Alpha-lipoic Acid Adjunctive Therapy in Schizophrenia

Schizophrenia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03788759
• Other study ID #: LipoicStudy
• Status: Completed
• Phase: Phase 2/Phase 3
• Start date: September 1, 2019
• Est. completion date: December 1, 2021

Study information

• Verified date: August 2022
• Source: Nucleo De Pesquisa E Desenvolvimento De Medicamentos Da Universidade Federal Do Ceara
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 48
• Est. completion date: December 1, 2021
• Est. primary completion date: December 1, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

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.

Related Conditions & MeSH terms

• Oxidative Stress
• Schizophrenia

Intervention

Drug:
• Alpha-lipoic acid
Administration of ALA (100 mg/day) for 4 months, as an adjunct to antipsychotic medication.
• Placebo Oral Tablet
Administration of placebo, as an adjunct to antipsychotic medication.

Locations

Country	Name	City	State
Brazil	Núcleo de Pesquisa e Desenvolvimento de Medicamentos - UFC	Fortaleza	CE

Sponsors (2)

Lead Sponsor	Collaborator
Nucleo De Pesquisa E Desenvolvimento De Medicamentos Da Universidade Federal Do Ceara	Conselho Nacional de Desenvolvimento Científico e Tecnológico

Country where clinical trial is conducted

Brazil, 

References & Publications (20)

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Gysin R, Kraftsik R, Boulat O, Bovet P, Conus P, Comte-Krieger E, Polari A, Steullet P, Preisig M, Teichmann T, Cuénod 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. — View Citation

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. — View Citation

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. — View Citation

Perälä J, Suvisaari J, Saarni SI, Kuoppasalmi K, Isometsä E, Pirkola S, Partonen T, Tuulio-Henriksson A, Hintikka J, Kieseppä T, Härkänen T, Koskinen S, Lönnqvist J. Lifetime prevalence of psychotic and bipolar I disorders in a general population. Arch Gen Psychiatry. 2007 Jan;64(1):19-28. — View Citation

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. — View Citation

Reddy RD, Yao JK. Free radical pathology in schizophrenia: a review. Prostaglandins Leukot Essent Fatty Acids. 1996 Aug;55(1-2):33-43. Review. — View Citation

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. a-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. — View Citation

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. — View Citation

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. — View Citation

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. Epub 2005 Jan 17. — View Citation

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. — View Citation

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. — View Citation

Vasconcelos GS, Ximenes NC, de Sousa CN, Oliveira Tde Q, Lima LL, de Lucena DF, Gama CS, Macêdo 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. — View Citation

Ying Z, Kampfrath T, Sun Q, Parthasarathy S, Rajagopalan S. Evidence that a-lipoic acid inhibits NF-?B 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. — View Citation

* Note: There are 20 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	Brain resting state activity	Functional Magnetic Resonance Imaging (fMRI) scans before and after treatment	Baseline and 16 weeks
Secondary	Gut Microbiota Composition	Analyses of patient's gut microbiota	Baseline and 16 weeks
Secondary	Change in Body Mass Index (BMI)	Weight and height will be combined to report BMI in kg/m^2	Baseline and 16 weeks
Secondary	Change in Abdominal Circumference	Abdominal Circumference in cm	Baseline and 16 weeks
Secondary	Change in plasma Aspartate Aminotransferase (AST)	AST in U/L	Baseline and 16 weeks
Secondary	Change in plasma Aspartate Aminotransferase (AST) Alanine Aminotransferase (ALT)	ALT in U/L	Baseline and 16 weeks
Secondary	Change in Hemoglobin concentration (HC)	HC in g/dL	Baseline and 16 weeks
Secondary	Change in Hematocrit (Ht)	Ht in %	Baseline and 16 weeks
Secondary	Change in White blood cell count (WBC)	WBC in number per microliter	Baseline and 16 weeks
Secondary	Change in Neutrophil Count (NC)	NC in number per microliter	Baseline and 16 weeks
Secondary	Change in Platelet Count (PC)	PC in number per microliter	Baseline and 16 weeks
Secondary	Change in Glycohemoglobin (HbA1c)	HbA1c in %	Baseline and 16 weeks
Secondary	Change in serum level of Vitamin B12	Vitamin B12 in pg/mL	Baseline and 16 weeks
Secondary	Change in serum level of Folic Acid	Folic Acid in ng/mL	Baseline and 16 weeks
Secondary	Change in Plasma Glutathione (GSH)	GSH in ng/mL	Baseline and 16 weeks
Secondary	Change in serum level of Nitrite	Nitrite in nanomole/mililiter	Baseline and 16 weeks
Secondary	Change in serum level of Thiobarbituric acid reactive substances (TBARS)	TBARS in mmol of malonaldehyde/mL	Baseline and 16 weeks
Secondary	Change in serum level of Interleukin 1 ß (IL-1ß)	IL-1ß in pg/mL	Baseline and 16 weeks
Secondary	Change in serum level of Interleukin-4	IL-4 in pg/mL	Baseline and 16 weeks
Secondary	Change in serum level of Interferon gamma (IFN?)	IFN? in pg/mL	Baseline and 16 weeks
Secondary	Change in serum level of Tumor necrosis factor alpha (TNF-a)	TNF-a in pg/mL	Baseline and 16 weeks
Secondary	Change in Indoleamine 2,3-dioxygenase (IDO) enzymatic activity	IDO activity in U IDO mol^-1/mg^-1	Baseline and 16 weeks
Secondary	Change in serum level of Eotaxin	Eotaxin in ng/mL	Baseline and 16 weeks
Secondary	Change in serum level of Isoprostanes	Isoprostanes in pg/mL	Baseline and 16 weeks
Secondary	Change in serum level of Calprotectin	Serum Calprotectin in ng/mL	Baseline and 16 weeks
Secondary	Change in serum level of Serotonin	Serotonin in ng/mL	Baseline and 16 weeks
Secondary	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
Secondary	Change in serum level of Tryptophan	Tryptophan in micrograms/mL	Baseline and 16 weeks
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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