Focal adhesion is associated with lithium response in bipolar disorder: evidence from a network-based multi-omics analysis.

Lithium (Li) is one of the most effective drugs for treating bipolar disorder (BD), however, there is presently no way to predict response to guide treatment. The aim of this study is to identify functional genes and pathways that distinguish BD Li responders (LR) from BD Li non-responders (NR). An initial Pharmacogenomics of Bipolar Disorder study (PGBD) GWAS of lithium response did not provide any significant results. As a result, we then employed network-based integrative analysis of transcriptomic and genomic data. In transcriptomic study of iPSC-derived neurons, 41 significantly differentially expressed (DE) genes were identified in LR vs NR regardless of lithium exposure. In the PGBD, post-GWAS gene prioritization using the GWA-boosting (GWAB) approach identified 1119 candidate genes. Following DE-derived network propagation, there was a highly significant overlap of genes between the top 500- and top 2000-proximal gene networks and the GWAB gene list (Phypergeometric = 1.28E-09 and 4.10E-18, respectively). Functional enrichment analyses of the top 500 proximal network genes identified focal adhesion and the extracellular matrix (ECM) as the most significant functions. Our findings suggest that the difference between LR and NR was a much greater effect than that of lithium. The direct impact of dysregulation of focal adhesion on axon guidance and neuronal circuits could underpin mechanisms of response to lithium, as well as underlying BD. It also highlights the power of integrative multi-omics analysis of transcriptomic and genomic profiling to gain molecular insights into lithium response in BD.

Correction of depression-associated circadian rhythm abnormalities is associated with lithium response in bipolar disorder.

BACKGROUND: Bipolar disorder (BD) is characterized by episodes of depression and mania and disrupted circadian rhythms. Lithium is an effective therapy for BD, but only 30%-40% of patients are fully responsive. Preclinical models show that lithium alters circadian rhythms. However, it is unknown if the circadian rhythm effects of lithium are essential to its therapeutic properties. METHODS: In secondary analyses of a multi-center, prospective, trial of lithium for BD, we examined the relationship between circadian rhythms and therapeutic response to lithium. Using standardized instruments, we measured morningness, diurnal changes in mood, sleep, and energy (circadian rhythm disturbances) in a cross-sectional study of 386 BD subjects with varying lithium exposure histories. Next, we tracked symptoms of depression and mania prospectively over 12 weeks in a subset of 88 BD patients initiating treatment with lithium. Total, circadian, and affective mood symptoms were scored separately and analyzed. RESULTS: Subjects with no prior lithium exposure had the most circadian disruption, while patients stable on lithium monotherapy had the least. Patients who were stable on lithium with another drug or unstable on lithium showed intermediate levels of disruption. Treatment with lithium for 12 weeks yielded significant reductions in total and affective depression symptoms. Lithium responders (Li-Rs) showed improvement in circadian symptoms of depression, but non-responders did not. There was no difference between Li-Rs and nonresponders in affective, circadian, or total symptoms of mania. CONCLUSIONS: Exposure to lithium is associated with reduced circadian disruption. Lithium response at 12 weeks was selectively associated with the reduction of circadian depressive symptoms. We conclude that stabilization of circadian rhythms may be an important feature of lithium's therapeutic effects. CLINICAL TRIALS REGISTRY: NCT0127253.

Clinical predictors of non-response to lithium treatment in the Pharmacogenomics of Bipolar Disorder (PGBD) study.

BACKGROUND: Lithium is regarded as a first-line treatment for bipolar disorder (BD), but partial response and non-response commonly occurs. There exists a need to identify lithium non-responders prior to initiating treatment. The Pharmacogenomics of Bipolar Disorder (PGBD) Study was designed to identify predictors of lithium response. METHODS: The PGBD Study was an eleven site prospective trial of lithium treatment in bipolar I disorder. Subjects were stabilized on lithium monotherapy over 4 months and gradually discontinued from all other psychotropic medications. After ensuring a sustained clinical remission (defined by a score of ≤3 on the CGI for 4 weeks) had been achieved, subjects were followed for up to 2 years to monitor clinical response. Cox proportional hazard models were used to examine the relationship between clinical measures and time until failure to remit or relapse. RESULTS: A total of 345 individuals were enrolled into the study and included in the analysis. Of these, 101 subjects failed to remit or relapsed, 88 achieved remission and continued to study completion, and 156 were terminated from the study for other reasons. Significant clinical predictors of treatment failure (p < 0.05) included baseline anxiety symptoms, functional impairments, negative life events and lifetime clinical features such as a history of migraine, suicidal ideation/attempts, and mixed episodes, as well as a chronic course of illness. CONCLUSIONS: In this PGBD Study of lithium response, several clinical features were found to be associated with failure to respond to lithium. Future validation is needed to confirm these clinical predictors of treatment failure and their use clinically to distinguish who will do well on lithium before starting pharmacotherapy.

A Blockchain-Based Spatial Crowdsourcing System for Spatial Information Collection Using a Reward Distribution.

Due to the increasing relevance of spatial information in different aspects of location-based services, various methods are used to collect this information. The use of crowdsourcing due to plurality and distribution is a remarkable strategy for collecting information, especially spatial information. Crowdsourcing can have a substantial effect on increasing the accuracy of data. However, many centralized crowdsourcing systems lack security and transparency due to a trusted party's existence. With the emergence of blockchain technology, there has been an increase in security, transparency, and traceability in spatial crowdsourcing systems. In this paper, we propose a blockchain-based spatial crowdsourcing system in which workers confirm or reject the accuracy of tasks. Tasks are reports submitted by requesters to the system; a report comprises type and location. To our best knowledge, the proposed system is the first system that all participants receive rewards. This system considers spatial and non-spatial reward factors to encourage users' participation in collecting accurate spatial information. Privacy preservation and security of spatial information are considered in the system. We also evaluated the system efficiency. According to the experiment results, using the proposed system, information accuracy increased by 40%, and the minimum time for reviewing reports by facilities reduced by 30%. Moreover, we compared the proposed system with the current centralized and distributed crowdsourcing systems. This comparison shows that, although our proposed system omits the user's history to preserve privacy, it considers a consensus-based approach to guarantee submitted reports' accuracy. The proposed system also has a reward mechanism to encourage more participation.

Patterns of changes in bipolar depressive symptoms revealed by trajectory analysis among 482 patients with bipolar disorder.

INTRODUCTION: Depressive episodes are often prevalent among patients with bipolar disorder, but little is known regarding the differential patterns of development over time. We aimed to determine and characterize trajectories of depressive symptoms among adults with bipolar disorder during 6 months of systematic treatment. METHODS: The pragmatic clinical trial, Bipolar Clinical Health Outcomes Initiative in Comparative Effectiveness (CHOICE), randomized 482 outpatients with bipolar disorder to lithium or quetiapine. Depressive symptoms were rated at up to 9 visits using the Montgomery-Asberg Depression Rating Scale (MADRS). Growth mixture modeling was utilized to identify trajectories and multinomial regression analysis estimated associations with potential predictors. RESULTS: Four distinct trajectories of depressive symptoms were identified. The responding class (60.3%) with a rapid reduction and subsequent low level; the partial-responding class (18.4%) with an initial reduction followed by an increase during the remaining weeks; the fluctuating class (11.6%) with a fluctuation in depressive symptoms; and the non-responding class (9.7%) with sustained moderate-severe depressive symptoms. Bipolar type I predicted membership of the non-responding class and randomization to quetiapine predicted membership of either the responding or the non-responding class. CONCLUSION: Approximately 30% experienced a partial or fluctuating course, and almost 10% had a chronic course with moderate-severe depression during 6 months. Patients diagnosed with bipolar type 1 had higher risk of being categorized into a class with a worse outcome. While no differences in average overall outcomes occurred between the lithium and quetiapine groups, trajectory analysis revealed that the lithium group had more variable courses.

Psychosis in bipolar disorder: Does it represent a more "severe" illness?

OBJECTIVES: Although there is a common clinical assumption that bipolar disorder with psychotic features reflects greater severity than bipolar disorder without psychosis, the existing empirical literature is mixed. This study investigated the phenomenology of psychosis as well as demographic, clinical, functional, and neuropsychological features in a large, cross-sectional sample of participants with bipolar disorder divided by history of psychosis. METHODS: In a large single study, 168 affective-only bipolar disorder (BP-A) participants and 213 bipolar disorder with a history of psychosis (BP-P) participants completed a comprehensive clinical diagnostic interview and neuropsychological testing. t tests, chi-square tests, and Bayes factors were used to investigate group differences or lack thereof. RESULTS: The prevalence of psychosis in this sample (53%) was similar to published reports. Nearly half of BP-P participants experienced grandiose delusions, and relatively few endorsed "first-rank" hallucinations of running commentary or two or more voices conversing. There were no demographic or neuropsychological differences between groups. BP-A participants experienced greater chronicity of affective symptoms and a greater degree of rapid cycling than BP-P participants; there were no other clinical differences between groups. CONCLUSIONS: Overall, these results contradict the conventional notion that bipolar disorder with psychotic features represents a more severe illness than bipolar disorder without a history of psychosis. The presence of psychosis does not appear to be associated with poorer clinical/functional outcome or suggest a greater degree of neuropsychological impairment; conversely, the absence of psychosis was associated with affective chronicity and rapid cycling. Nosological and treatment implications are discussed.

A Preliminary Study of Central Nervous System Arousal and Sleep Quality in Bipolar Disorder.

Sleep disturbances are commonly reported in patients with bipolar I disorder (BPI) and are risk factors for mood episodes. In other populations, central nervous system (CNS) hyperarousal is associated with sleep initiation and maintenance problems, and CNS hypoarousal is associated with increased sleep drive. However, it is unclear whether CNS arousal levels are a useful index of sleep disruption in BPI. This study aimed to investigate daytime CNS arousal levels in relation to perceived sleep quality in BPI. Resting EEG, mood state, and self-reported sleep quality data were collected from 34 individuals with BPI. CNS hyperarousal was associated with pervasive poor subjective sleep quality including increased sleep disturbances, increased sleep latency, and reduced global sleep quality. CNS hypoarousal was associated with greater daytime sleepiness, indicating reduced arousal. These preliminary findings suggest that CNS arousal may be a useful index for identifying individuals at high risk for relapse into a mood episode. A limitation of this study is the use of self-report instruments for sleep quality assessment. Future research should investigate the temporal relationship of CNS arousal to sleep disturbances using objective measurements of sleep quality such as polysomnography. If these findings are replicated, measures of CNS arousals may allow for identification of high-risk patients with BPI.

Influence of cognitive reserve on neuropsychological functioning in bipolar disorder: Findings from a 5-year longitudinal study.

OBJECTIVES: The present study examined the 5-year longitudinal course of cognitive functioning in a large sample of well-characterized patients with bipolar disorder (BP), compared to healthy controls (HCs), and the influence of cognitive reserve factors (e.g., education and IQ) on cognitive change over time. METHODS: Participants included 159 individuals diagnosed with BP and 54 HCs recruited as part of a longitudinal naturalistic study of BP who had completed neuropsychological testing at the time of their enrollment and again 5 years later. RESULTS: The overall relative rate of change did not differ between the BP and HC groups. In total, 46.5% of the BP group and 37% of the HC group showed evidence of decline on at least one measure over time. T-test analyses did not find differences between BP 'decliners' and 'non-decliners' in cognitive reserve variables. However, we found that higher baseline intellectual ability was associated with more stability in cognitive test scores over time for the BP group. Results of linear regression modeling revealed that lower verbal IQ and education were related to increased cognitive decline in specific domains in the BP group. CONCLUSIONS: This study has explored the influence of cognitive reserve on preservation of specific cognitive abilities over time in BP. The BP group did not demonstrate accelerated cognitive decline over 5 years compared to the HC group. Although the trajectory of cognitive change over time was similar between BP patients and HCs, higher overall intellectual ability may be a protective factor against cognitive decline, particularly for BP patients.

Substance use disorders in adolescent and young adult relatives of probands with bipolar disorder: What drives the increased risk?

BACKGROUND: Adults with bipolar disorder (BD) have higher rates of substance use disorders (SUDs) compared to the general population. SUD rates in young offspring/relatives of BD probands, as well as factors which drive those rates, are not as well-characterized. METHODS: We aimed to examine SUD prevalence among adolescent/young adult offspring and relatives of probands with and without BD. Data were collected from five sites in the US and Australia during 2006-2011. Youth offspring/relatives ("Relatives of BD probands;" n=267; mean age=16.8years; ±2.9S.D.), identified through a proband family member with DSM-IV BD (Type I or II), were compared to offspring/relatives of control probands ("relatives of control probands;" n=149; mean age=17.4years; ±2.9S.D.). Logistic regression with generalized estimating equations was used to compare the groups across a range of substance use and SUD variables. Odds ratios were calculated for lifetime prevalence of substance outcomes. RESULTS: Bivariate analyses showed DSM-IV SUDs were more prevalent among relatives of BD probands than among relatives of control probands (29% vs. 18%; p=0.01). Generalized estimating equation models showed BD mood and childhood-onset externalizing disorders in adolescent and young adult relatives to each significantly increase the odds (OR=2.80-3.17; p<0.02) for the development of several substance variables among all relatives, whereas the risk of SUDs in relatives was not increased when the relatives had no mood or externalizing disorders themselves. CONCLUSION: Relatives of BD probands with lifetime mood and externalizing disorders report more substance use/SUDs than relatives of control probands. In contrast, SUD outcomes in relatives of BD probands without mood or externalizing disorders were no different from control relatives without psychopathology. Early recognition and treatment of psychiatric disorders may lead to less substance use in this highly vulnerable population.

Identification of non-reported bupropion metabolites in human plasma.

Bupropion and its three active metabolites exhibit clinical efficacy in the treatment of major depression, seasonal depression and smoking cessation. The pharmacokinetics of bupropion in humans is highly variable. It is not known if there are any non-reported metabolites formed in humans in addition to the three known active metabolites. This paper reports newly identified and non-reported metabolites of bupropion in human plasma samples. Human subjects were dosed with a single oral dose of 75 mg of an immediate release bupropion HCl tablet. Plasma samples were collected and analysed by LC-MS/MS at 0, 6 and 24 h. Two non-reported metabolites (M1 and M3) were identified with mass-to-charge (m/z) ratios of 276 (M1, hydration of bupropion) and 258 (M3, hydroxylation of threo/erythrohydrobupropion) from human plasma in addition to the known hydroxybupropion, threo/erythrohydrobupropion and the glucuronidation products of the major metabolites (M2 and M4-M7). These new metabolites may provide new insight and broaden the understanding of bupropion's variability in clinical pharmacokinetics. © 2016 The Authors Biopharmaceutics & Drug Disposition Published by John Wiley & Sons Ltd.

Complexity of illness and adjunctive benzodiazepine use in outpatients with bipolar I or II disorder: results from the Bipolar CHOICE study.

Benzodiazepines are widely prescribed for patients with bipolar disorders in clinical practice, but very little is known about the subtypes of patients with bipolar disorder or aspects of bipolar illness that contribute most to benzodiazepine use. We examined the prevalence of and factors associated with benzodiazepine use among 482 patients with bipolar I or II disorder enrolled in the Bipolar CHOICE study. Eighty-one subjects were prescribed benzodiazepines at study entry and were considered benzodiazepine users. Stepwise logistic regression was used to model baseline benzodiazepine use versus nonuse, using entry and exit criteria of P < 0.1. In bivariate analyses, benzodiazepine users were prescribed a significantly higher number of other psychotropic medications and were more likely to be prescribed lamotrigine or antidepressants as compared with benzodiazepine nonusers. Benzodiazepine users were more likely to have a diagnosis of bipolar I disorder and comorbid anxiety disorder, but not comorbid alcohol or substance use disorders. Benzodiazepine users also had experienced more anxiety and depressive symptoms and suicidality, but not irritability or manic symptoms, than did benzodiazepine nonusers. In the multivariate model, anxiety symptom level (regardless of diagnosis), lamotrigine use, number of concomitant psychotropic medications, college education, and high household income predicted benzodiazepine use. Benzodiazepine use in patients with bipolar disorders is associated with greater illness complexity as indicated by a higher number of concomitant psychotropic medications and higher anxiety symptom burden, regardless of a comorbid anxiety disorder diagnosis. Demographic factors were also important determinants of benzodiazepine use, which may be related to access to care and insurance coverage for benzodiazepines.

Medical burden in bipolar disorder: findings from the Clinical and Health Outcomes Initiative in Comparative Effectiveness for Bipolar Disorder study (Bipolar CHOICE).

OBJECTIVES: Individuals with bipolar disorder have high rates of other medical comorbidity, which is associated with higher mortality rates and worse course of illness. The present study examined common predictors of medical comorbidity. METHODS: The Clinical and Health Outcomes Initiative in Comparative Effectiveness for Bipolar Disorder study (Bipolar CHOICE) enrolled 482 participants with bipolar I or bipolar II disorder in a six-month, randomized comparative effectiveness trial. Baseline assessments included current and lifetime DSM-IV-TR diagnoses, demographic information, psychiatric and medical history, severity of psychiatric symptoms, level of functioning, and a fasting blood draw. Medical comorbidities were categorized into two groups: cardiometabolic (e.g., diabetes, hyperlipidemia, and metabolic syndrome) and non-cardiovascular (e.g., seizures, asthma, and cancer). Additionally, we looked at comorbid substance use (e.g., smoking and drug dependence). RESULTS: We found that 96.3% of participants had at least one other medical comorbidity. Older age predicted a greater likelihood of having a cardiometabolic condition. Early age of onset of bipolar symptoms was associated with a lower chance of having a cardiometabolic condition, but a greater chance of having other types of medical comorbidity. Additional predictors of other medical comorbidities in bipolar disorder included more time spent depressed, less time spent manic/hypomanic, and longer duration of illness. Medications associated with weight gain were associated with low high-density lipoprotein and abnormal triglycerides. CONCLUSIONS: There appears to be a substantial medical burden associated with bipolar disorder, highlighting the need for collaborative care among psychiatric and general medical providers to address both psychiatric and other medical needs concomitantly in this group of patients.

Psychotherapy use in bipolar disorder: Association with functioning and illness severity.

OBJECTIVE: This study examines characteristics of individuals with bipolar disorder who sought psychotherapy versus those who did not. METHODS: Bipolar CHOICE was an 11-site comparative effectiveness study of lithium versus quetiapine in symptomatic outpatients (N = 482) with bipolar disorder. At baseline, participants' psychotherapy use within the past 3 months, mood, functioning, and overall health were assessed. Logistic regressions were used to test whether psychotherapy users and non-users differed on various demographic and clinical variables at baseline. Mixed-effects regression was used to determine whether psychotherapy groups differed on response to treatment over the 6-month study. Kaplan-Meier plots and log-rank tests were employed to test whether there were any differences in time to recovery (CGI-BP ≤ 2 for at least 8 weeks) between the groups. RESULTS: Thirty one percent of participants reported using psychotherapy services. Psychotherapy users reported greater medication side effect burden than non-users and were more likely to have moderate to high suicide risk and at least one anxiety disorder. Participants not utilizing medications or psychotherapy had greater mania symptom severity, were younger, and less educated than medication only users. Medication only users were more likely to be married than the other participants. CONCLUSIONS: These data suggest that a minority of individuals with bipolar disorder attend psychotherapy services, and those that do have greater illness burden.

The double burden of age and disease on cognition and quality of life in bipolar disorder.

OBJECTIVE: Bipolar disorder (BPD) and normal aging are known to impact cognitive skills and health-related quality of life (HRQOL). This study investigated how aging and disease interact in predicting cognitive and psychosocial outcomes. METHODS: Eight cognitive and ten subjective HRQOL domain ratings were measured. Subjects included 80 young (18-29 years) and late middle-aged (50-65 years) BPD patients in the euthymic phase and 70 age-equivalent healthy comparison participants. RESULTS: An age X disease interaction was detected in three domains of cognitive functioning that reflect emotion processing, processing speed, and executive functioning skills, with BPD patients in the older group performing most poorly. There was a double burden of aging and disease on reported ability to perform physical tasks. However, regardless of age, disease status was associated with lower ratings of HRQOL in the psychosocial/affective sphere and the majority of cognitive domains. Post hoc analyses revealed that number of years ill was positively associated with select HRQOL ratings in older, but not younger BPD adults. CONCLUSIONS: These findings may stimulate future longitudinal study of cognition and quality of life in BPD patients across the life span, focusing on additive and interactive effects of aging and disease burden, which could culminate in developing more effective treatment and rehabilitation strategies for this traditionally challenging to treat population.

C9ORF72 expansion in a family with bipolar disorder.

OBJECTIVE: To investigate the role in bipolar disorder of the C9ORF72 hexanucleotide repeat expansion responsible for frontotemporal lobe dementia and amyotrophic lateral sclerosis. METHODS: Eighty-nine subjects from a previously described panel of individuals with bipolar disorder ascertained for genetic studies were screened to detect expansion of the C9ORF72 repeat. One two-generation family with bipolar disorder and an expanded repeat was characterized in depth using molecular diagnostics, imaging, histopathology, and neurological and neuropsychological evaluation. RESULTS: One proband, with the typical clinical presentation of bipolar disorder, carried an expanded C9ORF72 allele of heterogeneous length between 14 and 20 kilobases (kb) as assessed by Southern blot. The expanded allele was inherited from a parent with atypical, late onset clinical features of bipolar disorder, who subsequently progressed to frontotemporal lobe dementia. The expansion in peripheral blood of the parent ranged from 8.5 to 20 kb. Cultured lymphoblastoid cells from this parent exhibited a homogeneous expansion of only 8.5 kb. CONCLUSIONS: The disease course in the two generations described here demonstrates that expansion of the C9ORF72 may be associated with a form of bipolar disorder that presents clinically with classic phenomenology and progression to neurodegenerative disease. The frequency in our bipolar disorder cohort was only 1%, indicating that C9ORF72 is not a major contributor to bipolar disorder. DNA from cultured cells may be biased towards shorter repeats and nonrepresentative of the endogenous C9ORF72 expansion.

A New Treatment Program: Focused Integrated Team-based Treatment Program for Bipolar Disorder (FITT-BD).

OBJECTIVE: Bipolar disorder (BD) is complicated by a dynamic, chronic course along with multiple comorbid psychiatric and medical conditions, making it challenging for clinicians to treat and patients to thrive. To efficiently manage the complexity of BD and help patients recover, we developed a Focused Integrated Team-based Treatment Program for Bipolar Disorder (FITT-BD). The purpose of this paper is to describe how we developed this clinic and the lessons we learned. METHODS: We developed FITT-BD by integrating strategies from stepped care, collaborative care, and learning health care systems. We describe the rationale, details, and lessons learned in developing FITT-BD. RESULTS: By integrating stepped care, collaborative care, and a learning health care system approach, FITT-BD aims to reduce barriers to care, leverage the expertise of a multidisciplinary treatment team, ensure patient-centeredness, and use assessments to inform and continuously improve outcomes in real time. We learned that there are challenges in the creation of a web-based application that tracks the treatment of patients within a network of hospitals. CONCLUSIONS: The success of FITT-BD will be determined by the degree to which it can increase treatment access, improve treatment adherence, and help individuals with BD achieve their treatment goals. We expect that FITT-BD will improve outcomes in the context of ongoing clinical care. PUBLIC HEALTH SIGNIFICANCE: The treatment of BD is challenging and complex. We propose a new treatment model for BD: FITT-BD. We expect that this program will be a patient-centered approach that improves outcomes in the context of ongoing clinical care for patients with BD.

Differential executive functioning performance by phase of bipolar disorder.

OBJECTIVE: This study examined the influence of illness phase on executive functioning performance using factor-derived cognitive scores in a cross-sectional design. METHODS: Healthy control (HC) subjects (n = 57), and euthymic (E-BD) (n = 117), depressed (D-BD) (n = 73), and hypomanic/mixed (HM/M-BD) (n = 26) patients with bipolar disorder (BD) were evaluated using executive functioning measures (Wisconsin Card Sorting Test, Trail Making Test-Parts A and B, Verbal Fluency, Parametric Go/No-Go, Stroop, and Digit Symbol) comprising Conceptual Reasoning and Set-Shifting (CRSS), Processing Speed with Interference Resolution (PSIR), Verbal Fluency and Processing Speed (VFPS), and Inhibitory Control (IC) factor scores. RESULTS: Two of the four executive functioning factors were significantly different between groups based upon phase of illness. The HM/M group was significantly worse than both of the other BD groups and the HC group in IC. The VFPS factor was sensitive to the active phase of BD, with the HM/M-BD and D-BD groups worse than HC. Extending our prior work, the PSIR factor, and now the CRSS factor were significantly worse in BD relative to HC, irrespective of phase of illness. CONCLUSIONS: Phase of illness had differential cognitive profiles in executive functioning factors, even after considering and excluding the impact of clinical features, illness characteristics, medications, and demographics. Consolidating executive functioning tasks into reliable factor scores provides unique information to measure and define cognitive deficiencies throughout phases of BD, and to measure intermediate phenotypes in BD, and may aid in tracking and clarifying treatment focus.

Decreased Psychological Well-Being in Patients With Bipolar Disorder in Remission.

BACKGROUND: The goals of this study were to introduce psychological well-being as an important subject of inquiry in bipolar disorder, to compare well-being in a cohort of patients with bipolar disorder with that of a normative sample, and to assess whether common measures of well-being and mood measure empirically distinct phenomena. METHODS: Participants were outpatients with bipolar I disorder in remission (N=37) from the Enhancing Emotion Regulation in Bipolar Disorder (EERBD) study and a matched community normative sample from the Midlife in the United States (MIDUS) survey (N=6297). The Psychological Well-Being Scale (PWBS) was used to measure psychological well-being. We calculated means and SD of scores on the PWBS and evaluated the differences between the scores of the bipolar I and community samples. We also tested the association between raw and change scores in depression [Hamilton Rating Scale for Depression (HAM-D)] and eudaimonic well-being (PWBS) using Spearman correlation coefficients. RESULTS: The MIDUS survey sample (N=6297) was 48% male, with a mean age of 47 years (SD=13 y). The EERBD sample (N=37) was 27% male, with a mean age of 41 years (SD=11 y). In the bipolar sample, the baseline mean score on the HAM-D was 12.7 (SD=6.0) and the mean score on the Young Mania Rating Scale was 6.1 (SD=6.2). The baseline mean sum score on the PWBS in the normative community MIDUS sample was 100 (SD=14), while that of the bipolar I EERBD sample was 79 (SD=15) at baseline, 84 (SD=13) posttreatment, and 84 (SD=12) at the 3-month follow-up assessment. The effect sizes of the differences at all timepoints were large (Hedges g=1.42 at baseline, 1.11 at the end of treatment, and 1.06 at the 3-mo follow-up). No association was found between the PWBS and depression scores. CONCLUSIONS: Outpatients with bipolar disorder in remission demonstrated substantially impaired psychological well-being, despite low levels of depressive symptoms, compared with a normative community sample.

Illness stage and predominant polarity in bipolar disorder: Correlation with burden of illness and moderation of treatment outcome.

Bipolar disorder often follows a set progression best described in stages where advanced stages are associated with poorer outcomes. Bipolar disorder is also often characterized by a predominance of episode polarity, where some individuals experience more depressive episodes (termed predominant depressive polarity) while others experience more hypo/manic episodes (termed predominant hypo/manic polarity). We examined the associations between staging and predominant polarity with measures of illness burden and treatment outcome utilizing data from a six-month comparative effectiveness trial of lithium and quetiapine in bipolar disorder (Bipolar CHOICE). We used number of self-reported lifetime mood (depressive and hypo/manic) episodes as a proxy for staging and ratio of depressive to manic episodes to define predominant polarity. Polarity and staging were correlated with several measures of burden of illness. Childhood abuse was correlated with more lifetime mood episodes, while more depressive episodes and depressive polarity were correlated with more anxiety disorder comorbidity. Depressive polarity was also correlated with more past trials of psychotropics, particularly antidepressants. However, neither staging nor predominant polarity moderated the randomized treatment effect of lithium vs. quetiapine. Number of depressive episodes in the past year was identified as a potential predictor of overall worse treatment outcome, regardless of medication condition. In conclusion, though staging and predominant episode polarity correlated with several measures of illness burden, they were not associated with differential treatment outcomes. This could be because many of our patients presented for treatment at advanced stages of illness and further highlights the need for early intervention in bipolar disorder.

Developing Dimensional, Pandiagnostic Inhibitory Control Constructs With Self-Report and Neuropsychological Data.

Trait markers, or intermediate phenotypes linking different units of analysis (self-report, performance) from the Research Domain Criteria (RDoC) matrix across populations is a necessary step in identifying at-risk individuals. In the current study, 150 healthy controls (HC) and 456 individuals with bipolar disorder (BD) Type I or II, NOS (not otherwise specified) or Schizoaffective BD completed self-report neuropsychological tests of inhibitory control (IC) and executive functioning. Bifactor analyses were used to examine the factor structure of these measures and to evaluate for invariance across groups. Bifactor analyses found modest convergence of items from neuropsychological tests and self-report measures of IC among HC and BD. The factor scores showed evidence of a general IC construct (i.e., subdomain) across measures. Importantly, invariance testing indicated that the same construct was measured equally well across groups. Groups differed on the general factor for three of the four scales. Convergence on a general IC factor and invariance across diagnosis supports the use of combined dimensional measures to identify clinical risk and highlights how prospective RDoC studies might integrate units of analysis.