A case of steroid-induced mania following lamotrigine-induced drug reaction with eosinophilia and systemic symptoms (DRESS): a cautionary tale

Abstract

Drug reaction with eosinophilia and systemic symptoms is a severe cutaneous adverse reaction frequently associated with lamotrigine, an antiepileptic drug also used to treat bipolar disorder. Although a mainstay of therapy for drug reaction with eosinophilia and systemic symptoms is oral corticosteroids, steroids should be used with caution in patients with bipolar disorder, as mania is a well-known drug side effect. We present a case of a 21-year-old female patient with bipolar disorder who was treated with prednisone for lamotrigine-induced drug reaction with eosinophilia and systemic symptoms, and subsequently experienced steroid-induced mania, exacerbated by an unopposed antidepressant medication. This resulted in involuntary hospital admission under psychiatry, which was profoundly distressing for the patient. We present this case as a reminder to screen for risk of mania in patients receiving systemic corticosteroids, and to carefully assess concurrent antidepressant use when discontinuing mood stabilizers like lamotrigine.

Introduction

Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe cutaneous adverse reaction that manifests as fever, morbilliform eruption, facial edema, lymphadenopathy, and organ involvement. ¹ One of the most frequently implicated medications associated with DRESS is lamotrigine, an antiepileptic drug also used as a mood stabilizing treatment for bipolar disorder. ² Following the development of DRESS, discontinuation of lamotrigine is required, and treatment is typically initiated with oral corticosteroids. ¹ Complications such as decompensation of mania can arise in this instance from a combination of multiple factors. Here, we present the case of a 21-year-old female with bipolar II disorder who developed lamotrigine-induced DRESS and subsequently experienced mania requiring hospitalization, likely secondary to abrupt drug discontinuation, initiation of high-dose prednisone (a known trigger of mania), ³ and exacerbated by unopposed antidepressant use (a known trigger of mania in patients with bipolar disorder). ⁴ Informed consent was provided by the patient for publication.

Case report

A 21-year-old Sri Lankan female with known bipolar II disorder presented to psychiatry with depressive symptoms. She was prescribed escitalopram 5 mg/day and lamotrigine 25 mg/day for 2 weeks, with lamotrigine increased to 50 mg/day thereafter.

Three weeks later, she presented to the emergency department (ED) with a 4-day history of fever, cervical lymphadenopathy, and a pruritic morbilliform eruption to the extremities, trunk, and face. She denied other infectious symptoms such as abdominal pain, dysuria, diarrhea, nausea, or vomiting. Laboratory values demonstrated elevated alanine aminotransferase (ALT; 327 U/L) and gamma-glutamyl transferase (114 U/L). There was no eosinophilia (0.1 × 10⁹/L). Dermatology diagnosed DRESS secondary to lamotrigine based on history, clinical features, and RegiSCAR score of 5. Lamotrigine was immediately discontinued. Escitalopram was continued at 5 mg daily. She was prescribed prednisone 50 mg daily and topical betamethasone valerate (BMV) 0.1% cream on an outpatient basis. Cyclosporine 100 mg/day was also prescribed but not taken due to difficulty accessing the drug from her pharmacy.

She presented to the ED 2 days later due to worsening rash and facial swelling. ALT had increased to 359 U/L (RegiSCAR = 3). The dermatology service provided cyclosporine 100 mg twice daily for 5 days, and she was transitioned to a slow prednisone taper of 5 mg weekly a few days later.

Unfortunately, she developed progressive passive suicidal ideation, easy distractibility, anxiety, increased appetite, and severe insomnia. These psychiatric side effects were suspected to be secondary to prednisone; however, a faster prednisone taper was not favored due to the risk of rebounding DRESS.

Four weeks into steroid therapy, she presented to the ED with irritability, euphoria, decreased sleep, elevated energy, pressured speech, racing thoughts, and grandiose ideas. She was involuntarily admitted under psychiatry with a diagnosis of manic episode, bipolar I disorder versus steroid-induced. She was started on quetiapine 50 mg twice daily.

The on-call dermatology team recommended a faster prednisone taper in efforts to reduce steroid effects contributing to her mania – 30 mg for 3 days, then 20 mg for 3 days, then 10 mg for 5 days, and then 5 mg for 5 days. She was concurrently started on cyclosporine 100 mg twice daily. There was no recurrence of DRESS signs or symptoms, and liver function tests normalized. She did not experience symptoms of steroid withdrawal.

Two weeks later, she was discharged from the hospital. Her psychiatric medications on discharge included quetiapine immediate-release 100 mg, quetiapine extended-release 200 mg, and loxapine 20 mg daily, which established mood stabilization.

Discussion

Although no formal guidelines exist for DRESS, a recent Delphi-based international consensus outlines its diagnosis and management. ⁵ Based on this, our patient had moderately severe DRESS due to elevated liver enzymes (ALT 327 U/L, >4× normal upper limit), and treatment recommendations include high-potency topical steroids and systemic glucocorticoids tapered over 6 weeks–3 months. ⁵ Our patient was treated accordingly with an initial regimen of topical BMV 0.1% cream and oral prednisone.

Regular follow-up is also recommended by the consensus, including blood tests according to organ involvement, screening for autoantibodies and thyroid dysfunction, monitoring steroid adverse effects, and providing psychological support. ⁵ Specific monitoring for mania is not outlined, despite it being a well-documented steroid side effect. A systematic review on corticosteroid-induced mania in non-dermatologic disease found it particularly common with prednisone doses above 40 mg/day. ³

We underscore the importance of monitoring for manic symptoms while treating patients for DRESS with oral corticosteroids. The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) defines mania as “a distinct period of abnormally and persistently elevated, expansive, or irritable mood and abnormally and persistently goal-directed behavior or energy, lasting at least 1 week and present most of the day, nearly every day (or any duration if hospitalization is necessary).” ⁶ A helpful acronym to screen for symptoms of mania is “DIGFAST”: distractibility, indiscretion, grandiosity, flight of ideas, activity increases, sleep decreases, and talkativeness. Once there is sufficient concern or a diagnosis of mania is made, a faster prednisone tapering schedule may be warranted while balancing the risk for DRESS recurrence and steroid withdrawal effects. Alternatively, treatments such as cyclosporine and intravenous immunoglobulin may be considered, ⁵ either in lieu of steroids or as an adjunctive steroid-sparing therapy.

This patient’s mania was likely exacerbated by unopposed escitalopram. Antidepressant monotherapy is known to increase the risk for a manic switch in bipolar disease; however, this risk can be mitigated with concurrent use of a mood stabilizer such as lamotrigine. ⁴ In our case, escitalopram, an antidepressant, was continued as monotherapy after the discontinuation of lamotrigine.

This experience was profoundly distressing for the patient, who had significant psychological trauma as a result. Given that dermatologists often see patients for DRESS secondary to bipolar disorder treatments, we highlight the importance of evaluating concurrent antidepressant treatments and considering hospitalization for multidisciplinary care and stabilization of psychiatric medications.

This case demonstrates the perfect storm of steroid-induced mania exacerbated by unopposed antidepressants, underscoring the need to (1) assess the risk and benefit of using steroids versus other nonsteroid options in DRESS, (2) evaluate concurrent antidepressant use when discontinuing lamotrigine, and (3) screen for mania while patients are on prednisone therapy.