Balanced efficacy, safety, and tolerability recommendations for the clinical management of bipolar disorder

Objective:  To provide practical and clinically meaningful treatment recommendations that amalgamate clinical experience and research findings for each phase of bipolar disorder.

Methods:  A comprehensive search of the literature was undertaken using electronic database search engines (Medline, PubMed, Cochrane reviews) using key words (e.g., bipolar depression, mania, treatment). All relevant randomised controlled trials were examined, along with review papers, meta-analyses, and book chapters known to the authors. In addition, the recommendations from accompanying papers in this supplement have been distilled and captured in the form of summary boxes. The findings, in conjunction with the clinical experience of international researchers and clinicians who are practiced in treating mood disorders, formed the basis of the treatment recommendations within this paper.

Results:  Balancing clinical experience with evidence informed and lead to the development of practical clinical recommendations that emphasise the importance of safety and tolerability alongside efficacy in the clinical management of bipolar disorder.

Conclusions:  The current paper summarises the treatment recommendations relating to each phase of bipolar disorder while providing additional, evidence-based, practical insights. Medication-related side effects and monitoring strategies highlight the importance of safety and tolerability considerations, which, along with efficacy information, should be given equal merit.

Development of an online intervention for bipolar disorder. www.moodswings.net.au

We describe the development process and completed structure, of a self-help online intervention for bipolar disorder, known as MoodSwings (www.moodswings.net.au). The MoodSwings program was adapted as an Internet intervention from an efficacious and validated face-to-face, group-based psychosocial intervention. The adaptation was created by a psychologist, who had previously been involved with the validation of the face-to-face program, in collaboration with website designers. The project was conducted under the supervision of a team of clinician researchers. The website is available at no cost to registered participants. Self-help modules are accessed sequentially. Other features include a mood diary and a moderated discussion board. There has been an average of 1,475,135 hits on the site annually (2008 and 2009), with some 7400 unique visitors each year. A randomised controlled trial based on this program has been completed. Many people with bipolar disorder are accepting of the Internet as a source of treatment and, once engaged, show acceptable retention rates. The Internet appears to be a viable means of delivering psychosocial self-help strategies.

Maintenance N-acetyl cysteine treatment for bipolar disorder : a double-blind randomised placebo controlled trial

Background N-acetyl cysteine (NAC) is a glutathione precursor that has been shown to have antidepressant efficacy in a placebo-controlled trial. The current study aimed to investigate the maintenance effects of NAC following eight weeks of open-label treatment for bipolar disorder.

Method The efficacy of a double blind randomized placebo controlled trial of 2 g/day NAC as adjunct maintenance treatment for bipolar disorder was examined. Participants (n = 149) had a Montgomery Asberg Depression Rating Score of [greater than or equal to]12 at trial entry and, after eight weeks of open-label NAC treatment, were randomized to adjunctive NAC or placebo, in addition to treatment as usual. Participants (primarily outpatients) were recruited through public and private services and through newspaper advertisements. Time to intervention for a mood episode was the primary endpoint of the study, and changes in mood symptoms, functionality and quality of life measures were secondary outcomes.

Results There was a substantial decrease in symptoms during the eight-week open-label NAC treatment phase. During the subsequent double-blind phase, there was minimal further change in outcome measures with scores remaining low. Consequently, from this low plateau, between-group differences did not emerge on recurrence, clinical functioning or quality of life measures.

Conclusions There were no significant between-group differences in recurrence or symptomatic outcomes during the maintenance phase of the trial; however, these findings may be confounded by limitations. Trial Registration The trial was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12607000074493).

Co-prescription of medication for bipolar disorder and diabetes mellitus : a nationwide population based study with focus on gender differences

Background
Studies have shown a correlation between bipolar disorder and diabetes mellitus. It is unclear if this correlation is a part of common pathophysiological pathways, or if medication for bipolar disorder has negative effects on blood sugar regulation.
Methods
The Norwegian prescription database was analyzed. Prescriptions for lithium, lamotrigine, carbamazepine and valproate were used as proxies for bipolar disorder. Prescriptions for insulin and oral anti-diabetic agents were used as proxies for diabetes mellitus. We explored the association between medication for bipolar disorder and diabetes medication by logistic regression
Results
We found a strong association between concomitant use of medication to treat diabetes mellitus and mood stabilizers for the treatment of bipolar disorder. Females had a 30% higher risk compared to men of being treated for both disorders. Persons using oral anti-diabetic agents had higher odds of receiving valproate than either lithium or lamotrigine. Use of insulin as monotherapy seemed to have lower odds than oral anti-diabetic agents of co-prescription of mood stabilizers, compared to the general population.
Conclusions
This study showed a strong association between the use of mood stabilizers and anti-diabetic agents. The association was stronger among women than men.

Adjunctive antioxidants for bipolar disorder

To assess the effects of specific drugs with antioxidant properties, in comparison with placebo, as adjunctive treatment to standard mood-stabilising treatment for improving acute mood episodes and preventing relapse in people with bipolar disorder.

Given the diverse range of antioxidant drugs under consideration we will only seek to draw conclusions regarding the efficacy of individual drugs as an adjunct to mood stabilisers and there will be no comment on relative efficacy between different antioxidants.

Treatment and outcomes of an Australian cohort of outpatients with bipolar 1 or schizoaffective disorder over twenty-four months : implications for clinical practice

Background The Bipolar Comprehensive Outcomes Study (BCOS) is a 2-year, prospective, non-interventional, observational study designed to explore the clinical and functional outcomes associated with ‘real-world’ treatment of participants with bipolar I or schizoaffective disorder. All participants received treatment as usual. There was no study medication.

Methods Participants prescribed either conventional mood stabilizers (CMS; n = 155) alone, or olanzapine with, or without, CMS (olanzapine ± CMS; n = 84) were assessed every 3 months using several measures, including the Young Mania Rating Scale, 21-item Hamilton Depression Rating Scale, Clinical Global Impressions Scale – Bipolar Version, and the EuroQol Instrument. This paper reports 24-month longitudinal clinical, pharmacological, functional, and socioeconomic data.

Results On average, participants were 42 (range 18 to 79) years of age, 58%; were female, and 73%; had a diagnosis of bipolar I. Polypharmacy was the usual approach to pharmacological treatment; participants took a median of 5 different psychotropic medications over the course of the study, and spent a median proportion of time of 100%; of the study on mood stabilizers, 90%; on antipsychotics, 9%; on antidepressants, and 5%; on benzodiazepines/hypnotics. By 24 months, the majority of participants had achieved both symptomatic and syndromal remission of both mania and depression. Symptomatic relapse rates were similar for both the CMS alone (65%;) and the olanzapine ± CMS (61%;) cohorts.

Conclusions Participants with bipolar I or schizoaffective disorder in this study were receiving complex medication treatments that were often discordant with recommendations made in contemporary major treatment guidelines. The majority of study participants demonstrated some clinical and functional improvements, but not all achieved remission of symptoms or syndrome.

Cumulative morbidity and prognostic staging of illness in the systematic treatment enhancement program for Bipolar Disorder (STEP-BD)

Objective: Staging models may provide heuristic utility for intervention selection in psychiatry. Although a few proposals have been put forth, there is a need for empirical validation if they are to be adopted. Using data from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), we tested a previously elaborated hypothesis on the utility of using the number of previous episodes as a relevant prognostic variable for staging in bipolar disorder.

Methods: This report utilizes data from the multisite, prospective, open-label study ‘Standard Care Pathways’ and the subset of patients with acute depressive episodes who participated in the randomized trial of adjunctive antidepressant treatment. Outpatients meeting DSM-IV diagnostic criteria for bipolar disorder (n = 3345) were included. For the randomized pathway, patients met criteria for an acute depressive episode (n = 376). The number of previous episodes was categorized as less than 5, 5–10 and more than 10. We used disability at baseline, number of days well in the first year and longitudinal scores of depressive and manic symptoms, quality of life and functioning as validators of models constructed a priori.

Results: Patients with multiple previous episodes had consistently poorer cross-sectional and prospective outcomes. Functioning and quality of life were worse, disability more common, and symptoms more chronic and severe. There was no significant effect for staging with regard to antidepressant response in the randomized trial.

Conclusions: These findings confirm that bipolar disorder can be staged with prognostic validity. Stages can be used to stratify subjects in clinical trials and develop specific treatments.