Pharmacological treatment of mixed states

Mixed states in bipolar disorder have been neglected, and the data concerning treatment of these conditions have been relatively obscure. To address this, we systematically reviewed published pharmacological treatment data for “mixed states/episodes” in mood disorders, including “with mixed features” in DSM–5. We searched PubMed, MEDLINE, The Cochrane Library, clinicaltrials.gov, and controlled-trials.com (with different combinations of the following keywords: “mixed states/features,” “bipolar,” “depressive symptoms/bipolar depression,” “manic symptoms,” “treatment,” “DSM–5”) through to October 2016. We applied a quality-of-evidence approach: first-degree evidence=randomized placebo-controlled studies of pharmacological interventions used as monotherapy; second-degree evidence=a similar design in the absence of a placebo or of a combination therapy as a comparative group; third-degree evidence=case reports, case series, and reviews of published studies. We found very few primary double-blind, placebo-controlled studies on the treatment of mixed states: the preponderance of available data derives from subgroup analysis performed on studies that originally involved manic patients. Future research should study the effects of treatments in mixed states defined using current criteria.</p

A systematic review and meta-analysis on the comorbidity of premenstrual dysphoric disorder or premenstrual syndrome with mood disorders:prevalence, clinical and neurobiological correlates

BACKGROUND: Mood disorders are among the leading causes of disease burden worldwide, with 20-70% of affected individuals experiencing comorbid premenstrual disorders. This systematic review and meta-analysis investigated the comorbidity of premenstrual dysphoric disorder (PMDD) or premenstrual syndrome (PMS) with non-reproductive mood disorders.AIMS: We aimed to determine the pooled prevalence of PMDD/PMS with adult mood disorders, assess the impact of comorbidity on clinical course and summarise the associated neurobiological findings.METHOD: Eligible studies were identified through Embase, MEDLINE and APA PsycINFO from inception to 22 January 2024 (PROSPERO, no. CRD42021246796). Studies on women ('females') with diagnoses of PMDD/PMS and mood disorders were included. Risk of bias was assessed using National Institutes of Health quality assessment tools. A random-effects, pooled-prevalence meta-analysis was conducted using the Comprehensive Meta-Analysis software, categorising diagnostic sampling strategies as follows: mood disorders diagnosed first, PMDD/PMS diagnosed first or concurrent diagnoses. A narrative synthesis explored secondary outcomes, including illness course and biomarkers.RESULTS: A total of 39 studies were included, with 36 of these ( n = 3646) contributing to the meta-analysis. Seven studies focused on bipolar disorders, 18 on unipolar depressive disorders and 14 on mixed samples of bipolar and unipolar disorders. Random-effects pooled-prevalence meta-analyses showed consistently high comorbidity rates between PMDD/PMS and mood disorders, ranging from 42% (95% CI: 30%, 55%) to 49% (95% CI: 38%, 60%) across sampling strategies. Risk of bias varied, with methodological heterogeneity noted. CONCLUSIONS: This review underscores high comorbidity rates between PMDD/PMS and mood disorders, regardless of sampling strategy, and highlights the need for research into clinical and neurobiological characteristics specific to this comorbidity. Limitations include study heterogeneity, reliance on cross-sectional designs and provisional PMDD/PMS diagnoses. Future research should address these gaps to inform diagnostic and therapeutic advancements tailored to this population.</p

A systematic review and meta-analysis of treatments for rapid cycling bipolar disorder

Objectives: Rapid cycling is a common and disabling phenomenon in individuals with bipolar disorders. In the absence of a recent literature examination, this systematic review and meta-analysis aimed to synthesise the evidence of efficacy, acceptability and tolerability of treatments for individuals with rapid cycling bipolar disorder (RCBD). Method: A systematic search was conducted to identify randomised controlled trials assigning participants with RCBD to pharmacological and/or non-pharmacological interventions. Study inclusion and data extraction were undertaken by two reviewers independently. The primary outcome was continuous within-subject RCBD illness severity before and after treatment. Pre-post random effects meta-analyses were conducted for each outcome/intervention arm studied, generating a standardised effect size (hedge's g) and 95% confidence interval (CI). Results: A total of 34 articles describing 30 studies were included. A total of 16 separate pharmacological treatments were examined in contrast to 1 psychological therapy study. Only quetiapine and lamotrigine were assessed in &gt;5 studies. By assessing 95% CI overlap of within-subject efficacy effects compared to placebo, the only interventions suggesting significant depression benefits (placebo g = 0.60) were olanzapine (with/without fluoxetine; g = 1.01), citalopram (g = 1.10) and venlafaxine (g = 2.48). For mania, benefits were indicated for quetiapine (g = 1.01), olanzapine (g = 1.19) and aripiprazole (g = 1.09), versus placebo (g = 0.33). Most of these effect sizes were from only one trial per treatment. Heterogeneity between studies was variable, and 20% were rated to have a high risk of bias. Conclusions: While many interventions appeared efficacious, there was a lack of robust evidence for most treatments. Given the limited and heterogeneous evidence base, the optimal treatment strategies for people with RCBD are yet to be established.</p

A multinational study to pilot the modified Hypomania Checklist (mHCL) in the assessment of mixed depression

Background: Mixed depression is a common, dimensional phenomenon that is increasingly recognized in unipolar and bipolar disorders. We piloted a modified version of the Hypomania Checklist (mHCL-32) to assess the prevalence and clinical correlates of concurrent manic (hypo) symptoms in depressed patients. Methods: The mHCL-32, Young Mania Rating Scale (YMRS) and Hamilton Rating Scale for Depression (IAMD-24) were utilized in the assessment of unipolar (UP=61) and bipolar (BP=44) patients with an index major depressive episode confirmed by the Structured Clinical Interview for DSM-IV (SCID). Differential mHLC-32 item endorsement was compared between UP and BR Correlation analyses assessed the association of symptom dimensions measured by mHCL-32, YMRS and HAMD-24. Results: There was no significant difference between mood groups in the mean rnHCL-32 and YMRS scores. Individual mHLC-32 items of increased libido, quarrels, and caffeine intake were endorsed more in BP vs. UP patients. The mHCL-32 active elevated subscale score was positively correlated with the YMRS in BP patients and negatively correlated with HAMD-24 in UP patients. Conversely, the mHCL-32 irritable risk taking subscale score was positively correlated with HAMD-24 in BP and with YMRS in UP patients. Limitations: Small sample size and cross-sectional design. Conclusion: Modifying the HCL to screen for (hypo) manic symptoms in major depression may have utility in identifying mixed symptoms in both bipolar vs. unipolar depression. Further research is encouraged to quantify mixed symptoms with standardized assessments. (C) 2013 Published by Elsevier B.V.Mayo FoundationMayo Foundation

Different patterns of manic/hypomanic symptoms in depression: A pilot modification of the hypomania checklist-32 to assess mixed depression

Background: There are no self-report scales that assess manic/hypomanic symptoms in patients with depression. The aim of this study was to explore the use of a modified screening instrument for bipolar disorder to assess current manic/hypomanic symptoms in patients with a depressive episode. Methods: The study sample consisted of 188 patients with Structured Clinical Interview for DSM-IV-TR disorders (SCID) confirmed bipolar or major depressive disorder. We modified the Hypomania Checklist-32 (mHCL-32) to assess current instead of lifetime symptoms. An Exploratory Factor Analysis (EFA) was conducted to identify clusters of mHCL-32 items that were endorsed concurrently. A Latent Class Analysis (LCA) was carried out to identify groups of patients with similar mHCL-32 item endorsement patterns. Results: The EPA identified 3 factors: factor #1 (elation-disinhibition-increased goal directed activity), factor #2 (risk-taking-impulsivity-substance use) and factor #3 (distractibility-irritability). The LCA yielded 3 classes (2 showing manic/hypomanic features). While class #1 patients endorsed more items related to disinhibition and racing thoughts, class #2 patients recognized more items associated with irritability and substance use Limitations: Lack of an adequate gold standard measure of mixed depression to compare to, the cross-sectional design and the lack of a validation sample. Conclusions: The mHCL-32 scale allowed a comprehensive and convergent delineation of hypomanic/manic symptoms in depression. Further validation of these findings is needed. (C) 2014 Elsevier B.V. All rights reserved,Mayo FoundationMayo Foundation

Cognitive remediation therapy for patients with bipolar disorder: a randomised proof-of-concept trial

Objectives: Cognitive remediation therapy (CRT) may benefit people with bipolar disorder type I and II for whom cognitive impairment is a major contributor to disability. Extensive research has demonstrated CRT to improve cognition and psychosocial functioning in people with different diagnoses, but randomised trials of evidenced therapy programmes are lacking for bipolar disorders. The Cognitive Remediation in Bipolar (CRiB) study aimed to determine whether an established CRT programme is feasible and acceptable for people with bipolar disorders. Methods: This proof‐of‐concept, single‐blind randomised trial recruited participants aged 18‐65 with bipolar disorder, not currently experiencing an episode. They were 1:1 block randomised to treatment‐as‐usual (TAU) with or without individual CRT for 12 weeks. The partly computerised CRT programme (“CIRCuiTS”) was therapist‐led and is evidence‐based from trials in those with psychotic illnesses. Data were collected and analysed by investigators blinded to group allocation. The main outcomes (week 13 and 25) examined participant retention, intervention feasibility and putative effects of CRT on cognitive and psychosocial functioning via intention‐to‐treat analyses. Trial registration: ISRCTN ID32290525. Results: Sixty participants were recruited (02/2016‐06/2018) and randomised to CRT (n = 29) or TAU (n = 31). Trial withdrawals were equivalent (CRT n = 2/29; TAU n = 5/31). CRT satisfaction indicated high acceptability. Intention‐to‐treat analyses (N = 60) demonstrated greater improvements for CRT‐ than TAU‐randomised participants: at both week 13 and 25, CIRCuiTS participants showed larger improvements in the following domains (week 25 effect sizes reported here): IQ (SES = 0.71, 95% CI [0.29,1.13]), working memory (SES = 0.70, 95% CI [0.31,1.10]), executive function (SES = 0.93, 95% CI [0.33,1.54]), psychosocial functioning (SES = 0.49, 95% CI [0.18,0.80]) and goal attainment (SES = 2.02, 95% CI [0.89,3.14]). No serious adverse events were reported. Conclusions: CRT is feasible for individuals with bipolar disorders and may enhance cognition and functioning. The reported effect sizes from this proof‐of‐concept trial encourage further investigation in a definitive trial

Altered oxidative neurometabolic response to methylene blue in bipolar disorder revealed by quantitative neuroimaging

Background: Cerebral mitochondrial and hemodynamic abnormalities have been implicated in Bipolar Disorder pathophysiology, likely contributing to neurometabolic vulnerability–leading to worsen clinical outcomes and mood instability. To investigate neurometabolic vulnerability in patients with BD, we combined multi-modal quantitative MRI assessment of cerebral oxygenation with acute administration of Methylene Blue, a neurometabolic/hemodynamic modulator acting on cerebral mitochondria. Methods: Fifteen euthymic patients with chronic BD-type 1, and fifteen age/gender-matched healthy controls underwent two separate MRI sessions in a single-blinded randomized cross-over design, each after intravenous infusion of either MB (0.5 mg/kg) or placebo. MRI-based measures of Cerebral Blood Flow and Oxygen Extraction Fraction were integrated to compute Cerebral Metabolic Rate of Oxygen in Frontal Lobe, Anterior Cingulate, and Hippocampus–implicated in BD neurometabolic pathophysiology. Inter-daily variation in mood rating was used to assess mood instability. Results: A decrease in global CBF and CMRO2 was observed after acutely administrating MB to all participants. Greater regional CMRO2 reductions were observed after MB, in patients compared to controls in FL (mean = −14.2 ± 19.5 % versus 2.3 ± 14.8 %), ACC (mean = −14.8 ± 23.7 % versus 2.4 ± 15.7 %). The effects on CMRO2 in those regions were primarily driven by patients with longer disease duration and higher mood instability. Limitations: Sample size; medications potentially impacting on response to MB. Conclusions: An altered neurometabolic response to MB, a mitochondrial/hemodynamic modulator, was observed in patients, supporting the hypothesis of vulnerability to neurometabolic stress in BD. Integrating quantitative imaging of cerebral oxygen metabolism with a mitochondrial-targeting pharmacological challenge could provide a novel biomarker of neurometabolic and cerebrovascular pathophysiology in BD

A leaky umbrella has little value: evidence clearly indicates the serotonin system is implicated in depression.

A recent “umbrella” review examined various biomarkers relating to the serotonin system, and concluded there was no consistent evidence implicating serotonin in the pathophysiology of depression. We present reasons for why this conclusion is overstated, including methodological weaknesses in the review process, selective reporting of data, over-simplification, and errors in the interpretation of neuropsychopharmacological findings. We use the examples of tryptophan depletion and serotonergic molecular imaging, the two research areas most relevant to the investigation of serotonin, to illustrate this

A leaky umbrella has little value:evidence clearly indicates the serotonin system is implicated in depression

A recent “umbrella” review examined various biomarkers relating to the serotonin system, and concluded there was no consistent evidence implicating serotonin in the pathophysiology of depression. We present reasons for why this conclusion is overstated, including methodological weaknesses in the review process, selective reporting of data, over-simplification, and errors in the interpretation of neuropsychopharmacological findings. We use the examples of tryptophan depletion and serotonergic molecular imaging, the two research areas most relevant to the investigation of serotonin, to illustrate this

Country-level gender inequality is associated with structural differences in the brains of women and men

Gender inequality across the world has been associated with a higher risk to mental health problems and lower academic achievement in women compared to men. We also know that the brain is shaped by nurturing and adverse socio-environmental experiences. Therefore, unequal exposure to harsher conditions for women compared to men in gender-unequal countries might be reflected in differences in their brain structure, and this could be the neural mechanism partly explaining women’s worse outcomes in gender-unequal countries. We examined this through a random-effects meta-analysis on cortical thickness and surface area differences between adult healthy men and women, including a meta-regression in which country-level gender inequality acted as an explanatory variable for the observed differences. A total of 139 samples from 29 different countries, totaling 7,876 MRI scans, were included. Thickness of the right hemisphere, and particularly the right caudal anterior cingulate, right medial orbitofrontal, and left lateral occipital cortex, presented no differences or even thicker regional cortices in women compared to men in gender-equal countries, reversing to thinner cortices in countries with greater gender inequality. These results point to the potentially hazardous effect of gender inequality on women’s brains and provide initial evidence for neuroscience-informed policies for gender equality.</p