Actigraphic patterns, impulsivity and mood instability in bipolar disorder, borderline personality disorder and healthy controls.

OBJECTIVES: To differentiate the relation between the structure and timing of rest-activity patterns and symptoms of impulsivity and mood instability in bipolar disorder (BD), borderline personality disorder (BPD) and healthy controls (HC). METHODS: Eighty-seven participants (31 BD, 21 BPD and 35 HC) underwent actigraph monitoring for 28 days as part of the Automated Monitoring of Symptom Severity (AMoSS) study. Impulsivity was assessed at study entry using the BIS-11. Mood instability was subsequently longitudinally monitored using the digital Mood Zoom questionnaire. RESULTS: BPD participants show several robust and significant correlations between non-parametric circadian rest-activity variables and worsened symptoms. Impulsivity was associated with low interdaily stability (r = -0.663) and weak amplitude (r = -0.616). Mood instability was associated with low interdaily stability (r = -0.773), greater rhythm fragmentation (r = 0.662), weak amplitude (r = -0.694) and later onset of daily activity (r = 0.553). These associations were not present for BD or HCs. Classification analysis using actigraphic measures determined that later L5 onset reliably distinguished BPD from BD and HC but did not sufficiently discriminate between BD and HC. CONCLUSIONS: Rest-activity pattern disturbance indicative of perturbed sleep and circadian function is an important predictor of symptom severity in BPD. This appears to validate the greater subjective complaints of BPD individuals that are sometimes regarded as exaggerated by clinicians. We suggest that treatment strategies directed towards improving sleep and circadian entrainment may in the future be investigated in BPD.

Vitamin D, bone mineral density and risk of fracture in people with intellectual disabilities.

BACKGROUND: People with intellectual disabilities (IDs) have very high rates of osteoporosis and fractures, to which their widespread vitamin D deficiency and other factors could contribute. We aimed to assess in people with IDs previously treated for vitamin D deficiency (1) long-term adherence to vitamin D supplementation and (2) bone mineral density (BMD), as an indicator for risk of fractures, according to vitamin D supplementation and other factors. METHOD: We recorded height, weight, medical, pharmacological, dietary and lifestyle assessment. Blood sample were taken for vitamin D and related analytes. dual-energy X-ray absorptiometry for BMD was performed. RESULTS: Of 51 study participants (mean [standard deviation, SD] age 51.5 [13.6] years, 57% male), 41 (80.4%) were taking vitamin D and 10 were not. Mean [SD] serum vitamin D was 81.3 [21.3] vs. 25.2 [10.2] nmol/L (P < 0.0001), respectively. Thirty-six participants underwent a dual-energy X-ray absorptiometry scan, which showed osteoporosis in 23.7% and osteopenia in 52.6%. Participants on vitamin D had higher BMD than those who were not, a statistically significant difference when confounders (lack of mobility and hypogonadism) were removed. BMD was significantly different according to mobility, particularly in wheelchair users, in whom hip BMD was 33% lower (P < 0.0001) than in participants with normal mobility. Participants still taking vitamin D showed a 6.1% increase in BMD at the spine (P = 0.003) after mean [SD] 7.4 [1.5] years vitamin D treatment. CONCLUSIONS: In people with IDs and previous vitamin D deficiency, BMD increases on long-term vitamin D supplementation. However, additional strategies must be considered for osteoporosis and fracture prevention in this population.

Variability in phase and amplitude of diurnal rhythms is related to variation of mood in bipolar and borderline personality disorder.

Variable mood is an important feature of psychiatric disorders. However, its measurement and relationship to objective measureas of physiology and behaviour have rarely been studied. Smart-phones facilitate continuous personalized prospective monitoring of subjective experience and behavioural and physiological signals can be measured through wearable devices. Such passive data streams allow novel estimates of diurnal variability. Phase and amplitude of diurnal rhythms were quantified using new techniques that fitted sinusoids to heart rate (HR) and acceleration signals. We investigated mood and diurnal variation for four days in 20 outpatients with bipolar disorder (BD), 14 with borderline personality disorder (BPD) and 20 healthy controls (HC) using a smart-phone app, portable electrocardiogram (ECG), and actigraphy. Variability in negative affect, positive affect, and irritability was elevated in patient groups compared with HC. The study demonstrated convincing associations between variability in subjective mood and objective variability in diurnal physiology. For BPD there was a pattern of positive correlations between mood variability and variation in activity, sleep and HR. The findings suggest BPD is linked more than currently believed with a disorder of diurnal rhythm; in both BPD and BD reducing the variability of sleep phase may be a way to reduce variability of subjective mood.

Biochemical and genetic predictors and correlates of response to lamotrigine and folic acid in bipolar depression: Analysis of the CEQUEL clinical trial.

OBJECTIVES: CEQUEL (Comparative Evaluation of QUEtiapine plus Lamotrigine combination versus quetiapine monotherapy [and folic acid versus placebo] in bipolar depression) was a double-blind, randomized, placebo-controlled, parallel group, 2×2 factorial trial that examined the effect of adding lamotrigine and/or folic acid (FA) to quetiapine in bipolar depression. Lamotrigine improved depression, but its effectiveness was reduced by FA. We investigated the baseline predictors and correlates of clinical response, and the possible basis of the interaction. METHODS: The main outcome was change in depressive symptoms at 12 weeks, measured using the Quick Inventory for Depressive Symptoms-self report version 16 (QIDS-SR16). We examined the relationship between symptoms and lamotrigine levels, and biochemical measures of one-carbon metabolism and functional polymorphisms in catechol-O-methyltransferase (COMT), methylene tetrahydrofolate reductase (MTHFR) and folate hydrolase 1 (FOLH1). RESULTS: Lamotrigine levels were unaffected by FA and did not differ between those participants who achieved remission and those with persisting symptoms. When participants with subtherapeutic serum levels were excluded, there was a main effect of lamotrigine on the main outcome, although this remained limited to those randomized to FA placebo. None of the biochemical measures correlated with clinical outcome. The negative impact of FA on lamotrigine response was limited to COMT Met carriers. FOLH1 and MTHFR had no effect. CONCLUSIONS: Our results clarify that FA's inhibition of lamotrigine's efficacy is not a pharmacokinetic effect, and that low serum lamotrigine levels contributed to lamotrigine's lack of a main effect at 12 weeks. We were unable to explain the lamotrigine-FA interaction, but our finding that it is modulated by the COMT genotype provides a starting point for follow-on neurobiological investigations. More broadly, our results highlight the value of including biochemical and genetic indices in randomized clinical trials.

Remote mood monitoring for adults with bipolar disorder: An explorative study of compliance and impact on mental health service use and costs.

BACKGROUND: Remote monitoring of mood disorders may be an effective and low resource option for patient follow-up, but relevant evidence remains very limited. This study explores real-life compliance and health services impacts of mood monitoring among patients with bipolar disorder in the UK. METHODS: Patients with a diagnosis of bipolar disorder who were registered users of the True Colours monitoring system for at least 12months at study assessment were included in this retrospective cohort study (n=79). Compliance was measured as the proportion of valid depression and mania scale messages received in comparison to their expected numbers over the first 12months of monitoring. Mental health service use data were extracted from case notes, costed using national unit costs, and compared 12months before (pre-TC period) and 12months after (TC period) patients' engagement with monitoring. Associations with relevant patient factors were investigated in a multiple regression model. RESULTS: Average compliance with monitoring was 82%. Significant increases in the annual use and costs of psychiatrist contacts and total mental health services were shown for patients newly referred to the clinic during the pre-TC period but not for long-term patients of the clinic. Psychiatric medication costs increased significantly between the pre-TC and TC periods (£235, P=0.005) unrelated to patients' referral status. CONCLUSIONS: Remote mood monitoring has good compliance among consenting patients with bipolar disorder. We found no associations between observed changes in mental health service costs and the introduction of monitoring except for the increase in psychiatric medication costs.

Emotional blunting with antidepressant treatments: A survey among depressed patients.

BACKGROUND: Emotional blunting is regularly reported in depressed patients on antidepressant treatment but its actual frequency is poorly understood. We have previously used qualitative methods to develop an appropriate scale, the Oxford Questionnaire on the Emotional Side-Effects of Antidepressants (OQESA). METHODS RESULTS: Six hundred and sixty nine depressed patients on treatment and 150 recovered (formerly depressed) controls (aged ≥18 years) participated in this internet-based survey. The rate of emotional blunting in treated depressed patients was 46%, slightly more frequent in men than women (52% versus 44%) and in those with higher Hospital Anxiety and Depression (HAD) scale scores. There was no difference according to antidepressant agent, though it appeared less frequent with bupropion. Depressed patients with emotional blunting had much higher total blunting scores on OQESA than controls (42.83 ± 14.73 versus 25.73 ± 15.00, p < 0.0001) and there was a correlation between total blunting score and HAD-Depression score (r = 0.521). Thus, those with HAD-D score >7 (n = 170) had a higher total questionnaire score, 49.23±12.03, than those with HAD-D score ≤7 (n = 140), 35.07 ± 13.98, and the difference between the two groups was highly significant. However, patients with HAD-D score ≤7 (n = 140) had a higher total score (35.07 ± 13.98) than the recovered controls (n = 150) (25.73 ± 15.00), and the difference between the two groups was significant. Among the patients with emotional blunting, 37% had a negative perception of their condition and 38% positive. Men reported a more negative perception than women (p=0.008), and patients with a negative perception were more likely to have higher HAD scores. Higher levels of emotional blunting are associated with a more negative perception of it by the patient (r = -0.423). LIMITATIONS: Include self-evaluation and the modest size of the sample for detection of differences between antidepressants. CONCLUSIONS: Emotional blunting is reported by nearly half of depressed patients on antidepressants. It appears to be common to all monoaminergic antidepressants. The OQESA scores are highly correlated with HAD depression score; emotional blunting cannot be described simply as a side-effect of antidepressants, but also as a symptom of depression. A higher degree of emotional blunting is associated with a poorer quality of remission. The OQESA scale allows the detection of this phenomenon.

The dopamine hypothesis of bipolar affective disorder: the state of the art and implications for treatment.

Bipolar affective disorder is a common neuropsychiatric disorder. Although its neurobiological underpinnings are incompletely understood, the dopamine hypothesis has been a key theory of the pathophysiology of both manic and depressive phases of the illness for over four decades. The increased use of antidopaminergics in the treatment of this disorder and new in vivo neuroimaging and post-mortem studies makes it timely to review this theory. To do this, we conducted a systematic search for post-mortem, pharmacological, functional magnetic resonance and molecular imaging studies of dopamine function in bipolar disorder. Converging findings from pharmacological and imaging studies support the hypothesis that a state of hyperdopaminergia, specifically elevations in D2/3 receptor availability and a hyperactive reward processing network, underlies mania. In bipolar depression imaging studies show increased dopamine transporter levels, but changes in other aspects of dopaminergic function are inconsistent. Puzzlingly, pharmacological evidence shows that both dopamine agonists and antidopaminergics can improve bipolar depressive symptoms and perhaps actions at other receptors may reconcile these findings. Tentatively, this evidence suggests a model where an elevation in striatal D2/3 receptor availability would lead to increased dopaminergic neurotransmission and mania, whilst increased striatal dopamine transporter (DAT) levels would lead to reduced dopaminergic function and depression. Thus, it can be speculated that a failure of dopamine receptor and transporter homoeostasis might underlie the pathophysiology of this disorder. The limitations of this model include its reliance on pharmacological evidence, as these studies could potentially affect other monoamines, and the scarcity of imaging evidence on dopaminergic function. This model, if confirmed, has implications for developing new treatment strategies such as reducing the dopamine synthesis and/or release in mania and DAT blockade in bipolar depression.

Detecting Bipolar Depression From Geographic Location Data.

OBJECTIVE: This paper aims to identify periods of depression using geolocation movements recorded from mobile phones in a prospective community study of individuals with bipolar disorder (BD). METHODS: Anonymized geographic location recordings from 22 BD participants and 14 healthy controls (HC) were collected over 3 months. Participants reported their depressive symptomatology using a weekly questionnaire (QIDS-SR16). Recorded location data were preprocessed by detecting and removing imprecise data points and features were extracted to assess the level and regularity of geographic movements of the participant. A subset of features were selected using a wrapper feature selection method and presented to 1) a linear regression model and a quadratic generalized linear model with a logistic link function for questionnaire score estimation; and 2) a quadratic discriminant analysis classifier for depression detection in BD participants based on their questionnaire responses. R esults: HC participants did not report depressive symptoms and their features showed similar distributions to nondepressed BD participants. Questionnaire score estimation using geolocation-derived features from BD participants demonstrated an optimal mean absolute error rate of 3.73, while depression detection demonstrated an optimal (median ± IQR) [Formula: see text] score of 0.857 ± 0.022 using five features (classification accuracy: 0.849 ± 0.016; sensitivity: 0.839 ± 0.014; specificity: 0.872 ± 0.047). CONCLUSION: These results demonstrate a strong link between geographic movements and depression in bipolar disorder. S ignificance: To our knowledge, this is the first community study of passively recorded objective markers of depression in bipolar disorder of this scale. The techniques could help individuals monitor their depression and enable healthcare providers to detect those in need of care or treatment.

Experiences of remote mood and activity monitoring in bipolar disorder: A qualitative study.

BACKGROUND: Mobile technology enables high frequency mood monitoring and automated passive collection of data (e.g. actigraphy) from patients more efficiently and less intrusively than has previously been possible. Such techniques are increasingly being deployed in research and clinical settings however little is known about how such approaches are experienced by patients. Here, we explored the experiences of individuals with bipolar disorder engaging in a study involving mood and activity monitoring with a range of portable and wearable technologies. METHOD: Patients were recruited from a wider sample of 50 individuals with Bipolar Disorder taking part in the Automated Monitoring of Symptom Severity (AMoSS) study in Oxford. A sub-set of 21 patients participated in a qualitative interview that followed a semi-structured approach. RESULTS: Monitoring was associated with benefits including increased illness insight, behavioural change. Concerns were raised about the potential preoccupation with, and paranoia about, monitoring. Patients emphasized the need for personalization, flexibility, and the importance of context, when monitoring mood. CONCLUSIONS: Mobile and electronic health approaches have potential to lend new insights into mental health and transform healthcare. Capitalizing on the perceived utility of these approaches from the patients' perspective, while addressing their concerns, will be essential for the promise of new technologies to be realised.

Associations between mood instability and emotional processing in a large cohort of bipolar patients.

BACKGROUND: Aberrant emotional biases have been reported in bipolar disorder (BD), but results are inconsistent. Despite the clinical relevance of chronic mood variability in BD, there is no previous research investigating how the extent of symptom fluctuations in bipolar disorder might relate to emotional biases. This exploratory study investigated, in a large cohort of bipolar patients, whether instability in weekly mood episode symptoms and other clinical and demographic factors were related to emotional bias as measured in a simple laboratory task. METHOD: Participants (N = 271, BDI = 206, BDII = 121) completed an 'emotional categorization and memory' task. Weekly self-reported symptoms of depression and mania were collected prospectively. In linear regression analyses, associations between cognitive bias and mood variability were explored together with the influence of demographic and clinical factors, including current medication. RESULTS: Greater accuracy in the classification of negative words relative to positive words was associated with greater instability in depressive symptoms. Furthermore, greater negative bias in free recall was associated with higher instability in manic symptoms. Participants diagnosed with BDII, compared with BDI, showed overall better word recognition and recall. Current antipsychotic use was associated with reduced instability in manic symptoms but this did not impact on emotional processing performance. CONCLUSIONS: Emotional processing biases in bipolar disorder are related to instability in mood. These findings prompt further investigation into the underpinnings as well as clinical significance of mood instability.

Evidence-based guidelines for treating bipolar disorder: Revised third edition recommendations from the British Association for Psychopharmacology.

The British Association for Psychopharmacology guidelines specify the scope and targets of treatment for bipolar disorder. The third version is based explicitly on the available evidence and presented, like previous Clinical Practice Guidelines, as recommendations to aid clinical decision making for practitioners: it may also serve as a source of information for patients and carers, and assist audit. The recommendations are presented together with a more detailed review of the corresponding evidence. A consensus meeting, involving experts in bipolar disorder and its treatment, reviewed key areas and considered the strength of evidence and clinical implications. The guidelines were drawn up after extensive feedback from these participants. The best evidence from randomized controlled trials and, where available, observational studies employing quasi-experimental designs was used to evaluate treatment options. The strength of recommendations has been described using the GRADE approach. The guidelines cover the diagnosis of bipolar disorder, clinical management, and strategies for the use of medicines in short-term treatment of episodes, relapse prevention and stopping treatment. The use of medication is integrated with a coherent approach to psychoeducation and behaviour change.

Subcortical volumetric abnormalities in bipolar disorder.

Considerable uncertainty exists about the defining brain changes associated with bipolar disorder (BD). Understanding and quantifying the sources of uncertainty can help generate novel clinical hypotheses about etiology and assist in the development of biomarkers for indexing disease progression and prognosis. Here we were interested in quantifying case-control differences in intracranial volume (ICV) and each of eight subcortical brain measures: nucleus accumbens, amygdala, caudate, hippocampus, globus pallidus, putamen, thalamus, lateral ventricles. In a large study of 1710 BD patients and 2594 healthy controls, we found consistent volumetric reductions in BD patients for mean hippocampus (Cohen's d=-0.232; P=3.50 × 10-7) and thalamus (d=-0.148; P=4.27 × 10-3) and enlarged lateral ventricles (d=-0.260; P=3.93 × 10-5) in patients. No significant effect of age at illness onset was detected. Stratifying patients based on clinical subtype (BD type I or type II) revealed that BDI patients had significantly larger lateral ventricles and smaller hippocampus and amygdala than controls. However, when comparing BDI and BDII patients directly, we did not detect any significant differences in brain volume. This likely represents similar etiology between BD subtype classifications. Exploratory analyses revealed significantly larger thalamic volumes in patients taking lithium compared with patients not taking lithium. We detected no significant differences between BDII patients and controls in the largest such comparison to date. Findings in this study should be interpreted with caution and with careful consideration of the limitations inherent to meta-analyzed neuroimaging comparisons.

Applications of time-series analysis to mood fluctuations in bipolar disorder to promote treatment innovation: a case series.

Treatment innovation for bipolar disorder has been hampered by a lack of techniques to capture a hallmark symptom: ongoing mood instability. Mood swings persist during remission from acute mood episodes and impair daily functioning. The last significant treatment advance remains Lithium (in the 1970s), which aids only the minority of patients. There is no accepted way to establish proof of concept for a new mood-stabilizing treatment. We suggest that combining insights from mood measurement with applied mathematics may provide a step change: repeated daily mood measurement (depression) over a short time frame (1 month) can create individual bipolar mood instability profiles. A time-series approach allows comparison of mood instability pre- and post-treatment. We test a new imagery-focused cognitive therapy treatment approach (MAPP; Mood Action Psychology Programme) targeting a driver of mood instability, and apply these measurement methods in a non-concurrent multiple baseline design case series of 14 patients with bipolar disorder. Weekly mood monitoring and treatment target data improved for the whole sample combined. Time-series analyses of daily mood data, sampled remotely (mobile phone/Internet) for 28 days pre- and post-treatment, demonstrated improvements in individuals' mood stability for 11 of 14 patients. Thus the findings offer preliminary support for a new imagery-focused treatment approach. They also indicate a step in treatment innovation without the requirement for trials in illness episodes or relapse prevention. Importantly, daily measurement offers a description of mood instability at the individual patient level in a clinically meaningful time frame. This costly, chronic and disabling mental illness demands innovation in both treatment approaches (whether pharmacological or psychological) and measurement tool: this work indicates that daily measurements can be used to detect improvement in individual mood stability for treatment innovation (MAPP).

Distinguishing bipolar disorder from borderline personality disorder: A study of current clinical practice.

BACKGROUND: Diagnosing mental illness is a central role for psychiatrists. Correct diagnosis informs both treatment and prognosis, and facilitates accurate communication. We sought to explore how psychiatrists distinguished two common psychiatric diagnoses: bipolar disorder (BD) and borderline personality disorder (BPD). METHODS: We conducted a qualitative study of psychiatrists to explore their practical experience. We then sought to validate these results by conducting a questionnaire study testing the theoretical knowledge and practical experience of a large number of UK psychiatrists. Finally we studied the assessment process in NHS psychiatric teams by analysing GP letters, assessments by psychiatrists, and assessment letters. RESULTS: There was broad agreement in both the qualitative and questionnaire studies that the two diagnoses can be difficult to distinguish. The majority of psychiatrists demonstrated in survey responses a comprehensive understanding DSM-IV-TR criteria although many felt that these criteria did not necessarily assist diagnostic differentiation. This scepticism about diagnostic criteria appeared to strongly influence clinical practice in the sample of clinicians we observed. In only a minority of assessments were symptoms of mania or BPD sufficiently assessed to establish the presence or absence of each diagnosis. CONCLUSION: Clinical diagnostic practice was not adequate to differentiate reliably BD and BPD. The absence of reliable diagnostic practice has widespread implications for patient care, service provision and the reliability of clinical case registries.

Borderline personality disorder, but not euthymic bipolar disorder, is associated with a failure to sustain reciprocal cooperative behaviour: implications for spectrum models of mood disorders.

BACKGROUND: Borderline personality disorder (BPD) and bipolar disorder (BD) have overlapping clinical presentations and symptoms - sources of persistent clinical confusion. Game-theory can characterize how social function might be sub-optimal in the two disorders and move the field beyond the anecdotal description of clinical history. Here, we tested the hypothesis that BPD and BD can be distinguished on the basis of diminished reciprocal altruism in iterated Prisoner's Dilemma (PD) games. METHOD: Twenty females with BPD, 20 females with euthymic BD and 20 healthy (non-clinical) females, matched for age and cognitive ability, were assessed for Axis-I and personality disorders, and completed psychometric measures of state affect, impulsivity and hostility. Participants completed two iterated PD games and a test of gaze-cueing. RESULTS: In the PD games, BPD participants failed to show statistically stable preferences to cooperate with social partners (playing tit-for-tat) and made significantly fewer cooperative responses compared to BD or controls (ANOVA main effect p = 0.03, post-hoc Tukey p < 0.05 for both comparisons). BPD participants were also less likely to sustain cooperation following experiences involving mutual cooperation than the other groups. Neither BPD nor BD participants demonstrated impairments in shifting visual attention on the basis of other peoples' gaze. CONCLUSIONS: These data indicate that BPD is (selectively) associated with difficulties in establishing, and then maintaining, reciprocal cooperation, involving altruism. These difficulties are not seen in euthymic BD. Our data support the differentiation of BPD from BD and offer fresh insights into the social difficulties experienced by individuals with diagnoses of BPD.

Altered plasma glutathione levels in bipolar disorder indicates higher oxidative stress; a possible risk factor for illness onset despite normal brain-derived neurotrophic factor (BDNF) levels.

BACKGROUND: Oxidative stress and neurotrophic factors have been implicated in the pathophysiology of bipolar disorder. Our objective was to determine whether plasma glutathione or brain-derived neurotrophic factor (BDNF) levels were abnormal in bipolar disorder and therefore useful as possible biomarkers. METHOD: Blood samples were collected from subsyndromal, medicated bipolar I patients (n = 50), recruited from OXTEXT, University of Oxford, and from 50 matched healthy controls. Total and oxidized glutathione levels were measured using an enzymatic recycling method and used to calculate reduced, percentage oxidized, ratio of reduced:oxidized and redox state. BDNF was measured using an enzyme-linked immunoassay. Self-monitored mood scores for the bipolar group were available (Quick Inventory of Depressive Symptomatology and the Altman Self-Rating Mania Scale) over an 8-week period. RESULTS: Compared with controls, bipolar patients had significantly lower levels of total glutathione and it was more oxidized. BDNF levels were not different. Age of illness onset but not current mood state correlated with total glutathione levels and its oxidation status, so that lower levels of total and reduced glutathione were associated with later onset of disease, not length of illness. CONCLUSIONS: Plasma glutathione levels and redox state detect oxidative stress even in subsyndromal patients with normal BDNF. It may relate to the onset and development of bipolar disorder. Plasma glutathione appears to be a suitable biomarker for detecting underlying oxidative stress and for evaluating the efficacy of antioxidant intervention studies.

Neuropsychological testing of cognitive impairment in euthymic bipolar disorder: an individual patient data meta-analysis.

OBJECTIVE: An association between bipolar disorder and cognitive impairment has repeatedly been described, even for euthymic patients. Findings are inconsistent both across primary studies and previous meta-analyses. This study reanalysed 31 primary data sets as a single large sample (N = 2876) to provide a more definitive view. METHOD: Individual patient and control data were obtained from original authors for 11 measures from four common neuropsychological tests: California or Rey Verbal Learning Task (VLT), Trail Making Test (TMT), Digit Span and/or Wisconsin Card Sorting Task. RESULTS: Impairments were found for all 11 test-measures in the bipolar group after controlling for age, IQ and gender (Ps ≤ 0.001, E.S. = 0.26-0.63). Residual mood symptoms confound this result but cannot account for the effect sizes found. Impairments also seem unrelated to drug treatment. Some test-measures were weakly correlated with illness severity measures suggesting that some impairments may track illness progression. CONCLUSION: This reanalysis supports VLT, Digit Span and TMT as robust measures of cognitive impairments in bipolar disorder patients. The heterogeneity of some test results explains previous differences in meta-analyses. Better controlling for confounds suggests deficits may be smaller than previously reported but should be tracked longitudinally across illness progression and treatment.