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Metabolic Brain Disease

, Volume 34, Issue 1, pp 39–52 | Cite as

Alpha-lipoic acid in the treatment of psychiatric and neurological disorders: a systematic review

  • Caren Nádia Soares de Sousa
  • Cláudio Manuel Gonçalves da Silva Leite
  • Ingridy da Silva Medeiros
  • Luna Costa Vasconcelos
  • Lucas Moraes Cabral
  • Cláudio Felipe Vasconcelos Patrocínio
  • Marianna Letícia Vasconcelos Patrocínio
  • Fayçal Mouaffak
  • Oussama Kebir
  • Danielle Macedo
  • Manoel Cláudio Azevedo Patrocínio
  • Silvânia Maria Mendes VasconcelosEmail author
Review Article
First Online:

Abstract

Despite the existence of many preclinical studies, scientific evidence is lacking on the clinical use of alpha-lipoic acid (ALA) for central nervous system disorders. Therefore, we aimed at revising the literature concerning the use of ALA for the treatment of psychiatric and neurological conditions and to point out what is missing for the introduction of this antioxidant to this purpose. For this systematic review we performed a search using PubMed and SCOPUS databases with the following keywords: “alpha-Lipoic Acid AND central nervous system OR psychiatric disorders OR neurological disorders OR mood disorders OR anxiety OR psychosis OR Alzheimer OR Parkinson OR stroke”. The total number of references found after automatically and manually excluding duplicates was 1061. After primary and secondary screening 32 articles were selected. Regarding psychiatric disorders, the studies of ALA in schizophrenia are advanced being ALA administration related to the improvement of schizophrenia symptoms and side effects of antipsychotic medication. In neurological disorders, ALA as a supplement was effective in the prevention of Alzheimer disease progression. For stroke, the use of the supplement ALAnerv® (containing 300 mg ALA) presented important results, since it was observed a reversal of clinical parameters and oxidative imbalance in these patients. For other neurological conditions, such as encephalopathy, multiple sclerosis, traumatic brain injury, mitochondrial disorders and migraine, the results are still preliminary. Overall, there is a need of well-designed clinical trials to enhance the clinical evidences of ALA effects for the treatment of neurological and psychiatric conditions.

Keywords

Alpha-lipoic acid Central nervous system Neurological disorders Psychiatric disorders 

Abbreviations

AD

Alzheimer disease

ADL/IADL

Activities of Daily Living/Instrumental Activities of Daily Living

ADAScog

Alzheimer’s disease assessment score cognitive subscale

AIDS

acquired immunodeficiency syndrome

ALA

alpha-lipoic acid

AOPP

advanced oxidation protein products

CGI-S

Clinical Global Impression Scale for Severity

CNS

central nervous system

DMR SOC

Dementia Questionnaire for Mentally Retarded Persons sum of cognitive scores

HAM-D

Hamilton Depression Rating Scale

HIV-1

human immunodeficiency virus type 1

IADL

Instrumental Activities of Daily Living

MADRS

Montgomery-Asberg Depression Rating Scale

MMSE

Mini-Mental State Examination

TAS

total antioxidant status

TBARS

thiobarbituric acid-reactive substances

YMRS

Young Mania Rating Scale.

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Notes

Acknowledgments

This study was supported by grants from the Brazilian National Council for Scientific and Technological Development (CNPq), Higher Education Personnel Improvement Coordination (CAPES) and Cearense Foundation for the Support of Scientific and Technological Development (FUNCAP).

Conflicts of interest

The authors declare no conflict of interests.

References

  1. Altschule M, Goncz R, Holliday P (1959) Carbohydrate metabolism in brain disease. XI. Effects of thioctic (alpha-lipoic) acid in chronic schizophrenia. AMA Arch Intern Med 103:726–729CrossRefGoogle Scholar
  2. Amen DG, Wu JC, Taylor D, Willeumier K (2011) Reversing brain damage in former NFL players: implications for traumatic brain injury and substance abuse rehabilitation. J Psychoactive Drugs 43:1–5.  https://doi.org/10.1080/02791072.2011.566489 CrossRefPubMedGoogle Scholar
  3. Arivazhagan P, Ayusawa D, Panneerselvam C (2006) Protective efficacy of α-lipoic acid on acetylcholinesterase activity in aged rat brain regions. Rejuvenation Res 9:198–201.  https://doi.org/10.1089/rej.2006.9.198 CrossRefPubMedGoogle Scholar
  4. Aubry E, Aeberhard C, Bally L, Nuoffer JM, Risch L, Mühlebach S, Burgunder JM, Stanga Z (2018) Are patients affected by mitochondrial disorders at nutritional risk? Nutrition 47:56–62.  https://doi.org/10.1016/J.NUT.2017.09.011 CrossRefPubMedGoogle Scholar
  5. Biewenga GP, Haenen GRMM, Bast A (1997) The pharmacology of the antioxidant: lipoic acid. Gen Pharmacol 29:315–331CrossRefGoogle Scholar
  6. Bilska A, Dubiel M, Sokołowska-Jezewicz M et al (2007) Alpha-lipoic acid differently affects the reserpine-induced oxidative stress in the striatum and prefrontal cortex of rat brain. Neuroscience 146:1758–1771.  https://doi.org/10.1016/j.neuroscience.2007.04.002 CrossRefPubMedGoogle Scholar
  7. Bragin V, Chemodanova M, Dzhafarova N et al (2005) Integrated treatment approach improves cognitive function in demented and clinically depressed patients. Am J Alzheimer’s Dis Other Dementias 20(21–26):6pGoogle Scholar
  8. Brennan BP, Jensen JE, Hudson JI, Coit CE, Beaulieu A, Pope HG Jr, Renshaw PF, Cohen BM (2013) A placebo-controlled trial of acetyl-L-carnitine and α-lipoic acid in the treatment of bipolar depression. J Clin Psychopharmacol. 33(5):627–35.  https://doi.org/10.1097/JCP.0b013e31829a83f5
  9. Chng HT, New LS, Neo AH, Goh CW, Browne ER, Chan ECY (2009) Distribution study of orally administered lipoic acid in rat brain tissues. Brain Res 1251:80–86.  https://doi.org/10.1016/j.brainres.2008.11.025 CrossRefPubMedGoogle Scholar
  10. Choi K-H, Park M-S, Kim J-T, Kim HS, Kim JH, Nam TS, Choi SM, Lee SH, Kim BC, Kim MK, Cho KH (2016) Lipoic acid use and functional outcomes after thrombolysis in patients with acute ischemic stroke and diabetes. PLoS One 11:e0163484.  https://doi.org/10.1371/journal.pone.0163484 CrossRefPubMedPubMedCentralGoogle Scholar
  11. Cinteza D, Berteanu M, Vladoiu S, Manolescu BN, Dinu H (2013) The consumption of alanerv® nutritional supplement and the dynamic of some inflammatory markers in post-acute stroke patients undergoing rehabilitation. Maedica (Buchar) 8:137–142Google Scholar
  12. Clayton BE, Dobbs RH, Patrick AD (1967) Leigh’s subacute necrotizing encephalopathy: clinical and biochemical study, with special reference to therapy with lipoate. Arch Dis Child 42:467–478CrossRefGoogle Scholar
  13. Constantinescu CS, Gran B (2010) Multiple sclerosis: autoimmune associations in multiple sclerosis. Nat Rev Neurol 6:591–592.  https://doi.org/10.1038/nrneurol.2010.147 CrossRefPubMedGoogle Scholar
  14. De Araújo DP, Lobato RDFG, Cavalcanti JRLDP et al (2011) The contributions of antioxidant activity of lipoic acid in reducing neurogenerative progression of Parkinson’s disease: a review. Int J Neurosci 121:51–57.  https://doi.org/10.3109/00207454.2010.535934 CrossRefPubMedGoogle Scholar
  15. Deslauriers J, Desmarais C, Sarret P, Grignon S (2013) α-Lipoic acid interaction with dopamine D2 receptor-dependent activation of the Akt/GSK-3β signaling pathway induced by antipsychotics: potential relevance for the treatment of schizophrenia. J Mol Neurosci 50:134–145.  https://doi.org/10.1007/s12031-012-9884-4 CrossRefPubMedGoogle Scholar
  16. Dutta R, Trapp BD (2014) Relapsing and progressive forms of multiple sclerosis: insights from pathology. Curr Opin Neurol 27:271–278.  https://doi.org/10.1097/WCO.0000000000000094 CrossRefPubMedPubMedCentralGoogle Scholar
  17. Emsley R, Chiliza B, Asmal L, du Plessis S, Phahladira L, van Niekerk E, van Rensburg SJ, Harvey BH (2014) A randomized, controlled trial of omega-3 fatty acids plus an antioxidant for relapse prevention after antipsychotic discontinuation in first-episode schizophrenia. Schizophr Res 158:230–235.  https://doi.org/10.1016/J.SCHRES.2014.06.004 CrossRefPubMedGoogle Scholar
  18. Ferreira PMP, Militão GCG, Freitas RM (2009) Lipoic acid effects on lipid peroxidation level, superoxide dismutase activity and monoamines concentration in rat hippocampus. Neurosci Lett 464:131–134.  https://doi.org/10.1016/j.neulet.2009.08.051 CrossRefPubMedGoogle Scholar
  19. Fried EI, Nesse RM (2014) Depression is not a consistent syndrome: an investigation of unique symptom patterns in the STAR*D study. J Affect Disord 172C:96–102.  https://doi.org/10.1016/j.jad.2014.10.010 CrossRefGoogle Scholar
  20. Gal EM (1965) Reversal of selective toxicity of (−)-α-lipoic acid by thiamine in thiamine-deficient rats. Nature 207:535CrossRefGoogle Scholar
  21. Galasko DR, Peskind E, Clark CM, Quinn JF, Ringman JM, Jicha GA, Cotman C, Cottrell B, Montine TJ, Thomas RG, Aisen P, Alzheimer's Disease Cooperative Study (2012) Antioxidants for Alzheimer disease. Arch Neurol 69:836–841.  https://doi.org/10.1001/archneurol.2012.85 CrossRefPubMedPubMedCentralGoogle Scholar
  22. Gorąca A, Huk-Kolega H, Piechota A, Kleniewska P, Ciejka E, Skibska B (2011) Lipoic acid - biological activity and therapeutic potential. Pharmacol Rep 63:849–858.  https://doi.org/10.1016/S1734-1140(11)70600-4 CrossRefPubMedGoogle Scholar
  23. Hager K, Marahrens A, Kenklies M, Riederer P, Münch G (2001) Alpha-lipoic acid as a new treatment option for Alzheimer [corrected] type dementia. Arch Gerontol Geriatr 32:275–282CrossRefGoogle Scholar
  24. Hager K, Kenklies M, McAfoose J et al (2007) Alpha-lipoic acid as a new treatment option for Alzheimer’s disease--a 48 months follow-up analysis. J Neural Transm Suppl:189–193Google Scholar
  25. Hermann R, Mungo J, Cnota PJ, Ziegler D (2014) Enantiomer-selective pharmacokinetics, oral bioavailability, and sex effects of various alpha-lipoic acid dosage forms. Clin Pharmacol Adv Appl 6:195–204.  https://doi.org/10.2147/CPAA.S71574 CrossRefGoogle Scholar
  26. Holder SD, Wayhs A (2014) Schizophrenia. Am Fam Physician 90:775–782.  https://doi.org/10.1016/S1674-6384(14)60051-4 CrossRefPubMedGoogle Scholar
  27. Kato T, Kato N (2000) Mitochondrial dysfunction in bipolar disorder. Bipolar Disord 2:180–190CrossRefGoogle Scholar
  28. Kessler RC (2012) The costs of depression. Psychiatr Clin North Am 35:1–14.  https://doi.org/10.1016/j.psc.2011.11.005 CrossRefPubMedGoogle Scholar
  29. Khalili M, Azimi A, Izadi V, Eghtesadi S, Mirshafiey A, Sahraian MA, Motevalian A, Norouzi A, Sanoobar M, Eskandari G, Farhoudi M, Amani F (2014a) Does lipoic acid consumption affect the cytokine profile in multiple sclerosis patients: a double-blind, placebo-controlled, randomized clinical trial. Neuroimmunomodulation 21:291–296.  https://doi.org/10.1159/000356145 CrossRefPubMedGoogle Scholar
  30. Khalili M, Eghtesadi S, Mirshafiey A, Eskandari G, Sanoobar M, Sahraian MA, Motevalian A, Norouzi A, Moftakhar S, Azimi A (2014b) Effect of lipoic acid consumption on oxidative stress among multiple sclerosis patients: a randomized controlled clinical trial. Nutr Neurosci 17:16–20.  https://doi.org/10.1179/1476830513Y.0000000060 CrossRefPubMedGoogle Scholar
  31. Kim E, Park D-W, Choi S-H, Kim JJ, Cho HS (2008) A preliminary investigation of alpha-lipoic acid treatment of antipsychotic drug-induced weight gain in patients with schizophrenia. J Clin Psychopharmacol 28:138–146.  https://doi.org/10.1097/JCP.0b013e31816777f7 CrossRefPubMedGoogle Scholar
  32. Leigh PN, Al-Sarraj S, DiMauro S (2015) Impact commentaries. Subacute necrotising encephalomyelopathy (Leigh’s disease; Leigh syndrome). J Neurol Neurosurg Psychiatry 86:363–365.  https://doi.org/10.1136/jnnp-2012-304601 CrossRefPubMedGoogle Scholar
  33. Liu D, Ke Z, Luo J (2017) Thiamine deficiency and neurodegeneration: the interplay among oxidative stress, endoplasmic reticulum stress, and autophagy. Mol Neurobiol 54:5440–5448CrossRefGoogle Scholar
  34. Lott IT, Doran E, Nguyen VQ, Tournay A, Head E, Gillen DL (2011) Down syndrome and dementia: a randomized, controlled trial of antioxidant supplementation. Am J Med Genet Part A 155:1939–1948.  https://doi.org/10.1002/ajmg.a.34114 CrossRefGoogle Scholar
  35. Maczurek A, Hager K, Kenklies M, Sharman M, Martins R, Engel J, Carlson DA, Münch G (2008) Lipoic acid as an anti-inflammatory and neuroprotective treatment for Alzheimer’s disease. Adv Drug Deliv Rev 60:1463–1470.  https://doi.org/10.1016/j.addr.2008.04.015 CrossRefPubMedGoogle Scholar
  36. Magis D, Ambrosini A, Sándor P, Jacquy J, Laloux P, Schoenen J (2007) A randomized double-blind placebo-controlled trial of Thioctic acid in migraine prophylaxis. Headache J Head Face Pain 47:52–57.  https://doi.org/10.1111/j.1526-4610.2006.00626.x CrossRefGoogle Scholar
  37. Manolescu BN, Berteanu M, Cintezã D (2013) Effect of the nutritional supplement ALAnerv® on the serum PON1 activity in post-acute stroke patients. Pharmacol Rep 65:743–750CrossRefGoogle Scholar
  38. Manolescu BN, Cinteza D, Berteanu M, Busu C, Oprea E (2014) The relationship between alanerv(®) consumption and erythrocytes’ redox status in post-acute stroke patients undergoing rehabilitation. Maedica (Buchar) 9:248–254Google Scholar
  39. Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group (2010) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Int J Surg 8:336–341.  https://doi.org/10.1016/j.ijsu.2010.02.007 CrossRefPubMedGoogle Scholar
  40. Moylan S, Berk M, Dean OM, Samuni Y, Williams LJ, O’Neil A, Hayley AC, Pasco JA, Anderson G, Jacka FN, Maes M (2014) Oxidative & nitrosative stress in depression: why so much stress? Neurosci Biobehav Rev 45:46–62.  https://doi.org/10.1016/j.neubiorev.2014.05.007 CrossRefPubMedGoogle Scholar
  41. Oprea E, Berteanu M, Cintezã D, Manolescu BN (2013) The effect of the ALAnerv nutritional supplement on some oxidative stress markers in postacute stroke patients undergoing rehabilitation. Appl Physiol Nutr Metab 38:613–620.  https://doi.org/10.1139/apnm-2012-0436 CrossRefPubMedGoogle Scholar
  42. Ou P, Tritschler HJ, Wolff SP (1995) Thioctic (lipoic) acid: a therapeutic metal-chelating antioxidant? Biochem Pharmacol 50:123–126.  https://doi.org/10.1016/0006-2952(95)00116-H CrossRefPubMedGoogle Scholar
  43. Prabhakaran S, Ruff I, Bernstein RA (2015) Acute stroke intervention: a systematic review. JAMA. J Am Med Assoc 313:1451–1462CrossRefGoogle Scholar
  44. Ratliff JC, Palmese LB, Reutenauer EL, Tek C (2015) An open-label pilot trial of alpha-lipoic acid for weight loss in patients with schizophrenia without diabetes. Clin Schizophr Relat Psychoses 8:196–200.  https://doi.org/10.3371/CSRP.RAPA.030113 CrossRefPubMedGoogle Scholar
  45. Riccio P, Rossano R, Larocca M, Trotta V, Mennella I, Vitaglione P, Ettorre M, Graverini A, de Santis A, di Monte E, Coniglio MG (2016) Anti-inflammatory nutritional intervention in patients with relapsing-remitting and primary-progressive multiple sclerosis: a pilot study. Exp Biol Med (Maywood) 241:620–635.  https://doi.org/10.1177/1535370215618462 CrossRefGoogle Scholar
  46. Rodriguez MC, MacDonald JR, Mahoney DJ et al (2007) Beneficial effects of creatine, CoQ10, and lipoic acid in mitochondrial disorders. Muscle Nerve 35:235–242.  https://doi.org/10.1002/mus.20688 CrossRefPubMedGoogle Scholar
  47. Sacktor N, Kieburtz K, Schifitto G et al (1998) A randomized, double-blind, placebo-controlled trial of deprenyl and thioctic acid in human immunodeficiency virus-associated cognitive impairment. Neurology 50:645–651CrossRefGoogle Scholar
  48. Salinthone S, Yadav V, Schillace RV, Bourdette DN, Carr DW (2010) Lipoic acid attenuates inflammation via cAMP and protein kinase a signaling. PLoS One 5:e13058.  https://doi.org/10.1371/journal.pone.0013058 CrossRefPubMedPubMedCentralGoogle Scholar
  49. Sanders LLO, de Souza Menezes CE, Chaves Filho AJM, de Almeida Viana G, Fechine FV, Rodrigues de Queiroz MG, Gonçalvez da Cruz Fonseca S, Mendes Vasconcelos SM, Amaral de Moraes ME, Gama CS, Seybolt S, de Moura Campos E, Macêdo D, Freitas de Lucena D (2017) α-Lipoic acid as adjunctive treatment for schizophrenia. J Clin Psychopharmacol 37:697–701.  https://doi.org/10.1097/JCP.0000000000000800 CrossRefPubMedGoogle Scholar
  50. Santos IMDS, De FRLM, Saldanha GB et al (2010) Alterations on monoamines concentration in rat hippocampus produced by lipoic acid. Arq Neuropsiquiatr 68:362–366.  https://doi.org/10.1590/S0004-282X2010000300006 CrossRefPubMedGoogle Scholar
  51. Schwedt TJ (2014) Chronic migraine. BMJ 348:g1416. doi:  https://doi.org/10.1136/BMJ.G1416
  52. Shinto L, Quinn J, Montine T, Dodge HH, Woodward W, Baldauf-Wagner S, Waichunas D, Bumgarner L, Bourdette D, Silbert L, Kaye J (2014) A randomized placebo-controlled pilot trial of omega-3 fatty acids and alpha lipoic acid in Alzheimer’s disease. J Alzheimers Dis 38:111–120.  https://doi.org/10.3233/JAD-130722 CrossRefPubMedGoogle Scholar
  53. Silva MCC, De Sousa CNS, Sampaio LRL et al (2013) Augmentation therapy with alpha-lipoic acid and desvenlafaxine: a future target for treatment of depression? Naunyn Schmiedeberg's Arch Pharmacol 386:685–695.  https://doi.org/10.1007/s00210-013-0867-y CrossRefGoogle Scholar
  54. Silva MCC, de Sousa CNS, Gomes PXL, de Oliveira GV, Araújo FYR, Ximenes NC, da Silva JC, Silva Vasconcelos G, Leal LKAM, Macêdo D, Vasconcelos SMM (2016) Evidence for protective effect of lipoic acid and desvenlafaxine on oxidative stress in a model depression in mice. Prog Neuro-Psychopharmacol Biol Psychiatry 64:142–148.  https://doi.org/10.1016/j.pnpbp.2015.08.002 CrossRefGoogle Scholar
  55. Smania N, Avesani R, Roncari L, Ianes P, Girardi P, Varalta V, Gambini MG, Fiaschi A, Gandolfi M (2013) Factors predicting functional and cognitive recovery following severe traumatic, anoxic, and cerebrovascular brain damage. J Head Trauma Rehabil 28:131–140.  https://doi.org/10.1097/HTR.0b013e31823c0127 CrossRefPubMedGoogle Scholar
  56. Summers CR, Ivins B, Schwab KA (2009) Traumatic brain injury in the United States: an epidemiologic overview. Mt Sinai J med a J Transl. Pers Med 76:105–110.  https://doi.org/10.1002/msj.20100 CrossRefGoogle Scholar
  57. Suzuki YJ, Aggarwal BB, Packer L (1992) α-Lipoic acid is a potent inhibitor of NF-κB activation in human T cells. Biochem Biophys Res Commun 189:1709–1715.  https://doi.org/10.1016/0006-291X(92)90275-P CrossRefPubMedGoogle Scholar
  58. The Dana Consortium on the Therapy of HIV Dementia and Related Cognitive Disorders (1998) A randomized, double-blind, placebo-controlled trial of deprenyl and thiotic acid in human immunodeficiency virus-associated cognitive impairment. Neurology 50:645–651.  https://doi.org/10.1212/WNL.50.3.645
  59. Tymianski M (2014) Stroke in 2013: disappointments and advances in acute stroke intervention. Nat Rev Neurol 10:66–68CrossRefGoogle Scholar
  60. Vasconcelos GS, Ximenes NC, de Sousa CNS, Oliveira TQ, Lima LLL, de Lucena DF, Gama CS, Macêdo D, Vasconcelos SMM (2015) Alpha-lipoic acid alone and combined with clozapine reverses schizophrenia-like symptoms induced by ketamine in mice: participation of antioxidant, nitrergic and neurotrophic mechanisms. Schizophr Res 165:163–170.  https://doi.org/10.1016/j.schres.2015.04.017 CrossRefPubMedGoogle Scholar
  61. Vidović B, Milovanović S, Dorđević B, Kotur-Stevuljević J, Stefanović A, Ivanišević J, Miljković M, Spasić S, Stojanović D, Pantović M (2014) Effect of alpha-lipoic acid supplementation on oxidative stress markers and antioxidative defense in patients with schizophrenia. Psychiatr Danub 26:205–213PubMedGoogle Scholar
  62. Vidović B, Milovanović S, Stefanović A, Kotur-Stevuljević J, Takić M, Debeljak-Martačić J, Pantović M, Đorđević B (2017) Effects of alpha-lipoic acid supplementation on plasma adiponectin levels and some metabolic risk factors in patients with schizophrenia. J Med Food 20:79–85.  https://doi.org/10.1089/jmf.2016.0070 CrossRefPubMedGoogle Scholar
  63. WHO (2017) WHO | Dementia. In: WHO Dementia a public health priorityGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Caren Nádia Soares de Sousa
    • 1
  • Cláudio Manuel Gonçalves da Silva Leite
    • 1
  • Ingridy da Silva Medeiros
    • 1
  • Luna Costa Vasconcelos
    • 1
  • Lucas Moraes Cabral
    • 1
  • Cláudio Felipe Vasconcelos Patrocínio
    • 2
  • Marianna Letícia Vasconcelos Patrocínio
    • 2
  • Fayçal Mouaffak
    • 3
  • Oussama Kebir
    • 4
  • Danielle Macedo
    • 1
  • Manoel Cláudio Azevedo Patrocínio
    • 2
    • 5
  • Silvânia Maria Mendes Vasconcelos
    • 1
    Email author
  1. 1.Neuropsychopharmacology Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of MedicineFederal University of CearáFortalezaBrazil
  2. 2.School of MedicineUniversity Center Christus-UnichristusFortalezaBrazil
  3. 3.Department of Seine Saint DenisVille Evrard Psychiatric HospitalParisFrance
  4. 4.Laboratory of Pathophysiology of Psychiatric Diseases, Center for Psychiatry and Neurosciences, INSERM U894University Paris DescartesParisFrance
  5. 5.Department of AnesthesiologyDr. Jose Frota Institute Hospital/IJFFortalezaBrazil

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