Naturalistic Study: Treating the Acutely Agitated Patient

Andrew Francis, MD, PhDAssociate Professor

State University of New York at Stony BrookHealth Sciences Center

Medical DirectorInpatient Psychiatric and Day Treatment Services

University Hospital at Stony BrookStony Brook, New York

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.

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:

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

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

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

IM Sedative Used

Male

Female

LZ

Drop/LZ

Drop

Hal

Hal/LZ

Number of Cases

0 100 200

LZ = lorazepam; Drop = droperidol; Hal = haloperidol.

Lorazepam Droperidol Combination(n = 17) (n = 54) (n = 26)

IM Sedative

Hou

rs R

estr

aine

d (M

ean

± S

EM

)4

3

2

1

0

P < .05

Duration of Restraint: Intoxicated Cases

SUNY Stony Brook2002 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

SUNY Stony BrookCPEP 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.

SUNY Stony BrookCPEP 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)

SUNY Stony BrookCPEP 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)

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

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

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.

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

0 1 h 2 h 0 1 h 2 h 3 h 4 h

Impr

ovem

ent

Cha

nge

from

Bas

elin

e (B

AR

S)

15 m

in

30 m

in

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.

†

†

††

†

†

‡

SUNY Stony Brook CPEP Study: Comparison with Daniel et al Data

7

6

5

4

3

2

1

00 15 30 45 60 90 120

Minutes After IM Rx

BA

RS

Sco

re

Daniel et al Ziprasidone 20 mg (n = 41)

SUNY Ziprasidone 20 mg (n = 69)SUNY Miscellaneous Rx (n = 7)

(cont)

7

6

5

4

3

2

1

00 15 30 45 60 90 120

Minutes After IM RX

BA

RS

Sco

r eDaniel 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.

SUNY Stony Brook CPEP StudyRestraint Times

0

10

20

30

40

50

60

70

80

90

100

September 2002Before Ziprasidone

(n = 80)

Ziprasidone 20 mgOctober-December

2002 (n = 51)

Miscellaneous RxOctober-December

2002 (n = 3)

Min

utes

± S

EM

QTc IM Ziprasidone

• N = 17/69, ~ 30 minutes post-Rx

• Mean = 0.418

• SEM = 0.026

• Median = 0.410

• Range = 0.370-0.462

Total Time in CPEP for Cases Restrained + IM Rx Day Shift

0

2

4

6

8

10

12

Ziprasidone (n = 9) Other (n = 10)

Hou

rs ±

SE

M

SUNY Stony BrookCPEP 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?

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