Alpha-lipoic Acid Adjunctive Therapy in Schizophrenia

Alpha-lipoic Acid Adjunctive Therapy in Schizophrenia: A Randomized, Double-blind, Placebo-controlled Trial

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.

Study Overview

• Status: Completed
• Conditions: Schizophrenia; Oxidative Stress
• Intervention / Treatment: Drug: Alpha-lipoic acid; Drug: Placebo Oral Tablet

Detailed Description

The underlying pathogenesis of schizophrenia remains unknown, but aberrant reduction-oxidation has gained increasing support as an hypothesis to help explain the pathophysiology of the disease. Alpha-lipoic acid (ALA) is a naturally occurring antioxidant, essential for the function of different enzymes of mitochondria's oxidative metabolism, that is currently approved to treat diabetic neuropathic pain9. ALA and its reduced form, dihydrolipoic acid (DHLA), have important advantages over other antioxidant agents such as vitamin E and C, partly due to their amphiphilic properties, which confer antioxidant actions in the membrane as well as in the cytosol. A preclinical study conducted in our lab showed that ALA alone and combined with clozapine reverses schizophrenia associated symptoms and pro-oxidant changes induced by ketamine in mice. Before the widespread use of antipsychotics, two studies found that low doses of ALA relieved symptoms in patients with schizophrenia.

More recently, my colleagues and I conducted an open label proof of concept study that provided encouraging evidence that low doses of ALA might be an effective adjunctive treatment for schizophrenia. Based on promising preliminary results, the investigators will now test ALA in a more rigorous placebo-controlled clinical study.

Specific Aim1: To conduct a prospective, randomized, double-blind, placebo-controlled trial to evaluate the efficacy of adjuvant treatment with low doses (100mg) of ALA to treat cognitive and negative symptoms of patients with schizophrenia. The investigators will randomize 50 patients over 4 months.

Specific Aim 2: To quantify changes in biomarkers of oxidative stress in response to adjunctive treatment with ALA. The hypothesis is that changes in these biomarkers will mediate the clinical response to ALA.

Research Plan: To carry out a proof of concept 4-month prospective, randomized, double-blind, controlled trial of alpha-lipoic acid, at doses of 100 mg/day or identical placebo tablets, added to ongoing antipsychotics in 50 stable patients (ages 18-60 years, 25 patients per group) with diagnosis of schizophrenia. The study will be conducted at the Drug Research and Development Center (NPDM), at the Universidade Federal do Ceará, Fortaleza, Brazil. This center has a long history of performing placebocontrolled trials in clinical medicine (http://www.npdm.ufc.br/) and has the necessary infrastructure to successfully complete the proposed study protocol. All participants will give written informed consent prior to study enrollment.

• Study Type: Interventional
• Enrollment (Actual): 48
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Brazil
  • CE
    • Fortaleza, CE, Brazil, 60430-275
      • Núcleo de Pesquisa e Desenvolvimento de Medicamentos - UFC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 58 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 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

Exclusion Criteria:

• 6-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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Experimental group; 25 subjects will be randomized to 100mg of alpha-lipoic acid.	Drug: Alpha-lipoic acid; Administration of ALA (100 mg/day) for 4 months, as an adjunct to antipsychotic medication.
Placebo Comparator: Placebo group; 25 subjects will be randomized to placebo.	Drug: Placebo Oral Tablet; Administration of placebo, as an adjunct to antipsychotic medication.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in the Simpson-Angus Extrapyramidal Symptoms Scale (SAS) scores	10-item rating scale to assess extrapyramidal symptoms; each item is scored 0-4, yielding a total between 0 and 40.	Baseline and 16 weeks
Brain resting state activity	Functional Magnetic Resonance Imaging (fMRI) scans before and after treatment	Baseline and 16 weeks
Gut Microbiota Composition	Analyses of patient's gut microbiota	Baseline and 16 weeks
Change in Body Mass Index (BMI)	Weight and height will be combined to report BMI in kg/m^2	Baseline and 16 weeks
Change in Abdominal Circumference	Abdominal Circumference in cm	Baseline and 16 weeks
Change in plasma Aspartate Aminotransferase (AST)	AST in U/L	Baseline and 16 weeks
Change in plasma Aspartate Aminotransferase (AST) Alanine Aminotransferase (ALT)	ALT in U/L	Baseline and 16 weeks
Change in Hemoglobin concentration (HC)	HC in g/dL	Baseline and 16 weeks
Change in Hematocrit (Ht)	Ht in %	Baseline and 16 weeks
Change in White blood cell count (WBC)	WBC in number per microliter	Baseline and 16 weeks
Change in Neutrophil Count (NC)	NC in number per microliter	Baseline and 16 weeks
Change in Platelet Count (PC)	PC in number per microliter	Baseline and 16 weeks
Change in Glycohemoglobin (HbA1c)	HbA1c in %	Baseline and 16 weeks
Change in serum level of Vitamin B12	Vitamin B12 in pg/mL	Baseline and 16 weeks
Change in serum level of Folic Acid	Folic Acid in ng/mL	Baseline and 16 weeks
Change in Plasma Glutathione (GSH)	GSH in ng/mL	Baseline and 16 weeks
Change in serum level of Nitrite	Nitrite in nanomole/mililiter	Baseline and 16 weeks
Change in serum level of Thiobarbituric acid reactive substances (TBARS)	TBARS in mmol of malonaldehyde/mL	Baseline and 16 weeks
Change in serum level of Interleukin 1 β (IL-1β)	IL-1β in pg/mL	Baseline and 16 weeks
Change in serum level of Interleukin-4	IL-4 in pg/mL	Baseline and 16 weeks
Change in serum level of Interferon gamma (IFNγ)	IFNγ in pg/mL	Baseline and 16 weeks
Change in serum level of Tumor necrosis factor alpha (TNF-α)	TNF-α in pg/mL	Baseline and 16 weeks
Change in Indoleamine 2,3-dioxygenase (IDO) enzymatic activity	IDO activity in U IDO mol^-1/mg^-1	Baseline and 16 weeks
Change in serum level of Eotaxin	Eotaxin in ng/mL	Baseline and 16 weeks
Change in serum level of Isoprostanes	Isoprostanes in pg/mL	Baseline and 16 weeks
Change in serum level of Calprotectin	Serum Calprotectin in ng/mL	Baseline and 16 weeks
Change in serum level of Serotonin	Serotonin in ng/mL	Baseline and 16 weeks
Change in Block Corsi Test	This test assesses visuo-spatial short term working memory. Participants are asked to mimick a researcher as he/she taps a sequence of up to nine identical spatially separated blocks. The test measures both the number of correct sequences and the longest sequence remembered.	Baseline and 16 weeks
Change in serum level of Tryptophan	Tryptophan in micrograms/mL	Baseline and 16 weeks
Change in Trail Making Test	Trail Making Test measured in time and number of errors. It tests visual attention and task switching. It consists of two parts in which the subject is instructed to connect a set of 25 dots as quickly as possible while still maintaining accuracy. Provide information about visual search speed, scanning, speed of processing, mental flexibility, executive functioning.	Baseline and 16 weeks
Change in Subtest Digit Span	Individual tries to repeat digits forward, backward, and in ascending order. This test measures short term memory, working memory. The score is the maximum number of digits correctly remembered.	Baseline and 16 weeks
Category (Animal) Fluency	Participants have to produce as many words as possible from a category in a given time (usually 60 seconds). Performance measure is the total number of words	Baseline and 16 weeks
F-A-S test	It assesses phonemic fluency by requesting an individual to orally produce as many words as possible that begin with the letters F, A, and S within a prescribed time frame, usually 1 min.	Baseline and 16 weeks
Rey Auditory Verbal Learning Test	Participants are asked to repeat list of 15 unrelated words; another list of 15 unrelated words are given and participants must again repeat the original list of 15 words and then again after 30 minutes. Score range: 0-15	Baseline and 16 weeks

Collaborators and Investigators

• Sponsor: Nucleo De Pesquisa E Desenvolvimento De Medicamentos Da Universidade Federal Do Ceara
• Collaborators: Conselho Nacional de Desenvolvimento Científico e Tecnológico
• Investigators: Principal Investigator: Lia LO Sanders, MD, PhD, Núcleo de Pesquisa e Desenvolvimento de Medicamentos

Publications and helpful links

General Publications

• 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.
• Perala J, Suvisaari J, Saarni SI, Kuoppasalmi K, Isometsa E, Pirkola S, Partonen T, Tuulio-Henriksson A, Hintikka J, Kieseppa T, Harkanen T, Koskinen S, Lonnqvist J. Lifetime prevalence of psychotic and bipolar I disorders in a general population. Arch Gen Psychiatry. 2007 Jan;64(1):19-28. doi: 10.1001/archpsyc.64.1.19.
• Foussias G, Agid O, Fervaha G, Remington G. Negative symptoms of schizophrenia: clinical features, relevance to real world functioning and specificity versus other CNS disorders. Eur Neuropsychopharmacol. 2014 May;24(5):693-709. doi: 10.1016/j.euroneuro.2013.10.017. Epub 2013 Nov 11.
• Reddy RD, Yao JK. Free radical pathology in schizophrenia: a review. Prostaglandins Leukot Essent Fatty Acids. 1996 Aug;55(1-2):33-43. doi: 10.1016/s0952-3278(96)90143-x.
• 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.
• 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.
• Prabakaran S, Swatton JE, Ryan MM, Huffaker SJ, Huang JT, Griffin JL, Wayland M, Freeman T, Dudbridge F, Lilley KS, Karp NA, Hester S, Tkachev D, Mimmack ML, Yolken RH, Webster MJ, Torrey EF, Bahn S. Mitochondrial dysfunction in schizophrenia: evidence for compromised brain metabolism and oxidative stress. Mol Psychiatry. 2004 Jul;9(7):684-97, 643. doi: 10.1038/sj.mp.4001511.
• 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.
• 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.
• 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.
• GIAMATTEI L. [Thioctic acid in therapy of schizophrenia]. Osp Psichiatr. 1957 Apr-Jun;25(2):221-8. No abstract available. Italian.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2019
• Primary Completion (Actual): December 1, 2021
• Study Completion (Actual): December 1, 2021

Study Registration Dates

• First Submitted: December 20, 2018
• First Submitted That Met QC Criteria: December 23, 2018
• First Posted (Actual): December 28, 2018

Study Record Updates

• Last Update Posted (Actual): August 29, 2022
• Last Update Submitted That Met QC Criteria: August 26, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Keywords: Schizophrenia; Adjuvant treatment; Alpha-lipoic acid; Drug repurposing
• Additional Relevant MeSH Terms: Mental Disorders; Schizophrenia Spectrum and Other Psychotic Disorders; Schizophrenia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Protective Agents; Micronutrients; Vitamins; Antioxidants; Vitamin B Complex; Thioctic Acid
• Other Study ID Numbers: LipoicStudy

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No