Maintenance N-acetyl cysteine treatment for bipolar disorder: A double-blind randomized placebo controlled trial

BMC Medicine Maintenance N-acetyl cysteine treatment for bipolar disorder: A double-blind randomized placebo controlled trial Michael Berk 0 Olivia M Dean 0 Sue M Cotton Clarissa S Gama Flavio Kapczinski Brisa Fernandes Kristy Kohlmann Susan Jeavons Karen Hewitt Kirsteen Moss Christine Allwang Ian Schapkaitz Heidi Cobb Ashley I Bush Seetal Dodd 0 Gin S Malhi 0 Deakin University, School of Medicine , Barwon Health, P.O. Box 291, Geelong, 3220 , Australia 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 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). N-acetyl cysteine; depression; bipolar disorder; maintenance; mania; oxidative - Background Bipolar disorder is a recurrent illness with the vast majority of individuals experiencing relapses throughout their lives. The prevention of further episodes is of critical importance to individuals with the disorder, as recurrent episodes can result in hospitalization, suicide and loss of functionality. There appears to be an active process of neuroprogression associated with acute episodes of illness [1]. Maintenance of well-being is, therefore, of paramount importance [2]. Existing agents are imperfect, as many have limitations in terms of either efficacy or tolerability for long-term treatment. Lithium is the mainstay of prophylaxis in bipolar disorder although it is more effective in preventing manic relapses than depression [3] though recent data suggest that it is more effective in relapse prevention than valproate [4]. Interestingly, lithium is more effective in preventing manic relapses as opposed to depression whereas lamotrigine is more effective in the prevention of depressive episodes [3]. Atypical antipsychotics also appear to have maintenance properties, although all except quetiapine are less effective in depression than mania. Given the limitations of these agents, polypharmacy is the routine rather than the exception [5] and most have significant tolerability issues that require routine safety monitoring [6]. In this context there are preliminary data from preclinical studies that N-acetyl cysteine (NAC) might prevent lithium-induced renal dysfunction in animal models. This makes it an attractive adjunct therapy both because of its potential clinical benefits and the reduction of iatrogenic adverse effects [7]. This is particularly interesting because it is consistent with evidence of dysregulated redox biology in bipolar disorder. Data supporting this comes from five main areas; i) evidence of dysregulated oxidative defenses, ii) effects of oxidative stress on cellular constituents (particularly lipids, proteins and nuclear and mitochondrial DNA), iii) concordant structural evidence of neuroprogressive processes, iv) studies showing that established bipolar disorder treatments have significant influences on oxidative processes, and v) association studies of polymorphisms of key genes in the glutathione pathway [8]. In particular, glutathione, which is the principal endogenous antioxidant in the brain, is vulnerable to depletion, and is substantially reduced in bipolar disorder [9]. NAC provides L-cysteine, the rate limiting factor in glutathione synthesis, and thereby increases central and peripheral glutathione [10]. Additionally, NAC modulates glutamate, has anti-inflammatory properties and enhances neurogenesis and mitochondrial function [11]. Given this context, the aim of this study was to investigate the efficacy of adjunctive NAC, in addition to treatment as usual, in the maintenance treatment of bipolar depression in a double-blind randomized multi-center placebo-controlled trial. Time to intervention for a mood episode was the primary outcome measure. Secondary outcome measures included changes in mood symptoms, functioning and quality of life (QoL). It was hypothesized that NAC would reduce the recurrence of episodes in the maintenance phase of the disorder. Methods This maintenance study included participants screened for the presence of depression at trial entry (beginning of the open-label phase) [12]. All participants received 2 grams of NAC (1 gram twice daily) for eight weeks and were subsequently randomized to continued NAC treatment or placebo in a double blind design for a further 24 weeks. The assessment schedule is shown in Additional File 1. In addition to the clinical interviews, some participants provided blood samples for peripheral analysis of oxidative stress markers and a sub-group was involved in a magnetic resonance spectroscopy study (data presented elsewhere). In order to reduce enrichment bias, response to NAC in the open label phase was not an inclusion criterion, and all participants proceeded to the randomized phase (week 8 to week 32). Methodological details and data from the open-label phase of the study are presented elsewhere [13]. All participants remained on treatment as usual for the duration of the trial. This included any pharmacological or psychological intervention (stable for at least one month as per the inclusion criteria). In order to capture the diversity of treatment settings and enhance generalizability, potential participants were recruited through a variety of avenues, including the participants case clinicians, newspaper advertisement, flyers in public areas (including flyers placed at shopping centers and pathology collection centers) and web-based advertisements on bipolar disorder-relevant websites, a (...truncated)