Alpha-lipoic Acid Adjunctive Therapy in Schizophrenia

NCT03788759 | Completed Phase 2

• 1 other identifier: LipoicStudy
• Study Type: interventional
• Target: 48
• Locations: 1 country
• Sites: 1

Brief Summary

Schizophrenia is a devastating mental disorder with a prevalence of approximately 1% worldwide. While effective in reducing positive symptoms, current treatments have limited effects on cognitive and social cognition/processing deficits of schizophrenia, which are closely linked to real-world dysfunction and lack of socio-occupational integration. There is compelling evidence for impaired antioxidant defense system and inflammatory abnormalities in schizophrenia. A new therapeutic approach to the disease might well be to hinder oxidative damage, inflammation and its clinical sequelae. Alpha-lipoic acid (ALA) is a naturally occurring compound, synthesized in the mitochondria, that is currently approved to treat diabetic neuropathic pain. Drug repurposing is a fast, and cost-effective method that can overcome drug discovery challenges of targeting neuropsychiatric disorders. In a pilot investigation, adjunctive treatment with ALA led to robust improvement in negative and cognitive symptoms of ten patients with schizophrenia. This project aims to investigate the efficacy of ALA as a disease-modifying drug for the treatment of schizophrenia, by improving sociability and cognition, as well as to correlate patients' response with biomarkers that will shed light on the pathophysiology of this complex disease. It comprises 1) a prospective, randomized, double-blind, placebo-controlled trial to evaluate efficacy of ALA to treat cognitive and negative symptoms of patients with schizophrenia and 2) an investigation of changes in biomarkers of oxidative stress in response to adjunctive treatment with ALA. The proposed study could establish a new adjunctive treatment for schizophrenia, recognize a novel pharmacological approach and help unveil the biological basis of the disease.

Conditions

Schizophrenia; Oxidative Stress

Keywords

Schizophrenia; Drug repurposing; Alpha-lipoic acid; Adjuvant treatment

Outcome Measures

Primary Outcomes (1)

• Change in the Brief Psychiatry Rating Scale (BPRS) scores

  18-item rating scale to assess changes in psychopathology; each item is scored 0-6, yielding a total between 0 and 108.

  Baseline and 16 weeks

Secondary Outcomes (34)

• Change in the Simpson-Angus Extrapyramidal Symptoms Scale (SAS) scores

  Baseline and 16 weeks

• Brain resting state activity

  Baseline and 16 weeks

• Gut Microbiota Composition

  Baseline and 16 weeks

• Change in Body Mass Index (BMI)

  Baseline and 16 weeks

• Change in Abdominal Circumference

  Baseline and 16 weeks

Study Arms (2)

Experimental group

EXPERIMENTAL

25 subjects will be randomized to 100mg of alpha-lipoic acid.

Drug: Alpha-lipoic acid

Placebo group

PLACEBO COMPARATOR

25 subjects will be randomized to placebo.

Drug: Placebo Oral Tablet

Interventions

Alpha-lipoic acid DRUG

Administration of ALA (100 mg/day) for 4 months, as an adjunct to antipsychotic medication.

Experimental group

Placebo Oral Tablet DRUG

Administration of placebo, as an adjunct to antipsychotic medication.

Placebo group

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Capacity to provide informed consent;
• Schizophrenia diagnosis (made by research psychiatrists using the Structured Clinical Interview, SCID-5, for Diagnostic and Statistical Manual of Mental Disorders);
• Negative and/or cognitive symptoms despite adequate antipsychotic treatment;
• Ages 18-60 years

You may not qualify if:

• month history of any drug or alcohol abuse or dependence;
• Changes in psychotropic medications within the last 4 weeks;
• Actual valproate use (potential interaction with ALA);
• General medical illness including autoimmune disorders, known chronic infections such as HIV or hepatitis C, and liver or renal failure that could adversely impact on patient outcome;
• Women who are planning to become pregnant, are pregnant, or are breastfeeding.

Sponsors & Collaborators

• Nucleo De Pesquisa E Desenvolvimento De Medicamentos Da Universidade Federal Do Ceara: lead
• Conselho Nacional de Desenvolvimento Científico e Tecnológico: collaborator

Study Sites (1)

Núcleo de Pesquisa e Desenvolvimento de Medicamentos - UFC

Fortaleza, Ceará, 60430-275, Brazil

Location

Related Publications (22)

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• Bitanihirwe BK, Woo TU. Oxidative stress in schizophrenia: an integrated approach. Neurosci Biobehav Rev. 2011 Jan;35(3):878-93. doi: 10.1016/j.neubiorev.2010.10.008. Epub 2010 Oct 23.

  PMID: 20974172 BACKGROUND

• Gysin R, Kraftsik R, Boulat O, Bovet P, Conus P, Comte-Krieger E, Polari A, Steullet P, Preisig M, Teichmann T, Cuenod M, Do KQ. Genetic dysregulation of glutathione synthesis predicts alteration of plasma thiol redox status in schizophrenia. Antioxid Redox Signal. 2011 Oct 1;15(7):2003-10. doi: 10.1089/ars.2010.3463. Epub 2010 Oct 30.

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• Fournier M, Ferrari C, Baumann PS, Polari A, Monin A, Bellier-Teichmann T, Wulff J, Pappan KL, Cuenod M, Conus P, Do KQ. Impaired metabolic reactivity to oxidative stress in early psychosis patients. Schizophr Bull. 2014 Sep;40(5):973-83. doi: 10.1093/schbul/sbu053. Epub 2014 Mar 31.

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  PMID: 15098003 BACKGROUND

• Vallianou N, Evangelopoulos A, Koutalas P. Alpha-lipoic Acid and diabetic neuropathy. Rev Diabet Stud. 2009 Winter;6(4):230-6. doi: 10.1900/RDS.2009.6.230. Epub 2009 Dec 30.

  PMID: 20043035 BACKGROUND

• Scott BC, Aruoma OI, Evans PJ, O'Neill C, Van der Vliet A, Cross CE, Tritschler H, Halliwell B. Lipoic and dihydrolipoic acids as antioxidants. A critical evaluation. Free Radic Res. 1994 Feb;20(2):119-33. doi: 10.3109/10715769409147509.

  PMID: 7516789 BACKGROUND

• Vasconcelos GS, Ximenes NC, de Sousa CN, Oliveira Tde Q, Lima LL, de Lucena DF, Gama CS, Macedo D, Vasconcelos SM. 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. 2015 Jul;165(2-3):163-70. doi: 10.1016/j.schres.2015.04.017. Epub 2015 Apr 30.

  PMID: 25937462 BACKGROUND

• GIAMATTEI L. [Thioctic acid in therapy of schizophrenia]. Osp Psichiatr. 1957 Apr-Jun;25(2):221-8. No abstract available. Italian.

  PMID: 13526963 BACKGROUND

• ALTSCHULE MD, GONCZ RM, HOLLIDAY PD. Carbohydrate metabolism in brain disease. XI. Effects of thioctic (alpha-lipoic) acid in chronic schizophrenia. AMA Arch Intern Med. 1959 May;103(5):726-9. doi: 10.1001/archinte.1959.00270050048008. No abstract available.

  PMID: 13636491 BACKGROUND

• Emsley R, Chiliza B, Asmal L, du Plessis S, Phahladira L, van Niekerk E, van Rensburg SJ, Harvey BH. A randomized, controlled trial of omega-3 fatty acids plus an antioxidant for relapse prevention after antipsychotic discontinuation in first-episode schizophrenia. Schizophr Res. 2014 Sep;158(1-3):230-5. doi: 10.1016/j.schres.2014.06.004. Epub 2014 Jul 2.

  PMID: 24996507 BACKGROUND

• Kim E, Park DW, Choi SH, Kim JJ, Cho HS. A preliminary investigation of alpha-lipoic acid treatment of antipsychotic drug-induced weight gain in patients with schizophrenia. J Clin Psychopharmacol. 2008 Apr;28(2):138-46. doi: 10.1097/JCP.0b013e31816777f7.

  PMID: 18344723 BACKGROUND

• Seybolt SE. Less is more. Schizophr Res. 2014 Dec;160(1-3):222-3. doi: 10.1016/j.schres.2014.10.022. Epub 2014 Oct 31. No abstract available.

  PMID: 25458573 BACKGROUND

• Sanders LLO, de Souza Menezes CE, Chaves Filho AJM, de Almeida Viana G, Fechine FV, Rodrigues de Queiroz MG, Goncalvez da Cruz Fonseca S, Mendes Vasconcelos SM, Amaral de Moraes ME, Gama CS, Seybolt S, de Moura Campos E, Macedo D, Freitas de Lucena D. alpha-Lipoic Acid as Adjunctive Treatment for Schizophrenia: An Open-Label Trial. J Clin Psychopharmacol. 2017 Dec;37(6):697-701. doi: 10.1097/JCP.0000000000000800.

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• Steibliene V, Bunevicius A, Savickas A, Prange AJ Jr, Nemeroff CB, Bunevicius R. Triiodothyronine accelerates and enhances the antipsychotic effect of risperidone in acute schizophrenia. J Psychiatr Res. 2016 Feb;73:9-16. doi: 10.1016/j.jpsychires.2015.11.007. Epub 2015 Dec 1.

  PMID: 26679760 BACKGROUND

• Ying Z, Kampfrath T, Sun Q, Parthasarathy S, Rajagopalan S. Evidence that alpha-lipoic acid inhibits NF-kappaB activation independent of its antioxidant function. Inflamm Res. 2011 Mar;60(3):219-25. doi: 10.1007/s00011-010-0256-7. Epub 2010 Oct 7.

  PMID: 20927568 BACKGROUND

• Sola S, Mir MQ, Cheema FA, Khan-Merchant N, Menon RG, Parthasarathy S, Khan BV. Irbesartan and lipoic acid improve endothelial function and reduce markers of inflammation in the metabolic syndrome: results of the Irbesartan and Lipoic Acid in Endothelial Dysfunction (ISLAND) study. Circulation. 2005 Jan 25;111(3):343-8. doi: 10.1161/01.CIR.0000153272.48711.B9. Epub 2005 Jan 17.

  PMID: 15655130 BACKGROUND

• Kanchanatawan B, Hemrungrojn S, Thika S, Sirivichayakul S, Ruxrungtham K, Carvalho AF, Geffard M, Anderson G, Maes M. Changes in Tryptophan Catabolite (TRYCAT) Pathway Patterning Are Associated with Mild Impairments in Declarative Memory in Schizophrenia and Deficits in Semantic and Episodic Memory Coupled with Increased False-Memory Creation in Deficit Schizophrenia. Mol Neurobiol. 2018 Jun;55(6):5184-5201. doi: 10.1007/s12035-017-0751-8. Epub 2017 Sep 5.

  PMID: 28875464 BACKGROUND

• Frota IJ, de Oliveira ALB, De Lima DN Jr, Costa Filho CWL, Menezes CES, Soares MVR, Chaves Filho AJM, Los DB, Moreira RTA, Viana GA, Campos EM, Vasconcelos SMM, Seeman MV, Macedo DS, Sanders LLO. Decrease in cognitive performance and increase of the neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios with higher doses of antipsychotics in women with schizophrenia: a cross-sectional study. BMC Psychiatry. 2023 Aug 2;23(1):558. doi: 10.1186/s12888-023-05050-x.

  PMID: 37532985 DERIVED

• De Lima DN Jr, Costa Filho CWL, Frota IJ, de Oliveira ALB, Menezes CES, Chaves Filho AJM, Viana GA, Campos EM, Collares M, de Queiroz MGR, da Cruz Fonseca SG, Vasconcelos SMM, Macedo DS, Sanders LLO. alpha-Lipoic Acid as Adjunctive Treatment for Schizophrenia: A Randomized Double-Blind Study. J Clin Psychopharmacol. 2023 Jan-Feb 01;43(1):39-45. doi: 10.1097/JCP.0000000000001639.

  PMID: 36584248 DERIVED

MeSH Terms

Conditions

Schizophrenia

Interventions

Thioctic Acid

Condition Hierarchy (Ancestors)

Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Carboxylic Acids; Organic Chemicals; Thiophenes; Sulfur Compounds; Coenzymes; Enzymes and Coenzymes; Fatty Acids; Lipids

Study Officials

• Lia LO Sanders, MD, PhD

  Núcleo de Pesquisa e Desenvolvimento de Medicamentos

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: Proof of concept 4-month prospective, randomized, double-blind, controlled trial

Study Record Dates

• First Submitted: December 20, 2018
• First Posted: December 28, 2018
• Study Start: September 1, 2019
• Primary Completion: December 1, 2021
• Study Completion: December 1, 2021
• Last Updated: August 29, 2022

Record last verified: 2022-08

Locations

BR (1)