Online mindfulness-based intervention for late-stage bipolar disorder: pilot evidence for feasibility and effectiveness

OBJECTIVES: People in the late stage of bipolar disorder (BD) experience elevated relapse rates and poorer quality of life (QoL) compared with those in the early stages. Existing psychological interventions also appear less effective in this group. To address this need, we developed a new online mindfulness-based intervention targeting quality of life (QoL) in late stage BD. Here, we report on an open pilot trial of ORBIT (online, recovery-focused, bipolar individual therapy). METHODS: Inclusion criteria were: self-reported primary diagnosis of BD, six or more episodes of BD, under the care of a medical practitioner, access to the internet, proficient in English, 18-65 years of age. Primary outcome was change (baseline - post-treatment) on the Brief QoL.BD (Michalak and Murray, 2010). Secondary outcomes were depression, anxiety, and stress measured on the DASS scales (Lovibond and Lovibond, 1993). RESULTS: Twenty-six people consented to participate (Age M=46.6 years, SD=12.9, and 75% female). Ten participants were lost to follow-up (38.5% attrition). Statistically significant improvement in QoL was found for the completers, t(15)=2.88, 95% CI:.89-5.98, p=.011, (Cohen׳s dz=.72, partial η(2)=.36), and the intent-to-treat sample t(25)=2.65, 95% CI:.47-3.76, (Cohen׳s dz=.52; partial η(2)=.22). A non-significant trend towards improvement was found on the DASS anxiety scale (p=.06) in both completer and intent-to-treat samples, but change on depression and stress did not approach significance. LIMITATIONS: This was an open trial with no comparison group, so measured improvements may not be due to specific elements of the intervention. Structured diagnostic assessments were not conducted, and interpretation of effectiveness was limited by substantial attrition. CONCLUSION: Online delivery of mindfulness-based psychological therapy for late stage BD appears feasible and effective, and ORBIT warrants full development. Modifications suggested by the pilot study include increasing the 3 weeks duration of the intervention, adding cautions about the impact of extended meditations, and addition of coaching support/monitoring to optimise engagement.

Effects of asenapine in bipolar I patients meeting proxy criteria for moderate-to-severe mixed major depressive episodes: a post hoc analysis

OBJECTIVE: Depression is the predominant psychosocial and suicide burden in bipolar disorder, yet there is a paucity of evidence-based treatments for bipolar depression. METHODS: This post hoc subgroup analysis of data pooled from two 3-week, randomized, placebo- and olanzapine-controlled trials (December 2004-April 2006, N = 489 and November 2004-April 2006, N = 488) examined a subgroup of patients meeting criteria for moderate-to-severe mixed major depressive episodes, defined using DSM-IV-TR criteria for mixed episodes (mania and major depression simultaneously) with a baseline Montgomery-Asberg Depression Rating Scale (MADRS) total score ≥ 20. RESULTS: Decreases in MADRS scores (least squares mean [SE]), the a priori primary outcome, were significantly greater in the asenapine group than in the placebo group from baseline to day 7 (-11.02 [1.82] vs -4.78 [1.89]; P = .0195), day 21 (-14.03 [2.01] vs -7.43 [2.09]; P = .0264), and endpoint (-10.71 [1.76] vs -5.19 [1.98]; P = .039). Decreases in MADRS scores with asenapine were significantly greater than with olanzapine from baseline to day 7 (-6.26 [1.47]; P = .0436). Decreases in Young Mania Rating Scale mean total score were greater with asenapine than with placebo or olanzapine at all time points assessed. A significantly greater reduction from baseline to day 21 in the Short Form-36 mental component summary score was observed with asenapine, but not olanzapine, compared with placebo (16.57 vs 5.97; P = .0093). Asenapine was generally well tolerated. CONCLUSIONS: These data provide support for the potential efficacy of asenapine in mixed major depressive episodes; however, these data cannot be linearly extrapolated to nonmixed major depression.

Serotonin 1a receptor and associated G-protein activation in schizophrenia and bipolar disorder

Abnormalities in the serotonergic signalling system, including the serotonin 1a receptor, have been implicated in the pathogenesis of schizophrenia and bipolar 1 disorder. However, there is no consensus on whether the density of the serotonin 1a receptor and/or the activity of the G-proteins linking the receptor to the intracellular cascade are altered in these disease states. To address these issues, tissue obtained postmortem from four cortical regions was used to measure [3H] 8-hydroxy-2-(dipropylamino)tetralin hydrobromide (8-OH-DPAT) binding and 8-OH-DPAT-stimulated guanosine 5′-[γ-thio]triphosphate (GTPγS) binding to determine if either parameter is altered in schizophrenia or bipolar I disorder. There was an effect of diagnosis on the level of [3H] 8-OH-DPAT binding that may indicate a global change in the density of serotonin 1a receptors, although this effect did not reach significance in any individual brain region. The activation of serotonin 1a receptors did not differ significantly with diagnoses. However, in the outer cortical layers, there appeared to be a dissociation between the number of receptors available and the extent of ligand-induced GTPγS binding, suggesting considerable receptor reserve. In addition, comparing gender independent of diagnoses, a decrease in the levels of serotonin 1a receptors was observed in the cortex of female subjects. These data indicates that there may be subtle changes in serotonin 1a receptors across the cortex in schizophrenia or bipolar I disorder and suggests a gender discordance in receptor levels.

N-Ethylmaleimide sensitive factor in the cortex of subjects with schizophrenia and bipolar I disorder

N-Ethylmaleimide sensitive factor (NSF) is a presynaptic protein that has been suggested to be differentially expressed in the cortex of schizophrenic subjects through both high-throughput proteomic and genomic screening studies. Thus, to expand upon these studies we measured NSF using Western blotting in four regions of the cortex (BA9, 10, 40 and 46), in a cohort comprising 20 schizophrenic subjects, 8 bipolar I disorder subjects, and 20 control subjects. There was no significant difference in NSF levels between diagnostic cohorts in any of the four cortical regions. These findings highlight the importance of validating findings from high-throughput screening studies and do not support changes in cortical NSF as being of significance in schizophrenia or bipolar 1 disorder.

Regionally specific changes in levels of cortical S100β in bipolar 1 disorder but not schizophrenia

Objective: To determine if levels of the glial-derived proteins S100β and glial acidic fibrillary protein (GFAP) and the pro- and antiapoptotic proteins p53 and Bcl-2 were altered in the cortex of subjects with schizophrenia or bipolar 1 disorder.
Method: Levels of S100β, GFAP, p53 and Bcl-2 were measured in cortex (Brodmann's Areas (BAs) 9, 10, 46 and 40) of control subjects and subjects with schizophrenia, bipolar 1 disorder and in the cortex of rats treated with haloperidol or lithium using protein-specific antibodies and western blot analysis.
Results: Levels of S100β were decreased in BA 9 and increased in BA 40 from subjects with bipolar 1 disorder. Levels of this protein were not altered in other CNS regions, in schizophrenia or in the cortex of rats treated with haloperidol or lithium. No changes in levels of the other three proteins were detected across diagnoses.
Conclusions: Regionally selective changes in cortical S100β may be associated with the pathology of bipolar 1 disorder and may reflect derangements in neuronal death or survival

Impact of cannabis use on long-term remission in bipolar I and schizoaffective disorder

OBJECTIVE: To investigate the impact of regular cannabis use on long-term remission of mood symptoms in bipolar spectrum disorders. METHODS: The 24-month prospective observational study included patients (n=239) with bipolar I disorder and schizoaffective disorder, bipolar type. Participants were classified as regular cannabis users (three times or more per week) or non-users. The primary outcome measure was the achievement of remission on the evaluations during the 24 months. RESULTS: Of the 234 participants for whom data was available, 25 (10.7%) were regular cannabis users, and the group comprised significantly more males than females. In the total population, cannabis use was significantly associated with decreased likelihood of remission during the 24-month follow-up period. Subgroup analyses showed that cannabis use was significantly associated with lower remission rates on the Hamilton Depression Rating Scale in females (n=139) and patients prescribed mood stabilizers alone (n=151), whereas in males (n=95) and patients prescribed olanzapine and/or a mood stabilizer (n=83), cannabis use was significantly associated with lower remission rates on the Young Mania Rating Scale. Remission rates were lowest in the concurrent cannabis and tobacco smoking group (n=22) followed by the tobacco smoking only group (n=97), and the non-smoker group (n=116). The post-hoc analysis revealed that all remission rates were significantly lower in the concurrent cannabis and the tobacco smoking group compared to the non-smoker group. CONCLUSION: Cannabis use negatively affects the long-term clinical outcome in patients with bipolar spectrum disorders. A comprehensive assessment and integrated management of cannabis use are required to achieve better treatment outcomes for bipolar spectrum disorders.

Diet and bipolar disorder: a review of its relationship and potential therapeutic mechanisms of action

OBJECTIVES: It is well accepted that diet quality has an important role in the prevention and treatment of several physical diseases. However, its influence on mental health has received far less attention, although there is increasing evidence to support a relationship with depression. In this narrative review, investigations into the relationship between diet and bipolar disorder are examined and the potential implications in the management and treatment of bipolar disorder are reviewed. METHODS: The authors provide a narrative review of the relevant information. RESULTS: Research is limited, although there are preliminary findings to suggest a relationship between diet and bipolar disorder. Findings from cross-sectional research suggest that people with bipolar disorder consume an unhealthier dietary pattern. This has significant treatment implications as bipolar disorder has a high comorbidity with several physical diseases. In addition, diet also influences several biological processes that are dysregulated in bipolar disorder, namely monoaminergic activity, immune/inflammatory processes, oxidative stress, mitochondrial activity, and neuroprogression. CONCLUSIONS: The role of diet in bipolar disorder requires further attention in research as it presents as a factor that may contribute to the worsening course of this condition and may potentially enhance current treatment outcomes.

Reduced mu suppression and altered motor resonance in euthymic bipolar disorder: evidence for a dysfunctional mirror system?

Social cognitive difficulties are common in the acute phase of bipolar disorder and, to a lesser extent, during the euthymic stage, and imaging studies of social cognition in euthymic bipolar disorder have implicated mirror system brain regions. This study aimed to use a novel multimodal approach (i.e., including both transcranial magnetic stimulation (TMS) and electroencephalogram (EEG)) to investigate mirror systems in bipolar disorder. Fifteen individuals with euthymic bipolar disorder and 16 healthy controls participated in this study. Single-pulse TMS was applied to the optimal site in the primary motor cortex (M1), which stimulates the muscle of interest during the observation of hand movements (goal-directed or interacting) designed to elicit mirror system activity. Single EEG electrodes (C3, CZ, C4) recorded mu rhythm modulation concurrently. Results revealed that the patient group showed significantly less mu suppression compared to healthy controls. Surprisingly, motor resonance was not significantly different overall between groups; however, bipolar disorder participants showed a pattern of reduced reactivity on some conditions. Although preliminary, this study indicates a potential mirror system deficit in euthymic bipolar disorder, which may contribute to the pathophysiology of the disorder.

Future directions for pharmacotherapies for treatment-resistant bipolar disorder

Current pharmacological treatments for bipolar disorder (BD) are limited and efficacy has historically been discovered through serendipity. There is now scope for new drug development, focused on the underlying biology of BD that is not targeted by current therapies. The need for novel treatments is urgent when considering treatment resistant BD, where current therapies have failed. While established drugs targeting the monoamine systems continue to be worthwhile, new biological targets including inflammatory and oxidative an nitrosative pathways, apoptotic and neurotrophic pathways, mitochondrial pathways, the N-methyl-Daspartate (NMDA)-receptor complex, the purinergic system, neuropeptide system, cholinergic system and melatonin pathways are all being identified as potential anchors for the discovery of new agents. Many agents are experimental and efficacy data is limited, however further investigation may provide a new line for drug discovery, previously stalled by lack of corporate interest.

Evaluating discussion board engagement in the MoodSwings online self-help program for bipolar disorder: protocol for an observational prospective cohort study

BACKGROUND: Online, self-guided programs exist for a wide range of mental health conditions, including bipolar disorder, and discussion boards are often part of these interventions. The impact engagement with these discussion boards has on the psychosocial well-being of users is largely unknown. More specifically we need to clarify the influence of the type and level of engagement on outcomes. The primary aim of this exploratory study is to determine if there is a relationship between different types (active, passive or none) and levels (high, mid and low) of discussion board engagement and improvement in outcome measures from baseline to follow up, with a focus on self-reported social support, stigma, quality of life and levels of depression and mania. The secondary aim of this study is to identify any differences in demographic variables among discussion users.

METHODS/DESIGN: The present study is a sub-study of the MoodSwings 2.0 3-arm randomised controlled trial (discussion board only (arm 1), discussion board plus psychoeducation (arm 2), discussion board, psychoeducation plus cognitive behavioural therapy-based tools (arm 3)). Discussion engagement will be measured via online participant activity monitoring. Assessments include online self-report as well as blinded phone interviews at baseline, 3, 6, 9 and 12 months follow up.

DISCUSSION: The results of this study will help to inform future programs about whether or not discussion boards are a beneficial inclusion in online self-help interventions. It will also help to determine if motivating users to actively engage in online discussion is necessary, and if so, what level of engagement is optimal to produce the most benefit. Future programs may benefit through being able to identify those most likely to poorly engage, based on demographic variables, so motivational strategies can be targeted accordingly.

Regulators of mitochondrial complex I activity: a review of literature and evaluation in postmortem prefrontal cortex from patients with bipolar disorder

Phenomenologically, bipolar disorder (BD) is characterized by biphasic increases and decreases in energy. As this is a state-related phenomenon, identifying regulators responsible for this phasic dysregulation has the potential to uncover key elements in the pathophysiology of BD. Given the evidence suggesting mitochondrial complex I dysfunction in BD, we aimed to identify the main regulators of complex I in BD by reviewing the literature and using the published microarray data to examine their gene expression profiles. We also validated protein expression levels of the main complex I regulators by immunohistochemistry. Upon reviewing the literature, we found PARK-7, STAT-3, SIRT-3 and IMP-2 play an important role in regulating complex I activity. Published microarray studies however revealed no significant direction of regulation of STAT-3, SIRT-3, and IMP-2, but a trend towards downregulation of PARK-7 was observed in BD. Immunocontent of DJ-1 (PARK-7-encoded protein) were not elevated in post mortem prefrontal cortex from patients with BD. We also found a trend towards upregulation of DJ-1 expression with age. Our results suggest that DJ-1 is not significantly altered in BD subjects, however further studies are needed to examine DJ-1 expression levels in a cohort of older patients with BD.