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Discussion| Volume 31, ISSUE 1, P101-109, January 2013

Psychiatric medications: Adverse cutaneous drug reactions

DOI:https://doi.org/10.1016/j.clindermatol.2011.11.014
Psychiatric medications: Adverse cutaneous drug reactions
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      Abstract

      Psychiatric medications are among the most widely prescribed medications in the United States. Adverse cutaneous drug reactions are associated with psychiatric medications in approximately 2% to 5% of the individuals for whom they are prescribed. Although most adverse cutaneous drug reactions associated with psychotropic medications are benign and easily treated, some can be disfiguring or life-threatening, particularly those associated with the mood stabilizers. Adverse cutaneous drug reactions associated with antidepressants, antipsychotics, and mood stabilizers are reviewed, and important issues that are of concern for the dermatologist who must consider when and how to safely discontinue a psychotropic medication in their patients are presented.

      Introduction

      Adverse cutaneous drug reactions (ACDRs) are the most frequent adverse events in patients receiving drug therapy, with higher rates being associated with psychotropic medications.
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      Compounding the concern is that psychotropic medications are among the most highly prescribed medications in the United States. The most recent National Center for Health Statistics report on prescription drug use found that in 2007 to 2008, antidepressants were the most commonly prescribed drugs used by adults in the United States aged 20 to 59 years, surpassing even analgesics in frequency.
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      As these data suggest, the prevalence of psychiatric illness is very high. The most recent National Comorbidity Survey Replication estimated the 12-month prevalence of any Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision disorder to be 26.2% in the general population, with 22.3% of these being classified as serious.
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      Although most ACDRs associated with psychotropic medications are benign and easily treated, some can be life-threatening, and particularly those associated with the mood stabilizers. Because it is often necessary to use more than one agent concurrently to obtain remission of severe bipolar mood episodes, this risk is increased in the more severely ill patient who is taking combinations of mood stabilizers.
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      -
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      In addition, cross-sensitivity between these medications has been noted.
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      The decision to discontinue a psychotropic medication vs symptomatic treatment of a less serious ACDR can be difficult for the dermatologist, because the severity of a patient’s psychiatric illness and risk of relapse may not be immediately apparent. With severe ACDRs, the appropriate options for the dermatologist to consider with drug discontinuation can also be challenging, particularly in a patient with a severe mental illness. The decision to remove a possibly offending agent should be weighed carefully, because relapse of mania or severe depression poses a serious risk of morbidity and even mortality. In this contribution, the most common, serious, and general ACDRs associated with antidepressants, mood stabilizers, and antipsychotics will be discussed. Advice concerning when and how to safely discontinue a psychotropic medication will also be presented.

      Special questions and considerations when discontinuing a psychiatric medication secondary to an ACDR

      Any time a medication is discontinued secondary to an ADCR, the decision is based on the severity of the skin reaction vs the risk of relapse or exacerbation of the original condition for which the medication was prescribed. When the offending medication is a psychotropic, however, this process can be even more difficult than with other classes of medications. In a busy dermatology practice, it can be time consuming, and perhaps overwhelming, to evaluate a patient’s current mental stability to understand fully the severity of their psychiatric condition. Further increasing the difficulty of the decision is the frequent practice in psychiatry of using one psychiatric medication to treat several different disorders or symptoms in the same patient. Also, patients are sometimes unaware of which symptoms each medication may be treating; however, to simplify the decision, the essential duty is to always evaluate the patient’s immediate safety. Given that approximately 33,000 people in America die each year by suicide; this is the main risk that must be assessed before the patient leaves your office. It is easy to get overwhelmed or side-tracked when attempting this task, but there are a few high-yield questions that can help you achieve accurate assessments in a short amount of time:

      Have you recently had any thoughts that you should take your own life?

      If the answer to this question is yes, this warrants further questioning. Ask if the patient has a plan, means to follow through with that plan (guns in the home or pill stashes), or intent to suicide. Suicidal ideation with intent or with a plan, or both, is a medical emergency. Despite the severity of the ACDR, if the patient is suicidal, then it is the most prudent response to transfer the patient immediately for an assessment for possible admission to an inpatient psychiatric facility. The medication potentially causing the ACDR can then be withdrawn in a safe environment, other medications initiated, and the appropriate follow-up arranged. If the ACDR requires hospitalization in a medical facility, make sure that these suicidal thoughts are communicated with the accepting medical team and a psychiatric consult is obtained.
      If the patient is reporting recent vague suicidal ideation without an intent or plan, or if he or she has had previous suicide attempts, the patient remains at high risk if the medication is discontinued. The next level of treatment would depend upon the severity of the ACDR. If the ACDR is severe and, therefore, the drug must be discontinued, then inpatient treatment is the safest choice. If the ACDR is not severe or life-threatening, then immediate referral to a psychiatrist for assessment, preferably before drug withdrawal, is warranted. Remember that it is always best to err on the side of caution and arrange for an emergency assessment for the need for inpatient treatment.

      Have you ever been hospitalized in a psychiatric hospital?

      The current standards for inpatient psychiatric treatment are stringent, typically requiring evidence of imminent harm to self or others, or grave deterioration in functioning. Suicide risk is highest in the first few months after inpatient psychiatric treatment than at any other time.
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      It is probably safe to assume that a patient recently discharged from a psychiatric hospital is not fully stable. A recent hospitalization indicates that the patient would be at high risk of exacerbation or relapse if the psychiatric medication is withdrawn. Even a more distant hospitalization is indicative of a higher severity of the patient’s illness. In these cases, unless the ACDR is severe, consultation with the patient’s psychiatrist or prescribing doctor should be made before drug withdrawal. In the case of a severe ACDR, inpatient withdrawal of the medication may be considered.

      Have you recently had a relapse of your psychiatric disorder?

      A recent relapse could indicate a moderate risk of recurrence of psychiatric symptoms if the drug is withdrawn. Recent severe depression or relapse of anxiety would warrant an emergency appointment with the patient’s psychiatrist or prescriber for close monitoring during drug discontinuation for a severe ACDR. If the ACDR is not severe, then consultation with a psychiatrist or a cross-taper (decreasing offending agent while slowly starting a drug from another class) is an option, usually depending on the type of drug being discontinued. An antidepressant should be tapered over at least 2 weeks to decrease the risk of relapse of the psychiatric disorder.
      Once the immediate safety of the patient has been established, there are also pertinent issues relating to morbidity if a medication is withdrawn due to an ACDR. In general, antipsychotics and mood stabilizers are used for severely debilitating psychotic or manic symptoms, or when the severity of a patient’s depression requires augmentation after numerous antidepressant failures. Extreme care should be taken when deciding upon withdrawal of these medications. Medication noncompliance in these patients can be a difficult barrier for treatment, so premature withdrawal of a medication can have a very serious deleterious effect on future compliance. It is also often difficult to elucidate the symptoms for which the drug is prescribed, because patients with chronic schizophrenia or delusional disorders will frequently be hesitant to discuss the reason for their medications.
      Owing to these issues, if the eruption is not severe, consulting with the psychiatrist prior to withdrawal is recommended. If this is not feasible, then beginning another antipsychotic with less risk of causing an ACDR while tapering the offending agent is prudent. If the eruption is severe and requires immediate withdrawal of the antipsychotic, then contacting family members or an emergency consultation with the psychiatrist is necessary.

      Most common ACDRS that can occur with psychotropic medications

      Pruritus

      Pruritus usually occurs secondary to another drug reaction, but it can be a common primary adverse effect of any of the antidepressants, mood stabilizers, or antipsychotics.
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      Adverse cutaneous reactions to psychotropic drugs.
      Acta Derm Venereol Suppl (Stockh). 1991; 158: 1-12
      Pruritus alone would rarely be a cause of discontinuation of a psychotropic medication when considering the risk of relapse of the patient’s disorder. Although pruritus can occur with any psychotropic agent, see Table 1, Table 2, Table 3 for specific drugs more frequently associated with pruritus.
      Table 1Common and general acute cutaneous drug reactions associated with frequently used antidepressants
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      ReactionAntidepressants
      FluParSertCitFluvVenBupMirTrazNefazTCA
      PruritusXXXXXXXXXXX
      Exanthematous reactionsXXXXXXXXXXX
      UrticariaXXXXXXXXXXX
      AngioedemaXXXXXXXXXXX
      Fixed drug eruptionsXXXXXXXXXXX
      Photo-sensitivityXXXXXXX
      Drug-induced pigmentationXXXXXXXa
      AlopeciaXXXXXXXXXXX
      Acneiform eruptionsXXXXXXXXXX
      Psoriasiform reactionsXXXX
      Seborrheic dermatitisXXXXX
      HyperhidrosisXX
      See text for specific tricyclic antidepressants.
      Bup, bupropion; Cit, citalopram; Fluox, fluoxetine; Fluv, fluvoxamine; Mirt, mirtazapine; Nefaz, nefazodone; Parox, paroxetine; Sert, sertraline; TCA, tricyclic antidepressants; Traz, trazodone; Ven, venlafaxine.
      a See text for specific tricyclic antidepressants.
      Table 2Common and general acute cutaneous drug reactions associated with mood stabilizers
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      Stevens-Johnson syndrome associated with concomitant use of lamotrigine and valproic acid.
      J Am Acad Dermatol. 2000; 43: 898-899
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      • Hes J.P.
      • Brenner S.
      Adverse cutaneous reactions to psychotropic drugs.
      Acta Derm Venereol Suppl (Stockh). 1991; 158: 1-12
      , 
      • Atkin D.H.
      • Fitzpatrick R.E.
      Laser treatment of impramine-induced hyperpigmentation.
      J Am Acad Dermatol. 2000; 43: 77-80
      ,
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      Patch testing in cutaneous reactions caused by carbamazepine.
      Contact Dermatitis. 1993; 29: 254-257
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      Psoriasiform eruption induced by anticonvulsants.
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      ReactionMood stabilizers
      CBZOCBZLithiumGBPLTGTPMVPA
      PruritusXXXXXXX
      Exanthematous reactions
      ReactionsXXXXXXX
      UrticariaXXX
      AngioedemaXXXXXX
      Fixed drug
      EruptionsXXX
      PhotosensitivityXXXXX
      Drug-induced pigmentationXXXX
      AlopeciaXXXXXXX
      Acneiform
      EruptionsXXXXX
      Psoriasiform reactionsXXXXX
      Seborrheic dermatitisXXXXX
      HyperhidrosisXXXXX
      CBZ, carbamazepine; GBP, gabapentin; LTG, lamotrigine; OCBZ, oxcarbazepine; TPM, topiramate; VPA, valproic acid.
      Table 3Common and general acute cutaneous drug reactions associated with frequently used antipsychotic drugs
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      • Brenner S.
      Adverse cutaneous reactions to psychotropic drugs.
      Acta Derm Venereol Suppl (Stockh). 1991; 158: 1-12
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      • Harris J.C.
      • Nousari H.C.
      Critical overview: adverse cutaneous reactions to psychotropic medications.
      J Clin Psychiatry. 1999; 60: 714-725
      , 
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      Photosensitivity associated with antipsychotics, antidepressants, and anxiolytics.
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      ReactionAntipsychotic drugs
      RisperOlanzQuetZiprzAripClozHaldol
      PruritusXXXX
      Exanthematous reactionsXXXXXXX
      UrticariaXXXX
      Fixed drug eruptionsXXXX
      PhotosensitivityXXXXXX
      Drug Induced
      PigmentationXXXXX
      AlopeciaXXXXX
      Acneiform
      EruptionsXXXX
      Psoriasiform
      ReactionsXX
      Seborrheic
      DermatitisXX
      HyperhydrosisXXXX
      Arip, aripiprazole; Cloz, clozapine; Olanz, olanzapine; Quet, quetiapine; Risper, risperidone; Zipr, ziprasidone.

      Exanthematous reactions

      Exanthematous reactions are the most common ACDR with psychotropic medications. Although they can occur with any of the antidepressants, mood stabilizers, or antipsychotics,
      • Srebrnik A.
      • Hes J.P.
      • Brenner S.
      Adverse cutaneous reactions to psychotropic drugs.
      Acta Derm Venereol Suppl (Stockh). 1991; 158: 1-12
      they are more likely to be an initial symptom of a more severe or life-threatening reaction with the mood stabilizers.
      The initial eruption usually occurs within the first 2 weeks after a patient starts the medication, and a rechallenge reaction may occur within days. Exanthems usually resolve within 2 weeks after an antidepressant has been discontinued; however, in some cases, the eruption may subside without discontinuation of the offending agent.
      • Kimyai-Asadi A.
      • Harris J.C.
      • Nousari H.C.
      Critical overview: adverse cutaneous reactions to psychotropic medications.
      J Clin Psychiatry. 1999; 60: 714-725
      , 
      • Nigen S.
      • Knowles S.R.
      • Shear N.H.
      Drug eruptions: approaching the diagnosis of drug-induced skin diseases.
      J Drugs Dermatol. 2003; 2: 279-299
      The decision to stop the medication should be weighed carefully. Painful skin lesions or fever may indicate a more severe ACDR, such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TENS), or hypersensitivity syndrome. In these cases, the offending agent should be stopped immediately and appropriate steps taken to assure the patient’s safety during drug withdrawal (Table 1, Table 2, Table 3).

      Urticaria and angioedema

      Urticaria is the second most common adverse cutaneous reaction that can occur with any antidepressant, mood stabilizer, or antipsychotic.
      • Kimyai-Asadi A.
      • Harris J.C.
      • Nousari H.C.
      Critical overview: adverse cutaneous reactions to psychotropic medications.
      J Clin Psychiatry. 1999; 60: 714-725
      Wheals of varying size may appear within minutes, a few hours, or even days after the initiation of the drug. Although individual lesions will typically not last more than 1 day, new lesions may continuously arise. After drug discontinuation, lesions can recur within hours after a rechallenge. Urticaria may be accompanied by angioedema, but angioedema alone is rare. Although they can occur with any psychotropic agent, see Tables 1-3 for specific drugs more frequently associated with urticarial eruptions and angioedema.

      Fixed drug eruptions

      Fixed drug eruptions are common and may be associated with any of the antidepressants.
      • Kimyai-Asadi A.
      • Harris J.C.
      • Nousari H.C.
      Critical overview: adverse cutaneous reactions to psychotropic medications.
      J Clin Psychiatry. 1999; 60: 714-725
      They can also occur with any mood stabilizer but have been specifically found in patients taking carbamazepine,
      • Alanko K.
      Patch testing in cutaneous reactions caused by carbamazepine.
      Contact Dermatitis. 1993; 29: 254-257
      lithium carbonate,
      • Srebrnik A.
      • Hes J.P.
      • Brenner S.
      Adverse cutaneous reactions to psychotropic drugs.
      Acta Derm Venereol Suppl (Stockh). 1991; 158: 1-12
      and gabapentin.
      • Kimyai-Asadi A.
      • Harris J.C.
      • Nousari H.C.
      Critical overview: adverse cutaneous reactions to psychotropic medications.
      J Clin Psychiatry. 1999; 60: 714-725
      All antipsychotics have been implicated as well, but notably with olanzapine,
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      • Soltani K.
      Fixed drug eruption. A brief review.
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      quietiapine,
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      Fixed drug eruption. A brief review.
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      risperidone,
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      • Soltani K.
      Fixed drug eruption. A brief review.
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      haloperidol,
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      and prochlorperazine
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      Fluoxetine-induced psoriasis.
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      (Tables 1-3).
      Initial lesions may appear with in hours of drug ingestion and typically resolve within several weeks after drug discontinuation. Reintroduction of the offending agent, or occasionally a similar agent, can cause a recurrence of lesions at the previous sites or even additional lesions, potentially leading to increased hyperpigmentation.
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      • Harris J.C.
      • Nousari H.C.
      Critical overview: adverse cutaneous reactions to psychotropic medications.
      J Clin Psychiatry. 1999; 60: 714-725
      , 
      • Nigen S.
      • Knowles S.R.
      • Shear N.H.
      Drug eruptions: approaching the diagnosis of drug-induced skin diseases.
      J Drugs Dermatol. 2003; 2: 279-299
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      • Knowles S.R.
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      Cutaneous reactions to drugs.
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      • Wintroub B.U.
      Cutaneous drug reactions.
      in: Kasper D.L. Braunwald E. Fauci A.S. Harrison’s principles of internal medicine. 16th ed. McGraw-Hill, New York2005: 318-324
      Treatment generally starts with discontinuation of the offending agent, and again, the clinician must consider the severity of the lesions vs risk of relapse of the psychiatric disorder. (See the “Special questions…” section for questions to ask the patient.)

      Photosensitivity

      Numerous antidepressants, mood stabilizers, and antipsychotics have been associated with photosensitivity (Tables 1-3). Two types of reactions—phototoxic and photoallergic—can occur with ultraviolet light exposure while patients are taking these medications.
      • Harth Y.
      • Rapoport M.
      Photosensitivity associated with antipsychotics, antidepressants, and anxiolytics.
      Drug Saf. 1996; 14: 252-259
      If the photosensitivity reaction is severe, then drug discontinuation may be warranted; however, preventative measures, such as sun avoidance, sunscreen, and appropriate clothing, may allow continued use of the medication if it has been successful in controlling psychiatric symptoms or if the patient is felt to be at high risk for decompensation or relapse.
      • Moore D.E.
      Drug-induced cutaneous photosensitivity: incidence, mechanism, prevention and management.
      Drug Saf. 2002; 25: 345-372

      Drug-induced pigmentation

      Blue, gray, or brown discoloration in sun-exposed areas has been associated with many of the tricyclic antidepressants, including amitriptyline,
      • Basler R.S.
      • Goetz C.S.
      Synergism of minocycline and amitriptyline in cutaneous hyperpigmentation.
      J Am Acad Dermatol. 1985; 12 ([letter]): 577
      imipramine,
      • Ming M.E.
      • Bhawan J.
      • Stefanato C.M.
      • et al.
      Imipramine-induced hyperpigmentation: four cases and a review of the literature.
      J Am Acad Dermatol. 1999; 40: 159-166
      , 
      • Hashimoto K.
      • Joselow S.A.
      • Tye M.J.
      Imipramine hyperpigmentation: a slate-gray discoloration caused by long-term imipramine administration.
      J Am Acad Dermatol. 1991; 25: 357-361
      , 
      • Atkin D.H.
      • Fitzpatrick R.E.
      Laser treatment of impramine-induced hyperpigmentation.
      J Am Acad Dermatol. 2000; 43: 77-80
      desipramine,
      • Steele T.E.
      • Ashby J.
      Desipramine-related slate-gray skin pigmentation.
      J Clin Psychopharmacol. 1993; 13 ([letter]): 76-77
      , 
      • Narurkar V.
      • Smoller B.R.
      • Hu C.H.
      • et al.
      Desipramine-induced blue-gray photosensitive pigmentation.
      Arch Dermatol. 1993; 129: 474-476
      and clomipramine.
      • Tunca Z.
      • Tunca M.I.
      • Dilsiz A.
      • et al.
      Clomipramine- induced pseudocyanotic pigmentation.
      Am J Psychiatry. 1989; 146: 552-553
      Hair and nail changes may also be involved. These discolorations generally occur after long-term exposure and can take months or years to resolve after drug discontinuation. Selective serotonin reuptake inhibitors (SSRIs) may rarely cause a more general pigmentation change. Pigmentary changes have also been seen with some mood stabilizers and antipsychotics, most notably with thioridazine
      • Berger H.
      Pigmentation after thioridazine.
      Arch Dermatol. 1969; 100 ([letter]): 487
      , 
      • Ban T.A.
      • Guy W.
      • Wilson W.H.
      Neuroleptic-induced skin pigmentation in chronic hospitalized schizophrenic patients.
      Can J Psychiatry. 1985; 30: 406-408
      and chlorpromazine.
      • Ban T.A.
      • Guy W.
      • Wilson W.H.
      Neuroleptic-induced skin pigmentation in chronic hospitalized schizophrenic patients.
      Can J Psychiatry. 1985; 30: 406-408
      , 
      • Zelickson A.S.
      Skin pigmentation and chlorpromazine.
      JAMA. 1965; 194: 670-672
      In addition to skin pigmentation changes with chlorpromazine, the cornea and lens may also be involved.
      • Garnis-Jones S.
      Dermatologic side effects of psychopharmacologic agents.
      Dermatol Clin. 1996; 14: 503-508
      , 
      • Bond W.S.
      • Yee G.C.
      Occular and cutaneous effects of chronic phenothiazines therapy.
      Am J Hosp Pharm. 1980; 37: 74-78
      , 
      • Wolf M.E.
      • Richer S.
      • Berk M.A.
      • et al.
      Cutaneous and ocular changes associated with the use of cholorpromazine.
      Int J Clin Pharmacol Ther Toxicol. 1993; 31: 365-367
      Treatment may include drug discontinuation; however, reports have noted successful use of laser treatment on a patient with imipramine-induced slate-gray hyperpigmentation without discontinuing drug therapy.
      • Atkin D.H.
      • Fitzpatrick R.E.
      Laser treatment of impramine-induced hyperpigmentation.
      J Am Acad Dermatol. 2000; 43: 77-80

      Alopecia

      Alopecia has been associated with various antidepressants, mood stabilizers, and antipsychotics (Tables 1-3). Because this is a benign condition, the decision to discontinue the drug is based on the level of the patient’s distress from the alopecia vs risk of relapse of the psychiatric condition.

      Severe and life-threatening ACDRs that can occur with psychotropic medications

      Erythema multiforme

      Although rare with antidepressants and antipsychotics, fluoxetine,
      • Wernicke J.F.
      The side effect profile and safety of fluoxetine.
      J Clin Psychiatry. 1985; 46: 59-67
      paroxetine,
      • MacMorran W.S.
      • Krahn L.E.
      Adverse cutaneous reactions to psychotropic drugs.
      Psychosomatics. 1997; 38: 413-422
      bupropion,
      • Lineberry T.W.
      • Peters Jr, G.E.
      • Bostwick J.M.
      Bupropion-induced erythema multiforme.
      Mayo Clin Proc. 2001; 76: 664-666
      clozapine,
      • MacMorran W.S.
      • Krahn L.E.
      Adverse cutaneous reactions to psychotropic drugs.
      Psychosomatics. 1997; 38: 413-422
      and risperidone,
      • MacMorran W.S.
      • Krahn L.E.
      Adverse cutaneous reactions to psychotropic drugs.
      Psychosomatics. 1997; 38: 413-422
      have been associated with erythema multiformelike eruptions. Erythema multiformelike eruptions have also been found in patients being treated with carbamazepine,
      • Alanko K.
      Patch testing in cutaneous reactions caused by carbamazepine.
      Contact Dermatitis. 1993; 29: 254-257
      valproic acid,
      • MacMorran W.S.
      • Krahn L.E.
      Adverse cutaneous reactions to psychotropic drugs.
      Psychosomatics. 1997; 38: 413-422
      lamotrigine,
      • MacMorran W.S.
      • Krahn L.E.
      Adverse cutaneous reactions to psychotropic drugs.
      Psychosomatics. 1997; 38: 413-422
      gabapentin,
      • MacMorran W.S.
      • Krahn L.E.
      Adverse cutaneous reactions to psychotropic drugs.
      Psychosomatics. 1997; 38: 413-422
      and oxcarbazepine.
      • MacMorran W.S.
      • Krahn L.E.
      Adverse cutaneous reactions to psychotropic drugs.
      Psychosomatics. 1997; 38: 413-422
      Treatment must include immediate discontinuation of the offending drug with inpatient psychiatric or medical hospitalization determined by the severity of the reaction or current psychiatric symptoms. (See the “Special questions…” section for a discussion of safety issues related to psychiatric drug discontinuation.)

      SJS and TEN

      Although both conditions are not typically associated with antidepressant use, SJS has rarely been associated with some of the SSRIs,
      • Gales B.J.
      • Gales M.A.
      Erythema multiforme and angioedema with indapamide and sertraline.
      Am J Hosp Pharmacy. 1994; 51: 118-119
      and TEN has in a few instances been reported with amoxapine.
      • Camisa C.
      • Grines C.
      Amoxapine: a cause of toxic epidermal necrolysis?.
      Arch Dermatol. 1983; 119: 709-710
      With antipsychotics, SJS and TEN have rarely been seen with clozapine and chlorpromazine.
      • Simpson G.H.
      • Pi E.H.
      • Sramek J.J.
      Neuroleptics and anti-psychotics.
      in: Dukes M.N.G. Meyer’s side effects of drugs. Elsevier, Amsterdam1982: 95-108
      The main concern is with the mood stabilizers. SJS has been associated with carbamazepine,
      • Welykyj S.
      • Gradini R.
      • Nakao J.
      • Massa M.
      Carbamazepine-induced eruption histologically mimicking mycosis fungoides.
      J Cutan Pathol. 1990; 17: 111-116
      , 
      • Friedmann P.S.
      • Strickland I.
      • Pirmohamed M.
      • et al.
      Investigation of mechanisms in toxic epidermal necrolysis induced by carbamazepine.
      Arch Dermatol. 1994; 130: 598-604
      valproic acid,
      • MacMorran W.S.
      • Krahn L.E.
      Adverse cutaneous reactions to psychotropic drugs.
      Psychosomatics. 1997; 38: 413-422
      and significantly with lamotrigine,
      • Messenheimer J.A.
      • Giorgi L.
      • Risner M.E.
      The tolerability of lamotrigine in children.
      Drug Saf. 2000; 22: 303-312
      , 
      • Schlienger R.G.
      • Shapiro L.E.
      • Shear N.H.
      Lamotrigine-induced severe cutaneous adverse reactions.
      Epilepsia. 1998; 39: S22-S26
      -
      • Sachs B.
      • Rönnau A.C.
      • von Schmiedeberg S.
      • et al.
      Lamotrigine-induced Stevens-Johnson syndrome: demonstration of specific lymphocyte reactivity in vitro.
      Dermatology. 1997; 195: 60-64
      , 
      • MacMorran W.S.
      • Krahn L.E.
      Adverse cutaneous reactions to psychotropic drugs.
      Psychosomatics. 1997; 38: 413-422
      which has an incidence of 1% in children
      • Culy C.R.
      • Goa K.L.
      Lamotrigine. A review of its use in childhood epilepsy.
      Paediatr Drugs. 2000; 2: 299-330
      , 
      • Guberman A.H.
      • Besag F.M.
      • Brodie M.J.
      • et al.
      Lamotrigine-associated rash: risk/benefit considerations in adults and children.
      Epilepsia. 1999; 40: 985-991
      and 0.3% in adults.
      • Culy C.R.
      • Goa K.L.
      Lamotrigine. A review of its use in childhood epilepsy.
      Paediatr Drugs. 2000; 2: 299-330
      , 
      • Guberman A.H.
      • Besag F.M.
      • Brodie M.J.
      • et al.
      Lamotrigine-associated rash: risk/benefit considerations in adults and children.
      Epilepsia. 1999; 40: 985-991
      SJS risk is increased further when valproic acid is used in combination with lamotrigine
      • Culy C.R.
      • Goa K.L.
      Lamotrigine. A review of its use in childhood epilepsy.
      Paediatr Drugs. 2000; 2: 299-330
      -
      • Li L.M.
      • Russo M.
      • O’Donoghue M.F.
      • et al.
      Allergic skin rash with lamotrigine and concomitant valproate therapy: evidence for an increased risk.
      Arqu Neuropsiquiatr. 1996; 54: 47-49
      or carbamazepine
      • Herbert A.A.
      • Ralston J.P.
      Cutaneous reactions to anticonvulsant medications.
      J Clin Psychiatry. 2001; 62: 22-26
      , 
      • Yoon Y.
      • Jagoda A.
      New antiepileptic drugs and preparations.
      Emerg Med Clin North Am. 2000; 18: 755-765
      (Table 4). Because the patient will require hospitalization, an inpatient psychiatric consult should be obtained to assess the patient’s safety after discharge or make recommendations for disposition and also to obtain recommendations concerning future medication management of their psychiatric disorder. The offending drug should never be readministered because symptoms can reoccur rapidly within hours or days of reexposure.
      Table 4Psychotropic medications associated with serious acute cutaneous drug reactions
      • Messenheimer J.A.
      • Giorgi L.
      • Risner M.E.
      The tolerability of lamotrigine in children.
      Drug Saf. 2000; 22: 303-312
      , 
      • Schaub N.
      • Bircher A.J.
      Severe hypersensitivity syndrome to lamotrigine confirmed by lymphocyte stimulation in vitro.
      Allergy. 2000; 55: 191-193
      ,
      • Schlienger R.G.
      • Shapiro L.E.
      • Shear N.H.
      Lamotrigine-induced severe cutaneous adverse reactions.
      Epilepsia. 1998; 39: S22-S26
      , 
      • Page II, R.L.
      • O’Neil M.G.
      • Yarborough III, D.R.
      • et al.
      Fatal toxic epidermal necrolysis related to lamotrigine administration.
      Pharmacotherapy. 1998; 18: 392-398
      , 
      • Sachs B.
      • Rönnau A.C.
      • von Schmiedeberg S.
      • et al.
      Lamotrigine-induced Stevens-Johnson syndrome: demonstration of specific lymphocyte reactivity in vitro.
      Dermatology. 1997; 195: 60-64
      ,
      • Lineberry T.W.
      • Peters Jr, G.E.
      • Bostwick J.M.
      Bupropion-induced erythema multiforme.
      Mayo Clin Proc. 2001; 76: 664-666
      , 
      • Gillet-Terver M.N.
      • Modiano P.
      • Tréchot P.
      • et al.
      Fluvoxamine photosensitivity.
      Australas J Dermatol. 1996; 37: 62
      , 
      • Epstein J.H.
      • Wintroub B.U.
      Photosensitivity due to drugs.
      Drugs. 1985; 30: 42-57
      ,
      • Alanko K.
      Patch testing in cutaneous reactions caused by carbamazepine.
      Contact Dermatitis. 1993; 29: 254-257
      , 
      • Welykyj S.
      • Gradini R.
      • Nakao J.
      • Massa M.
      Carbamazepine-induced eruption histologically mimicking mycosis fungoides.
      J Cutan Pathol. 1990; 17: 111-116
      , 
      • Dooley J.
      • Camfield P.
      • Gordon K.
      • et al.
      Lamotrigine-induced rash in children.
      Neurology. 1996; 46: 240-242
      ,
      • Srebrnik A.
      • Bar-Nathan E.A.
      • Ilie B.
      • et al.
      Vaginal ulcerations due to lithium carbonate therapy.
      Cutis. 1991; 48: 65-66
      , 
      • DeToledo J.C.
      • Minagar A.
      • Lowe M.R.
      • et al.
      Skin eruption with gabapentin in a patient with repeated AED-induced Stevens-Johnson’s syndrome.
      Ther Drug Monit. 1999; 21: 137-138
      , 
      • Kimyai-Asadi A.
      • Harris J.C.
      • Nousari H.C.
      Critical overview: adverse cutaneous reactions to psychotropic medications.
      J Clin Psychiatry. 1999; 60: 714-725
      ,
      • Panuska J.R.
      • King T.R.
      • Korenblat P.E.
      • et al.
      Hypersensitivity reaction to desipramine.
      J Allergy Clin Immunol. 1987; 80: 18-23
      , 
      • Cullinan S.A.
      • Bower G.C.
      Acute pulmonary hypersensitivity to carbamazepine.
      Chest. 1975; 68: 580-581
      , 
      • Powell Jr, W.J.
      • Koch-Weser J.
      • Williams R.
      Lethal hepatic necrosis after therapy with imipramine and despipramine.
      JAMA. 1968; 206: 642-645
      , 
      • Troost R.J.
      • Oranje A.P.
      • Lijnen R.L.
      • et al.
      Exfoliative dermatitis due to immunologically confirmed carbamazepine hypersensitivity.
      Pediatr Dermatol. 1996; 13: 316-320
      , 
      • Miranda-Romero A.
      • Pérez-Olivia N.
      • Aragoneses H.
      • et al.
      Carbamazepine hypersensitivity syndrome mimicking mycosis fungoides.
      Cutis. 2001; 67: 47-51
      , 
      • Schlienger R.G.
      • Shear N.H.
      Antiepileptic drug hypersensitivity syndrome.
      Epilepsia. 1998; 39: S3-S7
      , 
      • Tennis P.
      • Stern R.S.
      Risk of serious cutaneous disorders after initiation of use of phenytoin, carbamazepine, or sodium valproate: a record linkage study.
      Neurology. 1997; 49: 542-546
      , 
      • Scerri L.
      • Shall L.
      • Zaki I.
      Carbamazepine-induced anticonvulsant hypersensitivity syndrome—pathogenic and diagnostic considerations.
      Clin Exp Dermatol. 1993; 18: 540-542
      , 
      • Okuyama R.
      • Ichinohasama R.
      • Tagami H.
      Carbamazepine induced erythroderma with systemic lymphadenopathy.
      J Dermatol. 1996; 23: 489-494
      , 
      • Sarzi-Puttini P.
      • Panni B.
      • Cazzola M.
      • et al.
      Lamotrigine-induced lupus.
      Lupus. 2000; 9: 555-557
      , 
      • De Vriese A.S.
      • Philippe J.
      • Van Renterghem D.M.
      • et al.
      Carbamazepine hypersensitivity syndrome: report of 4 cases and review of the literature.
      Medicine (Baltimore). 1995; 74: 144-151
      , 
      • Sterker M.
      • Berrouschot J.
      • Schneider D.
      Fatal course of toxic epidermal necrolysis under treatment with lamotrigine.
      Int J Clin Pharmacol Ther. 1995; 33: 595-597
      , 
      • Chaffin J.J.
      • Davis S.M.
      Suspected lamotrigine-induced toxic epidermal necrolysis.
      Ann Pharmacother. 1997; 31: 720-723
      , 
      • Fogh K.
      • Mai J.
      Toxic epidermal necrolysis after treatment with lamotrigine (Lamictal).
      Seizure. 1997; 6: 63-65
      , 
      • Pavlidakey G.P.
      • Hashimoto K.
      • Heller G.L.
      • et al.
      Chlorpromazine-induced lupus-like disease: case report and review of the literature.
      J Am Acad Dermatol. 1985; 13: 109-115
      , 
      • McNevin S.
      • MacKay M.
      Chlorprothixene-induced systemic lupus erythematosus.
      J Clin Psychopharmacol. 1982; 2: 411-412
      , 
      • Scuderi S.
      • Gift T.E.
      Thiothixene induced edema.
      Psychiatr Med. 1986; 4: 249-252
      MedicationReaction
      EMSJS/TENDRESSDHVEDEN
      Mood stabilizers
       CarbamazepineXXXXXX
       GabapentinXXX
       LamotrigineXXXXX
       Lithium carbonateX
       OxcarbazepineXXX
       TopiramateXX
       Valproic AcidXXX
      Antipsychotics
       RisperidoneXX
       OlanzapineX
       QuetiapineXX
       ZiprasidoneX
       Aripiprazole
       ClozapineXXX
       HaldolX
      Antidepressants
       FluoxetineXXXXX
       SertralineXXX
       ParoxetineXXXXX
       FluvoxamineXXX
       VenlafaxineXX
       DuloxetineXX
       BupropionXXX
       MirtazepineX
       TrazodoneX
       TCAs⁎XX
      DHV, drug hypersensitivity vasculitis; DRESS, drug rash with eosinophilia and systemic symptoms; ED, erythroderma; EM, erythema multiforme; EN, erythema nodosum; SJS/TENS, Stevens-Johnson syndrome/toxic epidermal necrolysis.

      Drug rash with eosinophilia and systemic symptoms

      Drug rash with eosinophilia and systemic symptoms is a potentially life-threatening hypersensitivity syndrome that presents as a triad of fever, rash, and internal organ involvement.
      • Bachot N.
      • Roujeau J.C.
      Differential diagnosis of severe cutaneous drug eruptions.
      Am J Clin Dermatol. 2003; 4: 561-572
      Drug rash with eosinophilia and systemic symptoms has almost always been associated with antiepileptic medications, but desipramine,
      • Panuska J.R.
      • King T.R.
      • Korenblat P.E.
      • et al.
      Hypersensitivity reaction to desipramine.
      J Allergy Clin Immunol. 1987; 80: 18-23
      amitriptyline,
      • Milionis H.J.
      • Skopelitou A.
      • Elisaf M.S.
      Hypersensitivity syndrome caused by amitriptyline administration.
      Postgrad Med J. 2000; 76: 361-363
      imipramine,
      • Panuska J.R.
      • King T.R.
      • Korenblat P.E.
      • et al.
      Hypersensitivity reaction to desipramine.
      J Allergy Clin Immunol. 1987; 80: 18-23
      and fluoxetine have been associated with this severe ACDR. Of the antipsychotics, olanzapine
      • Raz A.
      • Bergman R.
      • Eilam O.
      • et al.
      A case report of olanzapine-induced hypersensitivity syndrome.
      Am J Med Sci. 2001; 321: 156-158
      and perphenazine have been implicated. Mood stabilizing agents that have been associated with drug rash with eosinophilia and systemic symptoms are carbamazepine,
      • Cullinan S.A.
      • Bower G.C.
      Acute pulmonary hypersensitivity to carbamazepine.
      Chest. 1975; 68: 580-581
      , 
      • Vittorio C.C.
      • Muglia J.J.
      Anticonvulsant hypersensitivity syndrome.
      Arch Intern Med. 1995; 155: 2285-2290
      , 
      • Scerri L.
      • Shall L.
      • Zaki I.
      Carbamazepine-induced anticonvulsant hypersensitivity syndrome: pathogenic and diagnostic considerations.
      Clin Exp Dermatol. 1993; 18: 540-542
      , 
      • Horneff G.
      • Lenard H.G.
      • Wahn V.
      Severe adverse reaction to carbamazepine: significance of humoral and cellular reactions to the drug.
      Neuropediatrics. 1992; 23: 272-275
      , 
      • Robbie M.J.
      • Scurry J.P.
      • Stevenson P.
      Carbamazepine-induced severe systemic hypersensitivity reaction with eosinophilia.
      Drug Intell Clin Pharm. 1988; 22: 783-784
      lamotrigine,
      • Schaub N.
      • Bircher A.J.
      Severe hypersensitivity syndrome to lamotrigine confirmed by lymphocyte stimulation in vitro.
      Allergy. 2000; 55: 191-193
      oxcarbazepine, and valproic acid. Because inpatient hospitalization may be necessary for rapid and timely treatment, a psychiatric consult is recommended. (See the “Special questions…” section for a discussion for safety issues related to psychiatric drug discontinuation.)

      Drug hypersensitivity vasculitis

      Drug hypersensitivity vasculitis is characterized by inflammation and necrosis of the walls of blood vessels that occurs within a few weeks of drug initiation. It has rarely been associated with clozapine, trazodone,
      • Kimyai-Asadi A.
      • Harris J.C.
      • Nousari H.C.
      Critical overview: adverse cutaneous reactions to psychotropic medications.
      J Clin Psychiatry. 1999; 60: 714-725
      maprotilin,
      • Oakley A.M.
      • Hodge L.
      Cutaneous vasculitis with maprotiline.
      Aust N Z J Med. 1985; 15: 256-257
      fluoxetine, fluvoxamine, paroxetine, and sertrali. The suspected offending agent should be discontinued immediately, and treatment may include topical anti-inflammatory agents for cutaneous reactions. For systemic involvement, systemic anti-inflammatory or immunosuppressants can be used. (See the “Special questions…” section for a discussion of safety issues related to psychiatric drug discontinuation.)

      Erythroderma (exfoliative dermatitis)

      Erythroderma, also known as exfoliative dermatitis, has been associated with a number of antidepressants. Most of the tricyclic antidepressants have been implicated including desipramine, protriptyline, nortriptyline, amitriptyline, doxepin, trimipramine, clomipramine, and imipramine.
      • Powell Jr, W.J.
      • Koch-Weser J.
      • Williams R.
      Lethal hepatic necrosis after therapy with imipramine and despipramine.
      JAMA. 1968; 206: 642-645
      In addition, fluvoxamine, fluoxetine, sertraline, bupropion, venlafaxine and mirtazapine have also been associated with exfoliative dermatitis. Of the mood stabilizers, carbamazepine,
      • Alanko K.
      Patch testing in cutaneous reactions caused by carbamazepine.
      Contact Dermatitis. 1993; 29: 254-257
      , 
      • Troost R.J.
      • Oranje A.P.
      • Lijnen R.L.
      • et al.
      Exfoliative dermatitis due to immunologically confirmed carbamazepine hypersensitivity.
      Pediatr Dermatol. 1996; 13: 316-320
      lithium carbonate, and gabapentin have been implicated. Antipsychotics are rare causes of this disorder, but it has been reported with quetiapine, risperidone, ziprasidone, and the phenothiazines. Symptoms typically appear in the first few weeks of drug initiation, and the dermatitis may appear abruptly or be a progression of another benign skin eruption. Treatment includes medication discontinuation, antihistamines, and topical corticosteroids. (See the “Special questions…”section for a discussion of safety issues related to psychiatric drug discontinuation)

      Erythema nodosum

      Erythema nodosum is an acute inflammatory immunologic reaction to a medication consisting of painful, bright to dark-red deep-seated nodules. Erythema nodosum has rarely been associated with paroxetine and venlafaxine. Like the other serious ACDRs, immediate drug discontinuation is necessary. (See “Special questions…” for a discussion of safety issues related to psychiatric drug discontinuation.)

      General conditions associated with psychotropic medications

      Acneiform eruptions

      Acneiform eruptions have been associated with almost all antidepressants. Lithium,
      • Srebrnik A.
      • Hes J.P.
      • Brenner S.
      Adverse cutaneous reactions to psychotropic drugs.
      Acta Derm Venereol Suppl (Stockh). 1991; 158: 1-12
      topiramate, lamotrigine, gabapentin, and oxcarbazepine are the mood stabilizers that are associated with acne, and the antipsychotics of note are quetiapine and haloperidol.
      • Nigen S.
      • Knowles S.R.
      • Shear N.H.
      Drug eruptions: approaching the diagnosis of drug-induced skin diseases.
      J Drugs Dermatol. 2003; 2: 279-299
      Typically occurring on the face, chest, and upper back, the eruption consists of folliculocentric pustules, usually without comedones. Discontinuation of the agent will lead to improvement, but is not necessary as antibiotics with topical benzoyl peroxide can manage the eruption. Retinoids are often less helpful due to the lack of comedones.

      Psoriasiform reactions

      Antidepressants associated with psoriasiform reactions are fluoxetine,
      • Hemlock C.
      • Rosenthal J.S.
      • Winston A.
      Fluoxetine-induced psoriasis.
      Ann Pharmacother. 1992; 26: 211-212
      citalopram, venlafaxine, and trazodone.
      • Barth J.H.
      • Baker H.
      Generalized pustular psoriasis precipitated by trazodone in the treatment of depression.
      Br J Dermatol. 1986; 115: 629-630
      The mood stabilizers are carbamazepine,
      • Roberts D.L.
      • Marks R.
      Skin reactions to carbamazepine.
      Arch Dermatol. 1981; 117: 273-275
      , 
      • Brenner S.
      • Wolf R.
      • Landau M.
      • et al.
      Psoriasiform eruption induced by anticonvulsants.
      Isr J Med Sci. 1994; 30: 283-286
      lithium carbonate,
      • Srebrnik A.
      • Hes J.P.
      • Brenner S.
      Adverse cutaneous reactions to psychotropic drugs.
      Acta Derm Venereol Suppl (Stockh). 1991; 158: 1-12
      , 
      • Ghadirian A.M.
      • Lalinec-Michaud M.
      Report of a patient with lithium-related alopecia and psoriasis.
      J Clin Psychiatry. 1986; 47: 212-213
      valproic acid,
      • Camisa C.
      • Grines C.
      Amoxapine: a cause of toxic epidermal necrolysis?.
      Arch Dermatol. 1983; 119: 709-710
      gabapentin,
      • Nigen S.
      • Knowles S.R.
      • Shear N.H.
      Drug eruptions: approaching the diagnosis of drug-induced skin diseases.
      J Drugs Dermatol. 2003; 2: 279-299
      and oxcarbazepine.
      • Nigen S.
      • Knowles S.R.
      • Shear N.H.
      Drug eruptions: approaching the diagnosis of drug-induced skin diseases.
      J Drugs Dermatol. 2003; 2: 279-299
      Of the antipsychotics, quetiapine
      • Nigen S.
      • Knowles S.R.
      • Shear N.H.
      Drug eruptions: approaching the diagnosis of drug-induced skin diseases.
      J Drugs Dermatol. 2003; 2: 279-299
      and risperidone
      • Nigen S.
      • Knowles S.R.
      • Shear N.H.
      Drug eruptions: approaching the diagnosis of drug-induced skin diseases.
      J Drugs Dermatol. 2003; 2: 279-299
      are implicated. The severity of the psoriasis compared with the severity of the patient’s psychiatric disorder should be weighed carefully when considering drug discontinuation. (See “Special questions…”section.)

      Seborrheic dermatitis

      Seborrheic eruptions have been caused by paroxetine, fluvoxamine, fluoxetine, mirtazapine, and venlafaxine.
      • Nigen S.
      • Knowles S.R.
      • Shear N.H.
      Drug eruptions: approaching the diagnosis of drug-induced skin diseases.
      J Drugs Dermatol. 2003; 2: 279-299
      Of the mood stabilizers, carbamazepine,
      • Camisa C.
      • Grines C.
      Amoxapine: a cause of toxic epidermal necrolysis?.
      Arch Dermatol. 1983; 119: 709-710
      lithium carbonate,
      • DeToledo J.C.
      • Minagar A.
      • Lowe M.R.
      • et al.
      Skin eruption with gabapentin in a patient with repeated AED-induced Stevens-Johnson’s syndrome.
      Ther Drug Monit. 1999; 21: 137-138
      ,
      • Nigen S.
      • Knowles S.R.
      • Shear N.H.
      Drug eruptions: approaching the diagnosis of drug-induced skin diseases.
      J Drugs Dermatol. 2003; 2: 279-299
      valproic acid,
      • Brenner S.
      • Wolf R.
      • Landau M.
      • et al.
      Psoriasiform eruption induced by anticonvulsants.
      Isr J Med Sci. 1994; 30: 283-286
      gabapentin, and oxcarbazepine have been implicated. Seborrheic dermatitis can also be a very common ACDR in patients undergoing long-term treatment with phenothiazines. In addition to the phenothiazines, ACDR has been reported with olanzapine, quetiapine, and loxapine.

      Hyperhidrosis

      An increase in perspiration has been noted with clomipramine, nortriptyline, phenelzine, bupropion, and maprotiline. Hyperhidrosis has also been noted in patients taking carbamazepine, topiramate, lamotrigine, gabapentin, and oxcarbazepine. Of the antipsychotics, it has been noted with olanzapine, quetiapine, and pimozide. Treatment options include the various aluminum chloride compounds.

      Conclusions

      Although ACDRs are frequent with psychotropic medications, most of the skin lesions are benign and easily managed. When serious ACDRs occur, care must be taken to assess safety before withdrawal of the medication. In addition, consideration of the potential for severe morbidity when a drug is withdrawn should not be underestimated. Because many patients with debilitating psychiatric illnesses have almost always had numerous medication trials before an effective regimen is found, a thorough assessment of the necessity of drug withdrawal should always be undertaken. Of the psychotropic medications frequently used by physicians today in the United States, it is the mood-stabilizing agents that have the highest incidence of severe and potentially life-threatening ACDRs. Patients who are taking mood stabilizers must be assessed carefully, and when necessary for safety reasons, the drug should be withdrawn in an inpatient psychiatric or hospital setting. Immediate attention will hopefully reduce the risk of the ACDRs developing into serious lesions.

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      DOI: https://doi.org/10.1016/j.clindermatol.2011.11.014

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      © 2013 Elsevier Inc. Published by Elsevier Inc. All rights reserved.

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