Mitochondrial modulators for bipolar disorder: A pathophysiologically informed paradigm for new drug development

Australian and New Zealand Journal of Psychiatry

Volumn 47, Issue 1, 2013, Pages 26-42

  Nierenberg, Andrew A ^a   Kansky, Christine ^a   Brennan, Brian P ^a   Shelton, Richard C ^a   Perlis, Roy ^a   Iosifescu, Dan V ^a  

^a MASSACHUSETTS GENERAL HOSPITAL   (United States)

Author keywords

Bipolar disorder; mitochondria; modulators

Indexed keywords

ACETYL CARNITINE; ACETYLCYSTEINE; ADENOSINE TRIPHOSPHATE; ANTIDEPRESSANT AGENT; BRAIN DERIVED NEUROTROPHIC FACTOR; CLOMIPRAMINE; CREATINE; GLUTATHIONE; IMIPRAMINE; LITHIUM; MAPROTILINE; MELATONIN; MIANSERIN; MINAPRINE; MITOCHONDRIAL DNA; MITOCHONDRIAL MODULATOR; NICOTINAMIDE ADENINE DINUCLEOTIDE; NOMIFENSINE; PHENELZINE; PLACEBO; PROTEIN BCL 2; PSYCHOTROPIC AGENT; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE; S ADENOSYLMETHIONINE; SEROTONIN UPTAKE INHIBITOR; THIOCTIC ACID; UBIDECARENONE; UNCLASSIFIED DRUG; VALPROIC ACID; VENLAFAXINE;

ATTENTION DEFICIT DISORDER; BIPOLAR DISORDER; BRAIN METABOLISM; CEREBELLAR ATAXIA; DEMENTIA; DEPRESSION; DISORDERS OF MITOCHONDRIAL FUNCTIONS; DRUG POTENTIATION; DYSTHYMIA; ENERGY METABOLISM; GERIATRIC DISORDER; GLYCOLYSIS; HEPATIC ENCEPHALOPATHY; HUMAN; LIPID PEROXIDATION; MAJOR DEPRESSION; MIGRAINE; NEUROPROTECTION; OXIDATIVE STRESS; PSYCHOPHARMACOTHERAPY; REVIEW; SCHIZOPHRENIA; SYMPTOM; UNSPECIFIED SIDE EFFECT;

BIPOLAR DISORDER; BRAIN; DOWN-REGULATION; FREE RADICAL SCAVENGERS; GENES, MITOCHONDRIAL; GLYCOLYSIS; HUMANS; MITOCHONDRIA; NEUROPROTECTIVE AGENTS; NOOTROPIC AGENTS; OXIDATIVE PHOSPHORYLATION; OXIDATIVE STRESS; UP-REGULATION;

EID: 84873888319     PISSN: 00048674     EISSN: 14401614     Source Type: Journal    
DOI: 10.1177/0004867412449303     Document Type: Review

References (207)

1. Acuna-Castroviejo D, Escames G, Leon J, et al. Mitochondrial regulation by melatonin and its metabolites. Advances in Experimental Medicine and Biology. 2003 ; 527: 549-557
2. Acuna-Castroviejo D, Escames G, Lopez LC, et al. Melatonin and nitric oxide: Two required antagonists for mitochondrial homeostasis. Endocrine. 2005 ; 27: 159-168
3. Acuna-Castroviejo D, Escames G, Rodriguez MI, et al. Melatonin role in the mitochondrial function. Frontiers in Bioscience. 2007 ; 12: 947-963
4. Acuna-Castroviejo D, Martin M, Macias M, et al. Melatonin, mitochondria, and cellular bioenergetics. Journal of Pineal Research. 2001 ; 30: 65-74
5. Albarran MT, Lopez-Burillo S, Pablos MI, et al. Endogenous rhythms of melatonin, total antioxidant status and superoxide dismutase activity in several tissues of chick and their inhibition by light. Journal of Pineal Research. 2001 ; 30: 227-233
6. Aliev G, Liu J, Shenk JC, et al. Neuronal mitochondrial amelioration by feeding acetyl-L-carnitine and lipoic acid to aged rats. Journal of Cellular and Molecular Medicine. 2009 ; 13: 320-333
7. Al-Majed AA, Sayed-Ahmed MM, Al-Omar FA, et al. Carnitine esters prevent oxidative stress damage and energy depletion following transient forbrain ischaemia in the rat hippocampus. Clinical and Experimental Pharmacology and Physiology. 2006 ; 33: 725-733
8. Alpert JE, Papakostas G, Mischoulon D, et al. S-adenosyl-L-methionine (SAMe) as an adjunct for resistant major depressive disorder - An open trial following partial or nonresponse to selective serotonin reuptake inhibitors or venlafaxine. Journal of Clinical Psychopharmacology. 2004 ; 24: 661-664
9. Alvarez E, Udina C, Guillamat R. Shortening of latency period in depressed patients treated with SAMe and other antidepressant drugs. Cellular Biological Review. 1987 ; S1: 103-110
10. Ames A. CNS energy metabolism as related to function. Brain Research. Brain Research Reviews. 2000 ; 34: 42-68
11. Ames BN, Liu J. Delaying the mitochondrial decay of aging with acetylcarnitine. Annals of the New York Academy of Sciences. 2004 ; 1033: 108-116
12. Ametov AS, Barinov A, Dyck PJ, et al. The sensory symptoms of diabetic polyneuropathy are improved with alpha-lipoic acid: The SYDNEY trial. Diabetes Care. 2003 ; 26: 770-776
13. Amital D, Vishne T, Roitman S, et al. Open study of creatine monohydrate in treatment-resistant posttraumatic stress disorder. Journal of Clinical Psychiatry. 2006a ; 67: 836-837
14. Amital D, Vishne T, Rubinow A, et al. Observed effects of creatine monohydrate in a patient with depression and fibromyalgia. American Journal of Psychiatry. 2006b ; 163: 1840-1841
15. Andreassen OA, Dedeoglu A, Ferrante RJ, et al. Creatine increase survival and delays motor symptoms in a transgenic animal model of Huntington's disease. Neurobiology of Disease. 2001 ; 8: 479-491
16. A randomized, double-blind, placebo-controlled trial of deprenyl and thioctic acid in human immunodeficiency virus-associated cognitive impairment. Dana Consortium on the Therapy of HIV Dementia and Related Cognitive Disorders. Neurology. 1998 ; 50: 645-651
17. Arnold LE, Amato A, Bozzolo H, et al. Acetyl-L-carnitine (ALC) in attention-deficit/hyperactivity disorder: A multi-site, placebo-controlled pilot trial. Journal of Child and Adolescent Psychopharmacology. 2007 ; 17: 791-802
18. Atkuri KR, Mantovani JJ, Herzenberg LA, et al. N-Acetylcysteine - A safe antidote for cysteine/glutathione deficiency. Current Opinion in Pharmacology. 2007 ; 7: 355-359
19. Aureli T, Miccheli A, Ricciolini R, et al. Aging brain: Effect of acetyl-L-carnitine treatment on rat brain energy and phospholipid metabolism. A study by 31P and 1H NMR spectroscopy. Brain Research. 1990 ; 526: 108-112
20. Barbiroli B, Montagna P, Martinelli P, et al. Defective brain energy metabolism shown by in vivo 31P MR spectroscopy in 28 patients with mitochondrial cytopathies. Journal of Cerebral Blood Flow and Metabolism. 1993 ; 13: 469-474
21. Bella R, Biondi R, Raffaele R, et al. Effect of acetyl-L-carnitine on geriatric patients suffering from dysthymic disorders. International Journal of Clinical Pharmacology Research. 1990 ; 10: 355-360
22. Bender A, Koch W, Elstner M, et al. Creatine supplementation in Parkinson disease: A placebo-controlled randomized pilot trial. Neurology. 2006 ; 67: 1262-1264
23. Benes FM, Matzilevich D, Burke RE, et al. The expression of proapoptosis genes is increased in bipolar disorder, but not in schizophrenia. Molecular Psychiatry. 2006 ; 11: 241-251
24. Berk M, Copolov D, Dean O, et al. N-Acetyl cysteine as a glutathione precursor for schizophrenia - A double-blind, randomized, placebo-controlled trial. Biological Psychiatry. 2008a ; 64: 361-368
25. Berk M, Copolov DL, Dean O, et al. N-Acetyl cysteine for depressive symptoms in bipolar disorder - A double-blind randomized placebo-controlled trial. Biological Psychiatry. 2008b ; 64: 468-475
26. Berlanga C, Ortegasoto HA, Ontiveros M, et al. Efficacy of. S Psychiatry Research. 1992 ; 44: 257-262
27. Bernardi P, Colonna R, Costantini P, et al. The mitochondrial permeability transition. Biofactors. 1998 ; 8: 273-281
28. Bersani G, Garavini A. Melatonin add-on in manic patients with treatment resistant insomnia. Progress in Neuro-Psychopharmacology & Biological Psychiatry. 2000 ; 24: 185-191
29. Bertolino A, Frye M, Callicott JH, et al. Neuronal pathology in the hippocampal area of patients with bipolar disorder: A study with proton magnetic resonance spectroscopic imaging. Biological Psychiatry. 2003 ; 53: 906-913
30. Bonavita E. Study of the efficacy and tolerability of L-acetylcarnitine therapy in the senile brain. International Journal of Clinical Pharmacology, Therapy, and Toxicology. 1986 ; 24: 511-516
31. Bottiglieri T. Folate, vitamin B-12, and neuropsychiatric disorders. Nutrition Reviews. 1996 ; 54: 382-390
32. Bottiglieri T, Laundy M, Crellin R, et al. Homocysteine, folate, methylation, and monoamine metabolism in depression. Journal of Neurology Neurosurgery and Psychiatry. 2000 ; 69: 228-232
33. Calabrese JR, Guelfi JD, Perdrizet-Chevallier C. Agomelatine adjunctive therapy for acute bipolar depression: Preliminary open data. Bipolar Disorders. 2007 ; 9: 628-635
34. Cardinali DP, Brusco LI, Liberczuk C, et al. The use of melatonin in Alzheimer's disease. Neuro Endocrinology Letters. 2002 ; 23: 20-23
35. Carman JS, Post RM, Buswell R, et al. Negative effects of melatonin on depression. American Journal of Psychiatry. 1976 ; 133: 1181-1186
36. Carney MW, Chary TK, Bottiglieri T, et al. The switch mechanism and the bipolar/unipolar dichotomy. British Journal of Psychiatry. 1989 ; 154: 48-51
37. Cataldo AM, McPhie DL, Lange NT, et al. Abnormalities in mitochondrial structure in cells from patients with bipolar disorder. American Journal of Pathology. 2010 ; 177: 575-585
38. Chang YYC, Rapoport SI, Rao JS. Chronic administration of mood stabilizers upregulates BDNF and Bcl-2 expression levels in rat frontal cortex. Neurochemical Research. 2009 ; 34: 536-541
39. Chen G, Zeng WZ, Yuan PX, et al. The mood-stabilizing agents lithium and valproate robustly increase the levels of the neuroprotective protein bcl-2 in the CNS. Journal of Neurochemistry. 1999 ; 72: 879-882
40. Clark J. N-Acetyl aspartate: A marker for neuronal loss or mitochondrial dysfunction. Developmental Neuroscience. 1998 ; 20: 271-276
41. Clay HB, Sillivan S, Konradi C. Mitochondrial dysfunction and pathology in bipolar disorder and schizophrenia. International Journal of Developmental Neuroscience. 2011 ; 29: 311-324
42. Cui J, Shao L, Young LT, et al. Role of glutathione in neuroprotective effects of mood stabilizing drugs lithium and valproate. Neuroscience. 2007 ; 144: 1447-1453
43. Cui X, Zuo P, Zhang Q, et al. Chronic systemic d-galactose exposure induces memory loss, neurodegeneration, and oxidative damage in mice: Protective effects of R-a-lipoic acid. Journal of Neuroscience Research. 2006 ; 83: 1584-1590
44. Culmsee C, Mattson M. p53 in neuronal apoptosis. Biochemical and Biophysical Research Communications. 2005 ; 331: 761-777
45. Dager SR, Friedman SD, Parow A, et al. Brain metabolic alterations in medication-free patients with bipolar disorder. Archives of General Psychiatry. 2004 ; 61: 450-458
46. Dechent P, Pouwels PJ, Wilken B, et al. Increase of total creatine in human brain after oral supplementation of creatine-monohydrate. American Journal of Physiology. 1999 ; 277: R698 - R704
47. De Grandis D, Minardi C. Acetyl-L-carnitine (levacecarnine) in the treatment of diabetic neuropathy. A long-term, randomised, double-blind, placebo-controlled study. Drugs in R & D. 2002 ; 3: 223-231
48. Deicken R, Pegues M, Anzalone S, et al. Lower concentration of hippocampal. N American Journal of Psychiatry. 2003 ; 160: 873-882
49. Eleff S, Barker P, Blackband S, et al. Phosphorus magnetic resonance spectroscopy of patients with mitochondrial cytopathies demonstrates decreased levels of brain phosphocreatine. Annals of Neurology. 1990 ; 27: 626-630
50. Elmslie JL, Porter RJ, Joyce PR, et al. Carnitine does not improve weight loss outcomes in valproate-treated bipolar patients consuming an energy-restricted, low-fat diet. Bipolar Disorders. 2006 ; 8: 503-507
51. Erecinska M, Silver IA. ATP and brain function. Journal of Cerebral Blood Flow and Metabolism. 1989 ; 9: 2-19
52. Estrada DE, Ewart HS, Tsakiridis T, et al. Stimulation of glucose uptake by the natural coenzyme alpha-lipoic acid/thioctic acid: Participation of elements of the insulin signaling pathway. Diabetes. 1996 ; 45: 1798-1804
53. Feigin A, Kieburtz K, Como P, et al. Assessment of coenzyme Q10 tolerability in Huntington's disease. Movement Disorders. 1996 ; 11: 321-323
54. Femiano F, Scully C. Burning mouth syndrome (BMS): Double blind controlled study of alpha-lipoic acid (thioctic acid) therapy. Journal of Oral Pathology & Medicine. 2002 ; 31: 267-269
55. Ferreira MAR, O'Donovan MC, Meng YA, et al. Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder. Nature Genetics. 2008 ; 40: 1056-1058
56. Frey BN, Stanley JA, Nery FG, et al. Abnormal cellular energy and phospholipid metabolism in the left dorsolateral prefrontal cortex of medication-free individuals with bipolar disorder: An in vivo 1H MRS study. Bipolar Disorders. 2007a ; 9: 119-127
57. Frey BN, Walss-Bass C, Stanley JA, et al. Brain-derived neurotrophic factor val66met polymorphism affects prefrontal energy metabolism in bipolar disorder. Neuroreport. 2007b ; 18: 1567-1570
58. Fulgente T, Onofrj M, Del Re ML, et al. Laevo-acetylcarnitine (Nicetile) treatment of senile depression. Clinical Trials Journal. 1990 ; 27: 155-163
59. Garcia JJ, Reiter RJ, Guerrero JM, et al. Melatonin prevents changes in microsomal membrane fluidity during induced lipid peroxidation. FEBS Letters. 1997 ; 408: 297-300
60. Garzya G, Corallo D, Fiore A, et al. Evaluation of the effects of L-acetylcarnitine on senile patients suffering from depression. Drugs Under Experimental and Clinical Research. 1990 ; 16: 101-106
61. Gecele M, Francesetti G, Meluzzi A. Acetyl-L-carnitine in aged subjects with major depression: Clinical efficacy and effects on the circadian rhythym of cortisol. Dementia. 1991 ; 2: 333-337
62. Ghaemi SN, Hsu DJ, Thase ME, et al. Pharmacological treatment patterns at study entry for the first 500 STEP-BD participants. Psychiatric Services. 2006 ; 57: 660-665
63. Grant JE, Kim SW, Odlaug BL. N-Acetyl cysteine, a glutamate-modulating agent, in the treatment of pathological gambling: A pilot study. Biological Psychiatry. 2007 ; 62: 652-657
64. Groeneveld GJ, Veldink JH, van der Tweel I, et al. A randomized sequential trial of creatine in amyotrophic lateral sclerosis. Annals of Neurology. 2003 ; 53: 437-445
65. Hagen T, Liu J, Lykkesfeldt J, et al. Feeding acetyl-L-carnitine and lipoic acid to old rats significantly improves metabolic function while decreasing oxidative stress. Proceedings of the National Academy of Sciences of the United States of America. 2002a ; 99: 1870-1875
66. Hagen TM, Ingersoll RT, Lykkesfeldt J, et al. (R)-Alpha-lipoic acid-supplemented old rats have improved mitochondrial function, decreased oxidative damage, and increased metabolic rate. FASEB Journal. 1999 ; 13: 411-418
67. Hagen TM, Moreau R, Suh JH, et al. Mitochondrial decay in the aging rat heart. Annals of the New York Academy of Sciences. 2002b ; 959: 491-507
68. Hager K, Kenklies M, McAfoose J, et al. Alpha-lipoic acid as a new treatment option for Alzheimer's disease - A 48 months follow-up analysis. Journal of Neural Transmission. 2007 ;: 189-193
69. Hahm JR, Kim BJ, Kim KW. Clinical experience with thioctacid (thioctic acid) in the treatment of distal symmetric polyneuropathy in Korean diabetic patients. Journal of Diabetes and its Complications. 2004 ; 18: 79-85
70. Hamakawa H, Kato T, Murashita J, et al. Quantitative proton magnetic resonance spectroscopy of the basal ganglia in patients with affective disorders. European Archives of Psychiatry and Clinical Neuroscience. 1998 ; 248: 53-58
71. Hamakawa H, Murashita J, Yamada N, et al. Reduced intracellular pH in the basal ganglia and whole brain measured by P-MRS in bipolar disorder. Psychiatry Clinical Neuroscience. 2004 ; 58: 53-59
72. Hao Y, Basile AS, Chen G, et al. Glutamate-induced over-expression of GAD is down-regulated by acetyl-L-carnitine in rat islet cells. Endocrine Research. 2004 ; 30: 107-116
73. Hart AM, Wilson AD, Montovani C, et al. Acetyl-L-carnitine: A pathogenesis based treatment for HIV-associated antiretroviral toxic neuropathy. AIDS. 2004 ; 18: 1549-1560
74. Hershey AD, Powers SW, Vockell ALB, et al. Coenzyme Q10 deficiency and response to supplementation in pediatric and adolescent migraine. Headache. 2007 ; 47: 73-80
75. Hidaka T, Fujii K, Funahashi I, et al. Safety assessment of coenzyme Q-10 (CoQ-10). Biofactors. 2008 ; 32: 199-208
76. Hoppel C. The role of carnitine in normal and altered fatty acid metabolism. American Journal of Kidney Diseases. 2003 ; 41: S4 - S12
77. Jacob S, Ruus P, Hermann R, et al. Oral administration of RAC-alpha-lipoic acid modulates insulin sensitivity in patients with type-2 diabetes mellitus: A placebo-controlled pilot trial. Journal of Free Radicals in Biology & Medicine. 1999 ; 27: 309-314
78. Judd LL, Schettler PJ, Akiskal HS, et al. Residual symptom recovery from major affective episodes in bipolar disorders and rapid episode relapse/recurrence. Archives of General Psychiatry. 2008 ; 65: 386-394
79. Juhn MS, Tarnopolsky M. Oral creatine supplementation and athletic performance: A critical review. Clinical Journal of Sport Medicine. 1998 ; 8: 286-297
80. Kapczinski F, Vieta E, Andreazza AC, et al. Allostatic load in bipolar disorder: Implications for pathophysiology and treatment. Neuroscience and Biobehavioral Reviews. 2008 ; 32: 675-692
81. Kaptsan A, Odessky A, Osher Y, et al. Lack of efficacy of 5 grams daily of creatine in schizophrenia: A randomized, double-blind, placebo-controlled trial. Journal of Clinical Psychiatry. 2007 ; 68: 881-884
82. Kato T. Role of mitochondrial DNA in calcium signaling abnormality in bipolar disorder. Cell Calcium. 2008 ; 44: 92-102
83. Kato T, Murashita J, Kamiya A, et al. Decreased brain intracellular pH measured by P-31-MRS in bipolar disorder: A confirmation in drug-free patients and correlation with white matter hyperintensity. European Archives of Psychiatry and Clinical Neuroscience. 1998 ; 248: 301-306
84. Kato T, Shioiri T, Murashita J, et al. Lateralized abnormality of high energy phosphate metabolism in the frontal lobes of patients with bipolar disorder detected by phase-encoded 31P-MRS. Psychological Medicine. 1995 ; 25: 557-566
85. Kato T, Takahashi S, Shioiri T, et al. Reduction of brain phosphocreatine in bipolar II disorder detected by phosphorus-31 magnetic resonance spectroscopy. Journal of Affective Disorders. 1994 ; 31: 125-133
86. Kazuno A, Munakata K, Kato N, et al. Mitochondrial DNA-dependent effects of valproate on mitochondrial calcium levels in transmitochondrial cybrids. International Journal of Neuropsychopharmacology. 2008 ; 11: 71-78
87. Klivenyi P, Ferrante RJ, Matthews RT, et al. Neuroprotective effects of creatine in a transgenic animal model of amyotrophic lateral sclerosis. Nature Medicine. 1999 ; 5: 347-350
88. Konradi C, Eaton M, MacDonald ML, et al. Molecular evidence for mitochondrial dysfunction in bipolar disorder. Archives of General Psychiatry. 2004 ; 61: 301-308
89. Korkmaz A, Reiter RJ, Topal T, et al. Melatonin: An established antioxidant worthy of use in clinical trials. Molecular Medicine. 2009 ; 15: 43-50
90. Kwong LK, Kamzalov S, Rebrin I, et al. Effects of coenzyme Q10 administration on its tissue concentrations, mitochondrial oxidant generation, and oxidative stress in the rat. Free Radical Biology and Medicine. 2002 ; 33: 627-638
91. Lafer B, Renshaw PF, Sachs G, et al. Proton MRS of the basal ganglia in bipolar disorder. Biological Psychiatry. 1994 ; 35: 685
92. Lahiri DK, Chen D, Ge YW, et al. Dietary supplementation with melatonin reduces levels of amyloid beta-peptides in the murine cerebral cortex. Journal of Pineal Research. 2004 ; 36: 224-231
93. Lawler JM, Barnes WS, Wu G, et al. Direct antioxidant properties of creatine. Biochemical and Biophysical Research Communications. 2002 ; 290: 47-52
94. Leibenluft E, Feldman-Naim S, Turner EH, et al. Effects of exogenous melatonin administration and withdrawal in five patients with rapid-cycling bipolar disorder. Journal of Clinical Psychiatry. 1997 ; 58: 383-388
95. Leon J, Acuña-Castroviejo D, Escames G, et al. Melatonin mitigates mitochondrial malfunction. Journal of Pineal Research. 2005 ; 38: 1-9
96. Leon J, Acuña-Castroviejo D, Sainz RM, et al. Melatonin and mitochondrial function. Life Sciences. 2004 ; 75: 765-790
97. Leppamaki S, Partonen T, Vakkuri O, et al. Effect of controlled-release melatonin on sleep quality, mood, and quality of life in subjects with seasonal or weather-associated changes in mood and behaviour. European Neuropsychopharmacology. 2003 ; 13: 137-145
98. Lewy AJ, Bauer VK, Cutler NL, et al. Melatonin treatment of winter depression: A pilot study. Psychiatry Research. 1998 ; 77: 57-61
99. Lipinski JF, Cohen BM, Frankenburg F, et al. Open trial of S-adenosylmethionine for treatment of depression. American Journal of Psychiatry. 1984 ; 141: 448-450
100. Liu J. The effects and mechanisms of mitochondrial nutrient alpha-lipoic acid on improving age-associated mitochondrial and cognitive dysfunction: An overview. Neurochemical Research. 2008 ; 33: 194-203
101. Liu J, Atamna H, Kuratsune H, et al. Delaying brain mitochondrial decay and aging with mitochondrial antioxidants and metabolites. Annals of the New York Academy of Sciences. 2002a ; 959: 133-166
102. Liu J, Head E, Gharib AM, et al. Memory loss in old rats is associated with brain mitochondrial decay and RNA/DNA oxidation: Partial reversal by feeding acetyl-L-carnitine and/or R-alpha-lipoic acid. Proceedings of the National Academy of Sciences of the United States of America. 2002b ; 99: 2356-2361
103. Lopez-Burillo S, Tan DX, Mayo JC, et al. Melatonin, xanthurenic acid, resveratrol, EGCG, vitamin C and alpha-lipoic acid differentially reduce oxidative DNA damage induced by Fenton reagents: A study of their individual and synergistic actions. Journal of Pineal Research. 2003 ; 34: 269-277
104. Lyoo IK, Kong SW, Sung SM, et al. Multinuclear magnetic resonance spectroscopy of high-energy phosphate metabolites in human brain following oral supplementation of creatine-monohydrate. Psychiatry Research. 2003 ; 123: 87-100
105. Magis D, Ambrosini A, Sandor P, et al. A randomized double-blind placebo-controlled trial of thioctic acid in migraine prophylaxis. Headache. 2007 ; 47: 52-57
106. Malaguarnera M, Gargante MP, Cristaldi E, et al. Acetyl-L-carnitine treatment in minimal hepatic encephalopathy. Digestive Diseases and Sciences. 2008 ; 53: 3018-3025
107. Malaguarnera M, Pistone G, Astuto M, et al. Effects of L-acetylcarnitine on cirrhotic patients with hepatic coma: Randomized double-blind, placebo-controlled trial. Digestive Diseases and Sciences. 2006 ; 51: 2242-2247
108. Manji H, Moore G, Chen G. Clinical and preclinical evidence for the neurotrophic effects of mood stabilizers: Implications for the pathophysiology and treatment of manic-depressive illness. Biological Psychiatry. 2000 ; 48: 740-754
109. Marshall AW, Graul RS, Morgan MY, et al. Treatment of alcohol-related liver disease with thioctic acid: A six month randomised double-blind trial. Gut. 1982 ; 23: 1088-1093
110. Mathew SJ, Manji HK, Charney DS. Novel drugs and therapeutic targets for severe mood disorders. Neuropsychopharmacology. 2008 ; 33: 2080-2092
111. Mattson M, Liu D. Mitochondrial potassium channels and uncoupling proteins in synaptic plasticity and neuronal cell death. Biochemical and Biophysical Research Communications. 2003 ; 304: 539-549
112. Mayer M, Noble M. N-acetyl-L-cysteine is a pluripotent protector against cell death and enhancer of trophic factor-mediated cell survival in vitro. Proceedings of the National Academy of Sciences of the United States of America. 1994 ; 91: 7496-7500
113. Merikangas KR, Akiskal HS, Angst J, et al. Lifetime and 12-month prevalence of bipolar spectrum disorder in the National Comorbidity Survey replication. Archives of General Psychiatry. 2007 ; 64: 543-552
114. Modica-Napolitano J, Renshaw PF. Ethanolamine and phosphoethanolamine inhibit mitochondrial function in vitro: Implications for mitochondrial dysfunction hypothesis in depression and bipolar disorder. Biological Psychiatry. 2004 ; 55: 273-277
115. Moore CM, Breeze JL, Gruber SA, et al. Choline, myo-inositol and mood in bipolar disorder: A proton magnetic resonance spectroscopic imaging study of the anterior cingulate cortex. Bipolar Disorders. 2000 ; 2: 207-216
116. Müller D, de Luca V, Sicard T, et al. Brain-derived neurotrophic factor (BDNF) gene and rapid-cycling bipolar disorder: Family-based association study. British Journal of Psychiatry. 2006 ; 189: 317-323
117. Munakata K, Fujii K, Nanko S, et al. Sequence and functional analyses of mtDNA in a maternally inherited family with bipolar disorder and depression. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis. 2007 ; 617: 119-124
118. Munakata K, Tanaka M, Mori K, et al. Mitochondrial DNA 3644T→C mutation associated with bipolar disorder. Genomics. 2004 ; 84: 1041-1050
119. Murphy A, Bredesen D, Cortopassi G, et al. Bcl-2 potentiates the maximal calcium uptake capacity of neural cell mitochondria. Proceedings of the National Academy of Sciences of the United States of America. 1996 ; 93: 9893-9898
120. Nasca D, Zurria G, Aguglia E. Action of acetyl-L-carnitine in association with mianserine on depressed old people. New Trends in Clinical Neuropharmacology. 1989 ; 3: 225-230
121. Naydenov AV, MacDonald ML, Ongur D, et al. Differences in lymphocyte electron transport gene expression levels between subjects with bipolar disorder and normal controls in response to glucose deprivation stress. Archives in General Psychiatry. 2007 ; 64: 555-564
122. Negrişanu G, Roşu M, Bolte B, et al. Effects of 3-month treatment with the antioxidant alpha-lipoic acid in diabetic peripheral neuropathy. Romanian Journal of Internal Medicine. 1999 ; 37: 297-306
123. Ng F, Berk M, Dean O, et al. Oxidative stress in psychiatric disorders: Evidence base and therapeutic implications. International Journal Neuropsychopharmacology. 2008 ; 11: 851-876
124. Nicholls D, Ward M. Mitochondrial membrane potential and neuronal glutamate excitotoxicity: Mortality and millivolts. Trends in Neuroscience. 2000 ; 23: 166-174
125. Nicoletti VG, Marino VM, Cuppari C, et al. Effect of antioxidant diets and mitochondrial gene expression in rat brain during aging. Neurochemical Research. 2005 ; 30: 737-752
126. A randomized, double-blind, futility clinical trial of creatine and minocycline in early Parkinson disease. Neurology. 2006 ; 66: 664-671
127. Packer L, Witt EH, Tritschler HJ. alpha-Lipoic acid as a biological antioxidant. Free Radical Biology & Medicine. 1995 ; 19: 227-250
128. Papakostas GI, Mischoulon D, Shyu I, et al. S-adenosyl methionine (SAMe) augmentation of serotonin reuptake inhibitors for antidepressant nonresponders with major depressive disorder: A double-blind, randomized clinical trial. American Journal of Psychiatry. 2010 ; 167: 942-948
129. Pappolla M, Bozner P, Soto C, et al. Inhibition of Alzheimer beta-fibrillogenesis by melatonin. Journal of Biological Chemistry. 1998 ; 273: 7185-7188
130. Passeri M, Cucinotta D, Bonati PA, et al. Acetyl-L-carnitine in the treatment of mildly demented elderly patients. International Journal of Clinical Pharmacology Research. 1990 ; 10: 75-79
131. Patel T, Clark J. Synthesis of N-acetyl-L-aspartate by rat brain mitochondria and its involvement in mitochondrial/ cytosolic carbon transport. Biochemical Journal. 1979 ; 184: 539-546
132. Perlis RH, Ostacher MJ, Patel JK, et al. Predictors of recurrence in bipolar disorder: Primary outcomes from the systematic treatment enhancement program for bipolar disorder (STEP-BD). American Journal of Psychiatry. 2006 ; 163: 217-224
133. Peters A, Schweiger U, Pellerin L, et al. The selfish brain: Competition for energy resources. Neuroscience and Biobehavioral Reviews. 2004 ; 28: 143-180
134. Pettegrew JW, Klunk WE, Panchalingam K, et al. Clinical and neurochemical effects of acetyl-L-carnitine in Alzheimer's disease. Neurobiology of Aging. 1995 ; 16: 1-4
135. Pettegrew JW, Levine J, Gershon S, et al. 31P-MRS study of acetyl-L-carnitine treatment in geriatric depression: Preliminary results. Bipolar Disorders. 2002 ; 4: 61-66
136. Purdon AD, Rapoport SI. Energy requirements for two aspects of phospholipid metabolism in mammalian brain. Biochemical Journal. 1998 ; 335: 313-318
137. Quiroz JA, Gray NA, Kato T, et al. Mitochondrially mediated plasticity in the pathophysiology and treatment of bipolar disorder. Neuropsychopharmacology. 2008 ; 33: 2551-2565
138. Rebouche CJ. Kinetics, pharmacokinetics, and regulation of L-carnitine and acetyl-L-carnitine metabolism. Annals of the New York Academy of Sciences. 2004 ; 1033: 30-41
139. Reiter RJ, Cabrera J, Sainz RM, et al. Melatonin as a pharmacological agent against neuronal loss in experimental models of Huntington's disease, Alzheimer's disease and parkinsonism. Annals of the New York Academy of Sciences. 1999 ; 890: 471-485
140. Reiter RJ, Tan DX, Allegra M. Melatonin: Reducing molecular pathology and dysfunction due to free radicals and associated reactants. Neuro Endocrinology Letters. 2002a ; 23: 3-8
141. Reiter RJ, Tan DX, Burkhardt S. Reactive oxygen and nitrogen species and cellular and organismal decline: Amelioration with melatonin. Mechanisms of Ageing and Development. 2002b ; 123: 1007-1019
142. Reiter RJ, Tan DX, Manchester LC, et al. Melatonin: Detoxification of oxygen and nitrogen-based toxic reactants. Advances in Experimental Medicine and Biology. 2003 ; 527: 539-548
143. Reljanovic M, Reichel G, Rett K, et al. Treatment of diabetic polyneuropathy with the antioxidant thioctic acid (alpha-lipoic acid): A two year multicenter randomized double-blind placebo-controlled trial (ALADIN II). Alpha Lipoic Acid in Diabetic Neuropathy. Free Radical Research. 1999 ; 31: 171-179
144. Richer C, Park J-W, Ames BN. Normal oxidative damage to mitochondrial and nuclear DNA is extensive. Proceedings of the National Academy of Sciences of the United States of America. 1988 ; 85: 6465-6467
145. Rodriguez C, Mayo JC, Sainz RM, et al. Regulation of antioxidant enzymes: A significant role for melatonin. Journal of Pineal Research. 2004 ; 36: 1-9
146. Rodriguez MC, MacDonald JR, Mahoney DJ, et al. Beneficial effects of creatine, CoQ10, and lipoic acid in mitochondrial disorders. Muscle & Nerve. 2007 ; 35: 235-242
147. Roitman S, Green T, Osher Y, et al. Creatine monohydrate in resistant depression: A preliminary study. Bipolar Disorders. 2007 ; 9: 754-758
148. Rosenfeld J, King RM, Jackson CE, et al. Creatine monohydrate in ALS: Effects on strength, fatigue, respiratory status and ALSFRS. Amyotrophic Lateral Sclerosis. 2008 ; 9: 266-272
149. Rosenfeldt FL, Haas SJ, Krum H, et al. Coenzyme Q(10) in the treatment of hypertension: A meta-analysis of the clinical trials. Journal of Human Hypertension. 2007 ; 21: 297-306
150. Rothman DL NMR in Physiology and Biomedicine. Gilles RJ, ed. San Diego, CA: Academic Press ; 1994: 353-372.
151. Rudich A, Tirosh A, Potashnik R, et al. Lipoic acid protects against oxidative stress induced impairment in insulin stimulation of protein kinase B and glucose transport in 3T3-L1 adipocytes. Diabetologia. 1999 ; 42: 949-957
152. Ruhnau KJ, Meissner HP, Finn JR, et al. Effects of 3-week oral treatment with the antioxidant thioctic acid (alpha-lipoic acid) in symptomatic diabetic polyneuropathy. Diabetic Medicine. 1999 ; 16: 1040-1043
153. Salvioli G, Neri M. L-Acetylcarnitine treatment of mental decline in the elderly. Drugs Under Experimental and Clinical Research. 1994 ; 20: 169-176
154. Sandor PS, Di Clemente L, Coppola G, et al. Efficacy of coenzyme Q10 in migraine prophylaxis: A randomized controlled trial. Neurology. 2005 ; 64: 713-715
155. Sano M, Bell K, Cote L, et al. Double-blind parallel design pilot study of acetyl levocarnitine in patients with Alzheimer's disease. Archives of Neurology. 1992 ; 49: 1137-1141
156. Sarris J, Mischoulon D, Schweitzer I. Adjunctive nutraceuticals with standard pharmacotherapies in bipolar disorder: A systematic review of clinical trials. Bipolar Disorders. 2011 ; 13: 454-465
157. Sauter A, Rudin M. Determination of creatine kinase kinetic parameters in rat brain by NMR magnetization transfer. Correlation with brain function. Journal of Biological Chemistry. 1993 ; 268: 13,166-13,171
158. Saxena R, de Bakker PIW, Singer K, et al. Comprehensive association testing of common mitochondrial DNA variation in metabolic disease. American Journal of Human Genetics. 2006 ; 79: 54-61
159. Shao L, Cui J, Young LT, et al. The effect of mood stabilizer lithium on expression and activity of glutathione s-transferase isoenzymes. Neuroscience. 2008a ; 151: 518-524
160. Shao L, Martin MV, Watson SJ, et al. Mitochondrial involvement in psychiatric disorders. Annals of Medicine. 2008b ; 40: 281-295
161. Shea TB. Effects of dietary supplementation with N-acetyl cysteine, acetyl-L-carnitine and S-adenosyl methionine on cognitive performance and aggression in normal mice and mice expressing human ApoE4. Neuromolecular Medicine. 2007 ; 9: 264-269
162. Shults CW, Haas R. Clinical trials of coenzyme Q10 in neurological disorders. Biofactors. 2005 ; 25: 117-126
163. Shults CW, Beal MF, Song D, et al. Pilot trial of high dosages of coenzyme Q(10) in patients with Parkinson's disease. Experimental Neurology. 2004 ; 188: 491-494
164. Shults CW, Haas RH, Passov D, et al. Coenzyme Q10 levels correlate with the activities of complexes I and II/III in mitochondria from parkinsonian and nonparkinsonian subjects. Annals of Neurology. 1997 ; 42: 261-264
165. Shults CW, Oakes D, Kieburtz K, et al. Effects of coenzyme Q10 in early Parkinson disease: Evidence of slowing of the functional decline. Archives of Neurology. 2002 ; 59: 1541-1550
166. Silva M, Aires C, Luis P, et al. Valproic acid metabolism and its effects on mitochondrial fatty acid oxidation: A review. Journal of Inherited Metabolic Disease. 2008 ; 31: 205-216
167. Sima AA, Calvani M, Mehra M, et al. Acetyl-L-carnitine improves pain, nerve regeneration, and vibratory perception in patients with chronic diabetic neuropathy: An analysis of two randomized placebo-controlled trials. Diabetes Care. 2005 ; 28: 89-94
168. Sklar P, Smoller JW, Fan J, et al. Whole-genome association study of bipolar disorder. Molecular Psychiatry. 2008 ; 13: 558-569
169. Soczynska JK, Kennedy SH, Chow CS, et al. Acetyl-L-carnitine and alpha-lipoic acid: Possible neurotherapeutic agents for mood disorders?. Expert Opinion on Investigational Drugs. 2008 ; 17: 827-843
170. Sohmiya M, Tanaka M, Tak NW, et al. Redox status of plasma coenzyme Q10 indicates elevated systemic oxidative stress in Parkinson's disease. Journal of the Neurological Sciences. 2004 ; 223: 161-166
171. Sorbi S, Forleo P, Fani C, et al. Double-blind, crossover, placebo-controlled clinical trial with L-acetylcarnitine in patients with degenerative cerebellar ataxia. Clinical Neuropharmacology. 2000 ; 23: 114-118
172. Spagnoli A, Lucca U, Menasce G, et al. Long-term acetyl-L-carnitine treatment in Alzheimer's disease. Neurology. 1991 ; 41: 1726-1732
173. Storch A, Jost WH, Vieregge P, et al. Randomized, double-blind, placebo-controlled trial on symptomatic effects of coenzyme Q10 in Parkinson disease. Archives of Neurology. 2007 ; 64: 938-944
174. Stork C, Renshaw PF. Mitochondrial dysfunction in bipolar disorder: Evidence from magnetic resonance spectroscopy research. Molecular Psychiatry. 2005 ; 10: 900-919
175. Strijks E, Kremer HPH, Horstink M. Q(10) therapy in patients with idiopathic Parkinson's disease. Molecular Aspects of Medicine. 1997 1997 ; 18: S237 - S240
176. Sullivan PG, Geiger JD, Mattson MP, et al. Dietary supplement creatine protects against traumatic brain injury. Annals of Neurology. 2000 ; 48: 723-729
177. Sun X, Wang J-F, Tseng M, et al. Downregulation in components of the mitochondrial electron transport chain in the postmortem frontal cortex of subjects with bipolar disorder. Journal of Psychiatry & Neuroscience. 2006 ; 31: 189-196
178. Tabrizi SJ, Blamire AM, Manners DN, et al. High-dose creatine therapy for Huntington disease: A 2-year clinical and MRS study. Neurology. 2005 ; 64: 1655-1656
179. Tan DX, Manchester LC, Reiter RJ, et al. A novel melatonin metabolite, cyclic 3-hydroxymelatonin: A biomarker of in vivo hydroxyl radical generation. Biochemical and Biophysical Research Communications. 1998 ; 253: 614-620
180. Tankova T, Koev D, Dakovska L. Alpha-lipoic acid in the treatment of autonomic diabetic neuropathy (controlled, randomized, open-label study). Romanian Journal of Internal Medicine. 2004 ; 42: 457-464
181. Tarnopolsky MA. The mitochondrial cocktail: Rationale for combined nutraceutical therapy in mitochondrial cytopathies. Advanced Drug Delivery Reviews. 2008 ; 60: 1561-1567
182. Tarnopolsky MA, Beal MF. Potential for creatine and other therapies targeting cellular energy dysfunction in neurological disorders. Annals of Neurology. 2001 ; 49: 561-574
183. Tarnopolsky MA, Mahoney DJ, Vajsar J, et al. Creatine monohydrate enhances strength and body composition in Duchenne muscular dystrophy. Neurology. 2004 ; 62: 1771-1777
184. Tarnopolsky MA, Roy BD, MacDonald JR. A randomized, controlled trial of creatine monohydrate in patients with mitochondrial cytopathies. Muscle & Nerve. 1997 ; 20: 1502-1509
185. Taylor RW, Turnbull DM. Mitochondrial DNA mutations in human disease. Nature Reviews. Genetics. 2005 ; 6: 389-402
186. Tempesta E, Casella L, Pirrongelli C, et al. L-Acetylcarnitine in depressed elderly subjects. A cross-over study vs placebo. Drugs Under Experimental and Clinical Research. 1987 ; 13: 417-423
187. Terjung RL, Clarkson P, Eichner ER, et al. American College of Sports Medicine roundtable. The physiological and health effects of oral creatine supplementation. Medicine and Science in Sports and Exercise. 2000 ; 32: 706-717
188. Torrioli MG, Vernacotola S, Mariotti P, et al. Double-blind, placebo-controlled study of L-acetylcarnitine for the treatment of hyperactive behavior in fragile X syndrome. American Journal of Medical Genetics. 1999 ; 87: 366-368
189. Torrioli MG, Vernacotola S, Peruzzi L, et al. A double-blind, parallel, multicenter comparison of L-acetylcarnitine with placebo on the attention deficit hyperactivity disorder in fragile X syndrome boys. American Journal of Medical Genetics. Part A. 2008 ; 146A: 803-812
190. Verbessem P, Lemiere J, Eijnde BO, et al. Creatine supplementation in Huntington's disease: A placebo-controlled pilot trial. Neurology. 2003 ; 61: 925-930
191. Villardita C, Smirni P, Vecchio I. Acetyl-L-carnitine in depressed geriatric patients. European Review for Medical and Pharmacological Sciences. 1983 ; 6: 1-12
192. Vincent HK, Bourguignon CM, Vincent KR, et al. Effects of alpha-lipoic acid supplementation in peripheral arterial disease: A pilot study. Journal of Alternative and Complementary Medicine. 2007 ; 13: 577-584
193. Virmani A, Gaetani F, Biniend Z. Effects of metabolic modifiers such as carnitines, coenzyme Q10, and PUFAs against different forms of neurotoxic insults: Metabolic inhibitors, MPTP, and methamphetamine. Annals of the New York Academy of Sciences. 2005 ; 1053: 183-191
194. Walter MC, Lochmuller H, Reilich P, et al. Creatine monohydrate in muscular dystrophies: A double-blind, placebo-controlled clinical study. Neurology. 2000 ; 54: 1848-1850
195. Wang J-F. Defects of mitochondrial electron transport chain in bipolar disorder: Implications for mood-stabilizing treatment. Canadian Journal of Psychiatry-Revue Canadienne De Psychiatrie. 2007 ; 52: 753-762
196. Weeber E, Levy M, Sampson M, et al. The role of mitochondrial porins and the permeability transition pore in learning and synaptic plasticity. Journal of Biological Chemistry. 2002 ; 277: 18,891-18,897
197. Weissman MM, Bland RC, Canino GJ, et al. Cross-national epidemiology of major depression and bipolar disorder. Journal of the American Medical Association. 1996 ; 276: 293-299
198. Winiarska K, Fraczyk T, Malinska D, et al. Melatonin attenuates diabetes-induced oxidative stress in rabbits. Journal of Pineal Research. 2006 ; 40: 168-176
199. Yadav V, Marracci G, Lovera J, et al. Lipoic acid in multiple sclerosis: A pilot study. Multiple Sclerosis. 2005 ; 11: 159-165
200. Yang F, He X, Russell J, et al. Ca2+ influx-independent synaptic potentiation mediated by mitochondrial Na(+)-Ca2+ exchanger and protein kinase C. Journal of Cell Biology. 2003 ; 163: 511-523
201. Yildiz A, Sachs GS, Dorer DJ, et al. P-31 Nuclear magnetic resonance spectroscopy findings in bipolar illness: A meta-analysis. Psychiatry Research Neuroimaging. 2001 ; 106: 181-191
202. Youle M, Osio M. A double-blind, parallel-group, placebo-controlled, multicentre study of acetyl L-carnitine in the symptomatic treatment of antiretroviral toxic neuropathy in patients with HIV-1 infection. HIV Medicine. 2007 ; 8: 241-250
203. Zanardi R, Smeraldi E. A double-blind, randomised, controlled clinical trial of acetyl-L-carnitine vs. amisulpride in the treatment of dysthymia. European Neuropsychopharmacology. 2006 ; 16: 281-287
204. Ziegler D, Ametov A, Barinov A, et al. Oral treatment with alpha-lipoic acid improves symptomatic diabetic polyneuropathy: The SYDNEY 2 trial. Diabetes Care. 2006 ; 29: 2365-2370
205. Ziegler D, Hanefeld M, Ruhnau KJ, et al. Treatment of symptomatic diabetic peripheral neuropathy with the anti-oxidant alpha-lipoic acid. A 3-week multicentre randomized controlled trial (ALADIN Study). Diabetologia. 1995 ; 38: 1425-1433
206. Ziegler D, Hanefeld M, Ruhnau KJ, et al. Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: A 7-month multicenter randomized controlled trial (ALADIN III Study). ALADIN III Study Group. Alpha-Lipoic Acid in Diabetic Neuropathy. Diabetes Care. 1999 ; 22: 1296-1301
207. Ziegler D, Schatz H, Conrad F, et al. Effects of treatment with the antioxidant alpha-lipoic acid on cardiac autonomic neuropathy in NIDDM patients. A 4-month randomized controlled multicenter trial (DEKAN Study). Deutsche Kardiale Autonome Neuropathie. Diabetes Care. 1997 ; 20: 369-373