Effectiveness and Cost of Olanzapine and Haloperidol in the Treatment of Schizophrenia

A Randomized Controlled Trial

Rosenheck, Robert MD
Perlick, Deborah PhD
Bingham, Stephen PhD
Liu-Mares, Wen PhD
Collins, Joseph ScD
Warren, Stuart JD, PharmD
Leslie, Douglas PhD
Allan, Edward MD
Campbell, E. Cabrina MD
Caroff, Stanley MD
Corwin, June PhD
Davis, Lori MD
Douyon, Richard MD
Dunn, Lawrence MD
Evans, Denise MD
Frecska, Ede MD
Grabowski, John MD
Graeber, David MD
Herz, Lawrence MD
Kwon, Kong MD
Lawson, William MD
Mena, Felicitas MD
Sheikh, Javaid MD
Smelson, David PhD
Smith-Gamble, Valerie MD

Department of Veterans Affairs Medical Center, West Haven, Conn (Drs Rosenheck, Perlick, Liu-Mares, and Leslie); Department of Psychiatry, Yale University School of Medicine, New Haven, Conn (Drs Rosenheck, Perlick, Liu-Mares, and Leslie); Department of Veterans Affairs Cooperative Studies Program Coordinating Center, Perry Point, Md (Drs Bingham and Collins); Department of Veterans Affairs Cooperative Studies Program Clinical Research Pharmacy Coordinating Center (Dr Warren) and Department of Veterans Affairs Medical Center (Dr Graeber), Albuquerque, NM; Department of Veterans Affairs Medical Center, Montrose, NY (Dr Allan); Department of Veterans Affairs Medical Center, Philadelphia, Pa (Drs Campbell and Caroff); Department of Veterans Affairs Medical Center, New York, NY (Dr Corwin); Department of Veterans Affairs Medical Center, Tuscaloosa, Ala (Dr Davis); Department of Veterans Affairs Medical Center, Miami, Fla (Dr Douyon); Department of Veterans Affairs Medical Center, Durham, NC (Dr Dunn); Department of Veterans Affairs Medical Center, Augusta, Ga (Dr Evans); Department of Veterans Affairs Medical Center, Bay Pines, Fla (Dr Frecska); Department of Veterans Affairs Medical Center, Detroit, Mich (Dr Grabowski); Department of Veterans Affairs Medical Center, Bedford, Mass (Dr Herz); Department of Veterans Affairs Medical Center, Brecksville, Ohio (Dr Kwon); Howard University Medical School, Washington, DC (Dr Lawson); Department of Veterans Affairs Medical Center, Tuskegee, Ala (Dr Mena); Department of Veterans Affairs Medical Center, Palo Alto, Calif (Dr Sheikh); Department of Veterans Affairs Medical Center, Lyons, NJ (Dr Smelson); and Department of Veterans Affairs Medical Center, Indianapolis, Ind (Dr Smith-Gamble).

Corresponding Author and Reprints: Robert Rosenheck, MD, Northeast Program Evaluation Center (182), VA Connecticut Health Care System, 950 Campbell Ave, West Haven, CT 06516 (e-mail: [email protected]).

Financial Disclosures: Dr Rosenheck has received grant support from Astra-Zeneca and Bristol-Myers Squibb, both of which manufacture products that compete with olanzapine in the marketplace, and has received funds for other research efforts from Lilly. Dr Davis has received research grants from Lilly. Dr Evans has served as a consultant to Janssen and Lilly. Dr Herz has served as a consultant and speaker and has received research grant support from Lilly.

Author Contributions: Dr Rosenheck, as principal investigator, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Rosenheck, Perlick, Bingham, Collins, Evans.

Acquisition of data: Rosenheck, Perlick, Bingham, Warren, Allan, Campbell, Caroff, Corwin, Davis, Douyon, Dunn, Evans, Frecska, Grabowski, Graeber, Herz, Kwon, Lawson, Mena, Sheikh, Smelson, Smith-Gamble.

Analysis and interpretation of data: Rosenheck, Perlick, Bingham, Liu-Mares, Collins, Leslie.

Drafting of the manuscript: Rosenheck, Collins, Kwon, Smelson.

Critical revision of the manuscript for important intellectual content: Perlick, Bingham, Liu-Mares, Collins, Warren, Leslie, Allan, Campbell, Caroff, Corwin, Davis, Douyon, Dunn, Evans, Frecska, Grabowski, Graeber, Herz, Lawson, Mena, Sheikh, Smith-Gamble.

Statistical expertise: Rosenheck, Bingham, Liu-Mares, Collins, Leslie.

Obtained funding: Rosenheck, Collins.

Administrative, technical, or material support: Rosenheck, Perlick, Bingham, Collins, Warren, Corwin, Davis, Dunn, Evans, Grabowski, Graeber, Lawson, Smith-Gamble.

Study supervision: Rosenheck, Perlick, Collins, Allan, Davis, Dunn, Grabowski, Kwon, Mena, Sheikh, Smelson.

Members of the Department of Veterans Affairs Cooperative Study Group on the Cost-Effectiveness of Olanzapine:Executive Committee: J. Haroldson, PharmD, BCPS, Albuquerque, NM; J. Buckelew, BS, Albuquerque, NM; R. Douyon, MD, Miami, Fla; D. Evans, MD, Augusta, Ga; L. Herz, MD, Bedford, Mass. Data and Safety Monitoring Board: B. Burns, PhD, Durham, NC; D. Salkever, PhD, Baltimore, Md; C. A. Tamminga, MD, Baltimore, Md; N. R. Schooler, PhD, Glen Oaks, NY; R. J. Wyatt, MD, Bethesda, Md; N. M. Laird, PhD, Boston, Mass. Planning Committee: Dennis Charney, MD, Bethesda, Md. Pharmacy Activities: Jeffery Haroldson, PharmD, BCPS, Albuquerque, NM; Jolene Day, Albuquerque, NM; Mike Sather, MS, Albuquerque, NM. Good Clinical Practices Monitoring Unit: Julia Buckelew, BS, Albuquerque, NM, Cena Burge, BA, Overland Park, Kan; Pat S. Manning, RN, MA, Albuquerque, NM; Donna Smith, BS, Montgomery, Ala; Barbara J. Curtis, Albuquerque, NM. Neuropsychology Training and Certification Unit: Judith Jaeger, PhD, MPA, Glen Oaks, NY; Stefanie Berns, PhD, Glen Oaks, NY; Anne Hoff, PhD, Sacramento, Calif. VA Cooperative Studies Coordinating Center: Anne Horney, BS, Janie Smith, Cindy Howell. VA Northeast Program Evaluation Center: Michael Sernyak, MD, Jennifer Cahill, MS, Yuri Agrawal, Joyce Cramer.

Funding/Support: This study was supported by Lilly, which provided study drug and placebo, and the VA Cooperative Studies Program.

Role of the Sponsor: Employees of Lilly (Alan Breier, MD, Robert Obenchain, PhD, and John Kreuger) participated in the study design and commented on the analyses and on the manuscript. The analyses and writing of the manuscript were carried out by the authors independent of the sponsor.

JAMA: The Journal of the American Medical Association 290(20):p 2693-2702, November 26, 2003.

Context

Although olanzapine has been widely adopted as a treatment of choice for schizophrenia, its long-term effectiveness and costs have not been evaluated in a controlled trial in comparison with a standard antipsychotic drug.

Objective

To evaluate the effectiveness and cost impact of olanzapine compared with haloperidol in the treatment of schizophrenia.

Design and Setting

Double-blind, randomized controlled trial with randomization conducted between June 1998 and June 2000 at 17 US Department of Veterans Affairs medical centers.

Participants

Three hundred nine patients with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnosis of schizophrenia or schizoaffective disorder, serious symptoms, and serious dysfunction for the previous 2 years. Fifty-nine percent fully completed and 36% partially completed follow-up assessments.

Interventions

Patients were randomly assigned to receive flexibly dosed olanzapine, 5 to 20 mg/d, with prophylactic benztropine, 1 to 4 mg/d (n = 159); or haloperidol, 5 to 20 mg/d (n = 150), for 12 months.

Main Outcome Measures

Standardized measures of symptoms, quality of life, neurocognitive status, and adverse effects of medication. Veterans Affairs administrative data and interviews concerning non-VA service use were used to estimate costs from the perspective of the VA health care system and society as a whole (ie, consumption of all resources on behalf of these patients).

Results

There were no significant differences between groups in study retention; positive, negative, or total symptoms of schizophrenia; quality of life; or extrapyramidal symptoms. Olanzapine was associated with reduced akathisia in the intention-to-treat analysis (P<.001) and with lower symptoms of tardive dyskinesia in a secondary analysis including only observations during blinded treatment with study drug. Small but significant advantages were also observed on measures of memory and motor function. Olanzapine was also associated with more frequent reports of weight gain and significantly greater VA costs, ranging from $3000 to $9000 annually. Differences in societal costs were somewhat smaller and were not significant.

Conclusion

Olanzapine does not demonstrate advantages compared with haloperidol (in combination with prophylactic benztropine) in compliance, symptoms, extrapyramidal symptoms, or overall quality of life, and its benefits in reducing akathisia and improving cognition must be balanced with the problems of weight gain and higher cost.