Abstract
Background:
Valproic acid (VPA) is the medication prescribed for the treatment of bipolar disorder, epilepsy, and migraine. It is reported that the VPA treatment leads to biotin deficiency due to the low serum biotinidase activity. Alopecia or hair loss is another common side effect of valproate administration.
Aim:
The study aims to investigate hair loss complaint in people, who are on Valproate and find the association between valproate levels, serum biotinidase activity and hair loss in persons treated with valproate.
Methods:
This two years cross sectional comparative study involving 150 participants was performed at department of Psychiatry of a tertiary care teaching hospital. The study group had 75 persons taking Valproate compared with 75 persons in the control group. Blood samples were collected for estimation of serum VPA levels and serum biotinidase activity. Quantification of alopecia biomarker Interleukin (IL)-2 was estimated. Data was analyzed by using student T test, Pearson’s correlation, and Mann Whitney U test.
Results:
The study group comprised of 40 males and 35 females with a mean age of 42.04 (±12.85) years. The control group had 39 males and 36 females with a mean age of 38.38 (±14.42) years. Hair loss was reported in 18 (24%) persons of study cohort compared to 2 (2.66%) among the control group. There was a statistically significant difference between biotinidase levels across the participants with hair loss complaint and those without hair loss complaint. (Mean rank of participants with hair loss complaint = 43.30, mean rank of participants without hair loss complaint = 80.45, U = 656.000, P ≤ 0.001). There was a statistically significant difference between the distribution of IL2 across the study and control groups. (Mean rank of study group = 57.73, mean rank of control group = 83.27, U = 3,395.00, P = 0.025).
Conclusion:
It can be concluded that there is an association between Valproate levels, biotinidase activity and hair loss.
Keywords: Alopecia, biotin levels, hair, valproic acid
INTRODUCTION
Valproic acid (VPA) is a medication prescribed for the treatment of bipolar disorder, epilepsy, and migraine.[1,2] 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 extracellular signal-regulated kinase (ERK) and Wnt-beta-Catenin signaling pathways.[3,4] VPA 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]
It is reported that the VPA treatment leads to biotin deficiency due to the low serum biotinidase activity. Alopecia or hair loss is another common side effect of VPA administration.[6] There are studies reporting the association between serum biotinidase levels and alopecia in small sample population (up to n = 75).[7] 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 biotinidasedepletion in these patients.[8] A few 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 long time had non-compliance 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.[9] Patient receiving 300 mg of valproate chrono twice daily for three months for the treatment of epilepsy reported hair loss and this condition was retracted upon drug discontinuation.[10] 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]
A few studies have reported the association between serum biotinidase levels and alopecia in small sample population.[7] Children with epilepsy upon treatment with VPA experienced hyperammonemia and hair loss.[12] Oral administration of biotin (10 mg/day) for 3 months reversed alopecia in these subjects. A prospective study on 78 subjects receiving sodium valproate for different psychiatric conditions reported hair loss in 6% of the study subjects.[13] A double blinded study conducted to determine the concentration response of divalproex sodium monotherapy reported that alopecia occurred in 4% of the patients in low plasma valproate group (25–50 μg/ml), compared to 28% of patients in the high plasma valproate group (85–150 μg/ml).[14] Patient receiving 300 mg of valproate chrono twice daily for 3 months for the treatment of epilepsy reported hair loss and this condition was retracted upon drug discontinuation.[10] 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]
However, research studies correlating VPA levels, serum biotinidase activity and hair loss were conducted mainly on pediatric patients indicating the need for establishing the correlation between VPA levels and serum biotinidase activity in larger adult population.
Hence, this case control study is designed to investigate the hair loss complaint among people, who are on Valproate and the association between VPA levels, serum biotinidase activity and an alopecia marker IL-2 in persons treated with VPA in a large Indian population.
MATERIALS AND METHODS
Site
The study was conducted in the department of psychiatry of a tertiary care teaching hospital from 2018 to 2021. It was originally planned to be completed in 2020 however got delayed due to the Covid pandemic by 1 year.
Sample size
Sample size was calculated by using the formula n = Z2 p (1-p)/E2 where Z = 1.64, the standard normal score, P = 10% that was taken as the expected prevalence of hair fall, E = 6% the margin of error, with 90% confidence level the expected sample size was 68. The sample needed was 136 in total. There could be some samples unfit for testing at the end of the study; hence a total of 150 participants were targeted. Participants were recruited by convenient sampling method and blood samples were collected from 75 persons in VPA treatment group and 75 from control group.
Ethical clearance
The study was conducted after obtaining the approval from institutional ethics committee. (Protocol No: 2017/315).
Patient enrolment
Inclusion criteria for treatment group
Inclusion criteria were adult patients more than 18 years of age of any gender, who are currently on VPA monotherapy only for at least 3 months for any medical indication.
Exclusion criteria for treatment group
Exclusion criteria were patients treated with VPA in combination with other drugs, participants receiving biotin supplements in the last three months and pregnant and lactating women.
Inclusion criteria for control group
Participants for control group included first degree relatives of respective patients, who were willing to participate in the study. This was conducted to eliminate genetic, dietary, and environmental factors.
In case of non-willing first degree relative or upon unavailability of first degree relative of the patient, visitors of patients visiting the Medical College Hospital and volunteering to participate in the study were included.
The Participants were adults aged more than 18 years of any gender who are apparently healthy physically and mentally (no formal testing or evaluation conducted; however, should not have any diagnosed disease/disorders at the time of recruitment).
Exclusion criteria for control group
Any Participant who was on VPA treatment in the last 1 year, participants who received biotin supplements in last 3 months and Pregnant/lactating women were excluded.
We excluded pregnant and lactating persons as these conditions could affect the levels of the testing parameters and they are more likely to receive oral/parenteral supplements during this period.
Clinical data collection
After explaining the study and getting informed consent from the patients, socio-demographic details and a clinical data sheet was filled recording the details of the history and investigational findings. Hair loss during valproate therapy was enquired and documented. Dosage and route of administration of VPA was as directed by the treating clinician.
Sample collection
Blood samples were collected either 12 hours or 24 hours after the last dose of valproate, depending on the half-life. Blood was collected prior to the intake of next dosage. Blood samples (3 ml) was collected through routine venipuncture in red top tubes, transferred to the lab, and centrifuged at 3000 rpm for 15 min to separate the serum. Serum samples were frozen at −80°C till further analysis.
Experimental methodology
Estimation of serum VPA levels
VPA concentrations in serum were determined using liquid chromatography–mass spectrometry (LCMS) method. This was conducted in ultra-performance liquid chromatography (UPLC) Model – Agilent infinity II 1290, using Zorbax 1.8 microns, 2.1 mm dia, 5 cm column and reversed-phase liquid chromatography (RPLC) method. Mobile phase consisted of 0.1% formic acid and 90% ACN in 0.1% Formic acid. The extraction was done in 100% methanol; the run time was 15 mins in MS/MS, multiple reaction monitoring (MRM) mode. The Ion Source was ESI with IonDrive Turbo V technology. The samples were acquired using QTRAP 6500 (AB SCIEX, USA).
Estimation of serum biotinidase levels
Biotidinase activity was determined spectrophotometrically by measuring p-aminobenzoate liberation from N-biotinyl-p-aminobenzoate. The enzyme assay was initiated by the addition of 0.1 ml serum to 1.9 ml of a mixture containing 200 mmol potassium phosphate buffer, pH 6.0, 20 mmol ethylenediamine tetraacetic acid (EDTA), 0.5 mg serum albumin, and 0.3 mmol N-biotinyl-p-aminobenzoate bringing the final volume to 2 ml. The mixture was incubated for 30 min at 37°C and the reaction was terminated by the addition of 0.2 ml of 30% tri chloro acetic acid. The mixture was centrifuged at 2000 × g for 10 min. Then, 1.5 ml of the supernatant was added to 0.5 ml water. At room temperature, and at 3-min intervals, 0.2 ml of 0.1% sodium nitrite (prepared fresh daily), 0.2 mL of 0.5% ammonium sulfamate and 0.2 ml of 0.1% N-1-naphthyl ethylenediamine hydrochloride were added in succession and incubated for 10 min, and then the spectrophometric absorbance was measured at 546 nm. Biotidinase activity is expressed as nmol of p-aminobenzoate liberated per min per mL serum.
Quantification of alopecia biomarker IL-2
IL-2 concentration was estimated in serum samples using ELISA as per manufacturer’s specifications.
Data analysis
Student’s t test, Pearson’s correlation co-efficient and Spearman test was used for the statistical analysis of the results; P < 0.05 was considered as statistically significant.
RESULTS
Among 75 participants of the study group, 40 (53.3%) participants were male and 35 (46.7%) were female. 37 (49.3%) participants of the study group were taking Divalproex while 38 (50.7%) were taking Sodium valproate. Among 75 participants of the control group, 39 (52%) of them were male and 36 (48%) were female. 43 (57.3%) participants of the control group were first degree relatives of the participants, while 32 (42.7%) were neutral participants. Twelve screened study participants had refused consent [Table 1].
Table 1.
Demographic and clinical details of the participants of both groups
| Parameters | Study group | Control group | |
|---|---|---|---|
| Total participants | 75 | 75 | |
| Gender | Male | 40 (53.3%) | 39 (52%) |
| Female | 35 (46.7%) | 36 (48%) | |
| Form | Divalproex | 37 (49.3%) | NA |
| Sodium valproate | 38 (50.7%) | NA | |
| Dosage of VPA per day | ≤500 mg | 62 (82.7%) | NA |
| 501–1000 mg | 11 (14.7%) | NA | |
| 1001–1500 mg | 2 (2.7%) | NA | |
| Mean age | 42.04 (±12.85) years | 38.38 (±14.42) years | |
| Frequency | OD | 63 (84%) | NA |
| BD | 12 (16%) | NA | |
| Indication | Bipolar disorder | 70 (93.3%) | NA |
| Epilepsy | 4 (5.3%) | NA | |
| Schizoaffective disorder | 1 (1.3%) | NA | |
| Hair loss | Yes | 18 (24%) | 2 (2.66%) |
| No | 57 (76%) | 73 (97.33%) | |
| Mean total duration of valproate | 30.52 (±36.78) months | NA | |
| Mean monotherapy duration with valproate | 15.11 (±32.67) months | NA | |
| Mean biotinidase level | 2.96 (±0.43) nmol/min/ml | 3.68 (±1.09) nmol/min/ml | |
| Mean VPA level | 14.68 mcg/ml (±22.90) | NA | |
| Mean IL2 level | 59.78 (±100.28) pg/ml | 88.94 (±124.82) pg/ml | |
NA - Not Applicable
Mean age of the participants of study group was 42.04 years (±12.85; range 22–68 years). Mean age of the control group was 38.38 years (±14.42; range 17–76 years). Dosage of valproate for 62 (82.7%) patients of the study group was less than or equal to 500 mg/day; 11 (14.7%) patients were taking between 501–1000 mg/day and 2 (2.7%) patients were taking 1001 to 1500 mg/day. Frequency of intake of VPA was 63 (84%) patients of the study group was once daily (OD) and that of 12 (16%) was twice daily (BD). Indication for VPA intake in 70 (93.3%) patients of the study group was bipolar disorder, that for 4 (5.3%) was epilepsy and 1 (1.3%) was schizoaffective disorder.
Hair loss was reported in 18 (24%) patients of the study group, while 57 (76%) had no such complaints. No hair loss complaint was reported in 73 (97.33%) participants of the control group while it was reported by 2 (2.66%) of the control group.
Mean VPA level of the study group was 14.68 mcg/ml (±22.90; range 0.01 to 126.00 mcg/ml). Mean biotinidase level of the study group was 2.96 nmol/min/ml (±0.43) ranging between 0.01 to 3.18 nmol/min/ml. Mean biotinidase level of the control group was 3.68 nmol/min/ml (±1.09) ranging from 1.87 to 6.08 nmol/min/ml. Mean IL 2 level of the study group was 59.78 pg/ml (±100.28) ranging from 0.0 to 553.00 pg/ml. Mean IL 2 level of the control group was 88.94 pg/ml (±124.82) ranging from 0.0 to 690.00 pg/ml.
The parameters like age of the participants, total duration of valproate, duration of monotherapy with valproate, biotinidase level and valproic acid levels of the study group was tested for normality using Shapiro-Wilk test, it was found significant (P ≤ 0.001) and hence non-normal distribution.
A non-parametric test (Mann Whitney U test) was done to compare the distribution of age and that of biotinidase levels across the study group and control group. There was no statistically significant difference between the distribution of ages across the study group and control group. (Mean rank of study group = 82.23, Mean rank of control group = 68.77, U = 2,307.500, P = 0.058). There was a statistically significant difference between the distribution of biotinidase levels across the study and control groups. (Mean rank of study group = 42.37, Mean rank of control group = 108.63, U = 5,287.000, P ≤ 0.001) [Figure 1].
Figure 1.
Biotinidase levels among patients and controls
Mann Whitney U test was done to compare the biotinidase levels across the participants with hair loss complaint and those without hair loss complaint. There was a statistically significant difference between biotinidase levels across the participants with hair loss complaint and those without hair loss complaint. (Mean rank of participants with hair loss complaint = 43.30, Mean rank of participants without hair loss complaint = 80.45, U = 656.000, P ≤ 0.001) [Figure 2].
Figure 2.
Biotinidase levels among those with and without hair loss
An association between the hair loss complaint across all the male and female participants was explored using Pearson Chi square test. It was found that there was no statistical significance (P = 0.870) between hair loss complaint in males and that in females.
When Mann Whitney U test was done to compare the distribution of IL2 across the participants of study group and the control group, it was found that there was a statistically significant difference between the distribution of IL2 across the study and control groups (Mean rank of study group = 57.73, Mean rank of control group = 83.27, U = 3,395.00, P = 0.025) [Figure 3].
Figure 3.
Shows IL2 levels among controls and patient groups
Mann Whitney U test was conducted to compare the IL2 levels across the participants with hair loss complaint and those without hair loss complaint. It was found that there was no statistical significance (P = 0.157) between the IL2 levels across the participants with hair loss complaint and those without hair loss complaint.
A non-parametric test (Spearman’s rho correlation) was done to correlate the VPA and IL2 levels of the study group and there was no statistical significance (P = 0.196). When biotinidase and IL2 levels of all 150 participants were tested for Spearman’s rho correlation, it was also not found to be statistically significant (P = 0.06).
DISCUSSION
There was a significant number of people reporting hair loss in VPA treated group. It was found that there was low biotinidase levels in persons taking valproate as compared to the control group. The biotinidase level across the participants with hair loss complaint is comparatively less than the participants without hair loss complaint. There is a statistically significant difference between the IL2 (Interleukin-2; an alopecia biomarker) levels across the study and control groups.
The common adverse drug reactions reported on valproate administration are weight gain, tremor, gastro-intestinal disturbances, liver dysfunction, metabolic acidosis, thrombocytopenia, and hair loss. Valproate’s effect on hair is interesting and is very much essential in clinical practice.[15] VPA was significantly associated with a risk of alopecia compared to other drugs and the risk did not depend on the dose and treatment time.[16] Weight gain and alopecia were the most common patient reported cosmetic side effects in the study that was conducted to compare the cosmetic side effect profiles in a large specialty practice-based sample of patients taking both older and new antiepileptic drugs. Female patients were more likely to report cosmetic side effects.[17] When the literature on valproate associated hair abnormalities and the available treatment options were reviewed, it was concluded that hair abnormalities with valproate are common adverse effects and management includes general measures and specific treatment options.[18,19] The incidence of hair loss reported in literature varies from 3.5% to 12%.[10,13,18,20] It was higher in our study up to 24%. It possible that that patients taking valproate were conscious of this adverse event as it was discussed in detail at the time of recruitment and they reported it more compared to controls.
Authors in a case study of 16 years male who developed Pityriasis Amiantacea (PA) after the use of valproic acid proposed that the keratinocyte proliferative activity of valproic acid was mediated through the inhibition of glycogen synthase kinase 3β and subsequent activation of the Wnt/β-catenin pathway could play the role in the development of PA.[20] Molecules involved in alopecia are Interleukins (IL), T-Helper (TH), Erythroid differentiation regulator (ErDr), UL binding protein and C-Reactive protein (CRP).[21] A 1 year old castrated male cat was evaluated because of alopecia of approximately 4–5 months duration, as well as hyperactive behavior. It was later determined that the cat was ingesting valproic acid by food. The clinical signs slowly resolved after the source of valproic acid were removed.[22] Alopecia associated with valproate is a dose dependent and reversible side effect. Three cases of alopecia occurred in patients, who received sodium valproate for various neurological disorders. In all those cases, long term exposure of valproate therapy led to the development of alopecia that eventually resolved after dose reduction or discontinuation of valproate. It was found that valproate was a probable cause of alopecia in all those patients.[23]
This is one of the largest studies on this topic till date. The control population were from a similar background. Study looked at hair loss, biotinidase activity and IL2 levels in people taking VPA.
Limitations of the study include its cross-sectional nature, sampling technique, eligibility criteria as it is possible earlier drugs could have still influenced, the choice of control population taken, we could not get a family member for all participants, verbal responses were taken about hair loss that is subjective. We studied only one possible biomarker IL-2. Future studies can look at other potential biomarkers and see if valproate associated hair loss reverses with biotin supplements.
CONCLUSION
There is an association between valproic acid, biotinidase levels and hair loss. Clinicians should be watchful of hair loss complaint while prescribing valproate as it is a molecule frequently used by many specialties.
Statement
The author(s) attest that there was no use of generative artificial intelligence (AI) technology in the generation of text, figures, or other informational content of this manuscript.
Conflicts of interest
There are no conflicts of interest.
Acknowledgement
We acknowledge the support of Rekha PD and Aparna Hegde from the Yenepoya Research center at various stages of this study.
Funding Statement
The study was funded by research grant from Indian Association of Private Psychiatry (IAPP).
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