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Culprits of Medication-Induced Telogen Effluvium, Part 1
Author(s)
Donglin Zhang, BA
Charlotte Lasenna, MD
Bridget E. Shields, MD

Alopecia is a commonly reported side effect of various medications. Anagen effluvium and telogen effluvium (TE) are considered the most common mechanisms underlying medication-related hair loss. Anagen effluvium is associated with chemotherapeutic agents and radiation therapy, with anagen shedding typically occurring within 2 weeks of medication administration.1,2 Medication-induced TE is a diffuse nonscarring alopecia that is a reversible reactive process.3-5 Telogen effluvium is clinically apparent as a generalized shedding of scalp hair 1 to 6 months after an inciting cause.6 The underlying cause of TE may be multifactorial and difficult to identify given the delay between the trigger and the onset of clinically apparent hair loss. Other known triggers of TE include acute illness,7,8 nutritional deficiencies,4,9 and/or major surgery.10

Each hair follicle independently and sequentially progresses through anagen growth, catagen transition, and telogen resting phases. In the human scalp, the telogen phase typically lasts 3 months, at the end of which the telogen hair is extruded from the scalp. Anagen and telogen follicles typically account for an average of 90% and 10% of follicles on the human scalp, respectively.11 Immediate anagen release is hypothesized to be the mechanism underlying medication-induced TE.12 This theory suggests that an increased percentage of anagen follicles prematurely enter the telogen phase, with a notable increase in hair shedding at the conclusion of the telogen phase approximately 1 to 6 months later.12 First-line management of medication-induced TE is identification and cessation of the causative agent, if possible. Notable regrowth of hair is expected several months after removal of the inciting medication. In part 1 of this 2-part series, we review the existing literature to identify common culprits of medication-induced TE, including retinoids, antifungals, and psychotropic medications.

Retinoids

Retinoids are vitamin A derivatives used in the treatment of a myriad of dermatologic and nondermatologic conditions.13,14 Retinoids modulate sebum production,15 keratinocyte proliferation,16 and epithelial differentiation through signal transduction downstream of the ligand-activated nuclear retinoic acid receptors and retinoid X receptors.13,14,17 The recommended daily dosage of retinol is 900 µg retinol activity equivalent (3000 IU) for men and 700 µg retinol activity equivalent (2333 IU) for women. Retinoids are used in the treatment of acne vulgaris,18 psoriasis,19 and ichthyosis.20 The most commonly reported adverse effects of systemic retinoid therapy include cheilitis, alopecia, and xerosis.21 Retinoid-associated alopecia is dose and duration dependent.19,21-24 A prospective study of acitretin therapy in plaque psoriasis reported that more than 63% (42/66) of patients on 50 mg or more of acitretin daily for 6 months or longer experienced alopecia that reversed with discontinuation.23 A systematic review of isotretinoin use in acne showed alopecia was seen in 3.2% (18/565) of patients on less than 0.5 mg/kg/d of isotretinoin and in 5.7% (192/3375) of patients on 0.5 mg/kg/d or less of isotretinoin.24 In a phase 2 clinical trial of orally administered 9-cis-retinoic acid (alitretinoin) in the treatment of Kaposi sarcoma related to AIDS, 42% (24/57) of adult male patients receiving 60, 100, or 140 mg/m2 alitretinoin daily (median treatment duration, 15.1 weeks) reported alopecia as an adverse effect of treatment.25 In one case report, a patient who ingested 500,000 IU of vitamin A daily for 4 months and then 100,000 IU monthly for 6 months experienced diffusely increased shedding of scalp hair along with muscle soreness, nail dystrophy, diffuse skin rash, and refractory ascites; he was found to have severe liver damage secondary to hypervitaminosis A that required liver transplantation.26 Regarding the pathomechanism of retinoid-induced alopecia, animal and in vitro studies similarly have demonstrated that all-trans-retinoic acid appears to exert its inhibitory effects on hair follicle growth via the influence of the transforming growth factor β2 and SMAD2/3 pathway influence on dermal papillae cells.14,27 Development of hair loss secondary to systemic retinoid therapy may be managed with dose reduction or cessation.

Antifungals

Azole medications have broad-spectrum fungistatic activity against a wide range of yeast and filamentous fungi. Azoles inhibit sterol 14α-demethylase activity, impairing ergosterol synthesis and thereby disrupting plasma membrane synthesis and activity of membrane-bound enzymes.28 Fluconazole is a systemic oral agent in this class that was first approved by the US Food and Drug Administration (FDA) for use in the 1990s.29 A retrospective study by the National Institute of Allergy and Infectious Disease Mycoses Study Group followed the clinical course of 33 patients who developed alopecia while receiving fluconazole therapy for various mycoses.30 The majority (88% [29/33]) of patients received 400 mg or more of fluconazole daily. The median time to hair loss after starting fluconazole was 3 months, and the scalp was involved in all cases. In 97% (32/33) of patients, resolution of alopecia was noted following discontinuation of fluconazole or a dose reduction of 50% or more. In 85% (28/33) of patients, complete resolution of alopecia occurred within 6 months of fluconazole cessation or dose reduction.30 Fluconazole-induced TE was reproducible in an animal model using Wistar rats31; however, further studies are required to clarify the molecular pathways of its effect on hair growth.

Voriconazole is an azole approved for the treatment of invasive aspergillosis, candidemia, and fungal infections caused by Scedosporium apiospermum and Fusarium species. A retrospective survey study of patients who received voriconazole for 1 month or longer found a considerable proportion of patients developed diffuse reversible hair loss.32 Scalp alopecia was noted in 79% (120/152) of patients who completed the survey, with a mean (SD) time to alopecia of 75 (54) days after initiation of voriconazole. Notable regrowth was reported in 69% (79/114) of patients who discontinued voriconazole for at least 3 months. A subgroup of 32 patients were changed to itraconazole or posaconazole, and hair loss stopped in 84% (27/32) with regrowth noted in 69% (22/32) of patients.32 Voriconazole and fluconazole share structural similarity not present with other triazoles.33,34 Because voriconazole-associated alopecia was reversed in the majority of patients who switched to itraconazole or posaconazole, the authors hypothesized that structural similarity of fluconazole and voriconazole may underly the greater risk for TE that is not a class effect of azole medications.31

Psychotropic Medications

Various psychotropic medications have been associated with hair loss. Valproic acid (or sodium valproate) is an anticonvulsant and mood-stabilizing agent used for the treatment of seizures, bipolar disorder (BD), migraines, and neuropathic pain.35,36 Divalproex sodium (or divalproex) is an enteric-coated formulation of sodium valproate and valproic acid with similar indications. Valproate is a notorious culprit of medication-induced hair loss, with alopecia listed among the most common adverse reactions (reported >5%) on its structure product labeling document.37 A systemic review and meta-analysis by Wang et al38 estimated the overall incidence of valproate-related alopecia to be 11% (95% CI, 0.08-0.13). Although this meta-analysis did not find an association between incidence of alopecia and dose or duration of valproate therapy,38 a separate review suggested that valproate-induced alopecia is dose dependent and can be managed with dose reduction.39 A 12-month, randomized, double-blind study of treatment of BD with divalproex (valproate derivative), lithium, or placebo (2:1:1 ratio) showed a significantly higher frequency of alopecia in the divalproex group compared with placebo (16% [30/187] vs 6% [6/94]; P=.03).40 Valproate-related hair loss is characteristically diffuse and nonscarring, often noted 3 to 6 months following initiation of valproate.41,42 The proposed mechanism of valproate-induced alopecia includes chelation of zinc and selenium,43 and a reduction in serum biotinidase activity, thereby decreasing the availability of these essential micronutrients required for hair growth.41 Studies examining the effects of valproate administration and serum biotinidase activity in patients have yielded conflicting results.44-46 In a study of children with seizures including 57 patients treated with valproic acid, 17 treated with carbamazepine, and 75 age- and sex-matched healthy controls, the authors found no significant differences in serum biotinidase enzyme activity across the 3 groups.44 In contrast, a study of 75 children with seizures on valproic acid therapy stratified by dose (mean [SD])—group A: 28.7 [8.5] mg/kg/d; group B: 41.6 [4.9] mg/kg/d; group C: 64.5 [5.8] mg/kg/d—found that patients receiving higher doses (groups B and C) had significantly reduced serum biotinidase activity (1.22 [1.11] and 0.97 [0.07] mmol/min/L, respectively) compared with 50 healthy pediatric controls (5.20 [0.90] mmol/min/L; P<.001). The same study found biotin supplementation at 10 mg/d for 20 days led to resolution of alopecia in 22% (2/9) of patients with alopecia on valproic acid therapy.45 Despite hypothesized effects of valproate on micronutrients, the role of mineral supplementation in treating valproate-associated hair loss remains unclear. There is evidence to suggest that valproic acid–associated alterations in serum biotinidase activity may be transient. In a study of 32 pediatric patients receiving valproic acid for the treatment of epilepsy, serum biotinidase activity was significantly lower after 3 months of valproic acid therapy compared with pretreatment levels (P<.05); at 6 months, the serum biotinidase activity was increased compared with 3 months (P<.05) and not significantly different from pretreatment levels (P>.05).46 Hair regrowth has been observed following discontinuation or dose reduction of valproate therapy in some cases.39,47

Lithium carbonate (lithium) is used in the treatment of BD. Despite its efficacy and low cost, its potential for adverse effects, narrow therapeutic index, and subsequent need for routine monitoring are factors that limit its use.48 Some reported dermatologic adverse reactions on its structure product labeling include xerosis, thinning of hair, alopecia, xerosis cutis, psoriasis onset/exacerbation, and generalized pruritus.49 A systematic review and meta-analysis of 385 studies identified 24 publications reporting adverse effects of lithium on hair with no significantly increased risk of alopecia overall.50 The analysis included 2 randomized controlled trials comparing the effects of lithium and placebo on hair loss in patients with BD. Hair loss was reported in 7% (7/94) of patients taking lithium and 6% (6/94) of the placebo group in the 12-month study40 and in 3% (1/32) of the lithium group and 0% (0/28) of the divalproex group in the 20-month study.51 Despite anecdotal reports of alopecia associated with lithium, there is a lack of high-quality evidence to support this claim. Of note, hypothyroidism is a known complication of lithium use, and serum testing of thyroid function at 6-month intervals is recommended for patients on lithium treatment.52 Because thyroid abnormalities can cause alopecia distinct from TE, new-onset alopecia during lithium use should prompt serum testing of thyroid function. The development of hypothyroidism secondary to lithium is not a direct contraindication to its use53; rather, treatment should be focused on correction with thyroid replacement therapy (eg, supplementation with thyroxine).54

 

 

Commonly prescribed antidepressant medications include selective serotonin reuptake inhibitors (SSRIs) and bupropion. Selective serotonin reuptake inhibitors affect the neuronal serotonin transporter, increasing the concentration of serotonin in the synaptic cleft available for stimulation of postsynaptic serotonin receptors55,56; bupropion is an antidepressant medication that inhibits norepinephrine and dopamine reuptake at the synaptic cleft.57 Alopecia is an infrequent (1 in 100 to 1 in 1000 patients) adverse effect for several SSRIs.58-62 A recent systematic review identified a total of 71 cases of alopecia associated with SSRI use including citalopram (n=11), escitalopram (n=7), fluoxetine (n=27), fluoxvamine (n=5), paroxetine (n=4), and sertraline (n=20), with a median time to onset of hair shedding of 8.6 weeks (range, 3 days to 5 years). Discontinuation of the suspected culprit SSRI led to improvement and/or resolution in 63% (51/81) episodes of alopecia, with a median time to improvement and/or resolution of 4 weeks.63 A comparative retrospective cohort study using a large US health claims database from 2006 to 2014 included more than 1 million new and mutually exclusive patients taking fluoxetine, fluvoxamine, sertraline, citalopram, escitalopram, paroxetine, duloxetine, venlafaxine, desvenlafaxine, and bupropion.64 Overall, 1% (1569/150,404) of patients treated with bupropion received 1 or more physician visits for alopecia. Patients on SSRIs generally had a lower risk for hair loss compared with patients using bupropion (citalopram: hazard ratio [HR], 0.80 [95% CI, 0.74-0.86]; escitalopram: HR, 0.79 [95% CI, 0.74-0.86]; fluoxetine: HR, 0.68 [95% CI, 0.63-0.74]; paroxetine: HR, 0.68 [95% CI, 0.62-0.74]; sertraline: HR, 0.74 [95% CI, 0.69-0.79]), with the exception of fluvoxamine (HR, 0.93 [95% CI, 0.64-1.37]). However, the type of alopecia, time to onset, and time to resolution were not reported, making it difficult to assess whether the reported hair loss was consistent with medication-induced TE. Additionally, the authors acknowledged that bupropion may have been prescribed for smoking cessation, which may carry a different risk profile for the development of alopecia.64 Several other case reports have described alopecia following treatment with SSRIs, including sertraline,65 fluvoxamine,66 paroxetine,67 fluoxetine,68 and escitalopram.69

Overall, it appears that the use of SSRIs portends relatively low risk for alopecia and medication-induced TE. Little is known regarding the molecular effects of SSRIs on hair growth and the pathomechanism of SSRI-induced TE. The potential benefits of discontinuing a suspected culprit medication should be carefully weighed against the risks of medication cessation, and consideration should be given to alternative medications in the same class that also may be associated with TE. In patients requiring antidepressant therapy with suspected medication-induced TE, consider transitioning to a different class of medication with lower risk of medication-induced alopecia; for example, discontinuing bupropion in favor of an SSRI.

Final Thoughts

Medication-induced alopecia is an undesired side effect of many commonly used drugs and drug classes, including retinoids, azole antifungals, and mood stabilizers. Although the precise pathomechanisms of medication-induced TE remain unclear, the recommended management often requires identification of the likely causative agent and its discontinuation, if possible. Suspicion for medication-induced TE should prompt a thorough history of recent changes to medications, risk factors for nutritional deficiencies, underlying illnesses, and recent surgical procedures. Underlying nutritional, electrolyte, and/or metabolic disturbances should be corrected. In part 2 of this series, we will discuss medication-induced alopecia associated with anticoagulant and antihypertensive medications.

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  66. Parameshwar E. Hair loss associated with fluvoxamine use. Am J Psychiatry. 1996;153:581-582. doi:10.1176/ajp.153.4.581
  67. Zalsman G, Sever J, Munitz H. Hair loss associated with paroxetine treatment: a case report. Clin Neuropharmacol. 1999;22:246-247.
  68. Ananth J, Elmishaugh A. Hair loss associated with fluoxetinetreatment. Can J Psychiatry. 1991;36:621. doi:10.1177/070674379103600824
  69. Tirmazi SI, Imran H, Rasheed A, et al. Escitalopram-induced hair loss. Prim Care Companion CNS Disord. 2020;22:19l02496. doi:10.4088/PCC.19l02496
Article PDF
CT112006267.pdf
Author and Disclosure Information

From the Department of Dermatology, University of Wisconsin School of Medicine and Public Health, Madison.

Donglin Zhang and Dr. LaSenna report no conflict of interest. Dr. Shields has received a grant from the Dermatology Foundation.

This article is part 1 of a 2-part series. The second part will appear next month.

Correspondence: Bridget E. Shields, MD, Department of Dermatology, University of Wisconsin, 1 S Park St, Madison, WI 53715([email protected]).

Issue
Cutis - 112(6)
Publications
MDedge Dermatology
Cutis
Topics
Hair & Nails
Page Number
267-271
Sections
Food for Thought
Author(s)
Donglin Zhang, BA
Charlotte Lasenna, MD
Bridget E. Shields, MD
Author(s)
Donglin Zhang, BA
Charlotte Lasenna, MD
Bridget E. Shields, MD
Author and Disclosure Information

From the Department of Dermatology, University of Wisconsin School of Medicine and Public Health, Madison.

Donglin Zhang and Dr. LaSenna report no conflict of interest. Dr. Shields has received a grant from the Dermatology Foundation.

This article is part 1 of a 2-part series. The second part will appear next month.

Correspondence: Bridget E. Shields, MD, Department of Dermatology, University of Wisconsin, 1 S Park St, Madison, WI 53715([email protected]).

Author and Disclosure Information

From the Department of Dermatology, University of Wisconsin School of Medicine and Public Health, Madison.

Donglin Zhang and Dr. LaSenna report no conflict of interest. Dr. Shields has received a grant from the Dermatology Foundation.

This article is part 1 of a 2-part series. The second part will appear next month.

Correspondence: Bridget E. Shields, MD, Department of Dermatology, University of Wisconsin, 1 S Park St, Madison, WI 53715([email protected]).

Article PDF
CT112006267.pdf
Article PDF
CT112006267.pdf

Alopecia is a commonly reported side effect of various medications. Anagen effluvium and telogen effluvium (TE) are considered the most common mechanisms underlying medication-related hair loss. Anagen effluvium is associated with chemotherapeutic agents and radiation therapy, with anagen shedding typically occurring within 2 weeks of medication administration.1,2 Medication-induced TE is a diffuse nonscarring alopecia that is a reversible reactive process.3-5 Telogen effluvium is clinically apparent as a generalized shedding of scalp hair 1 to 6 months after an inciting cause.6 The underlying cause of TE may be multifactorial and difficult to identify given the delay between the trigger and the onset of clinically apparent hair loss. Other known triggers of TE include acute illness,7,8 nutritional deficiencies,4,9 and/or major surgery.10

Each hair follicle independently and sequentially progresses through anagen growth, catagen transition, and telogen resting phases. In the human scalp, the telogen phase typically lasts 3 months, at the end of which the telogen hair is extruded from the scalp. Anagen and telogen follicles typically account for an average of 90% and 10% of follicles on the human scalp, respectively.11 Immediate anagen release is hypothesized to be the mechanism underlying medication-induced TE.12 This theory suggests that an increased percentage of anagen follicles prematurely enter the telogen phase, with a notable increase in hair shedding at the conclusion of the telogen phase approximately 1 to 6 months later.12 First-line management of medication-induced TE is identification and cessation of the causative agent, if possible. Notable regrowth of hair is expected several months after removal of the inciting medication. In part 1 of this 2-part series, we review the existing literature to identify common culprits of medication-induced TE, including retinoids, antifungals, and psychotropic medications.

Retinoids

Retinoids are vitamin A derivatives used in the treatment of a myriad of dermatologic and nondermatologic conditions.13,14 Retinoids modulate sebum production,15 keratinocyte proliferation,16 and epithelial differentiation through signal transduction downstream of the ligand-activated nuclear retinoic acid receptors and retinoid X receptors.13,14,17 The recommended daily dosage of retinol is 900 µg retinol activity equivalent (3000 IU) for men and 700 µg retinol activity equivalent (2333 IU) for women. Retinoids are used in the treatment of acne vulgaris,18 psoriasis,19 and ichthyosis.20 The most commonly reported adverse effects of systemic retinoid therapy include cheilitis, alopecia, and xerosis.21 Retinoid-associated alopecia is dose and duration dependent.19,21-24 A prospective study of acitretin therapy in plaque psoriasis reported that more than 63% (42/66) of patients on 50 mg or more of acitretin daily for 6 months or longer experienced alopecia that reversed with discontinuation.23 A systematic review of isotretinoin use in acne showed alopecia was seen in 3.2% (18/565) of patients on less than 0.5 mg/kg/d of isotretinoin and in 5.7% (192/3375) of patients on 0.5 mg/kg/d or less of isotretinoin.24 In a phase 2 clinical trial of orally administered 9-cis-retinoic acid (alitretinoin) in the treatment of Kaposi sarcoma related to AIDS, 42% (24/57) of adult male patients receiving 60, 100, or 140 mg/m2 alitretinoin daily (median treatment duration, 15.1 weeks) reported alopecia as an adverse effect of treatment.25 In one case report, a patient who ingested 500,000 IU of vitamin A daily for 4 months and then 100,000 IU monthly for 6 months experienced diffusely increased shedding of scalp hair along with muscle soreness, nail dystrophy, diffuse skin rash, and refractory ascites; he was found to have severe liver damage secondary to hypervitaminosis A that required liver transplantation.26 Regarding the pathomechanism of retinoid-induced alopecia, animal and in vitro studies similarly have demonstrated that all-trans-retinoic acid appears to exert its inhibitory effects on hair follicle growth via the influence of the transforming growth factor β2 and SMAD2/3 pathway influence on dermal papillae cells.14,27 Development of hair loss secondary to systemic retinoid therapy may be managed with dose reduction or cessation.

Antifungals

Azole medications have broad-spectrum fungistatic activity against a wide range of yeast and filamentous fungi. Azoles inhibit sterol 14α-demethylase activity, impairing ergosterol synthesis and thereby disrupting plasma membrane synthesis and activity of membrane-bound enzymes.28 Fluconazole is a systemic oral agent in this class that was first approved by the US Food and Drug Administration (FDA) for use in the 1990s.29 A retrospective study by the National Institute of Allergy and Infectious Disease Mycoses Study Group followed the clinical course of 33 patients who developed alopecia while receiving fluconazole therapy for various mycoses.30 The majority (88% [29/33]) of patients received 400 mg or more of fluconazole daily. The median time to hair loss after starting fluconazole was 3 months, and the scalp was involved in all cases. In 97% (32/33) of patients, resolution of alopecia was noted following discontinuation of fluconazole or a dose reduction of 50% or more. In 85% (28/33) of patients, complete resolution of alopecia occurred within 6 months of fluconazole cessation or dose reduction.30 Fluconazole-induced TE was reproducible in an animal model using Wistar rats31; however, further studies are required to clarify the molecular pathways of its effect on hair growth.

Voriconazole is an azole approved for the treatment of invasive aspergillosis, candidemia, and fungal infections caused by Scedosporium apiospermum and Fusarium species. A retrospective survey study of patients who received voriconazole for 1 month or longer found a considerable proportion of patients developed diffuse reversible hair loss.32 Scalp alopecia was noted in 79% (120/152) of patients who completed the survey, with a mean (SD) time to alopecia of 75 (54) days after initiation of voriconazole. Notable regrowth was reported in 69% (79/114) of patients who discontinued voriconazole for at least 3 months. A subgroup of 32 patients were changed to itraconazole or posaconazole, and hair loss stopped in 84% (27/32) with regrowth noted in 69% (22/32) of patients.32 Voriconazole and fluconazole share structural similarity not present with other triazoles.33,34 Because voriconazole-associated alopecia was reversed in the majority of patients who switched to itraconazole or posaconazole, the authors hypothesized that structural similarity of fluconazole and voriconazole may underly the greater risk for TE that is not a class effect of azole medications.31

Psychotropic Medications

Various psychotropic medications have been associated with hair loss. Valproic acid (or sodium valproate) is an anticonvulsant and mood-stabilizing agent used for the treatment of seizures, bipolar disorder (BD), migraines, and neuropathic pain.35,36 Divalproex sodium (or divalproex) is an enteric-coated formulation of sodium valproate and valproic acid with similar indications. Valproate is a notorious culprit of medication-induced hair loss, with alopecia listed among the most common adverse reactions (reported >5%) on its structure product labeling document.37 A systemic review and meta-analysis by Wang et al38 estimated the overall incidence of valproate-related alopecia to be 11% (95% CI, 0.08-0.13). Although this meta-analysis did not find an association between incidence of alopecia and dose or duration of valproate therapy,38 a separate review suggested that valproate-induced alopecia is dose dependent and can be managed with dose reduction.39 A 12-month, randomized, double-blind study of treatment of BD with divalproex (valproate derivative), lithium, or placebo (2:1:1 ratio) showed a significantly higher frequency of alopecia in the divalproex group compared with placebo (16% [30/187] vs 6% [6/94]; P=.03).40 Valproate-related hair loss is characteristically diffuse and nonscarring, often noted 3 to 6 months following initiation of valproate.41,42 The proposed mechanism of valproate-induced alopecia includes chelation of zinc and selenium,43 and a reduction in serum biotinidase activity, thereby decreasing the availability of these essential micronutrients required for hair growth.41 Studies examining the effects of valproate administration and serum biotinidase activity in patients have yielded conflicting results.44-46 In a study of children with seizures including 57 patients treated with valproic acid, 17 treated with carbamazepine, and 75 age- and sex-matched healthy controls, the authors found no significant differences in serum biotinidase enzyme activity across the 3 groups.44 In contrast, a study of 75 children with seizures on valproic acid therapy stratified by dose (mean [SD])—group A: 28.7 [8.5] mg/kg/d; group B: 41.6 [4.9] mg/kg/d; group C: 64.5 [5.8] mg/kg/d—found that patients receiving higher doses (groups B and C) had significantly reduced serum biotinidase activity (1.22 [1.11] and 0.97 [0.07] mmol/min/L, respectively) compared with 50 healthy pediatric controls (5.20 [0.90] mmol/min/L; P<.001). The same study found biotin supplementation at 10 mg/d for 20 days led to resolution of alopecia in 22% (2/9) of patients with alopecia on valproic acid therapy.45 Despite hypothesized effects of valproate on micronutrients, the role of mineral supplementation in treating valproate-associated hair loss remains unclear. There is evidence to suggest that valproic acid–associated alterations in serum biotinidase activity may be transient. In a study of 32 pediatric patients receiving valproic acid for the treatment of epilepsy, serum biotinidase activity was significantly lower after 3 months of valproic acid therapy compared with pretreatment levels (P<.05); at 6 months, the serum biotinidase activity was increased compared with 3 months (P<.05) and not significantly different from pretreatment levels (P>.05).46 Hair regrowth has been observed following discontinuation or dose reduction of valproate therapy in some cases.39,47

Lithium carbonate (lithium) is used in the treatment of BD. Despite its efficacy and low cost, its potential for adverse effects, narrow therapeutic index, and subsequent need for routine monitoring are factors that limit its use.48 Some reported dermatologic adverse reactions on its structure product labeling include xerosis, thinning of hair, alopecia, xerosis cutis, psoriasis onset/exacerbation, and generalized pruritus.49 A systematic review and meta-analysis of 385 studies identified 24 publications reporting adverse effects of lithium on hair with no significantly increased risk of alopecia overall.50 The analysis included 2 randomized controlled trials comparing the effects of lithium and placebo on hair loss in patients with BD. Hair loss was reported in 7% (7/94) of patients taking lithium and 6% (6/94) of the placebo group in the 12-month study40 and in 3% (1/32) of the lithium group and 0% (0/28) of the divalproex group in the 20-month study.51 Despite anecdotal reports of alopecia associated with lithium, there is a lack of high-quality evidence to support this claim. Of note, hypothyroidism is a known complication of lithium use, and serum testing of thyroid function at 6-month intervals is recommended for patients on lithium treatment.52 Because thyroid abnormalities can cause alopecia distinct from TE, new-onset alopecia during lithium use should prompt serum testing of thyroid function. The development of hypothyroidism secondary to lithium is not a direct contraindication to its use53; rather, treatment should be focused on correction with thyroid replacement therapy (eg, supplementation with thyroxine).54

 

 

Commonly prescribed antidepressant medications include selective serotonin reuptake inhibitors (SSRIs) and bupropion. Selective serotonin reuptake inhibitors affect the neuronal serotonin transporter, increasing the concentration of serotonin in the synaptic cleft available for stimulation of postsynaptic serotonin receptors55,56; bupropion is an antidepressant medication that inhibits norepinephrine and dopamine reuptake at the synaptic cleft.57 Alopecia is an infrequent (1 in 100 to 1 in 1000 patients) adverse effect for several SSRIs.58-62 A recent systematic review identified a total of 71 cases of alopecia associated with SSRI use including citalopram (n=11), escitalopram (n=7), fluoxetine (n=27), fluoxvamine (n=5), paroxetine (n=4), and sertraline (n=20), with a median time to onset of hair shedding of 8.6 weeks (range, 3 days to 5 years). Discontinuation of the suspected culprit SSRI led to improvement and/or resolution in 63% (51/81) episodes of alopecia, with a median time to improvement and/or resolution of 4 weeks.63 A comparative retrospective cohort study using a large US health claims database from 2006 to 2014 included more than 1 million new and mutually exclusive patients taking fluoxetine, fluvoxamine, sertraline, citalopram, escitalopram, paroxetine, duloxetine, venlafaxine, desvenlafaxine, and bupropion.64 Overall, 1% (1569/150,404) of patients treated with bupropion received 1 or more physician visits for alopecia. Patients on SSRIs generally had a lower risk for hair loss compared with patients using bupropion (citalopram: hazard ratio [HR], 0.80 [95% CI, 0.74-0.86]; escitalopram: HR, 0.79 [95% CI, 0.74-0.86]; fluoxetine: HR, 0.68 [95% CI, 0.63-0.74]; paroxetine: HR, 0.68 [95% CI, 0.62-0.74]; sertraline: HR, 0.74 [95% CI, 0.69-0.79]), with the exception of fluvoxamine (HR, 0.93 [95% CI, 0.64-1.37]). However, the type of alopecia, time to onset, and time to resolution were not reported, making it difficult to assess whether the reported hair loss was consistent with medication-induced TE. Additionally, the authors acknowledged that bupropion may have been prescribed for smoking cessation, which may carry a different risk profile for the development of alopecia.64 Several other case reports have described alopecia following treatment with SSRIs, including sertraline,65 fluvoxamine,66 paroxetine,67 fluoxetine,68 and escitalopram.69

Overall, it appears that the use of SSRIs portends relatively low risk for alopecia and medication-induced TE. Little is known regarding the molecular effects of SSRIs on hair growth and the pathomechanism of SSRI-induced TE. The potential benefits of discontinuing a suspected culprit medication should be carefully weighed against the risks of medication cessation, and consideration should be given to alternative medications in the same class that also may be associated with TE. In patients requiring antidepressant therapy with suspected medication-induced TE, consider transitioning to a different class of medication with lower risk of medication-induced alopecia; for example, discontinuing bupropion in favor of an SSRI.

Final Thoughts

Medication-induced alopecia is an undesired side effect of many commonly used drugs and drug classes, including retinoids, azole antifungals, and mood stabilizers. Although the precise pathomechanisms of medication-induced TE remain unclear, the recommended management often requires identification of the likely causative agent and its discontinuation, if possible. Suspicion for medication-induced TE should prompt a thorough history of recent changes to medications, risk factors for nutritional deficiencies, underlying illnesses, and recent surgical procedures. Underlying nutritional, electrolyte, and/or metabolic disturbances should be corrected. In part 2 of this series, we will discuss medication-induced alopecia associated with anticoagulant and antihypertensive medications.

Alopecia is a commonly reported side effect of various medications. Anagen effluvium and telogen effluvium (TE) are considered the most common mechanisms underlying medication-related hair loss. Anagen effluvium is associated with chemotherapeutic agents and radiation therapy, with anagen shedding typically occurring within 2 weeks of medication administration.1,2 Medication-induced TE is a diffuse nonscarring alopecia that is a reversible reactive process.3-5 Telogen effluvium is clinically apparent as a generalized shedding of scalp hair 1 to 6 months after an inciting cause.6 The underlying cause of TE may be multifactorial and difficult to identify given the delay between the trigger and the onset of clinically apparent hair loss. Other known triggers of TE include acute illness,7,8 nutritional deficiencies,4,9 and/or major surgery.10

Each hair follicle independently and sequentially progresses through anagen growth, catagen transition, and telogen resting phases. In the human scalp, the telogen phase typically lasts 3 months, at the end of which the telogen hair is extruded from the scalp. Anagen and telogen follicles typically account for an average of 90% and 10% of follicles on the human scalp, respectively.11 Immediate anagen release is hypothesized to be the mechanism underlying medication-induced TE.12 This theory suggests that an increased percentage of anagen follicles prematurely enter the telogen phase, with a notable increase in hair shedding at the conclusion of the telogen phase approximately 1 to 6 months later.12 First-line management of medication-induced TE is identification and cessation of the causative agent, if possible. Notable regrowth of hair is expected several months after removal of the inciting medication. In part 1 of this 2-part series, we review the existing literature to identify common culprits of medication-induced TE, including retinoids, antifungals, and psychotropic medications.

Retinoids

Retinoids are vitamin A derivatives used in the treatment of a myriad of dermatologic and nondermatologic conditions.13,14 Retinoids modulate sebum production,15 keratinocyte proliferation,16 and epithelial differentiation through signal transduction downstream of the ligand-activated nuclear retinoic acid receptors and retinoid X receptors.13,14,17 The recommended daily dosage of retinol is 900 µg retinol activity equivalent (3000 IU) for men and 700 µg retinol activity equivalent (2333 IU) for women. Retinoids are used in the treatment of acne vulgaris,18 psoriasis,19 and ichthyosis.20 The most commonly reported adverse effects of systemic retinoid therapy include cheilitis, alopecia, and xerosis.21 Retinoid-associated alopecia is dose and duration dependent.19,21-24 A prospective study of acitretin therapy in plaque psoriasis reported that more than 63% (42/66) of patients on 50 mg or more of acitretin daily for 6 months or longer experienced alopecia that reversed with discontinuation.23 A systematic review of isotretinoin use in acne showed alopecia was seen in 3.2% (18/565) of patients on less than 0.5 mg/kg/d of isotretinoin and in 5.7% (192/3375) of patients on 0.5 mg/kg/d or less of isotretinoin.24 In a phase 2 clinical trial of orally administered 9-cis-retinoic acid (alitretinoin) in the treatment of Kaposi sarcoma related to AIDS, 42% (24/57) of adult male patients receiving 60, 100, or 140 mg/m2 alitretinoin daily (median treatment duration, 15.1 weeks) reported alopecia as an adverse effect of treatment.25 In one case report, a patient who ingested 500,000 IU of vitamin A daily for 4 months and then 100,000 IU monthly for 6 months experienced diffusely increased shedding of scalp hair along with muscle soreness, nail dystrophy, diffuse skin rash, and refractory ascites; he was found to have severe liver damage secondary to hypervitaminosis A that required liver transplantation.26 Regarding the pathomechanism of retinoid-induced alopecia, animal and in vitro studies similarly have demonstrated that all-trans-retinoic acid appears to exert its inhibitory effects on hair follicle growth via the influence of the transforming growth factor β2 and SMAD2/3 pathway influence on dermal papillae cells.14,27 Development of hair loss secondary to systemic retinoid therapy may be managed with dose reduction or cessation.

Antifungals

Azole medications have broad-spectrum fungistatic activity against a wide range of yeast and filamentous fungi. Azoles inhibit sterol 14α-demethylase activity, impairing ergosterol synthesis and thereby disrupting plasma membrane synthesis and activity of membrane-bound enzymes.28 Fluconazole is a systemic oral agent in this class that was first approved by the US Food and Drug Administration (FDA) for use in the 1990s.29 A retrospective study by the National Institute of Allergy and Infectious Disease Mycoses Study Group followed the clinical course of 33 patients who developed alopecia while receiving fluconazole therapy for various mycoses.30 The majority (88% [29/33]) of patients received 400 mg or more of fluconazole daily. The median time to hair loss after starting fluconazole was 3 months, and the scalp was involved in all cases. In 97% (32/33) of patients, resolution of alopecia was noted following discontinuation of fluconazole or a dose reduction of 50% or more. In 85% (28/33) of patients, complete resolution of alopecia occurred within 6 months of fluconazole cessation or dose reduction.30 Fluconazole-induced TE was reproducible in an animal model using Wistar rats31; however, further studies are required to clarify the molecular pathways of its effect on hair growth.

Voriconazole is an azole approved for the treatment of invasive aspergillosis, candidemia, and fungal infections caused by Scedosporium apiospermum and Fusarium species. A retrospective survey study of patients who received voriconazole for 1 month or longer found a considerable proportion of patients developed diffuse reversible hair loss.32 Scalp alopecia was noted in 79% (120/152) of patients who completed the survey, with a mean (SD) time to alopecia of 75 (54) days after initiation of voriconazole. Notable regrowth was reported in 69% (79/114) of patients who discontinued voriconazole for at least 3 months. A subgroup of 32 patients were changed to itraconazole or posaconazole, and hair loss stopped in 84% (27/32) with regrowth noted in 69% (22/32) of patients.32 Voriconazole and fluconazole share structural similarity not present with other triazoles.33,34 Because voriconazole-associated alopecia was reversed in the majority of patients who switched to itraconazole or posaconazole, the authors hypothesized that structural similarity of fluconazole and voriconazole may underly the greater risk for TE that is not a class effect of azole medications.31

Psychotropic Medications

Various psychotropic medications have been associated with hair loss. Valproic acid (or sodium valproate) is an anticonvulsant and mood-stabilizing agent used for the treatment of seizures, bipolar disorder (BD), migraines, and neuropathic pain.35,36 Divalproex sodium (or divalproex) is an enteric-coated formulation of sodium valproate and valproic acid with similar indications. Valproate is a notorious culprit of medication-induced hair loss, with alopecia listed among the most common adverse reactions (reported >5%) on its structure product labeling document.37 A systemic review and meta-analysis by Wang et al38 estimated the overall incidence of valproate-related alopecia to be 11% (95% CI, 0.08-0.13). Although this meta-analysis did not find an association between incidence of alopecia and dose or duration of valproate therapy,38 a separate review suggested that valproate-induced alopecia is dose dependent and can be managed with dose reduction.39 A 12-month, randomized, double-blind study of treatment of BD with divalproex (valproate derivative), lithium, or placebo (2:1:1 ratio) showed a significantly higher frequency of alopecia in the divalproex group compared with placebo (16% [30/187] vs 6% [6/94]; P=.03).40 Valproate-related hair loss is characteristically diffuse and nonscarring, often noted 3 to 6 months following initiation of valproate.41,42 The proposed mechanism of valproate-induced alopecia includes chelation of zinc and selenium,43 and a reduction in serum biotinidase activity, thereby decreasing the availability of these essential micronutrients required for hair growth.41 Studies examining the effects of valproate administration and serum biotinidase activity in patients have yielded conflicting results.44-46 In a study of children with seizures including 57 patients treated with valproic acid, 17 treated with carbamazepine, and 75 age- and sex-matched healthy controls, the authors found no significant differences in serum biotinidase enzyme activity across the 3 groups.44 In contrast, a study of 75 children with seizures on valproic acid therapy stratified by dose (mean [SD])—group A: 28.7 [8.5] mg/kg/d; group B: 41.6 [4.9] mg/kg/d; group C: 64.5 [5.8] mg/kg/d—found that patients receiving higher doses (groups B and C) had significantly reduced serum biotinidase activity (1.22 [1.11] and 0.97 [0.07] mmol/min/L, respectively) compared with 50 healthy pediatric controls (5.20 [0.90] mmol/min/L; P<.001). The same study found biotin supplementation at 10 mg/d for 20 days led to resolution of alopecia in 22% (2/9) of patients with alopecia on valproic acid therapy.45 Despite hypothesized effects of valproate on micronutrients, the role of mineral supplementation in treating valproate-associated hair loss remains unclear. There is evidence to suggest that valproic acid–associated alterations in serum biotinidase activity may be transient. In a study of 32 pediatric patients receiving valproic acid for the treatment of epilepsy, serum biotinidase activity was significantly lower after 3 months of valproic acid therapy compared with pretreatment levels (P<.05); at 6 months, the serum biotinidase activity was increased compared with 3 months (P<.05) and not significantly different from pretreatment levels (P>.05).46 Hair regrowth has been observed following discontinuation or dose reduction of valproate therapy in some cases.39,47

Lithium carbonate (lithium) is used in the treatment of BD. Despite its efficacy and low cost, its potential for adverse effects, narrow therapeutic index, and subsequent need for routine monitoring are factors that limit its use.48 Some reported dermatologic adverse reactions on its structure product labeling include xerosis, thinning of hair, alopecia, xerosis cutis, psoriasis onset/exacerbation, and generalized pruritus.49 A systematic review and meta-analysis of 385 studies identified 24 publications reporting adverse effects of lithium on hair with no significantly increased risk of alopecia overall.50 The analysis included 2 randomized controlled trials comparing the effects of lithium and placebo on hair loss in patients with BD. Hair loss was reported in 7% (7/94) of patients taking lithium and 6% (6/94) of the placebo group in the 12-month study40 and in 3% (1/32) of the lithium group and 0% (0/28) of the divalproex group in the 20-month study.51 Despite anecdotal reports of alopecia associated with lithium, there is a lack of high-quality evidence to support this claim. Of note, hypothyroidism is a known complication of lithium use, and serum testing of thyroid function at 6-month intervals is recommended for patients on lithium treatment.52 Because thyroid abnormalities can cause alopecia distinct from TE, new-onset alopecia during lithium use should prompt serum testing of thyroid function. The development of hypothyroidism secondary to lithium is not a direct contraindication to its use53; rather, treatment should be focused on correction with thyroid replacement therapy (eg, supplementation with thyroxine).54

 

 

Commonly prescribed antidepressant medications include selective serotonin reuptake inhibitors (SSRIs) and bupropion. Selective serotonin reuptake inhibitors affect the neuronal serotonin transporter, increasing the concentration of serotonin in the synaptic cleft available for stimulation of postsynaptic serotonin receptors55,56; bupropion is an antidepressant medication that inhibits norepinephrine and dopamine reuptake at the synaptic cleft.57 Alopecia is an infrequent (1 in 100 to 1 in 1000 patients) adverse effect for several SSRIs.58-62 A recent systematic review identified a total of 71 cases of alopecia associated with SSRI use including citalopram (n=11), escitalopram (n=7), fluoxetine (n=27), fluoxvamine (n=5), paroxetine (n=4), and sertraline (n=20), with a median time to onset of hair shedding of 8.6 weeks (range, 3 days to 5 years). Discontinuation of the suspected culprit SSRI led to improvement and/or resolution in 63% (51/81) episodes of alopecia, with a median time to improvement and/or resolution of 4 weeks.63 A comparative retrospective cohort study using a large US health claims database from 2006 to 2014 included more than 1 million new and mutually exclusive patients taking fluoxetine, fluvoxamine, sertraline, citalopram, escitalopram, paroxetine, duloxetine, venlafaxine, desvenlafaxine, and bupropion.64 Overall, 1% (1569/150,404) of patients treated with bupropion received 1 or more physician visits for alopecia. Patients on SSRIs generally had a lower risk for hair loss compared with patients using bupropion (citalopram: hazard ratio [HR], 0.80 [95% CI, 0.74-0.86]; escitalopram: HR, 0.79 [95% CI, 0.74-0.86]; fluoxetine: HR, 0.68 [95% CI, 0.63-0.74]; paroxetine: HR, 0.68 [95% CI, 0.62-0.74]; sertraline: HR, 0.74 [95% CI, 0.69-0.79]), with the exception of fluvoxamine (HR, 0.93 [95% CI, 0.64-1.37]). However, the type of alopecia, time to onset, and time to resolution were not reported, making it difficult to assess whether the reported hair loss was consistent with medication-induced TE. Additionally, the authors acknowledged that bupropion may have been prescribed for smoking cessation, which may carry a different risk profile for the development of alopecia.64 Several other case reports have described alopecia following treatment with SSRIs, including sertraline,65 fluvoxamine,66 paroxetine,67 fluoxetine,68 and escitalopram.69

Overall, it appears that the use of SSRIs portends relatively low risk for alopecia and medication-induced TE. Little is known regarding the molecular effects of SSRIs on hair growth and the pathomechanism of SSRI-induced TE. The potential benefits of discontinuing a suspected culprit medication should be carefully weighed against the risks of medication cessation, and consideration should be given to alternative medications in the same class that also may be associated with TE. In patients requiring antidepressant therapy with suspected medication-induced TE, consider transitioning to a different class of medication with lower risk of medication-induced alopecia; for example, discontinuing bupropion in favor of an SSRI.

Final Thoughts

Medication-induced alopecia is an undesired side effect of many commonly used drugs and drug classes, including retinoids, azole antifungals, and mood stabilizers. Although the precise pathomechanisms of medication-induced TE remain unclear, the recommended management often requires identification of the likely causative agent and its discontinuation, if possible. Suspicion for medication-induced TE should prompt a thorough history of recent changes to medications, risk factors for nutritional deficiencies, underlying illnesses, and recent surgical procedures. Underlying nutritional, electrolyte, and/or metabolic disturbances should be corrected. In part 2 of this series, we will discuss medication-induced alopecia associated with anticoagulant and antihypertensive medications.

References
  1. Saleh D, Nassereddin A, Cook C. Anagen effluvium. StatPearls. StatPearls Publishing; 2023. https://www.ncbi.nlm.nih.gov/books/NBK482293/
  2. Guerrero-Putz MD, Flores-Dominguez AC, Castillo-de la Garza RJ, et al. Anagen effluvium after neurointerventional radiation: trichoscopy as a diagnostic ally. Skin Appendage Disord. 2021;8:102-107. doi:10.1159/000518743
  3. Patel M, Harrison S, Sinclair R. Drugs and hair loss. Dermatol Clin. 2013;31:67-73. doi:https://doi.org/10.1016/j.det.2012.08.002
  4. Chen V, Strazzulla L, Asbeck SM, et al. Etiology, management, and outcomes of pediatric telogen effluvium: a single-center study in the United States. Pediatr Dermatol. 2023;40:120-124. doi:10.1111/pde.15154
  5. Watras MM, Patel JP, Arya R. Traditional anticoagulants and hair loss: a role for direct oral anticoagulants? a review of the literature. Drugs Real World Outcomes. 2016;3:1-6. doi:10.1007/s40801-015-0056-z
  6. Hughes EC, Saleh D. Telogen effluvium. StatPearls. StatPearls Publishing; 2023. https://www.ncbi.nlm.nih.gov/books/NBK430848/
  7. Nguyen B, Tosti A. Alopecia in patients with COVID-19: a systematic review and meta-analysis. JAAD Int. 2022;7:67-77. doi:10.1016/j.jdin.2022.02.006
  8. Starace M, Piraccini BM, Evangelista V, et al. Acute telogen effluvium due to dengue fever mimicking androgenetic alopecia. Ital J Dermatol Venerol. 2023;158:66-67. doi:10.23736/s2784-8671.22.07369-8
  9. Patel KV, Farrant P, Sanderson JD, et al. Hair loss in patients with inflammatory bowel disease. Inflamm Bowel Dis. 2013;19:1753-1763. doi:10.1097/MIB.0b013e31828132de
  10. Cohen-Kurzrock RA, Cohen PR. Bariatric surgery–induced telogen effluvium (bar site): case report and a review of hair loss following weight loss surgery. Cureus. 2021;13:E14617. doi:10.7759/cureus.14617
  11. Price VH. Treatment of hair loss. N Engl J Med. 1999;341:964-973. doi:10.1056/nejm199909233411307
  12. Headington JT. Telogen effluvium: new concepts and review. Arch Dermatol. 1993;129:356-363. doi:10.1001/arcderm.1993.01680240096017
  13. Lee DD, Stojadinovic O, Krzyzanowska A, et al. Retinoid-responsive transcriptional changes in epidermal keratinocytes. J Cell Physiol. 2009;220:427-439. doi:10.1002/jcp.21784
  14. Foitzik K, Spexard T, Nakamura M, et al. Towards dissecting the pathogenesis of retinoid-induced hair loss: all-trans retinoic acid induces premature hair follicle regression (catagen) by upregulation of transforming growth factor-beta2 in the dermal papilla. J Invest Dermatol. 2005;124:1119-1126. doi:10.1111/j.0022-202X.2005.23686.x
  15. Karlsson T, Vahlquist A, Kedishvili N, et al. 13-cis-retinoic acid competitively inhibits 3 alpha-hydroxysteroid oxidation by retinol dehydrogenase RoDH-4: a mechanism for its anti-androgenic effects in sebaceous glands? Biochem Biophys Res Commun. 2003;303:273-278. doi:10.1016/s0006-291x(03)00332-2
  16. Chapellier B, Mark M, Messaddeq N, et al. Physiological and retinoid-induced proliferations of epidermis basal keratinocytes are differently controlled. EMBO J. 2002;21:3402-3413. doi:10.1093/emboj/cdf331
  17. Geiger JM. Retinoids and sebaceous gland activity. Dermatology. 1995;191:305-310. doi:10.1159/000246581
  18. Oge LK, Broussard A, Marshall MD. Acne vulgaris: diagnosis and treatment. Am Fam Physician. 2019;100:475-484.
  19. Pilkington T, Brogden RN. Acitretin. Drugs. 1992;43:597-627. doi:10.2165/00003495-199243040-00010
  20. Zaenglein AL, Levy ML, Stefanko NS, et al. Consensus recommendations for the use of retinoids in ichthyosis and other disorders of cornification in children and adolescents. Pediatr Dermatol. 2021;38:164-180. doi:10.1111/pde.14408
  21. Katz HI, Waalen J, Leach EE. Acitretin in psoriasis: an overview of adverse effects. J Am Acad Dermatol. 1999;41(3 suppl):S7-S12. doi:10.1016/s0190-9622(99)70359-2
  22. Tran PT, Evron E, Goh C. Characteristics of patients with hair loss after isotretinoin treatment: a retrospective review study. Int J Trichology. 2022;14:125-127. doi:10.4103/ijt.ijt_80_20
  23. Gupta AK, Goldfarb MT, Ellis CN, et al. Side-effect profile of acitretin therapy in psoriasis. J Am Acad Dermatol. 1989;20:1088-1093. doi:10.1016/s0190-9622(89)70138-9
  24. Lytvyn Y, McDonald K, Mufti A, et al. Comparing the frequency of isotretinoin-induced hair loss at <0.5-mg/kg/d versus ≥0.5-mg/kg/d dosing in acne patients: a systematic review. JAAD Int. 2022;6:125-142. doi:10.1016/j.jdin.2022.01.002
  25. Aboulafia DM, Norris D, Henry D, et al. 9-cis-Retinoic acid capsules in the treatment of AIDS-related Kaposi sarcoma: results of a phase 2 multicenter clinical trial. Arch Dermatol. 2003;139:178-186. doi:10.1001/archderm.139.2.178
  26. Cheruvattath R, Orrego M, Gautam M, et al. Vitamin A toxicity: when one a day doesn’t keep the doctor away. Liver Transpl. 2006;12:1888-1891. doi:10.1002/lt.21007
  27. Nan W, Li G, Si H, et al. All-trans-retinoic acid inhibits mink hair follicle growth via inhibiting proliferation and inducing apoptosis of dermal papilla cells through TGF-β2/Smad2/3 pathway. Acta Histochem. 2020;122:151603. doi:10.1016/j.acthis.2020.151603
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  31. Thompson GR 3rd, Krois CR, Affolter VK, et al. Examination of fluconazole-induced alopecia in an animal model and human cohort. Antimicrob Agents Chemother. 2019;63:e01384-18. doi:10.1128/aac.01384-18
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References
  1. Saleh D, Nassereddin A, Cook C. Anagen effluvium. StatPearls. StatPearls Publishing; 2023. https://www.ncbi.nlm.nih.gov/books/NBK482293/
  2. Guerrero-Putz MD, Flores-Dominguez AC, Castillo-de la Garza RJ, et al. Anagen effluvium after neurointerventional radiation: trichoscopy as a diagnostic ally. Skin Appendage Disord. 2021;8:102-107. doi:10.1159/000518743
  3. Patel M, Harrison S, Sinclair R. Drugs and hair loss. Dermatol Clin. 2013;31:67-73. doi:https://doi.org/10.1016/j.det.2012.08.002
  4. Chen V, Strazzulla L, Asbeck SM, et al. Etiology, management, and outcomes of pediatric telogen effluvium: a single-center study in the United States. Pediatr Dermatol. 2023;40:120-124. doi:10.1111/pde.15154
  5. Watras MM, Patel JP, Arya R. Traditional anticoagulants and hair loss: a role for direct oral anticoagulants? a review of the literature. Drugs Real World Outcomes. 2016;3:1-6. doi:10.1007/s40801-015-0056-z
  6. Hughes EC, Saleh D. Telogen effluvium. StatPearls. StatPearls Publishing; 2023. https://www.ncbi.nlm.nih.gov/books/NBK430848/
  7. Nguyen B, Tosti A. Alopecia in patients with COVID-19: a systematic review and meta-analysis. JAAD Int. 2022;7:67-77. doi:10.1016/j.jdin.2022.02.006
  8. Starace M, Piraccini BM, Evangelista V, et al. Acute telogen effluvium due to dengue fever mimicking androgenetic alopecia. Ital J Dermatol Venerol. 2023;158:66-67. doi:10.23736/s2784-8671.22.07369-8
  9. Patel KV, Farrant P, Sanderson JD, et al. Hair loss in patients with inflammatory bowel disease. Inflamm Bowel Dis. 2013;19:1753-1763. doi:10.1097/MIB.0b013e31828132de
  10. Cohen-Kurzrock RA, Cohen PR. Bariatric surgery–induced telogen effluvium (bar site): case report and a review of hair loss following weight loss surgery. Cureus. 2021;13:E14617. doi:10.7759/cureus.14617
  11. Price VH. Treatment of hair loss. N Engl J Med. 1999;341:964-973. doi:10.1056/nejm199909233411307
  12. Headington JT. Telogen effluvium: new concepts and review. Arch Dermatol. 1993;129:356-363. doi:10.1001/arcderm.1993.01680240096017
  13. Lee DD, Stojadinovic O, Krzyzanowska A, et al. Retinoid-responsive transcriptional changes in epidermal keratinocytes. J Cell Physiol. 2009;220:427-439. doi:10.1002/jcp.21784
  14. Foitzik K, Spexard T, Nakamura M, et al. Towards dissecting the pathogenesis of retinoid-induced hair loss: all-trans retinoic acid induces premature hair follicle regression (catagen) by upregulation of transforming growth factor-beta2 in the dermal papilla. J Invest Dermatol. 2005;124:1119-1126. doi:10.1111/j.0022-202X.2005.23686.x
  15. Karlsson T, Vahlquist A, Kedishvili N, et al. 13-cis-retinoic acid competitively inhibits 3 alpha-hydroxysteroid oxidation by retinol dehydrogenase RoDH-4: a mechanism for its anti-androgenic effects in sebaceous glands? Biochem Biophys Res Commun. 2003;303:273-278. doi:10.1016/s0006-291x(03)00332-2
  16. Chapellier B, Mark M, Messaddeq N, et al. Physiological and retinoid-induced proliferations of epidermis basal keratinocytes are differently controlled. EMBO J. 2002;21:3402-3413. doi:10.1093/emboj/cdf331
  17. Geiger JM. Retinoids and sebaceous gland activity. Dermatology. 1995;191:305-310. doi:10.1159/000246581
  18. Oge LK, Broussard A, Marshall MD. Acne vulgaris: diagnosis and treatment. Am Fam Physician. 2019;100:475-484.
  19. Pilkington T, Brogden RN. Acitretin. Drugs. 1992;43:597-627. doi:10.2165/00003495-199243040-00010
  20. Zaenglein AL, Levy ML, Stefanko NS, et al. Consensus recommendations for the use of retinoids in ichthyosis and other disorders of cornification in children and adolescents. Pediatr Dermatol. 2021;38:164-180. doi:10.1111/pde.14408
  21. Katz HI, Waalen J, Leach EE. Acitretin in psoriasis: an overview of adverse effects. J Am Acad Dermatol. 1999;41(3 suppl):S7-S12. doi:10.1016/s0190-9622(99)70359-2
  22. Tran PT, Evron E, Goh C. Characteristics of patients with hair loss after isotretinoin treatment: a retrospective review study. Int J Trichology. 2022;14:125-127. doi:10.4103/ijt.ijt_80_20
  23. Gupta AK, Goldfarb MT, Ellis CN, et al. Side-effect profile of acitretin therapy in psoriasis. J Am Acad Dermatol. 1989;20:1088-1093. doi:10.1016/s0190-9622(89)70138-9
  24. Lytvyn Y, McDonald K, Mufti A, et al. Comparing the frequency of isotretinoin-induced hair loss at <0.5-mg/kg/d versus ≥0.5-mg/kg/d dosing in acne patients: a systematic review. JAAD Int. 2022;6:125-142. doi:10.1016/j.jdin.2022.01.002
  25. Aboulafia DM, Norris D, Henry D, et al. 9-cis-Retinoic acid capsules in the treatment of AIDS-related Kaposi sarcoma: results of a phase 2 multicenter clinical trial. Arch Dermatol. 2003;139:178-186. doi:10.1001/archderm.139.2.178
  26. Cheruvattath R, Orrego M, Gautam M, et al. Vitamin A toxicity: when one a day doesn’t keep the doctor away. Liver Transpl. 2006;12:1888-1891. doi:10.1002/lt.21007
  27. Nan W, Li G, Si H, et al. All-trans-retinoic acid inhibits mink hair follicle growth via inhibiting proliferation and inducing apoptosis of dermal papilla cells through TGF-β2/Smad2/3 pathway. Acta Histochem. 2020;122:151603. doi:10.1016/j.acthis.2020.151603
  28. Georgopapadakou NH, Walsh TJ. Antifungal agents: chemotherapeutic targets and immunologic strategies. Antimicrob Agents Chemother. 1996;40:279-291. doi:10.1128/aac.40.2.279
  29. Sheehan DJ, Hitchcock CA, Sibley CM. Current and emerging azole antifungal agents. Clin Microbiol Rev. 1999;12:40-79. doi:10.1128/cmr.12.1.40
  30. Pappas PG, Kauffman CA, Perfect J, et al. Alopecia associated with fluconazole therapy. Ann Intern Med. 1995;123:354-357. doi:10.7326/0003-4819-123-5-199509010-00006
  31. Thompson GR 3rd, Krois CR, Affolter VK, et al. Examination of fluconazole-induced alopecia in an animal model and human cohort. Antimicrob Agents Chemother. 2019;63:e01384-18. doi:10.1128/aac.01384-18
  32. Malani AN, Kerr L, Obear J, et al. Alopecia and nail changes associated with voriconazole therapy. Clin Infect Dis. 2014;59:E61-E65. doi:10.1093/cid/ciu275
  33. Greer ND. Voriconazole: the newest triazole antifungal agent. Proc (Bayl Univ Med Cent). 2003;16:241-248. doi:10.1080/08998280.2003.11927910
  34. Drabin´ska B, Dettlaff K, Kossakowski K, et al. Structural and spectroscopic properties of voriconazole and fluconazole—experimental and theoretical studies. Open Chemistry. 2022;20:1575-1590. doi:10.1515/chem-2022-0253
  35. Löscher W. Valproate: a reappraisal of its pharmacodynamic properties and mechanisms of action. Prog Neurobiol. 1999;58:31-59. doi:10.1016/s0301-0082(98)00075-6
  36. Gill D, Derry S, Wiffen PJ, et al. Valproic acid and sodium valproate for neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev. 2011;2011:CD009183. doi:10.1002/14651858.CD009183.pub2
  37. Depakote, Prescribing information. Abbott Laboratories; 2011. Accessed November 20, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/018723s037lbl.pdf
  38. Wang X, Wang H, Xu D, et al. Risk of valproic acid-related alopecia: a systematic review and meta-analysis. Seizure. 2019;69:61-69. doi:10.1016/j.seizure.2019.04.003
  39. Mercke Y, Sheng H, Khan T, et al. Hair loss in psychopharmacology. Ann Clin Psychiatry. 2000;12:35-42. doi:10.1023/a:1009074926921
  40. Bowden CL, Calabrese JR, McElroy SL, et al. A randomized, placebo-controlled 12-month trial of divalproex and lithium in treatment of outpatients with bipolar I disorder. Divalproex Maintenance Study Group. Arch Gen Psychiatry. 2000;57:481-489. doi:10.1001/archpsyc.57.5.481
  41. Praharaj SK, Munoli RN, Udupa ST, et al. Valproate-associated hair abnormalities: pathophysiology and management strategies. Hum Psychopharmacol. 2022;37:E2814. doi:10.1002/hup.2814
  42. Wilting I, van Laarhoven JH, de Koning-Verest IF, et al. Valproic acid-induced hair-texture changes in a white woman. Epilepsia. 2007;48:400-401. doi:10.1111/j.1528-1167.2006.00933.x
  43. Potter WZ, Ketter TA. Pharmacological issues in the treatment of bipolar disorder: focus on mood-stabilizing compounds. Can J Psychiatry. 1993;38(3 suppl 2):S51-S56.
  44. Castro-Gago M, Gómez-Lado C, Eirís-Pun´al J, et al. Serum biotinidase activity in children treated with valproic acid and carbamazepine. J Child Neurol. 2009;25:32-35. doi:10.1177/0883073809336118
  45. Schulpis KH, Karikas GA, Tjamouranis J, et al. Low serum biotinidase activity in children with valproic acid monotherapy. Epilepsia. 2001;42:1359-1362. doi:10.1046/j.1528-1157.2001.47000.x
  46. Yilmaz Y, Tasdemir HA, Paksu MS. The influence of valproic acid treatment on hair and serum zinc levels and serum biotinidase activity. Eur J Paediatr Neurol. 2009;13:439-443. doi:10.1016/j.ejpn.2008.08.007
  47. Henriksen O, Johannessen SI. 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. doi:10.1111/j.1600-0404.1982.tb03106.x
  48. Fountoulakis KN, Tohen M, Zarate CA Jr. Lithium treatment of bipolar disorder in adults: a systematic review of randomized trials and meta-analyses. Eur Neuropsychopharmacol. 2022;54:100-115. doi:10.1016/j.euroneuro.2021.10.003
  49. Lithium carbonate. Prescribing information. West-Ward Pharmaceuticals; 2018. Accessed November 20, 2023. https://ww.accessdata.fda.gov/drugsatfda_docs/label/2018/017812s033,018421s032,018558s027lbl.pdf
  50. McKnight RF, Adida M, Budge K, et al. Lithium toxicity profile: a systematic review and meta-analysis. Lancet. 2012;379:721-728. doi:10.1016/s0140-6736(11)61516-x
  51. Calabrese JR, Shelton MD, Rapport DJ, 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. doi:10.1176/appi.ajp.162.11.2152.
  52. Duce HL, Duff CJ, Zaidi S, et al. Evaluation of thyroid function monitoring in people treated with lithium: advice based on real-world data. Bipolar Disord. 2023;25:402-409. doi:10.1111/bdi.13298
  53. Bocchetta A, Loviselli A. Lithium treatment and thyroid abnormalities. Clin Pract Epidemiol Ment Health. 2006;2:23. doi:10.1186/1745-0179-2-23.
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Issue
Cutis - 112(6)
Issue
Cutis - 112(6)
Page Number
267-271
Page Number
267-271
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MDedge Dermatology
Cutis
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MDedge Dermatology
Cutis
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Hair & Nails
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Culprits of Medication-Induced Telogen Effluvium, Part 1
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Culprits of Medication-Induced Telogen Effluvium, Part 1
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Practice Points

  • Medications are a common culprit of telogen effluvium (TE), and medication-induced TE should be suspected in patients presenting with diffuse nonscarring alopecia who are taking systemic medication(s).
  • A careful history of new medications and dose adjustments 1 to 6 months prior to notable hair loss may identify the most likely inciting cause.
  • Medication-induced TE often improves with cessation or dose reduction of the culprit medication.
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