High-dose ziprasidone in treatment-resistant schizophrenia and affective spectrum disorders: a case series.

To the Editors: The efficacy of the atypical antipsychotic drug ziprasidone has been established in clinical trials, where dosages ranged from 40 to 200 mg/d. Evidence for dose response in patients with schizophrenia has been presented, with dosages of 120 to 160 mg/d producing significantly larger effect sizes than 40 to 80 mg/d in pooled fixed-dose studies. Within the current recommended range, higher doses of ziprasidone have not been shown to increase the risk for serious adverse events. Ziprasidone carries a Food and Drug Administration warning concerning prolongation of the corrected QT (QTc) interval. In a safety study using ziprasidone at dosages of 320 mg/d in patients with schizophrenia or schizoaffective disorder, effects on the QTc interval were found to be comparable with those seen at 160 mg/d. It is unclear whether further efficacy can be obtained above 160 to 200 mg/d, particularly for patients who remain partially treatment resistant at lower doses, because no controlled data above these doses are available. We undertook a retrospective electronic record review to determine the safety, efficacy, and tolerability of ziprasidone administered at higher dosages (>160 mg/d; maximum, 640 mg/d) in a treatment-resistant psychiatric population. Currently, dosages above 160 mg/d are not Food and Drug Administration approved or recommended by the manufacturer. A review of a 14,000 patient data set from July 1998 to November 2004 identified 106 evaluable records of patients with schizophrenia and affective spectrum disorders treated with higher doses of ziprasidone in inpatient, partial hospital, and outpatient settings at a community general hospital in the southwest suburbs of Cleveland, OH. Patients were offered the option of highdose therapy if they had a partial response to 160 mg/d of ziprasidone, if they were free from side effects at this dose level, if sufficient time had elapsed while the patient was receiving 160 mg/d for a complete response to be seen (average of 6 to 12 months), and if they, or an appropriate other, provided consent for Boff-label[ high-dose treatment. Patients received a higher dose of ziprasidone for periods varying from less than 1 month to more than 2 years, with a mean of 138.3 days (SD, 201.6). Dosages ranged from 180 to 640 mg/d (mean, 283.8 mg/d; SD, 71.3). The most common dosages were 240 (n = 45) and 320 mg/d (n = 41). Almost all patients had a trial at dosages of 160 mg/d before being increased to dosages higher than 160 mg/d. An estimate of the efficacy of the higher dose was obtained by comparing scores for symptom severity and Global Assessment of Functioning scores from the initiation of higher dose treatment to the last date of higher dose treatment. Symptom rating (and side effect recording) was completed by experienced psychiatrists (primarily by D.A.D.). Symptom severity was assessed using a 5-point Likert scale (1 = no symptoms; 5 = extreme symptoms) for psychotic (eg, disorganized thoughts, delusions, paranoia, and hallucinations), affective (eg, rapid mood changes, irritability, insomnia, depression, and mood swings), behavioral (eg, anger, impulsivity), anxiety (eg, panic attacks, obsessions), and risk (homicidal impulses, suicidal thoughts or gestures) symptoms. Effect size (Cohen’s d) was calculated by dividing the improvement (change in Likert scale value) by the SD for each symptom. Safety and tolerability data were gathered from medical record notes of events observed by physicians and spontaneous reporting by patients. A logistic regression analysis was used to explore the relationship between adverse events and doses. A higher dose of ziprasidone was associated with large improvement (effect size, Q1.0) of psychotic symptoms: disorganized thought (1.87), delusions (1.40), internal preoccupation (1.11), and bizarre elements (1.05). Large improvement was also noted for suicide risk (1.65) and anger (1.36). Symptoms showing moderately large improvement (effect size between 0.7 and 0.99) included insomnia (0.95), irritability (0.86), and rapid mood changes (0.84). Most patients (77.4%; n = 82) treated with a higher dose of ziprasidone reported no adverse events. Of the 24 patients who did report adverse events (33 adverse events), only 2 patients (1.9%) required ziprasidone discontinuation (1 because of restless legs and 1 because of akathisia). The most commonly reported adverse events were sedation (9.4%), extrapyramidal symptoms (7.5%), and other central nervous system adverse events (6.6%) (Table 1). Significant weight gain was not reported by, or observed in, any patient. There was no significant relationship between doses and adverse events. The odds of reporting an adverse event increased 1.11-fold (11%) for each increase of 80 mg/d (95% confidence interval, 0.74–1.68; t = 0.42; P = 0.673). Some patients reported a worsening of adverse events at higher doses and improvement with dose reduction; others exhibited transient effects that did not worsen, and still others improved upon further treatment or dose escalation. Corrected QT interval measurements, taken at local hospital electrocardiogram laboratories (mainly Southwest General Health Center), were obtained for 47 patients treated with higher dosages of ziprasidone. A single QTc measurement was available for 33 patients. For these patients, the relationship between ziprasidone dosages and QTc was evaluated using linear regression. Two or more QTc measurements were available for 14 patients (19 pairs of observations). Corrected QT interval value change for each pair was evaluated with a paired t test. Letters to the Editors