Schizophrenia, Oxidative Stress
Conditions
Keywords
Schizophrenia, Drug repurposing, Alpha-lipoic acid, Adjuvant treatment
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.
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.
Interventions
Administration of ALA (100 mg/day) for 4 months, as an adjunct to antipsychotic medication.
DRUGPlacebo Oral Tablet
Administration of placebo, as an adjunct to antipsychotic medication.
Sponsors
Conselho Nacional de Desenvolvimento Científico e Tecnológico
Nucleo De Pesquisa E Desenvolvimento De Medicamentos Da Universidade Federal Do Ceara
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Proof of concept 4-month prospective, randomized, double-blind, controlled trial
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| Change in serum level of Serotonin | Baseline and 16 weeks | Serotonin in ng/mL |
| 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 serum level of Calprotectin | Baseline and 16 weeks | Serum Calprotectin 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 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 |
| Change in Plasma Glutathione (GSH) | Baseline and 16 weeks | GSH in ng/mL |
Countries
Brazil
Outcome results
None listed