Neuroleptic malignant syndrome following clozapine withdrawal

Dear Editor, Neuroleptic malignant syndrome (NMS) occurs as an adverse reaction to dopamine receptor-antagonist drugs or due to rapid withdrawal of dopaminergic medications. It must be considered in the differential diagnosis of any patient presenting with fever and mental status changes because it needs early identification to prevent significant morbidity and death. With the advent of second-generation antipsychotics, the incidence has declined to 0.01% from 0.02%.[1] Young adults are most vulnerable to the syndrome but it has been identified in all age groups from 0.9 to 78 years.[2] Rarely, clozapine withdrawal can present with catatonia and NMS. A 38-year-old male with schizophrenia presented with complaints of decreased food intake, vacant staring, and decreased responsiveness. He was well-maintained on oral clozapine 200 mg per day but had discontinued treatment for 2 days. On examination, his vitals were stable and systemic examinations were within normal limits. His laboratory investigations revealed high serum urea (101 mg/dL) and serum creatine (2.1 mg/dL), and mild elevation in leucocyte count. A provisional diagnosis of hypoactive delirium was made and symptomatic management of delirium was initiated with oral quetiapine 25 mg SOS. On the 3rd day of admission, he was agitated with profuse sweating, tachycardia, and a blood pressure of 170 / 100 mm Hg. He also developed fever and rigidity in all four limbs. Investigations revealed elevated total leucocyte count with serum CPK values of 5500 IU/mL. He was diagnosed with NMS and shifted to the medical intensive care unit. His clinical condition worsened rapidly and he needed non-invasive ventilation due to respiratory distress. He was managed with intravenous fluids, intravenous dantrolene, and lorazepam (6 mg per day). Oral bromocriptine was started later at a dose of 7.5 mg per day and gradually tapered over the next ten days. By day 7 of admission serum CPK values had come down to 2000 IU/mL and his respiratory condition also improved; he was weaned off the ventilator and by day 14 his vitals including blood pressure became normal. The dose of lorazepam was tapered down to 2 mg over 2 weeks. Serial CPK values had a declining trend and by day twenty serum CPK was 230 IU/mL. Clozapine re-challenge was attempted on day 25 of admission and over 2 weeks a dose of 125 mg HS was reached following which he was discharged after advising the need for strict drug adherence and routine follow-up. Our patient developed NMS within a few days of discontinuing clozapine. The close temporal relationship between the sudden clozapine withdrawal and the abrupt appearance of signs of NMS with no other plausible causes of NMS identified explains that it could be secondary to the clozapine withdrawal. Mental status changes are seen in up to 82% of patients with NMS.[3] It is usually seen as agitated delirium with confusion rather than psychosis. Catatonic signs with mutism are commonly seen and progression to encephalopathy with stupor and coma is also seen among patients with NMS.[4] Rapid clozapine withdrawal is associated with anxiety, insomnia, altered consciousness, dyskinetic movements, nausea, diaphoresis, and psychomotricity disturbance such as motor restlessness or mute withdrawal have been reported and these symptoms could be attributed to cholinergic rebound.[5] Cholinergic rebound could have been the reason for some of the symptoms in our patient. Our patient was started on benzodiazepines which aided improvement by modulating the GABA dopamine modulation pathway.[6] This could also be the mechanism of triggering NMS when clozapine; a drug with involvement of multiple neurotransmitter mechanisms was suddenly withdrawn. The exact pathophysiology of NMS still remains a topic of active research. Clinicians need a high index of suspicion of NMS even when an antipsychotic, especially clozapine, is abruptly withdrawn. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.