Alpha-lipoic Acid Adjunctive Therapy in Schizophrenia

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.

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.