Valproate: It's Effects on Hair.

Valproate is a drug used in the treatment of various seizure disorders, bipolar disorder, migraine prophylaxis, and off label in many indications by various specialists. The common adverse drug reactions reported on valproate administration are tremor, weight gain, gastrointestinal disturbances, liver dysfunction, metabolic acidosis, thrombocytopenia, and hair loss. An internet search with keywords "valproate" and "hair" was done on Google Search and PubMed for articles related to the topic. Recognition of cosmetically significant side effects on hair is necessary and neglect of which might result in poor compliance. Valproate-induced hair loss is diffused, nonscarring, and dose related. Other hair-related adverse events are curling of hair, graying, dirty appearance, and changes in texture. In contrast to oral ingestions causing hair loss, experiments with topical valproic acid have shown some initial evidence on hair regeneration. This makes valproate's effects on hair interesting and understanding it's effects on hair is very much essential in clinical practice.

INTRODUCTION

Valproate is used regularly in the treatment of various seizure disorders, bipolar disorder, migraine prophylaxis, and off label in many other conditions.[12] It is a histone deacetylase inhibitor, exerting its action through modification of chromatin structure and gene expression. It is also involved in the modulation of ERK and Wnt-beta-Catenin signaling pathways.[34] Valproate inhibits the cellular sodium influx by blocking voltage-dependent sodium channels and induces chloride influx by gamma hydroxyl butyric acid (GABA)-mimetic effect. It also reduces the release of GABA, thereby attenuating neuronal excitation induced by glutamate receptors.[5]

Valproic acid (VPA) also interferes with arachidonate and inositol metabolisms in vivo. Alterations in multiple gene expressions are reported with valproate treatment. These genes are known for their role in cell survival, transcriptional regulation, ion homeostasis, and signal transduction. VPA also binds to activator protein-1 DNA and directly inhibits histone deacetylases.[6]

The common adverse drug reactions reported in valproate administration are tremor, weight gain, gastrointestinal disturbances, liver dysfunction, metabolic acidosis, thrombocytopenia, and hair loss. An internet search with keywords “valproate” and “hair” was done on Google Search and PubMed for articles on the topic. Alopecia or hair loss is cosmetic side effect of VPA administration.[7] Hair loss with valproate is diffused, nonscarring, and dose related. Recognition of cosmetically significant side effects on hair is necessary and neglect of which might result in poor compliance.[8] Starting with a low dose and progressive increase in the dosage is considered as a key strategy in counteracting valproate-induced hair loss.[9]

Case studies on VPA-induced hair loss are reported. Alopecia occurred in patients who received sodium valproate for different psychiatric conditions. Patient receiving 800 mg/day of sodium valproate for a long time had noncompliance with therapy due to hair loss. Chronic valproate therapy increased hair loss in patient with epilepsy, and VPA-induced alopecia was reduced after 84 days of drug discontinuation.[10] Results of this study indicated that there is a possibility of developing alopecia in patients with high plasma concentrations of valproate. A woman treated with 800 mg/day of VPA for bipolar disorder, experienced hair loss, and noncompliance with the treatment with significantly higher concentrations of VPA in plasma. Patient receiving 300 mg of Valproate Chrono tablets twice daily for 3 months for the treatment of epilepsy reported hair loss and this condition was retracted upon drug discontinuation.[8] A pediatric patient receiving sodium valproate 500 mg BD daily for epilepsy incurred hair loss 25 days after the treatment, and upon the modification of antiepileptic medicine, the condition was reversed.[11]

The incidence of valproate causing hair loss is 3.5%,[12] 6%,[13] and 12%[10] among various studies. A double-blind concentration-response clinical trial of divalproex sodium monotherapy reported that alopecia occurred in 4% of patients in low plasma valproate group (25–50 μg/ml), compared to 28% of patients in high plasma valproate group (85–150 μg/ml).[14] To prevent valproate-induced hair loss, starting therapy with a low dose and progressively increasing the dose should be considered, as this strategy seems to minimize hair loss side effects.[12]

Curly hair is uncommon side effect of sodium valproate. A study on a group who used sodium valproate indicated that 5 out of 295 patients who were using sodium valproate experienced curling of hair.[15] There are case reports of valproate causing hair texture changes and color.[1617] In another study from Iran, 6 out of 211 epileptic patients (3.5%) experienced hair loss and curling of hair. Their results showed that the mean age of patients with hair loss was lower than those who do not show this side effect. The patients also experienced graying and dirty appearance of hair associated with alopecia. The study concluded that sodium valproate can cause hair loss and curliness as a reversible side effect. The derangement can be observed 3 months after starting dose or later,[18] and the time to development of alopecia in patients treated with valproate was around 93 days.[19]

It is reported that the VPA treatment leads to biotin deficiency due to low serum biotinidase activity. Alopecia with valproate is dose dependent and there is a reduction in biotinidase activity during valproate therapy, and it could be prevented by administering biotin in experimental rats.[10] In a study on 75 pediatric patients administered with valproate, it was found that valproate dose and biotinidase activity were inversely proportional.[20] Results of another study found that serum biotinidase activity in 57 children treated with valproate had no significant difference compared to controls. Three female children had hair loss in their samples.[11] Hair and serum zinc levels and serum biotinidase activity were measured before and in the 3rd and 6th months of treatment in 32 pediatric patients receiving valproate treatment. The mean serum and hair zinc levels were found to be reduced in the 3rd and 6th months of treatment as compared with the pretreatment values, while the mean serum biotinidase activity was lower than the pretreatment values in the 3rd month of treatment but returned to initial values in the 6th month of treatment.[21] The study involved 41 pediatric epilepsy patients on valproate and concluded that there is no zinc deficiency during valproate therapy.[22]

There are studies reporting the association between serum biotinidase levels and alopecia in small sample population (up to n = 75).[23] VPA treatment impaired the liver mitochondrial functions, resulting in low biotinidase activity. A study conducted on a small cohort of pediatric patients revealed that VPA treatment induced alopecia, which was attributed to zinc and biotinidase depletion in these patients.[24]

Mechanisms of hair loss promotion by VPA include telogen effluvium and propensity of the patients to develop alopecia. In patients with VPA oral administration, deficiencies of trace elements such as copper, zinc, magnesium, and inactivation of metallic enzymes involved in keratinization and hair growth are reported.[12]

In contrast to oral ingestions causing hair loss, experiments with topical VPA showed hair regeneration. An experimental study in South Korea was done by taking murine models and human dermal papilla cells to check the effect of topical VPA in androgenic alopecia. VPA was applied topically to male C3H mice and hair regrowth was noted. Effects of VPA and minoxidil on human dermal papilla cells were compared. It was seen that beta-catenin, alkaline phosphatase, and BMP4 expression was greatly increased by treatment with VPA but not minoxidil.[25]

VPA is known to inhibit glycogen synthase kinase 3ß and activation of Wnt/βcatenin pathway, which in turn, is associated with hair regeneration and anagen induction.[25] In preclinical studies with VPA conducted on rats, it was shown that administration of higher dosages of VPA resulted in increased acetylation and activation of histone-3 and PI3K pathway proteins. It is also reported to have cytoprotective abilities when administered in split lower doses.

In a randomized interventional study, 7.2% spray of sodium valproate applied twice daily on scalp up to 24 weeks showed the efficacy of VPA spray on androgenic alopecia. Study participants included patients in the age group of 19–45 years, diagnosed with androgenic alopecia according to Hamilton and Norwood Grade III–IV, and those whose follow-up would be possible up to 24 weeks. Participants with severe medical conditions and received alopecia treatment with surgical methods such as hair transplantation were excluded from the study. Primary outcome parameters assessed were linear hair growth rate, and secondary outcome measures included final hair density over a time frame of 24 weeks. All the measures were compared with a placebo-treated group.[26]

A randomized, double-blind, placebo-controlled clinical trial was done to assess the efficacy of topical valproate for treating androgenic alopecia. Male patients with moderate androgenic alopecia underwent treatment with either VPA (sodium valproate, 8.3%) or placebo spray for 24 weeks. The primary end point for efficacy was the change in hair count during treatment, which was assessed by phototrichogram analysis. The mean change in total hair count was significantly higher in the VPA group than in the placebo group.[27]

CONCLUSION

Valproate is a common drug used by various specialties. It is reported to be associated with hair loss upon oral administration which is a cosmetic problem, and on the other hand, topical valproate applications are showing initial evidence to promote hair regeneration. More research on this duality and understanding valproate's effect on hair is very much essential for clinical practice.

Financial support and sponsorship

The authors would like to acknowledge the financial grant from Indian Association of Private Psychiatry for the IAPP project titled: Association of valproic acid levels, biotinidase activity, and hair loss in Indian population.

Conflicts of interest

There are no conflicts of interest.