NR330 Efficacy of Ziprasidone Against Hostility in Schizophrenia:

Post-Hoc Analysis of a Randomized, Open-Label Study

Leslie Citrome, MD, MPH1; Jan Volavka, MD, PhD1; Pal Czobor, PhD1; Shlomo Brook, MD2; Antony Loebel, MD 3; Francine S. Mandel, PhD 3
1
Nathan S. Kline Institute for Psychiatric Research and the New York University School of Medicine, Orangeburg, NY; 2Sterkfontein Hospital, Krugersdorp, South Africa; 3 Pfizer Inc., New York, NY

Patients Figure 2. Decreases in Hostility With Ziprasidone and Haloperidol ■ This difference in effect on akathisia was evident from the first time period (Days 1–3) (mean
RESULTS
ABSTRACT ■ Hospitalized men and women, age 18 to 70 years (no adjustment for covariates) change for ziprasidone [SD]= – 0.02 [0.55]; paired t test, t=0.63, P = 0.532 vs mean change for
haloperidol [SD]= 0.30 [0.81]; paired t test, t=4.24; P < 0.0001)
■ DSM-IV diagnosis of acute exacerbation of schizophrenia or schizoaffective disorder Figure 1. Disposition of Patients
Objective: To determine the effects of sequential intramuscular and oral ziprasidone compared ■ The incidence of new cases of treatment-emergent akathisia over the 6 weeks of the study in
with haloperidol, on hostility. ■ BPRS total score of ≥40 Ziprasidone
Assigned to Treatment the haloperidol group was 32.6% (of which 17.5% resolved), and in the ziprasidone group it was
Method: A total of 572 inpatients diagnosed with DSM-IV schizophrenia or schizoaffective disorder ■ Exclusions 30 Haloperidol
n = 572 13.2% (of which 46.8% resolved)
were studied in a randomized, rater-blinded, 6-week, open-label trial comparing sequential – Treatment with an investigational agent within the past 6 months, clozapine within the past
‡ ■ Because of the baseline differences in the BAS global scores between the ziprasidone and
intramuscular and oral ziprasidone with haloperidol. The principal outcome measure was the Brief 3 months, an antipsychotic within the past 12 hours, a depot injection of an antipsychotic 25
within the past 2 weeks haloperidol groups, additional tests were conducted for confirmation of the above findings
Psychiatric Rating Scale (BPRS). To determine the effect of ziprasidone on hostility, post-hoc
analyses of scores on the hostility item from the BPRS were conducted. Introducing positive 20 * P< 0.01 – Analysis of covariance, using the baseline BAS score in order to adjust for the baseline
– History of resistance to conventional drugs on at least 2 occasions within the past 2 years IM Ziprasidone N = 429* Days IM Haloperidol N = 138*

Odds Ratio
† P < 0.05
symptoms and akathisia as covariates tested the specific effect of the medication on hostility. Completers N = 425 (99.1%) 1–3 Completers N = 135 (97.8%) † difference, did not substantially affect the results we have reported
– Substance abuse within the past 3 months (or a positive urine screen for amphetamines, 15
‡ P = 0.056
Results: Ziprasidone demonstrated specific antihostility effects over time throughout the study cocaine, or opioids) ■ Stratification of the sample based on baseline presence or absence of akathisia showed that
period and was statistically superior to haloperidol on the hostility item of the BPRS in the first – Previous diagnosis of organic mental disease including mental retardation ziprasidone’s superiority to haloperidol for akathisia was heightened in the group with
10 †
week of treatment (P=0.015 at first evaluation on day 1, 2, or 3; P=0.036 at day 7). Oral Ziprasidone N = 425 To Oral Haloperidol N = 135 † baseline akathisia
– Immediate risk of harm to self or others
Conclusion: Ziprasidone is an effective treatment for hostility in patients with schizophrenia or Completers N = 292 (68.1%) 6 Weeks Completers N = 91 (65.9%) 5 * ■ Haloperidol-treated patients also exhibited significantly greater increases in Extrapyramidal
■ Concomitant medications were permitted, including anticholinergic medications as needed for
schizoaffective disorder. Symptom Rating Scale at end of IM treatment and at endpoint than ziprasidone-treated patients
extrapyramidal symptoms, propranolol for akathisia, benzodiazepines for additional sedation, Detailed flowchart available in Brook S, et al.7
0 (P<0.0001). (Data not shown but shown in Brook S, et al.7)
and temazepam (up to 20 mg per night) for insomnia *Received 1 or more doses.
1–3 7 14 28 42
Abbreviations: BAS=Barnes Akathisia Scale; BPRS=Brief Psychiatric Rating Scale; CI=confidence interval; Treatments Day
GEE=generalized estimating equations; IM=intramuscular; OR=odds ratio; SD=standard deviation ■ Transition from intramuscular to oral administration was done when clinically appropriate. Oral P values represent between-groups comparisons
Table 1. Baseline Demographic and Treatment Characteristics
ziprasidone was started at 80 mg/day, and oral haloperidol at 10 mg/day CONCLUSIONS
Ziprasidone Haloperidol
Assessments Characteristic (N=429) (N=138) ■ Ziprasidone effectively treated hostility in patients with schizophrenia or schizoaffective disorder.
BACKGROUND ■ BPRS at baseline; upon transition to oral medication (day 1, 2, or 3); day 5; week 1; week 2;
Men, N (%) 286 (66.7) 91 (65.9) Figure 3. Decreases in Hostility With Ziprasidone and Haloperidol Sequential intramuscular-to-oral ziprasidone was superior to haloperidol in reducing hostility,
week 4; and week 6 or at early termination (after adjustment for covariates — specific antihostility effect) showing evidence of a specific antihostility effect in the first week of treatment.
■ Assessing the effects of antipsychotic agents in treating aggression is important for their Race, N (%)
■ BAS at baseline; upon transition to oral medication (day 1, 2, or 3 ); week 1; week 4; and week ■ Ziprasidone’s specific effect on hostility was superior to that of haloperidol, even after correcting
clinical use 1
6 or at early termination White 338 (78.8) 110 (79.7) for the akathisia observed in the haloperidol group. This difference was statistically significant
– Agitated or hostile behavior is a frequent reason for admission to a psychiatric inpatient facility Ziprasidone for the IM treatment period (P=0.002) and was a trend at study end point (P=0.15)
Statistical Analysis Black 64 (14.9) 19 (13.8)
– Continuation of such behaviors after admission can prolong the hospitalization 3.5 Haloperidol P= 0.15 ■ Ziprasidone demonstrated superior tolerability to haloperidol with respect to akathisia and EPS
■ Primary outcome measure for this post-hoc analysis was the BPRS hostility item. This item is Asian 8 (1.9) 3 (2.2)
■ The standard of care for agitated or aggressive behavior in patients with psychotic disorders defined as “animosity, contempt, belligerence, and disdain for other people outside the
Other 19 (4.4) 6 (4.3) 3
has been the short-term use of intramuscular haloperidol (at times combined with lorazepam), interview situation” and is scored on a scale ranging from 1 (indicating not present) to 7 (very
followed by oral antipsychotics 2 Age, mean (SD)/range, yr 34.0 (10.5)/18–67 34.6 (10.5)/17–65 P= 0.077 P = 0.068
severe) 2.5 P = 0.015 P= 0.036
Choice of acute intramuscular agent has expanded recently to include rapid-acting REFERENCES

Odds Ratio
■ ■ Safety measures included the BAS global score Schizophrenia, N (%) 384 (89.5) 121 (87.7)
2
intramuscular formulations of second-generation antipsychotics 3-6 ■ P=0.05 (2-sided) was adopted for all analyses for statistical significance BPRS total, mean (SD) 57 (10.5) 57 (9.6)
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■ A randomized, open-label study found sequential administration of intramuscular and oral ■ Principal statistical approach for this analysis: GEE BPRS positive symptoms, mean (SD)* 19.44 (4.85) 19.24 (4.46) Science, Treatment, and Prevention of Antisocial Behaviors: Evidence-Based Practice. 1st ed. Kingston, NJ: Civic
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METHODS ■ Effect size for change in hostility status over time ■ Without accounting for any covariates, both the ziprasidone group and the haloperidol group disorder. J Clin Psychiatry. 2005;66:1362–1366.
improved with respect to hostility over time. However, ziprasidone was superior to haloperidol Safety and Tolerability 07. Brook S, Walden J, Benattia I, et al. Ziprasidone and haloperidol in the treatment of acute exacerbation of
– Estimated using the OR computed from the GEE
Study Design in the likelihood of reduction of hostility, as noted by OR >1 for the effect of treatment and time Akathisia schizophrenia and schizoaffective disorder: comparison of intramuscular and oral formulations in a 6-week,
– The analysis comparing ziprasidone with haloperidol was set up so that the OR indicates the (Figure 2) randomized, blinded-assessment study. Psychopharmacology (Berl). 2005;178:514–523.
■ 42-day, international (20 countries), multicenter (76 sites) study
likelihood (odds) of shifting 1 point down on the hostility item in the ziprasidone group Table 2. BAS Global Scores 08. Citrome L, Volavka J, Czobor P, et al. Efficacy of ziprasidone against hostility in schizophrenia: post hoc analysis
■ Randomized, parallel-group, open-label, flexible-dose design
■ Statistically significant differences were maintained until day 42, at which point the differences
compared to the haloperidol group (thus, an OR >1 would indicate superiority for ziprasidone) of randomized open-label study data. J Clin Psychiatry. 2006;67:638–642.
reached trend levels (P=0.056) Mean (SD)
■ All assessments were conducted by evaluators blinded to drug allocation ■ Testing for specific antihostility effect Ziprasidone Haloperidol 09. Keckich WA. Neuroleptics: violence as a manifestation of akathisia. JAMA. 1978;240:2185.
■ When the analysis controlled for general antipsychotic effect and akathisia, the ziprasidone
■ Subjects were randomly assigned in a 3:1 ratio to receive either ziprasidone or haloperidol – Controlling for general antipsychotic effect, as well as akathisia, permitted the testing for 10. Crowner ML, Douyon R, Convit A, et al. Akathisia and violence. Psychopharmacol Bull. 1990;26:115–117.
group demonstrated a statistically significant improvement in hostility at each time point, Baseline 0.35 (0.72) 0.51 (0.86)
specific antihostility effect 9,10 whereas the haloperidol group showed no significant improvement in hostility over baseline
– Controlling for general antipsychotic effect was done by introducing into the model the (i.e., the lower limit of the 95% CI was always >1 for the ziprasidone group and always <1 for Endpoint change –0.03* (0.82) 0.41† (1.09)
change in the sum of the BPRS items of suspiciousness, grandiosity, unusual thought the placebo group)
Supported by funding from Pfizer Inc. content, conceptual disorganization, and hallucinatory behavior as a single covariate ■ The between-group comparison also significantly favored ziprasidone over haloperidol (effect of
* Indicates nonstatistically significant improvement (t=0.72; P=0.474)
† Indicates worsening of akathisia (paired t test, t=4.32; P<0.0001)

Presented at the American Psychiatric Association, Toronto, Canada, May 20–25, 2006. – Controlling for akathisia was done by introducing the BAS global score as a covariate treatment and time) until day 14 (Figure 3)