Michelle Tanious

Potential Mechanisms of Action of Lithium in Bipolar Disorder

Lithium has been used for over half a century for the treatment of bipolar disorder as the archetypal mood stabilizer, and has a wealth of empirical evidence supporting its efficacy in this role. Despite this, the specific mechanisms by which lithium exerts its mood-stabilizing effects are not well understood. Given the inherently complex nature of the pathophysiology of bipolar disorder, this paper aims to capture what is known about the actions of lithium ranging from macroscopic changes in mood, cognition and brain structure, to its effects at the microscopic level on neurotransmission and intracellular and molecular pathways. A comprehensive literature search of databases including MEDLINE, EMBASE and PsycINFO was conducted using relevant keywords and the findings from the literature were then reviewed and synthesized. Numerous studies report that lithium is effective in the treatment of acute mania and for the long-term maintenance of mood and prophylaxis; in comparison, evidence for its efficacy in depression is modest. However, lithium possesses unique anti-suicidal properties that set it apart from other agents. With respect to cognition, studies suggest that lithium may reduce cognitive decline in patients; however, these findings require further investigation using both neuropsychological and functional neuroimaging probes. Interestingly, lithium appears to preserve or increase the volume of brain structures involved in emotional regulation such as the prefrontal cortex, hippocampus and amygdala, possibly reflecting its neuroprotective effects. At a neuronal level, lithium reduces excitatory (dopamine and glutamate) but increases inhibitory (GABA) neurotransmission; however, these broad effects are underpinned by complex neurotransmitter systems that strive to achieve homeostasis by way of compensatory changes. For example, at an intracellular and molecular level, lithium targets second-messenger systems that further modulate neurotransmission. For instance, the effects of lithium on the adenyl cyclase and phospho-inositide pathways, as well as protein kinase C, may serve to dampen excessive excitatory neurotransmission. In addition to these many putative mechanisms, it has also been proposed that the neuroprotective effects of lithium are key to its therapeutic actions. In this regard, lithium has been shown to reduce the oxidative stress that occurs with multiple episodes of mania and depression. Further, it increases protective proteins such as brain-derived neurotrophic factor and B-cell lymphoma 2, and reduces apoptotic processes through inhibition of glycogen synthase kinase 3 and autophagy. Overall, it is clear that the processes which underpin the therapeutic actions of lithium are sophisticated and most likely inter-related.

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.

The efficacy of adjunctive N-acetylcysteine in major depressive disorder: a double-blind, randomized, placebo-controlled trial.

OBJECTIVE Major depressive disorder (MDD) is one of the most common psychiatric disorders, conferring considerable individual, family, and community burden. To date, treatments for MDD have been derived from the monoamine hypothesis, and there is a paucity of emerging antidepressants, especially with novel mechanisms of action and treatment targets. N-acetylcysteine (NAC) is a redox-active glutathione precursor that decreases inflammatory cytokines, modulates glutamate, promotes neurogenesis, and decreases apoptosis, all of which contribute to the neurobiology of depression. METHOD Participants with a current episode of MDD diagnosed according to DSM-IV-TR criteria (N = 252) were treated with NAC or placebo in addition to treatment as usual for 12 weeks and were followed to 16 weeks. Data were collected between 2007 and 2011. RESULTS The omnibus interaction between group and visit for the Montgomery-Asberg Depression Rating Scale (MADRS), the primary outcome measure, was not significant (F₁,₅₂₀.₉ = 1.98, P = .067), and the groups did not separate at week 12 (t₃₆₀.₃ = -1.12, P = .265). However, at week 12, the scores on the Longitudinal Interval Follow-Up Evaluation-Range of Impaired Functioning Tool (LIFE-RIFT) differed from placebo (P = .03). Among participants with a MADRS score ≥ 25, NAC separated from placebo at weeks 6, 8, 12, and 16 (P < .05). Additionally, the rate of change between baseline and week 16 was significant (t₂₂₁.₀₃ = -2.11, P = .036). NAC treatment was superior to placebo at week 16 for secondary readouts of function and clinical impression. Remission and response were greater in the NAC group at week 16, but not at week 12. The NAC group had a greater rate of gastrointestinal and musculoskeletal adverse events. CONCLUSIONS Being negative at the week 12 end point, and with some positive secondary signals, the study provides only limited support for the role of NAC as a novel adjunctive therapy for MDD. These data implicate the pathways influenced by NAC in depression pathogenesis, principally oxidative and inflammatory stress and glutamate, although definitive confirmation remains necessary. TRIAL REGISTRATION www.anzctr.org.au Identifier: ACTRN12607000134426.

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.

Optimal frequency of lithium administration in the treatment of bipolar disorder: clinical and dosing considerations.

Bipolar disorder is a recurrent chronic illness distinguished by periods of mania and depression. Lithium has been used for about 60 years as a ‘mood stabilizer’ for bipolar disorder with proven efficacy in preventing relapse of both mania and depression. Despite its long history and ongoing use in current management of bipolar disorder, the optimal dosing of lithium is still the subject of ongoing debate. This article aims to evaluate different dosing schedules, in the light of the unique pharmacokinetic and pharmacodynamic properties of lithium, as well as its adverse-effect and toxicity profiles. This is all the more important given the narrow therapeutic index of lithium. Current recommendations mostly advocate that lithium be administered in multiple daily doses. However, single daily or alternate daily schedules may be viable options for administration. Multiple daily schedules are thought to be advantageous in maintaining more constant plasma lithium concentrations than single daily regimens, which are associated with significant fluctuations throughout the day. When comparing these two schedules with respect to plasma lithium concentrations, adverse-effect profiles and recurrence of symptoms, there are no significant differences between the two regimens. In fact, a single daily regimen may have added advantages in reducing the risk of long-term renal damage and increasing compliance. The evidence for alternate daily dosing is somewhat varied with regard to symptom recurrence; however, this schedule has been shown to be associated with decreased adverse effects, and further research into this issue is therefore warranted. Presently, therefore, clinicians should consider single daily administration of lithium to potentially minimize adverse effects and enhance compliance.

Interpretation in Consultations With Immigrant Patients With Cancer: How Accurate Is It?

PURPOSE Immigrants with cancer often have professional and/or family interpreters to overcome challenges communicating with their health team. This study explored the rate and consequences of nonequivalent interpretation in medical oncology consultations. PATIENTS AND METHODS Consecutive immigrant patients with newly diagnosed with incurable cancer, who spoke Arabic, Cantonese, Mandarin, or Greek, were recruited from the practices of 10 medical oncologists in nine hospitals. Their first two consultations were audio taped, transcribed, translated into English and coded. RESULTS Thirty-two of 78 participants had an interpreter at 49 consultations; 43% of interpreters were family, 35% professional, 18% both a professional and family, and 4% a health professional. Sixty-five percent of professional interpretations were equivalent to the original speech versus 50% for family interpreters (P= .02). Seventy percent of nonequivalent interpretations were inconsequential or positive; however, 10% could result in misunderstanding, in 5% the tone was more authoritarian than originally intended, and in 3% more certainty was conveyed. There were no significant differences in interpreter type for equivalency of interpretations. CONCLUSION Nonequivalent interpretation is common, and not always innocuous. Our study suggests that there may remain a role for family or telephone versus face-to-face professional interpreters. PRACTICE IMPLICATIONS careful communication between oncologists and interpreters is required to ensure optimal communication with the patient.

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. TRIAL REGISTRATION Australian and New Zealand Clinical Trial Registry ACTRN12612000830897.

Differential engagement of the fronto-limbic network during emotion processing distinguishes bipolar and borderline personality disorder.

Differential engagement of the fronto-limbic network during emotion processing distinguishes bipolar and borderline personality disorder

Should culture affect practice? A comparison of prognostic discussions in consultations with immigrant versus native-born cancer patients

OBJECTIVE Poor prognosis is difficult to impart, particularly across a cultural divide. This study compared prognostic communication with immigrants (with and without interpreters) versus native-born patients in audio-taped oncology consultations. METHODS Ten oncologists, 78 patients (31 Australian-born, 47 immigrants) and 115 family members participated. The first two consultations after diagnosis of incurable disease were audiotaped, transcribed and coded. 142 consultations were included in the analysis. RESULTS Fifty percent of doctor and 59% of patient prognostic speech units were not interpreted or interpreted non-equivalently when an interpreter was present. Immigrant status predicted few prognostic facts, and oncologist characteristics no prognostic facts, disclosed. Oncologists were significantly less likely to convey hope to immigrants (p=0.0004), and more likely to use medical jargon (p=0.009) than with Australian-born patients. Incurable disease status and a limited life span were commonly acknowledged, generally with no timeframe provided. Physical issues were discussed more commonly than emotional aspects. CONCLUSIONS While culture did not appear to influence doctor speech, interpreters filtered or blocked much prognostic communication. PRACTICE IMPLICATIONS Initiatives to empower all patients to attain needed information, optimise communication when an interpreter is present and train cancer health professionals in culturally appropriate care, are urgently required.

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.