Vitamin B6 and B12 in the Treatment of Movement Disorders Induced by Antipsychotics

Sponsor

Nucleo De Pesquisa E Desenvolvimento De Medicamentos Da Universidade Federal Do Ceara (Other)

Overall Status

Unknown status

CT.gov ID

NCT03790345

Collaborator

(none)

Enrollment

Location

Arms

Anticipated Duration (Months)

1.7

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Schizophrenia Drug Induced Movement Disorder, Unspecified Oxidative Stress	Drug: Pyridoxine Drug: Cobalamin Drug: Placebo Oral Tablet	Phase 2/Phase 3

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

45 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Proof of concept 12-week prospective, randomized, double-blind, controlled trialProof of concept 12-week prospective, randomized, double-blind, controlled trial

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

Effect of Vitamin B6 and B12 in the Treatment of Movement Disorders Induced by Antipsychotics

Actual Study Start Date :

Sep 3, 2019

Anticipated Primary Completion Date :

Jun 3, 2020

Anticipated Study Completion Date :

Nov 3, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Experimental group 1 15 subjects will be randomly assigned to adjuvant treatment with 200mg of vitamin B6 (pyridoxine).	Drug: Pyridoxine Adjuvant daily treatment with 200mg of pyridoxine Other Names: Vitamin B6
Experimental: Experimental group 2 15 subjects will be randomly assigned to adjuvant treatment with 2mg of vitamin B12 (cobalamin).	Drug: Cobalamin Adjuvant daily treatment with 2mg of cobalamin Other Names: Vitamin B12
Sham Comparator: Placebo oral tablet 15 subjects will be randomly assigned to adjuvant treatment with placebo.	Drug: Placebo Oral Tablet Adjuvant daily treatment with placebo

Arm

Intervention/Treatment

Experimental: Experimental group 1

15 subjects will be randomly assigned to adjuvant treatment with 200mg of vitamin B6 (pyridoxine).

Drug: Pyridoxine

Adjuvant daily treatment with 200mg of pyridoxine

Other Names:

Vitamin B6

Experimental: Experimental group 2

15 subjects will be randomly assigned to adjuvant treatment with 2mg of vitamin B12 (cobalamin).

Drug: Cobalamin

Adjuvant daily treatment with 2mg of cobalamin

Other Names:

Vitamin B12

Sham Comparator: Placebo oral tablet

15 subjects will be randomly assigned to adjuvant treatment with placebo.

Drug: Placebo Oral Tablet

Adjuvant daily treatment with placebo

Outcome Measures

Primary Outcome Measures

Change in the Simpson-Angus Extrapyramidal Symptoms Scale (SAS) scores [Baseline and 12 weeks]
10-item rating scale to assess extrapyramidal symptoms; each item is scored 0-4, yielding a total between 0 and 40.
Change in the Barnes Akathisia Rating Scale (BAS, BARS) scores [Baseline and 12 weeks]
Objective Akathisia, Subjective Awareness of Restlessness and Subjective Distress Related to Restlessness are rated on a 4-point scale from 0 - 3 and are summed yielding a total score ranging from 0 to 9. The Global Clinical Assessment of Akathisia uses a 5-point scale ranging from 0 - 4.
Change in the Abnormal Involuntary Movement Scale (AIMS) scores [Baseline and 12 weeks]
10-item rating scale to assess involuntary movements; items are rated on a five-point scale of severity from 0-4, yielding a total between 0 and 40.

Secondary Outcome Measures

Change in the Brief Psychiatry Rating Scale (BPRS) scores [Baseline and 12 weeks]
18-item rating scale to assess changes in psychopathology; each item is scored 0-6, yielding a total between 0 and 40.
Change in Plasma Glutathione (GSH) [Baseline and 12 weeks]
GSH in ng/mL
Change in serum level of Nitrite [Baseline and 12 weeks]
Nitrite in nanomole/mililiter
Change in serum level of Thiobarbituric acid reactive substances (TBARS) [Baseline and 12 weeks]
TBARS in mmol of malonaldehyde/mL
Change in serum level of Interleukin 1 β (IL-1β) [Baseline and 12 weeks]
IL-1β in pg/mL
Change in serum level of Interleukin-4 [Baseline and 12 weeks]
IL-4 in pg/mL
Change in serum level of Interferon gamma (IFNγ) [Baseline and 12 weeks]
IFNγ in pg/mL
Change in serum level of Tumor necrosis factor alpha (TNF-α) [Baseline and 12 weeks]
TNF-α in pg/mL
Change in Indoleamine 2,3-dioxygenase (IDO) enzymatic activity [Baseline and 12 weeks]
IDO activity in U IDO mol^-1/mg^-1

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 60 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.