Alpha-lipoic Acid Adjunctive Therapy in Schizophrenia
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2/Phase 3 |
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 Design
Arms and Interventions
| 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.
|
Outcome Measures
Primary Outcome Measures
- Change in the Brief Psychiatry Rating Scale (BPRS) scores [Baseline and 16 weeks]
18-item rating scale to assess changes in psychopathology; each item is scored 0-6, yielding a total between 0 and 108.
Secondary Outcome Measures
- Change in the Simpson-Angus Extrapyramidal Symptoms Scale (SAS) scores [Baseline and 16 weeks]
10-item rating scale to assess extrapyramidal symptoms; each item is scored 0-4, yielding a total between 0 and 40.
- Brain resting state activity [Baseline and 16 weeks]
Functional Magnetic Resonance Imaging (fMRI) scans before and after treatment
- Gut Microbiota Composition [Baseline and 16 weeks]
Analyses of patient's gut microbiota
- Change in Body Mass Index (BMI) [Baseline and 16 weeks]
Weight and height will be combined to report BMI in kg/m^2
- Change in Abdominal Circumference [Baseline and 16 weeks]
Abdominal Circumference in cm
- Change in plasma Aspartate Aminotransferase (AST) [Baseline and 16 weeks]
AST in U/L
- Change in plasma Aspartate Aminotransferase (AST) Alanine Aminotransferase (ALT) [Baseline and 16 weeks]
ALT in U/L
- Change in Hemoglobin concentration (HC) [Baseline and 16 weeks]
HC in g/dL
- Change in Hematocrit (Ht) [Baseline and 16 weeks]
Ht in %
- Change in White blood cell count (WBC) [Baseline and 16 weeks]
WBC in number per microliter
- Change in Neutrophil Count (NC) [Baseline and 16 weeks]
NC in number per microliter
- Change in Platelet Count (PC) [Baseline and 16 weeks]
PC in number per microliter
- Change in Glycohemoglobin (HbA1c) [Baseline and 16 weeks]
HbA1c in %
- Change in serum level of Vitamin B12 [Baseline and 16 weeks]
Vitamin B12 in pg/mL
- Change in serum level of Folic Acid [Baseline and 16 weeks]
Folic Acid in ng/mL
- Change in Plasma Glutathione (GSH) [Baseline and 16 weeks]
GSH in ng/mL
- Change in serum level of Nitrite [Baseline and 16 weeks]
Nitrite in nanomole/mililiter
- Change in serum level of Thiobarbituric acid reactive substances (TBARS) [Baseline and 16 weeks]
TBARS in mmol of malonaldehyde/mL
- Change in serum level of Interleukin 1 β (IL-1β) [Baseline and 16 weeks]
IL-1β in pg/mL
- Change in serum level of Interleukin-4 [Baseline and 16 weeks]
IL-4 in pg/mL
- Change in serum level of Interferon gamma (IFNγ) [Baseline and 16 weeks]
IFNγ in pg/mL
- Change in serum level of Tumor necrosis factor alpha (TNF-α) [Baseline and 16 weeks]
TNF-α in pg/mL
- Change in Indoleamine 2,3-dioxygenase (IDO) enzymatic activity [Baseline and 16 weeks]
IDO activity in U IDO mol^-1/mg^-1
- Change in serum level of Eotaxin [Baseline and 16 weeks]
Eotaxin in ng/mL
- Change in serum level of Isoprostanes [Baseline and 16 weeks]
Isoprostanes in pg/mL
- Change in serum level of Calprotectin [Baseline and 16 weeks]
Serum Calprotectin in ng/mL
- Change in serum level of Serotonin [Baseline and 16 weeks]
Serotonin in ng/mL
- Change in Block Corsi Test [Baseline and 16 weeks]
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.
- Change in serum level of Tryptophan [Baseline and 16 weeks]
Tryptophan in micrograms/mL
- Change in Trail Making Test [Baseline and 16 weeks]
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.
- Change in Subtest Digit Span [Baseline and 16 weeks]
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.
- Category (Animal) Fluency [Baseline and 16 weeks]
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
- F-A-S test [Baseline and 16 weeks]
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.
- Rey Auditory Verbal Learning Test [Baseline and 16 weeks]
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
Eligibility Criteria
Criteria
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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Núcleo de Pesquisa e Desenvolvimento de Medicamentos - UFC | Fortaleza | CE | Brazil | 60430-275 |
Sponsors and Collaborators
- Nucleo De Pesquisa E Desenvolvimento De Medicamentos Da Universidade Federal Do Ceara
- Conselho Nacional de Desenvolvimento Científico e Tecnológico
Investigators
- Principal Investigator: Lia LO Sanders, MD, PhD, Núcleo de Pesquisa e Desenvolvimento de Medicamentos
Study Documents (Full-Text)
None provided.More Information
Publications
- 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.
- 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. Review.
- 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.
- 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.
- 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. Review.
- GIAMATTEI L. [Thioctic acid in therapy of schizophrenia]. Osp Psichiatr. 1957 Apr-Jun;25(2):221-8. Italian.
- 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.
- 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.
- 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.
- 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.
- 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.
- Reddy RD, Yao JK. Free radical pathology in schizophrenia: a review. Prostaglandins Leukot Essent Fatty Acids. 1996 Aug;55(1-2):33-43. Review.
- 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. α-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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Ying Z, Kampfrath T, Sun Q, Parthasarathy S, Rajagopalan S. Evidence that α-lipoic acid inhibits NF-κB 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.
- LipoicStudy