Can magnetic resonance imaging enhance the assessment of potential new treatments for cognitive impairment in mood disorders? A systematic review and position paper by the International Society for Bipolar Disorders Targeting Cognition Task Force.

BACKGROUND: Developing treatments for cognitive impairment is key to improving the functioning of people with mood disorders. Neuroimaging may assist in identifying brain-based efficacy markers. This systematic review and position paper by the International Society for Bipolar Disorders Targeting Cognition Task Force examines the evidence from neuroimaging studies of pro-cognitive interventions. METHODS: We included magnetic resonance imaging (MRI) studies of candidate interventions in people with mood disorders or healthy individuals, following the procedures of the Preferred Reporting Items for Systematic reviews and Meta-Analysis 2020 statement. Searches were conducted on PubMed/MEDLINE, PsycInfo, EMBASE, Cochrane Library, and Clinicaltrials.gov from inception to 30th April 2021. Two independent authors reviewed the studies using the National Heart, Lung, Blood Institutes of Health Quality Assessment Tool for Controlled Intervention Studies and the quality of neuroimaging methodology assessment checklist. RESULTS: We identified 26 studies (N = 702). Six investigated cognitive remediation or pharmacological treatments in mood disorders (N = 190). In healthy individuals, 14 studies investigated pharmacological interventions (N = 319), 2 cognitive training (N = 73) and 4 neuromodulatory treatments (N = 120). Methodologies were mostly rated as 'fair'. 77% of studies investigated effects with task-based fMRI. Findings varied but most consistently involved treatment-associated cognitive control network (CCN) activity increases with cognitive improvements, or CCN activity decreases with no cognitive change, and increased functional connectivity. In mood disorders, treatment-related default mode network suppression occurred. CONCLUSIONS: Modulation of CCN and DMN activity is a putative efficacy biomarker. Methodological recommendations are to pre-declare intended analyses and use task-based fMRI, paradigms probing the CCN, longitudinal assessments, mock scanning, and out-of-scanner tests.

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 >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.

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.

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.

Response inhibition and interference control in patients with bipolar I disorder and first-degree relatives.

OBJECTIVES: The current study aimed to assess both response inhibition (RI) and interference control (IC) in euthymic patients with bipolar disorder (BD-Ps) as well as asymptomatic first-degree relatives (BD-Rs) and healthy controls (HCs) in order to evaluate trait-as opposed to illness-associated features of these components. METHODS: BD-Ps (n = 35) who had been in the euthymic state for at least six months, BD-Rs (n = 30), and HCs (n = 33) completed a Stop-Signal Task (SST) and Stroop Task to assess RI and IC, respectively. Groups were compared on the stop-signal reaction time (SSRT), stop-signal delay (SSD), mean reaction time on go trials (go-RT), Stroop interference score (S-interference), and number of errors on the color-word-naming trial (S-error). Associations between the patient's clinical features and RI and IC, between the patient's treatment and RI and IC, and between RI and IC in each group were investigated. RESULTS: BD-Ps and BD-Rs had significantly shorter go-RT and SSD, and longer SSRT compared to HCs, with these scores being similar between the BD-Ps and BD-Rs. Also, both BD-Ps and BD-Rs made significantly more S-errors than HCs, whereas, the S-interference score was not significantly different between groups. There were no significant correlations between Stroop Task and SST scores within each group, nor between clinical features or treatment variables and RI and IC in BD-Ps. CONCLUSIONS: Overall, impairment in RI and IC (only on S-error score) was present in both patients and relatives. The persistence of these deficits in the absence of mood symptoms suggests that these features may represent candidate endophenotypes for bipolar disorder.

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.

Acetazolamide for Bipolar Disorders: A Scoping Review.

Acetazolamide, a carbonic anhydrase inhibitor, is used to treat a variety of ailments. It has been highlighted for its potential to benefit people with bipolar disorders, for whom there are clear current unmet treatment needs. This scoping review sought to synthesise all available evidence related to the potential effects of acetazolamide on symptoms related to bipolar disorder, acceptability and tolerability, and intervention characteristics (e.g., dose and duration). Following publication of the review protocol, the Pubmed, Embase, and PsycInfo databases were searched (all dated to 31 August 2022). A systematic approach was undertaken to identify eligible articles and extract relevant data from these. Five studies were included, assessing a total of 50 patients treated with acetazolamide. Most patients were from two open-label trials, while the others were case reports. Approximately one third of patients were experiencing psychosis or mania before treatment initiation, and one third had refractory depression. Forty-four percent of patients were estimated to achieve a response (not seemingly affected by the baseline episode type, acetazolamide dose, or duration), while a further 22% appeared to experience minimal benefits from the intervention. Acetazolamide was generally reported to be tolerated well and acceptable for up to 2 years, although reporting for acceptability and tolerability was suboptimal. The reviewed evidence is extremely limited in size and methodology (e.g., no randomised studies, blinding, or standardised outcome assessment). We posit that the current findings are sufficiently encouraging to recommend substantive clinical trials, but we emphasise that at present, the evidence is exceedingly preliminary, and there remains evident uncertainty as to whether acetazolamide could be a viable treatment for bipolar disorders.

Acute effects of mifepristone on emotional processing related brain activity: A functional MRI study.

The Hypothalamic-pituitary-adrenal (HPA) axis plays an important role in the pathophysiology of mood disorders, and preliminary data suggests that glucocorticoid receptor (GR) antagonism may be an important therapeutic mechanism. The effects of modulating HPA axis function on emotional processing related brain activity, which may be abnormal in depressed mood, is poorly understood. This study used a pharmacological functional magnetic resonance imaging (fMRI) design to determine the effects of the GR and progesterone receptor antagonist mifepristone on emotional faces processing task related brain activations in 19 right-handed healthy male participants. Each participant received 600 mg mifepristone or placebo on two separate imaging days and then performed an emotional processing fMRI task four hours later. The effect of mifepristone on task related brain activations was determined using Region-of-Interest (ROI) analyses and an exploratory whole brain voxel-wise analyses. No significant changes were observed in the defined ROIs (amygdala, anterior cingulate cortex, insula) or in the exploratory whole brain analyses that was associated with mifepristone administration in either the angry vs happy faces or angry and happy faces vs implicit baseline contrasts. Task reaction times and accuracy were similar in both mifepristone and placebo conditions (all p > 0.05). Our study failed to show significant evidence of modulation of emotional processing related brain activity associated with acute mifepristone administration. Future research should use fMRI to investigate the longer-term administration effects of mifepristone on mood in healthy participants and people with mood disorders to provide a deeper understanding of the potential effects on depressive symptoms.

Resting-state fMRI in depressive and (hypo)manic mood states in bipolar disorders: A systematic review.

OBJECTIVE: Abnormalities in spontaneous brain activity, measured with resting-state functional magnetic resonance imaging (rs-fMRI), may be key biomarkers for bipolar disorders. This systematic review compares rs-fMRI findings in people experiencing a bipolar depressive or (hypo)manic episode to bipolar euthymia and/or healthy participants. METHODS: Medline, Web of Science and Embase were searched up until April 2021. Studies without control group, or including minors, neurological co-morbidities or mixed episodes, were excluded. Qualitative synthesis was used to report results and risk of bias was assessed using the National Heart, Lung and Blood Institute tool for case-control studies. RESULTS: Seventy-one studies were included (3167 bipolar depressed/706 (hypo)manic). In bipolar depression, studies demonstrated default-mode (DMN) and frontoparietal network (FPN) dysfunction, altered baseline activity in the precuneus, insula, striatum, cingulate, frontal and temporal cortex, and disturbed regional homogeneity in parietal, temporal and pericentral areas. Functional connectivity was altered in thalamocortical circuits and between the cingulate cortex and precuneus. In (hypo)mania, studies reported altered functional connectivity in the amygdala, frontal and cingulate cortex. Finally, rs-fMRI disturbances in the insula and putamen correlate with depressive symptoms, cerebellar resting-state alterations could evolve with disease progression and altered amygdala connectivity might mediate lithium effects. CONCLUSIONS: Our results suggest DMN and FPN dysfunction in bipolar depression, whereas local rs-fMRI alterations might differentiate mood states. Future studies should consider controlling rs-fMRI findings for potential clinical confounding factors such as medication. Considerable heterogeneity of methodology between studies limits conclusions. Standardised clinical reporting and consistent analysis approaches would increase coherence in this promising field.

Clinical characteristics and impacts of HIV infection in people with bipolar disorders.

BACKGROUND: People with bipolar disorders (BD) may be at increased risk of Human Immunodeficiency Virus (HIV) infection but our understanding of the impacts of HIV infection on psychiatric outcomes is poor. This study aimed to examine the prevalence, temporal relationship, and clinical impact of HIV infection in people with BD. METHODS: In this retrospective case-control study, anonymised electronic case records of patients with BD who had been under the care of South London and Maudsley mental health services were used for data extraction. 54 HIV+ people with BD were identified and compared to a matched control group of 54 HIV- people with BD. RESULTS: The prevalence of HIV co-morbidity in the BD population was around 1%. 76% of HIV+ BD men identified as men who have sex with men (MSM). 65% of the HIV+ BD group were diagnosed with BD before becoming HIV+. The HIV+ BD group experienced significantly higher rates of stimulant, GBL/GHB and psychedelic use compared to the HIV- BD group. 85% of the HIV+ BD group were recorded as taking antiretroviral medications. LIMITATIONS: Retrospective and cross-sectional study design, and a relatively small sample size CONCLUSIONS: The prevalence of HIV comorbidity in BD was comparable to the local general population. HIV infection in BD is associated with MSM status and stimulant, GHB/GBL and psychedelics use suggesting that HIV prevention strategies should particularly target these groups. Lower use of antiretroviral medications by people with BD underlines the importance of engaging HIV+ BD people in HIV services.

Mifepristone enhances the neural efficiency of human visuospatial memory encoding and recall.

Glucocorticoid receptor (GR) antagonism is a promising new treatment for cognitive dysfunction in psychiatric disorders but the effects of GR antagonism on cognition related brain activity is poorly understood. This study examines the effects of the GR and progesterone receptor antagonist mifepristone on the neural correlates of visuospatial learning and working memory in healthy male participants. The study used a pharmacological functional magnetic resonance imaging (fMRI) design to determine mifepristone effects on visuospatial paired associates learning (vPAL) and n-back working memory (WM) fMRI task related brain activations. 20 right-handed healthy male participants received 600 mg mifepristone or placebo on two separate imaging days and each participant performed fMRI tasks four hours later. The effect of mifepristone on task related brain activations was determined using Region of Interest (ROI) fMRI analyses and an exploratory whole brain voxel-wise fMRI task analyses was also conducted. The vPAL task ROI analysis found that mifepristone administration was significantly associated with decreased fusiform cortex activations in first and second encoding blocks (p = 0.007, p = 0.04) and decreased angular and precuneal cortices activations in the first recall block (p = 0.01, p = 0.02). There were no significant differences in fMRI brain activations associated with mifepristone administration in the n-back task ROI's (all p > 0.05). Mifepristone administration did not significantly affect fMRI brain activations in the whole brain voxel-wise analyses for both tasks. N-back and vPAL task reaction times and accuracy were similar in both mifepristone and placebo conditions (all p > 0.05). Our finding of decreased fusiform, angular and precuneal vPAL task related brain activity associated with mifepristone administration for the same behavioural performance as found in the placebo condition may represent improved efficiency of visuospatial memory encoding and recall. These findings provide evidence that mifepristone may enhance the efficiency of human visuospatial memory and calls for further studies in patient populations using an fMRI approach to provide proof of concept for new treatments.

Pharmacological Treatment of Bipolar Depression: What are the Current and Emerging Options?

Depression accounts for the predominant burden associated with bipolar disorder. The identification and management of bipolar depression are challenging, since bipolar depression differs from unipolar depression, responding poorly to traditional antidepressants, which may also induce a switch to hypomania/mania, mixed states and/or cause rapid cycling. Current treatment options for bipolar depression are limited and guidelines vary greatly in their recommendations, reflecting gaps and inconsistencies in the current evidence base. Moreover, some treatment options, such as quetiapine and olanzapine-fluoxetine, although clearly efficacious, may be associated with adverse cardiometabolic side effects, which can be detrimental to the long-term physical health and well-being of patients, increasing the likelihood of treatment non-adherence and relapse. Evidence for some more recent therapeutic options, including lurasidone and cariprazine, suggests that patients' symptoms can be effectively managed without compromising their physical health. In addition, novel agents targeting alternative neurotransmitter pathways and inflammatory processes (such as ketamine and N-acetyl cysteine) are emerging as promising potential options for the treatment of bipolar depression in the future.

Unipolar mania: Identification and characterisation of cases in France and the United Kingdom.

BACKGROUND: Unipolar mania is a putative subtype of bipolar disorder (BD) in which individuals experience recurrent manic but not major depressive episodes. Few studies of unipolar mania have been conducted in developed countries and none in the UK. This study aimed to identify and characterise people with unipolar mania in the UK and France. METHODS: People with unipolar mania were ascertained using a South London UK electronic case register and a French BD case series. Each unipolar mania group was compared to a matched group of people with BD who have experienced depressive episodes. RESULTS: 17 people with unipolar mania were identified in South London and 13 in France. The frequency of unipolar mania as a percentage of the BD clinical population was 1.2% for the South London cohort and 3.3% for the French cohort. In both cohorts, people with unipolar mania experienced more manic episodes than people with BD, and in the French cohort were more likely to experience a psychotic illness onset and more psychiatric admissions. Treatment and self-harm characteristics of people with unipolar mania were similar to people with BD. LIMITATIONS: The relatively small number of people with unipolar mania identified by this study limits its power to detect differences in clinical variables. CONCLUSIONS: People with unipolar mania can be identified in France and the UK, and they may experience a higher frequency of manic episodes but have similar treatment and self-harm characteristics as people with BD.

Cortical thickness and surface area as an endophenotype in bipolar disorder type I patients and their first-degree relatives.

OBJECTIVES: So far, few studies have investigated cortical thickness (CT) and surface area (SA) measures in bipolar disorder type I (BDI) in comparison to a high genetic risk group such as first-degree relatives (FR). This study aimed to examine CT and SA differences between BDI, FR and healthy controls (HC). METHODS: 3D T1 magnetic resonance images were acquired from 27 euthymic BDI patients, 24 unaffected FR and 29 HC. CT and SA measures were obtained with FreeSurfer version 5.3.0. Generalized estimating equations were used to compare CT and SA between groups. Group comparisons were repeated with restricting the FR group to 17 siblings (FR-SB) only. RESULTS: \Mean age in years was 36.3 ±â€¯9.5 for BDI, 32.1 ±â€¯10.9 for FR, 34.7 ±â€¯9.8 for FR-SB and 33.1 ±â€¯9.0 for HC group respectively. BDI patients revealed larger SA of left pars triangularis (LPT) compared to HC (p = .001). In addition, increased SA in superior temporal cortex (STC) in FR-SB group compared to HC was identified (p = .0001). CONCLUSIONS: Our result of increased SA in LPT of BDI could be a disease marker and increased SA in STC of FR-SB could be a marker related with resilience to illness.

Validity and Reliability of the Turkish Version for DSM-5 Level 2 Anger Scale (Child Form for Children Aged 11-17 Years and Parent Form for Children Aged 6-17 Years).

INTRODUCTION: This study aimed to assess the validity and reliability of the Turkish version of Diagnostic and Statistical Manual of Mental Disorders (DSM-5) Level 2 Anger Scale. METHODS: The scale was prepared by translation and back translation of DSM-5 Level 2 Anger Scale. Study groups consisted of a clinical sample of cases diagnosed with depressive disorder and treated in a child and adolescent psychiatry unit and a community sample. The study was continued with 218 children and 160 parents. In the assessment process, child and parent forms of DSM-5 Level 2 Anger Scale and Children's Depression Inventory and Strengths and Difficulties Questionnaire-Parent Form were used. RESULTS: In the reliability analyses, the Cronbach alpha internal consistency coefficient values were found very high regarding child and parent forms. Item-total score correlation coefficients were high and very high, respectively, for child and parent forms indicating a statistical significance. As for construct validity, one factor was maintained for each form and was found to be consistent with the original form of the scale. As for concurrent validity, the child form of the scale showed significant correlation with Children's Depression Inventory, while the parent form showed significant correlation with Strengths and Difficulties Questionnaire-Parent Form. CONCLUSION: It was found that the Turkish version of DSM-5 Level 2 Anger Scale could be utilized as a valid and reliable tool both in clinical practice and for research purposes.

[Cavum Vergae and Schizophrenia: Brain Imaging Findings and Treatment Outcome of a Case with 25 Years of Untreated Psychosis]. / Kavum Vergae ve Sizofreni: 25 Yil Boyunca Tedavisiz Kalmis Bir Olguda Beyin Görüntüleme Bulgulari ve Klinik Izlem.

Psychotic symptoms and disorders can emerge due to structural brain abnormalities. The septum pellucidum is one of the midline brain structures, which consists of the fusion of two thin membranes. Cavum vergae is recognized as the most severe form of fusion defect in the membranes of septum pellucidum. Although cavum vergea is reported to be common in schizophrenia and other psychotic disorders, a significant relationship has been found only for anomalies greater than 6 mm. Large cavum vergae may be a marker of developmental anomalies in other midline structures and connections, which in turn may lead to psychotic symptoms and disorders. In this case report, we present cavum vergae in a schizophrenia case with a 25 year history of untreated psychosis, discuss the probable relation of psychotic symptoms to structural brain anomaly, and evaluate the treatment course.

Neuroanatomical correlates of genetic risk for bipolar disorder: A voxel-based morphometry study in bipolar type I patients and healthy first degree relatives.

BACKGROUND: Bipolar disorder (BD) is a highly heritable mental illness which is associated with neuroanatomical abnormalities. Investigating healthy individuals at high genetic risk for bipolar disorder may help to identify neuroanatomical markers of risk and resilience without the confounding effects of burden of illness or medication. METHODS: Structural magnetic resonance imaging scans were acquired from 30 euthymic patients with BD-I (BP), 28 healthy first degree relatives of BD-I patients (HR), and 30 healthy controls (HC). Data was analyzed using DARTEL for voxel based morphometry in SPM8. RESULTS: Whole-brain analysis revealed a significant main effect of group in the gray matter volume in bilateral inferior frontal gyrus, left parahippocampal gyrus, left lingual gyrus and cerebellum, posterior cingulate gyrus, and supramarginal gyrus (alphasim corrected (≤0.05 FWE)). Post-hoc t-tests showed that inferior frontal gyrus volumes were bilaterally larger both in BP and HR than in HC. BP and HR also had smaller cerebellar volume compared with HC. In addition, BP had smaller left lingual gyrus volume, whereas HR had larger left parahippocampal and supramarginal gyrus volume compared with HC. LIMITATIONS: This study was cross-sectional and the sample size was not large. All bipolar patients were on medication, therefore we were not able to exclude medication effects in bipolar group in this study. CONCLUSIONS: Our findings suggest that increased inferior frontal gyrus and decreased cerebellar volumes might be associated with genetic predisposition for bipolar disorder. Longitudinal studies are needed to better understand the predictive and prognostic value of structural changes in these regions.

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 EFA 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.

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 (HAMD-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 BP. 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 mHCL-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.