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Research Article| Volume 69, P61-69, July 2019

Risk of valproic acid-related alopecia: A systematic review and meta-analysis

Open ArchivePublished:April 05, 2019DOI:https://doi.org/10.1016/j.seizure.2019.04.003

      Highlights

      • We found the overall incidence of VPA induced alopecia was 11% and was higher than other drugs.
      • The risk of VPA-induced alopecia was more reported among epilepsy and migraine headache patients.
      • Results showed the risk of VPA-associated alopecia was not dose and treatment time related.

      Abstract

      Purpose

      We systematically reviewed studies to provide current evidence about the incidence and risk of alopecia in patients undergoing valproic acid (VPA) therapy.

      Methods

      We retrieved relevant publications and gathered data on alopecia in patients taking VPA and other drugs from prospective studies.

      Results

      Twenty-five articles met the inclusion criteria, and the overall incidence of alopecia in patients receiving VPA therapy was 11% (95% confidence interval (CI): 0.08–0.13). The pooled risk of alopecia showed a significant difference between patients treated with VPA and all other drugs (odds ratio (OR) 5.02, 95% CI: 3.58–7.03), other epileptic drugs (AEDs) (OR 4.82, 95% CI: 3.32–7.00) and other non-AEDs (OR 5.84, 95% CI: 2.67–12.81). Compared to other drugs, VPA increased the risk of alopecia both in patients with migraine headaches (OR 6.05, 95% CI: 2.89–12.63) and patients with epilepsy (OR 5.29, 95% CI: 3.53–7.92), and the increase risk was reported more frequently in patients with migraine. Both lower doses (OR 4.38, 95% CI: 2.32–8.25) and shorter treatments (OR 4.98, 95% CI: 2.41–10.25) with VPA posed a high risk of alopecia compared to other drugs, as did higher doses and longer treatment times.

      Conclusions

      Based on our findings, 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.

      Abbreviations:

      EP (epilepsy), BD (bipolar disorder), MA (migraine headache), VPA (valproic acid), LTG (lamotrigine), CBZ (carbamazepine), OXC (oxcarbazepine), TPM (topiramate), PHT (phenytoin), AED (antiepileptic drug), ADR (adverse drug reactions), DDD (daily drug dose), RCT (randomized controlled trial), M (month), Y (year), W (week), CI (confidence interval), OR (odds ratio)

      Keywords

      1. Introduction

      Valproic acid (VPA) is the most commonly administered first-generation antiepileptic drug (AED) and is also useful for a variety of other diseases, including bipolar disorder (BD) [
      • Bialer M.
      Why are antiepileptic drugs used for nonepileptic conditions?.
      ,
      • Soares-Weiser K.
      • et al.
      A systematic review and economic model of the clinical effectiveness and cost-effectiveness of interventions for preventing relapse in people with bipolar disorder.
      ], migraine headache (MA) [
      • Blumenfeld A.
      • Gennings C.
      • Cady R.
      Pharmacological synergy: the next frontier on therapeutic advancement for migraine.
      ,
      • Ghose K.
      • Niven B.
      Prophylactic sodium valproate therapy in patients with drug-resistant migraine.
      ,
      • Mathew N.T.
      Antiepileptic drugs in migraine prevention.
      ] and neuropathic pain [
      • Ross E.L.
      The evolving role of antiepileptic drugs in treating neuropathic pain.
      ,
      • Hardy J.R.
      • et al.
      A phase II study to establish the efficacy and toxicity of sodium valproate in patients with cancer-related neuropathic pain.
      ]. The side effects of antiepileptic drugs are often the main factors restricting treatment and drug retention for patients with epilepsy [
      • Bootsma H.P.
      • et al.
      The impact of side effects on long-term retention in three new antiepileptic drugs.
      ,
      • Chung S.
      • Wang N.
      • Hank N.
      Comparative retention rates and long-term tolerability of new antiepileptic drugs.
      ]. The clinical utility of VPA may be hindered by its adverse drug reactions (ADRs), such as tremors, weight gain, hair loss, gastrointestinal disturbances, heartburn, liver dysfunction, and thrombocytopenia [
      • Tomson T.
      • Battino D.
      • Perucca E.
      Valproic acid after five decades of use in epilepsy: time to reconsider the indications of a time-honoured drug.
      ].
      Alopecia is a well-known psychopharmacological phenomenon caused by VPA and must be investigated and diagnosed with the utmost caution. In some cases, hair loss was partially relieved after discontinuing therapy. Hair loss is also a relatively common occurrence in patients treated with other AEDs, such as carbamazepine (CBZ) and phenytoin (PHT), and the frequency of hair loss ranges from 0.3% to 6% in treated individuals [
      • Chen B.
      • et al.
      Cosmetic side effects of antiepileptic drugs in adults with epilepsy.
      ,
      • Verity C.M.
      • Hosking G.
      • Easter D.J.
      A multicentre comparative trial of sodium valproate and carbamazepine in paediatric epilepsy. The Paediatric EPITEG Collaborative Group.
      ,
      • Mattson R.H.
      • Cramer J.A.
      • Collins J.F.
      A comparison of valproate with carbamazepine for the treatment of complex partial seizures and secondarily generalized tonic-clonic seizures in adults. The Department of Veterans Affairs Epilepsy Cooperative Study No. 264 Group.
      ]. Tiagabine (TGB) and topiramate (TPM) may also cause alopecia in 1% of users [
      • Cohen J.S.
      Adverse drug effects, compliance, and initial doses of antihypertensive drugs recommended by the Joint National Committee vs the Physicians’ Desk Reference.
      ], as may gabapentin [
      • Picard C.
      • et al.
      Alopecia associated with gabapentin: first case.
      ], lamotrigine (LTG) [
      • Tengstrand M.
      • et al.
      Alopecia in association with lamotrigine use: an analysis of individual case safety reports in a global database.
      ] and vigabatrin [
      • Lampl Y.
      • et al.
      Hair loss - an adverse reaction to treatment with vigabatrin.
      ].
      Currently, although VPA-induced hair loss is well known, researchers have not clearly determined whether the dose affects how VPA increases the risk of developing alopecia compared to other drugs. The currently available information concerning VPA-associated hair loss in the existing medical literature is rather weak and often limited to case reports. In this study, we aim to systematically review related documents to provide more evidence about the incidence of VPA-related hair loss and compare this risk to other drugs.

      2. Methods

      Ethical approval was not necessary for the present study due to the lack of patient involvement. This study was conducted according to the PRISMA (preferred reporting items for systematic reviews and meta-analyses) [
      • Moher D.
      • et al.
      Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement.
      ] and MOOSE (meta-analysis of observational studies in epidemiology protocol) guidelines [
      • Stroup D.F.
      • et al.
      Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis of Observational Studies in Epidemiology (MOOSE) group.
      ]. The protocol used in this study was based on the Cochrane Review Methods (www.cochrane-handbook.org).

      2.1 Search strategy

      We searched the PubMed (1976 to September 20, 2018), Embase (1982 to September 20, 2018) and Cochrane Library databases (1987 to September 20, 2018) for relevant studies with no language restrictions. The search process was conducted through a combination of medical subject headings and text words, including “valproic acid”, “propylisopropylacetic acid”, “divalproex”, “depakene”, “divalproex sodium”, “valproate”, “valproate sodium”, “VPA”, “alopecia”, “hair loss”, and “baldness” (Table S1). Furthermore, we confined our literature search to human studies. Additionally, the references from all included studies or relevant reviews were screened to avoid accidental omissions.

      2.2 Selection criteria

      Clinical trials that met the following criteria were included in the meta-analysis: (1) prospective randomized controlled trials or open-label trials of patients receiving VPA treatment compared with a control group and (2) studies providing the original data for VPA-associated hair loss and comparisons to other drugs related to hair loss. Furthermore, we eliminated reviews, editorials, and single cases and case series, as well as studies that were exclusively published as abstracts, letters, and commentaries and studies that likely contained repeated data from duplicate populations.
      According to the inclusion and exclusion criteria, we finally identified a total of 25 prospective studies (one study had a prospective cohort design and the others were randomized controlled trials) (Table 1).
      Table 1Characteristics of included studies in the meta-analysis.
      StudyDesignCountryStudy

      field
      N

      (erolled)
      Treatment

      arm
      Gender

      (% male)
      Age (year)

      (range/mean)
      VPA dose

      (mean mg/d)
      No.

      analysis
      No.

      rash
      Follow

      up time
      Afshari, D. (2012) [
      • Afshari D.
      • Rafizadeh S.
      • Rezaei M.
      A comparative study of the effects of low-dose topiramate versus sodium valproate in migraine prophylaxis.
      ]
      RCTIranMA56TPM VPA50%18-65 year400289(32.1%)12 w
      Biton, V.

      (2001) [
      • Biton V.
      • et al.
      Weight change associated with valproate and lamotrigine monotherapy in patients with epilepsy.
      ]
      RCTUSAEP133LTG VPA43.6%12-76 year

      30.1 ± 14
      1822 ± 633687(10%)24 w
      Blumenfeld,

      A.M. (2008) [
      • Blumenfeld A.M.
      • Schim J.D.
      • Chippendale T.J.
      Botulinum toxin type A and divalproex sodium for prophylactic treatment of episodic or chronic migraine.
      ]
      RCTUSAMA59BoNTA

      VPA
      15.3%Adults

      42.4 ± 10.3
      500295(17.2%)10 m
      Bostani, A. (2013) [
      • Bostani A.
      • et al.
      The effects of cinnarizine versus sodium valproate in migraine prophylaxis.
      ]
      RCTIranMA104Cinnarizine

      VPA
      16.5%Adults

      31.85 ± 7.76
      4005414(25.9%)12 w
      Calabrese,J.R. (2005) [
      • Calabrese J.R.
      • et al.
      A 20-month, double-blind, maintenance trial of lithium versus divalproex in rapid-cycling bipolar disorder.
      ]
      RCTUSABD60Lithium

      VPA
      51.7%≥16 year

      37 ± 8.2
      500280(0%)20 m
      Christe, W.

      (1997) [
      • Christe W.
      • et al.
      A double-blind controlled clinical trial: oxcarbazepine versus sodium valproate in adults with newly diagnosed epilepsy.
      ]
      RCTmulticenterEP249OXC VPA51%15-65 year1146.212121(17.4%)45 m
      Craig, I.

      (1994) [
      • Craig I.
      • Tallis R.
      Impact of valproate and phenytoin on cognitive function in elderly patients: results of a single-blind randomized comparative study.
      ]
      RCT

      Single blind
      UKEP38PHT VPANot state62-88year688172(12%)1 y
      Donati, F.

      (2007) [
      • Donati F.
      • et al.
      The cognitive effects of oxcarbazepine versus carbamazepine or valproate in newly diagnosed children with partial seizures.
      ]
      RCT

      Open label
      SwitzerlandEP112CBZ OXC

      VPA
      45.5%6-16 yearNot state293(10.3%)6 m
      Fakhoury, T.A. (2004) [
      • Fakhoury T.A.
      • et al.
      Efficacy and tolerability of conversion to monotherapy with lamotrigine compared with valproate and carbamazepine in patients with epilepsy.
      ]
      RCT

      Open label
      USAEP302LTG VPA59%≥16 yearNot state536(11%)28 w
      Hebrani, P. (2009) [
      • Hebrani P.
      • Behdani F.
      • Manteghi A.A.
      Double-blind, randomized, clinical trial of topiramate versus sodium valproate for the treatment of bipolar disorder in adolescents.
      ]
      RCTIranBD120TPM VPA40%12-18 year1200612(3.3%)8 w
      Hesami,O.

      (2018) [
      • Hesami O.
      • et al.
      Comparing the effects of atorvastatin with sodium valproate (Divalproex) on frequency and intensity of frequent migraine headaches: a double-blind randomized controlled study.
      ]
      RCTIranMA82Atorvastatin

      VPA
      3.7%Adults

      30.25 ± 9.91
      500365(13.9%)3 m
      Kakkar,A.K. (2009) [
      • Kakkar A.K.
      • et al.
      Comparative efficacy and safety of oxcarbazepine versus divalproex sodium in the treatment of acute mania: a pilot study.
      ]
      RCTIndiaBD60OXC VPA50%18-50 year1280301(3.3%)12 w
      Levisohn.R.M (2007) [
      • Levisohn P.M.
      • Holland K.D.
      Topiramate or valproate in patients with juvenile myoclonic epilepsy: a randomized open-label comparison.
      ]
      RCT

      Open label
      USAEP28TPM VPA61%9-42 year75093(33%)26 w
      Mathew, N.T. (1995) [
      • Mathew N.T.
      • et al.
      Migraine prophylaxis with divalproex.
      ]
      RCTUSAMA107placebo

      VPA
      20%18-70 year1087709(13%)16 w
      Mattson, R.H. (1992) [
      • Mattson R.H.
      • Cramer J.A.
      • Collins J.F.
      A comparison of valproate with carbamazepine for the treatment of complex partial seizures and secondarily generalized tonic-clonic seizures in adults. The Department of Veterans Affairs Epilepsy Cooperative Study No. 264 Group.
      ]
      RCTUSAEP480CBZ VPA93%18-70 year2099 ± 82424029(12%)40 m
      Nejad,S.E.M. (2009) [
      • Nejad S.E.M.
      • et al.
      A randomized open-label comparison of lamotrigine and valproate in patients with juvenile myoclonic epilepsy.
      ]
      RCT

      Open label
      IranEP46LTG VPANot state8-30 year800233(13%)28 w
      Park. K.M. (2013) [
      • Park K.M.
      • et al.
      A randomized open-label observational study to compare the efficacy and tolerability between topiramate and valproate in juvenile myoclonic epilepsy.
      ]
      RCT

      Open label
      KoreaEP33TPM VPA50%13-42 year1200163(18.7%)24 w
      Richens, A. (1994) [
      • Richens A.
      • et al.
      A multicentre comparative trial of sodium valproate and carbamazepine in adult onset epilepsy.
      ]
      RCT

      Open-label
      multicenter

      in USA
      EP300CBZ VPANot state≥16 year9241745(2.9%)3 y
      Sarchielli, P. (2014) [
      • Sarchielli P.
      • et al.
      Sodium valproate in migraine without aura and medication overuse headache: a randomized controlled trial.
      ]
      RCTItalyMA88placebo VPA23.5%18-65 year800445(11.4%)6 m
      Shaygannejad, V. (2006) [
      • Shaygannejad V.
      • et al.
      Comparison of the effect of topiramate and sodium valporate in migraine prevention: a randomized blinded crossover study.
      ]
      RCTIranMA64TPM VPA43.7%14-57 year400321(3.1%)24 w
      Steinhoff,B.J (2005) [
      • Steinhoff B.J.
      • et al.
      The LAM-SAFE Study: lamotrigine versus carbamazepine or valproic acid in newly diagnosed focal and generalised epilepsies in adolescents and adults.
      ]

      Mattson,R.H. 1992
      RCT

      Open label
      GermanyEP239LTG VPANot state≥12 year1050303(10%)24 w
      Wheless, J.W. (2014) [
      • Privitera M.D.
      • et al.
      Topiramate, carbamazepine and valproate monotherapy: double-blind comparison in newly diagnosed epilepsy.
      ]
      RCTUSAEP613CBZ TPM

      VPA
      49.7%≥6 year12507814(18%)≥6 m
      Verity,C.M. (1995) [
      • Verity C.M.
      • Hosking G.
      • Easter D.J.
      A multicentre comparative trial of sodium valproate and carbamazepine in paediatric epilepsy. The Paediatric EPITEG Collaborative Group.
      ]
      RCTUKEP260CBZ VPA43.5%5-16 year7001185(4.2%)3 y
      Viteri, C.

      (2010) [
      • Viteri C.
      • et al.
      Quality of life and treatment satisfaction in Spanish epilepsy patients on monotherapy with lamotrigine or valproic acid.
      ]
      Open trial

      prospective
      SpanishEP107LTG VPA38.3%Adults

      30.4 ± 9.1
      Not state5413(24.5%)6 m
      Xu, L.

      (2015) [
      • Xu L.
      • et al.
      Olanzapine–valproate combination versus olanzapine or valproate monotherapy in the treatment of bipolar imania: a randomized controlled study in a chinese population group.
      ]
      RCTChinaBD114Olanzapine

      VPA
      8.2%Adults

      30.7 ± 7.8
      1530 ± 220383(7.5%)4 w
      EP = epilepsy, BD = bipolar disorder, MA = migraine headache, VPA = Valproic acid, LTG = Lamotrigine, CBZ = Carbamazepine, OXC = oxcarbazepine, TPM = topiramate, PHT = phenytoin.
      RCT = randomized controlled trial, m = month, y = year, w = week.

      2.3 Data extraction and quality assessment

      We used a standardized data abstraction form to acquire the relevant information required for analysis. Two independent investigators performed the data extraction (W.X.P. and W.H.J.), and any disagreement between the two investigators was resolved by discussion with the help of a third investigator (L.L.). For each study, the following information was obtained: the first author’s name, year of publication, study methods, number of enrolled subjects, treatment arms, number of patients in the treatment and control groups when available, median age, median treatment duration, and adverse outcomes of interest (alopecia).
      The quality of the included randomized controlled trials was assessed using the Cochrane collaboration tool for estimating the risk of bias (Fig. S1).

      2.4 Statistical analysis

      All the analyses were performed using STATA 12.0 software (StataCorp, College Station, Texas, USA). A p-value of less than 0.05 was considered statistically significant, and all the tests were two-sided. The crude odds ratios (ORs) and 95% confidence intervals (CIs) were used to express the risk of alopecia with VPA therapy compared to other drugs. Forest plots were used to depict the visual representation of the meta-analysis results. The meta-analysis was performed using fixed-effects [
      • Mantel N.
      • Haenszel W.
      Statistical aspects of the analysis of data from retrospective studies of disease.
      ] or random-effects [
      • DerSimonian R.
      • Kacker R.
      Random-effects model for meta-analysis of clinical trials: an update.
      ] models. Heterogeneity was assessed using Cochran’s Q statistic [
      • Zintzaras E.
      • Ioannidis J.P.
      Heterogeneity testing in meta-analysis of genome searches.
      ] and I2 metric statistics [
      • Lau J.
      • Ioannidis J.P.
      • Schmid C.H.
      Quantitative synthesis in systematic reviews.
      ]. For the Cochran Q test, heterogeneity was considered statistically significant when Phetero < 0.05. For I2, no evidence of heterogeneity was defined when I2 was 0, a low level of heterogeneity when I2 was < 25%, a moderate level of heterogeneity when I2 was 25–50%, and a high level of heterogeneity when I2 was > 50%. A fixed-effects model was applied when Phetero > 0.05 or I2 < 50%, and a random-effects model was also conducted to evaluate the stability of the results.
      Potential publication biases were estimated by performing a visual inspection of funnel plots and further identified using Egger’s linear regression test. A P-value < 0.05 was considered statistically significant. We performed the following analyses: different control groups (other antiepileptic drugs and other non-antiepileptic drugs) and different groups of patients (patients with epilepsy, bipolar disorder and migraine headache). We also analysed the pooled ORs of specified subgroups based on different VPA doses, sample sizes and follow-up times.

      3. Results

      3.1 Study selection and characteristics

      Our search yielded 1188 records describing the use of VPA and alopecia from the PubMed, Embase and Cochrane library databases. The selection process is summarized in Fig. 1. After the exclusion of duplicate studies and a review of the abstracts, 42 human clinical studies that presented information on VPA therapy and alopecia were identified. Full-text articles were retrieved for these records and carefully studied. Finally, based on the inclusion criteria, 25 prospective studies examining VPA-induced alopecia were used to evaluate the hair loss incidence [
      • Verity C.M.
      • Hosking G.
      • Easter D.J.
      A multicentre comparative trial of sodium valproate and carbamazepine in paediatric epilepsy. The Paediatric EPITEG Collaborative Group.
      ,
      • Mattson R.H.
      • Cramer J.A.
      • Collins J.F.
      A comparison of valproate with carbamazepine for the treatment of complex partial seizures and secondarily generalized tonic-clonic seizures in adults. The Department of Veterans Affairs Epilepsy Cooperative Study No. 264 Group.
      ,
      • Christe W.
      • et al.
      A double-blind controlled clinical trial: oxcarbazepine versus sodium valproate in adults with newly diagnosed epilepsy.
      ,
      • Richens A.
      • et al.
      A multicentre comparative trial of sodium valproate and carbamazepine in adult onset epilepsy.
      ,
      • Park K.M.
      • et al.
      A randomized open-label observational study to compare the efficacy and tolerability between topiramate and valproate in juvenile myoclonic epilepsy.
      ,
      • Biton V.
      • et al.
      Weight change associated with valproate and lamotrigine monotherapy in patients with epilepsy.
      ,
      • Privitera M.D.
      • et al.
      Topiramate, carbamazepine and valproate monotherapy: double-blind comparison in newly diagnosed epilepsy.
      ,
      • Levisohn P.M.
      • Holland K.D.
      Topiramate or valproate in patients with juvenile myoclonic epilepsy: a randomized open-label comparison.
      ,
      • Steinhoff B.J.
      • et al.
      The LAM-SAFE Study: lamotrigine versus carbamazepine or valproic acid in newly diagnosed focal and generalised epilepsies in adolescents and adults.
      ,
      • Viteri C.
      • et al.
      Quality of life and treatment satisfaction in Spanish epilepsy patients on monotherapy with lamotrigine or valproic acid.
      ,
      • Xu L.
      • et al.
      Olanzapine–valproate combination versus olanzapine or valproate monotherapy in the treatment of bipolar imania: a randomized controlled study in a chinese population group.
      ,
      • Mathew N.T.
      • et al.
      Migraine prophylaxis with divalproex.
      ,
      • Craig I.
      • Tallis R.
      Impact of valproate and phenytoin on cognitive function in elderly patients: results of a single-blind randomized comparative study.
      ,
      • Fakhoury T.A.
      • et al.
      Efficacy and tolerability of conversion to monotherapy with lamotrigine compared with valproate and carbamazepine in patients with epilepsy.
      ,
      • Hebrani P.
      • Behdani F.
      • Manteghi A.A.
      Double-blind, randomized, clinical trial of topiramate versus sodium valproate for the treatment of bipolar disorder in adolescents.
      ,
      • Hesami O.
      • et al.
      Comparing the effects of atorvastatin with sodium valproate (Divalproex) on frequency and intensity of frequent migraine headaches: a double-blind randomized controlled study.
      ,
      • Kakkar A.K.
      • et al.
      Comparative efficacy and safety of oxcarbazepine versus divalproex sodium in the treatment of acute mania: a pilot study.
      ,
      • Blumenfeld A.M.
      • Schim J.D.
      • Chippendale T.J.
      Botulinum toxin type A and divalproex sodium for prophylactic treatment of episodic or chronic migraine.
      ,
      • Bostani A.
      • et al.
      The effects of cinnarizine versus sodium valproate in migraine prophylaxis.
      ,
      • Donati F.
      • et al.
      The cognitive effects of oxcarbazepine versus carbamazepine or valproate in newly diagnosed children with partial seizures.
      ,
      • Sarchielli P.
      • et al.
      Sodium valproate in migraine without aura and medication overuse headache: a randomized controlled trial.
      ,
      • Shaygannejad V.
      • et al.
      Comparison of the effect of topiramate and sodium valporate in migraine prevention: a randomized blinded crossover study.
      ,
      • Nejad S.E.M.
      • et al.
      A randomized open-label comparison of lamotrigine and valproate in patients with juvenile myoclonic epilepsy.
      ,
      • Afshari D.
      • Rafizadeh S.
      • Rezaei M.
      A comparative study of the effects of low-dose topiramate versus sodium valproate in migraine prophylaxis.
      ,
      • Calabrese J.R.
      • et al.
      A 20-month, double-blind, maintenance trial of lithium versus divalproex in rapid-cycling bipolar disorder.
      ], as well as 2 articles with the same population, and we selected the publications with the largest sample sizes [
      • Biton V.
      Lamotrigine versus valproate monotherapy-associated weight change in adolescents with epilepsy: results from a post hoc analysis of a randomized, double-blind clinical trial.
      ,
      • Wheless J.W.
      • Neto W.
      • Wang S.
      Topiramate, carbamazepine, and valproate monotherapy: double-blind comparison in children with newly diagnosed epilepsy.
      ] (Table 1). In two studies, two different antiepileptic drugs were compared to VPA, and we considered them as four trials, bringing the total number of comparisons to 27 [
      • Privitera M.D.
      • et al.
      Topiramate, carbamazepine and valproate monotherapy: double-blind comparison in newly diagnosed epilepsy.
      ,
      • Donati F.
      • et al.
      The cognitive effects of oxcarbazepine versus carbamazepine or valproate in newly diagnosed children with partial seizures.
      ]. In this group, 1587 patients receiving VPA treatment were investigated, with a focus on a variety of diseases, including epilepsy (14 trials) [
      • Verity C.M.
      • Hosking G.
      • Easter D.J.
      A multicentre comparative trial of sodium valproate and carbamazepine in paediatric epilepsy. The Paediatric EPITEG Collaborative Group.
      ,
      • Mattson R.H.
      • Cramer J.A.
      • Collins J.F.
      A comparison of valproate with carbamazepine for the treatment of complex partial seizures and secondarily generalized tonic-clonic seizures in adults. The Department of Veterans Affairs Epilepsy Cooperative Study No. 264 Group.
      ,
      • Christe W.
      • et al.
      A double-blind controlled clinical trial: oxcarbazepine versus sodium valproate in adults with newly diagnosed epilepsy.
      ,
      • Richens A.
      • et al.
      A multicentre comparative trial of sodium valproate and carbamazepine in adult onset epilepsy.
      ,
      • Park K.M.
      • et al.
      A randomized open-label observational study to compare the efficacy and tolerability between topiramate and valproate in juvenile myoclonic epilepsy.
      ,
      • Biton V.
      • et al.
      Weight change associated with valproate and lamotrigine monotherapy in patients with epilepsy.
      ,
      • Privitera M.D.
      • et al.
      Topiramate, carbamazepine and valproate monotherapy: double-blind comparison in newly diagnosed epilepsy.
      ,
      • Levisohn P.M.
      • Holland K.D.
      Topiramate or valproate in patients with juvenile myoclonic epilepsy: a randomized open-label comparison.
      ,
      • Steinhoff B.J.
      • et al.
      The LAM-SAFE Study: lamotrigine versus carbamazepine or valproic acid in newly diagnosed focal and generalised epilepsies in adolescents and adults.
      ,
      • Viteri C.
      • et al.
      Quality of life and treatment satisfaction in Spanish epilepsy patients on monotherapy with lamotrigine or valproic acid.
      ,
      • Craig I.
      • Tallis R.
      Impact of valproate and phenytoin on cognitive function in elderly patients: results of a single-blind randomized comparative study.
      ,
      • Fakhoury T.A.
      • et al.
      Efficacy and tolerability of conversion to monotherapy with lamotrigine compared with valproate and carbamazepine in patients with epilepsy.
      ,
      • Kakkar A.K.
      • et al.
      Comparative efficacy and safety of oxcarbazepine versus divalproex sodium in the treatment of acute mania: a pilot study.
      ,
      • Donati F.
      • et al.
      The cognitive effects of oxcarbazepine versus carbamazepine or valproate in newly diagnosed children with partial seizures.
      ,
      • Nejad S.E.M.
      • et al.
      A randomized open-label comparison of lamotrigine and valproate in patients with juvenile myoclonic epilepsy.
      ], bipolar disorder (4 trials) [
      • Xu L.
      • et al.
      Olanzapine–valproate combination versus olanzapine or valproate monotherapy in the treatment of bipolar imania: a randomized controlled study in a chinese population group.
      ,
      • Hebrani P.
      • Behdani F.
      • Manteghi A.A.
      Double-blind, randomized, clinical trial of topiramate versus sodium valproate for the treatment of bipolar disorder in adolescents.
      ,
      • Kakkar A.K.
      • et al.
      Comparative efficacy and safety of oxcarbazepine versus divalproex sodium in the treatment of acute mania: a pilot study.
      ,
      • Calabrese J.R.
      • et al.
      A 20-month, double-blind, maintenance trial of lithium versus divalproex in rapid-cycling bipolar disorder.
      ], and migraine headache (7 trials) [
      • Mathew N.T.
      • et al.
      Migraine prophylaxis with divalproex.
      ,
      • Hesami O.
      • et al.
      Comparing the effects of atorvastatin with sodium valproate (Divalproex) on frequency and intensity of frequent migraine headaches: a double-blind randomized controlled study.
      ,
      • Blumenfeld A.M.
      • Schim J.D.
      • Chippendale T.J.
      Botulinum toxin type A and divalproex sodium for prophylactic treatment of episodic or chronic migraine.
      ,
      • Bostani A.
      • et al.
      The effects of cinnarizine versus sodium valproate in migraine prophylaxis.
      ,
      • Sarchielli P.
      • et al.
      Sodium valproate in migraine without aura and medication overuse headache: a randomized controlled trial.
      ,
      • Shaygannejad V.
      • et al.
      Comparison of the effect of topiramate and sodium valporate in migraine prevention: a randomized blinded crossover study.
      ,
      • Afshari D.
      • Rafizadeh S.
      • Rezaei M.
      A comparative study of the effects of low-dose topiramate versus sodium valproate in migraine prophylaxis.
      ]. The sample sizes ranged from 28 to 480 patients treated with VPA. The age range of the study participants was 5–88 years. The follow-up period ranged from 8 weeks to 3 years. The mean dose of VPA ranged from 400 mg/d to 2099 mg/d.
      Fig. 1
      Fig. 1Flow chart of selection of articles about alopecia in patients with VPA therapy, VPA = valproic acid.

      3.2 Incidence of alopecia

      The overall incidence of alopecia with VPA treatment was 11% (95% CI: 0.08–0.13, P < 0.05) in 24 prospective clinical trials, because one prospective study did not identify a patient who was treated with VPA and developed alopecia [
      • Calabrese J.R.
      • et al.
      A 20-month, double-blind, maintenance trial of lithium versus divalproex in rapid-cycling bipolar disorder.
      ] (Fig. 2). With Phetero = 0.00 and I2 = 70.6%, a random-effects model was conducted.
      Fig. 2
      Fig. 2Pooled analysis of the overall prevalence of VPA induced alopecia. VPA = Valproic Acid.

      3.3 Pooled estimates for outcomes

      3.3.1 Meta-analysis of various drugs

      We independently evaluated the ORs of VPA-associated alopecia compared to all other drugs, other AEDs and other non-AEDs to investigate the specific contribution of VPA to alopecia. Based on our results, the use of VPA was significantly associated with an increased risk of alopecia compared to all other drugs (OR 5.02, 95% CI: 3.58–7.03, P < 0.05) (Fig. 3A), other AEDs (20 articles, OR 4.82, 95% CI: 3.32–7.00, P < 0.05) (Fig. 3B), and other non-AEDs (7 articles, OR 5.84, 95% CI: 2.67–12.81, P < 0.05) (Fig. 3C). When we compared VPA to other AEDs separately, a significant difference in the alopecia risk was observed between patients treated with VPA and other AEDs [CBZ (4 studies): OR 5.84, 95% CI: 2.57–13.27; OXC (3 studies): OR 2.67, 95% CI: 1.30–5.48; LTG (5 studies): OR 6.29, 95% CI: 2.67–14.80; and TPM (6 studies): OR 5.59, 95% CI: 2.85–10.96] (Fig. 4). All of these comparisons exhibited little heterogeneity; therefore, we used a fixed-effects model and observed a significant difference in the risk of experiencing alopecia between VPA and all other drugs, other AEDs and other non-AEDs.
      Fig. 3
      Fig. 3A. The pooled OR of VPA-alopecia compared with all other drugs. VPA = Valproic Acid. B. The pooled OR of VPA-alopecia compared with all other AEDs. AED = antiepileptic drugs, VPA = Valproic Acid. C. The pooled OR of VPA-alopecia compared with all other non-AEDs. VPA = Valproic Acid, AEDs = antiepileptic drugs.
      Fig. 4
      Fig. 4The pooled OR of VPA-alopecia compared with other AEDs respectively. VPA = Valproic Acid, LTG = Lamotrigine, CBZ = Carbamazepine, OXC = oxcarbazepine, TPM = topiramate, PHT = phenytoin, AEDs = antiepileptic drugs.

      3.3.2 Meta-analysis of different groups of patients

      We compared VPA to other drugs among patients with epilepsy, BD and MA to clarify the distinct risk of VPA-induced alopecia among different groups of patients. VPA was significantly associated with an increased risk of alopecia in patients with epilepsy (14 articles, OR 5.29, 95% CI: 3.53–7.92, P < 0.05) and MA (7 articles, OR 6.05, 95% CI: 2.89–12.63, P < 0.05). However, among patients with BD, the risk of VPA-induced alopecia was similar to other drugs (4 articles, OR 1.75, 95% CI: 0.53–5.66, P = 0.360) (Fig. 5). These three comparisons exhibited little heterogeneity; therefore, we used a fixed-effects model, as shown in Fig. 5.
      Fig. 5
      Fig. 5The pooled OR of VPA-alopecia among different patients groups. VPA = Valproic Acid, EP = epilepsy patients, BD = bipolar disorders, MA = migraine headache.

      3.4 Subgroup analysis

      Although the former comparisons exhibited little heterogeneity, the sample size, drug dose and follow-up time substantially influenced the outcome, and therefore various subgroup analyses were conducted as described below. In the subgroup analysis of the sample size that included studies with more than 100 patients, the risk of VPA-related alopecia differed significantly from other drugs (OR 4.98, 95% CI: 3.29–7.55, P < 0.05), which also persisted in an analysis of studies with less than 100 patients (OR 3.78, 95% CI: 1.98–7.24; P = 0.001) (Fig. 6A). A subgroup analysis based on the follow-up time showed that taking VPA for longer than 6 months (OR 4.66, 95% CI: 3.13–6.93, P < 0.05) did not increase the risk of alopecia compared to taking VPA for less than 6 months (OR 4.98, 95% CI: 2.41–10.25, P < 0.05) (Fig. 6B). When combining the results from groups receiving different doses, the pooled estimate for alopecia caused by VPA was statistically significantly different from other drugs at doses that were both less than (OR 4.38, 95% CI: 2.32–8.25, P < 0.05) and greater than 750 mg/d (OR 4.14, 95% CI: 2.65–6.47, P < 0.05) (Fig. 6C), and the lower dose of VPA did not reduce the risk of alopecia.
      Fig. 6
      Fig. 6A. Subgroup analysis of VPA-alopecia compared with other drugs based on the sample size. VPA = Valproic Acid. B. Subgroup analysis of VPA-alopecia compared with other drugs based on the follow up time. VPA = Valproic Acid. C. Subgroup analysis of VPA-alopecia compared with other drugs based on the different drug dose. VPA = Valproic Acid.
      Among the studies with larger sample sizes, the risk of alopecia induced by VPA was greater than the studies with a small sample size, which reflected the stability of our meta-analysis.

      3.5 Sensitivity analysis

      The variations and ranges of the pooled ORs after switching model types are listed in Table S2.
      The stability of the pooled estimate was assessed by removing some studies from the meta-analysis according to various exclusion criteria, and this stability analysis is summarized in Table S3. The pooled estimate for VPA-induced alopecia did not significantly depend on some of the exclusion criteria that were used.

      3.6 Publication bias

      The inverted funnel plots of the outcome data in these studies were generally asymmetrical (Fig. S2). Egger’s linear regression test indicated a lack of publication bias for VPA-related alopecia compared to all other drugs and other AEDs (P = 0.477 and 0.583, respectively).

      4. Discussion

      To date, the evidence for valproic acid-induced hair loss has been well documented. A literature review mentioned 643 cases of valproate-induced alopecia in 1995 [
      • Pillans P.I.
      • Woods D.J.
      Drug-associated alopecia.
      ]; specifically, it reported a 0.5–12% frequency [
      • Davis R.
      • Peters D.H.
      • McTavish D.
      Valproic acid. A reappraisal of its pharmacological properties and clinical efficacy in epilepsy.
      ,
      • McKinney P.A.
      • Finkenbine R.D.
      • DeVane C.L.
      Alopecia and mood stabilizer therapy.
      ], while the incidence of severe hair loss was 0.03% [
      • Druschky K.
      • et al.
      Severe hair loss associated with psychotropic drugs in psychiatric inpatients-Data from an observational pharmacovigilance program in German-speaking countries.
      ]. In addition, the incidence of alopecia is now considered to depend on the dose and time, and dose reduction leads to the re-growth of hair [
      • Mercke Y.
      • et al.
      Hair loss in psychopharmacology.
      ]. However, this opinion has not been verified, and a suitable and tolerable dose is difficult to identify.
      A valuable and relatively complete description of the incidence and risk of VPA-associated alopecia compared to other drugs was provided in this meta-analysis. This meta-analysis includes 25 prospective studies, and the overall incidence of hair loss in patients receiving VPA therapy was estimated to be 11%. Our finding for the incidence was consistent with other studies, which showed that hair loss or changes in hair colour (greying) and structure caused by sodium valproate reached approximately 6–12% [
      • Chen B.
      • et al.
      Cosmetic side effects of antiepileptic drugs in adults with epilepsy.
      ,
      • Ramakrishnappa S.K.
      • Belhekar M.N.
      Serum drug level-related sodium valproate-induced hair loss.
      ]. Furthermore, we observed a significant difference among patients treated with VPA and all other drugs, other AEDs and non-AEDs. Patients taking VPA had an approximately 5-fold higher risk of developing alopecia than patients taking other drugs, and this risk was even approximately 6-fold higher than other non-AEDs. When compared to a single AED, the risk of VPA-induced alopecia was greater than CBZ, OXC, TPM and LTG (5.84, 2.67, 5.59 and 6.29 times, respectively). When only four different AEDs were compared, the incidence of hair loss associated with other AEDs was also reported, but only a few of the included studies reported these data and we were unable to calculate a pooled estimate. This result provided insights into methods to choose other AEDs to replace VPA.
      Notably, the results for VPA-induced alopecia among different patient groups differed from the overall conclusions in the literature. Only patients with epilepsy and patients with MA taking VPA experienced an approximate 5.3- and 6.05-fold higher risk of hair loss, respectively, than patients taking other drugs, but this outcome was not experienced by patients with BD. We predicted that patients with BD also take other psychotropic drugs, such as lithium, which caused hair loss in 10–19% of users [
      • Pillans P.I.
      • Woods D.J.
      Drug-associated alopecia.
      ,
      • Orwin A.
      Hair loss following lithium therapy.
      ,
      • Warnock J.K.
      Psychotropic medication and drug-related alopecia.
      ,
      • McCreadie R.G.
      • Morrison D.P.
      The impact of lithium in South-west Scotland. I. Demographic and clinical findings.
      ], and fluoxetine, which was reported to have a higher risk of causing hair loss [
      • Parameshwar E.
      Hair loss associated with fluvoxamine use.
      ,
      • Silvestri A.
      • Santonastaso P.
      • Paggiarin D.
      Alopecia areata during lithium therapy. A case report.
      ]. More female patients were included in studies of MA, and many case reports and studies reported more frequent hair loss in female patients [
      • McKinney P.A.
      • Finkenbine R.D.
      • DeVane C.L.
      Alopecia and mood stabilizer therapy.
      ,
      • Yassa R.
      • Ananth J.
      Hair loss in the course of lithium treatment: a report of two cases.
      ]. According to the results of our meta-analysis, a higher pooled OR of VPA-associated alopecia was observed among patients with MA than patients with epilepsy, but the result was not significantly different. Women tend to pay more attention to their skin and hair, and therefore they are more likely to complain than men, as reflected in other studies [
      • Mercke Y.
      • et al.
      Hair loss in psychopharmacology.
      ,
      • Orwin A.
      Hair loss following lithium therapy.
      ]. In addition, women are considered more vulnerable to medication-related hypothyroidism, which is a risk factor for hair loss [
      • Sarantidis D.
      • Waters B.
      A review and controlled study of cutaneous conditions associated with lithium carbonate.
      ,
      • Kirov G.
      Thyroid disorders in lithium-treated patients.
      ].
      According to case reports, sodium valproate causes alopecia in up to 8%–12% patients in a dose-dependent manner [
      • Thomson S.R.
      • Mamulpet V.
      • Adiga S.
      Sodium valproate induced alopecia: a case series.
      ]. Patients with high blood valproate concentrations tend to develop adverse effects [
      • Klotz U.
      • Schweizer C.
      Valproic acid in childhood epilepsy: anticonvulsive efficacy in relation to its plasma levels.
      ], and a decrease in the dosage reduces the occurrence of some common side effects, including alopecia [
      • Despland P.A.
      [Tolerance to and unwanted effects of valproate sodium].
      ]. One study reported that approximately 28% subjects with blood valproate levels of 80–150 mcg/L experienced hair loss compared to 4% of patients with concentrations between 25 and 50 mcg/L [
      • Beydoun A.
      • Sackellares J.C.
      • Shu V.
      Safety and efficacy of divalproex sodium monotherapy in partial epilepsy: a double-blind, concentration-response design clinical trial. Depakote Monotherapy for Partial Seizures Study Group.
      ]. In contrast, we drew a different conclusion in our meta-analysis of previous related publications. We divided the included studies into two groups according to the 50% daily drug dose (DDD) of VPA, and patients taking a lower dose (≤ 750 mg/d) had a similar risk of developing alopecia to patients who were administered a higher dose (> 750 mg/d). Dose-related alopecia was reported from case studies, but researchers have not completely established whether its impact on hair loss was dose-related, but a dosage reduction usually resulted in the re-growth of hair in individuals with valproate-associated alopecia [
      • Henriksen O.
      • Johannessen S.I.
      Clinical and pharmacokinetic observations on sodium valproate - a 5-year follow-up study in 100 children with epilepsy.
      ]. Nevertheless, based on our meta-analysis, if a patient experienced VPA-associated hair loss, reducing simple reduction in the VPA dose might fail to reduce the risk of alopecia. Thus, clinicians should be aware that valproate therapy may result in hair loss, even when the dose is within the therapeutic window, and once patients experience hair loss, a wise approach is to withdraw VPA instead of simply reducing the dose. No studies have examined VPA overdoses and hair loss, but these data lay the foundation for further studies, which would be profoundly meaningful [
      • Mercke Y.
      • et al.
      Hair loss in psychopharmacology.
      ].
      One study reported that hair loss began within 3–6 months after initiating therapy [
      • Pillans P.I.
      • Woods D.J.
      Drug-associated alopecia.
      ], and another found that this effect occurred after 1–4 months of treatment with VPA [
      • Lewis J.R.
      Valproic acid (Depakene). A new anticonvulsant agent.
      ]. Our meta-analysis confirmed this result. When we pooled the results of studies that followed patients for 6 months, the risk of alopecia was even higher than studies that followed patients for more than 6 months. Thus, clinicians should monitor VPA-induced alopecia within the first 6 months.
      However, our study also had some limitations. First, only a small number of patients experienced alopecia after receiving VPA therapy, and only 1587 patients were treated with VPA in the 25 prospective studies. Second, the included studies did not all employ a randomized, double-blinded design, and the quality of some studies was poor. Additionally, women tended to experience VPA- associated hair loss at a higher rate, but the data were unavailable for us to perform a pooled estimation and directly confirm this conclusion. Third, the numbers of included studies and the compared AEDs were small; therefore, we need to be cautious about drawing general conclusions. Finally, one way to semi-quantitatively analyse the severity of hair loss is to determine how often the drug was truly withdrawn due to hair loss; however, only a few studies mentioned this aspect, and the pooled results displayed substantial heterogeneity and were unbelievable.
      Nevertheless, our meta-analysis still has some strengths. First, we are the first researchers to clarify the overall incidence of VPA-induced alopecia and quantify the relative risk of VPA compared to other AEDs and non-AEDs, and we illustrated the risks among different patient groups. Second, we discussed the risk of VPA-associated alopecia in patients treated with different VPA doses for different periods. Third, subgroup and sensitivity analyses were also conducted to ensure the robustness of our conclusions. Our study provides a platform for examining vast heterogeneous data from studies exploring the risk of VPA-induced alopecia under a common analysis and provides some important insights.

      5. Conclusions

      Based on the findings of the present study and the existing literature, VPA-induced hair loss is more common than many clinicians have realized, and its overall incidence is 11%. VPA poses a higher risk of hair loss than other AEDs, and we recommend that VPA should be replaced with LTG if a need occurs, since it has the lowest risk of hair loss compared to VPA. VPA-induced alopecia does not depend on the dose, and reducing the drug dose does not reduce the risk. Patients taking VPA had a higher risk of suffering hair loss within the first 6 months, and patients should be advised about the risk. Taken together, these results support the need for large prospective population-based studies and clinical trials to confirm whether VPA increases the risk of developing hair loss compared to other drugs and whether this phenomenon is dose-dependent.

      Competing interests

      The authors have no competing interests to declare.

      Authors’ contributions

      WXP and LL conceived the study. WXP and WHJ finalized the search strategy. WXP and WHJ primarily screened studies and extracted data with supervision from ZLN and LL. WXP, WHJ and XD analysed the data. All authors participated in data interpretation, writing the manuscript and critically reviewing the manuscript. All authors read and approved the final manuscript.

      Sources of funding

      This research did not receive any specific grant from funding agencies in the public or commercial sectors.

      References

        • Bialer M.
        Why are antiepileptic drugs used for nonepileptic conditions?.
        Epilepsia. 2012; 53: 26-33
        • Soares-Weiser K.
        • et al.
        A systematic review and economic model of the clinical effectiveness and cost-effectiveness of interventions for preventing relapse in people with bipolar disorder.
        Health Technol Assess. 2007; 11 (p. iii-iv, ix-206)
        • Blumenfeld A.
        • Gennings C.
        • Cady R.
        Pharmacological synergy: the next frontier on therapeutic advancement for migraine.
        Headache. 2012; 52: 636-647
        • Ghose K.
        • Niven B.
        Prophylactic sodium valproate therapy in patients with drug-resistant migraine.
        Methods Find Exp Clin Pharmacol. 1998; 20: 353-359
        • Mathew N.T.
        Antiepileptic drugs in migraine prevention.
        Headache. 2001; 41: S18-24
        • Ross E.L.
        The evolving role of antiepileptic drugs in treating neuropathic pain.
        Neurology. 2000; 55 (p. S41-6; discussion S54-8)
        • Hardy J.R.
        • et al.
        A phase II study to establish the efficacy and toxicity of sodium valproate in patients with cancer-related neuropathic pain.
        J Pain Symptom Manage. 2001; 21: 204-209
        • Bootsma H.P.
        • et al.
        The impact of side effects on long-term retention in three new antiepileptic drugs.
        Seizure. 2009; 18: 327-331
        • Chung S.
        • Wang N.
        • Hank N.
        Comparative retention rates and long-term tolerability of new antiepileptic drugs.
        Seizure. 2007; 16: 296-304
        • Tomson T.
        • Battino D.
        • Perucca E.
        Valproic acid after five decades of use in epilepsy: time to reconsider the indications of a time-honoured drug.
        Lancet Neurol. 2016; 15: 210-218
        • Chen B.
        • et al.
        Cosmetic side effects of antiepileptic drugs in adults with epilepsy.
        Epilepsy Behav. 2015; 42: 129-137
        • Verity C.M.
        • Hosking G.
        • Easter D.J.
        A multicentre comparative trial of sodium valproate and carbamazepine in paediatric epilepsy. The Paediatric EPITEG Collaborative Group.
        Dev Med Child Neurol. 1995; 37: 97-108
        • Mattson R.H.
        • Cramer J.A.
        • Collins J.F.
        A comparison of valproate with carbamazepine for the treatment of complex partial seizures and secondarily generalized tonic-clonic seizures in adults. The Department of Veterans Affairs Epilepsy Cooperative Study No. 264 Group.
        N Engl J Med. 1992; 327: 765-771
        • Cohen J.S.
        Adverse drug effects, compliance, and initial doses of antihypertensive drugs recommended by the Joint National Committee vs the Physicians’ Desk Reference.
        Arch Intern Med. 2001; 161: 880-885
        • Picard C.
        • et al.
        Alopecia associated with gabapentin: first case.
        Ann Pharmacother. 1997; 31: 1260
        • Tengstrand M.
        • et al.
        Alopecia in association with lamotrigine use: an analysis of individual case safety reports in a global database.
        Drug Saf. 2010; 33: 653-658
        • Lampl Y.
        • et al.
        Hair loss - an adverse reaction to treatment with vigabatrin.
        Acta Ther. 1996; 22: 51-55
        • Moher D.
        • et al.
        Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement.
        Syst Rev. 2015; 4: 1
        • Stroup D.F.
        • et al.
        Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis of Observational Studies in Epidemiology (MOOSE) group.
        JAMA. 2000; 283: 2008-2012
        • Mantel N.
        • Haenszel W.
        Statistical aspects of the analysis of data from retrospective studies of disease.
        J Natl Cancer Inst. 1959; 22: 719-748
        • DerSimonian R.
        • Kacker R.
        Random-effects model for meta-analysis of clinical trials: an update.
        Contemp Clin Trials. 2007; 28: 105-114
        • Zintzaras E.
        • Ioannidis J.P.
        Heterogeneity testing in meta-analysis of genome searches.
        Genet Epidemiol. 2005; 28: 123-137
        • Lau J.
        • Ioannidis J.P.
        • Schmid C.H.
        Quantitative synthesis in systematic reviews.
        Ann Intern Med. 1997; 127: 820-826
        • Christe W.
        • et al.
        A double-blind controlled clinical trial: oxcarbazepine versus sodium valproate in adults with newly diagnosed epilepsy.
        Epilepsy Res. 1997; 26: 451-460
        • Richens A.
        • et al.
        A multicentre comparative trial of sodium valproate and carbamazepine in adult onset epilepsy.
        J Neurol Neurosurg Psychiatr. 1994; 57: 682-687
        • Park K.M.
        • et al.
        A randomized open-label observational study to compare the efficacy and tolerability between topiramate and valproate in juvenile myoclonic epilepsy.
        J Clin Neurosci. 2013; 20: 1079-1082
        • Biton V.
        • et al.
        Weight change associated with valproate and lamotrigine monotherapy in patients with epilepsy.
        Neurology. 2001; 56: 172-177
        • Privitera M.D.
        • et al.
        Topiramate, carbamazepine and valproate monotherapy: double-blind comparison in newly diagnosed epilepsy.
        Acta Neurol Scand. 2003; 107: 165-175
        • Levisohn P.M.
        • Holland K.D.
        Topiramate or valproate in patients with juvenile myoclonic epilepsy: a randomized open-label comparison.
        Epilepsy Behav. 2007; 10: 547-552
        • Steinhoff B.J.
        • et al.
        The LAM-SAFE Study: lamotrigine versus carbamazepine or valproic acid in newly diagnosed focal and generalised epilepsies in adolescents and adults.
        Seizure. 2005; 14: 597-605
        • Viteri C.
        • et al.
        Quality of life and treatment satisfaction in Spanish epilepsy patients on monotherapy with lamotrigine or valproic acid.
        Seizure. 2010; 19: 432-438
        • Xu L.
        • et al.
        Olanzapine–valproate combination versus olanzapine or valproate monotherapy in the treatment of bipolar imania: a randomized controlled study in a chinese population group.
        Neuropsychiatr Dis Treat. 2015; 11: 1265-1271
        • Mathew N.T.
        • et al.
        Migraine prophylaxis with divalproex.
        Arch Neurol. 1995; 52: 281-286
        • Craig I.
        • Tallis R.
        Impact of valproate and phenytoin on cognitive function in elderly patients: results of a single-blind randomized comparative study.
        Epilepsia. 1994; 35: 381-390
        • Fakhoury T.A.
        • et al.
        Efficacy and tolerability of conversion to monotherapy with lamotrigine compared with valproate and carbamazepine in patients with epilepsy.
        Epilepsy Behav. 2004; 5: 532-538
        • Hebrani P.
        • Behdani F.
        • Manteghi A.A.
        Double-blind, randomized, clinical trial of topiramate versus sodium valproate for the treatment of bipolar disorder in adolescents.
        Pak J Med Sci. 2009; 25: 247-252
        • Hesami O.
        • et al.
        Comparing the effects of atorvastatin with sodium valproate (Divalproex) on frequency and intensity of frequent migraine headaches: a double-blind randomized controlled study.
        Clin Neuropharmacol. 2018; 41: 94-97https://doi.org/10.1097/WNF.0000000000000280
        • Kakkar A.K.
        • et al.
        Comparative efficacy and safety of oxcarbazepine versus divalproex sodium in the treatment of acute mania: a pilot study.
        Eur Psychiatry. 2009; 24: 178-182
        • Blumenfeld A.M.
        • Schim J.D.
        • Chippendale T.J.
        Botulinum toxin type A and divalproex sodium for prophylactic treatment of episodic or chronic migraine.
        Headache. 2008; 48: 210-220
        • Bostani A.
        • et al.
        The effects of cinnarizine versus sodium valproate in migraine prophylaxis.
        Int J Neurosci. 2013; 123: 487-493https://doi.org/10.3109/00207454.2013.765419
        • Donati F.
        • et al.
        The cognitive effects of oxcarbazepine versus carbamazepine or valproate in newly diagnosed children with partial seizures.
        Seizure. 2007; 16: 670-679
        • Sarchielli P.
        • et al.
        Sodium valproate in migraine without aura and medication overuse headache: a randomized controlled trial.
        Eur Neuropsychopharmacol. 2014; 24: 1289-1297
        • Shaygannejad V.
        • et al.
        Comparison of the effect of topiramate and sodium valporate in migraine prevention: a randomized blinded crossover study.
        Headache. 2006; 46: 642-648
        • Nejad S.E.M.
        • et al.
        A randomized open-label comparison of lamotrigine and valproate in patients with juvenile myoclonic epilepsy.
        Int J Pharmacol. 2009; 5: 313-318
        • Afshari D.
        • Rafizadeh S.
        • Rezaei M.
        A comparative study of the effects of low-dose topiramate versus sodium valproate in migraine prophylaxis.
        Int J Neurosci. 2012; 122: 60-68
        • Calabrese J.R.
        • et al.
        A 20-month, double-blind, maintenance trial of lithium versus divalproex in rapid-cycling bipolar disorder.
        Am J Psychiatry. 2005; 162: 2152-2161
        • Biton V.
        Lamotrigine versus valproate monotherapy-associated weight change in adolescents with epilepsy: results from a post hoc analysis of a randomized, double-blind clinical trial.
        J Child Neurol. 2003; 18: 133-139
        • Wheless J.W.
        • Neto W.
        • Wang S.
        Topiramate, carbamazepine, and valproate monotherapy: double-blind comparison in children with newly diagnosed epilepsy.
        J Child Neurol. 2004; 19: 135-141
        • Pillans P.I.
        • Woods D.J.
        Drug-associated alopecia.
        Int J Dermatol. 1995; 34: 149-158
        • Davis R.
        • Peters D.H.
        • McTavish D.
        Valproic acid. A reappraisal of its pharmacological properties and clinical efficacy in epilepsy.
        Drugs. 1994; 47: 332-372
        • McKinney P.A.
        • Finkenbine R.D.
        • DeVane C.L.
        Alopecia and mood stabilizer therapy.
        Ann Clin Psychiatry. 1996; 8: 183-185
        • Druschky K.
        • et al.
        Severe hair loss associated with psychotropic drugs in psychiatric inpatients-Data from an observational pharmacovigilance program in German-speaking countries.
        Eur Psychiatry. 2018; 54: 117-123
        • Mercke Y.
        • et al.
        Hair loss in psychopharmacology.
        Ann Clin Psychiatry. 2000; 12: 35-42
        • Ramakrishnappa S.K.
        • Belhekar M.N.
        Serum drug level-related sodium valproate-induced hair loss.
        Indian J Pharmacol. 2013; 45: 187-188
        • Orwin A.
        Hair loss following lithium therapy.
        Br J Dermatol. 1983; 108: 503-504
        • Warnock J.K.
        Psychotropic medication and drug-related alopecia.
        Psychosomatics. 1991; 32: 149-152
        • McCreadie R.G.
        • Morrison D.P.
        The impact of lithium in South-west Scotland. I. Demographic and clinical findings.
        Br J Psychiatry. 1985; 146: 70-74
        • Parameshwar E.
        Hair loss associated with fluvoxamine use.
        Am J Psychiatry. 1996; 153: 581-582
        • Silvestri A.
        • Santonastaso P.
        • Paggiarin D.
        Alopecia areata during lithium therapy. A case report.
        Gen Hosp Psychiatry. 1988; 10: 46-48
        • Yassa R.
        • Ananth J.
        Hair loss in the course of lithium treatment: a report of two cases.
        Can J Psychiatry. 1983; 28: 132-133
        • Sarantidis D.
        • Waters B.
        A review and controlled study of cutaneous conditions associated with lithium carbonate.
        Br J Psychiatry. 1983; 143: 42-50
        • Kirov G.
        Thyroid disorders in lithium-treated patients.
        J Affect Disord. 1998; 50: 33-40
        • Thomson S.R.
        • Mamulpet V.
        • Adiga S.
        Sodium valproate induced alopecia: a case series.
        J Clin Diagn Res. 2017; 11: Fr01-fr02
        • Klotz U.
        • Schweizer C.
        Valproic acid in childhood epilepsy: anticonvulsive efficacy in relation to its plasma levels.
        Int J Clin Pharmacol Ther Toxicol. 1980; 18: 461-465
        • Despland P.A.
        [Tolerance to and unwanted effects of valproate sodium].
        Praxis (Bern 1994). 1994; 83: 1132-1139
        • Beydoun A.
        • Sackellares J.C.
        • Shu V.
        Safety and efficacy of divalproex sodium monotherapy in partial epilepsy: a double-blind, concentration-response design clinical trial. Depakote Monotherapy for Partial Seizures Study Group.
        Neurology. 1997; 48: 182-188
        • Henriksen O.
        • Johannessen S.I.
        Clinical and pharmacokinetic observations on sodium valproate - a 5-year follow-up study in 100 children with epilepsy.
        Acta Neurol Scand. 1982; 65: 504-523
        • Lewis J.R.
        Valproic acid (Depakene). A new anticonvulsant agent.
        JAMA. 1978; 240: 2190-2192