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The Efficacy of Adjunctive N-Acetylcysteine in Major Depressive Disorder: A Double-Blind, Randomized, Placebo-Controlled Trial
Open accessAbstract
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.
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“There is some evidence that NAC has clinical efficacy in unipolar depression and bipolar disorder.18,19”
From N-acetylcysteine for therapy-resistant tobacco use disorder: a pilot study (2015) · cites this paper as [19]
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“In addition, some studies showed that NAC could improve OCD-related trichotillomania (pathological nail-biting and skin-picking) [279].”
From Oxidative Stress Implications in the Affective Disorders: Main Biomarkers, Animal Models Relevance, Genetic Perspectives, and Antioxidant Approaches (2016) · cites this paper as [279]
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Metadata
- Authors
- Berk, M., Dean, O. M., Cotton, S. M., Jeavons, S., Tanious, M., Kohlmann, K., Hewitt, K., Moss, K., Allwang, C., Schapkaitz, I., Robbins, J., Cobb, H., Ng, F., Dodd, S., Bush, A. I., & Malhi, G. S.
- Affiliations
- Barwon Health (AU)
- Deakin University (AU)
- Corresponding author
- Berk, Michael
- ORCID
- Venue
- The Journal of Clinical Psychiatry
- Publisher
- Physicians Postgraduate Press, Inc
- Published
- 2014-06-15
- Volume
- 75
- Issue
- 06
- Pages
- 628-636
- ISSN
- 0160-6689 (ISSN-L)
- OpenAlex
- W2099204286
- Cited by
- 172
- References
- 49
- Citations by year
- 2026: 9 · 2025: 6 · 2024: 9 · 2023: 10 · 2022: 10 · 2021: 15 · 2020: 18 · 2019: 14 · 2018: 23 · 2017: 21 · 2016: 16 · 2015: 19 · 2014: 2
- FWCI
- 14.05
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Clinical Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- Minerva Access (University of Melbourne) (submittedVersion)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
- Keywords
- major depressive disorder, N-acetylcysteine, adjunctive therapy, glutathione precursor, oxidative stress, neuroinflammation, glutamate, antidepressant efficacy, adverse events, Montgomery-Asberg Depression Rating Scale, depression pathogenesis, redox signaling, neurogenesis, apoptosis, monoamine hypothesis, newer antidepressants, treatment-resistant depression
- MeSH terms
- Acetylcysteine, Adult, Antidepressive Agents, Major Depressive Disorder, Double-Blind Method, Drug Therapy, Combination, Female, Follow-Up Studies, Humans, Male, Middle Aged, Surveys and Questionnaires, Patient Satisfaction
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