We employed a Bayesian network meta-analysis for comparison of the efficacy and tolerability of US Food and Drug Administration (FDA)-approved atypical antipsychotics (AAPs) for the treatment of bipolar patients with depressive episodes. Sixteen randomized controlled trials with 7234 patients treated by one of the five AAPs (cariprazine, lumateperone, lurasidone, olanzapine, and quetiapine) were included. For the response rate (defined as an improvement of ≥50% from baseline on the Montgomery-Åsberg Depression Rating Scale [MADRS]), all AAPs were more efficacious than placebo. For the remission rate (defined as the endpoint of MADRS ≤12 or ≤ 10), cariprazine, lurasidone, olanzapine, and quetiapine had higher remission rates than placebo. In terms of tolerability, olanzapine was unexpectedly associated with lower odds of all-cause discontinuation in comparison with placebo, whereas quetiapine was associated with higher odds of discontinuation due to adverse events than placebo. Compared with placebo, lumateperone, olanzapine, and quetiapine showed higher odds of somnolence. Lumateperone had a lower rate of ≥ weight gain of 7% than placebo and other treatments. Olanzapine was associated with a significant increase from baseline in total cholesterol and triglycerides than placebo. These findings inform individualized prescriptions of AAPs for treating bipolar depression in clinical practice.

The possibility of atypical antipsychotics (AA) to induce manic symptoms has been raised by several articles. The objective of this study was to describe whether exposure to AA may induce mania in mood disorders.

We performed a systematic review following the preferred reporting items for systematic reviews and meta-analysis guidelines. The systematic search encompassed all relevant studies published until April 4th, 2022. A meta-analysis testing whether treatment emergent mania (TEM) is more frequent with the use of AA compared with placebo was performed.

A total of 52 studies were included in the systematic review. We found 24 case reports or case series describing 40 manic/hypomanic episodes allegedly induced by AA. Twenty-one placebo-controlled trials were included in a meta-analysis including 4823 individuals treated with AA and 3252 individuals receiving placebo. Our meta-analysis showed that the use of AA protects against the development of TEM (OR: 0.68 [95 % CI: 0.52-0.89], p = 0.005).

AA-induced mania/hypomania was not the primary outcome in any of the observational or interventional studies. TEM was not homogeneously defined across studies. In most case reports it was not possible to establish causality between the use of AA and the development of manic symptoms.

TEM is more frequent with placebo than with AA, which suggests that AA exposure does not represent a relevant risk for TEM. Mania/hypomania induced by an AA seems to be rare events, since anecdotal evidence from case reports and case series were not observed in observational prospective and interventional studies.

Several bipolar depression treatment guidelines have been designed to assist clinicians with medication selection. When ranking medications, none explicitly considered the inclusion/exclusion criteria or baseline severity scores of the reviewed clinical trials. This article aimed to determine if sufficient differences exist in these variables to justify their consideration when designing treatment guidelines.

Using Ovid and PubMed databases in May and September 2022, all published, short-term cross-over or parallel-group design studies comparing second generation antipsychotics (SGAs), mood stabilizers, or antidepressants versus placebo in bipolar depressed patients were identified. Included studies must have enrolled adult bipolar I/II depressed patients, randomized patients into two or more treatment groups, utilized a double-blind, prospective design written in English, and had primary outcome results that were statistically significant in favor of the investigational treatment.

Thirty studies met eligibility criteria, comprising a total of 8791 patients. Among those studies, there were seventeen antipsychotic trials, six lithium trials, one lamotrigine trial, three valproate trials, two carbamazepine trials, and two antidepressant trials. The analysis revealed substantial differences among the studies. Although this was seen among all the different drug classes, these differences are clearest when comparing the lithium trials to those of the SGAs.

Limitations included the selection of severity scores from the treatment arm with the most severe score and the exclusive focus on mood stabilizers, antidepressants, and SGAs.

Severity of the enrolled patient sample and treatment-resistance should be considered in addition to other factors when ranking medications in bipolar depression treatment guidelines.

Anxiety symptoms are highly prevalent among individuals with bipolar disorder (BD) but there is little guidance on pharmacotherapy for these symptoms. The objective of this systematic review and meta-analysis was to evaluate the available evidence for pharmacotherapy of comorbid anxiety symptoms in BD.

Completed randomized clinical trials (RCTs) of medications for BD published prior to December 2020 were identified through a systematic search of MEDLINE, Embase, PsycInfo, Web of Science, clinicaltrials.gov, and the ISRCTN. Data from RCTs measuring anxiety symptoms at baseline and endpoint and all-cause discontinuation were pooled to compare the efficacy and acceptability of medications with control conditions.

Thirty-seven RCTs met our inclusion criteria; 13 placebo-controlled RCTs with 2175 participants had sufficient data to be included in the meta-analysis assessing anxiety symptoms. Compared with placebo, the overall effect size of medications (primarily atypical antipsychotics) on anxiety symptoms was small with a standardized mean difference (SMD) = -0.22 (95% CI: -0.34 to -0.11). Study heterogeneity was low (I²  = 26%). The acceptability of these medications was comparable with placebo with odds ratio of discontinuation from all causes = 0.98 (95% CI: 0.91-1.06).

There is limited evidence for a small anxiolytic effect and good acceptability of pharmacotherapy (primarily atypical antipsychotics) in the treatment of comorbid anxiety symptoms in BD. These results highlight the need for further research on medications other than atypical antipsychotics.

While clinical trial evidence has firmly established the efficacy of several atypical antipsychotics (AAPs) for treating bipolar depression, no randomized controlled trials (RCT's) comparing AAPs have been conducted. This Bayesian network meta-analysis (NMA) compared the relative efficacy and tolerability of AAP monotherapy in adults with bipolar depression.

Efficacy measures included change in Montgomery Åsberg Depression Rating Scale (MADRS), Clinical Global Improvement - Bipolar Disorder (CGI-BP), response, and remission. Multiple tolerability outcomes were examined. Results from random effects models were reported as difference in change from baseline for continuous variables or odds ratios for dichotomous variables. Treatments were ranked using the surface under the curve cumulative ranking probabilities. Number needed to treat (NNT) and harm (NNH) were calculated.

Eighteen RCT's met inclusion criteria of the systematic literature review. On change in MADRS, lurasidone (- 4.71 [95% Crl - 6.98, - 2.41]), quetiapine (- 4.80 [- 5.93, - 3.72]), olanzapine (- 4.57 [- 5.92, - 3.20]), and cariprazine (- 2.29 [- 3.47, - 1.09]) were more efficacious than placebo. Lurasidone was associated with a significantly greater odds of response (≥50% improvement in MADRS) compared to cariprazine (1.78 [95% Crl 1.08, 2.77]), aripiprazole (2.38 [1.38, 3.85]), and ziprasidone (2.47 [1.41, 3.98]), but was similar to olanzapine (1.68 [0.99,2.65]) and quetiapine (1.25 [0.78, 1.90]). For change in CGI-BP-S-overall score, lurasidone was significantly better than cariprazine (- 0.38 [95% Crl - 0.66,-0.10]) and ziprasidone (- 0.58 [- 0.91,-0.26]), but similar to quetiapine (- 0.08 [- 0.36, 0.19])and olanzapine (- 0.04 [- 1.41, 1.46]). Lurasidone (0.34 kg [95% Crl - 0.22, 0.89]) and aripiprazole (0.20 kg [- 0.59, 1.00]) had a similar weight change compared to placebo, but olanzapine (2.88 kg [2.40, 3.36]), quetiapine (1.17 kg [0.84, 1.49]), and cariprazine (0.65 kg [0.34, 0.96]) were associated with greater weight gain. The NNT for response was the lowest for lurasidone (NNT = 5) followed by quetiapine (NNT = 6), olanzapine (NNT = 10) and cariprazine (NNT = 12).

In this NMA in adults with bipolar depression, which evaluated change in depressive symptoms (assessed by MADRS) across short-term trials, the largest improvement versus placebo was observed for lurasidone, olanzapine and quetiapine with cariprazine, showing a smaller treatment effect. Aripiprazole and ziprasidone were ineffective for the treatment of bipolar depression. Improvement in CGI-BP-S score for lurasidone was larger than cariprazine and ziprasidone but similar to quetiapine and olanzapine. Based on short term studies lurasidone and aripiprazole had similar weight gain compared to placebo.

Few studies have evaluated the influence of valproate on the deterioration of the lipid profile in psychiatric patients. This observational study aimed to compare the evolution of metabolic parameters in a sample of adult patients starting valproate (n = 39) with a control group (n = 39) of patients starting aripiprazole, a drug associated with a low risk of metabolic deterioration. Data were obtained from a prospective study including psychiatric patients with metabolic parameters monitored during the first year of treatment. During the first month of treatment with valproate (median: 31 days [IQR: 25-36]), mean body mass index increased significantly (from 24.8 kg/m² at baseline to 25.2 kg/m² after one month; P = .03) and mean HDL-C levels decreased significantly (from 1.39 mmol/L to 1.27 mmol/L; P = .02). In comparison, these metabolic variables remained stable during the first month of treatment with aripiprazole. The proportion of patients with early (ie during the first month of treatment) HDL-C decrease of ≥ 5% was significantly higher under valproate (54%) than aripiprazole (15%) treatment (P < .001). These findings remind the importance of a prospective metabolic monitoring in patients who initiate valproate treatment. Further research should be conducted on larger samples and should focus on finding effective interventions to prevent such metabolic adverse effects.

The Psychopharmacology Algorithm Project at the Harvard South Shore Program (PAPHSS) published algorithms for bipolar depression in 1999 and 2010. Developments over the past 9 years suggest that another update is needed.

The 2010 algorithm and associated references were reevaluated. A literature search was conducted on PubMed for recent studies and review articles to see what changes in the recommendations were justified. Exceptions to the main algorithm for special patient populations, including those with attention-deficit hyperactivity disorder (ADHD), posttraumatic stress disorder (PTSD), substance use disorders, anxiety disorders, and women of childbearing potential, and those with common medical comorbidities were considered.

Electroconvulsive therapy (ECT) is still the first-line option for patients in need of urgent treatment. Five medications are recommended for early usage in acute bipolar depression, singly or in combinations when monotherapy fails, the order to be determined by considerations such as side effect vulnerability and patient preference. The five are lamotrigine, lurasidone, lithium, quetiapine, and cariprazine. After trials of these, possible options include antidepressants (bupropion and selective serotonin reuptake inhibitors are preferred) or valproate (very small evidence-base). In bipolar II depression, the support for antidepressants is a little stronger but depression with mixed features and rapid cycling would usually lead to further postponement of antidepressants. Olanzapine+fluoxetine, though Food and Drug Administration (FDA) approved for bipolar depression, is not considered until beyond this point, due to metabolic side effects. The algorithm concludes with a table of other possible treatments that have some evidence.

This revision incorporates the latest FDA-approved treatments (lurasidone and cariprazine) and important new studies and organizes the evidence systematically.

We investigated the comparative efficacy and tolerability of pharmacological treatment strategies for the treatment of acute bipolar depression.

A systematic review and network meta-analysis was conducted by searching eight registries for published and unpublished, double-blind, randomized controlled trials of pharmacotherapies for the acute treatment of bipolar depression.

PRISMA guidelines were used for abstracting data, while the Cochrane Risk of Bias Tool was used to assess data quality. Data extraction was done independently by two reviewers, with discrepancies resolved by consensus. Data were pooled using a random-effects model.

Primary outcomes were efficacy (response and remission rate) and acceptability (completion of treatment and dropouts due to adverse events). Summary odds ratios (ORs) were estimated using pairwise and network meta-analysis with random effects.

Identified citations (4,404) included 50 trials comprising 11,448 participants. Escitalopram, phenelzine, moclobemide, carbamazepine, sertraline, lithium, paroxetine, aripiprazole, gabapentin and ziprasidone appear to be ineffective as compared to placebo in treatment of bipolar depression. Divalproex, olanzapine/fluoxetine, olanzapine, quetiapine, cariprazine, and lamotrigine, appear to be effective as compared to placebo in treatment of bipolar depression according to the network meta-analysis. Aripiprazole showed higher discontinuation rates versus placebo due to the appearance of any adverse event. Quetiapine was better than placebo at reducing treatment-emergent affective switches. For Bipolar I Disorder, cariprazine, fluoxetine, imipramine, lamotrigine, lurasidone, olanzapine-fluoxetine, and olanzapine were significantly better than placebo at response, while fluoxetine, imipramine, cariprazine, lurasidone, olanzapine-fluoxetine, and olanzapine were significantly better than placebo at remission.

These results could serve evidence-based practice and inform patients, physicians, guideline developers, and policymakers on the relative benefits of the different antidepressants, antipsychotics, and mood-stabilizing agents for the treatment of bipolar depression.

PROSPERO (CRD42019122172).

Metabolic disturbances, including lipid metabolism, bone metabolism, and glycometabolism, are common in depression. Omega-3 polyunsaturated fatty acids (ω-3 PUFAs), which are reported to possess antidepressant effect, have also been shown to regulate metabolism. To further clarify the potential link between ω-3 PUFAs and stress-induced metabolic disturbances, metabolic-related parameters including body weight, visceral fat, fatty acid composition and serum parameters, such as serum lipids, free fatty acid (FFA), glucose (GLU), calcium and phosphorus in rats were measured. Moreover, hepatic insulin induced gene (INSIG)/sterol regulatory element binding protein (SREBP) pathway was also investigated. After 5 weeks of chronic unpredicted mild stress (CUMS) administration, rats were induced to a depressive-like state and exhibited decreased serum high-density lipoprotein (HDL-c), body weight and visceral fat, accompanied by altered C18:2n6c and ω-3/ω-6 PUFAs. Supplement of ω-3 PUFAs showed robust antidepressant effects and has beneficial effects on lipid profile. On the contrary, ω-3 PUFAs deficiency induced the visceral fat accumulation and decreased the serum calcium and phosphorus in stressed rats. Additionally, CUMS significantly increased hepatic expressions of SREBP-cleavage activating protein (SCAP)/SREBP-1 and decreased the expression of INSIG-1. This disturbance of SREBPs system is aggravated by ω-3 PUFAs deficiency and alleviated by ω-3 PUFAs supplementation. This study discloses the novel findings that ω-3 PUFAs deficiency will exacerbate the metabolic disturbances in stressed rats. Furthermore, supplementation of ω-3 PUFAs on individuals with a high risk of depression might be an effective way to prevent metabolic disorders accompanied by depression with the involvement of INSIG/SREBP pathway.

Bipolar disorder (BD) is characterized by recurrent depressive and manic episodes. Lithium, valproate, lamotrigine, and some second-generation antipsychotics (SGAs) are the most typical pharmacological treatments for BD, the main goal being mood stabilization. However, despite these treatments, most patients continue to experience recurrent mood episodes and residual symptoms. Findings from several studies suggest that some SGAs may be beneficial beyond approved indications. The goal of the survey presented in this article was to examine Italian psychiatrists' attitudes concerning the off-label use of SGAs in depressive and maintenance phases of BD. A questionnaire about the off-label prescription of SGAs was e-mailed to 300 psychiatrists from Northern, Central, and Southern Italy affiliated with the Italian Society of Psychopharmacology (SINPF) to investigate the frequency of and motivation for off-label use of SGAs and evaluate the psychiatrists' attitude toward use of specific SGAs in BD; 202 questionnaires were completed. The respondents were equally distributed in terms of sex, and the mean age of respondents was 44.1 years. The majority of the sample reported use of SGAs for off-label indications either very often (16.7%), often (33.7%), or occasionally (34.7%). The main motivation for off-label use of the SGAs was the presence of published evidence (51.5%), followed by patients' nonresponse to previous treatment (37.1%). With regard to the use of specific SGAs in BD, off-label aripiprazole was considered appropriate for depressive episodes by 46% of the psychiatrists, followed by olanzapine which was considered appropriate by 33.7%. For maintenance treatment of BD, off-label asenapine was considered appropriate by 45% of the psychiatrists, followed by long-acting aripiprazole and olanzapine pamoate, which were considered appropriate by 37.1% and 23.8%, respectively. In summary, ~50% of Italian psychiatrists frequently (very often or often) prescribe SGAs for off-label indications. Given the relatively limited number of indicated effective treatments for BD, the use of some SGAs off-label may be considered appropriate when dealing with patients whose BD is resistant to medications with labeled indications for BD.

We previously hypothesized that depressive and manic states may be consecutive presentations of the same underlying neuronal plasticity, and that moderate impairments in neuronal plasticity cause depressive states while further impairment to neuronal plasticity causes manic states. Psychopathological or biological relationships between bipolar disorder and schizophrenia have also been revealed. Therefore, in addition to depressive and manic states, psychosis may also be considered a manifestation resulting from additional impairments to neuronal plasticity. In the present manuscript, we hypothesize that moderate and more severe impairments to neuronal plasticity cause depressive and manic states, respectively, and that more serious impairments to neuronal plasticity cause psychosis. Many studies have suggested that impairments in neuronal plasticity contribute to schizophrenia and other mental disorders with psychotic features, and that the impairment of neuronal plasticity in schizophrenia is more severe than that in bipolar disorder. Therefore, we hypothesize more specifically that impairments in neuronal plasticity may be more severe in the order of the cases featuring psychosis, mania, and depression. This progression notably overlaps with the arrangement of schizophrenia, bipolar disorder, and depressive disorder in the DSM-5. Psychotic symptoms are thought to appear further towards the base of the psychopathological hierarchy than are manic or depressive symptoms. If impairments to neuronal plasticity contribute to this psychopathological hierarchy, as we contest that they do, our hypothesis may serve as a bridge between clinical psychopathology, diagnosis, and biological psychiatry.

To assess the efficacy and tolerability of lurasidone versus other atypical antipsychotic monotherapy agents in patients with bipolar depression, using a Bayesian network meta-analysis.

Fourteen randomised clinical trials (6221 patients) of lurasidone, quetiapine (extended release and immediate release), aripiprazole, olanzapine, and ziprasidone for bipolar depression were included. Efficacy assessments included change in the Montgomery-Åsberg Depression Rating Scale (MADRS), rates of response (≥50% improvement in MADRS) and remission (MADRS ≤12 at study endpoint), and change in the Clinical Global Impressions-Bipolar Disorder-Severity (CGI-BP-S) scale. Tolerability outcomes included weight, somnolence, extrapyramidal symptoms (EPS), and all-cause discontinuation. Changes from baseline or odds ratios (OR) with 95% credible intervals (CrI) were evaluated.

Improvement in the MADRS associated with lurasidone treatment was significantly greater than placebo (-4.70, 95%CrI: -7.20, -2.21), aripiprazole (-3.62, 95%CrI: -7.04, -0.20), and ziprasidone (-3.38, 95%CrI: -6.68, -0.11), but not olanzapine (-0.15, 95%CrI: -3.12, 2.74) or quetiapine (0.10, 95%CrI: -2.68, 2.84). Results for improvement in the CGI-BP-S, and for response and remission were similar. Lurasidone was associated with less weight gain than olanzapine (-2.54 kg, 95%CrI: -3.42, -1.67) and quetiapine (-0.83kg, 95%CrI: -1.59, -0.08); and with lower rates of somnolence than quetiapine (OR: 0.33, 95%CrI: 0.11, 0.82) and ziprasidone (OR: 0.34, 95%CrI: 0.09, 0.93). No significant differences among atypical antipsychotic agents were observed in rates of discontinuation or in rates of EPS.

In this network meta-analysis, lurasidone was found to be more efficacious than aripiprazole and ziprasidone, and was associated with less weight gain than quetiapine and olanzapine and less somnolence than quetiapine and ziprasidone.

Bipolar I disorder (BD I) is complex with a chronic course that significantly impacts a sufferer's quality of life. As of right now, there are many available treatments that aim to rapidly treat manic or depressive episodes and stabilize mood. The purpose of this report is to provide an up-to-date comprehensive review of the available evidence-based trials of pharmacotherapy for the treatment of BD I.

This paper reviews randomized active comparator-controlled or placebo-controlled trials evaluating the use of current pharmacotherapy in adults with BD I from phase III to clinical practice. Monotherapy and combination therapy for acute and long-term treatment were reviewed for this purpose.

There are many treatments available for BD mania; however, the depressive and stabilization phases of the illness remain a clinical challenge. Unfortunately, randomized controlled trials do not represent 'real world' patients, as their strict inclusion and exclusion criteria do not allow for different features sometimes present in patients to be considered. Research efforts must also focus on treating cognitive deficits, which adds to lower functional outcome. The authors believe that there is dire need for new, more targeted treatments in BD I, with a critical view of the side effects.

Bipolar affective disorder is a debilitating illness that manifests as cyclical episodes of mood elevation and depression, but the treatment of the depressive episodes (i.e., bipolar depression) differs considerably from the treatment of major depressive disorder. In bipolar affective disorder, it is well known that patients spend a significantly greater amount of time in depressive episodes than manic or hypomanic episodes, yet there are currently just three Food and Drug Administration-approved agents for the treatment of bipolar depression: (1) olanzapine/fluoxetine combination (2) quetiapine, both immediate- and extended-release, and (3) lurasidone. The literature review presented here focuses on the clinical trials that led to the Food and Drug Administration-approval of these second generation antipsychotics in the treatment of bipolar depression. The discussion highlights key considerations regarding overall treatment strategies to aid clinicians in the selection of pharmacologic agents. Recommended monitoring parameters, potential adverse effects, and pertinent counseling points for second generation antipsychotics used in bipolar depression are included.

The current paper includes a systematic search of the literature, a detailed presentation of the results, and a grading of treatment options in terms of efficacy and tolerability/safety.

The PRISMA method was used in the literature search with the combination of the words 'bipolar,' 'manic,' 'mania,' 'manic depression,' and 'manic depressive' with 'randomized,' and 'algorithms' with 'mania,' 'manic,' 'bipolar,' 'manic-depressive,' or 'manic depression.' Relevant web pages and review articles were also reviewed.

The current report is based on the analysis of 57 guideline papers and 531 published papers related to RCTs, reviews, posthoc, or meta-analysis papers to March 25, 2016. The specific treatment options for acute mania, mixed episodes, acute bipolar depression, maintenance phase, psychotic and mixed features, anxiety, and rapid cycling were evaluated with regards to efficacy. Existing treatment guidelines were also reviewed. Finally, Tables reflecting efficacy and recommendation levels were created that led to the development of a precise algorithm that still has to prove its feasibility in everyday clinical practice.

A systematic literature search was conducted on the pharmacological treatment of bipolar disorder to identify all relevant random controlled trials pertaining to all aspects of bipolar disorder and graded the data according to a predetermined method to develop a precise treatment algorithm for management of various phases of bipolar disorder. It is important to note that the some of the recommendations in the treatment algorithm were based on the secondary outcome data from posthoc analyses.

Concerns about the generalizability of pharmacotherapy efficacy trials to "real-world" patients have been raised for more than 40 years. Almost all of this literature has focused on treatment studies of major depressive disorder (MDD).

The aim of the study was to review the psychiatric inclusion and exclusion criteria used in placebo-controlled trials that assessed the efficacy of medications for bipolar depression (bipolar disorder efficacy trials [BDETs]) and compare the criteria used in BDETs with those used in efficacy trials of antidepressants to treat MDD (antidepressant efficacy trials [AETs]).

We searched the MEDLINE, Embase, and PsycINFO databases for articles published from January 1995 through December 2014. We identified 170 placebo-controlled AETs and 22 BDETs published during these 20 years. Two of the authors independently reviewed each article and completed a pre-specified information extraction form listing the psychiatric inclusion and exclusion criteria used in the study.

Six inclusion/exclusion criteria were used in at least half of the BDETs: minimum severity on a depression symptom severity scale, significant suicidal ideation, diagnosis of alcohol or drug use disorder, presence of a comorbid nondepressive, nonsubstance use Axis I disorder, current episode of depression being too long, and absence of current manic symptoms. BDETs were significantly less likely than AETs to exclude patients with a history of psychotic features/disorders, borderline personality disorder, and post-traumatic stress disorder and more likely to exclude individuals who scored too low on the first item of the Hamilton Depression Rating Scale. Nearly two-thirds of the BDETs placed an upper limit on the duration of the current depressive episode, three times higher than the rate in the AETs. There was no difference on other variables between the AETs and BDETs.

Similar to treatment studies of nonbipolar MDD, the treatment studies of bipolar depression frequently excluded patients with comorbid psychiatric and substance use disorders and insufficient severity of depressive symptoms as rated on standardized scales. These findings indicate that concerns about the generalizability of data from trials of recently approved medications for the treatment of bipolar depression are as relevant as the concerns that have been raised about studies of antidepressants for nonbipolar depression.

The aim of this work is to investigate the impact of placebo response rates on the relative risk of response to drug versus placebo in randomized, double-blind, placebo-controlled clinical trials of pharmacological therapy in Bipolar Depression (BPD). Medline/PubMed publication databases were searched for randomized, double-blind, placebo-controlled trials of oral drugs used as monotherapy for the treatment of BPD. The search was limited to articles published between January 1980 and September 2015. Data extracted from 12 manuscripts and one poster with yet unpublished results, representing a total of 17 clinical trials were pooled (n = 6578). Pooled response rates for drug and placebo were 55.1% and 39.2%, corresponding to a risk ratio (RR) for responding to active treatment versus placebo of 1.29 (p < 0.001). Clinical response was defined as a 50% or greater reduction in depression scores, baseline to endpoint. A higher placebo response rate correlated with a significantly lower RR of responding to pharmacotherapy versus placebo (p = 0.002). The pooled drug and placebo response rates for studies with a placebo response rate ≤ 30% were 50.5% versus 26.6%, while corresponding values from studies with a placebo response rate >30 were 55.0% versus 41.6%. These results suggest that the relative efficacy of the active drug compared to placebo in clinical trials for BPD is highly heterogeneous across studies with different placebo response rates, with a worse performance in showing a superiority of the drug versus placebo for studies with placebo response rates >30%. It is important to maintain placebo response rates below this critical threshold, since this is one of the most challenging obstacles for new treatment development in BPD.

As part of a process to improve the quality of care, the French Society for Biological Psychiatry and Neuropsychopharmacology developed in 2010 formal consensus guidelines for the treatment of bipolar disorder. The evolution of therapeutic options available in France for the treatment of bipolar disorder has justified the update of this guideline. The purpose of this work was to provide an updated and ergonomic document to promote its use by clinicians. This update focuses on two of the six thematic previously published (acute treatment and long-term treatment). Aspects of the treatment of bipolar patients sparking debate and questions of clinicians (use of antidepressant, place of the bitherapy, interest of long-acting antipsychotics…) were also covered. Finally, we proposed graded recommendations taking into account specifically the risk-benefit balance of each molecule.

Treatment of bipolar depression is complicated by variable response and risk of switch to mania. Guidance is informed by the strength of evidence rather than by comparative data.

We performed a multiple-treatments meta-analysis of randomised, double-blind, controlled comparisons of 4-16 weeks in adults in bipolar depression. The primary efficacy outcome was effect size. The primary acceptability outcome was 'switch to mania'. Secondary outcomes were likelihood of response and withdrawals from trials.

Twenty-nine studies were included (8331 participants). Olanzapine + fluoxetine and olanzapine performed best on primary outcome measure being ranked highest for effect size. Switch to mania was least likely with ziprasidone and then quetiapine. Olanzapine + fluoxetine was also ranked the highest for response with lurasidone second, but olanzapine + fluoxetine and olanzapine had the optimal effect on response and withdrawal from treatment when the two parameters were considered together. Several treatments [monoamine oxidase inhibitors (MAOIs), ziprasidone, aripiprazole and risperidone] have limited or no therapeutic activity in bipolar depression.

Olanzapine + fluoxetine should be first-line treatment. Olanzapine, quetiapine, lurasidone, valproate and selective serotonin re-uptake inhibitors are also recommended. Tricyclic antidepressants and lithium are worthy of consideration but lamotrigine (high risk of switching, less robust efficacy) and MAOIs, ziprasidone, aripiprazole and risperidone (no evidence of efficacy) should not be used.