Safe and effective use of lithium

Lithium has proven efficacy in the treatment of bipolar disorder, both for acute mania and long-term mood stabilisation and prophylaxis. It is also useful in combating treatment-resistant depression. Compared to other mood stabilisers, lithium has a favourable efficacy-tolerability balance. Lithium is underused due to active marketing of alternatives and concerns regarding adverse effects, tolerability, and the perception that regular monitoring is difficult

Design and rationale of a 16-week adjunctive randomized placebo-controlled trial of mitochondrial agents for the treatment of bipolar depression

Objective: Bipolar disorder places a significant burden on individuals, caregivers and family, and the broader community. Current treatments are believed to be more effective against manic symptoms, leaving a shortfall in recovery during the depressive phase of the illness. The current study draws on recent evidence suggesting that, in addition to increased oxidative load, alterations in mitochondrial function occur in bipolar disorder. Methods: This 16-week study aims to explore the potential benefits of N-acetylcysteine (NAC) alone or in combination (CT) with selected nutraceuticals believed to enhance mitochondrial function. The study includes adults diagnosed with bipolar disorder currently experiencing an episode of depression. Participants are asked to take NAC, CT, or placebo in addition to any usual treatments. A post-discontinuation visit is conducted 4 weeks following the treatment phase. Results: The primary outcome of the study will be mean change on the Montgomery-Asberg Depression Rating Scale. Secondary outcomes include functioning, substance use, mania ratings, and quality of life. Blood samples will be collected at baseline and week 16 to explore biochemical alterations following treatment. Conclusion: This study may provide a novel adjunctive treatment for bipolar depression. Analysis of biological samples may assist in understanding the therapeutic benefits and the underlying etiology of bipolar depression

A randomised controlled trial of a mitochondrial therapeutic target for bipolar depression: mitochondrial agents, N-acetylcysteine, and placebo

A phasic dysregulation of mitochondrial bioenergetics may operate in bipolar disorder, increased in mania and decreased in depression. We aimed to examine efficacy of two add-on treatments in bipolar depression: N-acetylcysteine (NAC) and NAC with a combination of nutraceutical agents that may increase mitochondrial biogenesis. A three-arm 16-week, double-blind, randomised, placebo-controlled trial, adjunctive to usual treatment, was conducted. Participants (n = 181) with bipolar disorder and current depressive symptoms were randomised to 2000 mg/day NAC (n = 59), 2000 mg/day NAC with the combination nutraceutical treatment (CT, n = 61), or placebo (n = 61). The primary outcome was change in Montgomery-Åsberg Depression Rating Scale (MADRS) total score from baseline to week 16. Young Mania Rating Scale, Clinical Global Impression (CGI)-Improvement and CGI-Severity scales, Patient Global Impression scale, Social and Occupational Functioning Assessment Scale (SOFAS), Longitudinal Interval Follow-Up Evaluation - Range of Impaired Functioning Tool (LIFE-RIFT), and Quality of Life Enjoyment, and Satisfaction Questionnaire Short Form (Q-LES-Q-SF) were secondary outcomes. One hundred forty-eight participants had post-randomisation data and were analysed (NAC = 52, CT = 47, Placebo = 49). No between-group differences were found for the rate of change between baseline and 16 weeks on any of the clinical and functioning variables. Improvements in MADRS, BDRS, SOFAS, and LIFE-RIFT scores from baseline to the week 20 post-discontinuation visit were significantly greater in the CT group compared to those in the placebo. At week 20, the CGI-I was significantly lower in the CT group versus placebo. Gastrointestinal symptoms were significantly greater in the NAC than in the placebo group. These overall negative results, with no significant differences between groups detected at the primary outcome but some positive secondary signals, suggest either delayed benefit of the combination or an improvement of symptoms on withdrawal which warrants further exploration regarding the composition, mechanisms, and application of mitochondrial agents in illnesses characterised by mitochondrial dysfunction. ANZCTR ( ACTRN12612000830897 )

The science and practice of lithium therapy

Introduction: Despite more that 60 years of clinical experience, the effective use of lithium for the treatment of mood disorder, in particular bipolarity, is in danger of becoming obsolete. In part, this is because of exaggerated fears surrounding lithium toxicity, acute and long-term tolerability and the encumbrance of life-long plasma monitoring. Recent research has once again positioned lithium centre stage and amplified the importance of understanding its science and how this translates to clinical practice. Objective: The aim of this paper is to provide a sound knowledge base as regards the science and practice of lithium therapy. Method: A comprehensive literature search using electronic databases was conducted along with a detailed review of articles known to the authors pertaining to the use of lithium. Studies were limited to English publications and those dealing with the management of psychiatric disorders in humans. The literature was synthesized and organized according to relevance to clinical practice and understanding. Results: Lithium has simple pharmacokinetics that require regular dosing and monitoring. Its mechanisms of action are complex and its effects are multi-faceted, extending beyond mood stability to neuroprotective and anti-suicidal properties. Its use in bipolar disorder is under-appreciated, particularly as it has the best evidence for prophylaxis, qualifying it perhaps as the only true mood stabilizer currently available. In practice, its risks and tolerability are exaggerated and can be readily minimized with knowledge of its clinical profile and judicious application. Conclusion: Lithium is a safe and effective agent that should, whenever indicated, be used first-line for the treatment of bipolar disorder. A better understanding of its science alongside strategic management of its plasma levels will ensure both wider utility and improved outcomes. </jats:p

Bordering on bipolar: The overlap between borderline personality and bipolarity

Objective: There is much debate over whether borderline personality disorder (BPD) belongs to the bipolar spectrum. The diagnosis of bipolar disorder (BD) in BPD patients, and conversely, BPD in BD patients is common, indicating prevalent co-morbidity, as well as potential misdiagnosis in either group. BD and BPD are often indistinguishable given the core characteristics of emotional dysregulation and impulsivity that feature in both. However, it may be argued that the manifestation of these characteristics in the two groups is different, and that the symptoms are driven by distinct aetiological factors. The primary objective of this paper was to examine where potential areas of discrimination lie between BD and BPD. Methods: A literature search was conducted using MEDLINE and PubMed databases to identify studies that have researched BD and BPD across the recognised domains of emotional dysregulation, impulsivity, childhood trauma, and their putative neurobiological substrates. Results: Research comparing BD and BPD patients on self-report measures is limited, and no studies have examined their neurobiological underpinnings in the same design. One possible differentiating variable is childhood trauma which shapes the circumstances in which emotional dysregulation and impulsivity are triggered, the types of behaviours exhibited, and the frequency and duration of mood states. There is growing evidence that childhood trauma not only predisposes individuals to both disorders, but also modulates the clinical expression and course of bipolar illness, particularly rapid cycling BD, a form of bipolarity that resembles the clinical profile of BPD, yet presents quite distinctly from other BD subtypes. Conclusions: This paper provides an overview of BD and BPD with respect to emotional dysregulation, impulsivity, childhood factors, and neurobiological substrates. Based on findings predominantly within the independent areas of BD and BPD, it tentatively provides an integrated behavioural, aetiological and neurobiological approach for investigating the question of whether BPD belongs to the bipolar spectrum. </jats:p

Metabolite profiles in the anterior cingulate cortex of depressed patients differentiate those taking N-acetyl-cysteine versus placebo

Background: Increased oxidative stress is thought to contribute to the pathophysiology of major depressive disorder (MDD), which is in part due to diminished levels of glutathione, the primary anti-oxidant of the brain. Oral administration of N-acetyl-cysteine (NAC) replenishes glutathione and has therefore been shown to reduce depressive symptoms. Proton magnetic spectroscopy (1H-MRS) that allows quantification of brain metabolites pertinent to both MDD and oxidative biology may provide some novel insights into the neurobiological effects of NAC, and in particular metabolite concentrations within the anterior cingulate cortex (ACC) are likely to be important given the key role of this region in the regulation of affect.Objective: The aim of this study was to determine whether the metabolite profile of the ACC in MDD patients predicts treatment with adjunctive NAC versus placebo.Methods: This study was nested within a multicentre, randomized, double-blind, placebo-controlled study of MDD participants treated with adjunctive NAC. Participants (n = 76) from one site completed the spectroscopy component at the end of treatment (12 weeks). Spectra from a single-voxel in the ACC were acquired and absolute concentrations of glutamate (Glu), glutamate-glutamine (Glx), N-acetyl-aspartate (NAA) and myo-inositol (mI) were obtained. Binary logistic regression analysis was performed to determine whether metabolite profiles could predict NAC versus placebo group membership.Results: When predicting group outcome (NAC or placebo), Glx, NAA and mI were a significant model, and had 75% accuracy, while controlling for depression severity and sex. However, the Glu, NAA and mI profile was only predictive at a trend level, with 68.3% accuracy. For both models, the log of the odds of a participant being in the NAC group was positively related to NAA, Glx and Glu levels and negatively related to mI levels.Conclusion: The finding of higher Glx and NAA levels being predictive of the NAC group provides preliminary support for the putative anti-oxidative role of NAC in MDD.<br /