N-Acetyl Cysteine for Depressive Symptoms in Bipolar Disorder—A Double-Blind Randomized Placebo-Controlled Trial

The Mental Health Research Institute of Victoria, Victoria, Australia.
Biological psychiatry (Impact Factor: 10.26). 07/2008; 64(6):468-75. DOI: 10.1016/j.biopsych.2008.04.022
Source: PubMed


Treatment-resistant subthreshold depression is a major problem in bipolar disorder. Both depression and bipolar disorder are complicated by glutathione depletion. We hypothesized that treatment with N-acetyl cysteine (NAC), a safe, orally bioavailable precursor of glutathione, may improve the depressive component of bipolar disorder.
A randomized, double-blind, multicenter, placebo-controlled study of individuals (n = 75) with bipolar disorder in the maintenance phase treated with NAC (1 g twice daily) adjunctive to usual medication over 24 weeks, with a 4-week washout. The two primary outcomes were the Montgomery Asberg Depression Rating Scale (MADRS) and time to a mood episode. Secondary outcomes included the Bipolar Depression Rating Scale and 11 other ratings of clinical status, quality of life, and functioning.
NAC treatment caused a significant improvement on the MADRS (least squares mean difference [95% confidence interval]: -8.05 [-13.16, -2.95], p = .002) and most secondary scales at end point. Benefit was evident by 8 weeks on the Global Assessment of Functioning Scale and Social and Occupational Functioning Assessment Scale and at 20 weeks on the MADRS. Improvements were lost after washout. There was no effect of NAC on time to a mood episode (log-rank test: p = .968) and no significant between-group differences in adverse events. Effect sizes at end point were medium to high for improvements in MADRS and 9 of the 12 secondary readouts.
NAC appears a safe and effective augmentation strategy for depressive symptoms in bipolar disorder.


Available from: Olivia Dean
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    • "Following the interest raised by reports of the unique antidepressant pattern of sub-anesthetic doses of ketamine, much research has focused on glutamate modulators. Nacetylcysteine (NAC), a glutamate modulator devoid of the adverse effects common to most NMDA antagonists, have been reported to possess antidepressant-like effects in mice (Costa-Campos et al., 2013; Ferreira et al., 2008; Linck et al., 2012; Smaga et al., 2012) and in the depressive phase of bipolar patients (Berk et al., 2008). "
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    ABSTRACT: Circadian rhythm disturbances are among the risk factors for depression, but specific animal models are lacking. This study aimed to characterize the effects of acute rhythm disruption in mice and investigate the effects of imipramine and N-acetylcysteine (NAC) on rhythm disruption-induced changes. Mice were exposed to 12:12-hour followed by 10:10-hour light:dark cycles (LD); under the latter, mice were treated with saline, imipramine or NAC. Rhythms of rest/activity and temperature were assessed with actigraphs and iButtons, respectively. Hole-board and social preference tests were performed at the beginning of the experiment and again at the 8th 10:10 LD, when plasma corticosterone and IL-6 levels were also assessed. Actograms showed that the 10:10 LD schedule prevents the entrainment of temperature and activity rhythms for at least 13 cycles. Subsequent light regimen change activity and temperature amplitudes showed similar patterns of decline followed by recovery attempts. During the 10:10 LD schedule, activity and temperature amplitudes were significantly decreased (paired t test), an effect exacerbated by imipramine (ANOVA/SNK). The 10:10 LD schedule increased anxiety (paired t test), an effect prevented by NAC (30 mg/kg). This study identified mild but significant behavioral changes at specific time points after light regimen change. We suggest that if repeated overtime, these subtle changes may contribute to lasting behavioral disturbancess relevant to anxiety and mood disorders. Data suggest that imipramine may contribute to sustained rhythm disturbances, while NAC appears to prevent rhythm disruption-induced anxiety. Associations between sleep/circadian disturbances and the recurrence of depressive episodes underscore the relevance of potential drug-induced maintenance of disturbed rhythms.
    Chronobiology International 10/2014; 32(2):1-8. DOI:10.3109/07420528.2014.965315 · 3.34 Impact Factor
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    • "It is worth mentioning that we did not find any human trials with CoQ10, N-acetylcysteine , or alpha-lipoic acid, for unipolar MDD. However, N-acetyl-cysteine has been examined as treatment for bipolar disorder and showed promising results (Berk et al. 2008). In all trials listed in Table 2 modulators were administered orally. "
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    • "Recently it was shown that NAC is well-tolerated agent in substance use disorders across several abused substances [17] [26] [27]. The preclinical behavioral studies [28] [29] showed antidepressant-like effects of NAC in rodents, while some clinical trials supported the usefulness of NAC to depressive patients [30] [31] [32]. Based on these studies, we verified the hypothesis that NAC administration also influences the effects of cocaine in animals with depression phenotype. "
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