Alpha-lipoic Acid Adjunctive Therapy in Schizophrenia

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Schizophrenia, Oxidative Stress

Intervention / Treatment
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* Drug: Alpha-lipoic acid
* Drug: Placebo Oral Tablet


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Proof of concept 4-month prospective, randomized, double-blind, controlled trial
Masking: Quadruple


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Schizophrenia, Drug repurposing, Alpha-lipoic acid, Adjuvant treatment