Alpha-lipoic Acid Adjunctive Therapy in Schizophrenia
Condition: Schizophrenia; Oxidative Stress
MeSH terms: Schizophrenia
Study type: Interventional
Phase: Phase 2/Phase 3

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.
    

Intervention name(s): Alpha-lipoic acid; Placebo Oral Tablet
Intervention type(s): Drug; Drug
Intervention description(s): Administration of ALA (100 mg/day) for 4 months, as an adjunct to antipsychotic medication.; Administration of placebo, as an adjunct to antipsychotic medication.
Intervention MeSH terms: Thioctic Acid
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Proof of concept 4-month prospective, randomized, double-blind, controlled trial
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Schizophrenia; Drug repurposing; Alpha-lipoic acid; Adjuvant treatment