Design and rationale of a 16-week adjunctive randomized
                    placebo-controlled trial of mitochondrial agents for the treatment of bipolar
                    depression

Dean, Olivia M.; Turner, Alyna; Malhi, Gin S.; Ng, Chee; Cotton, Sue M.; Dodd, Seetal; Sarris, Jerome; Samuni, Yuval; Tanious, Michelle; Dowling, Nathan; Waterdrinker, Astrid; Smith, Deidre; Berk, Michael

doi:10.1590/1516-4446-2013-1341

Brazil

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ORIGINAL ARTICLES • Rev. Bras. Psiquiatr. 37 (01) • Jan-Mar 2015 • https://doi.org/10.1590/1516-4446-2013-1341 linkcopy

Design and rationale of a 16-week adjunctive randomized placebo-controlled trial of mitochondrial agents for the treatment of bipolar depression

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Objective: Bipolar disorder places a significant burden on individuals, caregivers and family, and the broader community. Current treatments are believed to be more effective against manic symptoms, leaving a shortfall in recovery during the depressive phase of the illness. The current study draws on recent evidence suggesting that, in addition to increased oxidative load, alterations in mitochondrial function occur in bipolar disorder.

Methods: This 16-week study aims to explore the potential benefits of N-acetylcysteine (NAC) alone or in combination (CT) with selected nutraceuticals believed to enhance mitochondrial function. The study includes adults diagnosed with bipolar disorder currently experiencing an episode of depression. Participants are asked to take NAC, CT, or placebo in addition to any usual treatments. A post-discontinuation visit is conducted 4 weeks following the treatment phase.

Results: The primary outcome of the study will be mean change on the Montgomery-Asberg Depression Rating Scale. Secondary outcomes include functioning, substance use, mania ratings, and quality of life. Blood samples will be collected at baseline and week 16 to explore biochemical alterations following treatment.

Conclusion: This study may provide a novel adjunctive treatment for bipolar depression. Analysis of biological samples may assist in understanding the therapeutic benefits and the underlying etiology of bipolar depression.

Trial registration: Australian and New Zealand Clinical Trial Registry ACTRN12612000830897.

Mitochondria; bipolar disorder; depression; acetylcysteine; oxidative stress

Visit	Visit 1a	Visit 1b^* * Screening and baseline visits may be conducted together or as two separate visits, depending on the participant's needs.	Phone call	Visit 3	Visit 4	Visit 5	Visit 6	Visit 7
Phase	Screening	Baseline	Treatment phase					Washout
Week/scale	Week 0	Week 0	Week 2	Week 4	Week 8	Week 12	Week 16	Week 20
Informed consent	X	-	-	-	-	-		-
MINI-Plus 5.0	X	-	-	-	-	-		-
Concomitant medication	X
Entrance criteria	X	-	-	-	-	-		-
SAPAS		-		X
Family history		X	-	-	-	-		-
Psychiatric history		X	-	-	-	-		-
Demographic information		X
Habits	-	X		X	X	X	X	X
Adverse events	-	-	X	X	X	X	X	X
Alcohol/substance use	-	X		X	X	X	X	X
MADRS with SIGMA	X	X		X	X	X	X	X
BDRS	-	X		X	X	X	X	X
HAM-A	-	X		X	X	X	X	X
YMRS	-	X		X	X	X	X	X
LIFE-RIFT	-	X		X	X	X	X	X
SOFAS	-	X		X	X	X	X	X
Q-LES-Q (short form)	-	X		X	X	X	X	X
CGI-BP severity	-	X		X	X	X	X	X
CGI-BP Improvement				X	X	X	X	X
PGI	-	-		X	X	X	X	X
Food Frequency Questionnaire	-			X
Qualitative data collection	X	X	X	X	X	X	X	X
Adherence to trial medication			X	X	X	X	X	X
Blood sampling (30 ml)	-	X	-	-	-		X	-

Capsule/component	Total/capsule	Total dose/day	Total no. capsules/day
Group 1: combination treatment
Capsule 1: N-acetylcysteine	500 mg	2,000 mg	4
Capsule 2: acetyl-l-carnitine	500 mg	1,000 mg	2
Capsule 3:			2
Ubiquinone (coenzyme Q10)	75 mg^* * Total dose of ubidecarenone is 200 mg and d-alpha-tocopherol is 40.32 mg (60 IU), combining capsules 4 and 5.	200 mg
d-alpha-Tocopherol (vitamin E)	3.36 mg (5 IU)^* * Total dose of ubidecarenone is 200 mg and d-alpha-tocopherol is 40.32 mg (60 IU), combining capsules 4 and 5.	40.32 mg (60 IU)
Alpha-lipoic acid	75 mg	150 mg
Magnesium (as orotate 500 mg)	32 mg	64 mg
Capsule 4:
Ubidecarenone (coenzyme Q10)	25 mg^* * Total dose of ubidecarenone is 200 mg and d-alpha-tocopherol is 40.32 mg (60 IU), combining capsules 4 and 5.		2
d-alpha-Tocopherol (vitamin E)	16.8 mg (25 IU)^* * Total dose of ubidecarenone is 200 mg and d-alpha-tocopherol is 40.32 mg (60 IU), combining capsules 4 and 5.
Thiamine hydrochloride	50 mg	100 mg
Riboflavin (vitamin B2)	50 mg	100 mg
Nicotinamide (vitamin B3)	100 mg	200 mg
Calcium pantothenate (equiv. pantothenic acid/vitamin B5)	50 mg (45 mg)	100 mg (90 mg)
Pyridoxine hydrochloride (equiv. pyridoxine/vitamin B6)	50 mg (41.1 mg)	100 mg (82.2 mg)
Folic acid (vitamin B9)	400 µg	800 µg
Cyanocobalamin (vitamin B12)	400 µg	800 µg
Calcium ascorbate dihydrate (equiv. ascorbic acid/vitamin C)	121 mg (100 mg)	242 mg (200 mg)
Retinyl palmitate (equiv. vitamin A)	450 µgRE (1,500 IU)	900 µgRE (3,000 IU)
Cholecalciferol (equiv. 250 IU vitamin D3)	6.25 µg (250 IU)	12.5 µg (500 IU)
Biotin (vitamin H)	300 µg	600 µg
Group 2: N-acetylcysteine group
Capsule 1: N-acetylcysteine	500 mg	2,000 mg	4
Capsules 5, 6, 7: equivalent placebos of Capsules 2, 3, 4			6
Group 3: Placebo group
Capsule 8: equivalent placebo of Capsule 1			4
Capsules 5, 6, 7: equivalent placebos of Capsules 2, 3, 4			6

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Associação Brasileira de Psiquiatria Rua Pedro de Toledo, 967 - casa 1, 04039-032 São Paulo SP Brazil, Tel.: +55 11 5081-6799, Fax: +55 11 3384-6799, Fax: +55 11 5579-6210 - São Paulo - SP - Brazil
E-mail: editorial@abp.org.br

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[TFN01t01] BDRS = Bipolar Depression Rating Scale; CGI-BP = Clinical Global Impression for Bipolar Disorder; HAM-A = Hamilton Anxiety Rating Scale; LIFE-RIFT = Longitudinal Interval Follow-up Evaluation - Range of Impairment Functioning Tool; MADRS = Montgomery-Asberg Depression Scale; MINI-Plus = Mini-International Neuropsychiatric Interview-Plus; PGI = Patient Global Impression; Q-LES-Q = Quality of Life Enjoyment and Satisfaction Questionnaire; SAPAS = Standard Assessment of Personality - Abbreviated Scale; SIGMA = Structured Interview Guide for the Montgomery-Asberg Depression Rating Scale; SOFAS = Social and Occupational Functioning Assessment Scale; YMRS = Young Mania Rating Scale.

[TFN02t01] * Screening and baseline visits may be conducted together or as two separate visits, depending on the participant's needs.