Relationship between subjective cognitive functioning and fluid and crystallized cognitive abilities in bipolar disorder.

OBJECTIVE: People with bipolar disorder (BD) often show inaccurate subjective ratings of their objective cognitive function. However, it is unclear what information individuals use to formulate their subjective ratings. This study evaluated whether people with BD are likely using information about their crystallized cognitive abilities (which involve an accumulated store of verbal knowledge and skills and are typically preserved in BD) or their fluid cognitive abilities (which involve the capacity for new learning and information processing in novel situations and are typically impaired in BD) to formulate their subjective cognitive ratings. METHOD: Eighty participants diagnosed with BD and 55 control volunteers were administered cognitive tests assessing crystallized and fluid cognitive abilities. Subjective cognitive functioning was assessed with the Cognitive Failures Questionnaire (CFQ), daily functioning was rated using the Multidimensional Scale of Independent Functioning (MSIF) and the Global Assessment of Functioning Scale (GAF), and quality of life was assessed with the Quality of Life in Bipolar Disorder scale (QoL.BD). RESULTS: The BD group exhibited considerably elevated subjective cognitive complaints relative to controls. Among participants with BD, CFQ scores were associated with fluid cognitive abilities including measures of memory and executive function, but not to crystallized abilities. After controlling for objective cognition and depression, higher cognitive complaints predicted poorer psychosocial outcomes. CONCLUSIONS: Cognitive self-reports in BD may represent a metacognitive difficulty whereby cognitive self-appraisals are distorted by a person's focus on their cognitive weaknesses rather than strengths. Moreover, negative cognitive self-assessments are associated with poorer daily functioning and diminished quality of life.

A Randomized Evaluation of MoodFX, a Patient-Centred e-Health Tool to Support Outcome Measurement for Depression: Une évaluation randomisée de MoodFX, un outil de santé en ligne centré sur le patient pour soutenir la mesure du résultat dans la dépression.

BACKGROUND: e-Health tools using validated questionnaires to assess outcomes may facilitate measurement-based care for psychiatric disorders. MoodFX was created as a free online symptom tracker to support patients for outcome measurement in their depression treatment. We conducted a pilot randomized evaluation to examine its usability, and clinical utility. METHODS: Patients presenting with a major depressive episode (within a major depressive or bipolar disorder) were randomly assigned to receive either MoodFX or a health information website as the intervention and control condition, respectively, with follow-up assessment surveys conducted online at baseline, 8 weeks and 6 months. The primary usability outcomes included the percentage of patients with self-reported use of MoodFX 3 or more times during follow up (indicating minimally adequate usage) and usability measures based on the System Usability Scale (SUS). Secondary clinical outcomes included the Quick Inventory of Depressive Symptomatology, Self-Rated (QIDS-SR) and Patient Health Questionnaire (PHQ-9). RESULTS: Forty-nine participants were randomized (24 to MoodFX and 25 to the control condition). Of the 23 participants randomized to MoodFX who completed the user survey, 18 (78%) used MoodFX 3 or more times over the 6 months of the study. The mean SUS score of 72.7 (65th-69th percentile) represents good usability. Compared to the control group, the MoodFX group had significantly better improvement on QIDS-SR and PHQ-9 scores, with large effect sizes and higher response rates at 6 months. There were no differences between conditions on other secondary outcomes such as functioning and quality of life. CONCLUSION: MoodFX demonstrated good usability and was associated with reduction in depressive symptoms. This pilot study supports the use of digital tools in depression treatment.

E-health tools may be useful for measuring and tracking symptoms and other outcomes during treatment for depression. This study is a randomized evaluation of MoodFX, a free web-based app that helps patients track their symptoms using validated questionnaires, and also offers depression information and self-management tips. A total of 49 participants with clinical depression were randomized to using MoodFX or a health information website, for 6 months. In a survey, the participants that used MoodFX found it easy and useful to use. In addition, the participants that used MoodFX had greater improvement in depressive symptoms after 6 months, compared to those who used the health information website. These results suggest that MoodFX may be a useful tool to monitor outcomes and support depression treatment.

Canadian Network for Mood and Anxiety Treatments (CANMAT) 2023 Update on Clinical Guidelines for Management of Major Depressive Disorder in Adults: Réseau canadien pour les traitements de l'humeur et de l'anxiété (CANMAT) 2023 : Mise à jour des lignes directrices cliniques pour la prise en charge du trouble dépressif majeur chez les adultes.

BACKGROUND: The Canadian Network for Mood and Anxiety Treatments (CANMAT) last published clinical guidelines for the management of major depressive disorder (MDD) in 2016. Owing to advances in the field, an update was needed to incorporate new evidence and provide new and revised recommendations for the assessment and management of MDD in adults. METHODS: CANMAT convened a guidelines editorial group comprised of academic clinicians and patient partners. A systematic literature review was conducted, focusing on systematic reviews and meta-analyses published since the 2016 guidelines. Recommendations were organized by lines of treatment, which were informed by CANMAT-defined levels of evidence and supplemented by clinical support (consisting of expert consensus on safety, tolerability, and feasibility). Drafts were revised based on review by patient partners, expert peer review, and a defined expert consensus process. RESULTS: The updated guidelines comprise eight primary topics, in a question-and-answer format, that map a patient care journey from assessment to selection of evidence-based treatments, prevention of recurrence, and strategies for inadequate response. The guidelines adopt a personalized care approach that emphasizes shared decision-making that reflects the values, preferences, and treatment history of the patient with MDD. Tables provide new and updated recommendations for psychological, pharmacological, lifestyle, complementary and alternative medicine, digital health, and neuromodulation treatments. Caveats and limitations of the evidence are highlighted. CONCLUSIONS: The CANMAT 2023 updated guidelines provide evidence-informed recommendations for the management of MDD, in a clinician-friendly format. These updated guidelines emphasize a collaborative, personalized, and systematic management approach that will help optimize outcomes for adults with MDD.

Brain age and cognitive functioning in first-episode bipolar disorder.

BACKGROUND: There is significant heterogeneity in cognitive function in patients with bipolar I disorder (BDI); however, there is a dearth of research into biological mechanisms that might underlie cognitive heterogeneity, especially at disease onset. To this end, this study investigated the association between accelerated or delayed age-related brain structural changes and cognition in early-stage BDI. METHODS: First episode patients with BDI (n = 80) underwent cognitive assessment to yield demographically normed composite global and domain-specific scores in verbal memory, non-verbal memory, working memory, processing speed, attention, and executive functioning. Structural magnetic resonance imaging data were also collected from all participants and subjected to machine learning to compute the brain-predicted age difference (brainPAD), calculated by subtracting chronological age from age predicted by neuroimaging data (positive brainPAD values indicating age-related acceleration in brain structural changes and negative values indicating delay). Patients were divided into tertiles based on brainPAD values, and cognitive performance compared amongst tertiles with ANCOVA. RESULTS: Patients in the lowest (delayed) tertile of brainPAD values (brainPAD range -17.9 to -6.5 years) had significantly lower global cognitive scores (p = 0.025) compared to patients in the age-congruent tertile (brainPAD range -5.3 to 2.4 yrs), and significantly lower verbal memory scores (p = 0.001) compared to the age-congruent and accelerated (brainPAD range 2.8 to 16.1 yrs) tertiles. CONCLUSION: These results provide evidence linking cognitive dysfunction in the early stage of BDI to apparent delay in typical age-related brain changes. Further studies are required to assess how age-related brain changes and cognitive functioning evolve over time.

The Differential Relation of Emotional, Physical, and Sexual Abuse Histories to Antidepressant Treatment Remission and Persistence of Anhedonia in Major Depression: A CAN-BIND-1 Report.

OBJECTIVE: Childhood maltreatment is a potent enviromarker of risk for poor response to antidepressant medication (ADM). However, childhood maltreatment is a heterogeneous construct that includes distinct exposures that have distinct neurobiological and psychological correlates. The purpose of the current study is to examine the differential associations of emotional, physical, and sexual maltreatment to ADM outcome and to examine the unique role of anhedonia in driving poor response in patients with specific maltreatment histories. METHODS: In a multicentre clinical trial of major depression, 164 individuals were assessed for childhood emotional, physical, and sexual maltreatment with a contextual interview with independent, standardized ratings. All individuals received 8 weeks of escitalopram, with nonresponders subsequently also receiving augmentation with aripiprazole, with outcomes measured with depression rating scales and an anhedonia scale. RESULTS: Greater severity of emotional maltreatment perpetrated by the mother was a significant and direct predictor of lower odds of week 16 remission (odds ratio [OR] = 1.68, P = 0.02). In contrast, the relations of paternal-perpetrated emotional maltreatment and physical maltreatment to week 16 remission were indirect, mediated through greater severity of anhedonia at week 8. CONCLUSIONS: We identify emotional maltreatment as a specific early exposure that places patients at the greatest risk for nonremission following pharmacological treatment. Further, we suggest that anhedonia is a key symptom domain driving nonremission in patients with particular maltreatment histories.

Blue-Light Therapy for Seasonal and Non-Seasonal Depression: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

OBJECTIVES: To determine the efficacy and safety of blue-light therapy in seasonal and non-seasonal major depressive disorder (MDD), by comparison to active and inactive control conditions. METHODS: We searched Web of Science, EMBASE, Medline, PsycInfo, and Clinicaltrials.gov through January 17, 2022, for randomized controlled trials (RCTs) using search terms for blue/blue-enhanced, light therapy, and depression/seasonal affective disorder. Two independent reviewers extracted data. The primary outcome was the difference in endpoint scores on the Structured Interview Guide for the Hamilton Depression Rating Scale - Seasonal Affective Disorder (SIGH-SAD) or the Structured Interview Guide for the Hamilton Depression Rating Scale with Atypical Depression Supplement (SIGH-ADS) between blue light and comparison conditions. Secondary outcomes were response (≥ 50% improvement from baseline to endpoint on a depression scale) and remission rates (endpoint score in the remission range). RESULTS: Of 582 articles retrieved, we included nine RCTs (n = 347 participants) assessing blue-light therapy. Seven studies had participants with seasonal MDD and two studies included participants with non-seasonal MDD. Four studies compared blue light to an inactive light condition (efficacy studies), and five studies compared it to an active condition (comparison studies). For the primary outcome, a meta-analysis with random-effects models found no evidence for the efficacy of blue-light conditions compared to inactive conditions (mean difference [MD] = 2.43; 95% confidence interval [CI], -1.28 to 6.14, P = 0.20); however, blue-light also showed no differences compared to active conditions (MD = -0.11; 95% CI, -2.38 to 2.16, P = 0.93). There were no significant differences in response and remission rates between blue-light conditions and inactive or active light conditions. Blue-light therapy was overall well-tolerated. CONCLUSIONS: The efficacy of blue-light therapy in the treatment of seasonal and non-seasonal MDD remains unproven. Future trials should be of longer duration, include larger sample sizes, and attempt to better standardize the parameters of light therapy.

Grey matter abnormalities in first-episode mania: A systematic review and meta-analysis of voxel-based morphometry studies.

OBJECTIVES: It has been proposed that different stages of bipolar disorder may be underpinned by distinct neurobiological substrates. However, structural neuroimaging studies in early stages of the illness are limited by small sample sizes yielding inconsistent findings. The purpose of this systematic review and meta-analysis, therefore, was to identify regional grey matter volume (GMV) changes that are consistently associated with first episode of mania (FEM). METHODS: Following PRISMA guidelines, we conducted a systematic search of the literature to identify Voxel-Based Morphometry (VBM) studies in FEM patients compared with healthy individuals. We then conducted a voxel-wise meta-analysis using Seed-based d-Mapping technique. Finally, we performed univariate meta-regression analyses to explore the potential effects of moderator variables including age, gender, and percentage of lithium users on GMV alterations. RESULTS: We identified 15 VBM studies and included 12 studies in the meta-analysis. Four studies found no regional differences in GM volumes while other 11 studies reported volume changes in frontal and temporal regions as well as anterior cingulate cortex (ACC), cerebellum and basal ganglia. The meta-analysis revealed a single cluster of GMV reduction in bilateral pregenual ACC in patients with FEM compared to healthy individuals (P < .001). The Egger's test showed no evidence of publication bias at peak voxel level (P = .447). Meta-regression analyses revealed no significant effects of moderators evaluated. CONCLUSIONS: Structural brain changes are evident in the early stages of bipolar disorder. GMV reduction in bilateral pregenual ACC is the most consistent finding in VBM studies of FEM.

Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) recommendations for the management of patients with bipolar disorder with mixed presentations.

OBJECTIVES: The 2018 Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) guidelines provided clinicians with pragmatic treatment recommendations for bipolar disorder (BD). While these guidelines included commentary on how mixed features may direct treatment selection, specific recommendations were not provided-a critical gap which the current update aims to address. METHOD: Overview of research regarding mixed presentations in BD, with treatment recommendations developed using a modified CANMAT/ISBD rating methodology. Limitations are discussed, including the dearth of high-quality data and reliance on expert opinion. RESULTS: No agents met threshold for first-line treatment of DSM-5 manic or depressive episodes with mixed features. For mania + mixed features second-line treatment options include asenapine, cariprazine, divalproex, and aripiprazole. In depression + mixed features, cariprazine and lurasidone are recommended as second-line options. For DSM-IV defined mixed episodes, with a longer history of research, asenapine and aripiprazole are first-line, and olanzapine (monotherapy or combination), carbamazepine, and divalproex are second-line. Research on maintenance treatments following a DSM-5 mixed presentation is extremely limited, with third-line recommendations based on expert opinion. For maintenance treatment following a DSM-IV mixed episode, quetiapine (monotherapy or combination) is first-line, and lithium and olanzapine identified as second-line options. CONCLUSION: The CANMAT and ISBD groups hope these guidelines provide valuable support for clinicians providing care to patients experiencing mixed presentations, as well as further influence investment in research to improve diagnosis and treatment of this common and complex clinical state.

Cognitive subgroups in first episode bipolar I disorder: Relation to clinical and brain volumetric variables.

OBJECTIVE: Distinct cognitive subgroups are seen in patients with long duration bipolar I disorder (BDI), possibly reflective of underlying pathophysiological differences. It is unknown whether such cognitive heterogeneity is present at illness onset. We applied latent class analysis (LCA) to cognitive test scores in first episode BDI patients. Exploratory analysis elucidated whether impaired subgroups were characterized by 'early neurodevelopmental' (low premorbid IQ and intracranial volume) versus 'later neurodevelopmental' (decline from premorbid to current IQ, changes in relative grey (GM)/white (WM) matter volumes) pathology. METHODS: Recently recovered first manic episode BDI patients (n = 91) and healthy controls (HC, n = 63) comprised the study sample. LCA identified subgroups based on processing speed, verbal memory, non-verbal memory, executive functioning, attention and working memory scores. Subgroups were compared amongst each other and HC on premorbid/current IQ, intracranial (ICV), total brain and regional volumes. RESULTS: Three cognitive subgroups emerged: (i) globally impaired (GI, n = 31), scoring 0.5-1 SD below demographically corrected norms across domains, (ii) selectively impaired (SI, n = 47), with predominant processing speed deficits and (iii) high performing (HP, n = 13), with above-average cognitive performance. GI patients showed a 'later neurodevelopmental' pattern, with normal ICV, significant decline from premorbid to current IQ, higher total GM and lower total WM (with respect to total brain volume) versus SI and HC (p = 0.003). GI patients had higher left frontal pole GM versus HC (p < 0.05, FWE corrected). CONCLUSIONS: A globally impaired patient subgroup is identifiable in first episode BDI, possibly characterized by unique neurodevelopmental pathologic processes proximal to illness onset.

New Developments in the Use of Atypical Antipsychotics in the Treatment of Bipolar Disorder: a Systematic Review of Recent Randomized Controlled Trials.

PURPOSE OF REVIEW: Atypical antipsychotics are increasingly used in the treatment of bipolar disorder (BD). This systematic review provides an overview of recently published randomized controlled trials (RCTs) on the efficacy and safety of atypical antipsychotics in BD. RECENT FINDINGS: Several studies supported efficacy of quetiapine monotherapy in acute bipolar I (BDI) and bipolar II (BDII) depression. Moreover, quetiapine adjunctive therapy showed superior efficacy to placebo in treatment-resistant bipolar depression. Cariprazine 1.5 mg was effective in treating bipolar I depression. Aripiprazole 400 mg IM once monthly was effective in preventing manic episodes with minimal metabolic effects. In youth with BD, lurasidone was effective and well-tolerated for acute depression while asenapine showed efficacy in treating acute manic and mixed episodes. Recently published RCTs generally support the efficacy of atypical antipsychotics in different phases of BD. Future studies should focus on understudied populations including pediatric BD and geriatric BD and BDII, as well as a focus on cognitive functioning and quality of life measures.

Impacts on Quality of Life with Escitalopram Monotherapy and Aripiprazole Augmentation in Patients with Major Depressive Disorder: A CAN-BIND Report.

INTRODUCTION: Many individuals with major depressive disorder (MDD) do not respond to initial antidepressant monotherapy. Adjunctive aripiprazole is recommended for treatment non-response; however, the impacts on quality of life (QoL) for individuals who receive this second-line treatment strategy have not been described. METHODS: We evaluated secondary QoL outcomes in patients with MDD (n=179). After 8 weeks of escitalopram, non-responders (<50% decrease in clinician-rated depression) were treated with adjunctive aripiprazole for 8 weeks (n=97); responders continued escitalopram (n=82). A repeated-measures ANOVA evaluated change in Quality of Life Enjoyment and Satisfaction Short Form scores. QoL was described relative to normative benchmarks. RESULTS: Escitalopram responders experienced the most QoL improvements in the first treatment phase. For non-responders, QoL improved with a large effect during adjunctive aripiprazole treatment. At the endpoint, 47% of patients achieving symptomatic remission still had impaired QoL. DISCUSSION: Individuals who were treated with adjunctive aripiprazole after non-response to escitalopram experienced improved QoL, but a substantial degree of QoL impairment persisted. Since QoL deficits may predict MDD recurrence, attention to ways to support this outcome is required.

Preservation of Gray Matter Volume in Early Stage of Bipolar Disorder: A Case for Early Intervention: Préservation du volume de matière grise au stade précoce du trouble bipolaire: un cas pour intervention précoce.

OBJECTIVE: It has been proposed that different stages of the bipolar disorder might have distinct neurobiological changes. However, the evidence for this has not been consistent, as the studies in early stages of the illness are limited by small sample sizes. The purpose of this study was to investigate the gray matter volume changes in bipolar patients who recently recovered from their first episode of mania (FEM). METHODS: Using a whole-brain voxel-based analysis, we compared the regional gray matter volumes of 61 bipolar patients who have recovered from their FEM in the past 3 months with 43 age- and gender-matched healthy participants. We also performed a series of subgroup analyses to determine the effects of hospitalization during the FEM, history of depressive episodes, and exposure to lithium. RESULTS: No statistically significant difference was found between gray matter volumes of FEM patients and healthy participants, even at a more liberal threshold (P < 0.001, uncorrected for multiple comparisons). Voxel-based subgroup analyses did not reveal significant gray matter differences except for a trend toward decreased gray matter volume in left lateral occipital cortex (P < 0.001, uncorrected) in patients with a previous history of depression. CONCLUSION: This study represents the largest structural neuroimaging investigation of FEM published to date. Early stage of bipolar disorder was not found to be associated with significant gray matter volume changes. Our findings suggest that there might be a window of opportunity for early intervention strategies to prevent or delay neuroprogression in bipolar disorder.

Cognition and Its Association with Psychosocial and Occupational Functioning during Treatment with Escitalopram in Patients with Major Depressive Disorder: A CAN-BIND-1 Report: La Cognition Et Son Association Avec Le Fonctionnement Psychosocial Et Professionnel Durant Le Traitement Par Escitalopram Chez Des Patients Souffrant De Trouble Dépressif Majeur: Une Étude Can-Bind-1.

OBJECTIVES: Major depressive disorder (MDD) is associated with impairments in both cognition and functioning. However, whether cognitive deficits significantly contribute to impaired psychosocial and occupational functioning, independent of other depressive symptoms, is not well established. We examined the relationship between cognitive performance and functioning in depressed patients before and after antidepressant treatment using secondary data from the first Canadian Biomarker Integration Network in Depression-1 study. METHODS: Cognition was assessed at baseline in unmedicated, depressed participants with MDD (n = 207) using the Central Nervous System Vital Signs computerized battery, psychosocial functioning with the Sheehan Disability Scale (SDS), and occupational functioning with the Lam Employment Absence and Productivity Scale (LEAPS). Cognition (n = 181), SDS (n = 175), and LEAPS (n = 118) were reassessed after participants received 8 weeks of open-label escitalopram monotherapy. A series of linear regressions were conducted to determine (1) whether cognitive functioning was associated with psychosocial and occupational functioning prior to treatment, after adjusting for overall depressive symptom severity and (2) whether changes in cognitive functioning after an 8-week treatment phase were associated with changes in psychosocial and occupational functioning, after adjusting for changes in overall symptom severity. RESULTS: Baseline global cognitive functioning, after adjusting for depression symptom severity and demographic variables, was associated with the SDS work/study subscale (ß = -0.17; P = 0.03) and LEAPS productivity subscale (ß = -0.17; P = 0.05), but not SDS total (ß = 0.19; P = 0.12) or LEAPS total (ß = 0.41; P = 0.17) scores. Although LEAPS and SDS scores showed significant improvements after 8 weeks of treatment (P < 0.001), there were no significant associations between changes in cognitive domain scores and functional improvements. CONCLUSION: Cognition was associated with occupational functioning at baseline, but changes in cognition were not associated with psychosocial or occupational functional improvements following escitalopram treatment. We recommend the use of more comprehensive functional assessments to determine the impact of cognitive change on functional outcomes in future research.

Childhood maltreatment and cognitive functioning in patients with major depressive disorder: a CAN-BIND-1 report.

BACKGROUND: Patients with major depressive disorder (MDD) display cognitive deficits in acutely depressed and remitted states. Childhood maltreatment is associated with cognitive dysfunction in adults, but its impact on cognition and treatment related cognitive outcomes in adult MDD has received little consideration. We investigate whether, compared to patients without maltreatment and healthy participants, adult MDD patients with childhood maltreatment display greater cognitive deficits in acute depression, lower treatment-associated cognitive improvements, and lower cognitive performance in remission. METHODS: Healthy and acutely depressed MDD participants were enrolled in a multi-center MDD predictive marker discovery trial. MDD participants received 16 weeks of standardized antidepressant treatment. Maltreatment and cognition were assessed with the Childhood Experience of Care and Abuse interview and the CNS Vital Signs battery, respectively. Cognitive scores and change from baseline to week 16 were compared amongst MDD participants with (DM+, n = 93) and without maltreatment (DM-, n = 90), and healthy participants with (HM+, n = 22) and without maltreatment (HM-, n = 80). Separate analyses in MDD participants who remitted were conducted. RESULTS: DM+ had lower baseline global cognition, processing speed, and memory v. HM-, with no significant baseline differences amongst DM-, HM+, and HM- groups. There were no significant between-group differences in cognitive change over 16 weeks. Post-treatment remitted DM+, but not remitted DM-, scored significantly lower than HM- in working memory and processing speed. CONCLUSIONS: Childhood maltreatment was associated with cognitive deficits in depressed and remitted adults with MDD. Maltreatment may be a risk factor for more severe and persistent cognitive deficits in adult MDD.

Cariprazine in the treatment of Bipolar Disorder: A systematic review and meta-analysis.

OBJECTIVES: Cariprazine is a partial agonist at D2/D3 receptors that has been approved for the treatment of mania associated with bipolar disorder (BD). This meta-analysis aimed to assess the efficacy and tolerability of cariprazine in the treatment of BD. METHODS: Randomized controlled trials investigating the efficacy of cariprazine in BD were included. Of the 391 studies yielded by search, 7 were included. The PRISMA protocol was followed and a set of analyses involving random-effects model with restricted maximum-likelihood estimator were used to synthesize effect sizes. RESULTS: Cariprazine was associated with a moderate and significant reduction of manic symptoms based on YMRS change scores (SMD: -0.52; 95%CI: -0.82 to -0.21; P = .018). Cariprazine resulted in significantly higher remission (OR: 2.05; 95%CI: 1.61-2.61; P = .006) and response rates (OR: 2.31; 95%CI: 1.35-3.95; P = .021) for manic and mixed episodes compared with placebo. Both cariprazine 1.5 mg and 3 mg doses were associated with small but significant reduction in depressive symptoms assessed with MADRS scores (SMD: -0.26, 95%CI: -0.49 to -0.02; P = .040) (SMD: -0.21, 95%CI: -0.41 to -0.01; P = .045), respectively. Cariprazine was significantly associated with the development of adverse effects but not with dropouts due to these adverse effects, when compared to placebo. CONCLUSION: Cariprazine appears to be safe and efficacious in the treatment of acute mania and mixed episodes associated with BD. Cariprazine at doses of 1.5-3 mg/day is efficacious in acute bipolar depression but the effect sizes were smaller. Controlled studies evaluating its efficacy for prophylaxis are needed.

Treatment of Mixed Features in Bipolar Disorder: an Updated View.

PURPOSE OF REVIEW: Mixed presentations in bipolar disorder have long posed clinical and nosological challenges. The DSM-5 mixed features specifier was developed to provide a more flexible and clinically relevant definition of mixed presentations compared with narrowly defined DSM-IV mixed episodes. However, there is little guidance on treating such presentations. Here, we summarize the evidence for biological treatments of DSM-5 and similarly defined mixed features (MFs). RECENT FINDINGS: The literature on treating MFs is almost exclusively based on post hoc analyses. Within this limited evidence base is preliminary positive data for aripiprazole, asenapine, cariprazine, olanzapine, risperidone, and ziprasidone in treating acute mania with MFs, and cariprazine, lurasidone, olanzapine, and ziprasidone for depressive symptoms in depression with MFs. Divalproex may also be efficacious for acute mania with MFs. The few extant maintenance studies suggest that divalproex and olanzapine may have long-term efficacy in those with index MFs or for the prevention of MFs, respectively. The existing evidence suggests that clinicians consider atypical antipsychotics and divalproex for treating acute mixed presentations. However, adequately powered treatment trials-and studies of maintenance and neurostimulation therapies-are needed. Additionally, data-driven techniques to identify relevant symptom clusters may help improve our conceptualization of mixed presentations.

Light Therapy for Patients With Bipolar Depression: Systematic Review and Meta-Analysis of Randomized Controlled Trials.

OBJECTIVE: Bipolar disorder (BD) is challenging to treat, and fewer treatments are available for depressive episodes compared to mania. Light therapy is an evidence-based nonpharmacological treatment for seasonal and nonseasonal major depression, but fewer studies have examined its efficacy for patients with BD. Hence, we reviewed the evidence for adjunctive light therapy as a treatment for bipolar depression. METHODS: We conducted a systematic review of databases from inception to June 30, 2019, for randomized, double-blind, placebo-controlled trials of light therapy in patients with BD (CRD42019128996). The primary outcome was change in clinician-rated depressive symptom score; secondary outcomes included clinical response, remission, acceptability, and treatment-emergent mood switches. We quantitatively pooled outcomes using meta-analysis with random-effects models. RESULTS: We identified seven trials representing 259 patients with BD. Light therapy was associated with a significant improvement in Hamilton Depression Rating Scale score (standardized mean difference = 0.43, 95% confidence interval [CI], 0.04 to 0.82, P = 0.03). There was also a significant difference in favor of light therapy for clinical response (odds ratio [OR] = 2.32; 95% CI, 1.12 to 4.81; P = 0.024) but not for remission. There was no difference in affective switches between active light and control conditions (OR = 1.30; 95% CI, 0.38 to 4.44; P = 0.67). Study limitations included different light treatment parameters, small sample sizes, short treatment durations, and variable quality across trials. CONCLUSION: There is positive but nonconclusive evidence that adjunctive light therapy reduces symptoms of bipolar depression and increases clinical response. Light therapy is well tolerated with no increased risk of affective switch.

Lithium vs valproate in the maintenance treatment of bipolar I disorder: A post- hoc analysis of a randomized double-blind placebo-controlled trial.

OBJECTIVE: Lithium and valproate are commonly used either in monotherapy or in combination with atypical antipsychotics in maintenance treatment of bipolar I disorder; however, their comparative efficacy is not well understood. This study aimed to compare the efficacy of valproate and lithium on mood stability either in monotherapy or in combination with atypical antipsychotics. METHODS: We performed a post hoc analysis using data from a 52-week randomized double-blind, placebo-controlled trial, that recruited 159 patients with recently remitted mania during treatment with lithium or valproate and adjunctive atypical antipsychotic therapy. Patients were randomized to discontinue adjunctive atypical antipsychotic at 0, 24 or 52 weeks. RESULTS: No significant differences in efficacy were observed between valproate and lithium (hazard ratio: 0.99; 95% confidence interval: [0.66, 1.48]) in time to any mood event. Valproate with 24 weeks of atypical antipsychotic was significantly superior to valproate monotherapy in preventing any mood relapse (hazard ratio: 0.46; 95% confidence interval: [0.22, 0.97]) while lithium with 24 weeks of atypical antipsychotic was superior to lithium monotherapy in preventing mania (hazard ratio: 0.27; 95% confidence interval: [0.09, 0.85]) but not depression. CONCLUSION: Overall, this study did not find significant differences in efficacy between the two mood-stabilizing agents when used as monotherapy or in combination with atypical antipsychotics. However, study design and small sample size might have precluded from detecting an effect if true difference in efficacy existed. Further head-to-head investigations with stratified designs are needed to evaluate maintenance therapies.

The prevalence of depressive symptoms in frontotemporal dementia: a meta-analysis.

BACKGROUND: Depression is common in Alzheimer's and vascular dementia and is associated with poorer outcomes; however, less is known about the impact of depression on frontotemporal dementia (FTD). Here, we conducted a meta-analysis of diagnostic methods and the prevalence of depressive symptoms in FTD. METHODS: PubMed, EMBASE and PsychINFO were queried for 'depression' and/or 'depressive mood' in behavioral- and language-variant FTD. The prevalence and diagnosis of depressive symptoms were extracted from relevant studies and the results pooled using a random-effects model. RESULTS: We included 29 studies in this meta-analysis, with sample sizes ranging from 3 to 73 (n = 870). The omnibus estimated event rate of depressed mood was 0.334 (33%; 95% CI: 0.268-0.407). Symptoms were most commonly assessed via standardized neuropsychiatric rating scales, with other methods including subjective caregiver reports and chart reviews. The study results were heterogeneous due to the variability in diagnostic methods. CONCLUSIONS: Depressive symptoms similar to those in other dementias are commonly detected in FTD. However, the diagnostic methods are heterogeneous, and symptoms of depression often overlap with manifestations of FTD. Having a standardized diagnostic approach to depression in FTD will greatly facilitate future research in this area.