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

Adding the μ-opioid receptor agonist remifentanil to agents used to induce general anaesthesia in electroconvulsive therapy (ECT) can reduce the required doses of induction agents and their unfavourable effects on seizure threshold and quality. However, whether remifentanil has favourable long-term treatment effects in terms of response and remission rates, speed of response and remission, and side-effects has not been studied.This retrospective, register-based cohort study involved patients with major depression consecutively treated at two units at different hospitals in Norway with the same ECT procedure. Both units used thiopental for ECT anaesthesia, but only one unit added remifentanil (R+; n=47; 541 sessions), whereas the other did not (R-; n=119; 1166 sessions). A Cox proportional hazards model for interval-censored data was conducted to examine the effects of remifentanil on the time to response and remission from depressive symptoms, whilst adjusting for age, sex, and baseline depression score.Both R+ and R- patients showed substantial reductions of depressive symptoms, with no difference in the response (76% in both groups) or remission (63% vs 65%) rate. However, R+ patients responded (hazard ratio=0.59; 95% confidence interval: 0.4-0.8) and remitted (hazard ratio=0.72; 95% confidence interval: 0.5-1.0) more slowly, and reported more often side-effects of nausea (30% vs 8%; P0.001), dizziness (22% vs 8%; P=0.027), and headache (48% vs 23%; P=0.004).The use of adjunctive remifentanil was associated with more short-term side-effects and no favourable long-term clinical outcomes. The practice of routinely adding remifentanil to barbiturate anaesthesia should therefore be reconsidered.

Objectives Electroconvulsive therapy is an effective treatment for bipolar depression, but there are concerns about whether it causes long-term neurocognitive impairment. Methods In this multicenter randomized controlled trial, in-patients with treatment-resistant bipolar depression were randomized to either algorithm-based pharmacologic treatment or right unilateral electroconvulsive therapy. After the 6-week treatment period, all of the patients received maintenance pharmacotherapy as recommended by their clinician guided by a relevant treatment algorithm. Patients were assessed at baseline and at 6 months. Neurocognitive functions were assessed using the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery, and autobiographical memory consistency was assessed using the Autobiographical Memory Interview-Short Form. Results Seventy-three patients entered the trial, of whom 51 and 26 completed neurocognitive assessments at baseline and 6 months, respectively. The MATRICS Consensus Cognitive Battery composite score improved by 4.1 points in both groups (P = .042) from baseline to 6 months (from 40.8 to 44.9 and from 41.9 to 46.0 in the algorithm-based pharmacologic treatment and electroconvulsive therapy groups, respectively). The Autobiographical Memory Interview-Short Form consistency scores were reduced in both groups (72.3% vs 64.3% in the algorithm-based pharmacologic treatment and electroconvulsive therapy groups, respectively; P = .085). Conclusions This study did not find that right unilateral electroconvulsive therapy caused long-term impairment in neurocognitive functions compared to algorithm-based pharmacologic treatment in bipolar depression as measured using standard neuropsychological tests, but due to the low number of patients in the study the results should be interpreted with caution. Trial registration ClinicalTrials.gov: NCT00664976.

Improvement of sleep is a central treatment goal for patients in a manic state. Blue‐blocking (BB) glasses as adjunctive treatment hasten overall recovery from mania. This method is an evolvement from dark therapy and builds on the discovery of the blue‐light‐sensitive retinal ganglion cell that signals daytime to the brain. We report effects of adjunctive BB glasses on actigraphy‐derived sleep parameters for manic inpatients as compared to placebo. Hospitalized patients with bipolar disorder in a manic state aged 18–70 years were recruited from five clinics in Norway from February 2012 to February 2015. The participants were randomly allocated to wearing BB glasses or placebo (clear glasses) as an adjunctive treatment from 18:00 to 08:00 hours for seven consecutive nights. Sleep and wake were monitored by actigraphy. From 32 eligible patients, 10 patients in each group qualified for the group analyses. The BB group's mean sleep efficiency was significantly higher at night 5 as compared to the placebo group (92.6% vs. 83.1%, p = .027). The 95% confidence interval (CI) was 89.4%–95.8% in the BB group and 75.9%–90.3% in the placebo group. There were fewer nights of interrupted sleep in the BB group: 29.6% versus 43.8% in the placebo group. The BB group received less‐intensive sleep‐promoting pharmacological treatment and showed significantly higher sleep efficiency and more consolidated sleep as compared to the placebo group. Our findings suggest sleep‐promoting effects through deactivating mechanisms. Adjunctive BB glasses seem to be useful for improving sleep for manic patients in the hospital setting. publishedVersion

Bipolar disorder (BD) is a serious mood disorder associated with circadian rhythm abnormalities. Risk for BD is genetically encoded and overlaps with systems that maintain circadian rhythms. Lithium is an effective mood stabilizer treatment for BD, but only a minority of patients fully respond to monotherapy. Presently, we hypothesized that lithium-responsive BD patients (Li-R) would show characteristic differences in chronotype and cellular circadian rhythms compared to lithium non-responders (Li-NR). Selecting patients from a prospective, multi-center, clinical trial of lithium monotherapy, we examined morning vs. evening preference (chronotype) as a dimension of circadian rhythm function in 193 Li-R and Li-NR BD patients. From a subset of 59 patients, we measured circadian rhythms in fibroblasts longitudinally over 5 days using a bioluminescent reporter (Per2-luc). We then estimated circadian rhythm parameters (amplitude, period, phase) and the pharmacological effects of lithium on rhythms in cells from Li-R and Li-NR donors. Compared to Li-NRs, Li-Rs showed a difference in chronotype, with higher levels of morningness. Evening chronotype was associated with increased mood symptoms at baseline, including depression, mania, and insomnia. Cells from Li-R patients were more likely to exhibit a short circadian period, a linear relationship between period and phase, and period shortening effects of lithium. Common genetic variation in the IP3 signaling pathway may account for some of the individual differences in the effects of lithium on cellular rhythms. We conclude that circadian rhythms may influence response to lithium in maintenance treatment of BD. © 2018. This is the authors’ accepted and refereed manuscript to the article. Locked until 16.5.2019 due to copyright restrictions.

Background Bipolar disorder is a serious and common psychiatric disorder characterized by manic and depressive mood switches and a relapsing and remitting course. The cornerstone of clinical management is stabilization and prophylaxis using mood-stabilizing medications to reduce both manic and depressive symptoms. Lithium remains the gold standard of treatment with the strongest data for both efficacy and suicide prevention. However, many patients do not respond to this medication, and clinically there is a great need for tools to aid the clinician in selecting the correct treatment. Large genome wide association studies (GWAS) investigating retrospectively the effect of lithium response are in the pipeline; however, few large prospective studies on genetic predictors to of lithium response have yet been conducted. The purpose of this project is to identify genes that are associated with lithium response in a large prospective cohort of bipolar patients and to better understand the mechanism of action of lithium and the variation in the genome that influences clinical response. Methods/Design This study is an 11-site prospective non-randomized open trial of lithium designed to ascertain a cohort of 700 subjects with bipolar I disorder who experience protocol-defined relapse prevention as a result of treatment with lithium monotherapy. All patients will be diagnosed using the Diagnostic Interview for Genetic Studies (DIGS) and will then enter a 2-year follow-up period on lithium monotherapy if and when they exhibit a score of 1 (normal, not ill), 2 (minimally ill) or 3 (mildly ill) on the Clinical Global Impressions of Severity Scale for Bipolar Disorder (CGI-S-BP Overall Bipolar Illness) for 4 of the 5 preceding weeks. Lithium will be titrated as clinically appropriate, not to exceed serum levels of 1.2 mEq/L. The sample will be evaluated longitudinally using a wide range of clinical scales, cognitive assessments and laboratory tests. On relapse, patients will be discontinued or crossed-over to treatment with valproic acid (VPA) or treatment as usual (TAU). Relapse is defined as a DSM-IV manic, major depressive or mixed episode or if the treating physician decides a change in medication is clinically necessary. The sample will be genotyped for GWAS. The outcome for lithium response will be analyzed as a time to event, where the event is defined as clinical relapse, using a Cox Proportional Hazards model. Positive single nucleotide polymorphisms (SNPs) from past genetic retrospective studies of lithium response, the Consortium on Lithium Genetics (ConLiGen), will be tested in this prospective study sample; a meta-analysis of these samples will then be performed. Finally, neurons will be derived from pluripotent stem cells from lithium responders and non-responders and tested in vivo for response to lithium by gene expression studies. SNPs in genes identified in these cellular studies will also be tested for association to response. Discussion Lithium is an extraordinarily important therapeutic drug in the clinical management of patients suffering from bipolar disorder. However, a significant proportion of patients, 30–40 %, fail to respond, and there is currently no method to identify the good lithium responders before initiation of treatment. Converging evidence suggests that genetic factors play a strong role in the variation of response to lithium, but only a few genes have been tested and the samples have largely been retrospective or quite small. The current study will collect an entirely unique sample of 700 patients with bipolar disorder to be stabilized on lithium monotherapy and followed for up to 2 years. This study will produce useful information to improve the understanding of the mechanism of action of lithium and will add to the development of a method to predict individual response to lithium, thereby accelerating recovery and reducing suffering and cost. © 2016 Oedegaard et al.Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated

Electroconvulsive therapy (ECT) is regarded by many clinicians as the most effective treatment for treatment-resistant bipolar depression, but no randomized controlled trials have been conducted, to the authors' knowledge. They compared efficacy measures of ECT and algorithm-based pharmacological treatment in treatment-resistant bipolar depression.This multicenter, randomized controlled trial was carried out at seven acute-care psychiatric inpatient clinics throughout Norway and included 73 bipolar disorder patients with treatment-resistant depression. The patients were randomly assigned to receive either ECT or algorithm-based pharmacological treatment. ECT included three sessions per week for up to 6 weeks, right unilateral placement of stimulus electrodes, and brief pulse stimulation.Linear mixed-effects modeling analysis revealed that ECT was significantly more effective than algorithm-based pharmacological treatment. The mean scores at the end of the 6-week treatment period were lower for the ECT group than for the pharmacological treatment group: by 6.6 points on the Montgomery-Åsberg Depression Rating Scale (SE=2.05, 95% CI=2.5-10.6), by 9.4 points on the 30-item version of the Inventory of Depressive Symptomatology-Clinician-Rated (SE=2.49, 95% CI=4.6-14.3), and by 0.7 points on the Clinical Global Impression for Bipolar Disorder (SE=0.31, 95% CI=0.13-1.36). The response rate was significantly higher in the ECT group than in the group that received algorithm-based pharmacological treatment (73.9% versus 35.0%), but the remission rate did not differ between the groups (34.8% versus 30.0%).Remission rates remained modest regardless of treatment choice for this challenging clinical condition.

IntroductionElectroconvulsive therapy (ECT) is one of the most polarizing treatments in medicine. Although the treatment effect is well documented in clinical studies, there is a lack of data regarding patients treated in an ordinary clinical setting. In 2013, we established a regional register of neurostimulation treatment in Western Norway.ObjectivesTo describe the use of ECT at the Haukeland university hospital in Bergen.MethodsPatients treated with ECT between June 2013 and June 2015 were included in the register.ResultsOne hundred and forty-seven patients received ECT during the 2 years period. The mean age was 58.4 years (22–91 years), 67% were female. Half of the patients (49.7%) had been treated with ECT previously. Indication for treatment was depression in 137 patients (93.2%), of which 29 (19.7%) were moderately, and 69 patients (46.9%) severely depressed, and additional 37 patients (25.2%) presented with severe depression with psychotic features. All but two patients were treated with right unilateral electrode placement, with a mean of 9.7 (3–22) treatments.The mean MADRS before treatment was 34.2 (4–56) and after treatment 11.9 (0–39). One hundred and ten patients (74.8%) responded to treatment; of which 89 (60.5%) remitted (response defined as a 50% or greater decrease from MADRS baseline score, remission defined as MADRS ≤ 12). Twenty patients (13%) continued with continuation or maintenance ECT after the index series.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Background The aims of this study were to compare clinical characteristics and educational and occupational functioning in two Bipolar Disorder (BD) samples recruited respectively from acutely admitted inpatients and public outpatient clinics and to investigate if the two BD samples differed in the same way in education and work ability from the general population. Methods DSM-IV BD patients were consecutively recruited from acute wards throughout Norway (N = 252; 69.8% BD I; 25.0% BD II; 5.2% BD NOS) and from outpatient clinics in the Oslo region (N = 230; 60.4% BD I; 33.5% BD II; 6.1% BD NOS) and demographic and clinical characteristics were compared. A reference sample from the general population (N = 100 869) was used to compare levels of education, marital status and disability benefits. Results The acute ward sample was older, and had more men, more BD I disorder, more hospitalisations and suicide attempts, longer illness duration, an earlier age of onset and first treatment and used a higher number of antipsychotics, anticonvulsants and lithium than the outpatient sample. Both samples were educated to the same level as their respective reference populations, but received disability benefit and were single to a higher but similar degree. Conclusions Clinical differences between the BD samples had no consequence for educational achievement and receipt of disability benefit compared to the general population indicating that other factors than severity of illness play a role for education and work abilities in BD patients.

Introduction Electroconvulsive therapy (ECT) is a highly effective treatment option mainly in severe depression. ECTs longterm effects on cognitive function are currently unknown, limiting its use. Transcranial magnet stimulation (TMS), is considered less effective than ECT in treatment of severe depression, but is without cognitive side effects. TMS is studied to a less degree than ECT. Objectives There is a need of large scale studies of effect, side effects and patients’ subjective experience of ECT and TMS. Aims Generate data to better predict which patients will benefit from ECT and TMS by establishing a regional register including all patients referred to ECT and TMS as part of an ordinary clinical treatment practice in the western part of Norway. Methods All patients referred to ECT and TMS in Bergen and Stavanger will be asked to participate in the study. There are no exclusion criteria. Demographics and course of illness factors will be recorded before start of ECT. Severity of the depressive disorder and treatment effects will be evaluated with a mix of self evaluation and clinician administrated standardized rating instruments. There will be a follow up at 6 months. Date from the described register will be merged with other relevant central Norwegian health registers. Results We expect the described regional register to offer an opportunity to determine predictors for effect, side effects and subjective satisfaction of the treatments. Conclusion This register is investigator initiated, with the aim to investigate which patient will benefit from ECT and TMS without serious side effects.

ObjectiveThere is a positive correlation between level of education and working function in the general population. Bipolar disorder (BD) is often associated with disability in social and working function. There is conflicting evidence considering educational achievements in BD patients.AimsOur aim was to investigate how education was related to social and occupational function in BD.MethodPatients with DSM-IV BD (N=257; 69.3% BD I, 25.7% BD II, 5.1% BD NOS, 51.4% females) were consecutively recruited from mental health clinics throughout Norway. The majority of patients were recruited when in-patients. About 1/2 had at least once experienced a psychotic episode. The BD sample was compared with a geographically matched reference sample from the general population (N=56.540) on levels of education, marital status, income, and disability benefits. Further analyses of association were carried out using logistic regression analyses.ResultsA significantly higher proportion of subjects in the BD group than in the reference group was single, had low income, or was disabled. No between-group difference was found in educational level. In the reference group education was inversely correlated with the risk of being disabled, but no such relationship was found in the BD group. In BD patients rapid cycling and recurring depressive episodes were the only clinical characteristics associated with low educational level.ConclusionDespite similar levels of education, BD patients had lower socio-economic status than the general population, and no association was found between education and disability for BD patients.