Alpha-lipoic Acid Adjunctive Therapy in Schizophrenia: A Randomized, Double-blind, Placebo-controlled Trial
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 48
- 试验地点
- 1
- 主要终点
- Change in the Brief Psychiatry Rating Scale (BPRS) scores
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 60 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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.
研究组 & 干预措施
Experimental group
25 subjects will be randomized to 100mg of alpha-lipoic acid.
干预措施: Alpha-lipoic acid (Drug)
Placebo group
25 subjects will be randomized to placebo.
干预措施: Placebo Oral Tablet (Drug)
结局指标
主要结局
Change in the Brief Psychiatry Rating Scale (BPRS) scores
时间窗: 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.
次要结局
- Change in serum level of Interleukin-4(Baseline and 16 weeks)
- Change in serum level of Thiobarbituric acid reactive substances (TBARS)(Baseline and 16 weeks)
- Brain resting state activity(Baseline and 16 weeks)
- Change in plasma Aspartate Aminotransferase (AST)(Baseline and 16 weeks)
- Change in Neutrophil Count (NC)(Baseline and 16 weeks)
- Change in serum level of Interleukin 1 β (IL-1β)(Baseline and 16 weeks)
- Gut Microbiota Composition(Baseline and 16 weeks)
- Change in Hemoglobin concentration (HC)(Baseline and 16 weeks)
- Change in Glycohemoglobin (HbA1c)(Baseline and 16 weeks)
- Change in serum level of Eotaxin(Baseline and 16 weeks)
- Change in serum level of Isoprostanes(Baseline and 16 weeks)
- Rey Auditory Verbal Learning Test(Baseline and 16 weeks)
- Change in Body Mass Index (BMI)(Baseline and 16 weeks)
- Change in Abdominal Circumference(Baseline and 16 weeks)
- Change in serum level of Nitrite(Baseline and 16 weeks)
- Change in serum level of Tumor necrosis factor alpha (TNF-α)(Baseline and 16 weeks)
- Change in serum level of Tryptophan(Baseline and 16 weeks)
- F-A-S test(Baseline and 16 weeks)
- Change in the Simpson-Angus Extrapyramidal Symptoms Scale (SAS) scores(Baseline and 16 weeks)
- Change in White blood cell count (WBC)(Baseline and 16 weeks)
- Change in serum level of Folic Acid(Baseline and 16 weeks)
- Change in serum level of Serotonin(Baseline and 16 weeks)
- Change in Block Corsi Test(Baseline and 16 weeks)
- Category (Animal) Fluency(Baseline and 16 weeks)
- Change in plasma Aspartate Aminotransferase (AST) Alanine Aminotransferase (ALT)(Baseline and 16 weeks)
- Change in Hematocrit (Ht)(Baseline and 16 weeks)
- Change in Platelet Count (PC)(Baseline and 16 weeks)
- Change in serum level of Vitamin B12(Baseline and 16 weeks)
- Change in Plasma Glutathione (GSH)(Baseline and 16 weeks)
- Change in serum level of Interferon gamma (IFNγ)(Baseline and 16 weeks)
- Change in Trail Making Test(Baseline and 16 weeks)
- Change in Indoleamine 2,3-dioxygenase (IDO) enzymatic activity(Baseline and 16 weeks)
- Change in serum level of Calprotectin(Baseline and 16 weeks)
- Change in Subtest Digit Span(Baseline and 16 weeks)
研究者
Lia Sanders
Principal Investigator
Nucleo De Pesquisa E Desenvolvimento De Medicamentos Da Universidade Federal Do Ceara