Risks of Clozapine Rapid Titration

Background Clinical guidelines suggest a gradual titration of clozapine over two weeks to reduce the risks of adverse events such as seizures, hypotension, agranulocytosis, and myocarditis. Slow titration delays time to therapeutic response, often requiring concomitant administration of multiple antipsychotics. Case Presentation Mr. A is a 21-year-old African American former college student, diagnosed with schizophrenia and methamphetamine use disorder. He was admitted to a residential facility with command auditory hallucinations, delusions, insomnia, and disorganization. He was guarded, aggressive, had catatonic episodes, and homicidal ideation towards his physician, staff and mother. Medications on admission included duloxetine 60mg daily, oxcarbazepine 600mg twice daily, Abilify Maintena 400mg IM monthly, and lorazepam 2mg as needed. His agitation necessitated repeated medication doses. There was minimal improvement after trials of risperidone and chlorpromazine. Rapid titration of clozapine was initiated on 12/30/14 and Depakote ER was started on 1/6/15. He continued to require seclusions and restraints and remained disorganized. On 1/8/15 he became rigid, disoriented, P=120, febrile to 106F, and CK level= 2733, on Clozapine 300mg daily. Patient was transferred to a medical unit with diagnosis of NMS. Clozapine was discontinued. Conclusion This case illustrates risks associated with rapid clozapine titration and treatment with multiple antipsychotics. It remains unclear if the adverse reaction was due to rapid clozapine titration or use of multiple antipsychotics during titration. Limited data suggests possible interaction between sodium valproate and clozapine due to competing protein binding. There remains a need for clinical trials to systematically assess the safety of rapid clozapine titration.