Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression.

BACKGROUND: Psilocybin is being studied for use in treatment-resistant depression. METHODS: In this phase 2 double-blind trial, we randomly assigned adults with treatment-resistant depression to receive a single dose of a proprietary, synthetic formulation of psilocybin at a dose of 25 mg, 10 mg, or 1 mg (control), along with psychological support. The primary end point was the change from baseline to week 3 in the total score on the Montgomery-Åsberg Depression Rating Scale (MADRS; range, 0 to 60, with higher scores indicating more severe depression). Secondary end points included response at week 3 (≥50% decrease from baseline in the MADRS total score), remission at week 3 (MADRS total score ≤10), and sustained response at 12 weeks (meeting response criteria at week 3 and all subsequent visits). RESULTS: A total of 79 participants were in the 25-mg group, 75 in the 10-mg group, and 79 in the 1-mg group. The mean MADRS total score at baseline was 32 or 33 in each group. Least-squares mean changes from baseline to week 3 in the score were -12.0 for 25 mg, -7.9 for 10 mg, and -5.4 for 1 mg; the difference between the 25-mg group and 1-mg group was -6.6 (95% confidence interval [CI], -10.2 to -2.9; P<0.001) and between the 10-mg group and 1-mg group was -2.5 (95% CI, -6.2 to 1.2; P = 0.18). In the 25-mg group, the incidences of response and remission at 3 weeks, but not sustained response at 12 weeks, were generally supportive of the primary results. Adverse events occurred in 179 of 233 participants (77%) and included headache, nausea, and dizziness. Suicidal ideation or behavior or self-injury occurred in all dose groups. CONCLUSIONS: In this phase 2 trial involving participants with treatment-resistant depression, psilocybin at a single dose of 25 mg, but not 10 mg, reduced depression scores significantly more than a 1-mg dose over a period of 3 weeks but was associated with adverse effects. Larger and longer trials, including comparison with existing treatments, are required to determine the efficacy and safety of psilocybin for this disorder. (Funded by COMPASS Pathfinder; EudraCT number, 2017-003288-36; ClinicalTrials.gov number, NCT03775200.).

Using a generative model of affect to characterize affective variability and its response to treatment in bipolar disorder.

The affective variability of bipolar disorder (BD) is thought to qualitatively differ from that of borderline personality disorder (BPD), with changes in affect persisting longer in BD. However, quantitative studies have not been able to confirm this distinction. It has therefore not been possible to accurately quantify how treatments like lithium influence affective variability in BD. We assessed the affective variability associated with BD and BPD as well as the effect of lithium using a computational model that defines two subtypes of variability: affective changes that persist (volatility) and changes that do not (noise). We hypothesized that affective volatility would be raised in the BD group, noise would be raised in the BPD group, and that lithium would impact affective volatility. Daily affect ratings were prospectively collected for up to 3 y from patients with BD or BPD and nonclinical controls. In a separate experimental medicine study, patients with BD were randomized to receive lithium or placebo, with affect ratings collected from week -2 to +4. We found a diagnostically specific pattern of affective variability. Affective volatility was raised in patients with BD, whereas affective noise was raised in patients with BPD. Rather than suppressing affective variability, lithium increased the volatility of positive affect in both studies. These results provide a quantitative measure of the affective variability associated with BD and BPD. They suggest a mechanism of action for lithium, whereby periods of persistently low or high affect are avoided by increasing the volatility of affective responses.

Effect of CYP2C19 polymorphisms on antidepressant prescription patterns and treatment emergent mania in bipolar disorder.

Antidepressant medication is used extensively to treat bipolar depression despite uncertain efficacy. The cytochrome P450 (CYP) 2C19 enzyme metabolize several antidepressants, and polymorphisms in the corresponding gene CYP2C19 influence plasma concentration and hence treatment outcomes in major depressive disorder. Here, we investigate if CYP2C19 polymorphisms are associated with antidepressant treatment patterns and the risk of mania when antidepressants are used in bipolar disorder. Two single nucleotide polymorphisms (rs4244285 and rs12248560) were used to classify 5019 bipolar disorder patients into CYP2C19 metabolic phenotypes ranging from poor to ultra-rapid metabolizers. We used Swedish national registry data 2005-2017 on dispensed medications and inpatient care to estimate risks for early-treatment persistence, treatment discontinuation, switching to a new antidepressant medication, and mania within 3 months of treatment initiation in patients treated with citalopram, escitalopram, sertraline, amitriptyline, and clomipramine. Metabolic phenotypes of CYP2C19 were not robustly associated with the investigated treatment outcomes based on dispense patterns. Slower metabolism was associated with an increased risk of treatment emergent mania for sertraline (hazard ratio [HR] = 1.3, 95% CI = 1.04-1.62, p = 0.02) and the tricyclic antidepressants amitriptyline and clomipramine (HR = 1.46, 95% CI = 1.05-2.02, p = 0.024). In a large study of the impact of CYP2C19 metabolic phenotypes on antidepressant treatment of bipolar depression, we found an association between slower CYP2C19 metabolism and higher risk of treatment emergent mania, which is a step towards personalized risk assessments. There were, however, no clear associations with early treatment persistence, treatment discontinuation, and switching to a new antidepressant.

Patient fibroblast circadian rhythms predict lithium sensitivity in bipolar disorder.

Bipolar disorder is a chronic neuropsychiatric condition associated with mood instability, where patients present significant sleep and circadian rhythm abnormalities. Currently, the pathophysiology of bipolar disorder remains elusive, but treatment with lithium continues as the benchmark pharmacotherapy, functioning as a potent mood stabilizer in most, but not all patients. Lithium is well documented to induce period lengthening and amplitude enhancement of the circadian clock. Based on this, we sought to investigate whether lithium differentially impacts circadian rhythms in bipolar patient cell lines and crucially if lithium's effect on the clock is fundamental to its mood-stabilizing effects. We analyzed the circadian rhythms of bipolar patient-derived fibroblasts (n = 39) and their responses to lithium and three further chronomodulators. Here we show, relative to controls (n = 23), patients exhibited a wider distribution of circadian period (p < 0.05), and that patients with longer periods were medicated with a wider range of drugs, suggesting lower effectiveness of lithium. In agreement, patient fibroblasts with longer periods displayed muted circadian responses to lithium as well as to other chronomodulators that phenocopy lithium. These results show that lithium differentially impacts the circadian system in a patient-specific manner and its effect is dependent on the patient's circadian phenotype. We also found that lithium-induced behavioral changes in mice were phenocopied by modulation of the circadian system with drugs that target the clock, and that a dysfunctional clock ablates this response. Thus, chronomodulatory compounds offer a promising route to a novel treatment paradigm. These findings, upon larger-scale validation, could facilitate the implementation of a personalized approach for mood stabilization.

Smoking and the risk for bipolar disorder: evidence from a bidirectional Mendelian randomisation study.

BACKGROUND: There is increasing evidence that smoking is a risk factor for severe mental illness, including bipolar disorder. Conversely, patients with bipolar disorder might smoke more (often) as a result of the psychiatric disorder. AIMS: We conducted a bidirectional Mendelian randomisation (MR) study to investigate the direction and evidence for a causal nature of the relationship between smoking and bipolar disorder. METHOD: We used publicly available summary statistics from genome-wide association studies on bipolar disorder, smoking initiation, smoking heaviness, smoking cessation and lifetime smoking (i.e. a compound measure of heaviness, duration and cessation). We applied analytical methods with different, orthogonal assumptions to triangulate results, including inverse-variance weighted (IVW), MR-Egger, MR-Egger SIMEX, weighted-median, weighted-mode and Steiger-filtered analyses. RESULTS: Across different methods of MR, consistent evidence was found for a positive effect of smoking on the odds of bipolar disorder (smoking initiation ORIVW = 1.46, 95% CI 1.28-1.66, P = 1.44 × 10-8, lifetime smoking ORIVW = 1.72, 95% CI 1.29-2.28, P = 1.8 × 10-4). The MR analyses of the effect of liability to bipolar disorder on smoking provided no clear evidence of a strong causal effect (smoking heaviness betaIVW = 0.028, 95% CI 0.003-0.053, P = 2.9 × 10-2). CONCLUSIONS: These findings suggest that smoking initiation and lifetime smoking are likely to be a causal risk factor for developing bipolar disorder. We found some evidence that liability to bipolar disorder increased smoking heaviness. Given that smoking is a modifiable risk factor, these findings further support investment into smoking prevention and treatment in order to reduce mental health problems in future generations.

Efficacy of digital cognitive behavioral therapy for moderate-to-severe symptoms of generalized anxiety disorder: A randomized controlled trial.

BACKGROUND: Cognitive behavioral therapy (CBT) is an efficacious intervention for generalized anxiety disorder (GAD). Digital CBT may provide a scalable means of delivering CBT at a population level. We investigated the efficacy of a novel digital CBT program in those with GAD for outcomes of anxiety, worry, depressive symptoms, sleep difficulty, wellbeing, and participant-specific quality of life. METHODS: This online, two-arm parallel-group superiority randomized controlled trial compared digital CBT with waitlist control in 256 participants with moderate-to-severe symptoms of GAD. Digital CBT (Daylight), was delivered using participants' own smartphones. Online assessments took place at baseline (Week 0; immediately preceding randomization), mid-intervention (Week 3; from randomization), post-intervention (Week 6; primary endpoint), and follow-up (Week 10). RESULTS: Overall, 256 participants were randomized and intention-to-treat analysis found Daylight reduced symptoms of anxiety compared with waitlist control at post-intervention, reflecting a large effect size (adjusted difference [95% CI]: 3.22 [2.14, 4.31], d = 1.08). Significant improvements were found for measures of worry; depressive symptoms, sleep difficulty, wellbeing, and participant-specific quality of life. CONCLUSION: Digital CBT (Daylight) appears to be safe and efficacious for symptoms of anxiety, worry, and further measures of mental health compared with waitlist control in individuals with GAD.

Opioid-Independent and Opioid-Mediated Modes of Pain Modulation.

Pain is regulated endogenously through both opioid and non-opioid mechanisms. We hypothesized that two novel pain modulation tasks, one drawing on context/expectations and one using voluntary reappraisal, would show differing levels of opioid dependence. Specifically, we expected that naloxone would block context-related analgesia, whereas mental imagery-based pain reappraisal would be opioid-independent.A double-blind, placebo-controlled intravenous naloxone versus saline crossover design was used. Twenty healthy volunteers completed the two modulation tasks with acute heat stimuli calibrated to induce moderate pain. In the mental imagery task, participants imagined either a "pleasant" or a "comparison" scenario during painful heat. In the relative relief task, moderate heat stimuli coincided with visual cues eliciting relief from the expectation of intense pain, and were compared with moderate heat stimuli delivered under the expectation of non-painful warmth. Both "pleasant imagery" and "relative relief" conditions significantly improved ratings of pain intensity and pleasantness during saline treatment. Indeed, the target stimuli in both tasks, which had been calibrated to induce moderate pain, were rated as mildly pleasant. Furthermore, consistently with the main hypothesis, blocking endogenous opioid signaling with naloxone did not significantly affect imagery-induced regulation of pain intensity or pleasantness. In contrast, the relative relief-induced pain regulation (i.e., context/expectation) was blocked by naloxone. We conclude that endogenous opioid signaling is necessary for expectation-related relative relief analgesia, but not for pain reappraisal through mental imagery. These results support mental imagery as a powerful and clinically relevant strategy for regulating pain affect also in patients where endogenous opioid mechanisms might be compromised.SIGNIFICANCE STATEMENT Neurotransmitter systems in the human brain can be probed through antagonist drugs. Studies using the opioid antagonist naloxone have demonstrated that the brain relies on both opioid and non-opioid mechanisms to downregulate pain. This holds clinical relevance given altered endogenous opioid processes in many chronic pain conditions. The present study used a double-blinded, placebo-controlled naloxone blockage of endogenous opioids in healthy humans to show differential opioid involvement in two pain modulation tasks. Context/expectation-driven (relative relief-related) analgesia was blocked by naloxone. In contrast, pain reappraisal through mental imagery was intact despite opioid receptor blockade, suggesting opioid independence. These results support mental imagery as a powerful, clinically relevant strategy for regulating pain as it does not rely on a functioning opioidergic system.

Treatment-resistant and multi-therapy-resistant criteria for bipolar depression: consensus definition.

BACKGROUND: Most people with bipolar disorder spend a significant percentage of their lifetime experiencing either subsyndromal depressive symptoms or major depressive episodes, which contribute greatly to the high levels of disability and mortality associated with the disorder. Despite the importance of bipolar depression, there are only a small number of recognised treatment options available. Consecutive treatment failures can quickly exhaust these options leading to treatment-resistant bipolar depression (TRBD). Remarkably few studies have evaluated TRBD and those available lack a comprehensive definition of multi-therapy-resistant bipolar depression (MTRBD).AimsTo reach consensus regarding threshold definitions criteria for TRBD and MTRBD. METHOD: Based on the evidence of standard treatments available in the latest bipolar disorder treatment guidelines, TRBD and MTRBD criteria were agreed by a representative panel of bipolar disorder experts using a modified Delphi method. RESULTS: TRBD criteria in bipolar depression was defined as failure to reach sustained symptomatic remission for 8 consecutive weeks after two different treatment trials, at adequate therapeutic doses, with at least two recommended monotherapy treatments or at least one monotherapy treatment and another combination treatment. MTRBD included the same initial definition as TRBD, with the addition of failure of at least one trial with an antidepressant, a psychological treatment and a course of electroconvulsive therapy. CONCLUSIONS: The proposed TRBD and MTRBD criteria may provide an important signpost to help clinicians, researchers and stakeholders in judging how and when to consider new non-standard treatments. However, some challenging diagnostic and therapeutic issues were identified in the consensus process that need further evaluation and research.Declaration of interestIn the past 3 years, M.B. has received grant/research support from the NIH, Cooperative Research Centre, Simons Autism Foundation, Cancer Council of Victoria, Stanley Medical Research Foundation, MBF, NHMRC, Beyond Blue, Rotary Health, Geelong Medical Research Foundation, Bristol Myers Squibb, Eli Lilly, Glaxo SmithKline, Meat and Livestock Board, Organon, Novartis, Mayne Pharma, Servier, Woolworths, Avant and the Harry Windsor Foundation, has been a speaker for Astra Zeneca, Bristol Myers Squibb, Eli Lilly, Glaxo SmithKline, Janssen Cilag, Lundbeck, Merck, Pfizer, Sanofi Synthelabo, Servier, Solvay and Wyeth and served as a consultant to Allergan, Astra Zeneca, Bioadvantex, Bionomics, Collaborative Medicinal Development, Eli Lilly, Grunbiotics, Glaxo SmithKline, Janssen Cilag, LivaNova, Lundbeck, Merck, Mylan, Otsuka, Pfizer and Servier. A.C. has received fees for lecturing from pharmaceutical companies namely Lundbeck and Sunovion. A.J.C. has in the past 3 years received honoraria for speaking from Astra Zeneca and Lundbeck, honoraria for consulting from Allergan, Janssen, Lundbeck and LivaNova and research grant support from Lundbeck. G.M.G. holds shares in P1Vital and has served as consultant, advisor or CME speaker for Allergan, Angelini, Compass pathways, MSD, Lundbeck, Otsuka, Takeda, Medscape, Minervra, P1Vital, Pfizer, Servier, Shire and Sun Pharma. J.G. has received research funding from National Institute for Health Research, Medical Research Council, Stanley Medical Research Institute and Wellcome. H.G. received grants/research support, consulting fees or honoraria from Gedeon Richter, Genericon, Janssen Cilag, Lundbeck, Otsuka, Pfizer and Servier. R.H.M.-W. has received support for research, expenses to attend conferences and fees for lecturing and consultancy work (including attending advisory boards) from various pharmaceutical companies including Astra Zeneca, Cyberonics, Eli Lilly, Janssen, Liva Nova, Lundbeck, MyTomorrows, Otsuka, Pfizer, Roche, Servier, SPIMACO and Sunovion. R.M. has received research support from Big White Wall, Electromedical Products, Johnson and Johnson, Magstim and P1Vital. S.N. received honoraria from Lundbeck, Jensen and Otsuka. J.C.S. has received funds for research from Alkermes, Pfizer, Allergan, J&J, BMS and been a speaker or consultant for Astellas, Abbott, Sunovion, Sanofi. S.W has, within the past 3 years, attended advisory boards for Sunovion and LivaNova and has undertaken paid lectures for Lundbeck. D.J.S. has received honoraria from Lundbeck. T.S. has reported grants from Pathway Genomics, Stanley Medical Research Institute and Palo Alto Health Sciences; consulting fees from Sunovion Pharamaceuticals Inc.; honoraria from Medscape Education, Global Medical Education and CMEology; and royalties from Jones and Bartlett, UpToDate and Hogrefe Publishing. S.P. has served as a consultant or speaker for Janssen, and Sunovion. P.T. has received consultancy fees as an advisory board member from the following companies: Galen Limited, Sunovion Pharmaceuticals Europe Ltd, myTomorrows and LivaNova. E.V. received grants/ research support, consulting fees or honoraria from Abbott, AB-Biotics, Allergan, Angelini, Dainippon Sumitomo, Ferrer, Gedeon Richter, Janssen, Lundbeck, Otsuka and Sunovion. L.N.Y. has received grants/research support, consulting fees or honoraria from Allergan, Alkermes, Dainippon Sumitomo, Janssen, Lundbeck, Otsuka, Sanofi, Servier, Sunovion, Teva and Valeant. A.H.Y. has undertaken paid lectures and advisory boards for all major pharmaceutical companies with drugs used in affective and related disorders and LivaNova. He has also previously received funding for investigator-initiated studies from AstraZeneca, Eli Lilly, Lundbeck and Wyeth. P.R.A.S. has received research funding support from Corcept Therapeutics Inc. Corcept Therapeutics Inc fully funded attendance at their internal conference in California USA and all related expenses. He has received grant funding from the Medical Research Council UK for a collaborative study with Janssen Research and Development LLC. Janssen Research and Development LLC are providing non-financial contributions to support this study. P.R.A.S. has received a presentation fee from Indivior and an advisory board fee from LivaNova.

Plasma glutathione suggests oxidative stress is equally present in early- and late-onset bipolar disorder.

OBJECTIVES: We previously demonstrated oxidative stress in bipolar patients and a relationship between the age of illness onset and total glutathione, a principal antioxidant. In this study, we sought to replicate these findings in a new cohort of patients. METHODS: We recruited bipolar patients from Warneford Hospital, Oxford, UK, of similar age and grouped them according to age of onset of illness. The early-onset group comprised patients with onset at <23 years, and the late group comprised patients with onset at >30 years. A third group, comprising age-matched healthy volunteers, was also included. Reduced and oxidized glutathione, cysteine, and cystine were determined in plasma, using high-performance liquid chromatography. Mitochondrial DNA copy number, measured in whole blood, was also compared between patients and healthy controls. RESULTS: Significant increases in oxidative stress were observed in the patient groups, compared with the control group; however, no differences in glutathione-related oxidative stress measures were detected between the early- and late-onset bipolar patient groups. No differences were observed in the amount of mitochondrial DNA, and there was no correlation with mood state. CONCLUSION: Using a more accurate method to quantify oxidative stress than in our previous study, we show that oxidative stress is a consistent feature of bipolar disorder. Although we did not reproduce our finding correlating age of onset of illness to oxidative stress, we have shown, once again, that oxidative stress is a consistent feature of bipolar disorder.

Comparative economic evaluation of quetiapine plus lamotrigine combination vs quetiapine monotherapy (and folic acid vs placebo) in patients with bipolar depression (CEQUEL).

OBJECTIVES: Although not licensed for acute bipolar depression, lamotrigine has evidence for efficacy in trials and its use is recommended in guidelines. So far there had been no prospective health economic evaluation of its use. METHODS: Cost-utility analysis of the CEQUEL trial comparing quetiapine plus lamotrigine vs quetiapine monotherapy (and folic acid vs placebo in an add-on factorial design) for patients with bipolar depression (n = 201) from the health and social care perspective. Differences in costs together with quality-adjusted life years (QALYs) between the groups were assessed over 52 weeks using a regression-based approach. RESULTS: Health-related quality of life improved substantially for all randomization groups during follow-up with no significant difference in QALYs between any of the comparisons (mean adjusted QALY difference: lamotrigine vs placebo -0.001 (95% CI: -0.05 to 0.05), folic acid vs placebo 0.002 (95% CI: -0.05 to 0.05)). While medication costs in the lamotrigine group were higher than in the placebo group (£647, P < 0.001), mental health community/outpatient costs were significantly lower (-£670, P < 0.001). Mean total costs were similar in the groups (-£180, P = 0.913). CONCLUSIONS: Lamotrigine improved clinical ratings in bipolar depression compared with placebo. This differential effect was not detected using the EQ-5D-3L. The additional cost of lamotrigine was balanced by significant savings in some other medical costs which made its use cost neutral to the health service. Compared to placebo, folic acid produced neither clinical nor significant health economic benefits. The study supports the use of lamotrigine in combination with other drugs to treat bipolar depression.

Effectiveness of maintenance therapy of lithium vs other mood stabilizers in monotherapy and in combinations: a systematic review of evidence from observational studies.

OBJECTIVES: For the first time to present a systematic review of observational studies on the efficiency of lithium monotherapy in comparison with other maintenance mood stabilizers in monotherapy and in combination. METHODS: As part of the International Society for Bipolar Disorders (ISBD) Task Force on Lithium Treatment, we undertook a systematic literature search of non-randomized controlled observational studies on (i) lithium monotherapy vs treatment with another maintenance mood stabilizer in monotherapy and (ii) lithium in combination with other mood stabilizers vs monotherapy. RESULTS: In eight out of nine identified studies including a total of < 14 000 patients, maintenance lithium monotherapy was associated with improved outcome compared with another mood stabilizer in monotherapy, including valproate, lamotrigine, olanzapine, quetiapine, unspecified anticonvulsants, carbamazepine/lamotrigine, unspecified atypical antipsychotics and unspecified antipsychotics. Among the four identified studies including a total of > 4000 patients comparing maintenance combination therapy with maintenance monotherapy, a few combination therapies were found to be superior to monotherapy in some analyses, but many were not. CONCLUSIONS: The results show the superiority in real life of lithium monotherapy compared with monotherapy with other maintenance mood stabilizers. The four largest register-based studies largely addressed confounding, but, as ever, residual confounding cannot be excluded. Nevertheless, the observational findings substantially add to the findings from randomized controlled trials, whose designs often limit the validity of comparison between medicines.

Group-Personalized Regression Models for Predicting Mental Health Scores From Objective Mobile Phone Data Streams: Observational Study.

BACKGROUND: Objective behavioral markers of mental illness, often recorded through smartphones or wearable devices, have the potential to transform how mental health services are delivered and to help users monitor their own health. Linking objective markers to illness is commonly performed using population-level models, which assume that everyone is the same. The reality is that there are large levels of natural interindividual variability, both in terms of response to illness and in usual behavioral patterns, as well as intraindividual variability that these models do not consider. OBJECTIVE: The objective of this study was to demonstrate the utility of splitting the population into subsets of individuals that exhibit similar relationships between their objective markers and their mental states. Using these subsets, "group-personalized" models can be built for individuals based on other individuals to whom they are most similar. METHODS: We collected geolocation data from 59 participants who were part of the Automated Monitoring of Symptom Severity study at the University of Oxford. This was an observational data collection study. Participants were diagnosed with bipolar disorder (n=20); borderline personality disorder (n=17); or were healthy controls (n=22). Geolocation data were collected using a custom Android app installed on participants' smartphones, and participants weekly reported their symptoms of depression using the 16-item quick inventory of depressive symptomatology questionnaire. Population-level models were built to estimate levels of depression using features derived from the geolocation data recorded from participants, and it was hypothesized that results could be improved by splitting individuals into subgroups with similar relationships between their behavioral features and depressive symptoms. We developed a new model using a Dirichlet process prior for splitting individuals into groups, with a Bayesian Lasso model in each group to link behavioral features with mental illness. The result is a model for each individual that incorporates information from other similar individuals to augment the limited training data available. RESULTS: The new group-personalized regression model showed a significant improvement over population-level models in predicting mental health severity (P<.001). Analysis of subgroups showed that different groups were characterized by different features derived from raw geolocation data. CONCLUSIONS: This study demonstrates the importance of handling interindividual variability when developing models of mental illness. Population-level models do not capture nuances in how different individuals respond to illness, and the group-personalized model demonstrates a potential way to overcome these limitations when estimating mental state from objective behavioral features.

Imagery-Focused Cognitive Therapy (ImCT) for Mood Instability and Anxiety in a Small Sample of Patients with Bipolar Disorder: a Pilot Clinical Audit.

BACKGROUND: Despite the global impact of bipolar disorder (BD), treatment success is limited. Challenges include syndromal and subsyndromal mood instability, comorbid anxiety, and uncertainty around mechanisms to target. The Oxford Mood Action Psychology Programme (OxMAPP) offered a novel approach within a cognitive behavioural framework, via mental imagery-focused cognitive therapy (ImCT). AIMS: This clinical audit evaluated referral rates, clinical outcomes and patient satisfaction with the OxMAPP service. METHOD: Eleven outpatients with BD received ImCT in addition to standard psychiatric care. Mood data were collected weekly from 6 months pre-treatment to 6 months post-treatment via routine mood monitoring. Anxiety was measured weekly from start of treatment until 1 month post-treatment. Patient feedback was provided via questionnaire. RESULTS: Referral and treatment uptake rates indicated acceptability to referrers and patients. From pre- to post-treatment, there was (i) a significant reduction in the duration of depressive episode relapses, and (ii) a non-significant trend towards a reduction in the number of episodes, with small to medium effect size. There was a large effect size for the reduction in weekly anxiety symptoms from assessment to 1 month follow-up. Patient feedback indicated high levels of satisfaction with ImCT, and underscored the importance of the mental imagery focus. CONCLUSIONS: This clinical audit provides preliminary evidence that ImCT can help improve depressive and anxiety symptoms in BD as part of integrated clinical care, with high patient satisfaction and acceptability. Formal assessment designs are needed to further test the feasibility and efficacy of the new ImCT treatment on anxiety and mood instability.

Network meta-analysis: drawing conclusions regarding trials of psychosocial interventions for bipolar disorder.

Network meta-analysis (NMA) is a statistical technique for making direct and indirect comparisons between different treatment and control groups. Despite its many advantages, NMA may be misleading when evaluating networks that are disconnected, inconsistent or of low reliability and validity. We review how well the analysis of trials of adjunctive psychosocial treatment in bipolar disorder is served by NMA. We conclude with recommendations for future treatment trials in bipolar disorder and guidelines for NMAs.

Pharmacological treatment and risk of psychiatric hospital admission in bipolar disorder.

BackgroundClinical trials have examined the efficacy of drugs to prevent relapse in patients with bipolar disorder, however, their design often limits generalisation to routine clinical practice.AimsTo estimate the effectiveness of drugs used for maintenance treatment in bipolar disorder.MethodWe used national registers to identify 35 022 individuals diagnosed with bipolar disorder and information on lithium, valproate, carbamazepine, lamotrigine, quetiapine and olanzapine treatment from 2006 to 2009. The main outcome was psychiatric hospital admissions. We used stratified cox regression to compare periods on and off medication within the same individual.ResultsMedication with lithium, valproate, lamotrigine, olanzapine and quetiapine was associated with reduced rates of admission to hospital. Lithium was more effective than quetiapine and olanzapine. The effects of specific drugs depended on the polarity of the mood episode.ConclusionsOur findings complement results from randomised controlled trails, but suggest that lithium is more effective than both quetiapine and olanzapine in routine clinical practice.

International multi-site survey on the use of online support groups in bipolar disorder.

BACKGROUND: Peer support is an established component of recovery from bipolar disorder, and online support groups may offer opportunities to expand the use of peer support at the patient's convenience. Prior research in bipolar disorder has reported value from online support groups. AIMS: To understand the use of online support groups by patients with bipolar disorder as part of a larger project about information seeking. METHODS: The results are based on a one-time, paper-based anonymous survey about information seeking by patients with bipolar disorder, which was translated into 12 languages. The survey was completed between March 2014 and January 2016 and included questions on the use of online support groups. All patients were diagnosed by a psychiatrist. Analysis included descriptive statistics and general estimating equations to account for correlated data. RESULTS AND CONCLUSIONS: The survey was completed by 1222 patients in 17 countries. The patients used the Internet at a percentage similar to the general public. Of the Internet users who looked online for information about bipolar disorder, only 21.0% read or participated in support groups, chats, or forums for bipolar disorder (12.8% of the total sample). Given the benefits reported in prior research, clarification of the role of online support groups in bipolar disorder is needed. With only a minority of patients using online support groups, there are analytical challenges for future studies.

Agomelatine or placebo as adjunctive therapy to a mood stabiliser in bipolar I depression: randomised double-blind placebo-controlled trial.

BACKGROUND: Adjunctive antidepressant therapy is commonly used to treat acute bipolar depression but few studies have examined this strategy. AIMS: To examine the efficacy of agomelatine v. placebo as adjuncts to lithium or valproate in bipolar depression. METHOD: Patients who were currently depressed despite taking lithium or valproate for at least 6 weeks were randomised to treatment with agomelatine (n = 172) or placebo (n = 172) for 8 weeks of acute therapy and 44 weeks of continuation therapy (trial registration: ISRCTN28588282). RESULTS: No significant differences in improvement of depressive symptoms were observed between the two groups either at 8 weeks or 52 weeks on the primary efficacy measure of change in Montgomery-Åsberg Depression Rating Scale scores from baseline to end-point. Adverse events including switches into mania/hypomania were low and similar in both groups. CONCLUSIONS: Agomelatine adjunctive therapy was not superior to placebo adjunctive therapy for acute bipolar depression.

Gambling problems in bipolar disorder in the UK: prevalence and distribution.

BACKGROUND: North American studies show bipolar disorder is associated with elevated rates of problem gambling; however, little is known about rates in the different presentations of bipolar illness. AIMS: To determine the prevalence and distribution of problem gambling in people with bipolar disorder in the UK. METHOD: The Problem Gambling Severity Index was used to measure gambling problems in 635 participants with bipolar disorder. RESULTS: Moderate to severe gambling problems were four times higher in people with bipolar disorder than in the general population, and were associated with type 2 disorder (OR = 1.74, P = 0.036), history of suicidal ideation or attempt (OR = 3.44, P = 0.02) and rapid cycling (OR = 2.63, P = 0.008). CONCLUSIONS: Approximately 1 in 10 patients with bipolar disorder may be at moderate to severe risk of problem gambling, possibly associated with suicidal behaviour and a rapid cycling course. Elevated rates of gambling problems in type 2 disorder highlight the probable significance of modest but unstable mood disturbance in the development and maintenance of such problems.