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Slide 1: Effectiveness and Cost of Olanzapine and Haloperidol in the Treatment of Schizophrenia    JAMA 2003;290:2693-2702 Lead author Robert Rosenheck, MD Competency: Practiced Based Learning: “To hold a mirror up to ourselves to document, assess and improve out practice” -acgme.org  By Corey Yilmaz, MD
Slide 2: Effectiveness and Cost of Olanzapine and Haloperidol in the Treatment of Schizophrenia    JAMA 2003;290:2693-2702 Lead author Robert Rosenheck, MD Competency: Practiced Based Learning: “To hold a mirror up to ourselves to document, assess and improve out practice” -acgme.org  By Corey Yilmaz, MD
Slide 3: Schizophrenia      Effects 2 million people Costs $16 billion in 1990 Most widely used is Olanzapine, with $3.7 billion in 2002, over 1/3 of Ely-Lilly’s profits (Risperidone may be currently) Other studies show fewer EPS, better QOL, lower total costs in some, but not all studies Review of 20 studies showed that large numbers leave the study early  we need more long term data
Slide 4: Olanzapine     Serious wt gain, DM, Hyperlipidemia (a fasting Glucose and Lipid profile is now recommended w starting all atypicals) Only long term data is comparing it to Clozapine, whose use is restricted, unfortunately Although Olanzapine costs >$4000/yr, if it saves overall health care costs, it may be worth it Hypothesis of this 12 month clinical trial: Olanzapine would outperform Haloperidol with fewer symptoms, better QOL, and lower costs as other studies had shown (this study was paid for by Lilly)
Slide 5: Methods    Between 1998 and 200, pts at 17 VAMC’s were randomly assigned to 2 treatment arms Pts included had Schizophrenia and Schizoaffective d/o Met criteria based on structured clinical interview, had serious symptoms, and had serious dysfunction occupationally or socially over the past 2 years
Slide 6: Methods, cont’d  4386 pt records were reviewed, and only 49% pt’s were eligible for further assessment, and of those:  35%/49% refused participation, 7%/49% could not participate, and only 7%/49% were randomized    Double blind Rx: either Olanzapine 5-20mg/d or Haloperidol 5-20mg/d with dosage adjustments at 5mg intervals Pts on Haloperidol received Benztropine 1-4mg/d for EPS and those on Olanzapine received placebo No other anti-psychotic meds were allowed (although this is becoming more common despite little evidence of benefit)
Slide 7: Outcome Measures  Assessed at baseline, 6 weeks, 3, 6, 9, and 12 months using:        PANNS Scale QOL Scale assessed social fxn, behavioral deficits Barnes Scale for Akathesia AIMS for TD Simpson-Angus Scale for EPS Clinical Global Impression Scale QOL with the 36 item health survey
Slide 8: Outcome Measures, cont’d  Assessed Neurocognitive Status using:      The learning/ recall/ recognition/ coding portions of the Repeatable Battery for the Assessment of Neuropsychological Status Grooved Pegboard (??) Wisconsin Card Sorting Test 64 Card Version Trail-Making Test Part B (switching sets) Controlled Oral Word Association Test
Slide 9: Outcome Measures, cont’d  Assessed Health Care Costs using:           Number of units of service X estimated 1998 unit costs Service utilization from inpatient and NH care Medical and mental health outpatient costs Group therapy Day treatment Intensive case management Psychosocial rehabilitation Non-VA unit costs Medication costs ($2.83/5mg pill through the VA, $4.84/5mg pill in the community for Olanzapine, $0.02/5mg pill for Haloperidol) Non-Health Care costs including: administrative costs, criminal justice costs
Slide 10: Statistical Analysis and Results   80% chance of detecting a 6% difference in Sx on the PANSS or 11% difference in the QOLS 54% of Olanzapine Users DC’d the study vs. 61% of Haloperidol Users (similar to CATIE) Medication Dose at 6 wks 1st 6 months Last 6 months Olanzapine 11.4mg/d Haloperidol 11.2 14.7 13.5 15.8 14.3
Slide 11: No Significant Difference in:      % who completed the entire trial 39%(Olanzapine) v 46%(Haloperidol), or in the reasons for DC in those who did not  Study Retention is equal DC b/c of adverse SE’s: 4% (Olanzapine) v 10% (Haloperidol)  Haldol + Cogentin has the same SEs as Zyprexa DC b/c of lack of efficacy: 13%(Haloperidol) v 18% (Olanzapine)  neither are more effective 8% Olanzapine users and 9% Haldol users took open label anti-cholinergics The QOLS, 0.2% in favor of Olanzapine (previous trials had shown a better QOL w Zyprexa)
Slide 12: No significant difference in:  PANSS total score (-1.3% in favor of Olanzapine) or in the + or – subscales
Slide 13: Akathesia  Olanzapine- lower on the Akathesia scale, but not on the AIM TD scale or on the EPS scale  6% of Olanzapine group vs. 10% Haloperidol group for moderate to severe akathesia (no one had a severe rating), and significant at 6 weeks and 3 months
Slide 14: Further Analysis  Secondary analysis after the 1st DC of study drug showed no difference in the PANSS or the QOLS, but more robust differences in the Barnes Akathesia scale (f=21.0, p<0.001) and significant differences on the AIMS (f=3.95, p<0.048)
Slide 15:   Olanzapine: greater motor fxn, memory, but not better on the Wisconsin Card Sorting Test Modest results- maximum SD of 0.16 on motor fxn and 0.22 on memory at 9 months Motor fxning, Memory and Card Sorting
Slide 16: Weight Gain and Restlessness  More reports on weight gain with Olanzapine, fewer reports of restlessness, reflecting lower levels of akathesia
Slide 17: Service Use and Cost   No significant differences on any measure of cost, exclusive of medication costs (previous studies had shown a cost benefit w Zyprexa) Including cost, the total health care costs were significantly greater with Olanzapine
Slide 18: Comments    No difference in compliance, symptoms, QOL, inpatient use or total cost Olanzapine had modestly reduced akathesia and no significant difference in TD, and this had no effect on QOL measurements Most surprising result- no difference in retention, termination due to adverse events, or EPS other than akathesia (can be easily treated) in this Ely-Lilly sponsored study
Slide 19: Comments, cont’d   These differences between this study and prior studies is the use of prophylactic Benztropine (recommended in young, African American, muscular males usually in clinical practice or for 10 days after dystonic reactions, and as recommended in a recent treatment overview) Studies more favorable to Olanzapine only allowed Benztropine after symptoms arose, not in advance (EPS is most likely with Haldol than any other antipsychotic)
Slide 20: Comments, cont’d   Studies more favorable to Olanzapine likely had rating biases because without prophylaxis, Haldol patients are easily identifiable Since no data was collected after EPS developed in these patients, there was no documentation of possible recovery from this highly treatable syndrome (with Benztropine or Benzodiazepines or Propanolol)
Slide 21: Comments, cont’d    In the international collaborative trial, Olanzapine had a higher continuation rate of 67% v 47% for Haloperidol at 6 weeks, which was originally attributed to lack of efficacy, but reflected the lack of prophylactic Benztropine This study found that 71% of prophylactically treated Haloperidol pts were retained at 6 weeks, similar to the 67% rate found in previous studies of Olanzapine Olanzapine did NOT reduce hospitalizations as had previously been reported, so there is no cost benefit to using Olanzapine
Slide 22: Limitations     Generalizability of results is unknown b/c of all male pts, only at VA facilities Use of other anti-psychotics at the same time, although there is really only evidence for augmenting clozapine with haloperidol Did not exclude pts w addictive d/o’s Strict upper limit of 20mg/d for both medications, although the avg dose of Olanzapine was similar to the 14mg/d avg dose in the VA and 12mg/d in the private sector
Slide 23: Further Limitations   Analysis did not show us whether the reduction in akathesia and improvements in neurocognitive fxn were worth the increased costs of Olanzapine, as well as the risk of DM and weight gain Of the 28 pts that cost more than $50,000 to Tx, 17 were in the Olanzapine groups
Slide 24: Discussion        Do we pay anything regardless of price for a statistically significant benefit? Does Zyprexa reduce hospitalizations as previously reported? Do we need to rethink what we are paying for these newer medications? More than 80% of schizophrenic at the VA take newer atypicals, is this worth it? Most psychiatrists view these newer medications as a costly but worth it 1st line Rx, is that based on evidence or the result of a great marketing campaign? Are we afraid to use older medications for the appearance that we are not giving our patients the best medications? Should we draw any conclusions from this one study? Is it so black and white?
Slide 25: Parenting: Nature vs. Nurture
Slide 26:  http://www.badmash.org/videos/harlan.php?v =george_bush_512K_Stream.flv&t=Harlan%20Mc