Investigation Request With Dossier to Research Ethics Consultation Service at the University of Minnesota

7/30/2019 Investigation Request With Dossier to Research Ethics Consultation Service at the University of Minnesota

1/595

Center for Bioethics N504 Boynton

410 Church Street

Minneapolis MN 55455

612-624-9440

Fax: 612-624-9108

www.bioethics.umn.eduDr. Debra DeBruinCenter for BioethicsUniversity of Minnesota410 Church Street SEMinneapolis MN 55455

October 16, 2012

Dear Deb:

I am writing to you in your capacity as director of the Clinical Research Ethics ConsultationService for the Clinical and Translational Science Institute. I would like to make a two-fold request.First, I would like to request a formal inquiry into the circumstances surrounding the suicide of DanMarkingson in an AstraZeneca-sponsored research study of Seroquel in the Department of Psychiatry.Second, I am concerned that the absence of adequate human subject protections demonstrated in thatcase may still be placing research subjects in danger, especially in the Department of Psychiatry. Forexample, the Department of Psychiatry has continued to work on AstraZeneca-funded studies ofSeroquel, despite the fact that in 2010 the company settled a $520 million lawsuit for fraudulentmarketing of Seroquel in which the Department of Psychiatry was allegedly implicated. For thatreason, I would like to request a formal inquiry into the adequacy of human subject protections at theuniversity, with special attention to the Department of Psychiatry.

I understand that this is an unusual consultation request. However, the Clinical and TranslationalScience Institute is listed as the sponsor of all clinical trials at the university, including trials currentlybeing conducted in the Department of Psychiatry. In addition, I have tried for several years to makeUniversity of Minnesota administrators aware of the gravity of this problem through every otherpossible channel, and I have had no success. In fact, as you will recall, in August I brought the case upin a meeting of Center for Bioethics faculty members and Dr. Aaron Friedman, the Vice President forHealth Sciences. He was not receptive to my concerns.

I should also mention that the Markingson case raises issues of concern to the federalgovernment in particular, to the Senate Finance Committee, which investigated the University ofMinnesota for conflict-of-interest violations in 2009. The study in which Markingson died waspublished with the aid of federal funding from the National Institutes of Mental Health (Attachment A.)

The medical care of Markingson was paid for by a health insurance company through an arrangementwith Minnesota Care, a public assistance program which also receives federal funds (Attachment B.)In order to make the case for action as forcefully as possible, I am including a summary of the

problems that I believe need to be investigated.

Summary

Dan Markingson was a 26 year-old man from St. Paul and a recent graduate of the University ofMichigan who began showing signs of mental illness in the summer of 2003. His thoughts became


2/595

paranoid and delusional, and he became convinced that he was part of a vast cult, which was calling onhim to murder people, including his mother. On November 12, 2003, Markingson was taken toFairview Hospital in Minneapolis, where he was seen by Dr. Stephen Olson, a psychiatrist at theUniversity of Minnesota. Olson recommended involuntary commitment, and a court agreed. Later,despite objections by his mother, Mary Weiss, Olson recruited Markingson into a clinical trial ofantipsychotic drugs.

The clinical trial, which was known as the CAF study (an acronym for Comparison ofAtypicals in First-Episode Schizophrenia), was sponsored by AstraZeneca, the manufacturer ofSeroquel (quetiapine), and managed by Quintiles, a Contract Research Organization (Attachment C.)The CAF study was a randomized, double-blind trial comparing the effectiveness of three differentatypical antipsychotic drugs: Zyprexa (olanzapine), Risperdal (risperidone) and Seroquel (quetiapine.)The University of Minnesota was one of 26 sites for the trial, which lasted a full year. AfterMarkingson was enrolled in the CAF study, he spent about two weeks in Fairview Hospital beforebeing discharged against his mothers wishes to a halfway house. Over the next five months Ms. Weissrepeatedly expressed her concerns about her sons medical condition, especially his increasing agitationand rage. Her warnings were largely ignored. Finally, in desperation, she warned the study coordinatorthat her son might kill himself.

On May 7, 2004, Markingson mutilated himself with a box cutter so violently that he nearlydecapitated himself. His body was found by halfway house workers in the shower, along with a suicidenote that said, I went through this experience smiling. Blood tests later showed that Markingson hadbeen taking Seroquel (Attachment D.)

In the two years since Markingsons suicide became public, officials at the University ofMinnesota have consistently maintained that the case has been thoroughly investigated, that theuniversity has broken no laws, and that neither the university nor the CAF study investigators bearany responsibility for Markingsons death. However, the CAF study investigators and the Universityof Minnesota IRB violated an alarming number of widely accepted ethical guidelines governing theconduct of medical research, which, if uncorrected, endanger the welfare of human subjects at theuniversity. Those violations include the following:

Markingson was coerced into the CAF study by the threat of involuntary commitment. Markingson was incompetent to consent to the study. The CAFE study improperly enrolled psychotic subjects at risk of homicide or violence. University of Minnesota investigators ignored warnings that Markingson was in danger of

committing suicide.

University of Minnesota investigators illegally released private health information to CAFstudy sponsors.

The CAF study consent form failed to disclose serious risks to subjects. The CAF study targeted vulnerable subjects for recruitment. AstraZeneca and a University of Minnesota investigator manipulated research results to

promote Seroquel.


3/595

University of Minnesota investigators failed to disclose important financial conflicts of interestto subjects.

In the following pages, I have provided further information for your review. I have also includedsupporting documentation in an appendix.

Markingson was coerced into the CAF study by the threat of involuntary commitment.Because of the fact that Markingson was under a commitment order, I do not believe that he was in

a position to give his voluntary informed consent for the CAF study. On November 12, 2003, whenMarkingson was admitted to Fairview Hospital, Dr. Olson recommended that he be involuntarilycommitted to a state mental institution, on the grounds that he was mentally ill and dangerous. TheDakota County court agreed. A week later, Olson asked the court to give Markingson a stay ofcommitment, which allowed Markingson to avoid involuntary confinement as long as he agreed tofollow the recommendations of his treatment team. Again, the court agreed. On November, 20, thecourt issued a legal order requiring Markingson to remain hospitalized, cooperate with the treatmentplan at Fairview University Medical Center until medical discharged, and follow all of the aftercare

recommendations of his treatment team. The day after the court issued an order requiring Markingsonto comply with the recommendations of his psychiatrist, Dr. Olson enrolled him in the CAF study.The CAF study coordinator had Markingson sign a consent form for the study when his mother wasnot present, and kept him in the study despite her objections. At no time did Dr. Olson inform the courtthat he had enrolled Markingson in a research study (Attachment E.)

Markingson was incompetent to consent to the study.

It is very unlikely that Markingson, who was acutely psychotic, was mentally capable ofconsenting to the CAF study. During the period leading up to his enrollment, Markingson had beenrepeatedly judged incapable of consenting to neuroleptic (antipsychotic) drugs. On November 14, 2003Dr. Olson signed a commitment document stating that Markingson lacks the ability to make decisionsregarding such treatment. (Attachment E). On November 17, a pre-petition screening teamrecommended commitment, noting Markingsons bizarre beliefs and his refusal to acknowledge hismental illness. On November 19, a clinical psychologist confirmed those assessments, writing thatMarkingson is believed not to have the capacity to make decisions regarding neuroleptic medication.Yet on November 21, when Markingson was asked to consent to the CAF study, this assessment of hismental state was reversed and the CAF study team judged him competent (Attachment F).

While it is possible that a psychotic patients mental capacity could have improved in two days,there are good reasons to doubt this happened. First, the final competence assessment was made not byan independent party, but by the study coordinator for the CAF study, Jean Kenney, whose job it wasto recruit subjects for the study. This is hardly an impartial, disinterested assessment. Second, Kenneywas a social worker, not a psychiatrist or psychologist trained to make competence assessments. Third,even after Mr. Markingson had been judged competent to consent to the CAF study, his involuntarycommitment order was not lifted. This suggests that his mental state had not changed dramatically.Finally, one of the most persistent features of Markingsons psychosis was a lack of insight into hiscondition. Markingson did not believe he had a mental illness (Attachment H). It is unlikely that hecould be competent to consent to a study comparing treatments for his mental illness when he wouldnot even acknowledge that he was mentally ill.

The CAFE study improperly enrolled psychotic subjects at risk of homicide or violence.


4/595

Most clinical trials of antipsychotic drugs prohibit researchers from enrolling subjects who areat risk of suicide or violence, to minimize the possibility that these subjects will harm themselves orothers in the trial. While the CAF study did not allow researchers to recruit subjects at risk of suicide,it permitted the recruitment of subjects at risk of violence (Attachment G). The University ofMinnesota Institutional Review Board approved the protocol without requiring that potentially violentsubjects be excluded. This allowed the CAF study team to enroll Markingson, who had been

involuntarily committed precisely because he was threatening homicide. In fact, at the time of hisenrollment, there seems to have been broad agreement that he was at high risk of acting out hisdelusions.

University of Minnesota investigators ignored warnings that Markingson was in danger ofcommitting suicide.

Records indicate that Markingson experienced little if any improvement during the five and ahalf months he was in the CAF study. The documents show a subject who, by the most generousinterpretation possible, failed to improve over a period of five and a half months; whose ownpsychiatrist acknowledged so little improvement that his stay of commitment could not be lifted; whosemother was convinced that his condition was spiraling dangerously downward; and whose life ended ina grisly suicide. As Markingson grew increasingly agitated, Mary Weiss repeatedly warned the CAFstudy investigators that he was in danger of killing himself. On April 15, 2004, Ms. Weiss called theCAF study coordinator and asked, Do we have to wait until he kills himself or someone else beforeanyone does anything? After two letters to Dr. Schulz went unanswered, Ms. Weiss wrote a third letteron April 26, warning him, Dan has a rage within him, just below the surface, and desperately needshelp in dealing with it. Please dont wait until it comes boiling out! (Attachment H). Nonetheless, theCAF study investigators dismissed the concerns of Ms. Weiss and left Markingson in the CAF studyuntil he stabbed himself to death.

CAF study investigators illegally released private health information to the study sponsors.

According to the Health Insurance Portability and Accountability Act (HIPAA), health careproviders cannot release a patients private health information for use in research without the expresswritten consent of the patient. Violation of the law is a felony. However, Markingsons private healthinformation was given to AstraZeneca and Quintiles without his authorization. Included inMarkingsons medical records from Fairview Hospital is an unsigned authorization form. When Dr.Olson was questioned about possible HIPAA violations in his deposition, he replied that he did notknow whether Mr. Markingson had authorized the release of his health information and that he did notknow the specifics of HIPAA requirements (Attachment I.)

The CAF study consent form failed to disclose serious risks to subjects.

According to the informed consent document for the CAF study, the main risks to studysubjects were the side-effects of the drugs being tested and the possibility that the drugs would not beeffective (Attachment E.) However, the consent document did not mention that subjects in the CAFwere also required to forgo important therapeutic advantages of being treated outside the study.Ordinarily, if a treatment is not effective or is causing serious side-effects, the treating psychiatrist cantry another treatment or add adjunct treatments. However, the CAF study placed limits on the kinds ofadjunct treatments that could be used, and subjects could not be changed to another treatment withoutbeing dropped from the study.

On May 12, 2004, Dr. Olson asked the University of Minnesota IRB to approve a new consent


5/595

form, which disclosed to subjects that all three study drugs carried the risk of diabetes. This change wasprompted by a warning issued by the FDA. However, litigation against AstraZeneca has subsequentlyrevealed that the company knew about the risk of diabetes and other metabolic side-effects as early as2000, three years before Mr. Markingson was recruited into the CAF study, and possibly as early as1997 (Attachment J.) AstraZeneca did not inform subjects of these risks until 2004.

The CAF study targeted vulnerable subjects for recruitment.Before Markingson was enrolled into the CAF study, Quintiles had placed the University of

Minnesota trial site on probation for being slow to recruit subjects. The Minnesota site was strugglingto get patients, according to internal email correspondence, and Quintiles and was pressuring it to stepup its efforts. However, as the St. Paul Pioneer Press has reported, in April 2003 the University ofMinnesotas Department of Psychiatry established a locked inpatient unit designed for severelypsychotic patients. On this psychosis unit, called Station 12, every patient could be evaluated forrecruitment as a potential research subject (Attachment K.) While the establishment of Station 12increased recruitment numbers dramatically, I am concerned that severely psychotic patients on alocked unit are especially vulnerable to coercion or undue influence.

A University of Minnesota investigator helped AstraZeneca manipulate research data.

In April 2010, AstraZeneca agreed to pay $520 million to settle two federal investigations and twowhistleblower lawsuits alleging that it had marketed Seroquel illegally and concealed its health risks.Documents unsealed in that litigation indicate that Dr. Charles Schulz, the co-investigator on the CAFstudy, was involved in the misleading presentation of least two AstraZeneca studies. As the St. PaulPioneer Press has reported, an AstraZeneca trial called Study 15 found that Seroquel performed worsethan Haldol, a older, generic antipsychotic drug, and also that Seroquel increased the risk weight gainand diabetes. Yet Schulz claimed publicly and in scientific presentations that Seroquel had been shownsuperior to Haldol (Attachment L).

Later, as reported in City Pages, Schulz helped AstraZeneca conduct a trial called Study 41,which found that extended-release Seroquel was no more effective than a placebo. AstraZeneca thenrepeated the study overseas in the developing world, where the results proved much better.Subsequently, AstraZeneca enlisted Schulz to publicize the positive study in press releases, whilekeeping the negative study quiet (Attachment L).

I am also concerned that the design of the CAF study was biased to produce a favorable resultfor Seroquel. As a meta-analysis in theAmerican Journal of Psychiatry has shown, 90% of similarhead-to-head comparisons of atypical antipsychotics come out positively for whichever company hasdesigned and funded the trial. Several experts, including the editor of the British Journal of Psychiatry,have argued that the CAF study was similarly biased (Attachment M.)

University of Minnesota investigators failed to disclose crucial financial conflicts of interest tosubjects.

Research subjects have a right to know if study investigators have financial conflicts of interestthat might influence their care. However, subjects in the CAF study were not informed that the studyinvestigators had significant financial relationships with AstraZeneca, the CAF study sponsor, as wellas the manufacturers of the other atypical antipsychotics being studied. According to the St. PaulPioneer Press, Dr. Charles Schulz, a co-investigator on the CAF study, received over $570, 000 fromthe pharmaceutical industry from 2002 to 2008, with $112,000 coming from AstraZeneca. Also,subjects were not informed that the Department of Psychiatry was paid $15,648 for each subject who


6/595

completed the CAF study. This payment was arranged so that the longer a subject stayed in the study,the more the university would be paid. In total, the CAF study generated $327,000 for the Universityof Minnesotas Department of Psychiatry (Attachment N.)

Almost as alarming as these ethical violations is the refusal of University of Minnesota officialsto address them. Many of the violations reflect larger structural problems with the oversight of clinicalresearch at this institution which continue to place subjects at risk. Ordinarily, the primary

responsibility for protecting human subjects rests with the Institutional Review Board (IRB). In thiscase, however, the Institutional Review Board compounded the problem by failing to address criticalproblems with the protocol, such as the inclusion of potentially violent subjects. In a deposition, thedirector of the IRB, Moira Keane, claimed that protecting subjects was not the responsibility of the IRB(Attachment O.)

The suicide of Markingson was first made public through a series of articles in the St. PaulPioneer Press in May 2008. Since that time, officials at the University of Minnesota have repeatedlyasserted that the case has already been reviewed and that the university has been cleared of any blame.This claim is misleading at best. To the best of my knowledge, the University of Minnesota hasconducted no internal investigation apart from the routine adverse event review by the IRB, whichwas itself implicated in the case. The only external investigations have resulted from complaints filedby Mary Weiss and Mike Howard (a family friend) to agencies which have little if any responsibilityfor the protection of human subjects, such as the Minnesota Board of Medical Practice. While it is truethat the FDA investigated the case in 2005, in response to a complaint by Mary Weiss and MikeHoward, the FDA inspector restricted its investigation to very narrow grounds and produced a deeplyflawed inspection report (Appendix P.)

I have been given no reason to believe that officials at the University of Minnesota are willingto address the problems raised by this case. Two months after a lawsuit filed by Mary Weiss wasdismissed on technical grounds, the University of Minnesota filed a legal action a notice to assesscosts -- against Ms. Weiss, demanding that she pay the university $57,000 (Attachment Q). InDecember 2010, a group of university faculty members sent a public letter to the Board of Regentsasking for an external investigation. That request was followed by a supporting letter from a campusorganization, Faculty for the Renewal of Public Education. In February, the Board of Regents refusedthat request, claiming that the case had already been investigated (Attachment R.) Since that time,similar communications have come from the Mark Rotenberg in the Office of the General Counsel;Aaron Friedman, the Vice-President for Health Sciences and Dean of Medicine; and Tim Mulcahy, theVice-President for Research (Appendix S). The continued failure of University of Minnesota officialsto take these troubling issues seriously has left me deeply concerned about the protection of researchsubjects at our institution.

I hope you will agree to look into my concerns. If you have any further questions, I would behappy to talk to you further.

Yours sincerely,

Carl Elliott MD PhDProfessor, Center for Bioethics


7/595

ATTACHMENT A


8/595

Article

1050 Am J Psychiatry 164:7, July 2007ajp.psychiatryonline.org

This article is featured in this months AJPAudio.

Efficacy and Tolerability of Olanzapine, Quetiapine,and Risperidone in the Treatment of Early Psychosis:A Randomized, Double-Blind 52-Week Comparison

Joseph P. McEvoy, M.D.

Jeffrey A. Lieberman, M.D.

Diana O. Perkins, M.D., M.P.H.

Robert M. Hamer, Ph.D.

Hongbin Gu, Ph.D.

Arthur Lazarus, M.D., M.B.A.

Dennis Sweitzer, Ph.D.

Christina Olexy

Peter Weiden, M.D.

Stephen D. Strakowski, M.D.

Objective: This 52-week randomized,

double-blind, flexible-dose, multicenter

study evaluated the overall effectiveness

(as measured by treatment discontinua-

tion rates) of olanzapine, quetiapine, and

risperidone in patients early in the course

of psychotic illness.

Method: Patients were randomly as-

signed to treatment with olanzapine (2.5

20 mg/day), quetiapine (100800 mg/

day), or risperidone (0.54 mg/day) ad-

ministered in twice-daily doses. Statistical

analyses tested for noninferiority in all-

cause treatment discontinuation rates up

to 52 weeks (primary outcome measure)

based on a prespecified noninferiority

margin of 20%.

Results: A total of 400 patients were ran-

domly assigned to treatment with olanza-

pine (N=133), quetiapine (N=134), or ris-

peridone (N=133). The mean modal

prescribed daily doses were 11.7 mg for

olanzapine, 506 mg for quetiapine, and

2.4 mg for risperidone. At week 52, all-

cause treatment discontinuation rates

were 68.4%, 70.9%, and 71.4% for olanza-

pine, quetiapine, and risperidone, respec-

tively. Reductions in total score on the

Positive and Negative Syndrome Scale

(PANSS) were similar for the three treat-

ment groups, but reductions in PANSS

positive subscale scores were greater in

the olanzapine group (at 12 weeks and at

52 weeks or withdrawal from study) and

the risperidone group (at 12 weeks). The

most common elicited adverse events for

olanzapine were drowsiness (53%), weight

gain (51%), and insomnia (38%); for que-

tiapine, drowsiness (58%), increased sleephours (42%), and weight gain (40%); and

for risperidone, drowsiness (50%), men-

strual irregularities in women (47%), and

weight gain (41%).

Conclusions: Olanzapine, quetiapine,

and risperidone demonstrated compara-

ble effectiveness in early-psychosis pa-

tients, as indicated by similar rates of all-

cause treatment discontinuation.

(Am J Psychiatry 2007; 164:10501060)

Patients experiencing a first episode of psychosis have abetter therapeutic response to antipsychotic medications

than do chronic, multiepisode patients (1, 2). Despite this

good clinical response, however, the majority of first-epi-

sode patients discontinue their initial antipsychotic medi-

cation, often not continuing treatment with another med-

ication (13), which places them at high risk of psychotic

relapse and clinical deterioration (4).

Comparative studies of atypical versus conventional an-

tipsychotics in patients with first-episode psychosis dem-

onstrate reduced extrapyramidal side effects and equal or

slightly superior efficacy for the atypical antipsychotics (510). First-episode patients respond to lower doses and

demonstrate a greater sensitivity to antipsychotic treat-

ment-related side effects (6, 7, 11) than do multiepisode

patients.

Few studies have compared atypical antipsychotics to

determine their relative effectiveness in a first-episode

population. Studies comparing olanzapine and risperi-

done in first-episode patients suggest similar efficacy for

the two treatments, with few extrapyramidal side effects,

although olanzapine is associated with more weight gain

(12, 13). Preliminary noncomparative studies suggest that

quetiapine is efficacious and well-tolerated in first-epi-

sode patients (1416). The purpose of this study was to de-

termine the overall effectiveness of quetiapine relative to

two established standards, olanzapine and risperidone, in

patients early in the course of psychotic illness. The pri-

mary outcome measure was the percentage of patients

discontinuing their assigned antipsychotic (all-cause

treatment discontinuation) during the 52 weeks of treat-

ment. This measure integrates the efficacy and tolerabilityof each drug over time. The primary hypothesis was that

quetiapine was not inferior to olanzapine or risperidone

in the rate of all-cause treatment discontinuation in early-

psychosis patients. No prior data suggested that superior-

ity for quetiapine was a likely outcome.

Previous studies suggested that first-episode patients

receive good therapeutic benefit from olanzapine with

doses in the range of 1015 mg/day (6) and that the effec-


9/595

Am J Psychiatry 164:7, July 2007 1051

MCEVOY, LIEBERMAN, PERKINS, ET AL.

ajp.psychiatryonline.org

tiveness of risperidone may be reduced by extrapyramidal

side effects if doses exceed 24 mg/day (3, 5, 9). Given que-

tiapines low liability for extrapyramidal side effects, we

speculated that doses up to 800 mg/day would be tolera-ble in our study population.

Secondary measures of psychopathology, quality of life,

and side effects were obtained to delineate differential ef-

fects of each drug on efficacy, tolerability, and safety.

Method

Study Design

This was a 52-week randomized, double-blind, flexible-dose,

multicenter study of patients early in the course of schizophrenia,

schizoaffective disorder, or schizophreniform disorder assigned to

treatment with olanzapine, quetiapine, or risperidone.

Study PopulationParticipants were recruited from inpatient, outpatient, and

emergency department services for the evaluation and treatment

of psychosis. The study was approved by the institutional review

board at each site, and written informed consent was obtained

from the patients or their legally authorized representatives. Pa-

tients had to be able to participate in the informed consent pro-

cess or have a legal guardian available to provide informed con-

sent. Consenting patients 1640 years of age were eligible for the

study if they met DSM-IV criteria for schizophrenia, schizo-

phreniform disorder, or schizoaffective disorder. Patients had to

be in the first episode of their psychotic illness and had to have

been continuously ill for at least 1 month and no more than 5

years. Patients were excluded if a prior psychotic episode had re-

mitted for 3 months or more or if they had prior antipsychotic

drug treatment for more than 16 cumulative weeks. All patients

had a score 4 on at least one Positive and Negative Syndrome

Scale (PANSS; 17) psychosis item (delusions, conceptual disorga-

nization, hallucinatory behavior, grandiosity, or suspiciousness/

persecution) and a score 4 (moderately ill) on the severity item

of the Clinical Global Impression scale (CGI; 19) at the point of

maximum severity of illness to date. Female participants of child-

bearing potential had to be using a medically acceptable form of

contraception.

We excluded patients who did not speak English; had a history

of mental retardation; were pregnant or nursing; had a serious,

unstable medical illness; had a known allergy to one of the study

medications; were at serious risk of suicide; or had participated in

an investigational drug trial within 30 days before the first treat-

ment visit.

Study TreatmentsPatients were randomly assigned to treatment with olanzapine

(2.520 mg/day), quetiapine (100800 mg/day), or risperidone

(0.54 mg/day). On days 1 and 2, each patient received one cap-

sule of olanzapine (2.5 mg), quetiapine (100 mg), or risperidone

(0.5 mg) in the evening. At the treating physicians discretion, the

dose could be increased by one capsule every other dayi.e., on

days 3 and 4, one capsule in the morning and one in the evening;

on days 5 and 6, one capsule in the morning and two in the

evening; and so on, up to a maximum of four capsules twice daily.

Any previous antipsychotic therapy was tapered and discontin-

ued during the first 2 weeks of double-blind treatment, and no

TABLE 1. Baseline Characteristics of 400 Early-Psychosis Patients Randomly Assigned to Treatment With Olanzapine,Quetiapine, or Risperidonea

Characteristic

Treatment Group

All Patients (N=400)Olanzapine (N=133) Quetiapine (N=134) Risperidone (N=133)

N % N % N % N %Female 32 24.1 42 31.3 34 25.6 108 27.0Ethnicity

White 61 45.9 66 49.3 78 58.7 205 51.3Black 61 45.9 60 44.8 51 38.4 172 43.0

Other 11 8.3 8 6.0 4 3.0 23 5.8DSM-IV diagnosis

Schizophrenia 81 60.9 75 56.0 75 56.4 231 57.8Schizophreniform disorder 35 26.3 42 31.3 38 28.6 115 28.8Schizoaffective disorder 17 12.8 17 12.7 20 15.0 54 13.5

Antipsychotic naive 32 24.2 36 26.9 28 21.1 96 24.1Illness onset >60 months

before baseline1 0.8 4 3.1 4 3.2 9 2.4

Inpatient treatment 29 21.8 29 21.6 26 19.7 84 21.1Age >40 years 3 2.3 2 1.5 2 1.5 7 1.8Previous antipsychotic

treatment 16 weeks total7 7.1 6 6.1 3 2.9 16 5.4

Mean/Median

SD/Range

Mean/Median

SD/Range

Mean/Median

SD/Range

Mean/Median

SD/Range

Duration of previousantipsychotic use (weeks)Mean (SD) 6.9 8.81 6.6 7.34 5.4 4.97 6.3 7.20

Median (range) 4.0 1.052.0 4.0 1.046.3 4.0 0.027.0 4.0 0.052.0Duration of illness (months)

Mean (SD) 11.0 12.86 15.1 20.04 12.7 17.90 12.9 17.29Median (range) 5.4 0.462.3 7.3 0.9166.4 6.1 0.4124.0 6.5 0.4166.4

Age (years)Mean (SD) 24.7 5.8 25.0 6.1 23.9 5.5 24.5 5.8Median (range) 23.1 16.542.0 23.0 16.444.4 22.6 16.543.9 23.0 16.444.4

Age at onset (years)Mean (SD) 23.4 5.3 23.9 5.7 23.0 5.7 23.5 5.6Median (range) 21.8 16.241.3 22.2 15.343.3 21.4 13.043.6 21.8 13.043.6

a Treatment groups did not differ significantly on any characteristic.


10/595

1052 Am J Psychiatry 164:7, July 2007

EFFICACY AND TOLERABILITY OF ATYPICAL ANTIPSYCHOTICS


subsequent use of an additional antipsychotic was permitted.

Treatment with an adjunctive antidepressant or mood stabilizer

during the first 8 weeks of treatment was not allowed unless ap-

proved by the project medical officer. Anticholinergic medications

for acute extrapyramidal side effects were permitted for up to a to-

tal of 2 weeks over the course of the trial. Clinicians were encour-

aged to lower the dose of antipsychotic to relieve extrapyramidal

side effects. Otherwise, adjunctive medications (prescribed to ad-

dress an aspect of psychopathology inadequately controlled by

the assigned antipsychotic) and concomitant medications (pre-

scribed to treat a side effect or a comorbid medical illness) could

be used without restriction. When an adjunctive or concomitant

medication was prescribed, its name, modal dose, and indication

(selected from forced-choice lists) were recorded.

Assessments

The screening evaluation included a diagnostic interview (the

Structured Clinical Interview for DSM-IV [1 8]), medical history,

physical examination, measurement of vital signs, and laboratory

tests. Confirmation that the illness met clinical severity criteria

TABLE 2. Least Square Mean (LSM) Change From Baseline on Efficacy Measures in Early-Psychosis Patients at Weeks 12 and52 of Treatment With Olanzapine, Quetiapine, or Risperidonea

Variable

Treatment Group

Olanzapine Quetiapine

Baseline (N=134) Week 12 (N=85) Week 52 (N=37) Baseline (N=133) Week 12 (N=96) Week 52 (N=44)

Mean SDLSM

Change SELSM

Change SE Mean SDLSM

Change SELSM

Change SE

Positive and NegativeSyndrome ScalePositive subscale score 18.8 5.12 5.2 0.36 7.1 0.51 18.6 4.99 4.0b 0.35 5.3c 0.51Negative subscale score 19.9 6.27 2.9 0.37 3.5 0.51 19.5 6.18 2.1 0.36 2.8 0.52General psychopatho-

logy subscale score35.6 8.56 6.3 0.57 7.9 0.81 36.1 8.28 5.5 0.56 7.6 0.82

Total score 74.3 16.27 14.3 1.12 18.4 1.60 74.2 15.15 11.6 1.11 15.6 1.61Clinical Global Impression

scale, severity item4.3 0.75 0.9 0.07 1.3 0.11 4.3 0.69 0.8 0.07 1.2 0.11

Calgary Depression Scalefor Schizophrenia score

12.9 4.15 1.1 0.23 1.2 0.33 13.2 4.30 1.5 0.23 2.1 0.33

Heinrichs-CarpenterQuality of Life Scale,social subscale

9.1 6.80 1.1 0.58 3.0 0.86 8.7 7.10 0.3 0.58 2.2 0.88

Heinrichs-CarpenterQuality of Life Scale,vocational subscale

20.4 10.18 1.6 0.85 4.7 1.25 20.5 9.64 0.2 0.85 2.9 1.29

a Analyzed using a mixed random coefficients model with fixed effects for treatment, baseline, and center and with random effects for the

intercept and log (time). The listed Ns for weeks 12 and 52 for each group are maximums for the visit. Because of sporadic missing data, thenumber used in the analysis for each specific variable may be slightly different.

b Week 12: quetiapine versus olanzapine, p=0.017; quetiapine versus risperidone, p=0.031.c Week 52: quetiapine versus olanzapine, p=0.013.

TABLE 3. Elicited Adverse Events of Moderate Severity or Worsea in 400 Early-Psychosis Patients During Treatment WithOlanzapine, Quetiapine, or Risperidone (Intent-to-Treat Population)

Adverse Event

Treatment Group

All Patients (N=400)Olanzapine (N=133) Quetiapine (N=134) Risperidone (N=133)

N % N % N % N %

Daytime drowsiness 71 53.4 77 57.5 66 49.6 214 53.5Weight gain 68 51.1 54 40.3 55 41.4 177 44.3Increased sleep hours 45 33.8 56 41.8 36 27.1 137 34.3Insomnia 51 38.4 39 29.1 45 33.8 135 33.8Menstrual irregularitiesb 10 31.3 10 23.8 16 47.1 36 33.3

Decreased sex drive 37 27.8 35 26.1 36 27.1 108 27.0Akinesia 32 24.1 33 24.6 36 27.1 101 25.3Dry mouth 29 21.8 46 34.3 21 15.8 96 24.0Akathisia 27 20.3 25 18.7 30 22.6 82 20.5Decreased sexual arousal 29 21.8 22 16.4 24 18.1 75 18.8Decreased orgasm 22 16.5 21 15.7 25 18.8 68 17.0Orthostatic faintness 15 11.3 26 19.4 17 12.8 58 14.5Constipation 11 8.3 16 11.9 18 13.5 45 11.3Sialorrhea 7 5.3 8 6.0 18 13.5 33 8.3Skin rash 10 7.5 7 5.2 9 6.8 26 6.5Gynecomastia 9 6.8 3 2.2 13 9.8 25 6.3Urinary hesitancy 7 5.3 7 5.2 4 3.0 18 4.5Incontinence or nocturia 5 3.8 5 3.7 4 3.0 14 3.5Galactorrhea 3 2.3 0 0.0 3 2.3 6 1.5a The table includes patients for whom adverse events were scored at least moderate in severity by the treating cl inician at some point during

the study.b Percentages are based on the total number of women in the study.


11/595




was established by a modified, abbreviated version of the PANSS

that included items P1P6 and rated symptom severity at the point

of maximum severity of illness.

Study visits occurred at baseline, at weekly intervals for the first

6 weeks, every other week for the next 6 weeks, and monthly there-

after. All clinical and laboratory assessments were obtained at

baseline, week 12, and week 52 or when the patient terminated the

study before week 52. Measures of psychopathology, function, tol-

erability, and safety were completed at intermediate visits as spec-

ified in a schedule of events for the study.The primary outcome measure was the proportion of patients

who withdrew from the study prior to 52 weeks of treatment (all-

cause pharmacological treatment discontinuation). The reason

for discontinuation was recorded according to a predetermined

algorithm: 1) administrative discontinuation due to an indepen-

dent external event (e.g., moving with family to another state); 2) a

clinician decision to discontinue treatment because of inadequate

therapeutic effect or intolerable side effects whether or not the pa-

tient wanted to discontinue; or 3) a patient decision to discon-

tinue although the clinician believed the treatment to be ade-

quately efficacious, tolerable, and safe.

Efficacy was measured in two domains: 1) psychopathology and

2) social and occupational functioning. Psychopathology was as-

sessed by the PANSS, the CGI, and the Calgary Depression Scale

for Schizophrenia (20). Social and occupational functioning was

assessed with the Heinrichs-Carpenter Quality of Life Scale (21).

Clinical response was defined as a score 3 on all PANSS items and

3 on the CGI severity item at any time during the trial.

The number of pills taken was determined by pill counts, and

use of concomitant or adjunctive medication was recorded at each

study visit. The modal dose for each patient within a treatment

group was the dose prescribed for that patient on the maximum

number of days during the trial. The mean modal dose for each

treatment group was defined as the mean of the modal doses pre-

scribed for the patients assigned to that treatment.

Clinicians rated the severity of 19 medication-related elicited

adverse events on a checklist at each visit. Severity of akathisia was

determined with the Barnes Akathisia Rating Scale (23), parkinso-

nian signs with the Simpson-Angus Scale (22), and dyskinetic

movements with the Abnormal Involuntary Movement Scale (19).

The most severe scores recorded at any time during the study pe-

riod are reported.

Laboratory tests evaluated glucose, lipids, and prolactin levels.

At each blood draw, the patients report of the number of hours

since consumption of any food or caloric drink was recorded. Fast-

ing was defined as no caloric consumption for 8 or more hours

prior to the blood draw. Weight and waist circumference were

recorded.

Risperidone

Baseline (N=133) Week 12 (N=86) Week 52 (N=37)

Mean SDLSM

Change SELSM

Change SE

18.4 5.15 5.1 0.36 6.6 0.5219.4 6.09 2.6 0.37 3.6 0.5235.1 8.73 6.2 0.57 8.4 0.83

73.0 15.94 13.7 1.12 18.5 1.634.2 0.85 0.9 0.07 1.3 0.11

13.0 4.01 1.0 0.24 1.3 0.33

9.0 7.20 1.2 0.59 3.7 0.91

21.7 11.09 1.5 0.86 5.7 1.32

FIGURE 1. Treatment Discontinuation by 52 Weeks in 400Early-Psychosis Patients Taking Olanzapine, Quetiapine, orRisperidone (Intent-to-Treat Population)a

a The Blackwelder noninferiority method (24) was used for compari-

sons between quetiapine and olanzapine or risperidone using aprotocol-defined 20% equivalence margin.

b Percentage differences, quetiapine versus olanzapine: 2.5 (95% CI=8.55to 13.50); quetiapine versus risperidone: 0.5 (95% CI=11.4 to 10.33).

c Percentage differences, quetiapine versus olanzapine: 6.7 (95% CI=0.58to 12.79); quetiapine versus risperidone: 0.7 (95% CI=6.56 to 7.90).

d Percentage differences, inadequate therapeutic effect, quetiapineversus olanzapine: 0.7 (95% CI=7.02 to 8.35); quetiapine versusrisperidone: 2.9 (95% CI=4.42 to .26); unacceptable side effects,quetiapine versus olanzapine: 0.8 (95% CI=8.06 to 6.41); quetia-pine versus risperidone: 0.1 (95% CI=7.19 to 7.04); patient deci-sion, quetiapine versus olanzapine: 4.1 (95% CI=15.8 to 7.73);quetiapine versus risperidone: 4.1 (95% CI=15.8 to 7.73).

Olanzapine(N=133)

Quetiapine(N=134)

Risperidone(N=133)

Continued

treatment(N=42, 31.6%)

Continued


Continued


Discontinuedtreatment, all

causes (N=91,68.4%):

Administrativecauses (N=5,

3.8%)

Clinical causes:Inadequate

therapeuticeffect (N=15,11.3%)

Unacceptableside effects(N=14, 10.5%)

Patient decision(N=57, 42.9%)


causes (N=95,70.9%)b:


10.5%)c

Clinical causesd:Inadequate




Total all-cause discontinuations (N=281, 70.3%):

Administrative causes (N=32, 8.0%)

Clinical causes:Inadequate therapeutic effect (N=43, 10.8%)Unacceptable side effects (N=40, 10.0%)

Patient decision (N=166, 41.5%)


causes (N=95,71.4%):


9.8%)

Clinical causes:Inadequate





12/595




Statistical Analysis

The protocol-designated primary hypothesis was that quetia-

pine was not inferior to olanzapine or risperidone in the rate of all-

cause treatment discontinuation in early-psychosis patients. The

primary hypothesis was tested with the protocol-designated sta-

tistical analysis of Blackwelders (24) noninferiority normal ap-

proximation method with a noninferiority margin of 0.20 (20%),

using a significance level of 0.025 for each of the two pairwise

comparisons. All analyses were specified in a statistical analysis

plan that was finalized before the blind was broken. Kaplan-Meier

survival curves and a log-rank test were used to assess time to dis-

continuation. Pairwise comparisons of time to discontinuation

between treatments were performed using the log-rank test.

Baseline measures of demographic and clinical characteristics

were compared using Fishers exact test for categorical variables

or a Kruskal-Wallis test for continuous variables. Efficacy mea-sures (PANSS, Calgary Depression Scale for Schizophrenia, CGI,

and Heinrichs-Carpenter Quality of Life Scale) were tested using a

mixed random coefficients model with fixed effects for treatment,

baseline, and center and with random effects for the intercept

and log (time).

Efficacy analyses used a modified intent-to-treat population,

defined as patients who were randomly assigned to a treatment

and returned for at least one postrandomization assessment.

Baseline descriptive statistics are presented using the intent-to-

treat population, which contained all patients who underwent

random assignment to a treatment.

TABLE 4. Change From Baseline in Weight and Related Measures in Early-Psychosis Patients at Weeks 12 and 52 ofTreatment With Olanzapine, Quetiapine, or Risperidonea

Measure

Olanzapine


Mean SDLSM

Change SELSM

Change SEWeight (lbs) 172.0 43.77 15.7b 1.01 24.4b 1.75

Male 172.9 38.90 16.1b 1.21 24.9b 2.05

Female 168.8 57.26 19.1 3.05 14.3 1.68Body mass index (kg/m2) 25.8 6.20 2.4d 0.15 3.7d 0.26

Male 25.0 4.66 2.3d 0.18 3.6d 0.30Female 28.5 9.17 2.4 0.28 3.8 0.52

Waist circumference (in)Male 35.2 5.16 1.7 0.30 3.5 0.51Female 35.6 7.58 2.2 0.57 3.2 1.30

N % N %Weight gain 7% 58 59.8f 28 80.0f

Male 43 59.7g 23 79.3Female 15 60.0 5 83.3

Body mass index increase 1 unit 75 78.1i 31 88.6Male 53 74.6 26 89.7j

Female 22 88.0k 5 83.3Male waist circumference >40 in 20 30.3 12 46.2Female waist circumference >35 in 14 82.4l 5 100.0a Changes in continuous measures were analyzed using a mixed model similar to that used for the efficacy measures, and changes in categor-

ical measures were analyzed using logistic regression with treatment as the predictor. The listed Ns for weeks 12 and 52 for each group aremaximums for the visit. Because of sporadic missing data, the number used in the analysis for each specific variable may be slightly different.

b Weight and male weight: quetiapine or risperidone vs. olanzapine (weeks 12 and 52), p


13/595




Postbaseline rates of elicited adverse events were compared us-

ing Fishers exact test. Between-groups differences that met the sig-nificance threshold of p0.05 are reported without adjustment for

multiple comparisons. Because extrapyramidal side effects were

minimized by reducing the antipsychotic dose as soon as possible

when symptoms appeared, the scores reported for the Simpson-

Angus Scale, the Abnormal Involuntary Movement Scale, and the

Barnes Akathisia Rating Scale represent worst-case postbaseline

values. These were compared using Fishers exact test for categori-

cal variables and the Kruskal-Wallis test for continuous variables.

Changes in continuous measures of weight, body mass index (BMI),

waist circumference, and metabolic parameters were analyzed us-

ing a mixed model similar to that used for the efficacy measures,

while changes in categorized measures of these parameters were

analyzed using logistic regression with treatment as the predictor.

Sensitivity analyses for secondary variables were performed us-

ing last observation carried forward and observed case analyses to

investigate whether the results of the mixed models were similar

to those obtained using the observed case and last observation

carried forward methods. All analyses of efficacy, weight, and met-

abolic measures were tested at the nominal significance threshold

of p0.05, without adjustment for multiple comparisons.

Results

Baseline Characteristics

Table 1 presents demographic and clinical characteris-

tics for the three treatment groups and the whole cohort.

There were no significant differences between treatment

groups. Patients showed moderate levels of psychopathol-ogy at baseline, with a mean total score of 73.8 (SD=15.8)

on the PANSS, a mean score of 4.3 (SD=0.8) on the CGI se-

verity item, and a mean total score of 13.0 (SD=4.2) on the

Calgary Depression Scale for Schizophrenia. After case-

by-case discussions with site investigators, the project

medical officer ( J.P.M.) allowed the enrollment of nine pa-

tients who had been ill for more than 60 months, seven pa-

tients who were over 40 years of age, and 16 patients who

had taken antipsychotics for more than 16 weeks.

Pharmacological Treatments

The mean modal number of capsules prescribed perday was 4.7 (SD=2.1) for olanzapine, 5.1 (SD=2.2) for que-

tiapine, and 4.7 (SD=2.0) for risperidone, which resulted in

a mean modal prescribed daily dose of 11.7 mg (SD=5.3)

for olanzapine, 506 mg (SD=215) for quetiapine, and 2.4

mg (SD=1.0) for risperidone. Over the course of the trial,

19% of patients in the olanzapine group, 20% of patients in

the quetiapine group, and 11% of patients in the risperi-

done group were brought to the maximum allowed dose of

four capsules twice daily.

Treatment Group

Quetiapine Risperidone


Mean SDLSM

Change SELSM


Change SELSM

Change SE170.3 41.12 8.12b 1.00 12.49b 1.73 173.1 42.43 8.87 1.01 14.5 1.74175.2 36.44 9.38b 1.28 15.2b 2.17 177.4 39.16 8.18 1.21 13.0 2.06

159.4 48.60 4.65c 1.41 6.47c 2.55 161.1 49.29 11.0 1.72 19.1 3.0525.5 5.22 1.2d 0.15 1.9d 0.26 26.1 5.62 1.4 0.15 2.3 0.2725.4 5.03 1.4d 0.19 2.2d 0.32 25.7 5.01 1.2 0.18 2.0 0.3025.9 5.67 0.8e 0.24 1.1e 0.43 27.2 7.01 1.8 0.29 3.1 0.51

34.9 5.08 1.1 0.32 2.1 0.59 35.4 5.55 1.2 0.31 2.4 0.5634.8 5.84 0.5 0.44 0.0 0.90 36.2 7.69 0.1 0.59 0.8 1.21

N % N % N % N %26 29.2f 15 50.0f 27 32.5g 19 57.6g

20 35.7 11 64.7 20 31.3 11 45.86 18.2h 4 30.8h 7 36.8 8 88.9

45 50.6i 19 63.3i 49 59.8 23 69.731 55.4j 12 70.6 39 61.9 15 62.514 42.4k 7 53.8 10 52.6 8 88.99 19.6 3 21.4 10 18.5 5 25.0

15 55.6 8 61.5 7 46.7 3 50.0


14/595




During the study, patients received adjunctive medica-

tions mainly for dysphoria/depression (25.7%), anxiety

(16.5%), insomnia (15.2%), and agitation/excitement(9.9%). There were no significant differences in postbase-

line adjunctive medication use between treatment groups.

Primary Outcome Measure

Figure 1 shows rates of all-cause treatment discontinua-

tion across the three treatment groups. Overall, 70% of pa-

tients discontinued treatment before 52 weeks: 68.4% of

those assigned to olanzapine, 70.9% of those assigned to

quetiapine, and 71.4% of those assigned to risperidone.

Based on the prespecified primary outcome measure of a

20% margin for clinically significant inferiority, quetiapine

proved noninferior to olanzapine or risperidone. The ab-

solute difference between quetiapine and olanzapine was

2.5%, with an upper-bound one-sided 97.5% confidence

interval (CI) of 13.5%, while the absolute difference be-

tween quetiapine and risperidone was 0.5%, with an up-

per-bound one-sided 97.5% CI of 10.3%. Patients receiving

olanzapine had fewer administrative discontinuations

(3.8%) than those receiving quetiapine (10.5%) or risperi-

done (9.8%), but there were no other notable differences

across the treatment groups in reasons for discontinua-

tion. The most frequent reason for discontinuation across

the entire study population was patient decision despite

the recommendations of the treating clinician to continue

treatment (41.5%). Only 10.8% discontinued because ofinadequate therapeutic effect, and only 10.0% because of

intolerable side effects.

Figure 2 displays the survival curves to all-cause treat-

ment discontinuation. The median times to all-cause

discontinuation for olanzapine (28 weeks), quetiapine

(25 weeks), and risperidone (25 weeks) did not differ

significantly.

Secondary Outcome Measures

Table 2 presents the least square mean change from

baseline scores on efficacy measures at 12 and 52 weeks.

All treatment groups showed improvements in symptoms,

with no significant differences across groups in PANSS to-

tal scores. At 12 weeks, the mean change from baseline in

the PANSS positive subscale scores showed greater reduc-

tions for olanzapine (5.2) and risperidone (5.1) than for

quetiapine (4.0; quetiapine versus olanzapine, p=0.017;

quetiapine versus risperidone, p=0.031), but this signifi-

cant difference persisted only with olanzapine at week 52

(5.3 for quetiapine versus 7.1 for olanzapine, p=0.013).

On all other measures, the three treatment groups did not

differ significantly.

TABLE 5. Change from Baseline in Metabolism-Related Measures and Prolactin Level in Early-Psychosis Patients at Weeks12 and 52 of Treatment With Olanzapine, Quetiapine, or Risperidonea

Variable

Olanzapine


Mean SDLSM

Change SELSM

Change SEFasting triglycerides level (mg/dl) 99.7 58.13 32.3 11.77 66.4 12.90b

Fasting glucose level (mg/dl) 85.3 9.83 1.7 1.39 8.6 1.59

Fasting total cholesterol level (mg/dl) 174.8 34.28 8.9 4.62 15.7 4.30Fasting high-density lipoprotein cholesterol level (mg/dl) 48.0 12.45 3.8 1.08d 6.5 0.91d

Male 47.5 12.25 3.9 1.17 6.7 0.98e

Female 50.0 13.58 2.5 2.59 3.9 2.37Prolactin level 27.9 27.70 16.4 2.76f 15.9 2.56f

Systolic blood pressure (mm Hg) 117.3 12.79 1.5 1.18g 8.5 1.22g

Diastolic blood pressure (mm Hg) 73.0 9.60 0.0 0.84 4.8 0.82h

N % N % N %Fasting 8 hours 80 64.0 59 62.1 78 75.0Fasting triglycerides level >150 mg/dl 6 7.7 11 25.0 22 40.0Fasting glucose level 100 mg/dl 4 5.13 5 11.9 14 25.5Fasting total cholesterol level 200 mg/dl 19 24.4 13 29.5 23 41.8Male fasting high-density lipoprotein cholesterol level


15/595




Sixty-four percent of patients in the olanzapine group,

58% of patients in the quetiapine group, and 65% of pa-

tients in the risperidone group met the treatment re-sponse criteria (3 for all PANSS items and 3 for the CGI

severity item) at some point during the study. The rates of

response were not significantly different between the

treatment groups.

Safety and Tolerability

Adverse Events. A total of 18 serious adverse events oc-

curred, four in the olanzapine group and seven each in the

quetiapine and risperidone groups. These events included

two suicide attempts and one alleged homicide in the

olanzapine group, two completed suicides and one case of

suicidal ideation in the quetiapine group, and one suicide

attempt in the risperidone group.

The rates of elicited adverse events that clinicians scored

as moderate or severe are presented in Table 3. The most

frequent adverse events in the olanzapine group were day-

time drowsiness (53%), weight gain (51%), and insomnia

(38%); in the quetiapine group, daytime drowsiness (58%),

increased sleep hours (42%), and weight gain (40%); in the

risperidone group, daytime drowsiness (50%), menstrual

irregularities in women (47%), and weight gain (41%). Dry

mouth was more common in the quetiapine group than in

the other two groups. Sialorrhea was more common in the

risperidone group than in the other two groups. Gyneco-

mastia was more common in the risperidone group than inthe quetiapine group. Hypersomnia was more common in

the quetiapine group than in the risperidone group.

Extrapyramidal Symptoms. Over the course of the

trial, only 16% of patients had a rating>1 (mild) on any

Simpson-Angus Scale item, only 7% had a rating>2 (mild)

on the global severity item of the Barnes Akathisia Rating

Scale, and only 1% had a score >2 (mild) on the global se-

verity item of the Abnormal Involuntary Movement Scale.

There were no significant differences across treatment

groups. The proportion of patients receiving concomitant

medications for parkinsonism or akathisia was lower in

the quetiapine group (4%) than in the olanzapine group(11%, p=0.021).

Physical Measures and Laboratory Tests

Weight and BMI. Olanzapine was associated with the

greatest increases in body weight and related measures

(Table 4). At week 12, the olanzapine group had more

weight gain, a greater increase in BMI, and a higher pro-

portion of patients with a BMI increase of at least 1 unit

compared with the quetiapine and risperidone groups.

Similar differences between olanzapine and quetiapine or

Treatment Group

Quetiapine Risperidone


Mean SDLSM

Change SELSM


Change SELSM

Change SE115.4 72.56 52.9 12.16 68.1 13.37b 116.1 68.38 18.2 12.81 19.1 13.92

85.8 9.25 3.8 1.42 6.2 1.67 86.5 12.31 1.5 1.50 4.8 1.70

180.5 38.50 19.3 4.78 25.2 4.46c

176.3 34.27 7.2 5.02 11.4 4.6548.7 12.99 2.2 1.12 3.6 0.95d 47.4 11.81 0.5 1.18 2.6 0.9947.5 13.11 3.0 1.37 3.6 1.12f 46.6 11.00 1.6 1.34 2.9 1.1351.5 12.51 1.2 1.81 4.5 1.73 49.8 14.08 3.2 2.25 1.9 1.9335.5 36.90 18.5 2.92f 18.7 2.66f 32.7 40.28 13.3 2.90 12.1 2.61

119.5 12.42 1.9 1.16g 7.5 1.21g 118.4 11.59 2.8 1.25 2.7 1.2775.7 10.56 0.5 0.83 4.1 0.82 73.9 9.57 1.5 0.89 1.8 0.86

N % N % N % N % N % N %80 62.5 56 62.9 74 72.5 80 63.0 48 58.5 70 72.215 19.0 22 53.7i 29 56.9i 16 20.5 10 27.0 14 29.88 10.4 5 12.5 10 20.0 6 7.6 1 2.8 6 12.5

22 27.9 19 46.3 23 45.1 17 21.8 13 35.1 18 38.315 28.3 9 33.3 15 41.7 16 28.1 9 32.1 12 34.39 40.9 6 42.9 9 60.0 9 50.0 4 44.4 7 58.3

34 25.8 26 25.5 40 35.7 23 18.3 12 13.8 24 23.819 14.4 18 17.6 32 28.6k 16 12.7 8 9.2 16 15.8


16/595




risperidone were also observed at week 52 except in the

proportion of patients with a BMI increase of at least 1 unit

in the risperidone group. Furthermore, 80% of patients in

the olanzapine group had gained 7% of their baseline

weight at week 52, compared with 50% and 58% of the

quetiapine and risperidone groups, respectively (observed

cases). Risperidone was associated with greater increases

than quetiapine in weight and BMI in women (p


17/595




Received Sept. 13, 2005; revisions received May 25 and Sept. 19,

2006, and Jan. 16, 2007; accepted Feb. 1, 2007. From the Duke Uni-

versity Medical Center, Durham, N.C.; the Department of Psychiatry,

College of Physicians and Surgeons, Columbia University, New York;

the Department of Psychiatry, University of North Carolina School of

Medicine, Chapel Hill, N.C.; AstraZeneca Pharmaceuticals LP, Wilm-

ington, Del.; SUNY Downstate Medical Center, Brooklyn, New York;

and the University of Cincinnati College of Medicine, Cincinnati, Ohio.

Address correspondence and reprint requests to Dr. McEvoy, Clini-

cal Research Service, John Umstead Hospital, 1003 12th St., Bldg. 32,

Butner, NC 27509; [email protected] (e-mail).

Dr.McEvoy has received research funding or speakingfees from As-

traZeneca, Eli Lilly, and Janssen. Dr. Lieberman has received research

funding from Acadia, Bristol-Myers Squibb, GlaxoSmithKline, Janssen,

Merck, Organon, and Pfizer and holds a patent related to work with

Repligen. He has also served without remuneration as a consultant

or on advisory boards for AstraZeneca, Eli Lilly, GlaxoSmithKline,

Lundbeck, Organon, and Pfizer. Dr. Perkins has received research

funding from AstraZeneca, Bristol-Myers Squibb, Otsuka, Eli Lilly, Jan-

ssen, and Pfizer and consulting and educational fees from AstraZen-

eca, Bristol-Myers Squibb, Eli Lilly, Janssen, GlaxoSmithKline, Forest

Labs, Pfizer, and Shire. Dr. Hamer has served in an advisory, consult-

ing, or data monitoring capacity for or has been involved in a con-

tract agreement between University of North Carolina and the fol-

lowing: Wyeth, Allergan, AstraZeneca, Corcept Pharmaceuticals, Epix

Pharmaceuticals, GlaxoSmithKline, Johnson & Johnson, Eli Lilly,

Pfizer, SAS Institute, Schwartz, Solvay, and Somerset Pharmaceuticals.

He or his wife holds shares of stock from Amgen, Bristol-Myers

Squibb, Eli Lilly, Genentech, Proctor & Gamble, and Sepracor. Dr.

Weiden has received grant support or speaker or consulting fees

from AstraZeneca, Bristol-Myers Squibb (Otsuka), Janssen, Langeloth

Foundation, NIMH, Pfizer, Shire, Solvay, and Vanda. Dr. Strakowski

has received grant support or speaker or consulting fees from Ab-

bott, AstraZeneca, DiMedix, Eli Lilly, France Foundation, Janssen, For-

est, Nutrition 21, Pfizer, and Repligen. Dr. Lazarus is an employee of

AstraZeneca and holds stock options with the firm. Dr. Sweitzer is an

employee of AstraZeneca, owns shares of AstraZeneca, and holds

stock options with the firm. Ms. Olexy is an employee of AstraZeneca.

Dr. Gu reports no competing interests.

The Comparison of Atypicals in First Episode of Psychosis research

program was coordinated by the University of North Carolina. Fund-

ing for this program was provided by AstraZeneca Pharmaceuticals

LP (5077IL/0114). The authors acknowledge the assistance of SandraWoolson for statistical programming.

This study is registered at www.ClinicalTrials.gov under the title

CAFE: Comparison of Atypicals in First Episode of Psychosis (gov-

Identifier: NCT00034892, Study ID Numbers: 5077IL/0114). All crite-

ria as stated in the Clinical Trial Registration policy have been met.

References

1. Lieberman J, Jody D, Geisler S, Alvir J, Loebel A, Szymanski S,

Woerner M, Borenstein M: Time course and biologic correlates

of treatment response in first-episode schizophrenia. Arch Gen

Psychiatry 1993; 50:369376

2. Robinson DG, Woerner MG, Alvir JMJ, Geisler S, Koreen A, Sheit-

man B, Chakos M, Mayerhoff D, Bilder R, Goldman R, Lieber-

man JA: Predictors of treatment response from a first episodeof schizophrenia or schizoaffective disorder. Am J Psychiatry

1999; 156:544549

3. Gaebel W, Moller HJ, Buchkremer G, Ohmann C, Riesbeck M,

Wolwer W, Von Wilmsdorff M, Bottlender R, Klingberg S: Phar-

macological long-term treatment strategies in first episode

schizophrenia: study design and preliminary results of an on-

going RCT within the German Research Network on Schizo-

phrenia. Eur Arch Psychiatry Clin Neurosci 2004; 254:129140

4. Lieberman JA: Is schizophrenia a neurodegenerative disorder?

a clinical and neurobiological perspective. Biol Psychiatry

1999; 46:729739

5. Emsley RA, Risperidone Working Group: Risperidone in the

treatment of first-episode psychotic patients: a double-blind

multicenter study. Schizophr Bull 1999; 25:721729

6. Sanger TM, Lieberman JA, Tohen M, Grundy S, Beasley C Jr,

Tollefson GD: Olanzapine versus haloperidol treatment in first-

episode psychosis. Am J Psychiatry 1999; 156:7987

7. Malla AK, Norman RM, Scholten DJ, Zirul S, Kotteda V: A com-

parison of long-term outcome in first-episode schizophrenia

following treatment with risperidone or a typical antipsychotic.

J Clin Psychiatry 2001; 62:1791848. Lieberman JA, Tollefson G, Tohen M, Green AI, Gur RE, Kahn R,

McEvoy J, Perkins D, Sharma T, Zipursky R, Wei H, Hamer MM

(HGDH Study Group): Comparative efficacy and safety of atypi-

cal and conventional antipsychotic drugs in first-episode psy-

chosis: a randomized, double-blind trial of olanzapine versus

haloperidol. Am J Psychiatry 2003; 160:13961404; correction,

160:1901

9. Schooler N, Rabinowitz J, Davidson M, Emsley R, Harvey PD, Ko-

pala L, McGorry PD, Van Hove I, Eerdekens M, Swyzen W, De

Smedt G (Early Psychosis Global Working Group): Risperidone

and haloperidol in first-episode psychosis: a long-term ran-

domized trial. Am J Psychiatry 2005; 162:947953

10. McEvoy JP, Hogarty GE, Steingard S: Optimal dose of neurolep-

tic in acute schizophrenia: a controlled study of the neurolep-

tic threshold and higher haloperidol dose. Arch Gen Psychiatry1991; 48:739745

11. Zhang-Wong J, Zipursky RB, Beiser M, Bean G: Optimal halo-

peridol dosage in first-episode psychosis. Can J Psychiatry

1999; 44:164167

12. Malla A, Norman R, Scholten D, Townsend L, Manchanda R, Ta-

khar J, Haricharan R: A comparison of two novel antipsychotics

in first episode non-affective psychosis: one-year outcome on

symptoms, motor side effects, and cognition. Psychiatry Res

2004; 129:159169

13. Montes JM, Ciudad A, Gascon J, Gomez JC; EFESO Study Group:

Safety, effectiveness, and quality of life of olanzapine in first-

episode schizophrenia: a naturalistic study. Prog Neuropsy-

chopharmacol Biol Psychiatry 2003; 27:667674

14. Good KP, Kiss I, Buiteman C, Woodley H, Rui Q, Whitehorn D,

Kopala L: Improvement in cognitive functioning in patientswith first-episode psychosis during treatment with quetiapine:

an interim analysis. Br J Psychiatry 2002; 43(suppl):S45S49

15. Tauscher-Wisniewski S, Kapur S, Tauscher J, Jones C, Daskalakis

ZJ, Papatheodorou G, Epstein I, Christensen BK, Zipursky RB:

Quetiapine: an effective antipsychotic in first-episode schizo-

phrenia despite only transiently high dopamine-2 receptor

blockade. J Clin Psychiatry 2002; 63:992997

16. Ohlsen RI, OToole MS, Purvis RG, Walters JT, Taylor TM, Jones

HM, Pilowsky LS: Clinical effectiveness in first-episode patients.

Eur Neuropsychopharmacol 2004; 14(suppl 4):S445S451

17. Kay SR, Fiszbein A, Opler LA: The Positive and Negative Syn-

drome Scale (PANSS) for schizophrenia. Schizophr Bull 1987;

13:261276

18. Guy W (ed): ECDEU Assessment Manual for Psychopharmacol-

ogy: Publication ADM 76-338. Washington, DC, US Departmentof Health, Education, and Welfare, 1976, pp 217222

19. Spitzer RL, Williams JBW, Gibbon M, First MB: Structured Clini-

cal Interview for DSM-IV (SCID). New York, New York State Psy-

chiatric Institute, Biometrics Research, 1995

20. Addington D, Addington J, Schissel B: A depression rating scale

for schizophrenics. Schizophr Res 1990; 3:247251

21. Heinrichs DW, Hanlon TE, Carpenter WT Jr: The Quality of Life

Scale: an instrument for rating the schizophrenic deficit syn-

drome. Schizophr Bull 1984; 10:388398

22. Barnes TRE: A rating scale for drug-induced akathisia. Br J Psy-

chiatry 1989; 154:672676


18/595




23. Simpson GM, Angus JWS: A rating scale for extrapyramidal side

effects. Acta Psychiatr Scand Suppl 1970; 212:1119

24. Blackwelder WC: Proving the null hypothesis in clinical trials.

Controlled Clin Trials 1982; 3:345353

25. Zhong KX, Lieberman JA, Hamer RM, Sweitzer D: Comparison

of quetiapine and risperidone in the treatment of schizophre-

nia: a randomized, double-blind, flexible-dose, 8-week study. J

Clin Psychiatry 2006; 67:10931103

26. Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA,Perkins DO, Keefe RS, Davis SM, Davis CE, Lebowitz BD, Severe

J, Hsiao JK; Clinical Antipsychotic Trials of Intervention Effec-

tiveness (CATIE) Investigators: Effectiveness of antipsychotic

drugs in patients with chronic schizophrenia. N Engl J Med

2005; 353:12091223

27. McEvoy JP, Lieberman JA, Stroup TS, Davis SM, Meltzer HY,

Rosenheck RA, Swartz MS, Perkins DO, Keefe RSE, Davis CE, Se-

vere J, Hsiao JK, CATIE Investigators: Effectiveness of clozapine

versus olanzapine, quetiapine, and risperidone in patients with

chronic schizophrenia who did not respond to prior atypical an-

tipsychotic treatment. Am J Psychiatry 2006; 163:600610

28. Stroup TS, Lieberman JA, McEvoy JP, Swartz MS, Davis SM,

Rosenheck RA, Perkins DO, Keefe RSE, Davis CE, Severe J, Hsiao

JK, CATIE Investigators: Effectiveness of olanzapine, quetiapine,

risperidone, and ziprasidone in patients with chronic schizo-phrenia following discontinuation of a previous atypical anti-

psychotic. Am J Psychiatry 2006; 163:611622

29. Bradford DW, Perkins DO, Lieberman JA: Pharmacological

management of first-episode schizophrenia and related nonaf-

fective psychoses. Drugs 2003; 63:22652283


19/595

ATTACHMENT B


20/595


21/595


22/595


23/595


24/595

ATTACHMENT C


25/595


26/595


27/595


28/595


29/595


30/595


31/595


32/595


33/595


34/595


35/595


36/595


37/595


38/595


39/595


40/595


41/595


42/595


43/595


44/595


45/595


46/595


47/595


48/595


49/595


50/595


51/595


52/595


53/595


54/595


55/595


56/595


57/595


58/595


59/595


60/595


61/595


62/595


63/595


64/595


65/595


66/595


67/595


68/595


69/595


70/595


71/595


72/595


73/595


74/595


75/595


76/595

ATTACHMENT D


77/595


78/595


79/595


80/595


81/595


82/595


83/595

ATTACHMENT E


84/595


85/595


86/595


87/595


88/595


89/595


90/595


91/595


92/595


93/595


94/595


95/595


96/595


97/595


98/595


99/595


100/595


101/595


102/595

EXCERPT

1

1 STATE OF MINNESOTA DISTRICT COURT

2 COUNTY OF HENNEPIN FOURTH JUDICIAL DISTRICT3 Court File No. 62 CO 06 11934

45 --------------------------------6 Mary Weiss, on her own behalf,

7 and as the next of kin and Trustee

8 of the estate of Dan Markingson, deceased,

910 Plaintiff,

11

12 vs.

1314 Board of Regents for the University of

15 Minnesota; Dr. Stephen Olson; Dr.16 Charles Schulz; Institutional Review Board

17 for the University of Minnesota; Astrazeneca

18 Pharmaceuticals LP, Astrazeneca LP and Zeneca, Inc.,

1920 Defendants.

21 ----------------------------------

2223 AUDIO VISUAL DEPOSITION OF

24 STEPHEN OLSON, M.D.25 MAY 1, 2007

VERBATIM COURT REPORTING 763-493-4535

2

3 The following is the deposition of STEPHEN

4 OLSON, M.D.; Mari Skalicky, Court Reporter, Notary

5 Public, pursuant to Notice of Taking Deposition, at6 701 Xenia Avenue South, Suite 600, Minneapolis,

7 Minnesota, commencing at approximately 9:00 a.m.,

8 MAY 1, 2007.

25 Q. (BY DR. BARDEN) Was the court ever informed

1 that Dan would be going into a research study?

2 MR. ALSOP: Object on the basis of

3 foundation. Go ahead, Doctor.


103/595

4 Q. (BY DR. BARDEN) Let me ask you this. Did you5 ever inform the court that Dan was actually

6 going into a research study?

7 A. Not directly, although, the county case manager8 who was responsible --

9 Q. Objection, move to strike. Go ahead and finish10 your answer and we'll ask for the time back the11 next day. Go ahead.

12 MR. ALSOP: We're not coming back a next

13 day.

14 DR. BARDEN: Let me just make for the15 record here. If the witness rambles on and if

16 we add up the time and at the end of the day

17 he's rambled on, obviously not answering my18 question and he's wasted a half an hour of our

19 time, we will seek that time back, period.

20 MR. ALSOP: You can go ahead and seek it.21 He's answered the question.

22 Q. (BY DR. BARDEN) So please, go ahead and answer

23 your -- give the answer that you think is

24 responsive to my question.25 A. Would you ask it again?


791 MR. ALSOP: Doctor, answer the question

2 the way you feel is most responsive. He's not

3 rambling, and he will answer the question as he4 sees fit.

5 A. Will you ask the question again?

6 Q. Would you read that back.7 (Record read back.)

8 A. I didn't inform the court directly but the

9 county case manager is required to make a

10 report to the court that the patient was11 meeting the terms of the stay of commitment

12 that he seek appropriate care. And I had

13 discussions with Mr. Pettit numerous times that14 the participation of the CAFE was one way that

15 he could receive appropriate care, although,

16 there were certainly other options had Dan17 chosen not to participate in the study.

18 Q. Objection. Move to strike the entire response

19 after the first sentence. Did you follow-up20 and make sure that the court was informed by


104/595

21 Mr. Pettit that Dan had not gone into treatment22 but in fact had gone into a clinical research

23 study?

24 A. No.25 Q. Other than Dan, were there any other subjects


80

1 in your study who were court-ordered into2 treatment, yet ended up in your research study?

3 MR. ALSOP: It's repetitious, but go

4 ahead.5 A. I don't recall but there may have been.

6 Q. (BY DR. BARDEN) But no one, the IRB, Dr.

7 Schulz, the University, no one raised any8 questions about that, correct?

9 MR. ALSOP: It's repetitious. Talk about

10 wasting time with multiple questions, that's

11 been asked and answered multiple times. Go12 ahead one more time.

13 A. Repeat the question.

14 (Record read back.)15 A. Not at the time and not after the conduct of

16 the study was investigated following Dan's17 death.


105/595

ATTACHMENT F


106/595


107/595


108/595


109/595

7/30/2019 Investigation Request With Dossier to Research Ethics Consultation Service at