What we learn about bipolar disorder from large-scale neuroimaging: Findings and future directions from the ENIGMA Bipolar Disorder Working Group.

MRI-derived brain measures offer a link between genes, the environment and behavior and have been widely studied in bipolar disorder (BD). However, many neuroimaging studies of BD have been underpowered, leading to varied results and uncertainty regarding effects. The Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Bipolar Disorder Working Group was formed in 2012 to empower discoveries, generate consensus findings and inform future hypothesis-driven studies of BD. Through this effort, over 150 researchers from 20 countries and 55 institutions pool data and resources to produce the largest neuroimaging studies of BD ever conducted. The ENIGMA Bipolar Disorder Working Group applies standardized processing and analysis techniques to empower large-scale meta- and mega-analyses of multimodal brain MRI and improve the replicability of studies relating brain variation to clinical and genetic data. Initial BD Working Group studies reveal widespread patterns of lower cortical thickness, subcortical volume and disrupted white matter integrity associated with BD. Findings also include mapping brain alterations of common medications like lithium, symptom patterns and clinical risk profiles and have provided further insights into the pathophysiological mechanisms of BD. Here we discuss key findings from the BD working group, its ongoing projects and future directions for large-scale, collaborative studies of mental illness.

Serotonin and social norms: tryptophan depletion impairs social comparison and leads to resource depletion in a multiplayer harvesting game.

How do people sustain resources for the benefit of individuals and communities and avoid the tragedy of the commons, in which shared resources become exhausted? In the present study, we examined the role of serotonin activity and social norms in the management of depletable resources. Healthy adults, alongside social partners, completed a multiplayer resource-dilemma game in which they repeatedly harvested from a partially replenishable monetary resource. Dietary tryptophan depletion, leading to reduced serotonin activity, was associated with aggressive harvesting strategies and disrupted use of the social norms given by distributions of other players' harvests. Tryptophan-depleted participants more frequently exhausted the resource completely and also accumulated fewer rewards than participants who were not tryptophan depleted. Our findings show that rank-based social comparisons are crucial to the management of depletable resources, and that serotonin mediates responses to social norms.

Psychiatric assessment of mood instability: qualitative study of patient experience.

BACKGROUND: Mood instability is a common reason for psychiatric referral. Very little is known about how patients with unstable mood experience assessment and diagnosis. AIMS: To investigate the experiences of assessment and diagnosis among patients with mood instability and to suggest improvements to this process. METHOD: Qualitative study, gathering data through individual interviews with 28 people experiencing mood instability and receiving a psychiatric assessment in secondary care. RESULTS: Participants described the importance of receiving an explanation for their symptoms; the value of a good interpersonal relationship with their clinician(s); being listened to and acknowledged; and being involved in and informed about clinical decisions. These needs were not, however, consistently met. Receiving a psychiatric diagnosis, including a diagnosis of bipolar disorder or borderline personality disorder, evoked both positive and negative responses among participants, relating to stigma, personal understanding and responsibility, prognosis and treatment. CONCLUSIONS: Patients with mood instability seek explanation for their symptoms and difficulties, empathetic care and consistent support as much as cure. Clinicians may incorrectly assume what patients' attitudes towards diagnosis are, a mismatch which may hamper the development of a strong therapeutic relationship. Clear, patient-centred communication, which acknowledges the patient's experience, may result in greater patient engagement and satisfaction.

Digital behavioural signatures reveal trans-diagnostic clusters of Schizophrenia and Alzheimer's disease patients.

The current neuropsychiatric nosological categories underlie pragmatic treatment choice, regulation and clinical research but does not encompass biological rationale. However, subgroups of patients suffering from schizophrenia or Alzheimer's disease have more in common than the neuropsychiatric nature of their condition, such as the expression of social dysfunction. The PRISM project presents here initial quantitative biological insights allowing the first steps toward a novel trans-diagnostic classification of psychiatric and neurological symptomatology intended to reinvigorate drug discovery in this area. In this study, we applied spectral clustering on digital behavioural endpoints derived from passive smartphone monitoring data in a subgroup of Schizophrenia and Alzheimer's disease patients, as well as age matched healthy controls, as part of the PRISM clinical study. This analysis provided an objective social functioning characterization with three differential clusters that transcended initial diagnostic classification and was shown to be linked to quantitative neurobiological parameters assessed. This emerging quantitative framework will both offer new ways to classify individuals in biologically homogenous clusters irrespective of their initial diagnosis, and also offer insights into the pathophysiological mechanisms underlying these clusters.

Health factors that influence sustainable behaviour in a single-player resource management game.

Encouraging sustainable use of limited natural, social, and economic resources requires understanding the variety of ways in which people think about how resources work and how they adjust their behaviour (or not) as available resources fluctuate. Previous investigations which have focused on understanding how individuals navigate erodible resources, have tended to use group-based, common pool games. However, such social games make it difficult to disentangle whether resource erosion is linked to difficulty navigating the dynamics of the resource or caused by social factors. Here, in two experiments, we recruited 781 participants to play a single-player resource management game in which individuals were invited to harvest monetary rewards from a fully depletable but stochastically replenishing resource over time. We find that the ability to sustain a resource over successive harvesting opportunities (in order to maximize the total harvested rewards) is reliably worse in individuals reporting elevated psychological distress, the often cooccurring hazardous alcohol use, and elevated rates of delay discounting. The associations between resource outcomes, harmful alcohol use, and psychological distress remained substantial even once we had controlled for elevated discounting rates (as a form of impulsivity and a strong risk factor for these health challenges). By contrast, individuals who reported higher levels of financial literacy and general well-being achieved better resource outcomes. Our observations demonstrate that the capacity to respond effectively to the dynamics of a resource are compromised in individuals at risk of psychological and alcohol-related disorders.

Relationships between social withdrawal and facial emotion recognition in neuropsychiatric disorders.

BACKGROUND: Emotion recognition constitutes a pivotal process of social cognition. It involves decoding social cues (e.g., facial expressions) to maximise social adjustment. Current theoretical models posit the relationship between social withdrawal factors (social disengagement, lack of social interactions and loneliness) and emotion decoding. OBJECTIVE: To investigate the role of social withdrawal in patients with schizophrenia (SZ) or probable Alzheimer's disease (AD), neuropsychiatric conditions associated with social dysfunction. METHODS: A sample of 156 participants was recruited: schizophrenia patients (SZ; n = 53), Alzheimer's disease patients (AD; n = 46), and two age-matched control groups (SZc, n = 29; ADc, n = 28). All participants provided self-report measures of loneliness and social functioning, and completed a facial emotion detection task. RESULTS: Neuropsychiatric patients (both groups) showed poorer performance in detecting both positive and negative emotions compared with their healthy counterparts (p < .01). Social withdrawal was associated with higher accuracy in negative emotion detection, across all groups. Additionally, neuropsychiatric patients with higher social withdrawal showed lower positive emotion misclassification. CONCLUSIONS: Our findings help to detail the similarities and differences in social function and facial emotion recognition in two disorders rarely studied in parallel, AD and SZ. Transdiagnostic patterns in these results suggest that social withdrawal is associated with heightened sensitivity to negative emotion expressions, potentially reflecting hypervigilance to social threat. Across the neuropsychiatric groups specifically, this hypervigilance associated with social withdrawal extended to positive emotion expressions, an emotional-cognitive bias that may impact social functioning in people with severe mental illness.

Effect of disease related biases on the subjective assessment of social functioning in Alzheimer's disease and schizophrenia patients.

BACKGROUND: Questionnaires are the current hallmark for quantifying social functioning in human clinical research. In this study, we compared self- and proxy-rated (caregiver and researcher) assessments of social functioning in Schizophrenia (SZ) and Alzheimer's disease (AD) patients and evaluated if the discrepancy between the two assessments is mediated by disease-related factors such as symptom severity. METHODS: We selected five items from the WHO Disability Assessment Schedule 2.0 (WHODAS) to assess social functioning in 53 AD and 61 SZ patients. Caregiver- and researcher-rated assessments of social functioning were used to calculate the discrepancies between self-rated and proxy-rated assessments. Furthermore, we used the number of communication events via smartphones to compare the questionnaire outcomes with an objective measure of social behaviour. RESULTS: WHODAS results revealed that both AD (p < 0.001) and SZ (p < 0.004) patients significantly overestimate their social functioning relative to the assessment of their caregivers and/or researchers. This overestimation is mediated by the severity of cognitive impairments (MMSE; p = 0.019) in AD, and negative symptoms (PANSS; p = 0.028) in SZ. Subsequently, we showed that the proxy scores correlated more strongly with the smartphone communication events of the patient when compared to the patient-rated questionnaire scores (self; p = 0.076, caregiver; p < 0.001, researcher-rated; p = 0.046). CONCLUSION: Here we show that the observed overestimation of WHODAS social functioning scores in AD and SZ patients is partly driven by disease-related biases such as cognitive impairments and negative symptoms, respectively. Therefore, we postulate the development and implementation of objective measures of social functioning that may be less susceptible to such biases.

Social dysfunction is transdiagnostically associated with default mode network dysconnectivity in schizophrenia and Alzheimer's disease.

OBJECTIVES: Social dysfunction is one of the most common signs of major neuropsychiatric disorders. The Default Mode Network (DMN) is crucially implicated in both psychopathology and social dysfunction, although the transdiagnostic properties of social dysfunction remains unknown. As part of the pan-European PRISM (Psychiatric Ratings using Intermediate Stratified Markers) project, we explored cross-disorder impact of social dysfunction on DMN connectivity. METHODS: We studied DMN intrinsic functional connectivity in relation to social dysfunction by applying Independent Component Analysis and Dual Regression on resting-state fMRI data, among schizophrenia (SZ; N = 48), Alzheimer disease (AD; N = 47) patients and healthy controls (HC; N = 55). Social dysfunction was operationalised via the Social Functioning Scale (SFS) and De Jong-Gierveld Loneliness Scale (LON). RESULTS: Both SFS and LON were independently associated with diminished DMN connectional integrity within rostromedial prefrontal DMN subterritories (pcorrected range = 0.02-0.04). The combined effect of these indicators (Mean.SFS + LON) on diminished DMN connectivity was even more pronounced (both spatially and statistically), independent of diagnostic status, and not confounded by key clinical or sociodemographic effects, comprising large sections of rostromedial and dorsomedial prefrontal cortex (pcorrected=0.01). CONCLUSIONS: These findings pinpoint DMN connectional alterations as putative transdiagnostic endophenotypes for social dysfunction and could aid personalised care initiatives grounded in social behaviour.

Cross-disorder and disorder-specific deficits in social functioning among schizophrenia and alzheimer's disease patients.

BACKGROUND: Social functioning is often impaired in schizophrenia (SZ) and Alzheimer's disease (AD). However, commonalities and differences in social dysfunction among these patient groups remain elusive. MATERIALS AND METHODS: Using data from the PRISM study, behavioral (all subscales and total score of the Social Functioning Scale) and affective (perceived social disability and loneliness) indicators of social functioning were measured in patients with SZ (N = 56), probable AD (N = 50) and age-matched healthy controls groups (HC, N = 29 and N = 28). We examined to what extent social functioning differed between disease and age-matched HC groups, as well as between patient groups. Furthermore, we examined how severity of disease and mood were correlated with social functioning, irrespective of diagnosis. RESULTS: As compared to HC, both behavioral and affective social functioning seemed impaired in SZ patients (Cohen's d's 0.81-1.69), whereas AD patients mainly showed impaired behavioral social function (Cohen's d's 0.65-1.14). While behavioral indices of social functioning were similar across patient groups, SZ patients reported more perceived social disability than AD patients (Cohen's d's 0.65). Across patient groups, positive mood, lower depression and anxiety levels were strong determinants of better social functioning (p's <0.001), even more so than severity of disease. CONCLUSIONS: AD and SZ patients both exhibit poor social functioning in comparison to age- and sex matched HC participants. Social dysfunction in SZ patients may be more severe than in AD patients, though this may be due to underreporting by AD patients. Across patients, social functioning appeared as more influenced by mood states than by severity of disease.

Blood pressure in bipolar disorder: evidence of elevated pulse pressure and associations between mean pressure and mood instability.

BACKGROUND: Bipolar disorder (BD) is associated with excess and premature cardiovascular mortality. Elevated blood pressure (BP) is a leading contributor to cardiovascular risk. However, few studies have examined BP in BD in comparison to other psychiatric disorders. Furthermore, the association between BP and mood instability is not presently clear despite increasing interest in repurposing existing antihypertensive medications as possible novel BD treatments. Thus we examined BP differences between BD and borderline personality disorder (BPD), a disorder with a similar symptom profile through chronic mood instability. METHODS: A total of 106 adults (38 BD, 25 BPD, and 43 healthy controls), evaluated in the Automated Monitoring of Symptom Severity (AMoSS) study, completed a week-long home blood pressure monitoring assessment and ecological momentary assessment of mood. We examined group-wise differences in mean BP and BP variability and their association with mood instability. RESULTS: BD individuals had a significantly wider resting pulse pressure (40.8 ± 7.4, mmHg) compared to BPD (35.7 ± 5.3, mmHg, P = 0.03) and control participants (37.3 ± 6.3, mmHg, P = 0.036). Systolic BP was negatively associated with sad mood instability, and all measures of mean BP (systolic, diastolic, and mean arterial pressure) were negatively associated with positive mood instability. CONCLUSIONS: This study demonstrates BP differences between BD and healthy and clinical controls that are within a normotensive range. Early pulse pressure widening may be a modifiable pathophysiological feature of BD that confers later cardiovascular risk. BP may be an important transdiagnostic predictor of mood instability and a potential explicit treatment target.

Digital Communication Biomarkers of Mood and Diagnosis in Borderline Personality Disorder, Bipolar Disorder, and Healthy Control Populations.

Background: Remote monitoring and digital phenotyping harbor potential to aid clinical diagnosis, predict episode course and recognize early signs of mental health crises. Digital communication metrics, such as phone call and short message service (SMS) use may represent novel biomarkers of mood and diagnosis in Bipolar Disorder (BD) and Borderline Personality Disorder (BPD). Materials and Methods: BD (n = 17), BPD (n = 17) and Healthy Control (HC, n = 21) participants used a smartphone application which monitored phone calls and SMS messaging, alongside self-reported mood. Linear mixed-effects regression models were used to assess the association between digital communications and mood symptoms, mood state, trait-impulsivity, diagnosis and the interaction effect between mood and diagnosis. Results: Transdiagnostically, self-rated manic symptoms and manic state were positively associated with total and outgoing call frequency and cumulative total, incoming and outgoing call duration. Manic symptoms were also associated with total and outgoing SMS frequency. Transdiagnostic depressive symptoms were associated with increased mean incoming call duration. For the different diagnostic groups, BD was associated with increased total call frequency and BPD with increased total and outgoing SMS frequency and length compared to HC. Depression in BD, but not BPD, was associated with decreased total and outgoing call frequency, mean total and outgoing call duration and total and outgoing SMS frequency. Finally, trait-impulsivity was positively associated with total call frequency, total and outgoing SMS frequency and cumulative total and outgoing SMS length. Conclusion: These results identify a general increase in phone call and SMS communications associated with self-reported manic symptoms and a diagnosis-moderated decrease in communications associated with depression in BD, but not BPD, participants. These findings may inform the development of clinical tools to aid diagnosis and remote symptom monitoring, as well as informing understanding of differential psychopathologies in BD and BPD.

The clinical effectiveness of using a predictive algorithm to guide antidepressant treatment in primary care (PReDicT): an open-label, randomised controlled trial.

Depressed patients often do not respond to the first antidepressant prescribed, resulting in sequential trials of different medications. Personalised medicine offers a means of reducing this delay; however, the clinical effectiveness of personalised approaches to antidepressant treatment has not previously been tested. We assessed the clinical effectiveness of using a predictive algorithm, based on behavioural tests of affective cognition and subjective symptoms, to guide antidepressant treatment. We conducted a multicentre, open-label, randomised controlled trial in 913 medication-free depressed patients. Patients were randomly assigned to have their antidepressant treatment guided by a predictive algorithm or treatment as usual (TaU). The primary outcome was the response of depression symptoms, defined as a 50% or greater reduction in baseline score of the QIDS-SR-16 scale, at week 8. Additional prespecified outcomes included symptoms of anxiety at week 8, and symptoms of depression and functional outcome at weeks 8, 24 and 48. The response rate of depressive symptoms at week 8 in the PReDicT (55.9%) and TaU (51.8%) arms did not differ significantly (odds ratio: 1.18 (95% CI: 0.89-1.56), P = 0.25). However, there was a significantly greater reduction of anxiety in week 8 and a greater improvement in functional outcome at week 24 in the PReDicT arm. Use of the PReDicT test did not increase the rate of response to antidepressant treatment estimated by depressive symptoms but did improve symptoms of anxiety at week 8 and functional outcome at week 24. Our findings indicate that personalisation of antidepressant treatment may improve outcomes in depressed patients.

Optimizing Behavioral Paradigms to Facilitate Development of New Treatments for Anhedonia and Reward Processing Deficits in Schizophrenia and Major Depressive Disorder: Study Protocol.

Background: Behavioral tasks focusing on different subdomains of reward processing may provide more objective and quantifiable measures of anhedonia and impaired motivation compared with clinical scales. Typically, single tasks are used in relatively small studies to compare cases and controls in one indication, but they are rarely included in larger multisite trials. This is due to limited systematic standardization as well as the challenges of deployment in international studies and stringent adherence to the high regulatory requirements for data integrity. The Reward Task Optimization Consortium (RTOC) was formed to facilitate operational implementation of reward processing tasks, making them suitable for use in future large-scale, international, multisite drug development studies across multiple indications. The RTOC clinical study aims to conduct initial optimization of a set of tasks in patients with major depressive disorder (MDD) or schizophrenia (SZ). Methods: We will conduct a multicenter study across four EU countries. Participants (MDD = 37, SZ = 37, with ≤80 age- and gender-matched healthy volunteers) will attend a study visit comprising screening, self-report and clinically rated assessments of anhedonia and symptom severity, and three reward processing tasks; specifically, the Grip Strength Effort task, the Doors task, and the Reinforcement Learning Working Memory task. The Grip Strength Effort and Doors tasks include simultaneous electroencephalography/event-related potential recordings. Outcomes will be compared using a two-way group design of MDD and SZ with matched controls, respectively. Further analyses will include anhedonia assessment scores as covariates. Planned analyses will assess whether our findings replicate previously published data, and multisite deployment will be evaluated through assessments of quality and conduct. A subset of participants will complete a second visit, to assess test-retest reliability of the task battery. Discussion: This study will evaluate the operational deployment of three reward processing tasks to the regulatory standards required for use in drug development trials. We will explore the potential of these tasks to differentiate patients from controls and to provide a quantitative marker of anhedonia and/or impaired motivation, establishing their usefulness as endpoints in multisite clinical trials. This study should demonstrate where multifaceted reward deficits are similar or divergent across patient populations. Registration: ClinicalTrials.gov (NCT04024371).

Circadian rest-activity patterns in bipolar disorder and borderline personality disorder.

Bipolar disorder (BD) and borderline personality disorder (BPD) are two psychiatric disorders with overlapping features that can be challenging to separate diagnostically. Growing evidence suggests that circadian rhythm disturbances are associated with psychiatric illness, however circadian patterns of behaviour have not been elucidated in BPD or differentiated from BD. This study compared the circadian structure and timing of rest-activity patterns in BPD with BD and healthy volunteers. Participants with BD (N = 31) and BPD (N = 21) and healthy controls (HC, N = 35) wore an actigraph on their non-dominant wrist for 28 day periods as part of the Automated Monitoring of Symptom Severity (AMoSS) study. Non-parametric circadian rhythm analysis of rest-activity patterns and cosinor analysis of distal temperature rhythms were conducted to elucidate circadian function between groups. Covariates controlled for included employment status, BMI and gender. Compared with HC and BD, individuals with BPD showed significantly delayed phase of night-time rest patterns ("L5 onset") (mean difference = 1:47 h, P < 0.001; mean difference = 1:38 h, P = 0.009, respectively), and relative to HC showed delayed daytime activity onset ("M10 onset") (mean difference = 2:13 h, P = 0.048) and delayed temperature phase (mean difference = 1:22 h, P = 0.034). These findings suggest that delayed circadian function may be a clinically important phenotype in individuals with BPD. Future work should interrogate the causality of this association and examine interventions which target delayed circadian function in the treatment of BPD.

Overview of the clinical implementation of a study exploring social withdrawal in patients with schizophrenia and Alzheimer's disease.

Trans-diagnostic, domain- or symptom-focused approaches have been heralded as advancing psychiatric research, but relatively few clinical research programmes have been undertaken to leverage their potential. In this manuscript we describe the approach and protocol for an exploratory study, PRISM (Psychiatric Ratings using Intermediate Stratified Markers), that will be conducted to explore the biomarkers in schizophrenia (SZ) and Alzheimer's Disease (AD) that may be related to a common symptom, social withdrawal. Patient participants (N = 72 SZ and N = 72 AD study completers), will complete a series of fMRI, EEG, and behavioural paradigms, as well as contributing blood-derived (e.g. epigenetic) and smartphone data related to social behaviour. Self- as well as caregiver- and researcher-reported assessments will be provided to characterise social withdrawal. Normative data will also be collected from a group of healthy controls (N = 48 study completers), half of whom will be matched in terms of age and gender distribution to the SZ and AD group, respectively. Thus we will explore both differentiation and cross-diagnostic overlap in the biomarkers associated with different levels of social withdrawal in SZ and AD. In this way we aim to provide a deeper understanding of the biological underpinnings of symptomatology common to both disorders, and provide insights into novel treatment targets and future drug development approaches.

Working definitions, subjective and objective assessments and experimental paradigms in a study exploring social withdrawal in schizophrenia and Alzheimer's disease.

Social withdrawal is one of the first and common signs of early social dysfunction in a number of important neuropsychiatric disorders, likely because of the enormous amount and complexity of brain processes required to initiate and maintain social relationships (Adolphs, 2009). The Psychiatric Ratings using Intermediate Stratified Markers (PRISM) project focusses on the shared and unique neurobiological basis of social withdrawal in schizophrenia, Alzheimer and depression. In this paper, we discuss the working definition of social withdrawal for this study and the selection of objective and subjective rating scales to assess social withdrawal chosen or adapted for this project. We also discuss the MRI and EEG paradigms selected to study the systems and neural circuitry thought to underlie social functioning and more particularly to be involved in social withdrawal in humans, such as the social perception and the social affiliation networks. A number of behavioral paradigms were selected to assess complementary aspects of social cognition. Also, a digital phenotyping method (a smartphone application) was chosen to obtain real-life data.

Desynchronization of diurnal rhythms in bipolar disorder and borderline personality disorder.

It has long been proposed that diurnal rhythms are disturbed in bipolar disorder (BD). Such changes are obvious in episodes of mania or depression. However, detailed study of patients between episodes has been rare and comparison with other psychiatric disorders rarer still. Our hypothesis was that evidence for desynchronization of diurnal rhythms would be evident in BD and that we could test the specificity of any effect by studying borderline personality disorder (BPD). Individuals with BD (n = 36), BPD (n = 22) and healthy volunteers (HC, n = 25) wore a portable heart rate and actigraphy device and used a smart-phone to record self-assessed mood scores 10 times per day for 1 week. Average diurnal patterns of heart rate (HR), activity and sleep were compared within and across groups. Desynchronization in the phase of diurnal rhythms of HR compared with activity were found in BPD (+3 h) and BD (+1 h), but not in HC. A clear diurnal pattern for positive mood was found in all subject groups. The coherence between negative and irritable mood and HR showed a four-cycle per day component in BD and BPD, which was not present in HC. The findings highlight marked de-synchronisation of measured diurnal function in both BD but particularly BPD and suggest an increased association with negative and irritable mood at ultradian frequencies. These findings enhance our understanding of the underlying physiological changes associated with BPD and BD, and suggest objective markers for monitoring and potential treatment targets. Improved mood stabilisation is a translational objective for management of both patient groups.

Longitudinal mood monitoring in bipolar disorder: Course of illness as revealed through a short messaging service.

BACKGROUND: Online self-monitoring of mood can be used to investigate differences in course patterns across patient groups. This study explored the feasibility of remote symptom capture with True Colours, a self-rated online mood monitoring tool completed on a weekly basis. METHODS: Participants with bipolar disorder (N = 297) completed weekly depression and mania questionnaires over an average of 27.5 months (range 1 -81 months). Subgroups defined by sex, age, and bipolar I vs. II status were compared on time in various mood states, number of episodes, and week-to-week mood variability. RESULTS: Compliance with weekly questionnaires was generally high (median, 92% of weeks). Mood symptoms occurred for an average of 55.4% of weeks across the follow-up period. Females spent more time with hypomanic/manic and depressive symptoms and had more depressive episodes compared to males. Younger participants were found to experience more hypomanic/manic episodes and showed greater variability in mood symptoms than older participants. No significant differences in mood symptoms or variability were observed between bipolar I and II patients. LIMITATIONS: This was a naturalistic study with a heterogeneous cohort, and did not include a control group. True Colours does not identify mood fluctuations that may occur in the days between weekly assessments. CONCLUSIONS: Monitoring moods through an online tool is both feasible and informative regarding course of illness in patients with bipolar disorder. Interventions aiming to reduce mood variability and manic/hypomanic episodes in the early phases of bipolar disorder may enhance the long-term symptomatic course of the illness.

The effects of medication and current mood upon facial emotion recognition: findings from a large bipolar disorder cohort study.

OBJECTIVES: Emotional processing abnormalities have been implicated in bipolar disorder (BD) but studies are typically small and uncontrolled. Here, facial expression recognition was explored in a large and naturalistically recruited cohort of BD patients. METHODS: 271 patients with BD completed the facial expression recognition task. The effects of current medication together with the influence of current mood state and diagnostic subtype were assessed whilst controlling for the effects of demographic variables. RESULTS: Patients who were currently receiving treatment with lithium demonstrated significantly poorer accuracy in recognising angry faces, an effect that held in a monotherapy sub-analysis comparing those participants on lithium only and those who were medication-free. Accuracy in recognising angry faces was also lower amongst participants currently taking dopamine antagonists (antipsychotics). Higher levels of current depressive symptoms were linked to poorer accuracy at identifying happy faces. CONCLUSION: Use of lithium and possibly dopamine antagonists may be associated with reduced processing of anger cues in BD. Findings support the existence of mood-congruent negative biases associated with depressive symptoms in BD. Observational cohort studies provide opportunities to explore the substantial effects of demographic, psychometric and clinical variables on cognitive performance and emotional processing.

Oxford Lithium Trial (OxLith) of the early affective, cognitive, neural and biochemical effects of lithium carbonate in bipolar disorder: study protocol for a randomised controlled trial.

BACKGROUND: Despite lithium's being the most effective drug for bipolar disorder and in clinical use for decades, we still know very little about its early effects relevant to its mode of action. METHODS/DESIGN: The Oxford Lithium Trial is a double-blind, randomised, placebo-controlled study of 6-week lithium treatment in participants with bipolar disorder and mood instability. Its aim is to identify early clinical, neurocognitive and biological effects. Participants (n = 40) will undergo an intensive battery of multi-modal investigations, including remote monitoring of mood, activity and physiology, as well as cognitive testing, fMRI and magnetoencephalography, together with biochemical and gene expression measurements to assess renal, inflammatory and circadian effects. DISCUSSION: The findings derived from this trial may be of value in predicting subsequent therapeutic response or side effects, not only relevant to the use of lithium but also providing a potential signature to help in more rapid evaluation of novel mood stabilisers. In this respect, OxLith is a step towards the development of a valid experimental medicine model for bipolar disorder. TRIAL REGISTRATION: ISRCTN91624955 . Registered on 22 January 2015.