Association between Adherence with an Atypical Antipsychotic and with Other Psychiatric Drugs in Patients with Bipolar Disorder.

BACKGROUND: Using U.S. pharmacy and medical claims, medication adherence patterns of patients with serious mental illness suggest that adherence to atypical antipsychotics may be related to adherence to other prescription drugs. This study investigated whether adherence to an atypical antipsychotic was related to adherence to other prescribed psychiatric drugs using self-reported data from patients with bipolar disorder. METHODS: Daily self-reported medication data were available from 123 patients with a diagnosis of bipolar disorder receiving treatment as usual who took at least 1 atypical antipsychotic over a 12-week period. Patients took a mean of 4.0±1.7 psychiatric drugs including the antipsychotic. The adherence rate for the atypical antipsychotic was compared to that for other psychiatric drugs to determine if the adherence rate for the atypical antipsychotic differed from that of the other psychiatric drug by at least ±10%. RESULTS: Of the 123 patients, 58 (47.2%) had an adherence rate for the atypical antipsychotic that differed from the adherence rate for at least 1 other psychiatric drug by at least±10%, and 65 (52.8%) patients had no difference in adherence rates. The patients with a difference took a larger total number of psychiatric drugs (p<0.001), had a larger daily pill burden (p=0.020) and a lower adherence rate with the atypical antipsychotic (p=0.007), and were more likely to take an antianxiety drug (p<0.001). CONCLUSION: Adherence with an atypical antipsychotic was not useful for estimating adherence to other psychiatric drugs in about half of the patients with bipolar disorder.

Melatonin suppression by melanopsin-weighted light in patients with bipolar I disorder compared to healthy controls

Background: Multiple lines of evidence suggest that the onset and course of bipolar disorder is influenced by environmental light conditions. Increased suppression of melatonin by light (supersensitivity) in patients with bipolar disorder has been postulated as an endophenotype by several studies. However, due to methodological shortcomings, the results of these studies remain inconclusive. This study investigated melatonin suppression in euthymic patients with bipolar I disorder using evening blue light specifically targeting the melanopsin system. Methods: Melatonin suppression was assessed in euthymic patients with bipolar I disorder and healthy controls by exposure to monochromatic blue light (λmax = 475 nm; photon density = 1.6 × 1013 photons/cm2/s) for 30 minutes at 2300 h, administered via a ganzfeld dome for highly uniform light exposure. Serum melatonin concentrations were determined from serial blood sampling via radioimmunoassay. All participants received mydriatic eye drops and were genotyped for the PER3 VNTR polymorphism to avoid or adjust for potential confounding. As secondary outcomes, serum melatonin concentrations during dark conditions and after monochromatic red light exposure (λmax = 624 nm; photon density = 1.6 × 1013 photons/cm2/s) were also investigated. Changes in subjective alertness were investigated for all 3 lighting conditions. Results: A total of 90 participants (57 controls, 33 bipolar I disorder) completed the study. Melatonin suppression by monochromatic blue light did not differ between groups (F1,80 = 0.56; p = 0.46). Moreover, there were no differences in melatonin suppression by monochromatic red light (F1,82 = 1.80; p = 0.18) or differences in melatonin concentrations during dark conditions (F1,74 = 1.16; p = 0.29). Healthy controls displayed a stronger increase in subjective alertness during exposure to blue light than patients with bipolar I disorder (t85 = 2.28; p = 0.027). Limitations: Large interindividual differences in melatonin kinetics may have masked a true difference. Conclusion: Despite using a large cohort and highly controlled laboratory conditions, we found no differences in melatonin suppression between euthymic patients with bipolar I disorder and healthy controls. These findings do not support the notion that supersensitivity is a valid endophenotype in bipolar I disorder.

What is the optimal serum level for lithium in the maintenance treatment of bipolar disorder? A systematic review and recommendations from the ISBD/IGSLI Task Force on treatment with lithium.

AIMS: To systematically review the existing trials on optimal serum levels for lithium for maintenance treatment of bipolar disorder and to develop clinical recommendations. METHODS: Systematic literature search. Discussion of major characteristics, limitations, methodological quality, and results of selected trials. Delphi survey consisting of clinical questions and corresponding statements. For statements endorsed by at least 80% of the members, consensus was considered as having been achieved. RESULTS: With strict inclusion criteria no studies could be selected, making it difficult to formulate evidence-based recommendations. After loosening the inclusion criteria 7 trials were selected addressing our aims at least to some extent. Four of these studies suggest better efficacy being associated with lithium serum levels in a range above a lower threshold around 0.45/0.60 and up to 0.80/1.00 mmol/L. These findings support the outcome of the Delphi survey. CONCLUSIONS: For adults with bipolar disorder there was consensus that the standard lithium serum level should be 0.60-0.80 mmol/L with the option to reduce it to 0.40-0.60 mmol/L in case of good response but poor tolerance or to increase it to 0.80-1.00 mmol/L in case of insufficient response and good tolerance. For children and adolescents there was no consensus, but the majority of the members endorsed the same recommendation. For the elderly there was also no consensus, but the majority of the members endorsed a more conservative approach: usually 0.40-0.60 mmol/L, with the option to go to maximally 0.70 or 0.80 mmol/L at ages 65-79 years, and to maximally 0.70 mmol/L over age 80 years.

A Novel Study Design to Systematically Explore the Impact of Trial Methodology on Psychopharmacological Treatment Outcome in Patients with Depression.

INTRODUCTION: Randomized, double-blind, placebo-controlled trials were developed to draw rather unbiased conclusions regarding the efficacy of antidepressants in the treatment of a major depressive episode (internal validity), mostly with the purpose of formal approval of new compounds in this indication. However, at the same time, data suggest that the very process of randomization and blinded administrations of placebo will have a significant impact on the efficacy of the antidepressant tested and therefore may limit the external validity of results obtained from this type of studies. Therefore, there is an urgent need to systematically study the impact of randomization/placebo control/blinding on patient population, efficacy, tolerability, and external validity in the psychopharmacological treatment of patients with a major depressive episode. METHODS: To develop a study design that allows the systematic exploration of the impact of trial design on characteristics of included patient population and outcome. RESULTS: We propose a study design including sample size calculation and statistical analysis in which patients with a major depressive episode are randomized to 3 distinct study designs that differ with regard to control, randomization, and blindness. DISCUSSION: The results of the proposed study design may have substantial consequences when it comes to how to best interpret the results of traditional randomized, double-blind, placebo-controlled trials in the acute treatment of major depressive disorder. Furthermore, they may lead to the implementation of new study designs that may be more suitable for assessing the effectiveness of new antidepressant compounds in everyday clinical practice.

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.

Effectiveness of smartphone-based ambulatory assessment (SBAA-BD) including a predicting system for upcoming episodes in the long-term treatment of patients with bipolar disorders: study protocol for a randomized controlled single-blind trial.

BACKGROUND: The detection of early warning signs is essential in the long-term treatment of bipolar disorders. However, in bipolar patients' daily life and outpatient treatment the assessment of upcoming state changes faces several difficulties. In this trial, we examine the effectiveness of a smartphone based automated feedback about ambulatory assessed early warning signs in prolonging states of euthymia and therefore preventing hospitalization. This study aims to assess, whether patients experience longer episodes of euthymia, when their treating psychiatrists receive automated feedback about changes in communication and activity. With this additional information an intervention at an earlier stage in the development of mania or depression could be facilitated. We expect that the amount of time will be longer between affective episodes in the intervention group. METHODS/DESIGN: The current study is designed as a randomized, multi-center, observer-blind, active-control, parallel group trial within a nationwide research project on the topic of innovative methods for diagnostics, prevention and interventions of bipolar disorders. One hundred and twenty patients with bipolar disorder will be randomly assigned to (1) the experimental group with included automated feedback or (2) the control group without feedback. During the intervention phase, the psychopathologic state of all participants is assessed every four weeks over 18 months. Kaplan-Meier estimators will be used for estimating the survival functions, a Log-Rank test will be used to formally compare time to a new episode across treatment groups. An intention-to-treat analysis will include data from all randomized patients. DISCUSSION: This article describes the design of a clinical trial investigating the effectiveness of a smartphone-based feedback loop. This feedback loop is meant to elicit early interventions at the detection of warning signs for the prevention of affective episodes in bipolar patients. This approach will hopefully improve the chances of a timely intervention helping patients to keep a balanced mood for longer periods of time. In detail, if our hypothesis can be confirmed, clinical practice treating psychiatrists will be enabled to react quickly when changes are automatically detected. Therefore, outpatients would receive an even more individually tailored treatment concerning time and frequency of doctor's appointments. TRIAL REGISTRATION: ClinicalTrials.gov : NCT02782910 : Title: "Smartphone-based Ambulatory Assessment of Early Warning Signs (BipoLife_A3)". Registered May 25 2016. Protocol Amendment Number: 03. Issue Date: 26 March 2018. Author(s): ES.

Efficacy and Effectiveness of Lithium in the Long-Term Treatment of Bipolar Disorders: An Update 2018.

For more than 40 years, lithium has been the gold standard in the long-term treatment of bipolar disorders. In the course of the last 15 years, other drugs have been approved in this indication and are widely used in clinical practice at the expense of lithium. New research from the last few years, however, indicates that lithium is still the first-line treatment in this indication. Against this background and lithium's proven acute antimanic efficacy, we should perhaps be using lithium more regularly (in combination with an atypical antipsychotic, if necessary) right from the start for the acute treatment of a manic episode and, once remission has been achieved and euthymia maintained during continuation treatment, to regularly taper off the atypical antipsychotic, if possible, and continue with lithium as monotherapy for prophylactic treatment. This might lead to lithium being used more consistently with the scientific evidence in the long-term treatment of bipolar disorders. It remains uncertain, however, to predict who will respond to and tolerate lithium prophylactically, and more research is needed to deliver the best possible individualized care to our patients.

[Update - Lithium in the Long-Term Treatment of Bipolar Disorders]. / Update ­ Lithium in der Phasenprophylaxe Bipolarer Störungen.

Lithium is the gold standard in the long-term treatment of bipolar disorders and the only substance with a convincing antisuicidal effect in affective disorders. Under regular monitoring, lithium represents mostly a well-tolerated and safe medication. Balancing risk and benefits shows that lithium can also be an off-label therapeutic option during pregnancy and breast feeding. Lithium may exhibit neuroprotective effects and has been linked to a reduced risk of Alzheimer's disease and stroke. In the future, biomarkers of lithium response may be available that enable development of more personalized therapies.

Longitudinal changes in the antecedent and early manifest course of bipolar disorder-A narrative review of prospective studies.

OBJECTIVE: Prospective study designs ideally allow patients to be followed from the first manifestations of the illness or even from an at-risk stage. It can thus provide data on the predictive value of changes in clinical symptomatology, cognition or further biological markers to broaden our understanding of the etiopathology and symptomatic trajectory of bipolar disorders. The scope of this narrative review is to summarize evidence from prospectively collected data on psychopathological and other clinical and biological changes in the early developmental course of bipolar disorders. METHODS: The narrative review was based on a literature search conducted in February 2016 within the PubMed library for prospective study data of persons in antecedent and early manifest stages of manifest bipolar disorder published within the last 15 years. RESULTS: A total of 19 prospective studies were included. Regarding psychopathological features; personality, temperament and character traits as well as changes in sleep and circadian rhythm, the evidence suggests that risk factors for the development of bipolar disorder can already be described and should be studied further to understand their interaction, mediation with other factors and timing in the developmental process of bipolar disorder. Apart from the positive family history, childhood anxiety, sleep problems, subthreshold (hypo)manic symptoms and certain character traits/emotionality should be identified and monitored already in clinical practice as their presence likely increases risk of bipolar disorder. Up to date no substantiated evidence was found from prospective studies addressing cognitive features, life events, immunological parameters and morphological central nervous system changes as potential risk factors for bipolar disorder. CONCLUSION: For an improved understanding of episodic disorders, longitudinal data collection is essential. Since the etiology of bipolar disorders is complex, a number of potential risk factors have been proposed. Prospective studies addressing this spectrum and resilience factors are critical and will be best conducted within multi-site research networks or initiatives.

Pharmacological treatment of unipolar depressive disorders: summary of WFSBP guidelines.

OBJECTIVE: Major depressive disorder (MDD) is a severe mood disorder affecting individuals of all ages and is characterised by single or recurrent major depressive episodes. Key elements of acute and maintenance treatment of MDD include pharmacotherapy, and psychological approaches such as psychoeducation and adherence monitoring. METHODS: This summary of the 'Practice guidelines for the biological treatment of unipolar depressive disorders' comprises acute, continuation and maintenance treatment developed by an international Task Force of the World Federation of Societies of Biological Psychiatry (WFSBP), and focuses on pharmacological treatment options. RESULTS: A variety of different antidepressants are available for the effective acute and prophylactic treatment of depressed patients. Randomised placebo-controlled efficacy studies indicate that all major classes of antidepressants are effective in acute treatment but also in preventing recurrence of depression showing about a two-fold higher relapse rate with placebo treatment. Evidence suggests that the 'newer' antidepressants have superior long-term effectiveness due to better tolerability and safety profile compared to traditional antidepressants, e.g., the tricyclic antidepressants (TCA). CONCLUSIONS: Despite progress in the availability of different treatment options there is still a substantial proportion of patients who do not achieve full remission. Several add-on pharmacological treatment options are among the best-evidenced strategies for refractory depressed patients.

DSM-5 reviewed from different angles: goal attainment, rationality, use of evidence, consequences­part 2: bipolar disorders, schizophrenia spectrum disorders, anxiety disorders, obsessive-compulsive disorders, trauma- and stressor-related disorders, personality disorders, substance-related and addictive disorders, neurocognitive disorders.

Part 1 of this paper discussed several more general aspects of Diagnostic and Statistical Manual of Mental Disorders (DSM-5) and offered a detailed, paradigmatic analysis of changes made to the chapter on depressive disorders. This second part focusses on several other disorders, including bipolar and schizophrenia spectrum disorders. The respective changes and their possible consequences are discussed under consideration of traditional psychiatric classification, particularly from the perspective of European traditions and on the basis of a PubMed search and review papers. The general conclusion is that even seemingly small changes such as the introduction of the mixed feature specifier can have far-reaching consequences. Contrary to the original plans, DSM-5 has not radically changed to become a primarily dimensional diagnostic system but has preserved the categorical system for most disorders. The ambivalence of the respective decision-making becomes apparent from the last minute decision to change the classification of personality disorders from dimensional back to categorical. The advantages and disadvantages of the different approaches are discussed in this context. In DSM-5, only the chapter on addictive disorders has a somewhat dimensional structure. Also in contrast to the original intentions, DSM-5 has not used a more neurobiological approach to disorders by including biological markers to increase the objectivity of psychiatric diagnoses. Even in the most advanced field in terms of biomarkers, the neurocognitive disorders, the primarily symptom-based, descriptive approach has been preserved and the well-known amyloid-related and other biomarkers are not included. This is because, even after so many years of biomarker research, the results are still not considered to be robust enough to use in clinical practice.

DSM-5 reviewed from different angles: goal attainment, rationality, use of evidence, consequences--part 1: general aspects and paradigmatic discussion of depressive disorders.

DSM-5 was published in 2013 after about 10 years of preparation. Part 1 of this paper discusses several more general aspects of DSM-5 and offers a detailed, paradigmatic analysis of changes made to the chapter on depressive disorders. The background for the changes is analysed on the basis of a PubMed search and review papers on the classification of mental disorders in general and on empirical knowledge about individual disorders. Contrary to the original plans, DSM-5 has not introduced a primarily dimensional diagnostic system but has widely preserved the categorical system of disorders. Also, it has not adopted a more neurobiological approach to disorders by including biological markers to increase the objectivity of psychiatric diagnoses but has maintained the primarily symptom-based, descriptive approach. The criteria for some disorders have been changed, including affective, schizophrenic and addiction disorders, and a few new disorders have been added. A minimal version of the dimensional approach was realised through the introduction of several transnosological specifiers and the option to make symptom- or syndrome-related severity and dimensional assessments. These specifiers and assessments might allow a more individualised description of a patient's psychopathological state and more personalised treatment. However, most of the symptom- and syndrome-related assessments are not mandatory and therefore may not be used in clinical practice.

Managing the risk of lithium-induced nephropathy in the long-term treatment of patients with recurrent affective disorders.

Lithium has been the most effective psychopharmacological drug in the long-term treatment of patients with recurrent unipolar and bipolar affective illness. As a result of its widespread and longtime use in patients with recurrent affective disorders, psychiatrists have become increasingly aware of the whole spectrum of lithium's potential side effects. One of the side effects associated with its chronic use is lithium-induced nephropathy. In a recent cross-sectional study published in BMC Medicine, Alberto Bocchetta et al. add further information to this topic, demonstrating that duration of lithium treatment is associated with impaired glomerular function in patients with recurrent or chronic affective disorders. The present paper will discuss the implications of this and other related recent research on our management of patients with recurrent affective disorders. In this context the importance of shared decision making and close monitoring of kidney function is highlighted, including the regular assessment of the glomerular filtration rate, to provide best possible care to our patients maintained on lithium treatment.See related research article here http://www.biomedcentral.com/1741-7015/11/33.

Quetiapine as combination treatment with citalopram in unipolar depression with prominent somatic symptoms: a randomised, double-blind, placebo-controlled pilot study.

BACKGROUND: Patients with major depressive disorder (MDD) accompanied by physical symptoms may be less responsive to antidepressant treatment. Quetiapine has been evaluated in the treatment of bipolar depression and has been recently approved as an add-on therapy for unipolar depression. Less is known about the efficacy of combination therapies in patients suffering from MDD with somatic symptoms. The aim of the present study was to evaluate the efficacy of quetiapine as adjunctive therapy to the SSRI citalopram in patients with MDD and somatic complaints. SUBJECTS AND METHODS: 41 inpatients with nonpsychotic DSM-IV MDD experiencing significant symptoms of somatic distress as defined by a baseline score on the SCL-90-R somatization subscale greater one standard deviation above adult nonpatient norms were randomly assigned to receive either citalopram 40 mg/day plus placebo (n=20) or citalopram 40 mg/day plus quetiapine, 300 to 600 mg/day (n=21) for 6 weeks. The primary outcome measure was the Hamilton Depression Rating Scale (HDRS) score. RESULTS: Mean changes in HDRS scores from baseline to week 6 using last-observation-carried-forward methods were -12.3±6.2 and -10.7±5.1 in the citalopram-quetiapine and citalopram-placebo group, respectively. Remission rates were significant higher in the citalopram-quetiapine-group (41.1%) than in the citalopram-placebo-group (26.3%), respectively. CONCLUSIONS: Although quetiapine as add-on to citalopram did not separate statistically from placebo on the HDRS score in improving depressive symptoms and somatic symptoms in patients with MDD and prominent somatic complaints, higher remission rates and other second outcome parameters showed advantages for quetiapine. Larger, double-blind, placebo-controlled trials of quetiapine as augmentation therapy in MDD with somatic symptoms are warranted.

Lithium prescription trends in psychiatric inpatient care 2014 to 2021: data from a Bavarian drug surveillance project.

OBJECTIVES: Lithium (Li) remains one of the most valuable treatment options for mood disorders. However, current knowledge about prescription practices in Germany is limited. The objective of this study is to estimate the prevalence of current Li use over time and in selected diagnoses, highlighting clinically relevant aspects such as prescription rates in elderly patients, concomitant medications, important drug-drug interactions, and serious adverse events. METHODS: We conducted a descriptive analysis of Li prescriptions, analyzing data from the ongoing Bavarian multicenter drug safety project Pharmaco-Epidemiology and Vigilance (Pharmako-EpiVig) from the years 2014-2021. Our study included 97,422 inpatients, 4543 of whom were prescribed Li. RESULTS: The Li prescription rate in unipolar depression (UD) remained constant at 4.6% over the observational period. In bipolar disorder (BD), the prescription rate increased significantly from 28.8% in 2014 to 34.4% in 2019. Furthermore, 30.3% of patients with Li prescriptions did not have a diagnosis of BD or UD, and 15.3% of patients with schizoaffective disorder were prescribed Li. The majority (64%) of patients with Li prescriptions were prescribed five or more drugs. Most of the 178 high-priority drug-drug interactions were due to hydrochlorothiazide (N = 157) followed by olmesartan (N = 16). CONCLUSION: Our study does not substantiate concerns about a decline in Li prescription. The decline in prescription rates observed in some diagnostic groups in 2020 and 2021 may be associated with the COVID-19 pandemic. The symptom-oriented use of Li beyond BD and UD is common. Polypharmacy and drug-drug interactions present a challenge in Li therapy. Old age and comorbid substance use disorder do not appear to be major deterrents for clinicians to initiate Li therapy.

Clinicians' preferences and attitudes towards the use of lithium in the maintenance treatment of bipolar disorders around the world: a survey from the ISBD Lithium task force.

BACKGROUND: Lithium has long been considered the gold-standard pharmacological treatment for the maintenance treatment of bipolar disorders (BD) which is supported by a wide body of evidence. Prior research has shown a steady decline in lithium prescriptions during the last two decades. We aim to identify potential factors explaining this decline across the world with an anonymous worldwide survey developed by the International Society for Bipolar Disorders (ISBD) Task Force "Role of Lithium in Bipolar Disorders" and distributed by diverse academic and professional international channels. RESULTS: A total of 886 responses were received of which 606 completed the entire questionnaire while 206 completed it partially. Respondents were from 43 different countries comprising all continents. Lithium was the most preferred treatment option for the maintenance of BD patients (59%). The most relevant clinical circumstances in which lithium was the preferred option were in patients with BD I (53%), a family history of response (18%), and a prior response during acute treatment (17%). In contrast, Lithium was not the preferred option in case of patients´ negative beliefs and/or attitudes towards lithium (13%), acute side-effects or tolerability problems (10%) and intoxication risk (8%). Clinicians were less likely to prefer lithium as a first option in BD maintenance phase when practising in developing economy countries [X2 (1, N = 430) = 9465, p = 0.002) ] and private sectors [X2 (1, N = 434) = 8191, p = 0.004)]. CONCLUSIONS: Clinicians' preferences and attitudes towards the use of lithium in the maintenance treatment of bipolar disorders appear to be affected by both the patients' beliefs and the professional contexts where clinicians provide their services. More research involving patients is needed for identifying their attitudes toward lithium and factors affecting its use, particularly in developing economies.

Mirroring everyday clinical practice in clinical trial design: a new concept to improve the external validity of randomized double-blind placebo-controlled trials in the pharmacological treatment of major depression.

BACKGROUND: Randomized, double-blind, placebo-controlled trials constitute the gold standard in clinical research when testing the efficacy of new psychopharmacological interventions in the treatment of major depression. However, the blinded use of placebo has been found to influence clinical trial outcomes and may bias patient selection. DISCUSSION: To improve clinical trial design in major depression so as to reflect clinical practice more closely we propose to present patients with a balanced view of the benefits of study participation irrespective of their assignment to placebo or active treatment. In addition every participant should be given the option to finally receive the active medication. A research agenda is outlined to evaluate the impact of the proposed changes on the efficacy of the drug to be evaluated and on the demographic and clinical characteristics of the enrollment fraction with regard to its representativeness of the eligible population. SUMMARY: We propose a list of measures to be taken to improve the external validity of double-blind, placebo-controlled trials in major depression. The recommended changes to clinical trial design may also be relevant for other psychiatric as well as medical disorders in which expectations regarding treatment outcome may affect the outcome itself.

Efficacy of pharmacotherapy in bipolar disorder: a report by the WPA section on pharmacopsychiatry.

The current statement is a systematic review of the available data concerning the efficacy of medication treatment of bipolar disorder (BP). A systematic MEDLINE search was made concerning the treatment of BP (RCTs) with the names of treatment options as keywords. The search was updated on 10 March 2012. The literature suggests that lithium, first and second generation antipsychotics and valproate and carbamazepine are efficacious in the treatment of acute mania. Quetiapine and the olanzapine-fluoxetine combination are also efficacious for treating bipolar depression. Antidepressants should only be used in combination with an antimanic agent, because they can induce switching to mania/hypomania/mixed states/rapid cycling when utilized as monotherapy. Lithium, olanzapine, quetiapine and aripiprazole are efficacious during the maintenance phase. Lamotrigine is efficacious in the prevention of depression, and it remains to be clarified whether it is also efficacious for mania. There is some evidence on the efficacy of psychosocial interventions as an adjunctive treatment to medication. Electroconvulsive therapy is an option for refractory patients. In acute manic patients who are partial responders to lithium/valproate/carbamazepine, adding an antipsychotic is a reasonable choice. The combination with best data in acute bipolar depression is lithium plus lamotrigine. Patients stabilized on combination treatment might do worse if shifted to monotherapy during maintenance, and patients could benefit with add-on treatment with olanzapine, valproate, an antidepressant, or lamotrigine, depending on the index acute phase. A variety of treatment options for BP are available today, but still unmet needs are huge. Combination therapy may improve the treatment outcome but it also carries more side-effect burden. Further research is necessary as well as the development of better guidelines and algorithms for the step-by-step rational treatment.

Omega-3 fatty acids in bipolar patients with a low omega-3 index and reduced heart rate variability: the "BIPO-3" trial.

BACKGROUND: Research suggests that a low omega-3 index may contribute to the low heart rate variability and the increased risk of cardiovascular morbidity and mortality in bipolar disorders. However, so far, no intervention trial with EPA and DHA has been conducted in bipolar patients attempting to increase their heart rate variability. METHODS: 119 patients with bipolar disorder according to DSM-IV were screened, with 55 euthymic bipolar patients-owing to inclusion criteria (e.g. low omega-3 index (< 6%), SDNN < 60 ms.)-being enrolled in a randomized, double-blind, 12-week parallel study design with omega-3 fatty acids (4 capsules of 530 mg EPA, 150 mg DHA) or corn oil as a placebo, in addition to usual treatment. Heart rate variability as well as the omega-3 index were measured at baseline and at the endpoint of the study. RESULTS: A total of 42 patients (omega-3: n = 23, corn oil: n = 19) successfully completed the study after 12 weeks. There was a significant increase in the omega-3 index (value at endpoint minus value at baseline) in the omega-3 group compared to the corn oil group (p < 0.0001). However, there was no significant difference in the change of the SDNN (value at endpoint minus value at baseline) between the treatment groups (p = 0.22). In addition, no correlation between changes in SDNN and change in the omega-3 index could be detected in the omega-3 group (correlation coefficient = 0.02, p = 0.94) or the corn oil group (correlation coefficient = - 0.11, p = 0.91). Similarly, no significant differences between corn oil and omega-3 group regarding the change of LF (p = 0.19), HF (p = 0.34) and LF/HF ratio (p = 0.84) could be demonstrated. CONCLUSIONS: In our randomized, controlled intervention trial in euthymic bipolar patients with a low omega-3 index and reduced heart rate variability no significant effect of omega-3 fatty acids on SDNN or frequency-domain measures HF, LF and LF/HF ratio could be detected. Possible reasons include, among others, the effect of psychotropic medication present in our trial and/or the genetics of bipolar disorder itself. Further research is needed to test these hypotheses. Trial registration ClinicalTrials.gov, NCT00891826. Registered 01 May 2009-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT00891826.