Clinical trial NCT03790345: Vitamin B6 and B12 in the Treatment of Movement Disorders Induced by Antipsychotics
Official title: Effect of Vitamin B6 and B12 in the Treatment of Movement Disorders Induced by Antipsychotics
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
PHASE3
Conditions: Schizophrenia
Drug Induced Movement Disorder, Unspecified
Oxidative Stress
Keywords: Schizophrenia
Cobalamin
Pyridoxine
Drug-induced movement disorder
Lead sponsor: Nucleo De Pesquisa E Desenvolvimento De Medicamentos Da Universidade Federal Do Ceara
Sponsor class: OTHER
First posted: 2018-12-31
Enrollment: 45
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 12-week prospective, randomized, double-blind, controlled trial
Primary purpose: TREATMENT

Brief summary: D2 dopaminergic receptor blockers, used to treat schizophrenia, can lead to the onset of movement disorders. Drug-induced movement disorders encompass several syndromes. Parkinsonism, dystonia, dyskinesia and akathisia are the most prevalent. All of them lead to poor adherence to the treatment instituted, decrease in the quality of life, relapses and hospitalizations. The pathophysiology of drug-induced movement disorders is complex and poorly understood, but seems to be associated with oxidative stress, as a result of an increase in free radicals generated from dopamine metabolism. Treatment strategies following the onset of drug-induced movement disorders include neuroleptic discontinuation, use of atypical antipsychotics and anticholinergics. A pre-clinical study showed that the antioxidant properties of vitamins B6 and B12, alone or in combination, prevented the development of orofacial dyskinesia induced by haloperidol. This clinical trial aims to evaluate the effects of vitamins B6 and B12 on the treatment of patients diagnosed with schizophrenia, schizoaffective or bipolar disorder who present with tardive dyskinesia, dystonia and parkinsonism.

Detailed description: D2 dopaminergic receptor blockers, used to treat schizophrenia, can lead to the onset of drug-induced movement disorders, such as parkinsonism, dystonia, dyskinesia and akathisia. They seem to be associated with oxidative stress, as a result of an increase in free radicals generated from dopamine metabolism. A preclinical study showed that vitamin B6 (pyridoxine) and B12 (cobalamin), alone or in combination, prevented the development of orofacial dyskinesia induced by haloperidol in an animal model of schizophrenia.

Specific Aim1: To conduct a prospective, randomized, double-blind, placebo-controlled trial to evaluate the efficacy of 12-week adjuvant treatment with 200mg of pyridoxine (B6) or 2mg of cobalamin (B12) to treat drug-induced movement disorders of patients with schizophrenia, schizoaffective or bipolar disorder. The investigators will randomly assign 45 patients into three groups: placebo, B6 or B12 and check whether administration of vitamin B6 (pyridoxine) or B12 (cobalamin) attenuates drug-induced movement disorders (IDDM) in patients with diagnosis of schizophrenia, schizoaffective or bipolar disorder.

Specific Aim 2: To quantify changes in serum markers of inflammation and biomarkers of oxidative stress in response to adjunctive treatment with B6 or B12. The hypothesis is that changes in these biomarkers will mediate the clinical response to them.

Research Plan: The investigators will carry out a proof of concept 12-week prospective, randomized, double-blind, controlled trial of vitamin B6 and B12, at doses of 200 mg/day and 2mg/day, respectively, or identical placebo tablets, added to ongoing antipsychotics in 45 stable patients (ages 18-60 years, 15 patients per group) with diagnosis of schizophrenia, schizoaffective or bipolar disorder. 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 (confirmed by Structured Clinical Interview (SCID);
* Movement disorders induced by psychotropic drugs of at least moderate severity;
* Exposure to psychotropic medication for at least three months prior of the appearance of movement disorders;.
* Disorders of movement for at least one year;
* Stable psychotropic regimen for at least one month prior to study entry.

Exclusion Criteria:

* 6-month history of any drug or alcohol abuse or dependence;
* Changes in psychotropic medications within the last 4 weeks;
* 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 Simpson-Angus Extrapyramidal Symptoms Scale (SAS) scores
timeFrame: Baseline and 12 weeks
measure: Change in the Barnes Akathisia Rating Scale (BAS, BARS) scores
timeFrame: Baseline and 12 weeks
measure: Change in the Abnormal Involuntary Movement Scale (AIMS) scores
timeFrame: Baseline and 12 weeks
Secondary outcomes:
measure: Change in the Brief Psychiatry Rating Scale (BPRS) scores
timeFrame: Baseline and 12 weeks
measure: Change in Plasma Glutathione (GSH)
timeFrame: Baseline and 12 weeks
measure: Change in serum level of Nitrite
timeFrame: Baseline and 12 weeks
measure: Change in serum level of Thiobarbituric acid reactive substances (TBARS)
timeFrame: Baseline and 12 weeks
measure: Change in serum level of Interleukin 1 β (IL-1β)
timeFrame: Baseline and 12 weeks
measure: Change in serum level of Interleukin-4
timeFrame: Baseline and 12 weeks
measure: Change in serum level of Interferon gamma (IFNγ)
timeFrame: Baseline and 12 weeks
measure: Change in serum level of Tumor necrosis factor alpha (TNF-α)
timeFrame: Baseline and 12 weeks
measure: Change in Indoleamine 2,3-dioxygenase (IDO) enzymatic activity
timeFrame: Baseline and 12 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
References: