d) plus Li or VPA. Patients who achieved consistent clinical stability were randomized to 28 weeks of double-blind treatment with lurasidone (20–80 mg/d) or placebo, plus Li or VPA.ResultsA total of 496 patients met stabilization criteria and were randomized to adjunctive lurasidone vs. placebo. Fewer patients in the lurasidone group had recurrence of any mood episode compared with the placebo group, with a hazard ratio of 0.71 (P = 0.078). In pre-planned secondary analyses, recurrence rates were significantly lower for the lurasidone group treated with a modal open-label dose of 80 mg/d (hazard ratio [HR], 0.35; P = 0.020); when patients presented with an index episode of depression (HR = 0.57; P = 0.039); and when outcome was time-to-all-cause discontinuation (HR = 0.72; P = 0.034), or time-to-recurrence based on symptom severity criteria (HR = 0.53; P = 0.025).ConclusionsIn patients stabilized on lurasidone plus Li or VPA, continued treatment was associated with non-significant reduction in risk of recurrence of any mood disorder (primary). Consistent with dose-response effects observed during acute treatment of bipolar depression, risk of recurrence on lurasidone was significantly reduced after open-label treatment with the 80 mg/d dose, and in the 20–80 mg/d dose in patients presenting with an index episode of depression.Clinicaltrials.gov: NCT01358357.Sponsored by Sunovion Pharmaceuticals Inc.Disclosure of interestDrs. Pikalov, Cucchiaro, Mao, and Loebel are employees of Sunovion Pharmaceuticals IncDr. Calabrese has received research support from Abbott, AstraZeneca, Bristol-Myers Squibb, Cephalon, Cleveland Foundation, Eli Lilly, GlaxoSmithKline, Janssen, Lundbeck, NARSAD, Repligen, Stanley Medical Research Institute, Takeda, and Wyeth. Dr. Calabrese consulted to or served on advisory boards of Abbott, AstraZeneca, Bristol-Myers Squibb, Cephalon, Dainippon Sumitomo, Elan, EPI-Q, Inc., Forest, France Foundation, GlaxoSmithKline, Hoffman LaRoche, Janssen, Johnson and Johnson, Lundbeck, Merck, Neurosearch, OrthoMcNeil, Otsuka, Pfizer, Repligen, Servier, Solvay, Sunovion, Supernus, Synosia, Takeda, Teva, and Wyeth. Dr. Calabrese has provided CME lectures supported by AstraZeneca, Bristol-Myers Squibb, France Foundation, GlaxoSmithKline, Janssen, Johnson and Johnson, Merck, Sanofi-Aventis, Schering-Plough, Pfizer, Solvay, Sunovion, and Wyeth.

Adjunctive Behavioral Activation for the Treatment of Bipolar Depression: A Proof of Concept Trial.

Grounded in a model focused on exposure to response-contingent positive reinforcement, and with evidence supporting its acute treatment effects for unipolar depression, an adjunctive behavioral activation (BA) intervention may be especially well suited to the treatment of bipolar depression. The goal of this study was to modify BA for the adjunctive treatment of bipolar depression and to pilot it in a proof of concept trial to assess its preliminary feasibility and acceptability for this population. Twelve adults with bipolar depression were recruited from hospital settings and enrolled in a 20-week open trial of the modified BA, delivered in 16 outpatient sessions, as an adjunct to community pharmacotherapy for bipolar disorder. Symptom severity was assessed at pretreatment and posttreatment by an independent evaluator. Patient satisfaction was also assessed posttreatment. Feasibility and acceptability were high, with 10 of 12 patients completing treatment, an average of 14.8 (SD=5.2) of 16 sessions attended, and high levels of self-reported treatment satisfaction. Patients exhibited statistically significant improvement from pretreatment to posttreatment on measures of depressive symptoms, manic symptoms, and severity of suicidal ideation. Although preliminary and requiring replication in a larger sample, these study data suggest that a modified BA intervention may offer promise as an adjunctive approach for the acute treatment of bipolar depression. Future studies that use more rigorous randomized controlled designs and that directly assess potential mechanisms of action are recommended.

Atypical Antipsychotics in the Treatment of Acute Bipolar Depression with Mixed Features: A Systematic Review and Exploratory Meta-Analysis of Placebo-Controlled Clinical Trials.

Evidence supporting the use of second generation antipsychotics (SGAs) in the treatment of acute depression with mixed features (MFs) associated with bipolar disorder (BD) is scarce and equivocal. Therefore, we conducted a systematic review and preliminary meta-analysis investigating SGAs in the treatment of acute BD depression with MFs. Two authors independently searched major electronic databases from 1990 until September 2015 for randomized (placebo-) controlled trials (RCTs) or open-label clinical trials investigating the efficacy of SGAs in the treatment of acute bipolar depression with MFs. A random-effect meta-analysis calculating the standardized mean difference (SMD) between SGA and placebo for the mean baseline to endpoint change in depression as well as manic symptoms score was computed based on 95% confidence intervals (CI). Six RCTs and one open-label placebo-controlled studies (including post-hoc reports) representing 1023 patients were included. Participants received either ziprasidone, olanzapine, lurasidone, quetiapine or asenapine for an average of 6.5 weeks across the included studies. Meta-analysis with Duval and Tweedie adjustment for publication bias demonstrated that SGA resulted in significant improvements of (hypo-)manic symptoms of bipolar mixed depression as assessed by the means of the total scores of the Young Mania Rating Scale (YMRS) (SMD −0.74, 95% CI −1.20 to −0.28, n SGA = 907, control = 652). Meta-analysis demonstrated that participants in receipt of SGA (n = 979) experienced a large improvement in the Montgomery–Åsberg Depression Rating Scale (MADRS) scores (SMD −1.08, 95% CI −1.35 to −0.81, p < 0.001) vs. placebo (n = 678). Publication and measurement biases and relative paucity of studies. Overall, SGAs appear to offer favorable improvements in MADRS and YMRS scores vs. placebo. Nevertheless, given the preliminary nature of the present report, additional original studies are required to allow more reliable and clinically definitive conclusions.

Pharmacotherapy of Acute Bipolar Depression in Adults: An Evidence Based Approach.

In the majority of cases of bipolar disorder, manic episodes are usually brief and typically responsive to currently available psychopharmacological agents. In contrast, depressive manifestations are more prevalent and persistent, and can present as major depressive/mixed episodes or residual interepisode symptoms. The depressive phase is often associated with other neuropsychiatric conditions, such as anxiety spectrum disorders, substance use disorders, stressor-related disorders, and eating disorders. It is viewed as a systemic disease with associated ailments such as metabolic syndrome, diabetes mellitus, and cardiovascular disease. There is an increased rate of mortality not only from suicide, but also from concomitant physical illness. This scenario is made worse by the fact that depressive symptoms, which represent the main disease burden, are often refractory to existing psychotropic drugs. As such, there is a pressing need for novel agents that are efficacious in acute depressive exacerbations, and also have applicable value in preventing recurrent episodes. The rationale of the present review is to delineate the pharmacotherapy of the depressive phase of bipolar disorder with medications for which there is evidence in the form of observational, open-label, or double-blind randomized controlled studies. In the treatment of acute bipolar depression in adults, a comprehensive appraisal of the extant literature reveals that among mood stabilizers, the most robust proof of efficacy exists for divalproex sodium; while atypical antipsychotics, which include olanzapine, quetiapine, lurasidone, and cariprazine, are also effective, as demonstrated in controlled trials.

Development of a level A in vitro-in vivo correlation for extended release dosage forms of quetiapine fumarate.

Quetiapine is an atypical antipsychotic recommended as first-line treatment for acute bipolar depression. The extended-release quetiapine formulation is intended to be administered as an once-daily dosing. The development of an in vitro-in vivo correlation (IVIVC) and the use of in vitro data to predict in vivo bioavailability parameters has been of great interest for the rational development and evaluation process for extended release dosage forms. The aim of this study was to develop an IVIVC for quetiapine extended release formulation. In vitro dissolution rate data were obtained using USP apparatus 2 at 50 rpm, in 3 bio-relevant dissolution media with different pH values (1.2, 4.5 and 6.8). The drug release profiles of the 2 extended release dosage forms were compared using the similarity factor (f 2). The relative bioavailability of quetiapine was evaluated by a single-dose, randomized-sequence, open-label, 2 period cross over study with 16 healthy volunteers. A linear level A IVIVC model was established using percentage of absorbed and dissolved data obtained at pH 1.2. The developed IVIVC model was employed to predict quetiapine concentration-time profiles, as well as the bioequivalence parameters for test formulation. Percent prediction errors were estimated for Cmax and AUC to evaluate the validity of the correlation. The values did not exceed 15%, proving the predictability of the correlation model. In conclusion, the established level A IVIVC model proved to be an excellent tool for predicting the rate and extent of quetiapine absorption as characterized by Cmax and AUC for test formulation.

Lurasidone for the treatment of bipolar depression: an evidence-based review.

Bipolar disorder (BD) is a debilitating and difficult-to-treat psychiatric disease that presents a serious burden to patients’ lives as well as health care systems around the world. The essential diagnostic criterion for BD is episodes of mania or hypomania; however, the patients report that the majority of their time is spent in a depressive phase. Current treatment options for this component of BD have yet to achieve satisfactory remission rates. Lurasidone is a drug in the benzisothiazole class approved by the US Food and Drug Administration in June 2013 for the acute treatment of bipolar depression. Its pharmacological profile features high-affinity antagonism at D2, 5-HT2A, and 5-HT7 receptors; moderate-affinity antagonism at α2C-adrenergic receptors; low- to very low-affinity antagonism at α1A-adrenergic, α2A-adrenergic, H1, M1, and 5-HT2C receptors; and high-affinity partial agonism at 5-HT1A. Preliminary findings from two recent double-blinded clinical trials suggest that lurasidone is efficacious in treating bipolar I depression, with clinical effects manifesting as early as the first 2–3 weeks of treatment (as measured by the Montgomery–Åsberg Depression Rating Scale and Clinical Global Impressions Scale for use in bipolar illness). Its therapeutic benefit appears to be comparable to the current US Food and Drug Administration-indicated treatments: quetiapine and olanzapine–fluoxetine, according to a measure of effect size known as number needed to treat. These studies reported relatively limited extrapyramidal and metabolic side effects as a result of treatment with lurasidone, with the most common side effect being nausea. Safety data drawn from these studies, as well as a more extensive body of schizophrenia research, indicate that in comparison with other atypical antipsychotics, treatment with lurasidone is less likely to result in metabolic side effects such as weight gain or disturbances of serum glucose or lipid levels. Lurasidone holds clinical potential as a novel, efficacious pharmacological treatment for bipolar depression. However, current data on its use for the treatment of BD are limited, and more extensive research, both longer in duration as well as independently conducted, is needed.

Efficacy and tolerability of treatments for bipolar depression

BackgroundDepression in bipolar disorder is a major therapeutic challenge associated with disability and excess mortality. MethodsWe 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). ResultsIncluded 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. ConclusionsSome 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. LimitationsThere 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.