A 23-year-old man presents to the emergency department. He was brought in by police for shouting on a subway. The patient claims that little people were trying to kill him and he was acting within his rights to defend himself. The patient has a medical history of marijuana and IV drug use as well as multiple suicide attempts. He is currently homeless. While in the ED, the patient is combative and refuses a physical exam. He is given IM haloperidol and diphenhydramine. The patient is transferred to the inpatient psychiatric unit and is continued on haloperidol throughout the next week. Though he is no longer aggressive, he is seen making "armor" out of paper plates and plastic silverware to defend himself. His temperature is 98.6°F (37°C), blood pressure is 115/71 mmHg, pulse is 72/min, and respirations are 12/min. The patient's treatment history is significant for failure to obtain symptom control with risperidone, haloperidol, and ziprasidone. Which of the following is the most appropriate next step in management?
Clozapine
Thioridazine
Chlorpromazine
Fluphenazine
Clozapine
This patient is presenting with symptoms of schizophrenia that are refractory to treatment with both typical and atypical antipsychotics. The most appropriate next step in management is treatment with clozapine.

Schizophrenia presents with auditory and/or visual hallucinations among many other findings. The most appropriate initial treatments are with a typical antipsychotic (haloperidol) or an atypical antipsychotic (risperidone). Once a patient has failed treatment with multiple medications (at least 2) from different classes, the next best step in management is clozapine. This medication is reserved for patients who have sustained treatment failure (because of the side effects of clozapine). These include weight gain, life-threatening agranulocytosis, and aplastic anemia. Regular complete blood count laboratory testing should be drawn while on clozapine to check for this side effect. Patients who develop this complication should immediately stop the medication but the side effect can be irreversible.

Khokhar et al. review the evidence regarding the use of clozapine to treat schizophrenia. They discuss how side effects of this medication include agranulocytosis, myocarditis, and seizures. They recommend using this medication with care and monitoring for the development of these complications.

Incorrect Answers:
Answer A: Chlorpromazine is a typical antipsychotic that is likely to fail given that haloperidol did not work for him. Important side effects of this medication include hypotension and sedation due to anticholinergic properties. This medication also has an idiosyncratic complication of corneal deposits.

Answer C: Fluphenazine is another typical anti-psychotic that is a strong D2 antagonist like haloperidol. If haloperidol failed, it is unlikely that another typical antipsychotic would work with such a similar mechanism of action. This medication has a high association with extrapyramidal side effects such as dystonia, akathisia, and tardive dyskinesia.

Answer D: Olanzapine is another atypical antipsychotic. Switching to another atypical antipsychotic is a viable option. Given that this patient has already failed another atypical antipsychotic and that his symptoms remain, the best therapy at this point would be clozapine. Side effects include weight gain and dyslipidemia.

Answer E: Thioridazine is a low-potency anti-psychotic that would likely not work if more potent drugs such as haloperidol or risperidone have already failed. Important side effects to be aware of include hypotension and sedation due to anticholinergic properties. This medication also has an idiosyncratic complication of retinal deposits.

Bullet Summary:
Clozapine is the treatment of choice in patients who have failed therapy with multiple different classes of antipsychotics and who have severe symptoms.