letter to susan berry and irb executive committee regarding seroquel borderline personality disorder...

8/9/2019 Letter to Susan Berry and IRB Executive Committee regarding Seroquel Borderline Personality Disorder study

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Center for Bioethics N504 Boynton

410 Church Street

Minneapolis MN 55455

612-624-9440

Fax: 612-624-9108

www.bioethics.umn.edu

Dr. Susan BerryChair, IRB Executive CommitteeUniversity of MinnesotaD528 Mayo Memorial Building420 Delaware St. SEMinneapolis, MN 55455-0392 January 5, 2015

Dear Sue:

I am writing to you in your capacity as Chair of the Executive Committee of the IRB. As a result

of documents acquired through state Data Practices Act requests, I have obtained informationsuggesting ethical and legal violations in the conduct and oversight of a clinical trial titled“Seroquel Extended Release for the Management of Borderline Personality Disorder”(NCT00880919), funded by AstraZeneca and conducted from 2008 to 2013 in the University ofMinnesota’s Department of Psychiatry. The principal investigator for the study was Dr. CharlesSchulz. Co-investigators include Dr. Scott Crow, Dr. Kathryn Cullen, Dr. Michael Miller, andDr. Richelle Moen.

I am writing to ask the Executive Committee to investigate this trial. My chief concerns includeissues involving 1) recruitment of subjects, 2) the independence of the Data Safety MonitoringBoard, and 3) conflicts of interest.

Background

Seroquel is an antipsychotic drug approved for the treatment of schizophrenia and bipolardisorder and as an adjunct treatment for depression. It has black box warnings for increased riskof death in elderly patients and for increased risk of suicidal ideation in children and youngadults. In 2010, AstraZeneca paid $520 million to settle federal investigations into illegalmarketing of the drug, including the payment of kickbacks to doctors to market Seroquel forunapproved uses. Numerous media reports have linked Dr. Charles Schulz, the Chairman of theDepartment of Psychiatry, to the controversy over illegal marketing of Seroquel.1

Seroquel is not approved for the treatment of Borderline Personality Disorder. In fact, nomedication is approved for the treatment of any personality disorder. According to a meta-analysis of pharmacological treatments for Borderline Personality Disorder conducted by theCochrane Collaboration in 2010, “Total Borderline Personality Disorder severity was not

1 Jeremy Olson, “U doctor scrutinized over drug research,” St. Paul Pioneer Press, March 19, 2009; Maura Lernerand Janet Moore, “Once-secret drug company records put U on the spot,” Minneapolis Star-Tribune, March 19,2009; Andy Mannix, “Charles Schulz under scrutiny for Seroquel study suicide,” City Pages, February 2, 2011.

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significantly influenced by any drug. No promising results are available for the core BorderlinePersonality Disorder symptoms of chronic feelings of emptiness, identity disturbance andabandonment.”2 Dr. Schulz has conducted studies of at least two other pharmacologicaltreatments for Borderline Personality Disorder, Zyprexa (olanzapine) and Depakote (divalproexsodium).3

In “Seroquel Extended Release for the Management of Borderline Personality Disorder,”investigators at the University of Minnesota and the University of Iowa randomized subjectsdiagnosed with Borderline Personality Disorder to one of three groups: 150 mg/day of Seroquel,300 mg/day of Seroquel, or placebo. Subjects were treated for eight weeks (Appendix A.)

Concerns

1) Recruitment from sex offender facility

On May 27, 2010, Dr. Schulz filed a Reporting Form for Unanticipated Problems Involving

Risks to Subjects or Others (Appendix B). He informed the IRB of an incident involving twosubjects recruited into the study from Alpha House, “a residential program which provides highlevels of structure and supervision for sex offenders.” The report states:

“ Redacted was employed as the full-time cook at Alpha House. Per Alexis on the morning of2010 BRE cooked and served oatmeal to 1520 persons at Alpha House, 4 of which were staffmembers. Some residents noticed pink particles in the oatmeal. After eating breakfast theresidents and staff reported feeling sedated and some were ‘knocked out’ for the remainder of theday. Staff asked redacted if he had put the study medication into the oatmeal and redacted denied it. After failing a polygraph test redacted was re-imprisoned.”

This alarming report raises at least two questions. The first is about the safety of the residentsand staff of Alpha House. Were any other residents or staff members harmed, and what stepswere taken by the investigators to determine whether any other such incidents occurred? There isno indication of concern by the IRB in any of their communications with the investigators, andno mention of the incident in the minutes of the Data Safety Monitoring Board.

The second question concerns the recruitment tactics employed in the study. What circumstancesled to residents of a sex offender facility licensed by the Minnesota Department of Corrections being recruited into this study? Were any other residents enrolled? Did study investigatorsrecruit subjects from other facilities licensed by the Department of Corrections? The documentsI was provided do not suggest that the IRB asked investigators about any of these issues.

2 Stoffers J1, Völlm BA, Rücker G, Timmer A, Huband N, Lieb K, “Pharmacological interventions for borderline personality disorder,” Cochrane Database Systematic Review 2010 Jun 16;(6):CD005653;http://www.ncbi.nlm.nih.gov/pubmed/20556762

3 Zanarini MC, Schulz SC, Detke HC, Tanaka Y, Zhao F, Lin D, Deberdt W, Kryzhanovskaya L, Corya S: A dosecomparison of olanzapine for the treatment of borderline personality disorder: a 12-week randomized, double-blind, placebo-controlled study. J Clin Psychiatry 2011; 72:1353–1362; “Depakote ER in Borderline Personality Disorder” NCT00222482; https://clinicaltrials.gov/ct2/show/NCT00222482

https://clinicaltrials.gov/ct2/show/NCT00222482https://clinicaltrials.gov/ct2/show/NCT00222482https://clinicaltrials.gov/ct2/show/NCT00222482https://clinicaltrials.gov/ct2/show/NCT00222482


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Because of widespread abuses in the 1960s and 1970s, Health and Human Services (HHS)regulations include special protections for prisoners (see 45 CFR part 46, subpart C). HHSregulations define prisoners as "any individual involuntarily confined or detained in a penalinstitution. The term is intended to encompass individuals sentenced to such an institution under

a criminal or civil statute, individuals detained in other facilities by virtue of statutes orcommitment procedures which provide alternatives to criminal prosecution or incarceration in a penal institution, and individuals detained pending arraignment, trial, or sentencing” [see 45 CFR part 46.303(c)].

The key questions for determining whether the subjects recruited from Alpha House count as prisoners under 45 CFR part 46.303(c) are 1) whether their ability to leave the facility wasrestricted, and 2) whether their confinement to Alpha House occurred as result of statutes orcommitment procedures which provide alternatives to criminal prosecution or incarceration in a penal institution. Without further investigation, it is hard to know for certain whether these twocriteria were met. However, the fact that one subject was “re-imprisoned” after failing a

polygraph test suggests that his confinement to Alpha House probably was an alternative toincarceration.

If so, then under the terms of the Federalwide Assurance (FWA) for the protection of humansubjects, the composition of the IRB panel that reviewed the study should have met therequirements of HHS regulations at 45 CFR 46.304(a) and (b). For example, the IRB panelreviewing the study should have included a prisoner or prisoner representative. In addition, anyresearch on prisoners must fall within the categories of research permissible under 45 CFR46.306(a)(2). It does not appear that these conditions were met.

According to the Continuing Review report for December 3, 2010 through January 25, 2012(Appendix C, page 37), one of the three initial sites for the study, McLean Hospital at HarvardUniversity, withdrew from the study because of its inability to recruit subjects. (This is notmentioned in the published paper.) The University of Minnesota, in contrast, managed to exceedits recruitment goals. On November 20, 2012, Dr. Schulz reported enrolling a total of 52subjects with only three screening failures (Appendix C, page 52). By the end of the study, theMinnesota site had enrolled 58 subjects (Appendix C, page 58). It would be worth investigatinghow and where these subjects were recruited, what steps were taken to confirm the diagnosis ofBorderline Personality Disorder, and whether the sponsor provided financial incentives forsubject recruitment.

2) Independence of Data Safety Monitoring Board

According to documents submitted to the IRB, Dr. Scott Crow, a faculty member in theDepartment of Psychiatry, served both as co-investigator for the study and as chair of the Dataand Safety Monitoring Board (DSMB.) This dual role constituted a conflict of interest andcompromised the independence of the DSMB. Every major set of research guidelinesconcerning the composition of DSMBs stipulates that such boards must be independent of theinvestigators and study sponsors and must not include members of the research team.


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For example, the World Health Organization’s Operational Guidelines for the Establishment andFunctioning of Data and Safety Monitoring Boards state, “Members should not be affiliated withthe sponsor, investigator(s), ethics committee(s), regulatory authority(ies), site(s) or study staff.Members should also not have vested conflicts of interest (e.g. a financial or other interest in anintervention or product similar to the intervention being studied).”4

The 2006 Food and Drug Administration’s Guidance for Clinical Trial Sponsors: Establishmentand Operation of Clinical Trial Data Monitoring Committees states, “We recommend thatsponsors avoid appointing to a DMC any individuals who have relationships with trialinvestigators or sponsor employees that could be considered reasonably likely to affect theirobjectivity.”5

The National Institutes of Health policy for data and safety monitoring states, “Ideally, participants in monitoring outcomes of a trial are in no way associated with the trial.”6

The European Medicine Agency’s Guideline on Data Monitoring Committees states,

“Furthermore, in order to allow for an unbiased assessment of study data and not to bias thefurther conduct of a clinical trial, any person (not only employees of the sponsor) involved in theconduct of the clinical trial (e.g. investigators) should not serve on the DMC.”7

At least one member of the University of Minnesota IRB appears to have recognized the problem. In the document labelled “Continuing Review of Approved Research” dated January26, 2011, Dr. Simone Ognjanovic asks, “Scott Crow was a member of DSMB (Data SafetyMonitoring Board) and a co-investigator?” However, the IRB apparently dismissed Dr.Ognjanovic’s concerns. The minutes for the January 26, 2011 meeting state, “This does notcreate a conflict of interest as researchers are required to monitor adverse events” (Appendix C, pages 33-4). It is unclear what reasoning the IRB used to justify this conclusion.

3) Conflicts of interest on IRB

In the Continuing Review dated December 17, 2008, it is noted that Dr. Scott Crow was not present for voting “due to conflict of interest” (Appendix C, page 9.) This note suggests that Dr.Crow, in addition to directing the Data Safety Monitoring Board and serving as Co-Investigatorfor the study, was also a member of the IRB panel evaluating the study. In later reviews, there isno indication that Dr. Crow abstained from voting, and all Continuing Reviews of the study passed with unanimous votes. If Dr. Crow continued to serve on the IRB and vote on the

4 World Health Organization, Operational Guidelines for the Establishment and Functioning of Data and Safety

Monitoring Boards, Geneva, Switzerland, 2005. See http://www.who.int/tdr/publications/documents/operational-guidelines.pdf?ua=1

5 Food and Drug Administration, Guidance for Clinical Trial Sponsors: Establishment and Operation of ClinicalTrial Data Monitoring Committees, Bethesda, Maryland, 2005. Seehttp://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm127073.pdf

6 http://grants.nih.gov/grants/guide/notice-files/not98-084.html

7 http://osp.od.nih.gov/sites/default/files/resources/WC500003635.pdf

http://www.who.int/tdr/publications/documents/operational-guidelines.pdf?ua=1http://www.who.int/tdr/publications/documents/operational-guidelines.pdf?ua=1http://www.who.int/tdr/publications/documents/operational-guidelines.pdf?ua=1http://www.who.int/tdr/publications/documents/operational-guidelines.pdf?ua=1http://www.who.int/tdr/publications/documents/operational-guidelines.pdf?ua=1http://www.who.int/tdr/publications/documents/operational-guidelines.pdf?ua=1


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Continuing Review of the study in question, his presence would constitute a clear conflict ofinterest.

4) Conflicts of interest involving the Principal Investigator

In the Continuing Review dated January 26, 2011, Dr. Ognjanovic noted that Dr. Schulz was amember of the AstraZeneca Scientific Advisory Board (Appendix C, page 33). She pointed outthat the study in question was being done to expand the use of Seroquel to unapprovedindications (Borderline Personality Disorder) and asked whether Dr. Schulz had a conflict ofinterest.

According to the policy set out by the Office of Institutional Compliance, “Managing Conflictsof Interest in Research,” serving on a sponsor’s Scientific Advisory Board does constitute aconflict of interest. According to the policy, if the financial interest was “significant,” it shouldhave prohibited Dr. Schulz from serving as Principal Investigator for this study. The policystates:

“A University professor cannot serve as PI or Co-I on human subjects research that the IRBdetermines is greater than minimal risk for human participants, while simultaneously holding asignificant financial or business interest in a business entity that could benefit from the research project.”8

However, the IRB appears to have taken no action. Schulz remained Principal Investigator forthe study. The Continuing Review form states: “The IRB committee notes that the Pl's conflictof interest management plan has been reviewed previously by the IRB Committee. Thecommittee acknowledges current, IRB approved language in the consent form that references thePl's role on the Scientific Advisory Board.”

However, there is no indication of what this conflict of interest management plan might be. Inaddition, the consent form that was provided to me by the Department of Psychiatry contains nomention of the role of Schulz on the AstraZeneca Scientific Advisory Board (Appendix D). It isunclear whether the IRB Committee was mistaken about the consent form, or whether theDepartment of Psychiatry used a different version of the consent form than the one it submittedto the IRB.

I would appreciate the opportunity to discuss these issues with you at your earliest convenience.

Yours sincerely,

Carl ElliottProfessor, Center for Bioethics

8 http://www.compliance.umn.edu/conflictResearch.htm


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Appendix A


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Article

Comparison of Low and Moderate Dosages of Extended-Release Quetiapine in Borderline Personality Disorder:

A Randomized, Double-Blind, Placebo-Controlled Trial

Donald W. Black, M.D.

Mary C. Zanarini, Ed.D.

Ann Romine, R.N.

Martha Shaw, B.A.

Jeff Allen, Ph.D.

S. Charles Schulz, M.D.

Objective: The authors compared theef cacy and tolerability of low and mod-erate dosages of extended-release quetia-pine in adults with borderline personalitydisorder.

Method: Ninety-ve participants withDSM-IV borderline personality disorder wererandomly assigned to receive 150 mg/day of quetiapine (the low-dosage group; N=33),300 mg/day of quetiapine (the moderate-dosage group; N=33), or placebo (N=29).Total score over time on the clinician-ratedZanarini Rating Scale for Borderline Person-

ality Disorder (“Zanariniscale”) wasanalyzedin a mixed-effects model accounting for in-formative dropout.

Results: Participants in the low-dosagequetiapine group had signicant improve-ment on the Zanarini scale compared withthose in the placebo group. Time to re-sponse (dened as a reduction of 50% ormore on the Zanarini scale total score) wassignicantly shorter for both the low-dosagequetiapinegroup(hazardratio=2.54,p=0.007)

and the moderate-dosage quetiapine group(hazard ratio=2.37, p=0.011) than for theplacebo group. Among participants whocompleted the study, 82% in the low-dosage quetiapine group were rated as“responders,” compared with 74% in themoderate-dosage group and 48% in theplacebo group. Treatment-emergent ad-verse events included sedation, changein appetite, and dry mouth. The overallcompletion rate for the 8-week double-blind treatment phase was 67% (67% forthe low-dosage quetiapine group, 58% for

the moderate-dosage quetiapine group,and 79% for the placebo group). Partic-ipants who experienced sedation weremore likely to drop out.

Conclusions: Participants treated with150 mg/day of quetiapine had a signicantreduction in the severity of borderlinepersonality disorder symptoms comparedwith those who received placebo. Adverseevents were more likely in participantstaking 300 mg/day of quetiapine.

(Am J Psychiatry 2014; 171:1174 –1182)

Borderline personality disorder is characterized by moodinstability, cognitive symptoms, impulsive behavior, anddisturbed relationships (1–3). A variety of psychotherapieshave been developed (4–6) and, while research on the useof medication is ongoing, no drug has been approved inthe United States or elsewhere for its treatment (7). Second-generation antipsychotics have been the most intensively studied, but randomized controlled trials of aripiprazole,olanzapine, and ziprasidone have produced mixed results(8–11). Five open-label studies found that quetiapine may be effective in treating a range of borderline symptoms(12–16). While encouraging, these studies involved smallsamples, and four of them (12–15) focused on impulsivity/hostility, not more general borderline psychopathology.

This study was designed to provide a rigorous test of extended-release quetiapine in the treatment of border-line personality disorder. Quetiapine is approved by theU.S. Food and Drug Administration for the treatment of

schizophrenia and for acute and maintenance treatmentof bipolar disorder. There is some evidence suggesting thatquetiapine couldbe effective in treatingborderline personality disorder. First, it is effective in treating bipolar disorder,and mood shifts observed in bipolar patients resembleaffective instability in borderline patients (17). Second,research suggests that quetiapine may curb impulsivity and self-harm (14, 18). Furthermore, open-label studies

have suggested that the drug has promise in treating bor-derline patients (12–16). We report the results of a randomized controlled trial

that compared low(150mg/day)and moderate (300mg/day)dosages of quetiapine in the treatment of borderline per-sonality disorder. Two active treatment arms were used inorder to determine the best dosage of quetiapine relativeto itsadverse effects. We expected that both dosages wouldbe superior to placebo, but that the higher one would havemore adverse effects.

This article is featured in this month’s AJP Audio, is an article that provides Clinical Guidance (p. 1182),and is discussed in an Editorial by Dr. Tohen (p. 1139) and Video by Dr. Pine

1174 ajp.psychiatryonline.org Am J Psychiatry 171:11, November 2014

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Method

The trial was conducted from January 2010 to March 2013 atthree academic medical centers. Participants gave written informedconsent according to procedures approved by a university-af liatedinstitutional review board.

The study proceeded in three phases: a screening periodlasting up to 2 weeks overall (visits 1–2); an 8-week double-blind

treatment phase with weekly visits (visits 2–

10); and a 1-week discontinuation phase (visit 11). The 8-week treatment phase wasconsidered suf cient to show a difference between groups.Participants who met enrollment criteria at both visits 1 and 2

were randomly assigned to receive treatment with 150 mg/day of extended-release quetiapine, 300 mg/day of extended-releasequetiapine, or placebo. Participants, site personnel, and inves-tigators were blind to treatment group assignment.

Quetiapine was started at 50 mg/day and adjusted to 150 mg/day after 1 week. For participants assigned to the higher dosage,the dosage was raised to 300 mg/day after 4 weeks. To preserveblinding, all participants received one bottle of 150-mg quetia-pine (or placebo) tablets initially, and then after 4 weeks receivedtwo bottles; the second bottle contained either 150-mg quetia-pine tablets (for the moderate-dosage group) or placebo tablets

(for the low-dosage and placebo groups).

Inclusion and Exclusion Criteria

Persons 18–45 years of age with moodiness, impulsivity, dis-trustfulness, and dif cult relationships were recruited through re-ferral, advertisements, and word of mouth. After screening withthe Diagnostic Interview for DSM-IV Personality Disorders (19) toconrm the presence of DSM-IV borderline personality disorder,

we administered the Structured Clinical Interview for DSM-IV toassess comorbid disorders (20). Participants had to meet RevisedDiagnostic Interview for Borderlines criteria (21) for borderline per-sonality disorder and could not meet current criteria for major de-pressive disorder, posttraumatic stress disorder, panic disorder, orobsessive-compulsive disorder. They were required to have a total

score $9 on the Zanarini Rating Scale for Borderline Personality Disorder (“Zanarini scale”) (22) at visit 2. Individuals were excludedif they had ever met criteria for a psychotic disorder, had a primary neurological condition, or were cognitively impaired; had currentsubstance dependence or had recently abused opiates, amphet-amine, barbiturates, cocaine, or hallucinogens; were medically unstable; had a history of lack of response to an atypical an-tipsychotic; were pregnant or lactating; or were acutely suicidal.

Participants entering the study could not begin any type of psy-chotherapy during the study. Concomitant use of benzodiazepines

was allowed at dosages equivalent to #1.0 mg/day of lorazepam;only one participant (in the placebo group) took benzodiazepinesduring the study. Episodic use of anticholinergics was allowed forsleep. No other psychotropic medication was permitted.

Ef cacy Assessments

Rater-administered scales included the Zanarini scale (22), theMontgomery-Åsberg Depression Rating Scale (MADRS) (23), theModied Overt Aggression Scale (24), the Young Mania Rating Scale (25), and the Global Assessment of Functioning Scale (GAF).Self-administered measures included a self-report version of theZanarini scale (26), the Borderline Evaluation of Severity Over Time(27), the Barratt Impulsiveness Scale (28), the Symptom Checklist–90–Revised (SCL-90-R) (29), and the Sheehan Disability Scale (30).

The primary outcome measure was the Zanarini scale totalscore. This semistructured interview has anchored ratings (0=nosymptoms, 4=severe symptoms) on nine items that correspondto the DSM-IV borderline personality disorder criteria. Its subscales

were considered secondary ef cacy measures. Other secondary

measures included the self-rated version of the Zanarini scale, theMADRS, the Borderline Evaluation of Severity Over Time, theModied Overt Aggression Scale, the GAF, the Barratt Impulsive-ness Scale, the SCL-90-R, the Young Mania Rating Scale, and theSheehan Disability Scale.

Safety Measures

Adverse events, vital signs, electrocardiogram ndings, labora-

tory values, and extrapyramidal symptoms were assessed. Labo-ratory tests included clinical chemistry, electrolyte levels, lipidprole, prolactin level, and hematology panels. A urine drug screenand pregnancy test were performed. These tests were performedat protocol-specied time points and when clinically indicated.Extrapyramidal symptoms were assessed with the Simpson-AngusRating Scale (31), the Barnes Akathisia Scale (32), and the AbnormalInvoluntary Movement Scale (33).

Statistical Analysis

A sample size of 33 in each group was considered suf cient fordetecting an effect size greater than 0.68 with a power of 0.80, analpha of 0.05 (two-tailed), and a 15% dropout rate. The num-bers of participants assigned to 150 mg/day of quetiapine (N=33),

300 mg/day of quetiapine (N=33), and placebo (N=29) were closeto those planned.

The analyses included comparisons of baseline (visit 2) severity and background variables, time to adverse events, time to study discontinuation, and treatment response. All participants who

were assigned to a treatment group and met study inclusioncriteria were included in each analysis. Statistical tests were per-formed using a two-sided alpha of 0.05.

Pearson’s chi-square test (or Fisher’s exact test) was used totest for categorical baseline group differences. The Kruskal-Wallistest was used to test for dimensional baseline group differences.Mean severity scores from the baseline visit were compared us-ing analysis of variance.

Adverse events were recorded as mild, moderate, or severe, with additional notations if an adverse event was thought to berelated to the study medication. Time to adverse event was de-ned as the rst postscreening visit with an adverse event re-ported, with censoring occurring if an event was not reported by the time of study discontinuation or study completion. In addi-tion, we considered time to different types of adverse events (e.g.,appetite change, bodily pain). Cox proportional hazards regres-sion analysis was performed to compare the treatment groups ontime to each denition of adverse event.

Time to discontinuation was dened as the last postscreening visit attended during the treatment phase, with censoring oc-curring if the participant attended visit 10. The analysis examinedpredictors of time to discontinuation. First, the three groups werecompared with no covariates. Next, we examined severity of ad-verse events as time-dependent predictors of discontinuation.

The analysis included any event, as well as the different types of adverse events. In addition, we examined illness severity (basedon Zanarini scale score) as a time-dependent predictor. This wasdone to provide a better understanding of factors related to dis-continuation. Cox proportional hazards regression analysis wasused to model time to discontinuation.

For the primary ef cacy variable, a mixed-effects model wasused that included terms for treatment group, linear time effect(weeks since visit 2 [baseline]), quadratic time effect, site, andtreatment-by-time interactions. (Because one site enrolled only three participants, those participants were pooled with the smallerof the two remaining sites.) Each participant’s outcome proleduring the 8-week treatment phase (visit 2 to visit 10) was sum-marized with a subject-specic intercept and slope. We tteda shared parameter model, where the treatment-response model

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(the mixed-effects model) and a time-to-discontinuation model were tted simultaneously, with the subject-specic intercepts andslopes from the response model used as predictors of discontin-uation (34). The shared-parameter model reduces bias in treatmenteffects caused by informative dropout (35). The NLMixed procedurein SAS was used to t the shared parameter model (36, 37). Thesame model was also used for all other response measures for

which data were collected at each visit. The mixed-effects model

was used for measures collected at visits 2, 6, and 10.The statistical tests for the null hypothesis were performed by testing differences in mean change from baseline for the groupsreceiving 150 mg/day or 300 mg/day of quetiapine compared

with the placebo group. For each group, mean change frombaseline (visit 2) to week 8 of treatment (visit 10) was calculatedas a function of the group’s linear and quadratic coef cients.Effect size (d) was dened as the group difference from placeboin change from visit 2 to visit 10, expressed in standard deviationunits. The same procedure was applied to secondary ef cacy var-iables and measures of extrapyramidal symptoms, as well as toevaluate changes in blood pressure and heart rate. Participants

were classied as responders if they had a reduction of $50% inZanarini scale total score; the Cox proportional hazards regressionmodel was used to model time to response. Among participants

who completed the study, number needed to treat was calculatedbased on the proportion of participants whose Zanarini scale totalscore at visit 10 represented a reduction of $50% relative to visit 2.Levels of serum electrolytes, glucose, lipids, and prolactin wereassessed at visit 2 and visit 10, and group differences in changes

were tested using analysis of variance.

Results

A total of 111 individuals were screened for the study,and 95 were randomly assigned to a treatment group: 33 were assigned to receive 150 mg/day of quetiapine (the low-dosage group), 33 were assigned to receive 300 mg/day of

quetiapine (the moderate-dosage group), and 29 were as-signed to receive placebo (N=29). Of those not assigned,eight did not meet inclusion or exclusion criteria, ve failedto appear after visit 1, and three withdrew consent. Base-line characteristics were similar for the three treatmentgroups (Table 1). While the rates of lifetime psychiatric dis-orders were not signicantly different between the groups,presence of a mood disorder was included as a covariate inthe treatment response models.

Between-group differences were observed for baselineillness severity as measured by the Zanarini scale total score(clinician- and self-rated versions); the Borderline Evalua-

tion of Severity Over Time total score as well as thethoughtsand feelings and negative behaviors subscales; the ModiedOvert Aggression Scale; the SCL-90-R general severity in-dex score; and the Sheehan DisabilityScale scores (Table 2).Baseline severity was greatest for the group receiving 300mg/day of quetiapine and least for the placebo group. Themixed-effects model accounts for the imbalance in baselineseverity because intercepts vary by group and individual.

Adverse Events

The numbers of participants reporting adverse eventsare presented in Table 3. Overall, 88% reported at least oneadverse event, with 82% reporting an adverse event thought

to be related to the study medication. Among all adverseevents, 68% were suspectedto be related to the study drug.No serious adverse events occurred.

Cox proportional hazards regression models were usedto test for group differences in time to adverse events. Risk of any type of adverse event was not signicantly differentfor the quetiapine groups compared with the placebo

group. Risk of an adverse event thought to be related to thestudy medication was higher for the moderate-dosagequetiapine group (hazard ratio=1.73), but the result wasnot signicant (p=0.074). For the moderate-dosage que-tiapine group, risk was elevated for sedation (hazardratio=2.16, p=0.021), change in appetite (hazard ratio=3.89,p=0.018), and dry mouth (hazard ratio=16.77, p=0.007). Forthe low-dosage quetiapine group, risk was higher for dry mouth (hazard ratio=9.32, p=0.034). The hazard ratiossuggest that sedation, change in appetite, dry mouth, anddizziness are more likely with higher dosages of quetiapine.

Study Discontinuation

Of all participants assigned to a treatment group, 64 (67%)completed the study, 23 of them in the placebo group, 22 inthe low-dosage quetiapine group, and 19 in the moderate-dosage quetiapine group. Eight participants dropped outbefore a postbaseline assessment. Risk of discontinuation was higher among participants who received quetiapine,but the differences from placebo were not signicant foreither dosage group. Illness severity (measured by theZanarini scale total score as a time-varying predictor) wasnot associated with discontinuation. Risk of discontinua-tion increased with severity of any adverse event (hazard

ratio=1.74, p=0.018). Sedation was predictive of discontin-uation (hazard ratio=1.77, p=0.025).

Ef cacy Results

For all treatment groups, Zanarini scale total score im-proved during the treatment phase (Figure 1). For thequetiapine groups, the rate of improvement was highestfrom visit 2 to visit 6; after that, improvement plateaued.For this reason, the model included a quadratic effect fortime. Ef cacy results (Table 4) are based on the sharedparameter model, which estimates each treatment group’schange from baseline, accounting for informative dropout.The difference in improvement between the low-dosagequetiapine group and the placebo group was statistically signicant (d=20.79, p=0.031); the difference between themoderate-dosage quetiapine group and the placebo group was not (d=20.41, p=0.265). The mean score decreased by 1.22 points per week for the low-dosage quetiapine group,0.99 points per week for the moderate-dosage quetiapinegroup, and 0.75 points per week for the placebo group. Thedifference between the two quetiapine groups was notsignicant. Time to treatment response was faster for thequetiapine groups relative to the placebo group (low-dosagegroup: hazard ratio=2.54, p=0.007; moderate-dosage group:hazard ratio=2.37, p=0.011). Including participants who


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discontinued before visit 10, the percentage classied asresponders for at least onepostbaseline visit was82% for thelow-dosage quetiapine group, 67% for the moderate-dosagequetiapine group, and 62% for the placebo group. (Someparticipants were classied as responders but were reclassi-ed as nonresponders by their last visit.) Among the 31

participants who did not complete the study, 10 (32%) wereresponders. Among participants who completed the study,the visit 10 response rates were 82% for the low-dosagequetiapine group, 74% for the moderate-dosage quetiapinegroup, and 48% for the placebo group. From these rates,number needed to treat is estimated at 2.9 for 150 mg/day of quetiapine and 3.9 for 300 mg/day of quetiapine.

Both quetiapine dosages were superior to placebo formany secondary ef cacy measures, including the self-rated Zanarini scale total score andsubscale scores(exceptimpulsivity); the Borderline Evaluation of Severity OverTime total score as well as the thoughts and feelings

subscale; the Modi

ed Overt Aggression Scale score; and work or school days lost because of symptoms (from theSheehan Disability Scale). Neither quetiapine dosage wassuperior to placebo with regard to the Barratt Impulsive-ness Score, but the moderate-dosage group had betterscores on the Young Mania Rating Scale (d=20.50, p=0.019)and the SCL-90-R general severity index (d=20.62, p=0.033)(Table 4).

Safety Results

The moderate-dosage quetiapine group experienceda signicant increase in heart rate (1.03 bpm/week). Thelow-dosage quetiapine group experienced a signicant

decrease in systolic blood pressure (0.53 mmHg/week).From visits 1 to 10, triglyceride levels increased 9.8 mg/dLon average (SD=52.1), with no signicant group differ-ences. There were no signicant group differences forserum levels of electrolytes, glucose, lipids, and prolactin.There were no signicant group differences with respect to

changes in extrapyramidal symptoms from baseline toendpoint. Urine pregnancy tests were conducted at visits1, 6, and 10. One woman tested positive at visit 6 anddiscontinued study participation; all other results werenegative.

Among participants who completed the study, the mean weight gained between visit 1 and visit 10 was 1.0 lb (SD=4.4)for the placebo group, 1.0 lb (SD=7.2) for low-dosagequetiapine group, and 3.0 lb (SD=9.2) for moderate-dosagequetiapine group. Standard deviations for weight gain were greater for the quetiapine groups relative to theplacebo group (p=0.028 for the low-dosage group, and

p=0.001 for the moderate-dosage group). Median weightgain was not signicantly different between groups.Sixty participants (63%) attended visit 11, which occurred

1 week after study medication was discontinued. Twelveparticipants (20%) reported a new adverse event, with threereports of increased moodiness or irritability and three of trouble sleeping. All adverse events were rated as mild.

Discussion

The results show that low-dosage extended-releasequetiapine was superior to placebo in reducing the overallseverity of borderline personality disorder. The estimated

TABLE 1. Demographic and Clinical Characteristics of Study Participants With Borderline Personality Disorder Who ReceivedQuetiapine or Placebo

Variable Placebo (N=29)

Low-DosageQuetiapine

(150 mg/day)(N=33)

Moderate-DosageQuetiapine

(300 mg/day)(N=33)

Mean SD Mean SD Mean SDAge (years) 30.1 8.8 28.2 8.0 30.2 8.1

Age at onset (years) 14.6 6.6 12.2 3.7 12.2 5.0Duration of illness (years) 16.2 8.9 15.4 9.4 17.9 8.5

Education (years) 14.5 1.7 14.3 2.7 14.1 3.0N % N % N %

Male 10 34 8 24 10 30Race/ethnicity

European-Caucasian 22 79 26 79 26 79

Other 6 21 7 21 7 21

Marital statusSingle 20 74 26 79 18 56Married 2 7 4 12 6 19

Other 5 19 3 9 8 25Any past psychiatric hospitalization 7 24 13 39 13 39

Lifetime psychiatric axis I disordersMood disorders 14 48 25 76 19 58Anxiety disorders 5 17 5 15 5 15Substance use disorders 6 21 11 33 13 39

Any axis I disorder 19 66 29 88 28 85





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TABLE 2. Baseline Clinical Measures for Study Participants With Borderline Personality Disorder Who Received Quetiapine or Placebo

Placebo (N=29)


(150 mg/day)(N=33)


(300 mg/day)(N=33) Analysis

Measure Mean SD Mean SD Mean SD F df p

Zanarini scale

a

Total score 14.6 4.8 15.8 3.4 17.7 5.3 3.7 2,92 0.029

Affective disturbance score 6.3 2.0 6.4 1.3 7.2 1.8 2.5 2,92 0.092Cognitive disturbance score 3.1 1.7 3.5 1.4 4.0 1.9 2.1 2,92 0.130

Impulsivity score 1.7 0.9 1.8 1.1 2.2 1.3 2.2 2,92 0.115Disturbed relationship score 3.5 1.4 4.0 1.4 4.3 1.5 2.4 2,92 0.093

Zanarini scale,a self-ratedTotal score 11.8 6.6 14.4 5.1 17.8 6.3 7.7 2,92 0.001

Affective disturbance score 5.3 2.5 6.1 2.2 7.7 2.5 7.7 2,91 0.001Cognitive disturbance score 2.4 2.2 3.1 2.2 3.7 2.1 2.5 2,91 0.088

Impulsivity score 1.5 1.4 1.5 1.3 2.3 1.6 2.9 2,91 0.061Disturbed relationship score 2.6 1.8 3.8 1.7 4.2 2.2 5.7 2,91 0.005

Borderline Evaluation of Severity Over TimeTotal score 32.6 10.6 36.6 9.6 40.9 12.0 4.6 2,92 0.013

Thoughts and feelings score 18.7 7.1 21.7 6.1 24.2 8.0 4.5 2,92 0.014Negative behaviors score 7.1 2.7 8.8 3.0 9.9 3.8 5.8 2,92 0.004

Positive behaviors score 8.3 3.0 8.9 2.5 8.2 2.5 0.7 2,92 0.505Montgomery-Åsberg Depression Rating Scale 15.0 6.7 16.9 5.6 18.8 7.2 2.7 2,91 0.075

Modied Overt Aggression Scale 11.3 9.2 18.7 14.9 22.6 17.8 4.7 2,91 0.011 Young Mania Rating Scale 3.6 2.9 3.3 2.8 4.4 3.6 1.1 2,91 0.346Global Assessment of Functioning Scale 62.3 6.0 61.1 7.9 58.4 6.4 2.6 2,91 0.078

Barratt Impulsiveness Scale 74.8 9.3 71.7 14.5 79.9 17.4 2.7 2,91 0.070

Symptom Checklist – 90 – Revised 1.0 0.7 1.3 0.6 1.7 0.7 7.3 2,91 0.001Sheehan Disability Scale

Total score 13.0 5.5 16.7 5.2 17.2 6.2 4.8 2,91 0.010

Work/school 3.3 2.1 4.5 2.7 5.3 2.8 4.2 2,81 0.019

Social life 0.1 0.3 0.1 0.4 0.2 0.4 0.6 2,79 0.538

Family life/home responsibilities 4.9 2.4 6.0 2.4 6.3 2.5 2.9 2,92 0.058Days lost 5.2 2.3 6.6 2.2 6.3 2.7 3.0 2,92 0.054Days unproductive 1.2 1.7 4.0 6.5 5.6 7.6 4.2 2,87 0.018

a Zanarini scale=Zanarini Rating Scale for Borderline Personality Disorder.

TABLE 3. Adverse Events Reported by Study Participants With Borderline Personality Disorder Who Received Quetiapine or Placebo

Placebo (N=29)


(150 mg/day)(N=33)


(300 mg/day)(N=33) Total

Related toStudy Drug

Event N % N % N % N % N %

Any adverse event 25 86 29 88 30 91 84 88 78 82

Sedation 15 52 25 76 28 85 68 71 67 70Change in appetite 4 14 9 27 13 39 26 27 25 26Dry mouth 1 3 9 27 14 42 24 25 24 25

Headache 8 28 7 21 13 39 28 29 23 24Bodily pain 12 41 11 33 12 36 35 37 20 21

Hypersomnia 3 10 5 15 8 24 16 17 15 16

Dizziness 1 3 5 15 7 21 13 14 13 14Forgetfulness or confusion 3 10 6 18 5 15 14 15 12 13Nausea or vomiting 8 28 8 24 9 27 25 26 12 13

Cold/u symptoms 4 14 8 24 7 21 19 20 0 0





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effect size (20.79) indicates that the drug had a large effecton the primary outcome; improvement was greatestbetween visit 2 and visit 6. The Zanarini scale total score

decreased 9.8 points (1.22 points per week) for the low-dosage (150 mg/day) quetiapine group, 7.9 points (0.99points per week) for the moderate-dosage quetiapine (300mg/day) group, and 6.0 points (0.75 points per week) forthe placebo group. Improvement of this magnitude iscomparable to or exceeds that seen in other treatmenttrials in which the Zanarini scale was used (6, 7, 9, 12).Improvement for the moderate-dosage quetiapine groupmirrored that of the low-dosage group through visit 6, butthen regressed (Figure 1). Because the moderate-dosagequetiapine group did not receive the full 300-mg/day dosage until after visit 6, this nding was not unexpected.The low and moderate dosages were both superior toplacebo on many of the secondary ef cacy variables. Thus,this study joins a growing body of evidence showing thata relatively brief course of quetiapine can provide clinically meaningful benet to borderline patients (12–16).

Improvement on the Modied Overt Aggression Scalefurther suggests that quetiapine is superior to placebo intreating verbal and physical aggression. This nding isconsistent with the improvement we observed among participants in the moderate-dosage group on the Young Mania Rating Scale, which taps irritability, aggression, andverbal outbursts. We were surprised that there were nosignicant differences on measures of impulsivity and

depression between the groups because these symptomshave been shown to improve in medication and psycho-therapy trials (8, 14).

Low-dosage bested moderate-dosage quetiapine on theprimary outcome variable, but when all ef cacy variablesare considered, the advantage of the lower dosage becomesless apparent. Perhaps because the moderate dosage isassociated with greater levels of sedation, patients may report feeling “ worse” and thus be rated as more symp-tomatic. Or it could be that the moderate dosage is not aseffective and that the lower dosage is optimal.

Overall, 67% of participants completed the study, andthe differences between groups in study completion werenot signicant. Adverse events were consistent with thosereported in previous studies in mixed groups of patients(38), including sedation, change in appetite, dry mouth,and dizziness; only sedation predicted discontinuation.Changes in weight, serum glucose level, and lipid levels were inconsistent and not signicantly different betweengroups, perhaps because of the relative brevity of the study.

Improvements were also observed in 62% of placeborecipients. High placebo response rates have been a fea-ture of controlled trials of borderline personality disorder(14), so this rate was not surprising. Nonetheless, highrates can lower statistical power and interfere with in-terpretation of study results. It is possible that placeborecipients improved from the nonspecic psychologicalsupport given during the study. One potential solution is

FIGURE 1. Changes in Mean Total Score on the Zanarini Rating Scale for Borderline Personality Disorder Among StudyParticipants Who Received Quetiapine or Placeboa

M e a n

C h a n g e F r o m B

a s e l i n e i n Z a n a r i n i S c a

l e T o t a l S c o r e

Visit

65432 7 8 9 10 –12

–10

–8

–6

–4

–2

0

Quetiapine, 300 mg (N=33)

Quetiapine, 150 mg (N=33)

Placebo (N=29)

a Solid lines represent least-square mean estimates; dashed lines represent estimates from the shared parameter model with linear andquadratic effects. Results do not align completely because of differences in how group means are modeled and because the sharedparameter model corrects for informative dropout.





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to conduct longer trials, but patients would have to be willing to participate in lengthier trials. Alternatively, stud-iescouldbenet from an extendedlead-in periodto minimizetheimpact of the placebo effect, since early responders wouldnot be randomized.

The study had several methodological limitations. First,the noncompletion rate was 33%. While this rate is notunusual for trials of borderline personality disorder (8, 13),investigators need to address the issue of attrition. Second,stringent criteria excluded people with current majordepression, posttraumatic stress disorder, panic disorder,obsessive-compulsive disorder, and substance depen-dence to ensure a greater focus on changes in borderlinesymptoms rather than in comorbid disorders. For that

reason, the results may not generalize to borderlinepatients with these disorders. Finally, while quetiapine was effective in treating many symptoms of borderlinepersonality disorder, its adverse effects must be taken intoconsideration. We believe the results should generalizeto the use of immediate-release quetiapine because theactive ingredient is identical to that in extended-releasequetiapine.

Additional trials are needed to conrm the ef cacy of quetiapine in borderline personality disorder. Trials in which quetiapine is tested against other psychotropicagents and combination trials in which quetiapine isadded to an evidence-based psychotherapy could also behelpful.

TABLE 4. Comparison of Ef cacy Measures for Study Participants With Borderline Personality Disorder Who ReceivedQuetiapine or Placeboa

Mean Change per Week

Low-DosageQuetiapine Versus

Placebo

Moderate-DosageQuetiapine Versus

PlaceboPlacebo


(150 mg/day)

Moderate-Dosage

Quetiapine(300 mg/day)

Measure Estimate SE Estimate SE Estimate SE d SE p d SE pZanarini scale

Total score – 0.75 0.15 – 1.22 0.15 – 0.99 0.16 – 0.79 0.36 0.031 – 0.41 0.36 0.265Affective disturbance – 0.32 0.06 – 0.48 0.07 – 0.38 0.07 – 0.78 0.42 0.068 – 0.32 0.43 0.456

Cognitive disturbance – 0.21 0.04 – 0.34 0.04 – 0.30 0.04 – 0.63 0.28 0.023 – 0.43 0.28 0.127Impulsivity – 0.09 0.03 – 0.14 0.03 – 0.13 0.03 – 0.37 0.26 0.156 – 0.30 0.27 0.269

Disturbed relationship – 0.18 0.05 – 0.32 0.05 – 0.27 0.05 – 0.75 0.38 0.051 – 0.48 0.38 0.204Zanarini scale, self-rated

Total score – 0.58 0.18 – 1.29 0.18 – 1.28 0.19 – 0.88 0.32 0.006 – 0.87 0.32 0.007

Affective disturbance – 0.25 0.08 – 0.47 0.08 – 0.53 0.09 – 0.70 0.34 0.040 – 0.87 0.34 0.013Cognitive disturbance – 0.15 0.06 – 0.34 0.06 – 0.35 0.06 – 0.71 0.29 0.016 – 0.73 0.29 0.013Impulsivity – 0.10 0.04 – 0.17 0.04 – 0.16 0.04 – 0.39 0.30 0.191 – 0.35 0.29 0.232

Disturbed relationship – 0.14 0.05 – 0.36 0.05 – 0.32 0.05 – 0.86 0.27 0.002 – 0.73 0.27 0.008

Borderline Evaluation of Severity Over Time

Total score – 0.91 0.31 – 2.10 0.32 – 1.97 0.33 – 0.85 0.32 0.009 – 0.75 0.32 0.020

Thoughts and feelings – 0.46 0.20 – 1.29 0.20 – 1.21 0.21 – 0.90 0.31 0.004 – 0.82 0.31 0.009Negative behaviors – 0.18 0.08 – 0.41 0.08 – 0.39 0.08 – 0.55 0.28 0.054 – 0.49 0.28 0.079Positive behaviors 0.25 0.08 0.42 0.08 0.35 0.09 0.52 0.35 0.146 0.30 0.36 0.407

Montgomery-Åsberg Depression Rating Scaleb – 0.59 0.18 – 0.85 0.19 – 1.05 0.19 – 0.31 0.32 0.328 – 0.56 0.32 0.083Modied Overt Aggression Scaleb – 0.37 0.43 – 1.92 0.42 – 1.82 0.43 – 0.82 0.32 0.014 – 0.76 0.32 0.020

Young Mania Rating Scaleb – 0.11 0.06 – 0.26 0.06 – 0.30 0.06 – 0.40 0.21 0.060 – 0.50 0.21 0.019Global Assessment of Functioning Scaleb 0.62 0.19 1.05 0.20 1.04 0.21 0.49 0.33 0.135 0.49 0 .33 0 .141

Barratt Impulsiveness Scaleb – 0.59 0.26 – 0.73 0.27 – 0.83 0.27 – 0.08 0.21 0.719 – 0.13 0.21 0.536Symptom Checklist – 90 – Revised – 0.07 0.02 – 0.11 0.02 – 0.12 0.02 – 0.47 0.28 0.099 – 0.62 0.29 0.033

Sheehan Disability Scaleb

Total score – 0.58 0.18 – 0.85 0.19 – 1.11 0.20 – 0.38 0.37 0.310 – 0.72 0.37 0.054

Work/school – 0.10 0.07 – 0.28 0.08 – 0.28 0.08 – 0.56 0.32 0.081 – 0.55 0.31 0.088Social life – 0.22 0.08 – 0.27 0.09 – 0.36 0.09 – 0.17 0.40 0.679 – 0.46 0.40 0.255

Family life/home responsibilities – 0.25 0.07 – 0.31 0.08 – 0.45 0.08 – 0.19 0.36 0.591 – 0.66 0.36 0.073Days lost 0.05 0.11 – 0.33 0.12 – 0.36 0.12 – 0.49 0.21 0.025 – 0.54 0.21 0.012

Days unproductive – 0.33 0.21 – 0.58 0.23 – 0.88 0.23 – 0.26 0.32 0.424 – 0.55 0.31 0.086a d=group difference mean change from baseline, divided by pooled baseline standard deviation; Zanarini scale=Zanarini Rating Scale for

Borderline Personality Disorder.b Shared parameter not used for outcomes that were measured only at visits 2, 6, and 10. Mean change per week was calculated using each

group’s linear and quadratic effects.





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Received Oct. 12, 2013; revisions received March 17 and April 28,

2014; accepted May 6, 2014 (doi: 10.1176/appi.ajp.2014.13101348).

From the Department of Psychiatry, University of Iowa Carver College

of Medicine, Iowa City; McLean Hospital, Harvard Medical School,

Belmont, Mass.; and the Department of Psychiatry, University of

Minnesota Medical Center, Fairview, Minneapolis. Address correspon-

dence to Dr. Black ([email protected]).

Dr. Black receives royalties from American Psychiatric Publishing,

Oxford University Press, and UpToDate. Dr. Schulz has receivedresearch support from Forum, Myriad RBM, and Sunovion and has

served as a consultant to Eli Lilly, Forum, Genentech, and Teva. Dr.

Zanarini receives royalties from American Psychiatric Publishing and

Jones & Bartlett. The other authors report no nancial relationships

with commercial interests.

Supported by a grant from AstraZeneca to Dr. Schulz, with

subcontracts to Drs. Black and Zanarini.

The authors thank Drs. Michael Burgard, Katherine Gilligan, Jeffrey

Jacobson, Dustin DeYoung, Tom Salter, and Siddharth Bajpai for

assisting with the study.

Clinicaltrials.gov identier: NCT00880919.

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14. Van den Eynde F, Senturk V, Naudts K, Vogels C, Bernagie K,Thas O, van Heeringen C, Audenaert K: Ef cacy of quetiapinefor impulsivity and affective symptoms in borderline personal-ity disorder. J Clin Psychopharmacol 2008; 28:147 – 155

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22. Zanarini MC, Vujanovic AA, Parachini EA, Boulanger JL, Frankenburg FR, Hennen J: Zanarini Rating Scale for Borderline PersonalityDisorder (ZAN-BPD): a continuous measure of DSM-IV border-

line psychopathology. J Pers Disord 2003; 17:233 – 24223. Montgomery SA, Åsberg M: A new depression scale designed to

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28. Barratt E: Anxiety and impulsiveness related to psychomotoref ciency. Percept Mot Skills 1959; 9:191 – 198

29. Derogatis LR: SCL-90-R Administration, Scoring, and ProceduresManual II. Towson, Md, Clinical Psychometric Research, 1983

30. Sheehan DV: The Anxiety Disease. New York, Scribner, 198331. Simpson GM, Angus JWS: A rating scale for extrapyramidal side

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34. Mori M, Woolson RF, Woodworth GG: Slope estimation in thepresence of informative right censoring: modeling the numberof observations as a geometric random variable. Biometrics1994; 50:39 – 50

35. Mazumdar S, Tang G, Houck PR, Dew MA, Begley AE, Scott J,Mulsant BH, Reynolds CF 3rd: Statistical analysis of longitudinalpsychiatric data with dropouts. J Psychiatr Res 2007; 41:1032 – 1041

36. Fitzmaurice GM, Laird NM, Ware JH: Applied LongitudinalAnalysis. New York, John Wiley & Sons, 2004

37. SAS Institute: SAS/STAT 9.1: Users Guide. Cary, NC, SAS Institute, 200438. Calabrese JR, Keck PE Jr, Macfadden W, Minkwitz M, Ketter TA,

Weisler RH, Cutler AJ, McCoy R, Wilson E, Mullen J BOLDER StudyGroup: A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression. Am JPsychiatry 2005; 162:1351 – 1360

Clinical Guidance: Quetiapine for Borderline PersonalityDisorder

Six weeks of extended-release quetiapine at a dosage of 150 mg/day signicantly reduces symptoms of borderline personality disorder. In the trial by Black et al.,300 mg/day was not signicantly superior to placebo and produced more sideeffects than low-dosage quetiapine. In an editorial, Tohen (p. 1139) cites the 3-lb weight gain in the group receiving 300 mg/day of quetiapine—compared with 1 lbfor placebo and low-dosage quetiapine—and stresses the need for consideration of long-term effects.





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Appendix B


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-I

for Unanticipated Problems Involving Risks t

ctsor Others

IRB S

tudy Number:

0709M16844

Current Principal Investigator

[Charles Schulz, MD

Primary Title:

Seroquel

X R

for the Management of Borderline

Personality Disorder BPD) ___

Provide the following information for

each unanticipated

problem/event that is serious and

possibly related to the research procedures. Attach

any

summary or report from sponsor or

DSMB with corresponding reference .

Reference

strazeneca Study IRUSQUET0454

Date of Event

010

Date of

Report

010

On-site Off-site

M

Initial report

Z

ollow up report

Describe problem event:

Misuse of study medication: study medication misused by two study subjects and given to others.

Incident report included with this document

Possibly related

L I I I

Probably related

LII

Definitely related

Does this problem/event alter risk to past, present or future subjects?

Yes

I I I

o

El

on’t Know (Insufficient Information) ]

Based on your, the local investigator’s judgment, should this problem/event be added to the

consent form as a potential risk?

Yes

Provide revised consent form with changes highlighted.

N o

Z

Explain why not:

The incident did involve a direct risk to study subjects taking the study medication.

Based on your, the local investigator’s, analysis of this problem/event,

should currently enrolled subjects be notified?

e S I

o

should subjects who have completed the study be notified? es

[

o

Explain:

The safety of the two study subjects was not affected by this incident

Principal InvestigatorSit Date


18/92

Study

Seroquel XR for the Management of Borderline Personality Disorder

(BPD)

P: S. Charles Schulz, MD

YJ

1

till,

l,i1iIItrr1Th

Date

o Report:

S S J

Study patient as enrolled into study on 010 and

randomized to study medication (Seroquel XR or placebo) on

010

current residence was Alpha House Residence. Alpha House is a

residential program which provides high levels of structure and supervision for

sex offenders within a therapeutic community setting and is licensed and certified

by the Minnesota Department of Corrections.

Study patient as enrolled in study on

010 and

randomized to study medication on 010. urrent residence was

Alpha House Residence, eturned to research clinic for study visit 3 on

2010.

id not return visit 2 study medication bottle stating he forgot

it at home. eminded to return study med bottle at next visit and he agreed.

received visit 3 assessments and new bottle of study medication was

dispensed to him, Seroquel XR or placebo, 30 tablets with instructions to take 3

tablets at bedtime (150mg or placebo). id not return to study visit 4 on

2010. Study coordinator phoned Alpha House residence line and

was not available. Study coordinator left message regarding

issed

appointment. Study coordinator then received a phone call from

ho was

calling in for final follow-up after study withdrawal, nformed study

coordinator that ad gone back to prison on

010.

On Tuesday 010 Study coordinator received phone call from

acquaintance of

tating ad got locked up again. Study coordinator

received second phone call from Alpha House staff person Alexis stating

had signed a release of information for study staff. Alexis stated ad been

re-imprisoned due to an incident involving the study medication as follows.

reported to Alpha House staff that he had only taken 1 dose of his study

medication (1 tablet of Seroquel XR 50mg or placebo) and did not like the effects

of the medication. He then gave

tablets of his study medication.

returned to research clinic for visit 3 on 18 MAY 2010 and returned his bottle of


19/92

study medication with 3 tablets remaining,

tated he felt overly sedated by

the study medication, and did not wish to continue in the study.

was employed as the full-time cook at Alpha House, Per Alexis on the

morning of

010 BRE cooked and served oatmeal to 1520 persons at

Alpha House, 4 of which were staff members. Some residents noticed pink

particles in the oatmeal. After eating breakfast the residents and staff reported

feeling sedated and some were knocked out for the remainder of the day.

Staff asked f he had put the study medication into the oatmeal and

denied it. After failing a polygraph test

as re-imprisoned.

Study medication blind was broken by Investigational Drug Services (IDS)

pharmacy at the University of Minnesota on

010. Blind reveals

was randomized to Seroquel 150mg arm and as randomized to

Seroquel 300mg arm. Both arms start out on daily dose of Seroquel XR 50mg at

bedtime for I week, and then increase to 150mg at bedtime for 2 weeks.

Remaining study drug for kits

nd o be returned to IDS

pharmacy for destruction.


20/92

UNIVERSITY OF MINNESOTA

Twin ities ampus

Human

esearch

Protection

Program

011ice ofthe Viii I’,rsjclejt fm Research

/)528 Maya Memorial Building

420 Delawase Street S. E

MMC 820

Minneapolis. MN 55455

Office: 6/2-626-5654

Icv. 612-620-6061

E-mail: jib

@ scm/s edo or jbc @ cmii i es /is

IVebsile: Iinp://researcli. (s,,in.edf/sisbfcts/

06/21/2010

Sellmann C Schulz

Psychiatry Department

F282/2A West-B

2450 Riverside

Minneapolis MN

55454

RE: Seroquel XR for the Management of Borderline Personality Disorder: A Randomized

Double-Blind Comparison with Placebo’

IRB Code Number: 7 9M16844

Dear Dr. Schulz:

At its meeting on June 17, 2010 the Institutional Review Board (IRB) reviewed and noted

unanticipated problem and adverse event report for the referenced study. The following reports

were included in this review: AstraZenica Study IRUSQUET0454, event date: May 17, 2010,

report date: May 27, 2010.

Thank you for keeping the IRB informed of the status of your research.

As Principal Investigator of this project, you are required by federal regulations to inform the

IRB of any proposed changes in your research that will affect human subjects. Changes should

not be initiated until written IRB approval is received. Unanticipated problems and adverse

events should be reported to the IRB as they occur. Research projects are subject to continuing

review and renewal.

If you have any questions, call the IRB office at 612 626 5654.


21/92

We have created a short survey that will only take a couple of minutes to complete. The

questions are basic, but will give us guidance on what areas are showing improvement and what

areas we need to focus on:

httt)s://umsurvev.umn.e.du/index.t)ho?sid=36122 langfum

Sincerely

rt--

Andrew Allen

Research Compliance Supervisor

AAIks

CC: Scott Crow, Peter Milev, Michael Miller, Richelle Moen, Ann Romine, John Vuchetich


22/92

Appendix C


23/92

University of Minnesota

-Continuing-Rev-iew-of-IRB-̂ Pending-

:Medca,LResearch ..—=̂

Review Period:

01/10/2008-01/09/2009

Rev; 03/01/2005

-Study Number:-0709M16844 --- - -..----.-

Principal Investigator: Sellmann C Schulz

Title(s): Seroquel XR for the Management of Borderline Personality Disorder:

A Randomized Double-Blind Comparison with Placebo

Study Status

A ctive (E nrolling Subjects)

Funding Source(s)

Funding Source:

Funding Type:

Funding Source: AstraZeneca

F unding Type: OT H E R

AGENDA.

i M̂ J MSL

Personnel

Schulz, Selimann (P. I .)

Crow, Scott (Co-lnvestigator)

Milev, Peter (Co-lnvestigator)

Miller, Michael (Co-lnvestigator)

Moen, Richelle (Co-lnvestigator)

Romine, Ann (Correspondent)

Investigational Drug(s)

IND Number: 45,456

IND.Holder: AstraZeneca (Sponsor)

I DS N umber: 3462

Study Enrollment

Number of Subjects Approved for study:

50

Number of subjects enrolled this review period:

MaeFemaeUnknown Total

T

T

0~T2~

The University of Minnesota is an equal opportunity educator & employer.

©2004 by the Regents of the University of Minnesota,

Page 1

P age 2


24/92

Number of subjects enrolled to date:

-Male- —- —-Female- ~~~" "Unkn'own •

_̂1=1——— -0 —̂ 2=̂

Is this a multi-center study?

Yes

Total national accrual to date; 2

Unanticipated Problem Reporting

Since the most recent IRB continuing review approval, have any participants withdrawn from the

research?

No

Since the most recent IRB continuing review approval, have any participants complained about the

research?

No

Have any serious and unexpected adverse events been reported to the IRB?

No

Study Suimmary

Summarize preliminary information about any results and/or trends:

In beginning phases of enrollment with 2 subjects enrolled.

Have there been any changes in protocol approved by the IRB since last continuing review?

No

Since the most recent IRB continuing review approval, have there been any progress reports on the

research?

N o

Since the most recent IRB continuing review approval, have there been any multi-c.enter trial reports?

N o

Since the most recent IRB continuing review approval, have there been any other information

relevant to this research discovered, especially information about the risks and benefits associated

with the research?

The University of Minnesota is an equal opportunity educator & amployer. Page 2

©2004 by the Regents of the University of Minnesota.

PageS


25/92

No

Since the most recent I RB continuing review approval, have subjects experienced any benefits?

Yes

2 acti.ve subjects report receiving benefit frpm.stydy.participatjon {hys_far,

External Findings

Is there anything in the relevant recent literature that the IRB should know about concerning this

research?

No

Consent/Assent Forms

Have there been any changes to the consent and/or assent form(s) since the last IRB approval?

No

Have. translated consent short forms been used in conjunction with an interpreter to obtain consent

for this study?

N o

Other Comments

Study start has been slgnigicantly delayed by contract hold-ups.

The University of Minnesota is an equal opportunity educator & employer. Page 3

©2004 by the Regents of the UnlvsrsityofMlnnssota.

P age 4


26/92

rP-Tr"—-—S-cbulz,:Sellman=̂ —•̂ ""—=—O.TiiveFsitŷ f-M:imeso'̂

HSC# 0709M16844 Research Subject's Protections Programs

Revewer: • nsttutona RevewBoard

-Meeting-Date:- -——• ——- -- "—-———- - —- —- —• —•-—

Full Committee Review—Continuing Review of Approved Research

I f you choose to submit this form eleytt-onically, please send to u-b(%umn.edu.

"/in I RS shall conduct 'continuing review of research covered by this policy ut inte.n'als appropriate to the

degree ofmk, but not less than once per year, andfsha/i have the aulhorUy to ohaen'e or have a third party

ohseri'e the consent process and the research."

21CFRS6.109 and 45CFR46.109

"Continuing, review ofresuurch must be siibslcuiiive and meamngfii l."

OffRP Guidance on Continumg Review 1-15-07

Study status: [X] Enrolling subjects

Following subjects

D On hold

Closed to enrollment

Study Enrollment: Note any issues. Is enrollment as expected, has PI overenroHed, is

there a lack of subjects or are they nearing approved totals? Is the PI requesting more

subjects OR should PI request more subjects?

2 of 50

Funding; Any changes in the last year? Q Yes • D No

Federallyfunded?. DYes DNo

Study personnel; Any personnel changes in the last year? Q Yes Q No

Are personnel lists in agreement with recent Con Ren form and consent forms?

D Yes D No

List discrepancies: Nathalie Vizueta, MA. listed on consent - not listed on con rev form

Conflict of Interest: Have there been any change in COI in the last year?

Yes QNo

Investigation al Drugs or Devices: Have there been any changes or additions in the

as yea?QYesQNo

UPTRTSOS (unanticipated problems or serious adverse events): Since the most recent

IRB continuing review approval have there been any UPIRTSOS to report?

D Yes D No

L ist issues or concerns: none given

Pa ge 22


27/92

Study Summary: I s the summary descriptive enough to assess ongoing risk and

benefit -in relation to the length and complexity of the study?

l-.Y-es-""QNo

Comments: study just star ted enrollment - two patients receiving medication have reported benefit

External Findings (such as interim analysis or DSMB reports, etc.): Tins report

should reflect how long the study as been open.

Yes QNo

Comments: none to report

Consent and Assent Forms: Are forms current for 1KB practice and/or standards?

D Yes D No

I f the risks and/or benefits are not described accurately the committee should discuss and

make a determination. (Please edit forms and hand in edited, forms to IRB staff.)

Comments:

Inclusion of Children in Research:

I f children are included in this research confirm that they should still be included m this

research. QYes DNo[X] NA

(According to Subpart D and tlie requirements for pennisyion by parents or guardians and

for assent by children, 45CFE46.408, see yellow sheets).

I f children are included this inclusion must meet one of the following criteria for

risk/beuefit assessment according to federal regulation (21CFR56 and 45CFR46 Subpart

D, see yellow sheets),

[_] (404) Minimal risk

I j (405) Greater Ami minimal risk; but holds prospect of direct benefits to subjects.

(406) Greater than minimal risk; no prospect of direct benefit to subjects, but likely to

yield generalizable knowledge about the subject's disorder or condition.

Page 23


28/92

Criteria for I KB_AKProva]:

Confirm that the criteria for IRB approval are still met.

(21CFR56.111 and45CJ ?R46.ni)

I I Risks to subjects arc minimi/.ed

[_] Risks to subjects are reasonable in relation to anticipated benefit, I f any, to subjects,

and the importance of the knowledge that may be expected to result

Q Selection of subjects is equitable

I I Informed consent will be sought from each prospective subject or the subject's legally

authorized representative, in accordance with 21CFR50 and/or 454CFR46.116

Q Informed consent will be appropriately documented, in accordance with 21CFR50.27

and/or45CTR46.U7

Where appropriate, research plans make adequate provisions for monitoring the data

collected to ensure the safety of subjects, QYes | [ NA

Where appropriate, there arc adequate provisions to protect the privacy of subjects and to

mantanconfidentiaityof data. • QYes DNA

Where appropriate, vzilncrable populations have adequate protection; risk and benefit

analysis confirms their inclusion in the research. [_J Yes Q NA

General questions:

**m' questions 1-4 are YE S please address and document in the comments and

discussion section.

1. Does the ongoing continuing review information indicate any alteration in the risk and

benefit balance or ratio from previous reviews? Q Yes Q No

2. Does the consent or assent form(s) require revision or updating? Q Yes ' | | No

3. Does the ongoing continuing review information prompt notification ofstudy subjects

areadyenroed?QYes QNo

4. Should the committee request or seek verification of information from other sources,

such as DSMB, fonder, sponsor, or literature search? [_] Yes D No

I f question 5 is NO please address and document in the con-iments and discussion section.

5. If vulnerable populations previously were subjects should they continue to be included

in this research? Q Yes • Q No DNA

Pa ge 24


29/92

-I .s-lh v-i'-vy-i tiW—iutciL v.d 1-s ti l l-ap.p r-o.pEii i.te-toi—this ŝ.tu.dy-i

For continuing review approval federal regulations state that studies need to be reviewed

no-iess-that yearly-but the-committcc may-set continuing-feview-at-a-morefi'equent-

interval.

Check the review interval appropriate for tllis study:

Annually

D Every 6 months

Q Quarterly

Other interval (state specific renewal interval and provide justification)

Committee Determination:

Cannot make "suggestions " due to automatic email, suggestions must be listed as

stipulations

Q Approved as Submitted: no change required in ongoing approval

Approved with Stipulations: as noted

Response to original reviewer

Q Response can be reviewed by expedited review (by senior staff)

Approval Deferred: additional information required. This is a serious decision as

deferral halls all research processes. Committee should 'consider subject status and

funding issues. Response will go back to the continuing review committee for review

Common stipulations:

Update Contacts and Questions section information on the consent forms;

i.e. "University of Minnesota Medical Center Fairview"

D Add HIPAA reference on the consent form.

D Add the human subject code numbcr/page numbers/version date to all pages of the

consent forms,

The 1RB should observe the consent process or the research,

n Reapply as required every 5 years,

I have completed a substantive and meamngfyl review based ou.the information

made available at this time.

Print name of reviewer: KG J ohnson

Signed name of reviewer;

Date: 12/17/2008

PagaZb


30/92

-D o Gum ent-items-fo î eommttee-iidis cus sioti b̂ elo w:-

Document "comments, changes, and stipulations" below:

(write out stipulations clearly)

Nathalie V izueta, M A. l isted on consent and not listed on con rev form

C orrect address for out-of study contact In formati on - remove room number, and correct street

number

P age 26


31/92

Committee Meeting Minutes

December 17, 2008

Agenda I tem:i

Continuing Review-Medical

Agenda Item: None

Agenda Item: None

PI : Schulz, Sellmann

Reviewer: J ohnsotf

Reviewer; Belew

Protocol Title arid HSC#"Seroquel^̂ ^̂ fo^

ARandomiZed ôublê UudG m̂paruoni? P̂lacebô

Item Description:

None;.l"?;

(Discussion of Controverted Issues Summary:

There were no controverted issues.

iRevisiftnSt


32/92

12/19/2008

SemnnCSchuz_. •, ̂M̂

PsychatryDepartment \ \̂ ^

•F2822AWsB•. ̂

2450 Ri verside

Minneapolis, MN 55454

RE; "Seroquel XR for the Management of Borderl ine Personality Disorder: A Randomized

Double-Blind Comparison with Placebo"

IRB Code Number: 0709M16844

Dear Dr. Schulz,

.At the meeting on December 17, 2008, the IRB; Human Subjects Committee reviewed the

referenced study. The following stipulations must be resolved, mid written approval should be

received, before renewed approval is confirmed,

The following changes to the consent form are stipulated;

• Correct the following standard language in the Contacts and Questions section of the

0 consent form: If you have any questions or concerns regarding the study and would like to

talk to someone other than the researcher(s), you are encouraged to contact the Fairview

Research Helpline at telephone number 612-672-7692 or toll free at 866-508-6961, You

may also contact this office in writing or in person at University of Minnesota Medical

Center, Fairview Riverside Campus, 2200 Riverside Avenue, Minneapolis, MN 55454.

^ . „. . •

Please provide a copy of the revised consent form for review.

We cannot confirm the renewal of the referenced study until these conditions are met, I f your

response is not received within ninety days, the study will be filed inactive.

Please send your response to RSPP (Mayo Mail Code 820; D-528 Mayo Memorial Building; 420

Delaware St, SE; Mmncapolis, MN 55455) The entire application does not need to be resubmitted;

your, response should address the sections requiring change. The signature of the Principal

Investigator is the only signature required with the response. Only one copy of the response is

necessary,

I f you have any questions, please contact the IRB office at 612-626-5654.

Sincerely,

Andrew Alien

Research Compliance Supervisor

AA/mq

CC: Scott Crow, Peter Milev, Michael Miller, Richelle Mocn,

letter to susan berry and irb executive committee regarding seroquel borderline personality disorder...

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