1. Naturalistic Study: Treating the Acutely Agitated Patient Andrew Francis, MD, PhD Associate Professor State University of New York at Stony Brook Health Sciences Center Medical Director Inpatient Psychiatric and Day Treatment Services University Hospital at Stony Brook Stony Brook, New York

2. Disclosure Type of Affiliation Commercial Entity Consultant Eli Lilly and Company, Janssen Pharmaceutica, Pfizer, Inc. Honorarium AstraZeneca Pharmaceuticals LP, Pfizer, Inc. Dr. Francis intends to discuss off-label/unapproved uses of products or devices.

3. Learning Objectives Identify agitated patients who may respond to IM sedation with atypical neuroleptic agents Identify an expected course of clinical response after receiving atypical neuroleptic parenteral sedatives Upon completion of this presentation, participants should be able to:

4. Comprehensive Psychiatric Emergency Program (CPEP): What Is it? ~ 15, New York State-sponsored/regulated 24-hour attending psychiatrist, psych RN, psychiatric social worker, resident, nursing aides Adjacent to ER Extended-observation bed (72 hours) SUNY Stony Brook: 6200-6700 cases/year

5. SUNY Stony Brook CPEP ~ 60% require police escort ~ 10% require extended-observation bed (up to 72 hours) ~ 40% involuntary admissions ~ 60%-80% major psychiatric illness and/or substance abuse, intoxication ~ 50% are medicated in CPEP

6. IM Sedative Study (1994-1997) SUNY Stony Brook CPEP site Restrained and IM-sedated cases Chart review using restraint log Era before droperidol abandoned, before atypical neuroleptics available as IM

7. IM Sedative Used Male Female LZ Drop/LZ Drop Hal Hal/LZ Number of Cases 0100200 LZ = lorazepam; Drop = droperidol; Hal = haloperidol.

8. LorazepamDroperidolCombination (n = 17)(n = 54)(n = 26) IM Sedative Hours Restrained (Mean ± SEM) 4321043210 P <.05 Duration of Restraint: Intoxicated Cases

9. SUNY Stony Brook 2002 CPEP Study: Rationale Droperidol abandoned Published ziprasidone studies (eg, Daniel et al) show promise, but excluded severe agitation, ETOH/substance intoxication Published study (20 mg): 50% drop in agitation scores in 2 hours (rapid enough?) Ziprasidone IM untested in routine CPEP cases Ziprasidone more costly that conventional alternatives (haloperidol/lorazepam) but there is question whether advantages outweigh cost

10. SUNY Stony Brook CPEP Study: Background Not industry-sponsored Droperidol abandoned June 2002 Advent of IM ziprasidone Initially, CQI (QA) project for internal use –Safe? –Effective? –Cost-benefit? Pharmacy restricted use to CPEP, inpatient psych (not medical ED!) CQI project Not “research” (ie, not planned for publication) IRB approval later obtained for retrospective reporting, publishing (converted QA data to research data) CQI = continuous quality improvement; QA = quality assurance.

11. SUNY Stony Brook CPEP Study: Design Naturalistic outcome – not random assignment Predominant sedative for October-December 2002 Typical CPEP cases: severe agitation, ETOH, substances Data: Behavioral Activity Rating Scale (BARS) at baseline and up to 120 minutes (nonobtrusive, practical time limit) Data: duration of restraints Data: post hoc disposition time from CPEP (cont)

12. SUNY Stony Brook CPEP Study: Design Compare to conventional sedatives – mostly haloperidol and/or lorazepam Routine clinical monitoring, 17/69 ECG Categorize cases as PSYCH agitation (toxicology negative), ETOH agitation (blood alcohol level range 50-460, median 285), SUBS agitation (miscellaneous substances including cocaine, marijuana, barbiturates, opiates, or combined with ETOH)

13. BARS Agitation Scale Simple, 1-item 7-point scale Used in published ziprasidone studies Validated against PANSS-agitation and CGI-S Entirely observational, not obtrusive High interrater reliability

14. Swift RH et al. J Psychiatr Res. 2002;36:87-95. Validated as a reliable measure of activity levels in acute agitation, responsive to treatment differences When evaluated by 342 experienced raters, demonstrated inter- and intrarater reliability When correlated to scores in the CGI-S and PANSS negative scales, convergent and divergent validity were displayed 7 Violent, requires restraint 6 Extremely or continuously active 5 Signs of overt activity; can be calmed 4 Quiet and awake 3 Drowsy, appears sedated 2 Asleep, but responds normally 1 Difficult or unable to rouse The BARS 7-Point Observational Scale

15. SUNY CPEP Study (N = 69) n = 43 Mean = 33.4 SEM = 11.7 Median = 34 Range 18-67 n = 26 Mean = 43.1 SEM = 11.7 Median = 43 Range 19-68 Males Females SEM = standard error of the mean.

16. Published IM Ziprasidone Studies: 10 and 20 mg (Change in Baseline BARS Scale) * † † * 5.0 4.5 4.0 3.5 3.0 2.5 2.0 01 h2 h01 h2 h3 h4 h Improvement Change from Baseline (BARS) 15 min30 min Ziprasidone 2 mg Control (n = 54) Ziprasidone 10 mg (n = 63) Ziprasidone 2 mg Control (n = 38) Ziprasidone 20 mg (n = 41) *P <.05. † P .001. ‡ P <.01. Brook S et al. J Clin Psychiatry. 2000;61:933-941. Daniel DG et al. Psychopharmacology (Berl). 2001;155:128-134. † † † † † † ‡

17. SUNY Stony Brook CPEP Study: Comparison with Daniel et al Data 7654321076543210 01530456090120 Minutes After IM Rx BARS Score Daniel et al Ziprasidone 20 mg (n = 41) SUNY Ziprasidone 20 mg (n = 69) SUNY Miscellaneous Rx (n = 7) (cont)

18. 7654321076543210 01530456090120 Minutes After IM RX BARS Score Daniel et al (n = 41) PSYCH (n = 40) ETOH (n =10) SUBS (n = 19) SUNY Stony Brook CPEP Study: Comparison with Daniel et al Data Ziprasidone 20 mg in all studies.

19. SUNY Stony Brook CPEP Study Restraint Times 0 10 20 30 40 50 60 70 80 90 100 September 2002 Before Ziprasidone (n = 80) Ziprasidone 20 mg October-December 2002 (n = 51) Miscellaneous Rx October-December 2002 (n = 3) Minutes ± SEM

20. QTc IM Ziprasidone N = 17/69, ~ 30 minutes post-Rx Mean = 0.418 SEM = 0.026 Median = 0.410 Range = 0.370-0.462

21. Total Time in CPEP for Cases Restrained + IM Rx Day Shift 0 2 4 6 8 10 12 Ziprasidone (n = 9)Other (n = 10) Hours ± SEM

22. SUNY Stony Brook CPEP Study: Results Routine CPEP cases more agitated than cases in published study (BARS 6.6 vs 5.0) ~ 50% drop in BARS scores in 30-45 minutes with ziprasidone 20 mg, clinically significant Preliminary data for reduced restraint times Equally effective for intoxicated cases Safe, well tolerated One dystonic reaction: 17 ECGs, no QTc changes More prompt interview and disposition?

23. General Conclusions Ziprasidone is safe and effective for acute agitation Equally effective for agitation of all types Like droperidol, ziprasidone is effective for agitation with intoxication