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

Revista Brasileira de Psiquiatria

Volumn 37, Issue 1, 2015, Pages 3-12

  Dean, Olivia M ^a,b   Turner, Alyna ^a,c   Malhi, Gin S ^d,e   Ng, Chee ^b   Cotton, Sue M ^b,f   Dodd, Seetal ^a,b   Sarris, Jerome ^b,g   Samuni, Yuval ^a   Tanious, Michelle ^d,e   Dowling, Nathan ^b   Waterdrinker, Astrid ^a   Smith, Deidre ^b   Berk, Michael ^a,b,f  

^a DEAKIN UNIVERSITY   (Australia)

^b UNIVERSITY OF MELBOURNE   (Australia)

^c UNIVERSITY OF NEWCASTLE   (Australia)

^d UNIVERSITY OF SYDNEY   (Australia)

^e Department of Psychiatry   (Australia)

^f THE NATIONAL CENTRE OF EXCELLENCE IN YOUTH MENTAL HEALTH   (Australia)

^g SWINBURNE UNIVERSITY OF TECHNOLOGY   (Australia)

Author keywords

Acetylcysteine; Bipolar disorder; Depression; Mitochondria; Oxidative stress

Indexed keywords

ACETYLCYSTEINE; ASCORBIC ACID; BIOTIN; CALCIUM ASCORBATE; COLECALCIFEROL; CYANOCOBALAMIN; FOLIC ACID; LEVACECARNINE; MAGNESIUM; NICOTINAMIDE; NUTRACEUTICAL; PANTOTHENATE CALCIUM; PLACEBO; PYRIDOXINE; RETINOL PALMITATE; RIBOFLAVIN; THIAMINE; THIOCTIC ACID; TOCOPHEROL; UBIDECARENONE; UBIQUINONE; VITAMIN D; ANTIDEPRESSANT AGENT; ANTIOXIDANT; IDEBENONE; MENADIONE; SCAVENGER; VITAMIN;

ADULT; ARTICLE; ASSESSMENT OF HUMANS; BIPOLAR DEPRESSION; CONTROLLED STUDY; DIET SUPPLEMENTATION; DOUBLE BLIND PROCEDURE; DRUG EFFICACY; FOLLOW UP; HUMAN; MAJOR CLINICAL STUDY; MANIA; METHODOLOGY; MITOCHONDRION; MONTGOMERY ASBERG DEPRESSION RATING SCALE; OUTCOME ASSESSMENT; QUALITY OF LIFE; RANDOMIZED CONTROLLED TRIAL; SUBSTANCE USE; TREATMENT OUTCOME; ANALOGS AND DERIVATIVES; BIPOLAR DISORDER; CLINICAL TRIAL; DEPRESSIVE DISORDER; DOSE RESPONSE; DRUG EFFECTS; FEMALE; MALE; MITOCHONDRIAL DISEASES; MULTICENTER STUDY; MULTIMODALITY CANCER THERAPY; NONPARAMETRIC TEST; PROCEDURES; PSYCHOLOGICAL RATING SCALE; TIME;

ACETYLCYSTEINE; ADULT; ANTIDEPRESSIVE AGENTS; ANTIOXIDANTS; BIPOLAR DISORDER; COMBINED MODALITY THERAPY; DEPRESSIVE DISORDER; DIETARY SUPPLEMENTS; DOSE-RESPONSE RELATIONSHIP, DRUG; DOUBLE-BLIND METHOD; FEMALE; FREE RADICAL SCAVENGERS; HUMANS; MALE; MITOCHONDRIA; MITOCHONDRIAL DISEASES; PLACEBOS; PSYCHIATRIC STATUS RATING SCALES; STATISTICS, NONPARAMETRIC; TIME FACTORS; TREATMENT OUTCOME; UBIQUINONE; VITAMIN K 3; VITAMINS;

EID: 84930948022     PISSN: 15164446     EISSN: None     Source Type: Journal    
DOI: 10.1590/1516-4446-2013-1341     Document Type: Article

References (76)

1. Judd LL, Akiskal HS, Schettler PJ, Endicott J, Maser J, Solomon DA, et al. The long-term natural history of the weekly symptomatic status of bipolar I disorder. Arch Gen Psychiatry. 2002;59:530-7.
2. Simpson SG, Jamison KR. The risk of suicide in patients with bipolar disorders. J Clin Psychiatry. 1999;60:53-6; discussion 75-6, 113-6.
3. Calabrese JR, Guelfi JD, Perdrizet-Chevallier C, Agomelatine Bipolar Study G. Agomelatine adjunctive therapy for acute bipolar depression: preliminary open data. Bipolar Disord. 2007;9:628-35.
4. McElroy SL, Suppes T, Frye MA, Altshuler LL, Stanford K, Martens B, et al. Open-label aripiprazole in the treatment of acute bipolar depression: a prospective pilot trial. J Affect Disord. 2007;101: 275-81.
5. Sachs GS, Nierenberg AA, Calabrese JR, Marangell LB, Wisniewski SR, Gyulai L, et al. Effectiveness of adjunctive antidepressant treatment for bipolar depression. N Engl J Med. 2007;356:1711-22.
6. Nierenberg AA, Kansky C, Brennan BP, Shelton RC, Perlis R, Iosifescu DV. Mitochondrial modulators for bipolar disorder: a pathophysiologically informed paradigm for new drug development. Aust N Z J Psychiatry. 2013;47:26-42.
7. Berk M, Malhi GS, Gray LJ, Dean OM. The promise of Nacetylcysteine in neuropsychiatry. Trends Pharmacol Sci. 2013; 34:167-77.
8. Chinnery PF, Majamaa K, Turnbull DM, Thornburn D. Treatment for mitochondrial disorders. Cochrane Database Sys Rev. 2006;25: CD004426.
9. Manji HK, Quiroz JA, Payne JL, Singh J, Lopes BP, Viegas JS, et al. The underlying neurobiology of bipolar disorder. World Psychiatry. 2003;2:136-46.
10. Fattal O, Link J, Quinn K, Cohen BH, Franco K. Psychiatric comorbidity in 36 adults with mitochondrial cytopathies. CNS Spectr. 2007;12:429-38.
11. Caliyurt O, Altiay G. Resting energy expenditure in manic episode. Bipolar Disord. 2009;11:102-6.
12. Baxter LR Jr, Phelps ME, Mazziotta JC, Schwartz JM, Gerner RH, Selin CE, et al. Cerebral metabolic rates for glucose in mood disorders. Studies with positron emission tomography and fluorodeoxyglucose F 18. Arch Gen Psychiatry. 1985;42:441-7.
13. Pettegrew JW, Levine J, Gershon S, Stanley JA, Servan-Schreiber D, Panchalingam K, et al. 31P-MRS study of acetyl-L-carnitine treatment in geriatric depression: preliminary results. Bipolar Disord. 2002;4:61-6.
14. Kato T, Takahashi S, Shioiri T, Inubushi T. Brain phosphorous metabolism in depressive disorders detected by phosphorus-31 magnetic resonance spectroscopy. J Affect Disord. 1992;26:223-30.
15. Kato T, Takahashi S, Shioiri T, Murashita J, Hamakawa H, Inubushi T. Reduction of brain phosphocreatine in bipolar II disorder detected by phosphorus-31 magnetic resonance spectroscopy. J Affect Disord. 1994;31:125-33.
16. Kato T, Shioiri T, Murashita J, Hamakawa H, Takahashi Y, Inubushi T, et al. Lateralized abnormality of high energy phosphate metabolism in the frontal lobes of patients with bipolar disorder detected by phase-encoded 31P-MRS. Psychol Med. 1995;25: 557-66.
17. Murashita J, Kato T, Shioiri T, Inubushi T, Kato N. Altered brain energy metabolism in lithium-resistant bipolar disorder detected by photic stimulated 31P-MR spectroscopy. Psychol Med. 2000;30: 107-15.
18. Kato T, Stine OC, McMahon FJ, Crowe RR. Increased levels of a mitochondrial DNA deletion in the brain of patients with bipolar disorder. Biol Psychiatry. 1997;42:871-5.
19. Sabunciyan S, Kirches E, Krause G, Bogerts B, Mawrin C, Llenos IC, et al. Quantification of total mitochondrial DNA and mitochondrial common deletion in the frontal cortex of patients with schizophrenia and bipolar disorder. J Neural Transm. 2007;114:665-74.
20. Fuke S, Kametani M, Kato T. Quantitative analysis of the 4977-bp common deletion of mitochondrial DNA in postmortem frontal cortex from patients with bipolar disorder and schizophrenia. Neurosci Lett. 2008;439:173-7.
21. Berk M, Dean O, Cotton SM, Gama CS, Kapczinski F, Fernandes BS, et al. The efficacy of N-acetylcysteine as an adjunctive treatment in bipolar depression: an open label trial. J Affect Disord. 2011;135:389-94.
22. Berk M, Dean OM, Cotton SM, Gama CS, Kapczinski F, Fernandes B, et al. Maintenance N-acetyl cysteine treatment for bipolar disorder: a double-blind randomized placebo controlled trial. BMC Med. 2012;10:91.
23. Berk M, Copolov DL, Dean O, Lu K, Jeavons S, Schapkaitz I, et al. N-acetyl cysteine for depressive symptoms in bipolar disorder–a double-blind randomized placebo-controlled trial. Biol Psychiatry. 2008;64:468-75.
24. Finsterer J. Treatment of mitochondrial disorders. Eur J Paediatr Neurol. 2010;14:29-44.
25. Berk M, Copolov D, Dean O, Lu K, Jeavons S, Schapkaitz I, et al. Nacetyl cysteine as a glutathione precursor for schizophrenia–a double-blind, randomized, placebo-controlled trial. Biol Psychiatry. 2008;64:361-8.
26. Lenaz G, D’Aurelio M, Merlo Pich M, Genova ML, Ventura B, Bovina C, et al. Mitochondrial bioenergetics in aging. Biochim Biophys Acta. 2000;1459:397-404.
27. Barbiroli B, Frassineti C, Martinelli P, Iotti S, Lodi R, Cortelli P, et al. Coenzyme Q10 improves mitochondrial respiration in patients with mitochondrial cytopathies. An in vivo study on brain and skeletal muscle by phosphorous magnetic resonance spectroscopy. Cell Mol Biol (Noisy-le-grand). 1997;43:741-9.
28. Brady K, Goldberg JF. Substance abuse and bipolar disorder. In: 9th Annual US Psychiatric and Mental Health Congress; 1996. November 14-17; 1996.
29. Bendahan D, Desnuelle C, Vanuxem D, Confort-Gouny S, Figarella-Branger D, Pellissier JF, et al. 31P NMR spectroscopy and ergometer exercise test as evidence for muscle oxidative performance improvement with coenzyme Q in mitochondrial myopathies. Neurology. 1992;42:1203-8.
30. Tsai G, Goff DC, Chang R, Flood J, Baer L, Coyle JT. Markers of glutamatergic neurotransmission and oxidative stress associated with tardive dyskinesia. Am J Psychiatry. 1998;155:1207-13.
31. Kermode JC, Zheng Q, Cook EP. Fluorescent indicators give biased estimates of intracellular free calcium change in aggregating platelets: Implications for studies with human von willebrand factor. Blood Cells Mol Dis. 1996;22:238-53.
32. Beal MF. Coenzyme Q10 administration and its potential for treatment of neurodegenerative diseases. Biofactors. 1999;9:261-6.
33. Shults CW, Beal MF, Fontaine D, Nakano K, Haas RH. Absorption, tolerability, and effects on mitochondrial activity of oral coenzyme Q10 in parkinsonian patients. Neurology. 1998;50:793-5.
34. Packer L, Tritschler HJ, Wessel K. Neuroprotection by the metabolic antioxidant alpha-lipoic acid. Free Radic Biol Med. 1997;22:359-78.
35. Silva-Adaya D, Perez-De La Cruz V, Herrera-Mundo MN, Mendoza- Macedo K, Villeda-Hernandez J, Binienda Z, et al. Excitotoxic damage, disrupted energy metabolism, and oxidative stress in the rat brain: antioxidant and neuroprotective effects of L-carnitine. J Neurochem. 2008;105:677-89.
36. Zanardi R, Smeraldi E. A double-blind, randomised, controlled clinical trial of acetyl-L-carnitine vs. amisulpride in the treatment of dysthymia. Eur Neuropsychopharmacol. 2006;16:281-7.
37. Castagnola M, Messana I, Inzitari R, Fanali C, Cabras T, Morelli A, et al. Hypo-phosphorylation of salivary peptidome as a clue to the molecular pathogenesis of autism spectrum disorders. J Proteome Res. 2008;7:5327-32.
38. Marangell LB, Bauer MS, Dennehy EB, Wisniewski SR, Allen MH, Miklowitz DJ, et al. Prospective predictors of suicide and suicide attempts in 1,556 patients with bipolar disorders followed for up to 2 years. Bipolar Disord. 2006;8:566-75.
39. Regenold WT, Phatak P, Marano CM, Sassan A, Conley RR, Kling MA. Elevated cerebrospinal fluid lactate concentrations in patients with bipolar disorder and schizophrenia: implications for the mitochondrial dysfunction hypothesis. Biol Psychiatry. 2009;65: 489-94.
40. Mingrone G, Greco AV, Capristo E, Benedetti G, Giancaterini A, De Gaetano A, et al. L-carnitine improves glucose disposal in type 2 diabetic patients. J Am Coll Nutr. 1999;18:77-82.
41. Hoyos B, Acin-Perez R, Fischman DA, Manfredi G, Hammerling U. Hiding in plain sight: uncovering a new function of vitamin A in redox signaling. Biochim Biophys Acta. 2012;1821:241-7.
42. Ubbenhorst A, Striebich S, Lang F, Lang UE. Exploring the relationship between vitamin D and basic personality traits. Psychopharmacology (Berl). 2011;215:733-7.
43. Lansdowne AT, Provost SC. Vitamin D3 enhances mood in healthy subjects during winter. Psychopharmacology (Berl). 1998;135: 319-23.
44. Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357:266-81.
45. Eyles DW, Burne TH, McGrath JJ. Vitamin D, effects on brain development, adult brain function and the links between low levels of vitamin D and neuropsychiatric disease. Front Neuroendocrinol. 2013;34:47-64.
46. Hedelin M, Lof M, Olsson M, Lewander T, Nilsson B, Hultman CM, et al. Dietary intake of fish, omega-3, omega-6 polyunsaturated fatty acids and vitamin D and the prevalence of psychotic-like symptoms in a cohort of 33,000 women from the general population. BMC Psychiatry. 2010;10:38.
47. Eleff S, Kennaway NG, Buist NR, Darley-Usmar VM, Capaldi RA, Bank WJ, et al. 31P NMR study of improvement in oxidative phosphorylation by vitamins K3 and C in a patient with a defect in electron transport at complex III in skeletal muscle. Proc Natl Acad Sci U S A. 1984;81:3529-33.
48. Naylor GJ. Reversal of vanadate-induced inhibition of Na-K ATPase. A possible explanation of the therapeutic effect of carbamazepine in affective illness. J Affect Disord. 1985;8:91-3.
49. Naylor GJ, Smith AH. Vanadium: a possible aetiological factor in manic depressive illness. Psychol Med. 1981;11:249-56.
50. Arrigoni O, De Tullio MC. Ascorbic acid: much more than just an antioxidant. Biochim Biophys Acta. 2002;1569:1-9.
51. Kagan V, Serbinova E, Packer L. Antioxidant effects of ubiquinones in microsomes and mitochondria are mediated by tocopherol recycling. Biochem Biophys Res Commun. 1990;169:851-7.
52. Naito E, Ito M, Takeda E, Yokota I, Yoshijima S, Kuroda Y. Molecular analysis of abnormal pyruvate dehydrogenase in a patient with thiamine-responsive congenital lactic acidemia. Pediatr Res. 1994; 36:340-6.
53. Depeint F, Bruce WR, Shangari N, Mehta R, O’Brien PJ. Mitochondrial function and toxicity: role of the B vitamin family on mitochondrial energy metabolism. Chem Biol Interact. 2006;163: 94-112.
54. Sauve AA. NAD+ and vitamin B3: from metabolism to therapies. J Pharmacol Exp Ther. 2008;324:883-93.
55. Kannan K, Jain SK. Effect of vitamin B6 on oxygen radicals, mitochondrial membrane potential, and lipid peroxidation in H2O2- treated U937 monocytes. Free Radic Biol Med. 2004;36:423-8.
56. Hall NC, Carney JM, Plante OJ, Cheng M, Butterfield DA. Effect of 2- cyclohexene-1-one-induced glutathione diminution on ischemia/ reperfusion-induced alterations in the physical state of brain synaptosomal membrane proteins and lipids. Neuroscience. 1997;77:283-90.
57. Alpert JE, Fava M. Nutrition and depression: the role of folate. Nutr Rev. 1997;55:145-9.
58. Reynolds EH, Preece JM, Bailey J, Coppen A. Folate deficiency in depressive illness. Br J Psychiatry. 1970;117:287-92.
59. Malouf M, Grimley EJ, Areosa SA. Folic acid with or without vitamin B12 for cognition and dementia. Cochrane Database Syst Rev. 2003;(4):CD004514.
60. Fafouti M, Paparrigopoulos T, Liappas J, Mantouvalos V, Typaldou R, Christodoulou G. Mood disorder with mixed features due to vitamin B(12) and folate deficiency. Gen Hosp Psychiatry. 2002; 24:106-9.
61. Saracaceanu E, Tramoni AV, Henry JM. An association between subcortical dementia and pernicious anemia–a psychiatric mask. Compr Psychiatry. 1997;38:349-51.
62. Storch A, Jost WH, Vieregge P, Spiegel J, Greulich W, Durner J, et al. Randomized, double-blind, placebo-controlled trial on symptomatic effects of coenzyme Q(10) in Parkinson disease. Arch Neurol. 2007;64:938-44.
63. Dommisse J. Subtle vitamin-B12 deficiency and psychiatry: a largely unnoticed but devastating relationship? Med Hypotheses. 1991; 34:131-40.
64. Goggans FC. A case of mania secondary to vitamin B12 deficiency. Am J Psychiatry. 1984;141:300-1.
65. Dhitavat S, Ortiz D, Rogers E, Rivera E, Shea TB. Folate, vitamin E, and acetyl-L-carnitine provide synergistic protection against oxidative stress resulting from exposure of human neuroblastoma cells to amyloid-beta. Brain Res. 2005;1061:114-7.
66. Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 1979;134:382-9.
67. Hamilton M. Development of a rating scale for primary depressive illness. Br J Soc Clin Psychol. 1967;6:278-96.
68. Berk M, Dodd S, Dean OM, Kohlmann K, Berk L, Malhi GS. The validity and internal structure of the Bipolar Depression Rating Scale: data from a clinical trial of N-acetylcysteine as adjunctive therapy in bipolar disorder. Acta Neuropsychiatrica. 2010;22:237-42.
69. Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry. 1978;133: 429-35.
70. Spearing MK, Post RM, Leverich GS, Brandt D, Nolen W. Modification of the Clinical Global Impressions (CGI) Scale for use in bipolar illness (BP): the CGI-BP. Psychiatry Res. 1997;73:159-71.
71. Morosini PL, Magliano L, Brambilla L, Ugolini S, Pioli R. Development, reliability and acceptability of a new version of the DSM-IV Social and Occupational Functioning Assessment Scale (SOFAS) to assess routine social functioning. Acta Psychiatr Scand. 2000;101:323-9.
72. Keller MB, Lavori PW, Friedman B, Nielsen E, Endicott J, McDonald- Scott P, et al. The Longitudinal Interval Follow-up Evaluation. A comprehensive method for assessing outcome in prospective longitudinal studies. Arch Gen Psychiatry. 1987;44:540-8.
73. Endicott J, Nee J, Harrison W, Blumenthal R. Quality of Life Enjoyment and Satisfaction Questionnaire: a new measure. Psychopharmacol Bull. 1993;29:321-6.
74. Moran P, Leese M, Lee T, Walters P, Thornicroft G, Mann A. Standardised Assessment of Personality - Abbreviated Scale (SAPAS): preliminary validation of a brief screen for personality disorder. Br J Psychiatry. 2003;183:228-32.
75. Berk M, Munib A, Dean O, Malhi GS, Kohlmann K, Schapkaitz I, et al. Qualitative methods in early-phase drug trials: broadening the scope of data and methods from an RCT of N-acetylcysteine in schizophrenia. J Clin Psychiatry. 2011;72:909-13.
76. Berk M, Kapczinski F, Andreazza AC, Dean OM, Giorlando F, Maes M, et al. Pathways underlying neuroprogression in bipolar disorder: focus on inflammation, oxidative stress and neurotrophic factors. Neurosci Biobehav Rev. 2011;35:804-17.