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Management of Psychotropic Drug–Induced DRESS Syndrome: A Systematic Review

      Abstract

      Drug rash with eosinophilia and systemic symptoms (DRESS) is a severe cutaneous eruption that has been linked to several common drugs and drug categories, including antiepileptics, allopurinol, sulfonamides, and various antibiotics; however, because of a number of recent case reports linking psychotropic medications to this condition, DRESS is increasingly recognized among psychiatrists. We systematically reviewed all psychotropic drugs linked to DRESS syndrome, and this article summarizes the clinical management relevant to psychiatric professionals. A comprehensive search was performed using Ovid MEDLINE, Ovid EMBASE, Ovid Cochrane Database of Systematic Reviews, Web of Science, Scopus, and Litt's Drug Eruption and Reaction Database for articles published in English during the past 20 years (1996-2015) using the search terms (1) psychotropic drugs OR serotonin uptake inhibitors AND DRESS or (2) psychotropic drugs AND drug reaction (or rash) eosinophilia systemic syndrome, and all article abstracts were screened for inclusion and exclusion criteria by 3 reviewers. Two independent reviewers examined the full text of 163 articles, of which 96 (25 original articles, 12 review articles, 55 case reports, and 4 letters to the editor) were included in the systematic review. We identified 1072 cases of psychotropic drug–induced DRESS, with carbamazepine, lamotrigine, phenytoin, valproate, and phenobarbital being the most implicated drugs. Based on our review of the literature, we outline management principles that include prompt withdrawal of the causative drug, hospitalization, corticosteroid therapy, and novel treatments, including intravenous immunoglobulin, cyclophosphamide, and cyclosporine, for corticosteroid-resistant DRESS. Finally, we outline strategies for treating comorbid psychiatric illness after a DRESS reaction to the psychotropic medication.

      Abbreviations and Acronyms:

      CBZ (carbamazepine), DRESS (drug rash with eosinophilia and systemic symptoms), FDA (US Food and Drug Administration), IVIG (intravenous immunoglobulin), LTG (lamotrigine), PB (phenobarbital), PHT (phenytoin), SJS (Stevens-Johnson syndrome), VPA (valproate), ZIP (ziprasidone)
      Article Highlights
      • Drug rash with eosinophilia and systemic symptoms (DRESS) is a severe cutaneous eruption that typically presents within 1 or 2 months of drug initiation. Common clinical features include maculopapular rash, elevated liver enzyme levels, lymphadenopathy, facial edema, and eosinophilia.
      • Our systematic review included 1072 cases of psychotropic drug–induced DRESS, with carbamazepine, lamotrigine, phenytoin, valproate, and phenobarbital being the most implicated drugs.
      • The cornerstones of DRESS management include prompt withdrawal of the implicated drug and administration of corticosteroids. For cases of corticosteroid-resistant DRESS, intravenous immunoglobulin, cyclophosphamide, cyclosporine, and immunosuppressants have had efficacy.
      • Management of comorbid psychiatric illness includes strict avoidance of the implicated drug and other drugs in the same class (eg, aromatic, nonaromatic) and identification of a replacement drug (eg, valproate for carbamazepine-induced DRESS).
      Drug rash with eosinophilia and systemic symptoms (DRESS) is a severe cutaneous drug eruption that is characterized by fever, rash, lymphadenopathy, internal organ involvement, and hematologic abnormalities. The most commonly affected organs are the liver, lungs, and kidneys, and characteristic blood abnormalities include lymphocytopenia, atypical lymphocytes, and eosinophilia.
      • Chen Y-C.
      • Cho Y-T.
      • Chang C-Y.
      • Chu C-Y.
      Drug reaction with eosinophilia and systemic symptoms: a drug-induced hypersensitivity syndrome with variable clinical features.
      DRESS syndrome can be difficult to diagnose because of its nonspecific presentation. Moreover, it often is asymptomatic until a considerable amount of time has passed after the initial drug exposure.
      • Camous X.
      • Calbo S.
      • Picard D.
      • Musette P.
      Drug reaction with eosinophilia and systemic symptoms: an update on pathogenesis.
      The pathogenesis of DRESS is unclear, although several models have been proposed, and it may have a genetic origin.
      • Camous X.
      • Calbo S.
      • Picard D.
      • Musette P.
      Drug reaction with eosinophilia and systemic symptoms: an update on pathogenesis.
      Viral reactivation may also have a significant role, with several studies reporting that reactivation of human herpesvirus 6 and 7, Epstein-Barr virus, and cytomegalovirus can occur at the onset of DRESS.
      • Picard D.
      • Janela B.
      • Descamps V.
      • et al.
      Drug reaction with eosinophilia and systemic symptoms (DRESS): a multiorgan antiviral T cell response.
      Several common drugs and drug categories have been associated with this condition, including antiepileptics, allopurinol, sulfonamides, and various antibiotics; however, recent case reports have linked psychotropic medications to this condition, and DRESS syndrome is becoming increasingly recognized among psychiatrists. Although the incidence rate of DRESS syndrome is unknown, prospective studies have estimated it to be about 1 per 1000 to 10,000 individuals exposed to commonly associated drugs. The mortality rate is estimated to be around 10% to 20%.
      • López-Rocha E.
      • Blancas L.
      • Rodríguez-Mireles K.
      • et al.
      Prevalence of DRESS syndrome.
      Recently implicated psychotropic drugs include benzodiazepines, bupropion, mirtazapine, and amitriptyline.
      • Laban E.
      • Hainaut-Wierzbicka E.
      • Pourreau F.
      • et al.
      Cyclophosphamide therapy for corticoresistant drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome in a patient with severe kidney and eye involvement and Epstein-Barr virus reactivation.
      • Iacob S.A.
      • Sotropa A.
      DRESS syndrome with hepatic involvement in a patient with depressive disorder.
      • Alexander T.
      • Iglesia E.
      • Park Y.
      • et al.
      Severe DRESS syndrome managed with therapeutic plasma exchange.
      • Bagshaw S.M.
      • Cload B.
      • Gilmour J.
      • Leung S.T.
      • Bowen T.J.
      Drug-induced rash with eosinophilia and systemic symptoms syndrome with bupropion administration.
      • Eppenberger M.
      • Hack D.
      • Ammann P.
      • Rickli H.
      • Maeder M.T.
      Acute eosinophilic myocarditis with dramatic response to steroid therapy: the central role of echocardiography in diagnosis and follow-up.
      Most studies have focused on aromatic antiepileptics, including phenytoin (PHT), carbamazepine (CBZ), and phenobarbital (PB), but little is known about psychotropic drug–induced DRESS syndrome. Moreover, consensus has not been established on the management and treatment of DRESS syndrome. The only management step that appears to be universally accepted is cessation of the causative agent.
      • Volcheck G.W.
      Clinical evaluation and management of drug hypersensitivity.
      The use of corticosteroids for DRESS is controversial because of the lack of randomized controlled trials assessing their efficacy, but they are nevertheless a widely accepted treatment.
      • Volcheck G.W.
      Clinical evaluation and management of drug hypersensitivity.
      Recently, other promising treatments have been applied to DRESS, including intravenous immunoglobulin (IVIG), plasma exchange, cyclosporine, and cyclophosphamide.
      • Chan J.C.
      • Chan H.H.L.
      • Yeung C.K.
      Drug reaction with eosinophilia and systemic symptoms (DRESS).
      Although these treatment options have been explored in individual case reports, little in the published literature guides psychiatric management of psychotropic drug–induced DRESS syndrome. The onset of DRESS syndrome can create a difficult clinical situation, even after the acute symptoms have resolved, because cessation of the causative agent may lead to recurrence and worsening of problematic psychiatric symptoms. Evidence-based recommendations are needed to guide clinical decision making for mental health professionals managing patients with DRESS syndrome. This article provides a systematic review of all psychotropic drugs linked to DRESS syndrome and summarizes the clinical management relevant to psychiatric professionals in a multidisciplinary context. To our knowledge, this is the first systematic review of psychotropic drug–induced DRESS syndrome and its clinical management.

      Methods

      Literature Search

      An experienced medical librarian designed a search strategy in Ovid MEDLINE and translated the strategy for Ovid EMBASE, Ovid Cochrane Database of Systematic Reviews, Web of Science, and Scopus. Litt's Drug Eruption and Reaction Database was also searched. The search was limited to articles published in English during the past 20 years (1996-2015; the first report of DRESS was published in 1996). The strategy included the US National Library of Medicine's medical subject headings and keywords, including (1) psychotropic drugs OR serotonin uptake inhibitors AND DRESS or (2) psychotropic drugs AND drug reaction (or rash) eosinophilia systemic syndrome. From this search, 394 articles were identified.

      Screening

      We aimed to include articles on DRESS syndrome involving any psychiatric or psychotropic medication such as antipsychotics or neuroleptics, mood stabilizers, antiepileptics, antidepressants, and antianxiety medications. We included pediatric and adult studies. We excluded articles that focused primarily on clinical and pathologic features, genotyping, patch testing, or other diagnostics that were not relevant to psychiatric medications. We also excluded articles that focused primarily on antiepileptic or anticonvulsant drugs exclusively for managing seizure disorder (ie, without psychiatric applications).
      Article abstracts were screened for inclusion and exclusion criteria by 3 authors (S.K., J.L.C., J.G.L.), and disagreements were resolved by consensus. At this stage, 231 articles were excluded. The full text of the 163 remaining articles was reviewed independently by 2 authors (M.I.L., T.J.B.). After applying the inclusion and exclusion criteria, 67 articles were subsequently eliminated (Figure).
      Figure thumbnail gr1
      FigureFlow diagram of references selected for study inclusion based on the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) method.

      Results

      We identified 1072 cases of psychotropic drug–induced DRESS, with CBZ, lamotrigine (LTG), PHT, valproate (VPA), and PB being the most implicated drugs.

      Original Articles

      We identified 25 original articles that described 997 cases of DRESS (Table 1).
      • Volcheck G.W.
      Clinical evaluation and management of drug hypersensitivity.
      • Sultan S.J.
      • Sameem F.
      • Ashraf M.
      Drug reaction with eosinophilia and systemic symptoms: manifestations, treatment, and outcome in 17 patients.
      • Um S.J.
      • Lee S.K.
      • Kim Y.H.
      • et al.
      Clinical features of drug-induced hypersensitivity syndrome in 38 patients.
      • Botelho L.F.
      • Higashi V.S.
      • Padilha M.H.
      • Enokihara M.M.
      • Porro A.M.
      DRESS: clinicopathological features of 10 cases from an university hospital in São Paulo.
      • Chiou C.C.
      • Yang L.C.
      • Hung S.I.
      • et al.
      Clinicopathological features and prognosis of drug rash with eosinophilia and systemic symptoms: a study of 30 cases in Taiwan.
      • Kardaun S.H.
      • Sekula P.
      • Valeyrie-Allanore L.
      • et al.
      RegiSCAR Study Group
      Drug reaction with eosinophilia and systemic symptoms (DRESS): an original multisystem adverse drug reaction; results from the prospective RegiSCAR study.
      • Karimzadeh P.
      • Bakrani V.
      Antiepileptic drug-related adverse reactions and factors influencing these reactions.
      • Sasidharanpillai S.
      • Riyaz N.
      • Rajan U.
      • et al.
      Drug reaction with eosinophilia and systemic symptoms: observations from a tertiary care institution.
      • Peyrière H.
      • Dereure O.
      • Breton H.
      • et al.
      Network of the French Pharmacovigilance Centers
      Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist?.
      • Phillips E.J.
      • Chung W.H.
      • Mockenhaupt M.
      • Roujeau J.C.
      • Mallal S.A.
      Drug hypersensitivity: pharmacogenetics and clinical syndromes.
      • Santiago F.
      • Gonçalo M.
      • Vieira R.
      • Coelho S.
      • Figueiredo A.
      Epicutaneous patch testing in drug hypersensitivity syndrome (DRESS).
      • Walsh S.
      • Diaz-Cano S.
      • Higgins E.
      • et al.
      Drug reaction with eosinophilia and systemic symptoms: is cutaneous phenotype a prognostic marker for outcome? a review of clinicopathological features of 27 cases.
      • Yang M.S.
      • Kang M.G.
      • Jung J.W.
      • et al.
      Clinical features and prognostic factors in severe cutaneous drug reactions.
      • Heinzerling L.M.
      • Tomsitz D.
      • Anliker M.D.
      Is drug allergy less prevalent than previously assumed? a 5-year analysis.
      • Pereira de Silva N.
      • Piquioni P.
      • Kochen S.
      • Saidon P.
      Risk factors associated with DRESS syndrome produced by aromatic and non-aromatic antipiletic drugs.
      • Lee H.Y.
      • Chou D.
      • Pang S.M.
      • Thirumoorthy T.
      Acute generalized exanthematous pustulosis: analysis of cases managed in a tertiary hospital in Singapore.
      • Boccara O.
      • Valeyrie-Allanore L.
      • Crickx B.
      • Descamps V.
      Association of hypogammaglobulinemia with DRESS (Drug Rash with Eosinophilia and Systemic Symptoms).
      • Sasidharanpillai S.
      • Riyaz N.
      • Khader A.
      • Rajan U.
      • Binitha M.P.
      • Sureshan D.N.
      Severe cutaneous adverse drug reactions: a clinicoepidemiological study.
      • Mokhtari F.
      • Nikyar Z.
      • Naeini B.A.
      • Esfahani A.A.
      • Rahmani S.
      Adverse cutaneous drug reactions: eight year assessment in hospitalized patients.
      • Grando L.R.
      • Schmitt T.A.
      • Bakos R.M.
      Severe cutaneous reactions to drugs in the setting of a general hospital.
      • Wei C.H.
      • Chung-Yee Hui R.
      • Chang C.J.
      • et al.
      Identifying prognostic factors for drug rash with eosinophilia and systemic symptoms (DRESS).
      • Yang C.Y.
      • Dao R.L.
      • Lee T.J.
      • et al.
      Severe cutaneous adverse reactions to antiepileptic drugs in Asians.
      • Maoz K.B.
      • Brenner S.
      Drug rash with eosinophilia and systemic symptoms syndrome: sex and the causative agent.
      • Chen Y.C.
      • Chiu H.C.
      • Chu C.Y.
      Drug reaction with eosinophilia and systemic symptoms: a retrospective study of 60 cases.
      • Avancini J.
      • Maragno L.
      • Santi C.G.
      • Criado P.R.
      Drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome: clinical features of 27 patients.
      The implicated psychotropic drugs were antiepileptics or mood stabilizers. Carbamazepine and PHT were most often associated with DRESS, as were LTG, topiramate, PB, oxcarbazepine, and VPA. No articles specifically mentioned antidepressants, anxiolytics, antipsychotics, sedatives, or hypnotics. The described time to presentation, when reported, was similar among studies (mean [SD], 24.3 [2.7] days). Management often included corticosteroids and removal of the suspected agent. One review article cited a mortality rate as high as 20%.
      • Botelho L.F.
      • Higashi V.S.
      • Padilha M.H.
      • Enokihara M.M.
      • Porro A.M.
      DRESS: clinicopathological features of 10 cases from an university hospital in São Paulo.
      Table 1Original Articles on DRESS Associated With Psychotropic Drugs
      ABC = abacavir; AED = antiepileptic drug; ALL = allopurinol; ALT = alanine aminotransferase; AMX = amoxicillin; CBZ = carbamazepine; CTX = ceftriaxone; DDS = dapsone; DRESS = drug rash with eosinophilia and systemic symptoms; IBU = ibuprofen; INM = indomethacin; IVIG = intravenous immunoglobulin; LEF = leflunomide; LTG = lamotrigine; MNC = minocycline; NA = not available; NTF = nitrofurantoin; NVP = nevirapine; OCBZ = oxcarbazepine; PB = phenobarbital; PHT = phenytoin; SIRS = systemic inflammatory response syndrome; SJS = Stevens-Johnson syndrome; TEN = toxic epidermal necrolysis; VAN = vancomycin; VPA = valproate.
      Reference, yearNo.Patient typeMedicationsResultsCommentTime to presentation (d), meanPresenting symptoms
      Sultan et al,
      • Sultan S.J.
      • Sameem F.
      • Ashraf M.
      Drug reaction with eosinophilia and systemic symptoms: manifestations, treatment, and outcome in 17 patients.
      2015
      17AdultsPHT, PB, CBZ, OCBZ, LTG, ALL, LEF, DDS, VAN, NTFRetrospective study

      Injectable dexamethasone as treatment

      Majority (76.5%) recovered completely
      Systemic corticosteroids usually first-line treatment for DRESS; however, use is controversial because of lack of randomized controlled trials22.35±5.83Many different presentations
      Um et al,
      • Um S.J.
      • Lee S.K.
      • Kim Y.H.
      • et al.
      Clinical features of drug-induced hypersensitivity syndrome in 38 patients.
      2010
      38AdultsLTG, CBZ, PB, PHT, IBU, ALL, CTXRetrospective study

      36 DRESS patients (94.8%) treated with corticosteroids (n=16) or antihistamines (n=22) recovered completely
      More information needed to evaluate the indications for systemic corticosteroids25.2Many different presentations
      Botelho et al,
      • Botelho L.F.
      • Higashi V.S.
      • Padilha M.H.
      • Enokihara M.M.
      • Porro A.M.
      DRESS: clinicopathological features of 10 cases from an university hospital in São Paulo.
      2012
      10AdultsALL, PHT, CBZRetrospective study

      Systemic corticosteroids as treatment

      8 Recovered; 2 died of septic shock
      NoneNAMany different presentations
      Chiou et al,
      • Chiou C.C.
      • Yang L.C.
      • Hung S.I.
      • et al.
      Clinicopathological features and prognosis of drug rash with eosinophilia and systemic symptoms: a study of 30 cases in Taiwan.
      2008
      29AdultsALL, PHT, CBZ, INM, VAN, DDSRetrospective study

      Treatment with systemic corticosteroid (n=22) or oral antihistamines plus supportive care (n=7)
      High absolute eosinophil counts and multiple underlying diseases were poor prognostic factors23.49Many different presentations
      Kardaun et al,
      • Kardaun S.H.
      • Sekula P.
      • Valeyrie-Allanore L.
      • et al.
      RegiSCAR Study Group
      Drug reaction with eosinophilia and systemic symptoms (DRESS): an original multisystem adverse drug reaction; results from the prospective RegiSCAR study.
      2013
      117AdultsCBZ, PHT, LTG, OCBZ, PB, ALL, VAN, AMX, piperacillin-tazobactamEarly recognition and prompt withdrawal of the drug were the most important steps to avoid disease progressionNone22Eosinophilia (95%)

      Visceral involvement (91%)

      High fever (90%)
      Karimzadeh and Bakrani,
      • Karimzadeh P.
      • Bakrani V.
      Antiepileptic drug-related adverse reactions and factors influencing these reactions.
      2013
      4ChildrenPBRetrospective study

      Of 70 pediatric patients with AED reactions, 4 had DRESS
      Higher rates of AED reactions with aromatic AEDs than nonaromatic AEDsNANA
      Sasidharanpillai et al,
      • Sasidharanpillai S.
      • Riyaz N.
      • Rajan U.
      • et al.
      Drug reaction with eosinophilia and systemic symptoms: observations from a tertiary care institution.
      2014
      28Adults and childrenPHT, PB, DDS, CBZ, LTG, VPARetrospective study

      Prednisolone (1 mg/kg) or dexamethasone was given to patients with >10-fold elevation in transaminase levels, hyperbilirubinemia, or multiorgan involvement

      Full recovery in all patients except 1 (nonadherent)
      Flare-ups during prednisolone withdrawal managed successfully by increasing dose followed by slow taper27.2Many different presentations
      Peyrière et al,
      • Peyrière H.
      • Dereure O.
      • Breton H.
      • et al.
      Network of the French Pharmacovigilance Centers
      Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist?.
      2006
      216Adults and childrenCBZ, PHT, LTG, ALL, MNC, NVP, ABCRetrospective study

      Clinical presentations of DRESS were variable
      A large prospective study is needed to better define DRESS and evaluate prognostic dataNAFever, cutaneous eruption, hepatic abnormalities, eosinophilia
      Phillips et al,
      • Phillips E.J.
      • Chung W.H.
      • Mockenhaupt M.
      • Roujeau J.C.
      • Mallal S.A.
      Drug hypersensitivity: pharmacogenetics and clinical syndromes.
      2011
      NANANANAHLA associations might be able to provide screening for specific drug-induced DRESS symptomsNANA
      Santiago et al,
      • Santiago F.
      • Gonçalo M.
      • Vieira R.
      • Coelho S.
      • Figueiredo A.
      Epicutaneous patch testing in drug hypersensitivity syndrome (DRESS).
      2010
      56Adults and childrenNAPositive patch tests were seen in 18 patients (32.1%), of which 17 were AEDsPatch testing was a safe and useful method to confirm the culprit drug in DRESS induced by AEDsNANA
      Walsh et al,
      • Walsh S.
      • Diaz-Cano S.
      • Higgins E.
      • et al.
      Drug reaction with eosinophilia and systemic symptoms: is cutaneous phenotype a prognostic marker for outcome? a review of clinicopathological features of 27 cases.
      2013
      38Adults and childrenNARetrospective studyCutaneous dermatologic signs of DRESS may have a potential prognostic value regarding the severity of visceral involvementNANA
      Yang et al,
      • Yang M.S.
      • Kang M.G.
      • Jung J.W.
      • et al.
      Clinical features and prognostic factors in severe cutaneous drug reactions.
      2013
      48Adults and childrenNARetrospective study

      Treatments included systemic corticosteroids alone (n=40) and both corticosteroids and IVIG (n=1); 7 were treated conservatively
      Leukocytosis at presentation was a prognostic factor for prolonged hospitalization21.5NA
      Heinzerling et al,
      • Heinzerling L.M.
      • Tomsitz D.
      • Anliker M.D.
      Is drug allergy less prevalent than previously assumed? a 5-year analysis.
      2012
      107Adults and childrenNARetrospective study

      Of 141 cases of suspected cutaneous drug reactions, 107 were due to a drug (34 [24%] were attributed to other causes)
      Clinical assessment overestimates the role of drug allergies in cutaneous reactionsNANA
      Pereira de Silva et al,
      • Pereira de Silva N.
      • Piquioni P.
      • Kochen S.
      • Saidon P.
      Risk factors associated with DRESS syndrome produced by aromatic and non-aromatic antipiletic drugs.
      2011
      8
      The discrepancy between the Number and Results is due to some patients receiving more than one treatment.
      NACBZ, LTG, PHTRetrospective study

      Treatments were diphenhydramine (n=4), loratadine (n=1), prednisone (dose, 30-60 mg/d; n=6), and both prednisone and antihistamines (n=3)
      None28.5Many different presentations
      Volcheck,
      • Volcheck G.W.
      Clinical evaluation and management of drug hypersensitivity.
      2004
      NANANATreatment should be supportive (volume replacement, nutritional support, antibiotics, skin care), but corticosteroids remain controversialAlthough case reports have described efficacy of corticosteroids, randomized controlled trials are needed to confirm their benefitNANA
      Lee et al,
      • Lee H.Y.
      • Chou D.
      • Pang S.M.
      • Thirumoorthy T.
      Acute generalized exanthematous pustulosis: analysis of cases managed in a tertiary hospital in Singapore.
      2010
      18Adults and childrenPHT, ALLRetrospective study

      DRESS constituted 18/97 (18.6%) of the reactions
      NoneNANA
      Boccara et al,
      • Boccara O.
      • Valeyrie-Allanore L.
      • Crickx B.
      • Descamps V.
      Association of hypogammaglobulinemia with DRESS (Drug Rash with Eosinophilia and Systemic Symptoms).
      2006
      NANANARetrospective study

      Hypogammaglobulinemia was significantly associated with DRESS
      NoneNANA
      Sasidharanpillai et al,
      • Sasidharanpillai S.
      • Riyaz N.
      • Khader A.
      • Rajan U.
      • Binitha M.P.
      • Sureshan D.N.
      Severe cutaneous adverse drug reactions: a clinicoepidemiological study.
      2015
      7AdultsVPARetrospective study

      Described incidence of adverse drug reactions on a dermatology ward during an 11-month period
      Rebound or flare-up reactions were noted for several patients with DRESS during the corticosteroid taper, which required reinitiation of higher doses of corticosteroidsNADRESS tended to present with less mucocutaneous involvement than SJS or TEN
      Mokhtari et al,
      • Mokhtari F.
      • Nikyar Z.
      • Naeini B.A.
      • Esfahani A.A.
      • Rahmani S.
      Adverse cutaneous drug reactions: eight year assessment in hospitalized patients.
      2014
      18Adults and childrenCBZ, VPA, VANRetrospective study

      DRESS reactions accounted for 6.4% of all adverse cutaneous drug reactions in an 8-year period
      DRESS should be in the differential diagnosis for any adverse drug reactionNANA
      Grando et al,
      • Grando L.R.
      • Schmitt T.A.
      • Bakos R.M.
      Severe cutaneous reactions to drugs in the setting of a general hospital.
      2014
      26Adults and childrenNARetrospective study

      DRESS was the most common severe cutaneous drug reaction in this sample
      Withdrawal of the causative drug is the most important step in management

      Corticosteroid use is controversial
      NANA
      Wei et al,
      • Wei C.H.
      • Chung-Yee Hui R.
      • Chang C.J.
      • et al.
      Identifying prognostic factors for drug rash with eosinophilia and systemic symptoms (DRESS).
      2011
      91Adults and childrenNARetrospective study

      Tachycardia, leukocytosis, tachypnea, coagulopathy, gastrointestinal bleeding, and SIRS were poor prognostic indicators of DRESS
      Early recognition and intervention are key in avoiding mortality in DRESSNANA
      Yang et al,
      • Yang C.Y.
      • Dao R.L.
      • Lee T.J.
      • et al.
      Severe cutaneous adverse reactions to antiepileptic drugs in Asians.
      2011
      39Adults and childrenCBZ, LTG, OCBZ, PHTRetrospective study

      DRESS was more likely to cause organ involvement, especially liver dysfunction, than SJS or TEN
      Corticosteroids (and sometimes IVIG) are frequently used to treat adverse cutaneous drug reactions, but this practice is controversialNANA
      Maoz and Brenner,
      • Maoz K.B.
      • Brenner S.
      Drug rash with eosinophilia and systemic symptoms syndrome: sex and the causative agent.
      2007
      8AdultsCBZ, PHTRetrospective study

      Women tended to present at a younger age and with a shorter time to onset of symptoms
      NoneNANA
      Chen et al,
      • Chen Y.C.
      • Chiu H.C.
      • Chu C.Y.
      Drug reaction with eosinophilia and systemic symptoms: a retrospective study of 60 cases.
      2010
      60Adults and childrenALL was the most common culprit drug (19/60 cases)Retrospective study

      75% of patients were treated with systemic corticosteroids (with IVIG for 2 patients, 1 of whom died)

      10 Patients received only supportive care

      6 Patients (10%) died

      Corticosteroid use did not affect mortality rates
      NoneNANA
      Avancini et al,
      • Avancini J.
      • Maragno L.
      • Santi C.G.
      • Criado P.R.
      Drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome: clinical features of 27 patients.
      2015
      27Adults and childrenPHT, CBZRetrospective study

      All patients were treated with corticosteroids

      Mortality rate was 4%
      An association may exist between the presence of atypical lymphocytes and elevated ALTNAMaculopapular exanthema (85.1%), fever (96.2%), hepatitis (85.1%)
      a ABC = abacavir; AED = antiepileptic drug; ALL = allopurinol; ALT = alanine aminotransferase; AMX = amoxicillin; CBZ = carbamazepine; CTX = ceftriaxone; DDS = dapsone; DRESS = drug rash with eosinophilia and systemic symptoms; IBU = ibuprofen; INM = indomethacin; IVIG = intravenous immunoglobulin; LEF = leflunomide; LTG = lamotrigine; MNC = minocycline; NA = not available; NTF = nitrofurantoin; NVP = nevirapine; OCBZ = oxcarbazepine; PB = phenobarbital; PHT = phenytoin; SIRS = systemic inflammatory response syndrome; SJS = Stevens-Johnson syndrome; TEN = toxic epidermal necrolysis; VAN = vancomycin; VPA = valproate.
      b The discrepancy between the Number and Results is due to some patients receiving more than one treatment.

      Review Articles

      We identified 12 review articles on DRESS with psychotropic agents (Table 2).
      • Chan J.C.
      • Chan H.H.L.
      • Yeung C.K.
      Drug reaction with eosinophilia and systemic symptoms (DRESS).
      • Choudhary S.
      • McLeod M.
      • Torchia D.
      • Romanelli P.
      Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome.
      • Jeung Y.J.
      • Lee J.Y.
      • Oh M.J.
      • Choi D.C.
      • Lee B.J.
      Comparison of the causes and clinical features of drug rash with eosinophilia and systemic symptoms and Stevens-Johnson syndrome.
      • Roujeau J.C.
      • Haddad C.
      • Paulmann M.
      • Mockenhaupt M.
      Management of nonimmediate hypersensitivity reactions to drugs.
      • Walsh S.A.
      • Creamer D.
      Drug reaction with eosinophilia and systemic symptoms (DRESS): a clinical update and review of current thinking.
      • Verma R.
      • Vasudevan B.
      • Pragasam V.
      Severe cutaneous adverse drug reactions.
      • Husain Z.
      • Reddy B.Y.
      • Schwartz R.A.
      DRESS syndrome, part I: clinical perspectives.
      • Kano Y.
      • Shiohara T.
      The variable clinical picture of drug-induced hypersensitivity syndrome/drug rash with eosinophilia and systemic symptoms in relation to the eliciting drug.
      • Cacoub P.
      • Musette P.
      • Descamps V.
      • et al.
      The DRESS syndrome: a literature review.
      • Criado P.R.
      • Criado R.F.
      • Avancini J.M.
      • Santi C.G.
      Drug reaction with Eosinophilia and Systemic Symptoms (DRESS)/Drug-induced Hypersensitivity Syndrome (DIHS): a review of current concepts.
      • Fernando S.L.
      Drug-reaction eosinophilia and systemic symptoms and drug-induced hypersensitivity syndrome.
      • Tas S.
      • Simonart T.
      Drug rash with eosinophilia and systemic symptoms (DRESS syndrome).
      The focus of the articles varied, but they generally addressed management recommendations and risk factors. Treatment recommendations consistently included discontinuation of the causative agent, hospitalization for initial stabilization and monitoring, and use of corticosteroids, although evidence supporting corticosteroid treatment is limited and results have been inconsistent.
      • Husain Z.
      • Reddy B.Y.
      • Schwartz R.A.
      DRESS syndrome, part I: clinical perspectives.
      • Su H.H.
      • Hsu C.C.
      • Fang C.K.
      Suspected drug reaction with eosinophilia and systemic symptoms (DRESS) secondary to quetiapine in an elderly patient.
      Intravenous corticosteroid administration is recommended when organ damage is evident,
      • Chen Y-C.
      • Cho Y-T.
      • Chang C-Y.
      • Chu C-Y.
      Drug reaction with eosinophilia and systemic symptoms: a drug-induced hypersensitivity syndrome with variable clinical features.
      • Choudhary S.
      • McLeod M.
      • Torchia D.
      • Romanelli P.
      Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome.
      and other common treatment alternatives included IVIG, cyclosporine, and plasma exchange.
      • Chen Y.C.
      • Chiu H.C.
      • Chu C.Y.
      Drug reaction with eosinophilia and systemic symptoms: a retrospective study of 60 cases.
      • Jeung Y.J.
      • Lee J.Y.
      • Oh M.J.
      • Choi D.C.
      • Lee B.J.
      Comparison of the causes and clinical features of drug rash with eosinophilia and systemic symptoms and Stevens-Johnson syndrome.
      • Kano Y.
      • Shiohara T.
      The variable clinical picture of drug-induced hypersensitivity syndrome/drug rash with eosinophilia and systemic symptoms in relation to the eliciting drug.
      • Cacoub P.
      • Musette P.
      • Descamps V.
      • et al.
      The DRESS syndrome: a literature review.
      Table 2Review Articles on DRESS Associated With Psychotropic Drugs
      Reference, yearClinical recommendations
      Chan et al,
      • Chan J.C.
      • Chan H.H.L.
      • Yeung C.K.
      Drug reaction with eosinophilia and systemic symptoms (DRESS).
      2012
      Early identification and prompt withdrawal of the causative agent are key. Patients are hospitalized for careful monitoring. Exclusion of rare symptoms such as myositis, myocarditis, pneumonitis, and pancreatitis is important in DRESS. Moderate- to high-dose corticosteroids should be started in patients with internal organ involvement; most commonly, prednisolone (1 mg/kg/d) is initiated and then tapered over 6-8 wk to prevent relapse of organ involvement. Other treatments with reported success have included IV methylprednisolone, IVIG, and plasmapheresis. In corticosteroid-resistant cases, cyclosporine A and cyclophosphamide have been effective
      Choudhary et al,
      • Choudhary S.
      • McLeod M.
      • Torchia D.
      • Romanelli P.
      Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome.
      2013
      It has been reported that the earlier the drug withdrawal, the better the prognosis. Treatment is largely symptomatic. Corticosteroids are often used, but the evidence regarding their effectiveness is minimal
      Jeung et al,
      • Jeung Y.J.
      • Lee J.Y.
      • Oh M.J.
      • Choi D.C.
      • Lee B.J.
      Comparison of the causes and clinical features of drug rash with eosinophilia and systemic symptoms and Stevens-Johnson syndrome.
      2010
      Corticosteroids are the mainstay of treatment for DRESS, and favorable results have been reported, although the dosage varies widely across case reports. Primary and secondary prevention have key roles in the management of DRESS
      Roujeau et al,
      • Roujeau J.C.
      • Haddad C.
      • Paulmann M.
      • Mockenhaupt M.
      Management of nonimmediate hypersensitivity reactions to drugs.
      2014
      The authors outline the treatment of DRESS, and prompt withdrawal of the causative drug is the first step. They suggest avoiding introducing new medications during the course of DRESS because of the risk of DRESS flare-up associated with new medications. Hospitalization is suggested for severe cutaneous manifestations. Fluid and electrolyte replacement and nutritional support are required for those with exfoliative dermatitis, and a warm and humid environment with gentle skin care (eg, warm baths or wet dressings) are suggested. An expert consensus group in France proposed that patients can be treated symptomatically if they have no clinical, laboratory, or imaging evidence of renal or pulmonary involvement and only modest elevations of liver enzymes. Relief of pruritus and skin inflammation is obtained with high-potency topical corticosteroids, applied 1-3 times per day for 1-2 wk; this treatment should be sufficient for complete recovery in patients without severe organ involvement. For patients with organ involvement, use of systemic corticosteroids is very important. Although the optimal dose and duration of corticosteroid therapy is undetermined, an initial prednisone dose of 1-2 mg/kg/d or equivalent is common
      Walsh and Creamer,
      • Walsh S.A.
      • Creamer D.
      Drug reaction with eosinophilia and systemic symptoms (DRESS): a clinical update and review of current thinking.
      2011
      DRESS can be treated with moderate- or high-dose oral corticosteroids; however, response may be suboptimal. Cyclosporine and other immunosuppressants are sometimes required in corticosteroid-resistant cases. Variation in outcomes of DRESS highlights the need for a clinical tool to define disease severity. Prognostic markers are needed to aid stratification of patient cohorts benefitting from early intervention with potent treatment
      Verma et al,
      • Verma R.
      • Vasudevan B.
      • Pragasam V.
      Severe cutaneous adverse drug reactions.
      2013
      Oral prednisolone (1-2 mg/kg) is the treatment of choice and should be continued for 2-3 mo. VPA, benzodiazepine, and gabapentin are ideal replacements for drugs causing anticonvulsant hypersensitivity syndrome. Hematologic, hepatic, and renal parameters must be monitored. Supportive care with fluid and electrolyte balance is important. Topical corticosteroids and antihistamines are helpful for cutaneous manifestations. Patients should avoid the same or related drugs. First-degree relatives must be counseled about their increased risk. A lymphocyte toxicity assay can be performed for relatives to confirm increased susceptibility
      Husain et al,
      • Husain Z.
      • Reddy B.Y.
      • Schwartz R.A.
      DRESS syndrome, part I: clinical perspectives.
      2013
      HLA-A*3101 is associated with an increased risk of DRESS with exposure to CBZ. HLA-DR3 and HLA-DQ2 alleles also are associated with CBZ-induced DRESS
      Kano and Shiohara,
      • Kano Y.
      • Shiohara T.
      The variable clinical picture of drug-induced hypersensitivity syndrome/drug rash with eosinophilia and systemic symptoms in relation to the eliciting drug.
      2009
      This article reviews the drugs associated with DRESS and DHS and reviews the variable clinical presentations. Drugs include CBZ, PHT, PB, LTG, ALL, MNC, and DDS
      Cacoub et al,
      • Cacoub P.
      • Musette P.
      • Descamps V.
      • et al.
      The DRESS syndrome: a literature review.
      2011
      This article analyzed 172 cases of DRESS in a 12-year period; cases were identified by searching PubMed. All patients were hospitalized, and the causative agent was stopped. Main treatment was corticosteroids. IVIG was combined with corticosteroids in 10 cases, and the mean (SD) recovery time was 6.4 (9.4) wk. Death occurred in 9 cases (cardiac or hepatic causes). The patients with fatal DRESS generally were older than those who recovered from DRESS. A total of 44 unique causative medications were identified, with CBZ being the most common
      Criado et al,
      • Criado P.R.
      • Criado R.F.
      • Avancini J.M.
      • Santi C.G.
      Drug reaction with Eosinophilia and Systemic Symptoms (DRESS)/Drug-induced Hypersensitivity Syndrome (DIHS): a review of current concepts.
      2012
      Prognosis of DRESS is generally worse in the elderly, whereas recovery is often faster and complete in children. Treatment is usually systemic corticosteroids (prednisone or equivalent dose ≥1-1.5 mg/kg/d). Dose should be tapered slowly over 6-8 wk. Abrupt worsening of symptoms is observed when the withdrawal is accidental or with a rapid reduction in dose. They recommend hospitalizing all patients, even when the initial presentation is mild. If symptoms worsen, other options include pulsed methylprednisolone (30 mg/kg IV for 3 d), IVIG, plasmapheresis, or a combination of these treatments. Special attention should be paid to possible reactivation of cytomegalovirus
      Fernando,
      • Fernando S.L.
      Drug-reaction eosinophilia and systemic symptoms and drug-induced hypersensitivity syndrome.
      2014
      Treatment with oral corticosteroids (1 mg/kg/d) tapered over 6-8 wk to prevent symptom relapse is recommended. If symptoms worsen, IVIG, plasma exchange, rituximab, valganciclovir, or a combination of these treatments can be considered
      Tas and Simonart,
      • Tas S.
      • Simonart T.
      Drug rash with eosinophilia and systemic symptoms (DRESS syndrome).
      1999
      The only undisputed treatment for DRESS at the time is prompt withdrawal of the causative agent. Corticosteroid treatment is controversial. The authors suggest the potential benefit of N-acetylcysteine. They report treating 2 patients with N-acetylcysteine, but therapy was interrupted because of the development of facial edema with unknown cause
      ALL = allopurinol; CBZ = carbamazepine; DDS = dapsone; DHS = drug-induced hypersensitivity syndrome; DRESS = drug rash with eosinophilia and systemic symptoms; IV = intravenous; IVIG = intravenous immunoglobulin; LTG = lamotrigine; MNC = minocycline; PB = phenobarbital; PHT = phenytoin; VPA = valproate.
      The causative agent identified most commonly in the review articles was CBZ.
      • Verma R.
      • Vasudevan B.
      • Pragasam V.
      Severe cutaneous adverse drug reactions.
      • Husain Z.
      • Reddy B.Y.
      • Schwartz R.A.
      DRESS syndrome, part I: clinical perspectives.
      The genomic allele HLA-A*3101 was identified as a risk factor for DRESS when CBZ is used.
      • Walsh S.A.
      • Creamer D.
      Drug reaction with eosinophilia and systemic symptoms (DRESS): a clinical update and review of current thinking.
      Another risk factor for DRESS development was a fever preceding cutaneous eruptions.
      • Walsh S.A.
      • Creamer D.
      Drug reaction with eosinophilia and systemic symptoms (DRESS): a clinical update and review of current thinking.
      Prognosis was poor for elderly patients, whereas a more rapid and complete recovery generally was seen in children.
      • Kano Y.
      • Shiohara T.
      The variable clinical picture of drug-induced hypersensitivity syndrome/drug rash with eosinophilia and systemic symptoms in relation to the eliciting drug.
      Counseling first-degree relatives about their increased risk,
      • Roujeau J-C.
      • Allanore L.
      • Liss Y.
      • Mockenhaupt M.
      Severe cutaneous adverse reactions to drugs (SCAR): definitions, diagnostic criteria, genetic predisposition.
      avoidance of new medication during management of DRESS,
      • Choudhary S.
      • McLeod M.
      • Torchia D.
      • Romanelli P.
      Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome.
      and use of alternative medications with lower risk
      • Roujeau J-C.
      • Allanore L.
      • Liss Y.
      • Mockenhaupt M.
      Severe cutaneous adverse reactions to drugs (SCAR): definitions, diagnostic criteria, genetic predisposition.
      were additional notable recommendations.

      Case Reports

      We identified 55 case reports of DRESS that described 75 patients (56 adults, 19 children and adolescents). The reports are summarized in the Supplemental Table (available online at http://www.mayoclinicproceedings.org).
      • López-Rocha E.
      • Blancas L.
      • Rodríguez-Mireles K.
      • et al.
      Prevalence of DRESS syndrome.
      • Laban E.
      • Hainaut-Wierzbicka E.
      • Pourreau F.
      • et al.
      Cyclophosphamide therapy for corticoresistant drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome in a patient with severe kidney and eye involvement and Epstein-Barr virus reactivation.
      • Iacob S.A.
      • Sotropa A.
      DRESS syndrome with hepatic involvement in a patient with depressive disorder.
      • Alexander T.
      • Iglesia E.
      • Park Y.
      • et al.
      Severe DRESS syndrome managed with therapeutic plasma exchange.
      • Bagshaw S.M.
      • Cload B.
      • Gilmour J.
      • Leung S.T.
      • Bowen T.J.
      Drug-induced rash with eosinophilia and systemic symptoms syndrome with bupropion administration.
      • Eppenberger M.
      • Hack D.
      • Ammann P.
      • Rickli H.
      • Maeder M.T.
      Acute eosinophilic myocarditis with dramatic response to steroid therapy: the central role of echocardiography in diagnosis and follow-up.
      • Aouam K.
      • Bel Hadj Ali H.
      • Youssef M.
      • et al.
      Carbamazepine-induced DRESS and HHV6 primary infection: the importance of skin tests.
      • Bakker C.V.
      • Hegt V.N.
      • Praag M.C.
      Lamotrigine hypersensitivity syndrome and spiking fever.
      • Bamanikar A.
      • Dhobale S.
      • Lokwani S.
      Pregabalin hypersensitivity in a patient treated for postherpetic neuralgia.
      • Didenko I.
      • Ferreira F.
      • Tomaz E.
      • Salgado M.
      • de Sousa A.V.
      • Inacio F.
      Carbamazepine-induced DRESS/DIHS: case report.
      • Ginory A.
      • Chaney-Catchpole M.
      • Demetree J.M.
      • Mayol Sabatier L.M.
      • Nguyen M.
      Drug reaction with eosinophilia and systemic symptoms (DRESS) in an adolescent treated with lamotrigine.
      • Oelze L.L.
      • Pillow M.T.
      Phenytoin-induced drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome: a case report from the emergency department.
      • Özaydin E.
      • Çayir A.
      • Gürler T.
      • Cengizlier R.
      • Köse G.
      • Vidinlisan S.
      Lamotrigine-induced hypersensitivity syndrome: case report.
      • Roquin G.
      • Peres M.
      • Lerolle N.
      • et al.
      First report of lamotrigine-induced drug rash with eosinophilia and systemic symptoms syndrome with pancreatitis.
      • Teng P.
      • Tan B.
      Carbamazepine-induced DRESS syndrome in a child: rapid response to pulsed corticosteroids.
      • Turcu G.
      • Ioana N.R.
      • Forsea D.
      Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) caused by lamotrigine: a case report and brief review.
      • Albayrak F.
      • Cerrah S.
      • Albayrak A.
      • Dursun H.
      • Yildirim R.
      • Uyanik A.
      DRESS syndrome with fatal results induced by sodium valproate in a patient with brucellosis and a positive cytoplasmic antineutrophilic cytoplasmic antibody test result.
      • Bourgeois G.P.
      • Cafardi J.A.
      • Groysman V.
      • et al.
      Fulminant myocarditis as a late sequela of DRESS: two cases.
      • Do-Pham G.
      • Charachon A.
      • Duong T.A.
      • et al.
      Drug reaction with eosinophilia and systemic symptoms and severe involvement of digestive tract: description of two cases.
      • Fsadni C.
      • Fsadni P.
      • Piscopo T.
      • Mallia Azzopardi C.
      Carbamazepine-induced drug reaction with eosinophilia and systemic symptoms syndrome in a 35-year-old man with epilepsy.
      • Ganeva M.
      • Gancheva T.
      • Lazarova R.
      • et al.
      Carbamazepine-induced drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome: report of four cases and brief review.
      • Halink D.A.
      • Marijnissen R.M.
      • Schut A.A.
      • Oude Voshaar R.C.
      Drug reaction with eosinophilia and systemic symptoms induced by carbamazepine: DRESSed to kill.
      • Kim C.W.
      • Choi G.S.
      • Yun C.H.
      • Kim D.I.
      Drug hypersensitivity to previously tolerated phenytoin by carbamazepine-induced DRESS syndrome.
      • Kocaoglu C.
      • Cilasun C.
      • Solak E.S.
      • Kurtipek G.S.
      • Arslan S.
      Successful treatment of antiepileptic drug-induced DRESS syndrome with pulse methylprednisolone.
      • Lo M.H.
      • Huang C.F.
      • Chang L.S.
      • et al.
      Drug reaction with eosinophilia and systemic symptoms syndrome associated myocarditis: a survival experience after extracorporeal membrane oxygenation support.
      • Mehta M.
      • Shah J.
      • Khakhkhar T.
      • Shah R.
      • Hemavathi K.G.
      Anticonvulsant hypersensitivity syndrome associated with carbamazepine administration: case series.
      • Mendiratta V.
      • Bhushan P.
      Phenytoin-induced DRESS with cross-reactivity to carbamazepine in a 10-year-old Indian child.
      • El Omairi N.
      • Abourazzak S.
      • Chaouki S.
      • Atmani S.
      • Hida M.
      Drug Reaction with Eosinophilia and Systemic Symptom (DRESS) induced by carbamazepine: a case report and literature review.
      • El Omairi N.
      • Abourazzak S.
      • Chaouki S.
      • Atmani S.
      • Hida M.
      Drug Reaction with Eosinophilia and Systemic Symptom (DRESS) induced by carbamazepine: a case report and literature review.
      • Brizendine C.E.
      • Naik P.J.
      Drug rash with eosinophilia and systemic symptoms syndrome associated with use of phenytoin, divalproex sodium, and phenobarbital.

      Gupta A, Srivastava VK, Rizvi I, Aziz A. DRESS syndrome. BMJ Case Rep. doi:10.1136/bcr-03-2012-6128.

      • Matsuda H.
      • Saito K.
      • Takayanagi Y.
      • et al.
      Pustular-type drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms due to carbamazepine with systemic muscle involvement.
      • Neri I.
      • Virdi A.
      • Piccolo V.
      • Patrizi A.
      Drug rash with eosinophilia and systemic symptoms (DRESS) due to lamotrigine in a 12-year-old girl.
      • Saha S.
      • Sengupta M.
      A rare cause of eosinophilia-anticonvulsant hypersensitivity syndrome.
      • Seth D.
      • Kamat D.
      • Montejo J.
      DRESS syndrome: a practical approach for primary care practitioners.
      • Singer E.M.
      • Wanat K.A.
      • Rosenbach M.A.
      A case of recalcitrant DRESS syndrome with multiple autoimmune sequelae treated with intravenous immunoglobulins.
      • Swanson E.A.
      • Low L.
      • Naini B.V.
      Severe enterocolitis associated with antiepileptic-induced drug reaction with eosinophilia and systemic symptoms.
      • Valencak J.
      • Ortiz-Urda S.
      • Heere-Ress E.
      • Kunstfeld R.
      • Base W.
      Carbamazepine-induced DRESS syndrome with recurrent fever and exanthema.
      • Suzuki Y.
      • Fukuda M.
      • Tohyama M.
      • Ishikawa M.
      • Yasukawa M.
      • Ishii E.
      Carbamazepine-induced drug-induced hypersensitivity syndrome in a 14-year-old Japanese boy.
      • Syn W.K.
      • Naisbitt D.J.
      • Holt A.P.
      • Pirmohamed M.
      • Mutimer D.J.
      Carbamazepine-induced acute liver failure as part of the DRESS syndrome.
      • Anjum N.
      • Polak M.E.
      • Ardern-Jones M.
      • Cooper H.L.
      Presence of the HLA-A*3101 allele in a familial case of drug reaction with eosinophilia and systemic symptoms, secondary to carbamazepine.
      • Aplyn M.
      Rash, organ dysfunction, and eosinophiles: it is a DRESS.
      • Ben Salem C.
      • Slim R.
      • Denguezli M.
      • Nouira R.
      • Hmouda H.
      • Bouraoui K.
      A recurrent drug rash with eosinophilia and systemic symptoms.
      • Bonaci-Nikolic B.
      • Jeremic I.
      • Nikolic M.
      • Andrejevic S.
      • Lavadinovic L.
      High procalcitonin in a patient with drug hypersensitivity syndrome.
      • Chang J.Y.
      • Kim S.C.
      Anticonvulsant hypersensitivity syndrome associated with Epstein-Barr virus reactivation.
      • Naveen K.N.
      • Ravindra M.S.
      • Pai V.V.
      • Rai V.
      • Athanikar S.B.
      • Girish M.
      Lamotrigine induced DRESS syndrome.
      • Gordon J.S.
      • Neyman K.M.
      • Wells R.D.
      • Chen S.C.
      Drug rash with eosinophilia and systemic symptoms (DRESS syndrome).
      • Kang S.Y.
      • Kim J.Y.
      • Kim M.Y.
      • et al.
      Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms syndrome induced by cilostazol and carbamazepine.
      • Allam J.P.
      • Paus T.
      • Reichel C.
      • Bieber T.
      • Novak N.
      DRESS syndrome associated with carbamazepine and phenytoin.
      • Cornell S.L.
      • DiBlasi D.
      • Arora N.S.
      Drug reaction with eosinophilia and systemic symptoms: DRESS following initiation of oxcarbazepine with elevated human herpesvirus-6 titer.
      • Yun S.J.
      • Lee J.B.
      • Kim E.J.
      • et al.
      Drug rash with eosinophilia and systemic symptoms induced by valproate and carbamazepine: formation of circulating auto-antibody against 190-kDa antigen.
      • D'Orazio J.L.
      Oxcarbazepine-induced Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS).
      • Bicknell L.T.
      • Sanches M.
      • Schatte D.J.
      Erythema multiforme vs. DRESS syndrome associated with the combined use of lamotrigine and cyclobenzaprine: a case report.
      • Amante M.F.
      • Filippini A.V.
      • Cejas N.
      • Lendoire J.
      • Imventarza O.
      • Parisi C.
      DRESS syndrome and fulminant hepatic failure induced by lamotrigine.
      • Chauhan A.
      • Anand S.
      • Thomas S.
      • Subramanya H.C.
      • Pradhan G.
      Carbamazepine induced DRESS syndrome.
      • Gaig P.
      • García-Ortega P.
      • Baltasar M.
      • Bartra J.
      Drug neosensitization during anticonvulsant hypersensitivity syndrome.
      Implicated drugs included CBZ (n=33), LTG (n=17), PHT (n=12), VPA (n=7), PB (n=4), and oxcarbazepine (n=2). Medications unlikely to provoke DRESS included armodafinil, bupropion, penicillin, clonazepam, ibuprofen, and ziprasidone (ZIP), with some of these medications given in combination with anticonvulsants. The time to presentation of symptoms ranged from 7 to 120 days (plus an outlier of 2 years); the mean was 35.6 days, and the median was 21 days. Myocarditis was a frequent symptom in late presentations of DRESS. Among the 252 symptoms noted, fever was most common (n=38), followed by maculopapular rash (n=32), elevated liver enzyme levels (n=32), lymphadenopathy (n=22), facial edema (n=16), and eosinophilia (n=16). Discontinuation of medication and corticosteroid use were the most common treatment approaches.

      Letters to the Editor

      We identified only 4 letters to the editor describing DRESS: implicated medications were quetiapine (n=1), VPA (n=1), and CBZ (n=2; one case was in combination with cilostazol).

      Discussion

      This systematic review underscores the vast amount of literature implicating psychotropic medication in the development of DRESS syndrome. Among psychotropic medications, anticonvulsants appeared to be most commonly associated with DRESS. Our review identified 1072 cases of psychotropic drug–induced DRESS, with CBZ, LTG, PHT, VPA, and PB being the most implicated drugs. However, we found very few reports linking antidepressants, anxiolytics, antipsychotics, and sedatives or hypnotics to DRESS syndrome. As DRESS gains greater recognition, we predict an increase in reports involving other psychotropic agents. A summary of evaluation and management recommendations for psychotropic drug–induced DRESS syndrome is presented in Table 3.
      Table 3Summary of Evaluation and Management Recommendations for Psychotropic Drug–Induced DRESS Syndrome
      Adapted from J Am Acad Dermatol,
      • Husain Z.
      • Reddy B.Y.
      • Schwartz R.A.
      DRESS syndrome, part II: management and therapeutics.
      with permission.
      • 1.
        Immediate withdrawal of the implicated drug through careful history taking
      • 2.
        If indicated, hospitalization for fluid and electrolyte replacement, skin care, and nutritional supplementation
      • 3.
        Evaluation with laboratory tests and imaging studies to assess internal organ involvement: complete blood count, 24-hour urine protein and eosinophil count, blood glucose, calcium, parathyroid hormone, C-reactive protein, lactate dehydrogenase, creatine phosphokinase, ferritin, quantitative polymerase chain reaction for human herpesvirus 6 and 7, Epstein-Barr virus and cytomegalovirus, triglycerides, blood cultures
        • a.
          Hepatic: liver function tests, partial thromboplastin time/prothrombin time/international normalized ratio, hepatitis panel
        • b.
          Cardiac: electrocardiography, echocardiography, cardiac enzymes
        • c.
          Pulmonary: chest radiography, pulmonary function tests
        • d.
          Renal: creatinine, serum urea nitrogen, urinalysis, renal ultrasonography
        • e.
          Endocrine: thyroid-stimulating hormone/thyroxine (T4)
        • f.
          Gastrointestinal: lipase level
        • g.
          Neurologic: head computed tomography or magnetic resonance imaging, electroencephalography, cerebrospinal fluid analysis
      • 4.
        For patients without clinical, laboratory, or imaging evidence of internal organ involvement and only modestly elevated liver enzyme levels, no further treatment is necessary
      • 5.
        If any of the measures in step 4 are present, prednisone (1-1.5 mg/kg/d or its equivalent) is recommended (see Table 4 for specific dosing information)
      • 6.
        If improvement is not seen with corticosteroids, several studies have found efficacy with intravenous immunoglobulin or plasma exchange; other treatment options include cyclophosphamide, cyclosporine, and immunosuppressants (see Table 4 for specific dosing information)
      DRESS = drug rash with eosinophilia and systemic symptoms.
      Clinicians should continue to report new cases to regulatory bodies and submit cases for publication because these activities ultimately increase patient safety. Recently, the US Food and Drug Administration (FDA) reexamined ZIP, a second-generation antipsychotic medication, because the FDA Adverse Event Reporting System had received 6 cases of ZIP-associated DRESS. The onset of DRESS ranged from 11 days to 1 month after initiating ZIP. Three cases were rechallenged with ZIP, and DRESS recurred in a shorter period compared with the initial presentation of DRESS. No deaths were reported, but several cases had serious outcomes necessitating hospitalization. The prescribing information for ZIP now highlights a risk of DRESS.
      Even with the extensive literature on psychotropic drug–induced DRESS syndrome and its clinical features, management guidelines and recommendations vary and are poorly established. Because mortality rates for DRESS of up to 20% have been reported,
      • Botelho L.F.
      • Higashi V.S.
      • Padilha M.H.
      • Enokihara M.M.
      • Porro A.M.
      DRESS: clinicopathological features of 10 cases from an university hospital in São Paulo.
      it is important to establish evidence-based diagnostic and treatment principles, including the management of comorbid psychiatric illness during and after the development of DRESS syndrome.
      Based on our review of the literature, prompt diagnosis of DRESS is highly dependent on clinical suspicion because its presentation varies and often is nonspecific. In the case reports, the time from drug initiation to presentation of symptoms ranged from 7 to 120 days (mean, 35.6 days), and common clinical features included maculopapular rash, elevated liver enzyme levels, lymphadenopathy, facial edema, and eosinophilia. The differential diagnosis of suspected DRESS should include Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis, acute generalized exanthematous pustulosis, hypereosinophilic syndromes, angioimmunoblastic T-cell lymphoma, Sézary syndrome, and cutaneous lupus erythematosus.

      Roujeau JC. Drug reaction with eosinophilia and systemic symptoms (DRESS). UpToDate website. http://www.uptodate.com/contents/drug-reaction-with-eosinophilia-and-systemic-symptoms-dress. Updated September 30, 2015. Accessed December 14, 2015.

      Clinical suspicion of DRESS should be augmented by a thorough history of exposure to high-risk drugs in the previous 6 months,
      • Oelze L.L.
      • Pillow M.T.
      Phenytoin-induced drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome: a case report from the emergency department.
      laboratory and imaging studies to determine internal organ involvement, and a skin biopsy.

      Roujeau JC. Drug reaction with eosinophilia and systemic symptoms (DRESS). UpToDate website. http://www.uptodate.com/contents/drug-reaction-with-eosinophilia-and-systemic-symptoms-dress. Updated September 30, 2015. Accessed December 14, 2015.

      Skin tests (patch and prick) can be important and useful in diagnosing DRESS.
      • Aouam K.
      • Bel Hadj Ali H.
      • Youssef M.
      • et al.
      Carbamazepine-induced DRESS and HHV6 primary infection: the importance of skin tests.
      The lymphocyte transformation test also has diagnostic utility (reported sensitivity, 60%-70%; specificity, 85%). This test has better diagnostic value than the patch test and should be performed 5 to 8 weeks after the onset of DRESS.
      • López-Rocha E.
      • Blancas L.
      • Rodríguez-Mireles K.
      • et al.
      Prevalence of DRESS syndrome.
      Importantly, the clinical utility of patch tests and the lymphocyte transformation test are limited because these tests are not widely used and often are informative only if the test result is positive.
      • Husain Z.
      • Reddy B.Y.
      • Schwartz R.A.
      DRESS syndrome, part II: management and therapeutics.
      Treatment should begin with the prompt withdrawal of the causative drug because the prognosis is better with earlier cessation.
      • Choudhary S.
      • McLeod M.
      • Torchia D.
      • Romanelli P.
      Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome.
      The best management practices after withdrawal are still controversial. Recommendations from the literature include hospitalization for continued monitoring and supportive treatment with fluid and electrolyte replacement and nutritional support. A warm and humid environment with gentle skin care (eg, warm baths or wet dressings) also is recommended.
      • Roujeau J.C.
      • Haddad C.
      • Paulmann M.
      • Mockenhaupt M.
      Management of nonimmediate hypersensitivity reactions to drugs.
      For patients without clinical, laboratory, or imaging evidence of internal organ involvement and only modestly elevated liver enzyme levels, no further treatment is necessary.
      • Roujeau J.C.
      • Haddad C.
      • Paulmann M.
      • Mockenhaupt M.
      Management of nonimmediate hypersensitivity reactions to drugs.
      However, if any of these measures are present, prednisone (1-1.5 mg/kg per day or its equivalent) is recommended.
      • López-Rocha E.
      • Blancas L.
      • Rodríguez-Mireles K.
      • et al.
      Prevalence of DRESS syndrome.
      Some prefer administering pulsed corticosteroid therapy over conventional oral doses because liver function returns to normal in a shorter time with pulsed corticosteroids.
      • Kocaoglu C.
      • Cilasun C.
      • Solak E.S.
      • Kurtipek G.S.
      • Arslan S.
      Successful treatment of antiepileptic drug-induced DRESS syndrome with pulse methylprednisolone.
      The use of corticosteroids in the treatment of DRESS has been debated because evidence is limited and results have been inconsistent
      • Husain Z.
      • Reddy B.Y.
      • Schwartz R.A.
      DRESS syndrome, part I: clinical perspectives.
      • Su H.H.
      • Hsu C.C.
      • Fang C.K.
      Suspected drug reaction with eosinophilia and systemic symptoms (DRESS) secondary to quetiapine in an elderly patient.
      ; however, the literature predominantly recommends either oral dosing or pulsed therapy, especially for patients with internal organ involvement.
      • Chen Y-C.
      • Cho Y-T.
      • Chang C-Y.
      • Chu C-Y.
      Drug reaction with eosinophilia and systemic symptoms: a drug-induced hypersensitivity syndrome with variable clinical features.
      • Choudhary S.
      • McLeod M.
      • Torchia D.
      • Romanelli P.
      Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome.
      Next, if improvement is not seen with corticosteroids, several investigators have reported efficacy with IVIG or plasma exchange.
      • El Omairi N.
      • Abourazzak S.
      • Chaouki S.
      • Atmani S.
      • Hida M.
      Drug Reaction with Eosinophilia and Systemic Symptom (DRESS) induced by carbamazepine: a case report and literature review.
      • Singer E.M.
      • Wanat K.A.
      • Rosenbach M.A.
      A case of recalcitrant DRESS syndrome with multiple autoimmune sequelae treated with intravenous immunoglobulins.
      Other treatment options for the management of corticosteroid-resistant DRESS that have been used with some success include cyclophosphamide, cyclosporine, and immunosuppressants.
      • López-Rocha E.
      • Blancas L.
      • Rodríguez-Mireles K.
      • et al.
      Prevalence of DRESS syndrome.
      • Syn W.K.
      • Naisbitt D.J.
      • Holt A.P.
      • Pirmohamed M.
      • Mutimer D.J.
      Carbamazepine-induced acute liver failure as part of the DRESS syndrome.
      Suggested dosing strategies for these treatments are included in Table 4.
      • Laban E.
      • Hainaut-Wierzbicka E.
      • Pourreau F.
      • et al.
      Cyclophosphamide therapy for corticoresistant drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome in a patient with severe kidney and eye involvement and Epstein-Barr virus reactivation.
      • Singer E.M.
      • Wanat K.A.
      • Rosenbach M.A.
      A case of recalcitrant DRESS syndrome with multiple autoimmune sequelae treated with intravenous immunoglobulins.
      • Husain Z.
      • Reddy B.Y.
      • Schwartz R.A.
      DRESS syndrome, part II: management and therapeutics.
      • Spriet S.
      • Banks T.A.
      Drug reaction with eosinophilia and systemic symptoms syndrome.
      • Joly P.
      • Janela B.
      • Tetart F.
      • et al.
      Poor benefit/risk balance of intravenous immunoglobulins in DRESS.
      • Zuliani E.
      • Zwahlen H.
      • Gilliet F.
      • Marone C.
      Vancomycin-induced hypersensitivity reaction with acute renal failure: resolution following cyclosporine treatment.
      • Bourgeois G.P.
      • Cafardi J.A.
      • Hughey L.C.
      • Groysman V.
      Fulminant myocarditis as a late sequelae of DRESS syndrome.
      • Mortezavi M.
      • Lomas J.M.
      • Looney R.J.
      Treatment of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) with mycophenolate mofetil as a steroid-sparing agent.
      • Shaughnessy K.K.
      • Bouchard S.M.
      • Mohr M.R.
      • Herre J.M.
      • Salkey K.S.
      Minocycline-induced drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome with persistent myocarditis.
      Table 4Pharmacotherapeutic Options for Drug Rash With Eosinophilia and Systemic Symptoms
      AgentExample dosingComment
      Corticosteroids(1) Prednisone or equivalent (1-1.5 mg/kg/d)

      (2) Methylprednisolone, 30 mg/kg intravenously for 3 d, if no improvement with oral corticosteroids or in severe cases
      • Husain Z.
      • Reddy B.Y.
      • Schwartz R.A.
      DRESS syndrome, part II: management and therapeutics.
      Oral corticosteroids are tapered over 3-6 mo
      Intravenous immunoglobulin(1) 0.5 g/kg/d for 2 consecutive days every month as a corticosteroid-sparing agent
      • Singer E.M.
      • Wanat K.A.
      • Rosenbach M.A.
      A case of recalcitrant DRESS syndrome with multiple autoimmune sequelae treated with intravenous immunoglobulins.


      (2) 2 g/kg divided over 5 d in severe, life-threatening cases
      • Spriet S.
      • Banks T.A.
      Drug reaction with eosinophilia and systemic symptoms syndrome.
      Poor tolerability and minimal benefit reported in a small, open-label study (n=10)
      • Joly P.
      • Janela B.
      • Tetart F.
      • et al.
      Poor benefit/risk balance of intravenous immunoglobulins in DRESS.


      Should be used in conjunction with corticosteroids, not as monotherapy
      Cyclophosphamide750 mg/m2 intravenously once; approximately 2 wk later, begin 100 mg orally daily for 6 mo
      • Laban E.
      • Hainaut-Wierzbicka E.
      • Pourreau F.
      • et al.
      Cyclophosphamide therapy for corticoresistant drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome in a patient with severe kidney and eye involvement and Epstein-Barr virus reactivation.
      Limited to individual reports
      Cyclosporine100 mg twice daily for 5 d
      • Zuliani E.
      • Zwahlen H.
      • Gilliet F.
      • Marone C.
      Vancomycin-induced hypersensitivity reaction with acute renal failure: resolution following cyclosporine treatment.
      • Bourgeois G.P.
      • Cafardi J.A.
      • Hughey L.C.
      • Groysman V.
      Fulminant myocarditis as a late sequelae of DRESS syndrome.
      Used after corticosteroid failure and taper
      • Zuliani E.
      • Zwahlen H.
      • Gilliet F.
      • Marone C.
      Vancomycin-induced hypersensitivity reaction with acute renal failure: resolution following cyclosporine treatment.
      Topical corticosteroids, H1 receptor antagonists, emollientsVariousRecommended for symptom control only if the patient has no systemic symptoms
      • Husain Z.
      • Reddy B.Y.
      • Schwartz R.A.
      DRESS syndrome, part II: management and therapeutics.
      AntiviralsVariousFor patients with evidence of viral reactivation

      Give in addition to corticosteroids, with or without intravenous immunoglobulin
      • Husain Z.
      • Reddy B.Y.
      • Schwartz R.A.
      DRESS syndrome, part II: management and therapeutics.
      Mycophenolate mofetil500-1500 mg twice daily
      • Bourgeois G.P.
      • Cafardi J.A.
      • Hughey L.C.
      • Groysman V.
      Fulminant myocarditis as a late sequelae of DRESS syndrome.
      • Mortezavi M.
      • Lomas J.M.
      • Looney R.J.
      Treatment of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) with mycophenolate mofetil as a steroid-sparing agent.
      • Shaughnessy K.K.
      • Bouchard S.M.
      • Mohr M.R.
      • Herre J.M.
      • Salkey K.S.
      Minocycline-induced drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome with persistent myocarditis.
      Corticosteroid-sparing agent; use for up to 1 y
      • Bourgeois G.P.
      • Cafardi J.A.
      • Hughey L.C.
      • Groysman V.
      Fulminant myocarditis as a late sequelae of DRESS syndrome.
      RituximabA 1-mo course of weekly rituximab
      • Shaughnessy K.K.
      • Bouchard S.M.
      • Mohr M.R.
      • Herre J.M.
      • Salkey K.S.
      Minocycline-induced drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome with persistent myocarditis.
      Dose not provided in report
      • Shaughnessy K.K.
      • Bouchard S.M.
      • Mohr M.R.
      • Herre J.M.
      • Salkey K.S.
      Minocycline-induced drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome with persistent myocarditis.
      As with other similar drug-induced inflammatory reactions, prevention is the most important management strategy. When starting a new psychotropic medication, especially aromatic anticonvulsants (eg, CBZ, PHT, PB, and LTG) and nonaromatic anticonvulsants (eg, VPA, topiramate, and gabapentin), it is important to obtain a thorough family history of prior drug reactions because a positive history is a major risk factor.
      • Anjum N.
      • Polak M.E.
      • Ardern-Jones M.
      • Cooper H.L.
      Presence of the HLA-A*3101 allele in a familial case of drug reaction with eosinophilia and systemic symptoms, secondary to carbamazepine.
      • van Zoelen M.A.
      • de Graaf M.
      • van Dijk M.R.
      • et al.
      Valproic acid-induced DRESS syndrome with acute liver failure.
      A lymphocyte toxicity assay can be offered to relatives to confirm increased susceptibility.
      • Verma R.
      • Vasudevan B.
      • Pragasam V.
      Severe cutaneous adverse drug reactions.
      Other risk factors for the development of DRESS include the genomic allele HLA-A*3101 and a personal history of drug-induced cutaneous eruptions.
      • Walsh S.A.
      • Creamer D.
      Drug reaction with eosinophilia and systemic symptoms (DRESS): a clinical update and review of current thinking.
      • Anjum N.
      • Polak M.E.
      • Ardern-Jones M.
      • Cooper H.L.
      Presence of the HLA-A*3101 allele in a familial case of drug reaction with eosinophilia and systemic symptoms, secondary to carbamazepine.
      Cross-reactivity within aromatic and nonaromatic anticonvulsants is particularly relevant in DRESS because cross-reactivity may be as high as 70% to 80%, respectively.
      • Ginory A.
      • Chaney-Catchpole M.
      • Demetree J.M.
      • Mayol Sabatier L.M.
      • Nguyen M.
      Drug reaction with eosinophilia and systemic symptoms (DRESS) in an adolescent treated with lamotrigine.
      • Aouam K.
      • Ben Romdhane F.
      • Loussaief C.
      • et al.
      Hypersensitivity syndrome induced by anticonvulsants: possible cross-reactivity between carbamazepine and lamotrigine.
      Significant cross-reactivity has been observed between CBZ and PHT
      • Fsadni C.
      • Fsadni P.
      • Piscopo T.
      • Mallia Azzopardi C.
      Carbamazepine-induced drug reaction with eosinophilia and systemic symptoms syndrome in a 35-year-old man with epilepsy.
      and between LTG and VPA.
      • Özaydin E.
      • Çayir A.
      • Gürler T.
      • Cengizlier R.
      • Köse G.
      • Vidinlisan S.
      Lamotrigine-induced hypersensitivity syndrome: case report.
      The anticonvulsants VPA and LTG are FDA approved for the treatment of bipolar disorder, whereas CBZ is used off-label for bipolar disorder. Psychiatric clinicians are likely more familiar with SJS, another severe cutaneous hypersensitivity reaction that is in the differential diagnosis of DRESS, than they are with DRESS because the FDA has posted black box warnings for SJS with CBZ use and because of clinical awareness of SJS with LTG use. For CBZ, the HLA-B*1502 genetic test can be performed to assess risk of SJS, especially in patients of Asian descent.
      Besides the clinical outcomes and considerable morbidity related to psychotropic drug–induced DRESS, management of the comorbid psychiatric illness is an important consideration. As part of the management of DRESS, strict avoidance of the implicated drug and other drugs of the same class (eg, aromatic or nonaromatic anticonvulsant) is recommended. Physicians should find a replacement drug that is well tolerated and efficacious. Valproate, which is FDA approved for bipolar mania, is an ideal replacement for patients with CBZ-induced DRESS.
      • Ganeva M.
      • Gancheva T.
      • Lazarova R.
      • et al.
      Carbamazepine-induced drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome: report of four cases and brief review.
      Several atypical antipsychotics are FDA approved for the treatment of bipolar disorder and can be considered, when appropriate, as alternatives to anticonvulsants. Finally, case studies have found that DRESS can develop in response to a previously tolerated medication after DRESS is induced by a different medication.
      • Kim C.W.
      • Choi G.S.
      • Yun C.H.
      • Kim D.I.
      Drug hypersensitivity to previously tolerated phenytoin by carbamazepine-induced DRESS syndrome.
      Patients should be monitored and observed after the administration of a replacement drug to avoid the subsequent recurrence of DRESS.
      The present study has several limitations. First, we identified only a relatively small number of studies describing psychotropic drug–induced DRESS. Second, the studies included in this systematic review had considerable heterogeneity with regard to variability in psychiatric comorbidities, indications for psychotropic use, patient inclusion criteria, outcome measures, and concurrent medications. Third, most of the literature on DRESS syndrome describes anticonvulsants being used to treat epileptic conditions. Although we attempted to screen for literature that dealt specifically with psychotropic drug–induced DRESS, some studies may have included patients receiving medications to treat nonpsychiatric illnesses.

      Conclusion

      DRESS is a severe cutaneous eruption that typically presents within 1 or 2 months of drug initiation. Common clinical features include maculopapular rash, elevated liver enzyme levels, lymphadenopathy, facial edema, and eosinophilia. Common psychotropic medications that have been implicated in this reaction are CBZ, LTG, PHT, VPA, and PB. Several case reports in the literature describe various approaches to management, the cornerstones of which are prompt withdrawal of the implicated drug and administration of corticosteroids. For cases of corticosteroid-resistant DRESS, IVIG, cyclophosphamide, cyclosporine, and immunosuppressants have had efficacy. Management of comorbid psychiatric illness includes strict avoidance of the implicated drug and other drugs in the same class (eg, aromatic, nonaromatic) and identification of a replacement drug (eg, VPA for CBZ-induced DRESS).

      Acknowledgments

      We thank Ms Ann M. Farrell for her work in conducting a literature review on psychotropic drug–induced DRESS syndrome.

      Supplemental Online Material

      Supplemental Online Material

      Supplemental material can be found online at: http://www.mayoclinicproceedings.org. Supplemental material attached to journal articles has not been edited, and the authors take responsibility for the accuracy of all data.

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