Brief report
The efficacy of N-acetylcysteine as an adjunctive treatment in bipolar depression: An open label trial

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Abstract

Background

Evidence is accumulating to support the presence of redox dysregulation in a number of psychiatric disorders, including bipolar disorder. This dysregulation may be amenable to therapeutic intervention. Glutathione is the predominant non-enzymatic intracellular free radical scavenger in the brain, and the most generic of all endogenous antioxidants in terms of action. N-acetylcysteine (NAC) is a glutathione precursor that effectively replenishes brain glutathione. Given the failure of almost all modern trials of antidepressants in bipolar disorder to demonstrate efficacy, and the limited efficacy of mood stabilisers in the depressive phase of the disorder, this is a major unmet need.

Method

This study reports data on the treatment of 149 individuals with moderate depression during the 2 month open label phase of a randomised placebo controlled clinical trial of the efficacy of 1 g BID of NAC that examined the use of NAC as a maintenance treatment for bipolar disorder.

Results

In this trial, the estimated mean baseline Bipolar Depression Rating Scale (BDRS) score was 19.7 (SE = 0.8), and the mean BDRS score at the end of the 8 week open label treatment phase was 11.1 (SE = 0.8). This reduction was statistically significant (p < 0.001). Improvements in functioning and quality of life were similarly evident.

Conclusion

These open label data demonstrate a robust decrement in depression scores with NAC treatment. Large placebo controlled trials of acute bipolar depression are warranted.

Introduction

Individuals with bipolar disorder spend three times longer in the depressive phase of the illness than in mania (Judd and Akiskal, 2003). Consequently, bipolar depression is highly disabling and confers marked occupational and social impairment. Together with depressive mixed states, the depressive phase of bipolar disorder is its most lethal period, as it is associated with substantial suicide risk. Hence its management is complicated and made more difficult by the absence of a range of established effective treatments. Indeed the efficacy of antidepressants in the treatment of bipolar depression remains unclear and extrapolation from unipolar depression data provides little assistance (Ghaemi, 2008). For instance, contemporary, large and methodologically rigorous trials of antidepressants in bipolar disorder have been largely negative (Tohen et al., 2009) and in practise the administration of antidepressants can precipitate mania and shorten the inter-episode window of euthymia. Similar to the paucity of evidence for pharmacotherapy there is a limited evidence base for psychological interventions for acute bipolar depression (Scott and Colom, 2005), however on the basis of efficacy in unipolar depression and in bipolar maintenance treatment, psychological treatments are frequently used. Even lithium is less effective in addressing acute depression than mania (Malhi et al., 2010), and the evidence for the deployment of valproate in bipolar depression is equivocal (Bond et al., 2010). Lamotrigine (van der Loos et al., 2009) and some atypical antipsychotics demonstrate efficacy in bipolar depression but have substantial pragmatic or tolerability issues (Ng et al., 2009). Thus the consensus in the bipolar field is that the unmet clinical need is greatest in bipolar depression (Malhi et al., 2009, Malhi et al., 2010).

Data confirming the role of redox dysregulation in bipolar disorder derives from five main areas: i) evidence of dysregulated oxidative defences; ii) data on effects of oxidative stress on cellular constituents, particularly lipids, proteins and DNA; iii) evidence that known bipolar treatments have profound influences on oxidative processes; iv) association studies of polymorphisms of key genes in the glutathione pathway (Fullerton et al., 2010); and v) structural evidence of a neuroprogressive process. These data have been reviewed in detail elsewhere (Berk et al., 2008c, Dean et al., 2009, Ng et al., 2008).

Glutathione, the primary endogenous antioxidant in the brain, is synthesised from the precursor amino acids, l-glutamate, l-cysteine and l-glycine, in two enzymatic steps. In oxidative stress states, glutathione is vulnerable to depletion. Enhancing l-cysteine supply, the rate limiting factor in glutathione synthesis via a precursor, N-acetylcysteine (NAC), leads to a rise in brain glutathione (Dean et al., 2004).

The aim of this study was to investigate the efficacy of adjunctive NAC in the treatment of major depressive episodes (MDE) in bipolar disorder in the initial open label phase of a randomised, double blind placebo-controlled maintenance trial. It was hypothesised that NAC would improve symptoms of depression in the open label phase of the trial.

Section snippets

Methods

The open label treatment phase of a double blind placebo controlled randomised controlled trial of the efficacy and tolerability of NAC 1 g BID in the maintenance phase of bipolar disorder is presented here. Depressive symptomatic severity, using the Bipolar Depression Rating Scale (BDRS) (Berk et al., 2007) was the primary outcome measure of this component of the study. Secondary outcomes included the Montgomery-Åsberg Depression Rating Scale (MADRS) (Montgomery and Asberg, 1979), the Clinical

Sample characteristics

One hundred and forty nine individuals meeting DSM-IV-TR criteria for bipolar disorder on a structured clinical interview (MINI-plus) were randomised. Participants were aged between 22 and 70 years of age and approximately two-thirds (67.8%) were female. Bipolar I disorder was the main diagnosis and the average length of illness since time of diagnosis was 10.0 years (see Table 1).

Precisely one third (33.6%) of the sample were current smokers. Almost half (46.3%) of the participants consumed

Discussion

The reduction in depressive symptomatology in this trial suggests that NAC may have efficacy in acute bipolar depression. Of note, there was a comparable reduction in measures of quality of life and functioning. These data are concordant with the only previous data examining NAC in bipolar disorder. In that 6-month bipolar disorder placebo controlled trial (N = 75), adjunctive NAC in participants with either bipolar I or II disorder significantly improved clinical outcomes, particularly

Role of funding source

This study received funding from grant 06TGF-996 from the Stanley Medical Research Institute for the expenses of the trial. Heidi Cobb benefited from support from NHMRC Program Grant ID 510135. The funding sources had no role in study design, management, data analysis or manuscript preparation.

Conflict of interest

Berk and Bush are co-inventors on two provisional patents regarding the use of NAC and related compounds for psychiatric indications, which, whilst assigned to the Mental Health Research Institute, could lead to personal remuneration upon a commercialisation event. Bush is a stock shareholder of Eucalyptus Biosciences and Prana Biotechnologies. Berk has served on advisory boards and received funds and/or honoraria from Astra Zeneca, Eli Lilly, Janssen Cilag, Lundbeck, Servier, Glaxo Smith

Acknowledgement

This research was supported by grant 06TGF-996 from the Stanley Medical Research Institute. We would like to thank Kirsteen Moss, and Carissa Coulston for their contributions to this study and support from NHMRC Program Grant ID 510135.

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