Clinical trial NCT03788759: Alpha-lipoic Acid Adjunctive Therapy in Schizophrenia
Official title: Alpha-lipoic Acid Adjunctive Therapy in Schizophrenia: A Randomized, Double-blind, Placebo-controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Schizophrenia
Oxidative Stress
Keywords: Schizophrenia
Drug repurposing
Alpha-lipoic acid
Adjuvant treatment
Lead sponsor: Nucleo De Pesquisa E Desenvolvimento De Medicamentos Da Universidade Federal Do Ceara
Sponsor class: OTHER
Collaborators: name: Conselho Nacional de Desenvolvimento Científico e Tecnológico
First posted: 2018-12-28
Enrollment: 48
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Proof of concept 4-month prospective, randomized, double-blind, controlled trial
Primary purpose: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Change in the Brief Psychiatry Rating Scale (BPRS) scores
timeFrame: Baseline and 16 weeks
Secondary outcomes:
measure: Change in the Simpson-Angus Extrapyramidal Symptoms Scale (SAS) scores
timeFrame: Baseline and 16 weeks
measure: Brain resting state activity
timeFrame: Baseline and 16 weeks
measure: Gut Microbiota Composition
timeFrame: Baseline and 16 weeks
measure: Change in Body Mass Index (BMI)
timeFrame: Baseline and 16 weeks
measure: Change in Abdominal Circumference
timeFrame: Baseline and 16 weeks
measure: Change in plasma Aspartate Aminotransferase (AST)
timeFrame: Baseline and 16 weeks
measure: Change in plasma Aspartate Aminotransferase (AST) Alanine Aminotransferase (ALT)
timeFrame: Baseline and 16 weeks
measure: Change in Hemoglobin concentration (HC)
timeFrame: Baseline and 16 weeks
measure: Change in Hematocrit (Ht)
timeFrame: Baseline and 16 weeks
measure: Change in White blood cell count (WBC)
timeFrame: Baseline and 16 weeks
measure: Change in Neutrophil Count (NC)
timeFrame: Baseline and 16 weeks
measure: Change in Platelet Count (PC)
timeFrame: Baseline and 16 weeks
measure: Change in Glycohemoglobin (HbA1c)
timeFrame: Baseline and 16 weeks
measure: Change in serum level of Vitamin B12
timeFrame: Baseline and 16 weeks
measure: Change in serum level of Folic Acid
timeFrame: Baseline and 16 weeks
measure: Change in Plasma Glutathione (GSH)
timeFrame: Baseline and 16 weeks
measure: Change in serum level of Nitrite
timeFrame: Baseline and 16 weeks
measure: Change in serum level of Thiobarbituric acid reactive substances (TBARS)
timeFrame: Baseline and 16 weeks
measure: Change in serum level of Interleukin 1 β (IL-1β)
timeFrame: Baseline and 16 weeks
measure: Change in serum level of Interleukin-4
timeFrame: Baseline and 16 weeks
measure: Change in serum level of Interferon gamma (IFNγ)
timeFrame: Baseline and 16 weeks
measure: Change in serum level of Tumor necrosis factor alpha (TNF-α)
timeFrame: Baseline and 16 weeks
measure: Change in Indoleamine 2,3-dioxygenase (IDO) enzymatic activity
timeFrame: Baseline and 16 weeks
measure: Change in serum level of Eotaxin
timeFrame: Baseline and 16 weeks
measure: Change in serum level of Isoprostanes
timeFrame: Baseline and 16 weeks
measure: Change in serum level of Calprotectin
timeFrame: Baseline and 16 weeks
measure: Change in serum level of Serotonin
timeFrame: Baseline and 16 weeks
measure: Change in Block Corsi Test
timeFrame: Baseline and 16 weeks
measure: Change in serum level of Tryptophan
timeFrame: Baseline and 16 weeks
measure: Change in Trail Making Test
timeFrame: Baseline and 16 weeks
measure: Change in Subtest Digit Span
timeFrame: Baseline and 16 weeks
measure: Category (Animal) Fluency
timeFrame: Baseline and 16 weeks
measure: F-A-S test
timeFrame: Baseline and 16 weeks
measure: Rey Auditory Verbal Learning Test
timeFrame: Baseline and 16 weeks
Other outcomes:
Locations:
city: Fortaleza
country: Brazil
facility: Núcleo de Pesquisa e Desenvolvimento de Medicamentos - UFC
state: CE
Study officials:
affiliation: Núcleo de Pesquisa e Desenvolvimento de Medicamentos
name: Lia LO Sanders, MD, PhD
role: PRINCIPAL_INVESTIGATOR
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