Randomized Controlled Trial

. 2019 Jan 25;17(1):18.

doi: 10.1186/s12916-019-1257-1.

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

Michael Berk^{1

2

3

4}, Alyna Turner^{5

6

7}, Gin S Malhi^{8

9

10}, Chee H Ng¹¹, Susan M Cotton^{12

13}, Seetal Dodd^{5

6

13}, Yuval Samuni⁵, Michelle Tanious⁸, Claire McAulay⁸, Nathan Dowling¹¹, Jerome Sarris^{11

14}, Lauren Owen¹⁵, Astrid Waterdrinker¹⁶, Deidre Smith¹¹, Olivia M Dean^{5

6

17}

Affiliations

¹ IMPACT Strategic Research Centre, School of Medicine, Barwon Health, Deakin University, P.O. Box 291, Geelong, VIC, Australia. mikebe@barwonhealth.org.au.
² Department of Psychiatry, University of Melbourne, Royal Melbourne Hospital, Level 1 North, Main Block, Parkville, VIC, Australia. mikebe@barwonhealth.org.au.
³ Florey Institute for Neuroscience and Mental Health, University of Melbourne, Kenneth Myer Building, 30 Royal Parade, Parkville, VIC, Australia. mikebe@barwonhealth.org.au.
⁴ Orygen, The National Centre of Excellence in Youth Mental Health, 35 Poplar Rd, Parkville, VIC, Australia. mikebe@barwonhealth.org.au.
⁵ IMPACT Strategic Research Centre, School of Medicine, Barwon Health, Deakin University, P.O. Box 291, Geelong, VIC, Australia.
⁶ Department of Psychiatry, University of Melbourne, Royal Melbourne Hospital, Level 1 North, Main Block, Parkville, VIC, Australia.
⁷ School of Medicine and Public Health, Faculty of Health and Medicine, the University of Newcastle, Callaghan, NSW, Australia.
⁸ CADE Clinic, Royal North Shore Hospital, Northern Sydney Local Health District, St Leonards, NSW, Australia.
⁹ Academic Department of Psychiatry, Kolling Institute, Northern Sydney Local Health District, St Leonards, NSW, Australia.
¹⁰ ARCHI, Sydney Medical School Northern, University of Sydney, Sydney, NSW, Australia.
¹¹ Department of Psychiatry, University of Melbourne, the Melbourne Clinic, 130 Church St Richmond, Melbourne, VIC, Australia.
¹² Orygen, The National Centre of Excellence in Youth Mental Health, 35 Poplar Rd, Parkville, VIC, Australia.
¹³ Centre for Youth Mental Health, The University of Melbourne, 35 Poplar Rd, Parkville, VIC, Australia.
¹⁴ NICM, School of Health and Science, Western Sydney University, Campbelltown, NSW, Australia.
¹⁵ School of Psychology, University of Central Lancashire, Preston, UK.
¹⁶ Melbourne Health, 300 Grattan St, Melbourne, VIC, Australia.
¹⁷ Florey Institute for Neuroscience and Mental Health, University of Melbourne, Kenneth Myer Building, 30 Royal Parade, Parkville, VIC, Australia.

PMID: 30678686
PMCID: PMC6346513
DOI: 10.1186/s12916-019-1257-1

Randomized Controlled Trial

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

Michael Berk et al. BMC Med. 2019.

. 2019 Jan 25;17(1):18.

doi: 10.1186/s12916-019-1257-1.

Authors

Affiliations

¹ IMPACT Strategic Research Centre, School of Medicine, Barwon Health, Deakin University, P.O. Box 291, Geelong, VIC, Australia. mikebe@barwonhealth.org.au.
² Department of Psychiatry, University of Melbourne, Royal Melbourne Hospital, Level 1 North, Main Block, Parkville, VIC, Australia. mikebe@barwonhealth.org.au.
³ Florey Institute for Neuroscience and Mental Health, University of Melbourne, Kenneth Myer Building, 30 Royal Parade, Parkville, VIC, Australia. mikebe@barwonhealth.org.au.
⁴ Orygen, The National Centre of Excellence in Youth Mental Health, 35 Poplar Rd, Parkville, VIC, Australia. mikebe@barwonhealth.org.au.
⁵ IMPACT Strategic Research Centre, School of Medicine, Barwon Health, Deakin University, P.O. Box 291, Geelong, VIC, Australia.
⁶ Department of Psychiatry, University of Melbourne, Royal Melbourne Hospital, Level 1 North, Main Block, Parkville, VIC, Australia.
⁷ School of Medicine and Public Health, Faculty of Health and Medicine, the University of Newcastle, Callaghan, NSW, Australia.
⁸ CADE Clinic, Royal North Shore Hospital, Northern Sydney Local Health District, St Leonards, NSW, Australia.
⁹ Academic Department of Psychiatry, Kolling Institute, Northern Sydney Local Health District, St Leonards, NSW, Australia.
¹⁰ ARCHI, Sydney Medical School Northern, University of Sydney, Sydney, NSW, Australia.
¹¹ Department of Psychiatry, University of Melbourne, the Melbourne Clinic, 130 Church St Richmond, Melbourne, VIC, Australia.
¹² Orygen, The National Centre of Excellence in Youth Mental Health, 35 Poplar Rd, Parkville, VIC, Australia.
¹³ Centre for Youth Mental Health, The University of Melbourne, 35 Poplar Rd, Parkville, VIC, Australia.
¹⁴ NICM, School of Health and Science, Western Sydney University, Campbelltown, NSW, Australia.
¹⁵ School of Psychology, University of Central Lancashire, Preston, UK.
¹⁶ Melbourne Health, 300 Grattan St, Melbourne, VIC, Australia.
¹⁷ Florey Institute for Neuroscience and Mental Health, University of Melbourne, Kenneth Myer Building, 30 Royal Parade, Parkville, VIC, Australia.

PMID: 30678686
PMCID: PMC6346513
DOI: 10.1186/s12916-019-1257-1

Erratum in

Correction to: A randomised controlled trial of a mitochondrial therapeutic target for bipolar depression: mitochondrial agents, N-acetylcysteine, and placebo.
Berk M, Turner A, Malhi GS, Ng CH, Cotton SM, Dodd S, Samuni Y, Tanious M, McAulay C, Dowling N, Sarris J, Owen L, Waterdrinker A, Smith D, Dean OM. Berk M, et al. BMC Med. 2019 Feb 17;17(1):35. doi: 10.1186/s12916-019-1280-2. BMC Med. 2019. PMID: 30771791 Free PMC article.

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: ANZCTR ( ACTRN12612000830897 ).

Keywords: Adjunctive; Bipolar disorder; Depression; Mitochondria; Nutraceutical; Oxidative stress.

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Conflict of interest statement

Authors’ information

Not applicable.

Ethics approval and consent to participate

Ethical approval was gained from the Barwon Health Human Research Ethics Committee (HREC/11/BICBH/21), The Melbourne Clinic Research Ethics Committee (Project 207), and the Northern Sydney Local Health Network Human Research Ethics Committee (HREC/12/HAWKE/26). All participants provided written informed consent.

Consent for publication

Not applicable.

Competing interests

MB has received Grant/Research Support from the NIH, Cooperative Research Centre, Simons Autism Foundation, Cancer Council of Victoria, Stanley Medical Research Foundation, MBF, NHMRC, Beyond Blue, Rotary Health, Geelong Medical Research Foundation, Bristol-Myers Squibb, Eli Lilly, Glaxo SmithKline, Meat and Livestock Board, Organon, Novartis, Mayne Pharma, Servier, Woolworths, Avant and the Harry Windsor Foundation, has been a speaker for Astra Zeneca, Bristol-Myers Squibb, Eli Lilly, Glaxo SmithKline, Janssen-Cilag, Lundbeck, Merck, Pfizer, Sanofi Synthelabo, Servier, Solvay and Wyeth, and served as a consultant to Allergan, Astra Zeneca, Bioadvantex, Bionomics, Collaborative Medicinal Development, Eli Lilly, Grunbiotics, Glaxo SmithKline, Janssen-Cilag, LivaNova, Lundbeck, Merck, Mylan, Otsuka, Pfizer and Servier. GSM has received grant or research support from National Health and Medical Research Council, Australian Rotary Health, NSW Health, Ramsay Health, American Foundation for Suicide Prevention, Ramsay Research and Teaching Fund, Elsevier, AstraZeneca and Servier; has been a speaker for AstraZeneca, Janssen-Cilag, Lundbeck, and Servier; and has been a consultant for AstraZeneca, Janssen-Cilag, Lundbeck and Servier. CN had served in the Servier, Janssen-Cilag, Wyeth and Eli Lilly Advisory Boards, received research grant support from Wyeth and Lundbeck, and speaker honoraria from Servier, Lundbeck, Bristol-Myers Squibb, Organon, Eli Lilly, GlaxoSmithKline, Janssen-Cilag, Astra-Zenaca, Wyeth, and Pfizer. SD has received grants/research support from the Stanley Medical Research Institute, NHMRC, Beyond Blue, ARHRF, Simons Foundation, Geelong Medical Research Foundation, Fondation FondaMental, Eli Lilly, Glaxo SmithKline, Organon, Mayne Pharma and Servier, speaker’s fees from Eli Lilly, advisory board fees from Eli Lilly and Novartis, and conference travel support from Servier. CM has received research/travel support from EP Nuffic. JS has received either presentation honoraria, travel support, clinical trial grants, book royalties, or independent consultancy payments from: Integria Healthcare & MediHerb, Pfizer, Scius Health, Key Pharmaceuticals, Taki Mai, Bioceuticals & Blackmores, Soho-Flordis, Healthworld, HealthEd, HealthMasters, Elsevier, Chaminade University, International Society for Affective Disorders, Complementary Medicines Australia, Terry White Chemists, ANS, Society for Medicinal Plant and Natural Product Research, UBiome, Omega-3 Centre, the National Health and Medical Research Council, CR Roper Fellowship. LO has received Grant/Research Support from; Marie Skłodowska-Curie Actions (MCSA) European Union/European Commission, Glaxo SmithKline, FIT- BioCeuticals, Cultech Ltd., Naturex, The Human Performance Institute (HPI), Omniblend, Dairy Innovations Australia, and Cyvex. OMD has received grant support from the Brain and Behavior Foundation, Simons Autism Foundation, Stanley Medical Research Institute, Deakin University, Lilly, NHMRC and ASBDD/Servier. She has also received in kind support from BioMedica Nutracuticals, NutritionCare and Bioceuticals. AT, SMC, YS, MT, ND, AW, and DS declare that they have no competing interests.

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Figures

**Fig. 1**
CONSORT flowchart depicting participant flow through the trial

**Fig. 2**
Estimated means (±SE) derived from MMRM for each of the clinical measures for the three groups and over the six time points. Note: YMRS, Young Mania Rating Scale; CGI-BP Clinical Global Impressions Scale - Bipolar; BDRS, Bipolar Depression Rating Scale; MADRS, Montgomery-Asberg Depression Rating Scale; Brief Psychiatric Rating Scale, BPRS; GAF, Global Assessment of Functioning ; SOFAS, Social and Occupational Assessment Scale; QLS, Quality of Life Scale; NAC N-acetylcysteine; CT Combination Treatment

See this image and copyright information in PMC

References

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

Affiliations

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

Authors

Affiliations

Erratum in

Abstract

Conflict of interest statement

Authors’ information

Ethics approval and consent to participate

Consent for publication

Competing interests

Publisher’s Note

Figures

References

Publication types

MeSH terms

Substances

Associated data

LinkOut - more resources

Full Text Sources

Medical