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Alpha-Lipoic Acid in the Treatment of Psychiatric and Neurological Disorders: a Systematic Review

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Alpha-Lipoic Acid in the Treatment of Psychiatric and Neurological Disorders: a Systematic Review Metabolic Brain Disease (2019) 34:39–52 https://doi.org/10.1007/s11011-018-0344-x REVIEW ARTICLE Alpha-lipoic acid in the treatment of psychiatric and neurological disorders: a systematic review Caren Nádia Soares de Sousa1 & Cláudio Manuel Gonçalves da Silva Leite1 & Ingridy da Silva Medeiros1 & Luna Costa Vasconcelos1 & Lucas Moraes Cabral1 & Cláudio Felipe Vasconcelos Patrocínio2 & Marianna Letícia Vasconcelos Patrocínio2 & Fayçal Mouaffak3 & Oussama Kebir4 & Danielle Macedo1 & Manoel Cláudio Azevedo Patrocínio2,5 & Silvânia Maria Mendes Vasconcelos1 Received: 7 June 2018 /Accepted: 12 November 2018 /Published online: 22 November 2018 # Springer Science+Business Media, LLC, part of Springer Nature 2018 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. * Silvânia Maria Mendes Vasconcelos Oussama Kebir [email protected]; [email protected] [email protected] Caren Nádia Soares de Sousa Danielle Macedo [email protected] [email protected] Cláudio Manuel Gonçalves da Silva Leite Manoel Cláudio Azevedo Patrocínio [email protected] [email protected] Ingridy da Silva Medeiros 1 [email protected] Neuropsychopharmacology Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Luna Costa Vasconcelos Faculty of Medicine, Federal University of Ceará, Coronel Nunes de [email protected] Melo Street, 1127, Fortaleza, CE 60431-270, Brazil 2 LucasMoraesCabral School of Medicine, University Center Christus-Unichristus, [email protected] Fortaleza, Ceará, Brazil 3 Department of Seine Saint Denis, Ville Evrard Psychiatric Hospital, Cláudio Felipe Vasconcelos Patrocínio Paris, France [email protected] 4 Laboratory of Pathophysiology of Psychiatric Diseases, Center for Marianna Letícia Vasconcelos Patrocínio Psychiatry and Neurosciences, INSERM U894, University Paris [email protected] Descartes, Paris, France Fayçal Mouaffak 5 Department of Anesthesiology, Dr. Jose Frota Institute Hospital/IJF, [email protected] Fortaleza, Brazil 40 Metab Brain Dis (2019) 34:39–52 Keywords Alpha-lipoic acid . Central nervous system . Neurological disorders . Psychiatric disorders Abbreviations et al. 1995;Bilskaetal.2007), thus contributing to oxidative AD Alzheimer disease homeostasis. ADL/IADL Activities of Daily Living/Instrumental Regarding the effects of ALA in the central nervous system Activities of Daily Living (CNS), preclinical studies have described an anti-inflammatory ADAScog Alzheimer’s disease assessment score activity of this compound as well as the prevention of neuronal cognitive subscale damage caused by reactive oxygen species (ROS) imbalance, a AIDS acquired immunodeficiency syndrome pathophysiological alteration observed in neurodegenerative ALA alpha-lipoic acid diseases (Maczurek et al. 2008;DeAraújoetal.2011;Silva AOPP advanced oxidation protein products et al. 2013). The anti-inflammatory effect of ALA is related to CGI-S Clinical Global Impression Scale for Severity the inhibition of nuclear factor-κB(NF-κB), a family of tran- CNS central nervous system scription factors responsible for the expression of several genes DMR SOC Dementia Questionnaire for Mentally related to inflammation, regulation of the amount of ROS in the Retarded Persons sum of cognitive scores cell, and apoptosis (Suzuki et al. 1992;Gorąca et al. 2011). HAM-D Hamilton Depression Rating Scale Furthermore, ALA is known to increase brain levels of norepi- HIV-1 human immunodeficiency virus type 1 nephrine and dopamine by unknown mechanisms (Santos et al. IADL Instrumental Activities of Daily Living 2010), to block D2 receptor (Deslauriers et al. 2013) in rodents, MADRS Montgomery-Asberg Depression Rating and to alter brain acetylcholinesterase activity in aged animals Scale (Arivazhagan et al. 2006). MMSE Mini-Mental State Examination Despite the great number of preclinical studies showing the TAS total antioxidant status benefits of ALA for the treatment of CNS disorders, there is a TBARS thiobarbituric acid-reactive substances lack of clinical studies in this field. Therefore, we aimed to YMRS Young Mania Rating Scale. systematically review published clinical studies regarding the use of ALA for treating neurological and psychiatric disorders to contribute to the clinical use of this antioxidant as well as to Introduction point out what is missing for the use of ALA to the treatment of neurological and psychiatric disorders. Alpha-lipoic acid (ALA-1,2-dithiolane-3-pentanoic acid), al- so known as thioic acid, is a natural antioxidant synthesized in Material and methods human body. Its structural formula comprises two thiol groups that can be oxidized or reduced, making it a redox pair (Fig. Search strategy 1). ALA exists as two enantiomers: S - (−)-lipoicacidandR- (+) - lipoic acid, the last being the naturally occurring form A systematic search was conducted between June 9th, 2017 that acts as an essential cofactor of mitochondrial pyruvate and February 1st, 2018 using PubMed and SCOPUS data- dehydrogenase (Ferreira et al. 2009; Hermann et al. 2014). bases. The following keywords were used to perform the Alpha-lipoic acid has been used to treat various diseases. search: “alpha-Lipoic Acid” [MeSH] AND “central nervous The effects of this antioxidant in human body range from free system” [MeSH] OR “psychiatric disorders” [MeSH] or “neu- radicals scavenger (Chng et al. 2009), reduction of lipid per- rological disorders” [MeSH] OR “mood disorders” [MeSH] oxidation (Vasconcelos et al. 2015; Silva et al. 2016), action as OR “anxiety disorders” [MeSH] OR “psychosis” [MeSH] OR a cofactor of enzymatic complexes (Biewenga et al. 1997), Alzheimer disease [MeSH] OR “Parkinson disease” [MeSH] regeneration of damaged tissues and chelation of metals (Ou OR “stroke” [MeSH]. Inclusion and exclusion criteria We included studies concerning the effects of ALA for the treat- ment of CNS disorders. As inclusion criteria we considered clin- ical trials performed in adult patients (mean age of included participants ≥18 years). To avoid language publication bias, no Fig. 1 Flat representation of alpha-lipoic acid. RCSB protein data bank restrictions on country of origin and language of the study were (2015) applied. Exclusion criteria were: experimental studies; in vitro Metab Brain Dis (2019) 34:39–52 41 studies; and other non-clinical studies. Narrative, systematic re- Emsley et al. (2014) performed a randomized, double- views and meta-analyses were excluded. blind, placebo-controlled study to assess whether the combi- This systematic review followed the recommendations of nation of ALA (300 mg/day) and omega-3 polyunsaturated the Preferred Reporting Items for Systematic Reviews and fatty acids was effective for relapse prevention in patients with Meta-Analyses (PRISMA) statement (Moher et al. 2010). full remission of symptoms due to antipsychotic therapy for at Three authors (I.S.M; L.C.V. and L.M.C.) performed the pri- least two years following the first episode of psychosis. mary (reading titles and abstracts) and secondary (reading each Twenty-one patients were allocated to the intervention group article in detail) screening independently. Disagreements were and 12 patients to the placebo group. In this trial recruitment resolved through consensus. was prematurely terminated due to the high relapse rates in both groups: 90% for intervention group and 75% for placebo. Authors concluded that the combination of ALA and omega-3 Results polyunsaturated fatty acids is not effective as maintenance therapy in schizophrenia (Emsley et al. 2014). The total number of references after automatic and manual Recently, an open label trial conducted in 10 patients suf- exclusion of duplicates was 1061. Following primary screen- fering from chronic schizophrenia revealed that the adjunctive ing, 991 references were excluded, remaining 70 studies
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