- Open Access
Mitochondrion-toxic drugs given to patients with mitochondrial psychoses
© finsterer; licensee BioMed Central Ltd. 2012
Received: 20 March 2012
Accepted: 26 August 2012
Published: 29 August 2012
A recent study, published in this journal, aimed to assess psychiatric abnormalities in mitochondrial disorders with a proven mtDNA defect. Twelve patients had a syndromic mitochondrial disorder (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), myoclonic epilepsy with ragged red fibers (MERRF), neuropathy, ataxia, and retinitis pigmentosa (NARP), progressive external ophthalmoplegia (PEO), Kearns-Sayre syndrome (KSS)) and seven patients had a non-syndromic mitochondrial disorder. The frequency of psychiatric diagnoses among these patients was reported to be 47%. Psychiatric conditions may be even more common in other studies and include major depression, agoraphobia and/or panic disorder, generalized anxiety disorder, social anxiety disorder, or psychotic syndromes. The medication these patients took at inclusion was provided for only nine patients. Among these drugs, however, several are reported to be mitochondrion-toxic. Two patients were medicated with valproic acid, two with quetiapine, and one each with carbamazepine, atorvastatin, mirtazepine, metformin, and trazodone.
The study did not address whether, and to what degree, anti-psychotic or other medication may worsen the underlying defect due to mitochondrion-toxicity of the applied medication. This is important since deterioration of the clinical presentation may not only be due to worsening of the underlying metabolic defect, but also due to mitochondrion-toxicity of the applied anti-psychotic medication. Since a number of mitochondrion-toxic drugs are used to treat mood and psychotic disorders and may worsen the underlying metabolic defect, it is essential to exclude a mitochondrial metabolic defect before applying these agents. In addition to anti-psychotic drugs, patients with mitochondrial disorders and mood and psychotic disorders may also take other drugs, which may be mitochondrion-toxic. For a number of anti-psychotic and other drugs, however, it is not well known whether they are truly mitochondrion-toxic, neutral or, rather, mitochondrion-protective.
Some agents described in the study have been reported to cause severe, sometimes even fatal, adverse reactions, such as valproic acid, which may cause irreversible liver failure, particularly in patients carrying POLG1 mutations. Other drugs may be mitochondrion-toxic without obvious major clinical side effects, such as atorvastatin, which reduces the coenzyme-Q content and generally decreases mitochondrial functions, mirtazepine, which decreases complex-I activity, metformin, which inhibits complex-I of the respiratory chain, quetiapine, which inhibits complex-I, or trazodone, which collapses the mitochondrial membrane potential and imposes oxidative stress. Antipsychotic medication may not only affect the function of respiratory chain complexes, but also activity of the pyruvate-dehydrogenase complex. Some of the drugs applied may also have a protective effect on mitochondrial functions, such as vinpocetine, trimetazidine, sertraline, levetiracetam, bisoprolol, or enalapril.
Based on these considerations, it is advisable that patients with mitochondrial disorders receive special attention when treated with agents whose effects on mitochondria are uncertain or definitively toxic. Not only may anti-psychotic compounds be mitochondrion-toxic but so could be a number of other agents used in the daily routine. Since mitochondrial disorders are gaining increasing attention and thus being diagnosed more often, care has to be taken when selecting drugs for these patients. Since some patients may be highly sensitive to various compounds, these patients should be treated like patients with myasthenia gravis, who also react to contra-indicated medication with severe, occasionally fatal side-effects. Animal and human studies on the compatibility of agents with already disturbed mitochondrial metabolism, however, are required to find out which of the drugs are tolerated by patients with mitochondrial disorders and which are toxic to them.
- Inczedy-Farkas G, Remenyi V, Gal A, Varga Z, Balla P, Meszaros A, Bereznai B, Molnar MJ: Psychiatric symptoms of patients with primary mitochondrial DNA disorders. Behav Brain Funct. 2012, 8: 9-10.1186/1744-9081-8-9.PubMed CentralView ArticlePubMedGoogle Scholar
- Clay HB, Sillivan S, Konradi C: Mitochondrial dysfunction and pathology in bipolar disorder and schizophrenia. Int J Dev Neurosci. 2011, 29: 311-324. 10.1016/j.ijdevneu.2010.08.007.PubMed CentralView ArticlePubMedGoogle Scholar
- Campos Y, García A, Eiris J, Fuster M, Rubio JC, Martín MA, del Hoyo P, Pintos E, Castro-Gago M, Arenas J: Mitochondrial myopathy, cardiomyopathy and psychiatric illness in a Spanish family harbouring the mtDNA 3303C > T mutation. J Inherit Metab Dis. 2001, 24: 685-687. 10.1023/A:1012719211505.View ArticlePubMedGoogle Scholar
- Guffon N, Lopez-Mediavilla C, Dumoulin R, Mousson B, Godinot C, Carrier H, Collombet JM, Divry P, Mathieu M, Guibaud P: 2-Ketoglutarate dehydrogenase deficiency, a rare cause of primary hyperlactataemia: report of a new case. J Inherit Metab Dis. 1993, 16: 821-830. 10.1007/BF00714273.View ArticlePubMedGoogle Scholar
- Regenold WT, Pratt M, Nekkalapu S, Shapiro PS, Kristian T, Fiskum G: Mitochondrial detachment of hexokinase 1 in mood and psychotic disorders: implications for brain energy metabolism and neurotrophic signaling. J Psychiatr Res. 2012, 46: 95-104. 10.1016/j.jpsychires.2011.09.018.View ArticlePubMedGoogle Scholar
- Young TM, Blakely EL, Swalwell H, Carter JE, Kartsounis LD, O'Donovan DG, Turnbull DM, Taylor RW, de Silva RN: Mitochondrial transfer RNA(Phe) mutation associated with a progressive neurodegenerative disorder characterized by psychiatric disturbance, dementia, and akinesia-rigidity. Arch Neurol. 2010, 67: 1399-1402. 10.1001/archneurol.2010.283.PubMedView ArticleGoogle Scholar
- Mancuso M, Orsucci D, Ienco EC, Pini E, Choub A, Siciliano G: Psychiatric involvement in adult patients with mitochondrial disease. Neurol Sci. 2011, in pressGoogle Scholar
- Pronicka E, Weglewska-Jurkiewicz A, Pronicki M, Sykut-Cegielska J, Kowalski P, Pajdowska M, Jankowska I, Kotulska K, Kalicinski P, Jakobkiewicz-Banecka J, Wegrzyn G: Drug-resistant epilepsia and fulminant valproate liver toxicity. Alpers-Huttenlocher syndrome in two children confirmed post mortem by identification of p.W748S mutation in POLG gene. Med Sci Monit. 2011, 17: CR203-209.PubMed CentralView ArticlePubMedGoogle Scholar
- Kucharska J, Ulicna O, Gvozdjakova A, Vancova O, Waczulikova I, Bozek P, Bada V: Effects of atorvastatin on heart mitochondrial function and coenzyme Q content in the experiment. Bratisl Lek Listy. 2011, 112: 603-604.PubMedGoogle Scholar
- Hroudova J, Fisar Z: Activities of respiratory chain complexes and citrate synthase influenced by pharmacologically different antidepressants and mood stabilizers. Neuro Endocrinol Lett. 2010, 31: 336-342.PubMedGoogle Scholar
- Viollet B, Guigas B, Sanz Garcia N, Leclerc J, Foretz M, Andreelli F: Cellular and molecular mechanisms of metformin: an overview. Clin Sci (Lond). 2012, 122: 253-270. 10.1042/CS20110386.View ArticleGoogle Scholar
- Modica-Napolitano JS, Lagace CJ, Brennan WA, Aprille JR: Differential effects of typical and atypical neuroleptics on mitochondrial function in vitro. Arch Pharm Res. 2003, 26: 951-959. 10.1007/BF02980205.View ArticlePubMedGoogle Scholar
- Dykens JA, Jamieson JD, Marroquin LD, Nadanaciva S, Xu JJ, Dunn MC, Smith AR, Will Y: In vitro assessment of mitochondrial dysfunction and cytotoxicity of nefazodone, trazodone, and buspirone. Toxicol Sci. 2008, 103: 335-345. 10.1093/toxsci/kfn056.View ArticlePubMedGoogle Scholar
- Sacks W, Esser AH, Sacks S: Inhibition of pyruvate dehydrogenase complex (PDHC) by antipsychotic drugs. Biol Psychiatry. 1991, 29: 176-182.View ArticlePubMedGoogle Scholar
- Tárnok K, Kiss E, Luiten PG, Nyakas C, Tihanyi K, Schlett K, Eisel UL: Effects of Vinpocetine on mitochondrial function and neuroprotection in primary cortical neurons. Neurochem Int. 2008, 53: 289-295. 10.1016/j.neuint.2008.08.003.View ArticlePubMedGoogle Scholar
- Morota S, Månsson R, Hansson MJ, Kasuya K, Shimazu M, Hasegawa E, Yanagi S, Omi A, Uchino H, Elmér E: Evaluation of putative inhibitors of mitochondrial permeability transition for brain disorders--specificity vs. toxicity. Exp Neurol. 2009, 218: 353-362. 10.1016/j.expneurol.2009.03.036.View ArticlePubMedGoogle Scholar
- Kumar P, Kumar A: Possible role of Sertraline against 3-nitropropionic acid induced behavioral, oxidative stress and mitochondrial dysfunctions in rat brain. Prog Neuropsychopharmacol Biol Psychiatry. 2009, 33: 100-108. 10.1016/j.pnpbp.2008.10.013.View ArticlePubMedGoogle Scholar
- Gibbs JE, Cock HR: Administration of levetiracetam after prolonged status epilepticus does not protect from mitochondrial dysfunction in a rodent model. Epilepsy Res. 2007, 73: 208-212. 10.1016/j.eplepsyres.2006.09.005.View ArticlePubMedGoogle Scholar
- Ichihara S, Yamada Y, Ichihara G, Kanazawa H, Hashimoto K, Kato Y, Matsushita A, Oikawa S, Yokota M, Iwase M: Attenuation of oxidative stress and cardiac dysfunction by bisoprolol in an animal model of dilated cardiomyopathy. Biochem Biophys Res Commun. 2006, 350: 105-113. 10.1016/j.bbrc.2006.09.026.View ArticlePubMedGoogle Scholar
- Boveris A, D'Amico G, Lores-Arnaiz S, Costa LE: Enalapril increases mitochondrial nitric oxide synthase activity in heart and liver. Antioxid Redox Signal. 2003, 5: 691-697. 10.1089/152308603770379982.View ArticlePubMedGoogle Scholar
- Finsterer J: Psychosis as a manifestation of cerebral involvement in mitochondrial disorders. Recent advances in clinical medicine. Proceedings of the International Conferences on Medical Pharmacology/Medical Histology and Embryology/Psychiatry and Psychotherapy / International Conference on Oncology. Edited by: Anninos P, Rossi M, Pham TD, Falugi C, Bussing A, Koukkou M. 2010, University of Cambridge, Cambridge, England, February, Recent Adv Clin Med, 90-96.Google Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.