Bias in emerging biomarkers for bipolar disorder

BACKGROUND: To date no comprehensive evaluation has appraised the likelihood of bias or the strength of the evidence of peripheral biomarkers for bipolar disorder (BD). Here we performed an umbrella review of meta-analyses of peripheral non-genetic biomarkers for BD. METHOD: The Pubmed/Medline, EMBASE and PsycInfo electronic databases were searched up to May 2015. Two independent authors conducted searches, examined references for eligibility, and extracted data. Meta-analyses in any language examining peripheral non-genetic biomarkers in participants with BD (across different mood states) compared to unaffected controls were included. RESULTS: Six references, which examined 13 biomarkers across 20 meta-analyses (5474 BD cases and 4823 healthy controls) met inclusion criteria. Evidence for excess of significance bias (i.e. bias favoring publication of 'positive' nominally significant results) was observed in 11 meta-analyses. Heterogeneity was high for (I 2 ⩾ 50%) 16 meta-analyses. Only two biomarkers met criteria for suggestive evidence namely the soluble IL-2 receptor and morning cortisol. The median power of included studies, using the effect size of the largest dataset as the plausible true effect size of each meta-analysis, was 15.3%. CONCLUSIONS: Our findings suggest that there is an excess of statistically significant results in the literature of peripheral biomarkers for BD. Selective publication of 'positive' results and selective reporting of outcomes are possible mechanisms.

Caregiver burden as a predictor of depression among family and friends who provide care for persons with bipolar disorder

OBJECTIVES: Over one-third of caregivers of people with bipolar disorder report clinically significant levels of depressive symptoms. This study examined the causal relationship between depression and caregiver burden in a large sample of caregivers of adult patients with bipolar disorder. METHODS: Participants were 500 primary caregivers of persons with bipolar disorder enrolled in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD).This study evaluates the strength and direction of the associations between caregiver burden and depressive symptoms at baseline and at six- and 12-month follow-up using cross-lagged panel analyses, controlling for the clinical status of patients and sociodemographic variables. RESULTS: Higher levels of overall caregiver burden at baseline were associated with increased levels of depressive symptoms among caregivers at follow-up (F = 8.70, df = 1,290, p < 0.001), after controlling for baseline caregiver depression, gender, race, age, social support, and patients' clinical status. By contrast, caregiver depression at baseline was not significantly associated with caregiver burden at follow-up (F = 1.65, p = 0.20). CONCLUSIONS: Caregiver burden is a stronger predictor of caregiver depressive symptoms over time than the reverse. Interventions that help alleviate caregiver burden may decrease depressive symptoms.

Bipolar disorder

Bipolar disorder is a recurrent chronic disorder characterised by fluctuations in mood state and energy. It affects more than 1% of the world's population irrespective of nationality, ethnic origin, or socioeconomic status. Bipolar disorder is one of the main causes of disability among young people, leading to cognitive and functional impairment and raised mortality, particularly death by suicide. A high prevalence of psychiatric and medical comorbidities is typical in affected individuals. Accurate diagnosis of bipolar disorder is difficult in clinical practice because onset is most commonly a depressive episode and looks similar to unipolar depression. Moreover, there are currently no valid biomarkers for the disorder. Therefore, the role of clinical assessment remains key. Detection of hypomanic periods and longitudinal assessment are crucial to differentiate bipolar disorder from other conditions. Current knowledge of the evolving pharmacological and psychological strategies in bipolar disorder is of utmost importance.

A cluster analytic approach to identifying predictors and moderators of psychosocial treatment for bipolar depression: results from STEP-BD

Background We sought to address how predictors and moderators of psychotherapy for bipolar depression - identified individually in prior analyses - can inform the development of a metric for prospectively classifying treatment outcome in intensive psychotherapy (IP) versus collaborative care (CC) adjunctive to pharmacotherapy in the Systematic Treatment Enhancement Program (STEP-BD) study. Methods We conducted post-hoc analyses on 135 STEP-BD participants using cluster analysis to identify subsets of participants with similar clinical profiles and investigated this combined metric as a moderator and predictor of response to IP. We used agglomerative hierarchical cluster analyses and k-means clustering to determine the content of the clinical profiles. Logistic regression and Cox proportional hazard models were used to evaluate whether the resulting clusters predicted or moderated likelihood of recovery or time until recovery. Results The cluster analysis yielded a two-cluster solution: 1) "less-recurrent/severe" and 2) "chronic/recurrent." Rates of recovery in IP were similar for less-recurrent/severe and chronic/recurrent participants. Less-recurrent/severe patients were more likely than chronic/recurrent patients to achieve recovery in CC (p=.040, OR=4.56). IP yielded a faster recovery for chronic/recurrent participants, whereas CC led to recovery sooner in the less-recurrent/severe cluster (p=.034, OR=2.62). Limitations Cluster analyses require list-wise deletion of cases with missing data so we were unable to conduct analyses on all STEP-BD participants. Conclusions A well-powered, parametric approach can distinguish patients based on illness history and provide clinicians with symptom profiles of patients that confer differential prognosis in CC vs. IP.

Internet use by patients with bipolar disorder: results from an international multisite survey

There is considerable international interest in online education of patients with bipolar disorder, yet little understanding of how patients use the Internet and other sources to seek information. 1171 patients with a diagnosis of bipolar disorder in 17 countries completed a paper-based, anonymous survey. 81% of the patients used the Internet, a percentage similar to the general public. Older age, less education, and challenges in country telecommunications infrastructure and demographics decreased the odds of using the Internet. About 78% of the Internet users looked online for information on bipolar disorder or 63% of the total sample. More years of education in relation to the country mean, and feeling very confident about managing life decreased the odds of seeking information on bipolar disorder online, while having attended support groups increased the odds. Patients who looked online for information on bipolar disorder consulted medical professionals plus a mean of 2.3 other information sources such as books, physician handouts, and others with bipolar disorder. Patients not using the Internet consulted medical professionals plus a mean of 1.6 other information sources. The percentage of patients with bipolar disorder who use the Internet is about the same as the general public. Other information sources remain important.

Mitochondrial dysfunction in bipolar disorder: evidence, pathophysiology and translational implications

Bipolar disorder (BD) is a chronic psychiatric illness characterized by severe and biphasic changes in mood. Several pathophysiological mechanisms have been hypothesized to underpin the neurobiology of BD, including the presence of mitochondrial dysfunction. A confluence of evidence points to an underlying dysfunction of mitochondria, including decreases in mitochondrial respiration, high-energy phosphates and pH; changes in mitochondrial morphology; increases in mitochondrial DNA polymorphisms; and downregulation of nuclear mRNA molecules and proteins involved in mitochondrial respiration. Mitochondria play a pivotal role in neuronal cell survival or death as regulators of both energy metabolism and cell survival and death pathways. Thus, in this review, we discuss the genetic and physiological components of mitochondria and the evidence for mitochondrial abnormalities in BD. The final part of this review discusses mitochondria as a potential target of therapeutic interventions in BD.

Study protocol for a systematic review of evidence for lifestyle interventions targeting smoking, sleep, alcohol/other drug use, physical activity, and healthy diet in people with bipolar disorder

BACKGROUND: People with bipolar disorder (BD) have a mortality gap of up to 20 years compared to the general population. Physical conditions, such as cardiovascular disease (CVD) and cancer, cause the majority of excess deaths in psychiatric populations and are the leading causes of mortality in people with BD. However, comparatively little attention has been paid to reducing the risk of physical conditions in psychiatric populations. Unhealthy lifestyle behaviors are among the potentially modifiable risk factors for a range of commonly comorbid chronic medical conditions, including CVD, diabetes, and obesity. This systematic review will identify and evaluate the available evidence for effective interventions to reduce risk and promote healthy lifestyle behaviors in BD.

METHODS/DESIGN: We will search MEDLINE, Embase, PsychINFO, Cochrane Database of Systematic Reviews, and CINAHL for published research studies (with at least an abstract published in English) that evaluate behavioral or psychosocial interventions to address the following lifestyle factors in people with BD: tobacco use, physical inactivity, unhealthy diet, overweight or obesity, sleep-wake disturbance, and alcohol/other drug use. Primary outcomes for the review will be changes in tobacco use, level of physical activity, diet quality, sleep quality, alcohol use, and illicit drug use. Data on each primary outcome will be synthesized across available studies in that lifestyle area (e.g., tobacco abstinence, cigarettes smoked per day), and panel of research and clinical experts in each of the target lifestyle behaviors and those experienced with clinical and research with individuals with BD will determine how best to represent data related to that primary outcome. Seven members of the systematic review team will extract data, synthesize the evidence, and rate it for quality. Evidence will be synthesized via a narrative description of the behavioral interventions and their effectiveness in improving the healthy lifestyle behaviors in people with BD.

DISCUSSION: The planned review will synthesize and evaluate the available evidence regarding the behavioral or psychosocial treatment of lifestyle-related behaviors in people with BD. From this review, we will identify gaps in our existing knowledge and research evidence about the management of unhealthy lifestyle behaviors in people with BD. We will also identify potential opportunities to address lifestyle behaviors in BD, with a view to reducing the burden of physical ill-health in this population.

Medical burden, body mass index and the outcome of psychosocial interventions for bipolar depression

Objective: Individuals with bipolar disorder experience a disproportionately high incidence of medical co-morbidity and obesity. These health-related problems are a barrier to recovery from mood episodes and have been linked with unfavorable responses to pharmacological treatment. However, little is known about whether and how these characteristics affect responses to adjunctive psychotherapy. Method: Embedded in the Systematic Treatment Enhancement Program for Bipolar Disorder was a randomized controlled trial of psychotherapy for bipolar depression comparing the efficacy of intensive psychotherapy plus pharmacotherapy with collaborative care (a three-session psycho-educational intervention) plus pharmacotherapy. We conducted a post-hoc analysis to evaluate whether medical burden and body mass index predicted and/or moderated the likelihood of recovery and time until recovery from a depressive episode among patients in the two treatments. Results: Participants who had medical co-morbidity and body mass index data constituted 199 of the 293 patients in the original Systematic Treatment Enhancement Program for Bipolar Disorder trial. Higher medical burden predicted a lower likelihood of recovery from depression in both treatment conditions (odds ratio = 0.89), but did not moderate responses to intensive psychotherapy vs collaborative care. Intensive psychotherapy yielded superior recovery rates for individuals of normal body mass index (odds ratio= 2.39) compared with collaborative care, but not among individuals who were overweight or obese. Conclusion: Medical co-morbidity and body weight impacts symptom improvement and attention to this co-morbidity may inform the development of more personalized treatments for bipolar disorder.

Effective self-management strategies for bipolar disorder: a community-engaged Delphi consensus consultation study

BACKGROUND: Self-management represents an important complement to psychosocial treatments for bipolar disorder (BD), but research is limited. Specifically, little is known about self-management approaches for elevated mood states; this study investigated self-management strategies for: (1) maintaining balance in mood, and (2) stopping progression into hypomania/mania. METHODS: To identify the common components of BD self-management, Delphi Consensus Consultation methods were combined with a Community-Based Participatory Research (CBPR) approach across five study phases: (1) Qualitative dataset content analysis; (2) Academic/grey literature reviews; (3) Content analysis; (4) Two Delphi rounds (rating strategies on a 5-point Likert scale, Very Unhelpful-Very Helpful), and; (5) Quantitative analysis and interpretation. Participants were people with BD and healthcare providers. RESULTS: Phases 1 and 2 identified 262 and 3940 candidate strategies, respectively; 3709 were discarded as duplicates/unintelligible. The remaining 493 were assessed via Delphi methods in Phase 4: 101 people with BD and 52 healthcare providers participated in Round 1; 83 of the BD panel (82%) and 43 of the healthcare provider panel (83%) participated in Round 2-exploratory factor analysis (EFA) was conducted on Round 2 results. LIMITATIONS: EFA was underpowered and sample was not ethnically diverse, limiting generalizability. DISCUSSION: High concordance was observed in ratings of strategy effectiveness between the two panels. Future research could usefully investigate the provisional discovery here of underlying factors which link individual strategies. For example, 'maintaining hope' underpinned strategies for maintaining balance, and 'decreasing use of stimulants' underpinned strategies to interrupt hypo/manic ascent. There is merit in combining CBPR and Delphi methods.

Online information seeking by patients with bipolar disorder: results from an international multisite survey

BACKGROUND: Information seeking is an important coping mechanism for dealing with chronic illness. Despite a growing number of mental health websites, there is little understanding of how patients with bipolar disorder use the Internet to seek information.

METHODS: A 39 question, paper-based, anonymous survey, translated into 12 languages, was completed by 1222 patients in 17 countries as a convenience sample between March 2014 and January 2016. All patients had a diagnosis of bipolar disorder from a psychiatrist. Data were analyzed using descriptive statistics and generalized estimating equations to account for correlated data.

RESULTS: 976 (81 % of 1212 valid responses) of the patients used the Internet, and of these 750 (77 %) looked for information on bipolar disorder. When looking online for information, 89 % used a computer rather than a smartphone, and 79 % started with a general search engine. The primary reasons for searching were drug side effects (51 %), to learn anonymously (43 %), and for help coping (39 %). About 1/3 rated their search skills as expert, and 2/3 as basic or intermediate. 59 % preferred a website on mental illness and 33 % preferred Wikipedia. Only 20 % read or participated in online support groups. Most patients (62 %) searched a couple times a year. Online information seeking helped about 2/3 to cope (41 % of the entire sample). About 2/3 did not discuss Internet findings with their doctor.

CONCLUSION: Online information seeking helps many patients to cope although alternative information sources remain important. Most patients do not discuss Internet findings with their doctor, and concern remains about the quality of online information especially related to prescription drugs. Patients may not rate search skills accurately, and may not understand limitations of online privacy. More patient education about online information searching is needed and physicians should recommend a few high quality websites.

C-reactive protein concentrations across the mood spectrum in bipolar disorder: a systematic review and meta-analysis

BACKGROUND: Inflammatory processes and neural-immune interactions have been implicated in the pathogenesis of psychiatric conditions, but studies in bipolar disorder are inconclusive so far. We aimed to investigate whether peripheral concentrations of C-reactive protein (CRP), an acute-phase response protein of inflammatory activity, are increased in bipolar disorder across the mood spectrum. METHODS: In this systematic review and meta-analysis, we searched MEDLINE, the Cochrane Library, Scopus, and Web of Knowledge from database inception to Aug 14, 2016, for studies that measured serum and plasma CRP concentrations in adult patients with bipolar disorder (as defined by DSM-IV-TR) and healthy controls. We extracted data from published reports. We did three between-group meta-analyses comparing CRP concentrations in patients in mania, depression, or euthymia, with those in healthy controls (cross-sectional studies), and two within-group meta-analyses comparing changes in CRP concentrations before and after treatment of an index manic or depressive episode (longitudinal studies). We used Hedges' adjusted g to calculate effect sizes and pooled results using random-effect models. We also did meta-regression analyses by mood state to investigate possible moderators of CRP concentrations. FINDINGS: We identified 27 studies representing 2161 patients with bipolar disorder and 81 932 healthy controls. Compared with healthy individuals, CRP concentrations were moderately increased in people with bipolar disorder during depression (g 0·67, 95% CI 0·23 to 1·11; p=0·003) and euthymia (0·65, 0·40 to 0·90; p<0·0001) and more substantially increased during mania (0·87, 0·58 to 1·15; p<0·0001). The extent of the increases in CRP concentrations in mania and depression was not related to symptom severity (p=0·256 for mania and p=0·626 for depression). CRP concentrations were moderately decreased after resolution of an index manic episode (-0·36, -0·66 to -0·05; p=0·022) and slightly decreased after resolution of an index depressive episode (-0·18, -0·30 to -0·07; p=0·002). INTERPRETATION: CRP concentrations are increased in bipolar disorder regardless of mood state, but are higher during mania than in depression and euthymia, suggesting an increased inflammatory burden in mania.