Dermatologic Concerns with Psychotropics

US Pharm. 2008;33(4):29-34.

Adverse drug reactions are a potential problem with all medications. One common and very notable result from drug reactions is skin-related manifestations. These are also called adverse cutaneous drug reactions (ACDRs). Some of the ACDRs include exanthematous reactions, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria, and photosensitivity. While it is true that these effects can occur with several types of medications, this article will focus on commonly reported ACDRs associated with psychotropics (TABLE 1).

Exanthematous Reactions
Morbilliform or maculopapular (with flat regions and elevated bumps) eruptions are the most common type of ACDR.^1,2 They are characterized by symmetrically distributed erythematous macules (flat lesions) and papules (raised bumps) that originate in the trunk and spread to the extremities.^1-3 The reaction can appear in a few days or in the course of several weeks. One common symptom is fever.²

Presentation may be unique to some of the medications. In the case of hydantoin derivatives (i.e., phenytoin), there is macular erythema spreading from the face to the trunk and then to the extremities during the first two weeks of treatment.^2,3 Additionally, patients may experience fever, lymphadenopathy, and facial edema. ³ This combination of symptoms is commonly referred to as the "phenytoin hypersensitivity syndrome."² If it is not recognized early, it can lead to enlargement of the liver and spleen and elevation in hepatic enzymes.⁴

With phenothiazines, erythematous macules and small papules appear within the first three weeks of treatment, spreading from the face to the trunk and then to the extremities; usually periorbital edema is present.² In the case of barbiturates, a diffuse macular eruption is seen, spreading from the face to the extremities in the first few days of treatment.² Dispersed erythema, spreading from the face to the rest of the body, is seen with carbamazepine, usually after two weeks of treatment.³ Facial edema is also seen with carbamazepine.³

Case reports with other drugs, including exanthematous reactions with olanzapine, have been published.⁵ Discontinuation of the offending agent is the most common treatment option for exanthematous reactions.

Angioedema and Urticaria

Angioedema and urticaria (hives) are cutaneous adverse reactions that can occur with any drug. Angioedema involves swelling of subcutaneous tissues, usually in the face, tongue, extremities, and larynx, which could be fatal.¹ Urticaria presents as round, red, swollen lesions generally associated with pruritus (itching) that can appear anywhere on the skin.¹ Because these reactions can occur with all medications, no particular presentation or higher frequency can be attributed to any specific psychotropic agent.

Photosensitivity

Photosensitivity requires photon energy absorption (sun exposure) by molecules, which can lead to energy distribution without any effect or to reactions that can result in damage at the molecular, cellular, and tissue level.⁶ There are two different types of photoreactions to medications: photoallergy and phototoxicity.^1,2 Phototoxicity may present with erythema, edema, and hyperpigmentation one to two days after treatment initiation.^1,2 Photoallergy is characterized by either itchy red lesions, swollen itchy areas, or blisterlike lesions and may present within the first few weeks after starting therapy.^1,2 One important differentiation is the onset of the lesions. Phototoxicity can occur in anyone after intake of the medication, but only patients who have undergone sensitization (production of antibodies) can have a photoallergic reaction. ²

Prevention is essential and can involve avoiding sun exposure, the use of topical sunscreens, and, if needed, discontinuation of the medication. Additionally, patients may be treated according to the severity of the skin lesions. These treatments include wet dressings and topical glucocorticoids; in the case of toxicity, hospitalization may be required.³

Several psychotropics have been associated with photosensitivity, including chlorpromazine and thioridazine, particularly at doses above 400 mg/day.⁷ Fluoxetine can produce a painful, burning, and persistent erythema after sun exposure; a patient may experience this even after being on the same dose for years.⁸ Additional reports have suggested photosensitivity reactions with risperidone and alprazolam.^9,1

Pigmentation Reactions
Pigmentation reactions can be a result of stimulation of melanin production by the medication, pigment deposits by either the drug or its metabolite, or both. ^2,11 Phenothiazines are the most common group of psychotropic medications associated with pigmentary reactions. The individual agent most commonly associated with this is chlorpromazine. Chlorpromazine can cause a blue or slate gray pigmentation, particularly on surfaces that have had sun exposure.¹² This discoloration can also appear in the lens and the cornea.¹ Imipramine, trifluopherazine, and olanzapine have also been reported to cause hyperpigmentation.^13-15

The discoloration produced by these medications can take several weeks, months, or even years to clear, and in some instances it might never go away.² Usually the causative agent needs to be removed for the discoloration to clear. In one particular report of four cases of imipramine-induced skin pigmentation, those treated with creams, laser therapy, and tretinoin without removal of imipramine (n = 2) continued showing the discoloration. For those in which imipramine was removed (n = 2), the discoloration eventually cleared.¹⁶

Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis are two very serious and potentially life-threatening ACDRs. Stevens-Johnson syndrome is characteristically preceded by a prodrome of fever and other flulike symptoms, followed by inflammation of the mucosal surfaces of the mouth and conjunctiva. ¹ Additionally, macules that are dark red and may have a necrotic center can be seen. If skin detachment reaches more than 30% of the skin surface, the condition is called toxic epidermal necrolysis.¹⁷ Toxic epidermal necrolysis carries a higher risk of death than SJS, primarily due to sepsis. ^1,2 The treatment involves drug removal, IV fluids, and systemic glucocorticoids.³

Stevens-Johnson syndrome has been reported with several anticonvulsants or mood stabilizers, including valproic acid, carbamazepine, and lamotrigine.^17-19 With long-term medications, the increased risk of rash occurs during the first two months of therapy.¹⁷ The mood stabilizers more commonly associated with this rash are carbamazepine and lamotrigine. The manufacturers of both of these products have had to provide boxed warnings for the increased risk of rash.

The incidence of serious rash (including SJS) with lamo!= trigine when used for adjunctive treatment of epilepsy is 0.8% (8/1,000) in pediatric patients and 0.3% (3/1,000) in adults. In adults being treated for bipolar disorder with lamotrigine, the incidence of serious rash is 0.08% (0.8/1,000) when the medication was used as initial monotherapy and 0.13% (1.3/1,000) when lamotrigine was used as an adjunct. ²⁰ The combination of valproic acid with lamotrigine can increase the risk for serious rash.^20,21

Carbamazepine's incidence of severe rash is approximately six in every 10,000 new drug users; these data are from countries with primarily Caucasian populations.²² However, in Asian countries, the incidence could be ten times higher.²² Recently, the FDA issued a statement in which it recommended that companies manufacturing carbamazepine include in their labeling a recommendation for genetic testing of the HLA-B*1502 allele, a human leukocyte antigen, in people of Asian descent.²³ Studies have shown the prevalence of this allele to correlate with a higher incidence of severe skin reaction with carbamazepine in the Asian population.

Chung et al conducted a study in which they genotyped for several CYP450 enzymes as well as several human leukocyte antigens.²⁴ A total of 238 Han Chinese were screened; 44 had developed rash with carbamazepine, 101 were on carbamazepine but had developed no rash, and 93 were normal subjects. The researchers found that 100% of the patients who developed rash with carbamazepine were positive for the HLA-B*1502 allele.

These results were replicated again, but with lower numbers, by Man et al.²⁵ In this study, the authors noted that eight patients (all Han Chinese) taking antiepileptic medications developed a severe cutaneous reaction, which could not be attributed to anything else, eight weeks after starting the medication. Of these eight patients, four were taking carbamazepine and 100% of them were positive for HLA-B*1502. In addition, two more patients were positive for HLA-B*1502; one of them was taking phenytoin and the other was taking lamotrigine.

Additional cases of SJS or toxic epidermal necrolysis have been reported with other drugs, including zonisamide and chlorpromazine.^26,2

Acne
Acneiform reactions usually present as papules and pustules (small, elevated skin lesions filled with white blood cells), generally appearing on the face, upper back, and chest.^1,2 Lithium has been associated with severe acneiform eruptions; more recently, lamotrigine has been reported to have caused acneiform eruptions as well.^28,29

Alopecia
Drug-induced hair loss primarily affects the scalp,† although the hair loss is usually reversible. Mood stabilizers are thought to precipitate follicles into a rest phase leading to telogen effluvium.^1,30 Telogen is the final stage of hair growth before it starts to fall.³⁰ Alopecia has been more commonly reported with valproic acid and lithium.^30,31 Hair loss has also been reported with lamotrigine, venlafaxine, fluoxetine, and paroxetine.^32-35 The effects can appear after years of treatment. While discontinuation of treatment is the common option, one report indicated cessation of hair loss and new hair growth occurring without stopping the medication.³⁰

Fixed-Drug Eruptions
Fixed-drug eruptions are drug-mediated reactions that can be characterized by rapidly appearing lesions after intake, which can be small or large in size and quantity; they are red and may blister or give a burning sensation. Characteristically, they disappear after drug removal, but in the case of rechallenge, they appear in the same surface areas as the first time.^1-3 Carbamazepine and temazepam have been reported to have caused this type of ACDR.^36,37

Lichenoid Reactions
Lichen planus is an inflammatory idiopathic condition of the skin characterized by pruritic "reddish-purple, flat-topped bumps."³⁸ Certain medications can produce a lichenoid-type eruption. The manifestations of this reaction can take several months to appear, manifest primarily in the trunk and extremities, and usually avoid the mucosa and genitalia, which is unlike lichen planus.^1,2 Lichenoid-type eruptions have been reported with carbamazepine.³⁹

Conclusion
While there may be additional types of ACDRs, the most common associated with psychotropics have been reviewed here (TABLE 2). What is important to note is that these reactions can occur with several psychotropics, and they may cause discomfort or present a danger to the patient. Therefore, it is important to be aware not only of their existence, presentation, and treatment, but also the fact that while they usually appear early in treatment, they may also appear after chronic and consistent dosing.

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