N‐acetylcysteine as an adjunctive treatment for bipolar depression: A systematic review and meta‐analysis of randomized controlled trials
Abstract
Objectives: Previous studies and meta‐analyses suggested that N‐acetylcysteine (NAC) was superior to placebo in improving depression in bipolar disorder. However, more recent data, including two larger trials, found that NAC was no more effective than placebo. We conducted a meta‐analysis to appraise the possible efficacy of NAC in treating bipolar depression. Methods: A systematic review and meta‐analysis of double‐blind, placebo‐controlled trials of NAC as a treatment augmentation strategy for bipolar depression was carried out in PubMed (1966–2020). We utilized random‐effect analysis to evaluate improvement in depressive symptoms from baseline to endpoint as the primary efficacy measure. Results: Six trials including 248 patients were included. Treatment augmentation with NAC showed a moderate effect size favoring NAC over placebo ( d = 0.45, 95% C.I.: 0.06–0.84). There was substantial heterogeneity ( I 2 = 49%). Meta‐regression analyses did not identify any moderator that might explain variation in heterogeneity, including baseline depressive symptom scores, mean NAC dose, or duration of study. Conclusions: Results from six clinical trials suggest that treatment augmentation with NAC for bipolar depression appears to be superior to placebo, with a moderate effect size, but a large confidence interval. Larger clinical trials, investigating possible moderating factors, such as NAC dose, treatment duration, baseline depression severity, or chronicity of illness, are warranted.
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A review of six clinical trials reported that N-acetyl Cysteine is superior to placebo in bipolar disorder, although with a mild effect and a large confidence interval.
“However, a review paper discussing six clinical trials reported that N-acetyl Cysteine is superior to placebo, although with a mild effect, but a large interval of confidence (Nery et al. 2021).”
From Reactive Oxygen Species, Toxicity, Oxidative Stress, and Antioxidants: Chronic Diseases and Aging (2023) · cites this paper as Nery et al. 2021
Cites
Preferred Reporting Items for Systematic Reviews and Meta-Analyses: the PRISMA statement
Moher, D., Liberati, A., Tetzlaff, J., Altman, D. G., & for the PRISMA Group (2009) · BMJ · doi:10.1136/bmj.b2535 · Cited by 83,823 · see citing works
Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement
Moher, D., Liberati, A., Tetzlaff, J., Altman, D. G., & The PRISMA Group (2009) · PLoS Medicine · doi:10.1371/journal.pmed.1000097 · Cited by 64,042 · see citing works
Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement
Moher, D., Liberati, A., Tetzlaff, J., Altman, D. G., & the PRISMA Group* (2009) · Annals of Internal Medicine · doi:10.7326/0003-4819-151-4-200908180-00135 · Cited by 37,554 · see citing works
RoB 2: a revised tool for assessing risk of bias in randomised trials
Sterne, J. A. C., Savović, J., Page, M. J., Elbers, R. G., Blencowe, N. S., Boutron, I., Cates, C. J., Cheng, H.-Y., Corbett, M. S., Eldridge, S. M., et al. (2019) · BMJ · doi:10.1136/bmj.l4898 · Cited by 33,583 · see citing works
Liberati, A., Altman, D. G., Tetzlaff, J., Mulrow, C., Gøtzsche, P. C., Ioannidis, J. P. A., Clarke, M., Devereaux, P. J., Kleijnen, J., & Moher, D. (2009) · PLoS Medicine · doi:10.1371/journal.pmed.1000100 · Cited by 28,164 · see citing works
Liberati, A., Altman, D. G., Tetzlaff, J., Mulrow, C., Gøtzsche, P. C., Ioannidis, J. P. A., Clarke, M., Devereaux, P. J., Kleijnen, J., & Moher, D. (2009) · Annals of Internal Medicine · doi:10.7326/0003-4819-151-4-200908180-00136 · Cited by 10,349 · see citing works
The Long-term Natural History of the Weekly Symptomatic Status of Bipolar I Disorder
Judd, L. L., Akiskal, H. S., Schettler, P. J., Endicott, J., Maser, J., Solomon, D. A., Leon, A. C., Rice, J. A., & Keller, M. B. (2002) · Archives of General Psychiatry · doi:10.1001/archpsyc.59.6.530 · Cited by 2,106 · see citing works
Yatham, L. N., Kennedy, S. H., Parikh, S. V., Schaffer, A., Bond, D. J., Frey, B. N., Sharma, V., Goldstein, B. I., Rej, S., Beaulieu, S., et al. (2018) · Bipolar Disorders · doi:10.1111/bdi.12609 · Cited by 1,852 · see citing works
Yatham, L. N., Kennedy, S. H., Parikh, S. V., Schaffer, A., Beaulieu, S., Alda, M., O’Donovan, C., MacQUEEN, G. M., McIntyre, R. S., Sharma, V., et al. (2012) · Bipolar Disorders · doi:10.1111/bdi.12025 · Cited by 1,209 · see citing works
Berk, M., Kapczinski, F., Andreazza, A. C., Dean, O. M., Giorlando, F., Maes, M., Yücel, M., Gama, C. S., Dodd, S., Dean, B., et al. (2011) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2010.10.001 · Cited by 1,178 · see citing works
Berk, M., Copolov, D. L., Dean, O., Lu, K., Jeavons, S., Schapkaitz, I., Anderson-Hunt, M., & Bush, A. I. (2008) · Biological Psychiatry · doi:10.1016/j.biopsych.2008.04.022 · Cited by 500 · see citing works
Clinical trials of N-acetylcysteine in psychiatry and neurology: A systematic review
Deepmala, Slattery, J., Kumar, N., Delhey, L., Berk, M., Dean, O., Spielholz, C., & Frye, R. (2015) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2015.04.015 · Cited by 463 · see citing works
Kupka, R. W., Altshuler, L. L., Nolen, W. A., Suppes, T., Luckenbaugh, D. A., Leverich, G. S., Frye, M. A., Keck, P. E., McElroy, S. L., Grunze, H., et al. (2007) · Bipolar Disorders · doi:10.1111/j.1399-5618.2007.00467.x · Cited by 397 · see citing works
Meta-analysis of randomised controlled trials
Kelly, C. P. (1997) · The Lancet · doi:10.1016/s0140-6736(05)63834-2 · Cited by 385 · see citing works
An updated meta-analysis of oxidative stress markers in bipolar disorder
Brown, N. C., Andreazza, A. C., & Young, L. T. (2014) · Psychiatry Research · doi:10.1016/j.psychres.2014.04.005 · Cited by 333 · see citing works
Measuring depression: comparison and integration of three scales in the GENDEP study
Uher, R., FARMER, A. E., Maier, W., Rietschel, M., Hauser, J., Marušić, A., Mors, O. N., Elkin, A., Williamson, R. J., Schmael, C., et al. (2007) · Psychological Medicine · doi:10.1017/s0033291707001730 · Cited by 290 · see citing works
The Montgomery Äsberg and the Hamilton ratings of depression: A comparison of measures
Carmody, T. J., Rush, A. J., Bernstein, I. H., Warden, D., Brannan, S. K., Burnham, D. B., Woo, A., & Trivedi, M. H. (2006) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2006.04.008 · Cited by 243 · see citing works
Bipolar depression: a major unsolved challenge
Baldessarini, R. J., Vázquez, G. H., & Tondo, L. (2020) · International Journal of Bipolar Disorders · doi:10.1186/s40345-019-0160-1 · Cited by 235 · see citing works
The responsiveness of the Hamilton Depression Rating Scale
Faries, D. E., Herrera, J. M., Rayamajhi, J., DeBrota, D. J., Demitrack, M. A., & Potter, W. Z. (2000) · Journal of Psychiatric Research · doi:10.1016/s0022-3956(99)00037-0 · Cited by 231 · see citing works
Gigante, A. D., Bond, D. J., Lafer, B., Lam, R. W., Young, L. T., & Yatham, L. N. (2012) · Bipolar Disorders · doi:10.1111/j.1399-5618.2012.01033.x · Cited by 226 · see citing works
Firth, J., Teasdale, S. B., Allott, K., Siskind, D., Marx, W., Cotter, J., Veronese, N., Schuch, F., Smith, L., Solmi, M., et al. (2019) · World Psychiatry · doi:10.1002/wps.20672 · Cited by 214 · see citing works
Yatham, L. N., Kennedy, S. H., Parikh, S. V., Schaffer, A., Bond, D. J., Frey, B. N., Sharma, V., Goldstein, B. I., Rej, S., Beaulieu, S., et al. (2019) · Own your potential (DEAKIN) · doi:10.3760/cma.j.issn.1006-7884.2019.01.101 · Cited by 213 · see citing works
Long-term morbidity in bipolar-I, bipolar-II, and unipolar major depressive disorders
Forte, A., Baldessarini, R. J., Tondo, L., Vázquez, G. H., Pompili, M., & Girardi, P. (2015) · Journal of Affective Disorders · doi:10.1016/j.jad.2015.02.011 · Cited by 203 · see citing works
Berk, M., Dean, O., Cotton, S. M., Gama, C. S., Kapczinski, F., Fernandes, B. S., Kohlmann, K., Jeavons, S., Hewitt, K., Allwang, C., et al. (2011) · Journal of Affective Disorders · doi:10.1016/j.jad.2011.06.005 · Cited by 181 · see citing works
Bipolar Depression: Overview and Commentary
Baldessarini, R. J., Vieta, E., Calabrese, J. R., Tohen, M. F., & Bowden, C. L. (2010) · Harvard Review of Psychiatry · doi:10.3109/10673221003747955 · Cited by 156 · see citing works
Firth, J., Stubbs, B., Teasdale, S. B., Ward, P. B., Veronese, N., Shivappa, N., Hebert, J. R., Berk, M., Yung, A. R., & Sarris, J. (2018) · World Psychiatry · doi:10.1002/wps.20571 · Cited by 145 · see citing works
Translating the HAM-D into the MADRS and vice versa with equipercentile linking
Leucht, S., Fennema, H., Engel, R. R., Kaspers–Janssen, M., & Szegedi, A. (2017) · Journal of Affective Disorders · doi:10.1016/j.jad.2017.09.042 · Cited by 117 · see citing works
N-acetylcysteine for major depressive episodes in bipolar disorder
Magalhães, P. V. D. S., Dean, O. M., Bush, A. I., Copolov, D., Malhi, G. S., Kohlmann, K., Jeavons, S., Schapkaitz, I., Anderson‐Hunt, M., & Berk, M. (2011) · Brazilian Journal of Psychiatry · doi:10.1590/s1516-44462011000400011 · Cited by 113 · see citing works
N-Acetylcysteine in Depressive Symptoms and Functionality
Fernandes, B. S., Dean, O. M., Dodd, S., Malhi, G. S., & Berk, M. (2016) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.15r09984 · Cited by 108 · see citing works
Berk, M., Turner, A., Malhi, G. S., Ng, C. H., Cotton, S., Dodd, S., Samuni, Y., Tanious, M., McAulay, C., Dowling, N. L., et al. (2019) · BMC Medicine · doi:10.1186/s12916-019-1257-1 · Cited by 101 · see citing works
Magalhães, P. V. D. S., Dean, O. M., Bush, A. I., Copolov, D., Malhi, G. S., Kohlmann, K., Jeavons, S., Schapkaitz, I., Anderson‐Hunt, M., & Berk, M. (2010) · Journal of Affective Disorders · doi:10.1016/j.jad.2010.08.001 · Cited by 100 · see citing works
N-Acetylcysteine for the Treatment of Psychiatric Disorders: A Review of Current Evidence
Ooi, S. L., Green, R., & Pak, S. C. (2018) · BioMed Research International · doi:10.1155/2018/2469486 · Cited by 99 · see citing works
The fading of reported effectiveness. A meta-analysis of randomised controlled trials
Gehr, B., Weiß, C., & Porzsolt, F. (2006) · BMC Medical Research Methodology · doi:10.1186/1471-2288-6-25 · Cited by 89 · see citing works
Zheng, W., Zhang, Q. ‐., Cai, D., Yang, X.-H., Qiu, Y., Ungvari, G. S., Ng, C. H., Berk, M., Ning, Y., & Xiang, Y. (2018) · Acta Psychiatrica Scandinavica · doi:10.1111/acps.12862 · Cited by 83 · see citing works
Andreazza, A. C., & Young, L. T. (2013) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145713000096 · Cited by 80 · see citing works
Zimmerman, M. A., Galione, J. N., Chelminski, I., Young, D., Dalrymple, K. L., & Ruggero, C. J. (2010) · Bipolar Disorders · doi:10.1111/j.1399-5618.2010.00869.x · Cited by 67 · see citing works
Bauer, I. E., Green, C., Colpo, G. D., Teixeira, A. L., Selvaraj, S., Durkin, K., Zunta‐Soares, G. B., & Soares, J. C. (2018) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.18m12200 · Cited by 54 · see citing works
N-Acetylcysteine ameliorates lithium-induced renal failure in rats
Efrati, S., Averbukh, M., Berman, S., et al. (2004) · Nephrology Dialysis Transplantation · doi:10.1093/ndt/gfh573 · Cited by 51 · see citing works
Ellegaard, P. K., Licht, R. W., Nielsen, R. E., Dean, O. M., Berk, M., Poulsen, H. E., Mohebbi, M., & Nielsen, C. T. (2018) · Journal of Affective Disorders · doi:10.1016/j.jad.2018.10.083 · Cited by 50 · see citing works
Porcu, M., Urbano, M. R., Verri, W. A., Jr., Barbosa, D. S., Baracat, M. M., Vargas, H. O., Machado, R. C. B. R., Pescim, R. R., & Nunes, S. O. V. (2018) · Psychiatry Research · doi:10.1016/j.psychres.2018.02.056 · Cited by 42 · see citing works
Kishi, T., Miyake, N., Okuya, M., Sakuma, K., & Iwata, N. (2020) · Psychopharmacology · doi:10.1007/s00213-020-05629-2 · Cited by 39 · see citing works
Interactive effects of N-acetylcysteine and antidepressants
Costa-Campos, L., Herrmann, A. P., Pilz, L. K., Michels, M., Noetzold, G., & Elisabetsky, E. (2013) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2013.02.008 · Cited by 37 · see citing works
Arvilommi, P., Suominen, K. H., Mantere, O., Valtonen, H., Leppämäki, S., & Isometsä, E. T. (2015) · Bipolar Disorders · doi:10.1111/bdi.12349 · Cited by 32 · see citing works
(7713920), W. Z., (15858581), Q. Z., (15858584), D. C., et al. (2024) · Figshare · Cited by 3 · see citing works
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- Authors
- Nery, F. G., Li, W., DelBello, M. P., & Welge, J. A.
- Affiliations
- University of Cincinnati (US)
- Sichuan University (CN)
- Corresponding author
- Nery, Fabiano G.
- Venue
- Bipolar Disorders
- Publisher
- Wiley
- Published
- 2021-01-15
- Volume
- 23
- Issue
- 7
- Pages
- 707-714
- ISSN
- 1398-5647 (ISSN-L)
- 1399-5618
- OpenAlex
- W3115983550
- Cited by
- 29
- References
- 44
- Citations by year
- 2026: 7 · 2025: 2 · 2024: 4 · 2023: 5 · 2022: 8 · 2021: 3
- FWCI
- 0.66
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Bipolar Disorders (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Keywords
- N-acetylcysteine, bipolar depression, augmentation therapy, adjunctive therapy, antidepressant efficacy, placebo comparison, depressive symptoms, illness chronicity
- MeSH terms
- Acetylcysteine, Bipolar Disorder, Double-Blind Method, Humans, Randomized Controlled Trials as Topic, Treatment Outcome
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