Psychosomatics 43:61-62, February 2002
© 2002 The Academy of Psychosomatic Medicine
Ziprasidone Treatment of Delirium
Laura Leso, M.D., and
Thomas L. Schwartz, M.D.
Received September 15, 2001; accepted September 24, 2001. From the Psychiatry Department, SUNY Upstate Medical University, Syracuse, New York. Address correspondence and reprint requests to Dr. Leso, Psychiatry Department, SUNY Upstate Medical University, 750 East Adams St, Syracuse, New York 13210.
Key Words: Delirium • Treatment • Ziprasidone
Ziprasidone is the most recently available antipsychotic agent approved by the U.S. Food and Drug Administration that is chemically unrelated to the phenothiazine or butyrophenone antipsychotic chemical families. In vitro, ziprasidone exhibits high-affinity blockade of the dopamine D2 and D3 receptors; the serotonin 5HT2A, 5HT2C, and 5HTID receptors; and the  l-adrenergic receptors.1 This pattern of receptor occupancy suggests a broad potential for therapeutic efficacy and minimal extrapyramidal and sedating side effects in the treatment of psychotic illness.
Many antipsychotics have electrophysiologic effects that resemble those of class Ia antiarrhythmic agents. A prolongation in the QT interval may occur, with the potential to cause torsade de pointes and sudden death. Some antipsychotics carry a high risk for this event, including thioridazine, mesoridazine, pimozide, and droperidol.2 Of the new atypical agents, sertindole (withdrawn from the market) carried a substantial risk, followed by ziprasidone and risperidone. Quetiapine, clozapine, and olanzapine are believed to have negligible effects on the QT interval. Certain risk factors for QT prolongation and ventricular arrhythmias have been demonstrated, including hypokalemia, hypomagnesemia, bradycardia, congenital long QT syndrome, and any underlying cardiac pathology.
We present the first known case of a patient with delirium successfully treated with ziprasidone. We outline some of the potential management issues involved in treating delirium with this agent.
Case Report
Mr. R. is a 34-year-old Hispanic male with a history of human immunodeficiency virus, pneumonia due to Pneumocystis carinii, hepatitis B and C, Clostridium difficile colitis, and recurrent cryptococcal meningitis. He was hospitalized in late April 2001 for complaints of the acute onset of lethargy, confusion, disorientation, and inability to ambulate. A brain scan on admission revealed ballooning of the frontal horns of the lateral ventricles bilaterally and dilation of the fourth ventricle. This finding was believed to be consistent with an obstructive hydrocephalus. There were also multiple enhancing nodular densities with surrounding edema in the subarachnoid space, which would be consistent with cryptococcal meningitis. Mr. R. was taken to surgery in a semi-emergent manner for placement of an external ventricular drainage catheter. Cerebrospinal fluid obtained during the procedure was positive for cryptococcal organisms.
Mr. R. experienced an initial period of improvement after endoscopic ventricular shunting plus amphotericin B treatment for cryptococcal meningitis. In early June 2001, however, the psychiatric on-call service was asked to evaluate Mr. R. because he had become confused, agitated, paranoid, and suicidal. Mr. R. denied ever seeing a psychiatrist before or ever being treated with any form of psychiatric medication. Mr. R. lived with his mother and was known to be noncompliant with medications.
Medications at the time of the interview were as follows: amphotericin B, lamivudine, stavudine, efavirenz, piperacillin–tazobactam, ranitidine, metronidazole, senna, and docusate.
Mental status examination at the time of the interview revealed a thin Hispanic gentleman who looked his stated age. He was lying in bed with a frightened expression. He was picking at his hair and clothes in a random, disorganized manner. He was unsure of where he was and was severely disoriented, as evidenced by incoherent speech and distractibility. Mr. R. scored 0 of 30 on a Folstein Mini-Mental State Exam because he was unable to focus on questions or to follow simple commands. He denied perceptual disturbances but appeared to be internally preoccupied. He was guarded in response to questioning.
The diagnosis at the time of evaluation was believed to be delirium due to cryptococcal meningitis because he was unable to sustain, focus, or shift attention. In addition, there were obvious changes in his cognition, and his symptoms developed rapidly and fluctuated with time. Initial recommendations included the prescription of risperidone (0.5 mg bid).
The next day, the Psychiatry Consultation & Liaison Service recommended that risperidone be stopped because Mr. R.'s concurrent central nervous system pathology would predispose him to extrapyramidal side effects. It was believed that ziprasidone would be a better choice of antipsychotic because of its lower risk of extrapyramidal symptoms as a result of lower dopamine-receptor affinity and lack of sedating side effects. Mr. R. was started on ziprasidone (20 mg bid). Serial electrocardiograms (ECGs) and serum potassium and magnesium were monitored throughout therapy. Mr. R.'s Delirium Rating Scale (DRS) score was calculated to be 26 before taking ziprasidone. He achieved a maximum dose of ziprasidone of 100 mg/day (40 mg/20 mg/40 mg), and his delirium cleared to a significant degree, as evidenced by improvement in his thought process, better ability to focus and shift attention, and a decrease in paranoia. These findings were coupled with a decrease in the DRS score from a high of 26 to 14.
However, he was unable to maintain a stable level of serum potassium or serum magnesium despite oral and intravenous replacement therapy. Additionally, ECGs on two separate occasions revealed premature ventricular contractions. This was in addition to a calculated 8.4% increase in the QTc interval during treatment. QTc intervals appeared to fluctuate regardless of the ziprasidone dose. Given the significant improvement in delirium and the presence of fluctuating electrolyte abnormalities, it was considered imprudent to continue ziprasidone. A rapid taper was undertaken, and haloperidol was instituted for the final few days of treatment. Mr. R. was subsequently discharged to a local nursing home. He had received antipsychotic therapy for his delirium for a total of 21 days while in the hospital.
Discussion
A myriad of conditions can cause delirium. Generally speaking, these conditions can be categorized into four major groups: systemic diseases secondarily affecting the brain, primary intracranial disease, exogenous toxic agents, and withdrawal from substances of abuse.3 The treatment of delirium encompasses the treatment of the causative etiology. In Mr. R.'s case, the cause of the delirium was believed to be cryptococcal meningitis and fluctuating electrolyte levels.
Neuroleptics are typically used to control the psychotic manifestations of delirium. In Mr. R.'s case, the paranoia, fear, and suicidal ideation were most distressful to him. The change in cognition and behavior put him at risk to act impulsively. Indeed, for a time during his hospitalization, he required a sitter to ensure his safety because he vocalized suicidal intent secondary to paranoia.
Ziprasidone was effective in treating the delirium, as noted by the improvement in DRS scores. However, the electrolyte abnormalities, cardiac arrhythmias, and prolongation of the QT interval were contraindications to the continued use of this agent.
This is the first known case report involving the atypical antipsychotic, ziprasidone. We hope that this report highlights the efficacy and the need to exercise caution with the use of ziprasidone for the treatment of delirium. Indeed, the American Psychiatric Association treatment guidelines for delirium strongly suggest that ECGs be obtained in a routine fashion for patients being treated with antipsychotic agents.4
Of note, other authors have used risperidone,5 olanzapine,6 and quetiapine7 for the treatment of delirium in small retrospective, open-label studies with reasonable efficacy, but different tolerability issues. Further case-control studies are needed to examine the use of ziprasidone and other atypical antipsychotics in the treatment of delirium.
REFERENCES
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Physicians' Desk Reference, 55th Edition. Montvale, NJ, Medical Economics Company, 2001
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Gury C, Canceil O, Iaria P: Antipsychotic drugs and cardiovascular safety: current studies of prolonged QT and ventricular arrhythmias. Encephale 2000; 26:62-72[Medline]
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Ebert MH, Loosen PT, Neucombe B (eds): Current Diagnosis and Treatment in Psychiatry. New York, McGraw-Hill, 2000, p 197
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American Psychiatric Association: Practice guideline for the treatment of patients with delirium. Am J Psychiatry 1999; 156(5 suppl):l-20
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Sipahimalani A, Sime RM, Masand PS: Treatment of delirium with risperidone. Int J Geriatr Psychopharmacol 1997; 1:24-26
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Sipahimalani A, Masand PS: Olanzapine in the treatment of delirium. Psychosomatics 1998; 39:422-430[Abstract/Free Full Text]
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Schwartz TL, Masand PS: Treatment of delirium with quetiapine. Primary Care Companion J Clin Psychiatry 2000; 2:10-12
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