Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
BMC Medicine
Published in: BMC Medicine 1/2019

Open Access 01-12-2019 | Affective Disorder | Research article

A randomised controlled trial of a mitochondrial therapeutic target for bipolar depression: mitochondrial agents, N-acetylcysteine, and placebo

Authors: Michael Berk, Alyna Turner, Gin S. Malhi, Chee H. Ng, Susan M. Cotton, Seetal Dodd, Yuval Samuni, Michelle Tanious, Claire McAulay, Nathan Dowling, Jerome Sarris, Lauren Owen, Astrid Waterdrinker, Deidre Smith, Olivia M. Dean

Published in: BMC Medicine | Issue 1/2019

Login to get access

Abstract

Background

A phasic dysregulation of mitochondrial bioenergetics may operate in bipolar disorder, increased in mania and decreased in depression. We aimed to examine efficacy of two add-on treatments in bipolar depression: N-acetylcysteine (NAC) and NAC with a combination of nutraceutical agents that may increase mitochondrial biogenesis.

Methods

A three-arm 16-week, double-blind, randomised, placebo-controlled trial, adjunctive to usual treatment, was conducted. Participants (n = 181) with bipolar disorder and current depressive symptoms were randomised to 2000 mg/day NAC (n = 59), 2000 mg/day NAC with the combination nutraceutical treatment (CT, n = 61), or placebo (n = 61). The primary outcome was change in Montgomery-Åsberg Depression Rating Scale (MADRS) total score from baseline to week 16. Young Mania Rating Scale, Clinical Global Impression (CGI)-Improvement and CGI-Severity scales, Patient Global Impression scale, Social and Occupational Functioning Assessment Scale (SOFAS), Longitudinal Interval Follow-Up Evaluation - Range of Impaired Functioning Tool (LIFE-RIFT), and Quality of Life Enjoyment, and Satisfaction Questionnaire Short Form (Q-LES-Q-SF) were secondary outcomes.

Results

One hundred forty-eight participants had post-randomisation data and were analysed (NAC = 52, CT = 47, Placebo = 49). No between-group differences were found for the rate of change between baseline and 16 weeks on any of the clinical and functioning variables. Improvements in MADRS, BDRS, SOFAS, and LIFE-RIFT scores from baseline to the week 20 post-discontinuation visit were significantly greater in the CT group compared to those in the placebo. At week 20, the CGI-I was significantly lower in the CT group versus placebo. Gastrointestinal symptoms were significantly greater in the NAC than in the placebo group.

Conclusions

These overall negative results, with no significant differences between groups detected at the primary outcome but some positive secondary signals, suggest either delayed benefit of the combination or an improvement of symptoms on withdrawal which warrants further exploration regarding the composition, mechanisms, and application of mitochondrial agents in illnesses characterised by mitochondrial dysfunction.

Trial registration

Literature
1.
Scaini G, Rezin GT, Carvalho AF, Streck EL, Berk M, Quevedo J. Mitochondrial dysfunction in bipolar disorder: evidence, pathophysiology and translational implications. Neurosci Biobehav Rev. 2016;68:694–713.CrossRef
2.
Malhi GS, Fritz K, Allwang C, et al. Agitation for recognition by DSM-5 mixed features specifier signals fatigue? Aust N Z J Psychiatry. 2015;49(6):499–501.CrossRef
3.
Manji H, Kato T, Di Prospero NA, Ness S, Beal MF, Krams M, Chen G. Impaired mitochondrial function in psychiatric disorders. Nat Rev Neurosci. 2012;13(5):293–307.CrossRef
4.
Morris G, Berk M. The many roads to mitochondrial dysfunction in neuroimmune and neuropsychiatric disorders. BMC Med. 2015;13:68 015–0310-y.CrossRef
5.
Morris G, Walder K, McGee SL, Dean OM, Tye SJ, Maes M, Berk M. A model of the mitochondrial basis of bipolar disorder. Neurosci Biobehav Rev. 2017;74(Pt A):1–20.CrossRef
6.
Dean OM, Turner A, Malhi GS, et al. Design and rationale of a 16-week adjunctive randomized placebo-controlled trial of mitochondrial agents for the treatment of bipolar depression. Rev Bras Psiquiatr. 2015;37(1):3–12.CrossRef
7.
Berk M, Copolov DL, Dean O, et al. N-acetyl cysteine for depressive symptoms in bipolar disorder--a double-blind randomized placebo-controlled trial. Biol Psychiatry. 2008;64(6):468–75.CrossRef
8.
Deepmala SJ, Kumar N, et al. Clinical trials of N-acetylcysteine in psychiatry and neurology: a systematic review. Neurosci Biobehav Rev. 2015;55:294–321.CrossRef
9.
Back SE, McCauley JL, Korte KJ, et al. A double-blind, randomized, controlled pilot trial of N-acetylcysteine in veterans with posttraumatic stress disorder and substance use disorders. J Clin Psychiatry. 2016;77(11):e1439–46.CrossRef
10.
Fernandes BS, Dean OM, Dodd S, Malhi GS, Berk M. N-acetylcysteine in depressive symptoms and functionality: a systematic review and meta-analysis. J Clin Psychiatry. 2016;77(4):e457–66.CrossRef
11.
Iovieno N, Nierenberg AA, Parkin SR, Hyung Kim DJ, Walker RS, Fava M, Papakostas GI. Relationship between placebo response rate and clinical trial outcome in bipolar depression. J Psychiatr Res. 2016;74:38–44.CrossRef
12.
Breier A, Liffick E, Hummer TA, Vohs JL, Yang Z, Mehdiyoun NF, Visco AC, Metzler E, Zhang Y, Francis MM. Effects of 12-month, double-blind N-acetyl cysteine on symptoms, cognition and brain morphology in early phase schizophrenia spectrum disorders. Schizophr Res. 2018;18:30164–6.
13.
Nierenberg AA, Ostergaard SD, Iovieno N, Walker RS, Fava M, Papakostas GI. Predictors of placebo response in bipolar depression. Int Clin Psychopharmacol. 2015;30(2):59–66.CrossRef
14.
Fornaro M, De Berardis D, Anastasia A, Novello S, Fusco A, Cattaneo CI, Solmi M, Monaco F, Veronese N, Kim YK, de Bartolomeis A. The identification of biomarkers predicting acute and maintenance lithium treatment response in bipolar disorder: a plea for further research attention. Psychiatry Res. 2018;269:658–72.CrossRef
Metadata
Title
A randomised controlled trial of a mitochondrial therapeutic target for bipolar depression: mitochondrial agents, N-acetylcysteine, and placebo
Authors
Michael Berk
Alyna Turner
Gin S. Malhi
Chee H. Ng
Susan M. Cotton
Seetal Dodd
Yuval Samuni
Michelle Tanious
Claire McAulay
Nathan Dowling
Jerome Sarris
Lauren Owen
Astrid Waterdrinker
Deidre Smith
Olivia M. Dean
Publication date
01-12-2019
Publisher
BioMed Central
Published in
BMC Medicine / Issue 1/2019
Electronic ISSN: 1741-7015
DOI
https://doi.org/10.1186/s12916-019-1257-1

Other articles of this Issue 1/2019

BMC Medicine 1/2019 Go to the issue

Correspondence

Interventions to prevent, delay or reverse frailty in older people: a journey towards clinical guidelines

Research article

Next-generation sequencing identifies monogenic diabetes in 16% of patients with late adolescence/adult-onset diabetes selected on a clinical basis: a cross-sectional analysis

Research article

Comparison of depression prevalence estimates in meta-analyses based on screening tools and rating scales versus diagnostic interviews: a meta-research review

Research article

Suicide prevention and depression apps’ suicide risk assessment and management: a systematic assessment of adherence to clinical guidelines

Correction

Correction to: Post-marketing withdrawal of 462 medicinal products because of adverse drug reactions: a systematic review of the world literature

Research article

Does regulation increase the rate at which doctors leave practice? Analysis of routine hospital data in the English NHS following the introduction of medical revalidation