Abstract
Introduction
Tardive dyskinesia (TD) is a severe delayed-onset iatrogenic movement disorder caused by dopamine receptor-blocking agents [Waln and Jankovic, 2013]. TD is a major side effect of long-term use of conventional or typical antipsychotics that can be debilitating and, in most cases, persistent [Margolese et al. 2005]. The aimless and uncontrollable movement seen in TD may involve the mouth, tongue, jaw, trunk and extremities. TD affects about 20% of individuals treated with neuroleptics [Kane and Smith, 1982]. In Nigeria, the prevalence of TD is 27% among psychiatric patients on antipsychotics [Gureje, 1989], while among other Africans and Asians, the prevalence of TD is 24% and 17.2%, respectively [Pandurangi and Aderibigbe, 1995]. Risk factors for TD include increasing age, female gender [Correll et al. 2004], alcohol and drug abuse, mood disorder and diabetes mellitus [Bhidayasiri and Boonyawairoj, 2011; Tarsy and Baldessarini, 2006]. In Asia and Africa, female gender is not a risk factor in TD, though long-term hospitalization and older age are associated with TD [Pandurangi and Aderibigbe, 1995]. The condition is associated with reduced quality-adjusted life-years (QALYs) and increased cost of healthcare [Ascher-Svanum et al. 2008; Rosenheck, 2007].
TD may be a potentially irreversible condition with most treatment modalities having less satisfactory outcome which may require complex dosing, have their own adverse effects and use for long periods that may not be desirable [Lerner et al. 2015; Waln and Jankovic, 2013]. Various treatments have been used including the use of clozapine and quietiapine [Emsley et al. 2004], dopamine-depleting agents like tetrabenazine and amantaidine [Aia et al. 2011; Kenney and Jankovi, 2006], gamma amino butyric acid (GABA) agonists like valproate and clonazepam [Aia et al. 2011; Aladed et al. 2011] and anticholinergic medications such as trihexyphenidyl [Fernandez and Friedman, 2003]. Less commonly studied agents which might be effective include pyridoxine [Waln and Jankovic, 2013].
Pyridoxine has been used experimentally in the past two decades [Lerner et al. 2015], with a number of case reports [Lerner and Liberman, 1998, 1999] and a randomized, double-blind, placebo-controlled, crossover study [Lerner et al. 2007]. A Cochrane review concluded that pyridoxine may be beneficial in reducing the severity of TD, but further studies are needed because of the limited number of existing studies and short follow-up periods [Adelufosi et al. 2015].
Here we present a case demonstrating the beneficial effect of pyridoxine in reducing the severity of TD in a patient with schizophrenia after clozapine had moderate effect on the movement disorder.
Ethical consideration
Ethical review and clearance was obtained from the Aminu Kano Teaching Hospital Ethical Committee. Thereafter an informed consent was sought from the patient and her guardian.
Case
YM is a 29-year old female being managed for treatment-resistant schizophrenia with TD. She was commenced on clozapine after both typical (haloperidol, trifluoperazine and flupenthixol decanoate) and atypical antipsychotics (olanzapine and risperidone) failed. Her Positive and Negative Symptoms Scale Score (PANSS) at the start of therapy with clozapine was 108. All other medications were stopped at the start of clozapine therapy. TD affected the legs, hands, facial and oral regions, and the trunk with puckering and pouting of the mouth, grimacing, choreic movement of the hands and fingers, feet squirming and twisting of shoulder and neck. The total severity score (item 8) of her Abnormal Involuntary Movement Scale (AIMS) at this period was 15, with a score of 4 for item 1, scores of 3 for items 2 and 3, and scores of 2 for items 5 and 7, while the score for item 9 (global severity score) was 4.
After 6 months on clozapine, at 400 mg daily, with remarkable improvement in her psychopathology (PANSS score of 62), TD was still a major problem limiting her functioning, with the total severity score of AIMS of 9 and the global severity score being 4. It was at this point that high dose of pyridoxine at 450 mg in 3 divided doses was introduced. Table 1 shows the total severity and global severity scores of AIMS at various periods on pyridoxine.
Showing improvement in the symptom of tardive dyskinesia from pyridoxine treatment.
AIMS, Abnormal Involuntary Movement Scale.
Within 4 weeks of starting on pyridoxine, which was escalated to 600 mg in 3 divided doses, the total severity was reduced by 44%; by the sixth week it was reduced by 56% and at 3 months the severity was reduced by 67%. After 6 months on pyridoxine, the total severity of the TD was reduced by 78%. At this point, pyridoxine was stopped, and at the ninth month, the total severity was still reduced by 78% from the baseline of commencement of pyridoxine. This improvement was maintained even after 18 months.
The patient was not on anticholinergics and did not have any side effects attributable to pyridoxine. There was no deterioration in her psychiatric symptoms, as the PANSS score continued to improve to 34 at 9 months. After month 9, clozapine was stopped because the patient could not cope with monthly blood monitoring and risperidone was introduced. The PANSS score was 38 at 18 months when she was on risperidone.
Discussion
Searches were performed during September 2015 on PubMed, EMBASE and Google Scholar with keywords including ‘high dose pyridoxine’, ‘pyridoxine’, ‘tardive dyskinesia’, ‘movement disorder’ and ‘Vitamin B6’. A number of articles on the use of pyridoxine were retrieved (Table 2).
Treatment of tardive dyskinesia using pyridoxine.
AIMS, Abnormal Involuntary Movement Scale; ESRS, Extrapyramidal Symptom Rating Scale; NS, not specified; TD, tardive dyskinesia.
The mechanism by which pyridoxine produces a beneficial effect in reducing the severity of TD is not fully understood. Recent studies have demonstrated that patients with schizophrenia and schizoaffective disorder who have TD have reduced level of pyridoxal 5′- phosphate [Miodownik et al. 2008]. Pyridoxal 5′-phosphate is a coenzyme in the decarboxylation of
TD is a very disabling condition with the tremendous clinical challenge of having drug treatments with little evidence to support their efficacy [Adelufosi et al. 2015]. However, medication like pyridoxine, even though it may cause peripheral neuropathy when given in high doses, has been known not to be associated with any side effects with doses as high as 1200 mg/day [Miodownik et al. 2008].
The patient in this study was given pyridoxine at a dose of 600 mg/day and had a 78% reduction in severity of TD by month 6. But even in the first 4 weeks after the commencement of medication, there was a 44% reduction in severity. This is similar to the study by Lerner and colleagues who reported a 68.6% reduction in symptoms from baseline to week 4 [Lerner et al. 2001] and a later study which reported about 40% reduction of severity of TD from baseline to week 12 [Lerner et al. 2007]. The endpoint dose of pyridoxine for our patient was 600 mg/day. Other studies reported endpoint pyridoxine dose of 400–1200 mg daily [Lerner et al. 2001; Lerner et al. 2007; Miodownik et al. 2003]. In some of the studies, use of high doses resulted in clinically significant improvement in TD symptoms while in others patients treated with lower doses also showed similar response [Lerner et al. 1999]. But it should be noted that all the studies which showed no significant clinical improvement used relatively lower doses of pyridoxine [Venegas et al. 2006; Crane et al. 1971]. This case has also shown that treatment benefit may be maintained up to 1 year after pyridoxine is stopped. It should also be noted that there was no washout period of clozapine and that therefore it may be difficult to determine if there was a synergistic effect from clozapine in our case.
It has been suggested that it is most likely that pyridoxine contributed to the various mechanisms associated with developing TD [Miodownik et al. 2008; Lerner et al. 2007]. It has also been shown to be beneficial in the management of neuroleptic-induced akathesia [ Miodownik et al. 2006] and lithium-induced tremors [Miodownik et al. 2002].
Conclusion
In the future there will be a need to conduct well-standardized, randomized controlled trials to determine the beneficial effect of pyridoxine on patients with TD.
Footnotes
Funding
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflict of interest statement
The authors declare no conflicts of interest in preparing this article.