The International Suicide Prevention Trial (InterSePT): Rationale and Design of a Trial Comparing the Relative Ability of Clozapine

and Olanzapine To Reduce Suicidal Behavior in Schizophrenia and Schizoaffective Patients

by Larry Mphs, Ravi Anand, M. Zahur Islam, Herbert Y. Meltzer, John M. Kane, Ranga Krishnan, Alan I. Qreen, Steven Potkin, Quy Chouinard, Jean'Pierre Lindenmayer, and Rob Kerwin
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Abstract
Suicidal behavior in patients with psychotic disorders represents a seriously undertreated life-threatening condition. The International Suicide Prevention Trial (InterSePT) is the first large-scale, prospective study designed to evaluate the potential of antipsychotic medications to reduce suicidal behaviors in patients with schizophrenia or schizoaffective disorder who are known to be at high risk for suicide. The unique challenges to study design and the solutions identified for the InterSePT study are described. These challenges included defining suicidal behavior in patients with psychosis, endpoint selection, determination of analytic strategy, and development of scales to assess suicidal behavior. Given the life-threatening nature of suicidal behavior, ethical considerations required that the design minimize suicide attempts and deaths. While the study focused primarily on treatment of suicide, opportunities were used to collect data in related areas of interest, including suicide risk factors, other efficacy measures (e.g., Positive and Negative Syndrome Scale, Covi Anxiety Scale, Calgary Depression Scale), adverse events, pharmacoeconomics, and pharmacogenetics. Because of the complexity of the design issues, a steering committee, suicide monitoring board, and publication committee were established to assist with their management Keywords: Suicide, suicidal behavior, schizophrenia, schizoaffective disorder, study design, clozapine, olanzapine. Schizophrenia Bulletin, 30(3):577-586, 2004. Bleuler referred to the suicidal drive as "the most serious of schizophrenic symptoms" (Bleuler 1911, p. 488).

Indeed, it is estimated that schizophrenia patients have a 50 percent lifetime risk of attempting suicide. Annual death rates from suicide in this population have been reported to be 0.4 percent to 0.8 percent, with a lifetime risk of 10 percent (Nyman and Jonsson 1986; Axelsson and Lagerkvist-Briggs 1992; Meltzer and Fatemi 1995). Although suicidal behavior is well documented in psychotic patients, the magnitude of the problem is not generally understood, risk factors are not well established or widely recognized, and little information on the treatment of suicidal patients is available. Consequently, a patient's suicide risk is seldom assessed in clinical practice. In addition, detection of suicide risk factors and prevention of suicide are particularly difficult because of the unique issues presented by patients with psychotic disorders. These patients are frequently beset with thought disorder, delusions, hallucinations, lack of insight, and negative symptoms, all of which interfere with their ability to communicate with their caregivers. Overall, suicidal behavior in patients with schizophrenia and related disorders represents a major public health problem that has not been adequately addressed by the medical community (Singh 1998). Existing data suggest that, for the most part, pharmacotherapy for schizophrenia has not affected the rate of suicide among patients with psychotic disorders. Studies with conventional antipsychotic medications have shown increased (Beisser and Blanchette 1961; Hussar 1962), decreased (Johnson et al. 1983), or unchanged (Kline 1959; Cohen et al. 1964; Planansky and Johnston 1971) rates of suicide in schizophrenia, and demonstrated that

Send reprint requests to Dr. L. Alphs, 765 Watershed Court, Ann Arbor, MI 48105; e-mail: larry.alphs@pfizer.com.

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the overall rate of suicide in schizophrenia was similar both before and after the introduction of classical antipsychotics (Meltzer 1999; Palmer et al. 1999). In one study, a 2 percent incidence of suicide was found among a cohort of 1,221 patients hospitalized for schizophrenia between 1913 and 1940 with a subsequent 11 years mean length of follow-up (Stephens et al 1999), suggesting a lower incidence of suicide in schizophrenia in an era without antipsychotics. Khan et al. (2001) analyzed data from a Food and Drug Administration (FDA) data base of 10,118 patients who had participated in pivotal clinical trials with olanzapine, risperidone, and quetiapine. They compared the rates of suicide and suicide attempts (in patients expected to be at reduced risk for suicide) during treatment with these drugs to those of patients randomized to placebo and to those taking established ("typical") antipsychotic drugs. Despite the large sample size, the rates for suicide attempts were not statistically different among these three treatment groups. Overall, these data are inconclusive, but suggest that neither typical nor atypical antipsychotic medications reduce suicidal behavior relative to placebo.

the use of concomitant medication, or the increased clinical contact required for blood monitoring during treatment with clozapine. The potential safety advantages of more recently introduced atypical antipsychotic agents highlight the need for controlled comparative studies to evaluate whether clozapine differs from these drugs in the management of suicidal behavior. The InterSePT study1 was conducted to address the limitations of previous clinical trials and to establish whether clozapine treatment is effective for reducing suicidal behavior among schizophrenia and schizoaffective patients who were preselected to be at high risk for suicide but were not otherwise treatment resistant. Because of the lack of prospective studies on which to model a protocol for this clinically unstable population, the designers of the InterSePT study had to address numerous challenges so that scientifically sound answers to the pressing questions regarding treatment of suicidality in psychotic patients could be found. Descriptions of the issues they faced and their solution in the InterSePT study follow.

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International Suicide Prevention Trial (InterSePT) Rationale for Clozapine Treatment of Suicidal Behavior in Schizophrenia
The studies reviewed above do not include data on clozapine, however, several large, retrospective studies suggest that clozapine may be effective for treating suicidal behavior in treatment-resistant schizophrenia patients who have not been preselected for suicide risk (Meltzer and Okayli 1995; Walker et al. 1997; Reid et al. 1998; Munro et al. 1999; Sernyak et al. 2001). All but one of these studies suggest that treatment with clozapine may significantly reduce suicide in this population. Only the study of Sernyak et al. failed to demonstrate the superiority of clozapine over alternative therapies. However, although this study included patients with a history of exposure to clozapine, it did not specify a minimal duration of treatment or whether patients were receiving active treatment with clozapine at the time of the index suicide attempt. AH of these studies leave open the question of whether a potential effect on suicidal behavior is limited to treatment-resistant patients or applies more generally to patients with schizophrenia or schizoaffective disorder who are at risk for suicide. Despite the evidence suggesting a clozapine effect on suicidal behavior, few comparative studies have been conducted, and those that have been were not controlled for the patient's risk of suicide, the dosage of drug treatment,

Selection of Study Objective and Endpoints

The primary objective of the InterSePT study was to establish whether clozapine provides therapeutic benefit for reducing suicidal behavior in schizophrenia and schizoaffective patients at high risk for suicide. Because manipulative behaviors, expressed as suicide gestures, are also seen in some subpopulations of schizophrenia patients (e.g., those with borderline personality features), serious suicide attempts were distinguished from gestures that patients might have made to control their social environment. In this study, both the seriousness of suicidal intent and the lethality of means used to make that attempt were evaluated by the patient's physician and by a blinded Suicide Monitoring Board (SMB). In a psychotic population, a unique problem in determining whether an event meets criteria for suicide arises because the disease itself may cause patients to unknowingly put themselves at risk of death. For example, patients may have command hallucinations that direct them to stop a moving train. If queried, such patients might deny that they are trying to kill themselves as the oncoming train, and certain death, approach. In studies of suicide, a priori decisions must be made regarding whether this behavior represents a true suicide attempt. Because of the ambiguities in defining the nature and limits of suicidal behavior and the particular difficulty in

'The principal results of the InterSePT study have been published elsewhere (Meltzer et al. 2003).

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ascertaining patients' motivations after their death, suicidal behaviors were defined in this study as behaviors committed by patients that put them at high risk of death and resulted from (1) willful intent, (2) a response to internal compulsions, or (3) disordered thinking. Medical ethics requires that therapeutic trials in patients optimize both the clinical needs of the patient and the scientific requirements of study conduct. In this study of patients at high risk for suicide, ethical considerations required that, at each contact made for collecting efficacy and safety data, every reasonable effort be made to prevent the patient from attempting suicide, even though this has the potential to affect study outcome. Because of the need to prevent these events, using suicide attempts (including completed suicides) as the only measure of outcome in the InterSePT study was unacceptable. In addition, the duration and sample size for a prospective study that only included suicide attempts or suicide deaths as endpoints would make it impracticable. As a consequence, interventions to prevent the immediate risk of suicide and clinical ratings indicating significant clinical worsening in suicidal behavior from baseline were included as primary endpoints. The numerous potential endpoints that might have been chosen for this study required clear a priori specification for statistical analysis. After extensive consultation with external clinical experts in psychiatry and statistics and the Neuropharmacology Division of the FDA, two types of primary endpoints were designated. A type I event was defined as the occurrence of a significant suicide attempt or hospitalization because of imminent suicide risk (including increased level of surveillance), which was confirmed by a blinded external group. A type II event, determined by a blinded psychiatrist, was defined as the occurrence of worsening of severity of suicidality, as indicated in a clinical global rating of suicidality of "much worse" or "very much worse" compared with baseline. Because patients with potential type n events were not always observed by a blinded psychiatrist, criteria for a significant level of worsening from baseline were also defined to have been met whenever a type I event occurred. The statistical management of these two diverse endpoints is described below (see "Statistical Analyses").

This study was limited to patients between the ages of 18 and 65 with a DSM-IV (APA 1994) diagnosis of schizophrenia or schizoaffective disorder who were considered to be at high risk of committing suicide. A high-risk patient was any patient with a medical history of suicidal behavior, including a previous serious suicide attempt or hospitalization to prevent a serious suicide attempt within the past 3 years. A serious suicide attempt was defined as a self-inflicted injury that put the patient at imminent risk of death. Alternatively, patients who demonstrated moderate to severe suicidal ideation with depressive symptoms or who had suffered from significant command hallucinations that put them at risk for self-harm at the time of initial evaluation were eligible for enrollment in the study. Patients who met inclusion criteria were excluded from participation if consent could not be obtained, if based on prior experience the patient was intolerant of clozapine or olanzapine, or if the patient would not be able to comply with the long-term followup required by the study. Schizophrenia and schizoaffective patients from a diverse group of multinational clinical settings were allowed to enter this study. They included patients from 67 sites in 11 countries2 who spoke at least eight languages and were from many subcultures, socioeconomic groups, and medical systems. The international character of this study created an increased need for translations of training materials and patient record-related outcome data.

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Site Selection
Because of the seriousness of the condition being examined, the criteria for site selection received particular scrutiny. Above all, investigational sites had to include a principal investigator familiar with treating psychotic patients at high risk for suicide. In addition, each site had to have sufficient support staff to be able to follow these patients during an extended period of observation. Staff at the site had to be familiar with the use of clozapine and be able to accommodate the stringent bloodmonitoring requirements for using this drug. To ensure adequate patient enrollment, the site was required to have a flow of patients sufficiently large to permit screening of approximately 10 patients per month who would meet study inclusion criteria. To ensure that frequent, regular contact (at least twice per month) with the patient could be maintained, the site had to be located near the patient's residence and have suffi-

Patient Selection
The InterSePT study was designed to include patients from a diverse population, enabling extrapolation of results to the larger group of patients with schizophrenia at risk for suicide. On the other hand, the population studied had to be sufficiently enriched so that it could be completed in a limited time frame with feasible sample size. Minimal limitations were imposed to meet these criteria.

The 11 countries were Argentina, Canada, Chile, Croatia, Czechoslovakia, France, Hungary, Italy, South Africa, the United Kingdom, and the United States.

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ciently trained medical staff to manage these high-risk patients. Finally, to comply with the requirements for blinded ratings, the site had to have a trained staff psychiatrist and usually one other skilled rater who could serve as a blinded evaluator ("blinded psychiatrist") of the patient at regular intervals during the period of observation.

Choice of Control Drug

Because standard ("typical") antipsychotic agents frequently produce extrapyramidal side effects, such as tardive dyskinesia and akathisia, which have been said to increase suicidal behavior (Margolese et al. 2001), their use in a long-term trial was considered unacceptable. Furthermore, because the newer atypical antipsychotic agents have improved safety over older therapies, they were considered more clinically relevant as potential comparators. From among these, olanzapine was chosen as the active comparator because of its broad availability at the time of study initiation, its pharmacological similarities to clozapine, and its favorable tolerability profile. In addition, the literature suggests that it might have a favorable impact on symptoms of suicidal behavior (Tran et al. 1997). Treatment with olanzapine in this international trial was complicated by the fact that, at the time of study initiation, the optimal dosing recommendations varied among the countries involved in this trial. In the United States, the use of doses exceeding 10 mg was not recommended, although clinical practice suggested that in certain patients the use of higher doses might be clinically indicated. Given the life-threatening condition being studied, permission was sought and gained from the U.S. regulatory authorities to allow the use of doses higher than 10 mg, based on the clinical assessment of the treating psychiatrist.

for the first 6 months and then biweekly visits for the remainder of the study. Some clinicians have speculated that the high frequency of contact with medical personnel that occurs as a consequence of clozapine blood-monitoring programs might explain reports of suicide reduction with this treatment. Failure to control for this contact has been considered a significant design flaw in previous studies. To eliminate the possible confounding effects of increased clinical contact, visit frequency and makeup in this study were identical for the clozapine and olanzapine treatment groups. All patients, no matter what their treatment assignment, were required to have frequent study-related visits. Clinical contact, including assessment for suicidality, was similar at each of these visits for both groups. Clozapine-treated patients had blood monitoring at each of these visits, and vital signs were assessed less frequently. Olanzapine-treated patients were not required to have such frequent blood monitoring, as it was clinically unnecessary. Instead, their vital signs were recorded during visits corresponding to the blood-monitoring visits for clozapine-treated patients.

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Blinding
The clinical side effect profiles of olanzapine and clozapine and the increased frequency of blood draws for clozapine-treated patients made it implausible that the treatment blind could be maintained for either the subject or the treating physician over a 2-year period of observation. Another concern was that, because participating subjects were at high risk for suicide, they required particularly close clinical monitoring that was comprehensive and flexible. To optimally provide this, knowledge of the patient's treatment regimen by the primary treating physician was considered essential. These constraints resulted in a decision to use an open-label study design. To meet requirements for a scientifically valid and well-controlled trial that would provide convincing evidence of a differential treatment response between clozapine and olanzapine for suicidal behavior, determination of primary endpoints had to be completed in a blinded fashion. Therefore, blinding was implemented at the site level and the study level. In addition, throughout the study, all endpoint and safety data reviewed by the study sponsor's clinical and administrative personnel were blinded. At the site level, a rater who was blinded to the patient's treatment assignment was needed to determine whether the patient demonstrated significant worsening of suicidal behavior from baseline. It was recommended that the number of raters per center be large enough to cover periods of illness and vacation but small enough and with

Visit Frequency
A requirement for treatment with clozapine is frequent hematological laboratory testing to ensure that patients do not develop agranulocytosis.3 Despite general agreement on the need for monitoring, the frequency varies by country. For this study, it was decided that the frequency of safety monitoring would reflect the most conservative requirements held by any of the participating countries. In addition, all local safety requirements for clozapine use were respected. Thus, patients were to have weekly visits

3 Agranulocytosis has been reported in 1 percent to 2 percent of patients treated with clozapine (Kane et al. 1989).

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minimal turnover to reduce interrater variability. In general, having two to three raters per center was recommended. At each study visit, raters documented whether they remained blinded to the patient's treatment condition. If they became unblinded, their ratings after the point of unblinding were disqualified and a new, blinded rater was identified. Study monitors systematically checked compliance with this requirement. In addition to blinded site raters, a centralized group of expert raters independent of the site and study sponsora Suicide Monitoring Board (SMB)was created to make blinded decisions about whether a potential endpoint met criteria for suicidal behavior and whether it represented an imminent risk of suicide. They also assessed the seriousness and lethality of the attempt. This single, centralized group was identified because such decisions needed to be made consistently across all centers. The SMB was composed of three experts not otherwise connected to the study: Ranga Krishnan from Duke University; Hannale Heila from the National Public Health Institute in Helsinki, Finland; and Isaac Sakinofsky from the University of Toronto. They were selected from different parts of the world on the basis of their expertise in suicidal behavior and their knowledge of both schizophrenia and the experimental design of suicide studies. Each had extensive experience in working with suicidal patients. The chair of the SMB, Dr. Krishnan, had experience in the design and operation of large multicenter clinical studies. This team remained constant for the duration of the study. At the onset of the study, this team developed the specific procedures for what and how data would be reviewed and set guidelines for how cases would be evaluated. Blinding of the SMB was monitored by Dr. Kevin Cox from Ingenix Pharmaceutical Services. He was responsible for ensuring that all data received by the SMB were blinded. The SMB members were forbidden to have contact related to the trial with sites and other participants in this study. The institutions for which the SMB members worked were not included as participant sites. Any questions SMB members had about the study were communicated to Dr. Cox, who then communicated with the study sites. All information received by the SMB underwent an extensive series of reviews to ensure that it was complete and blinded. This multistep process is illustrated in figure 1. As a first step in data blinding, the principal investigators at each site reviewed potential endpoint cases, removed information that might unblind the reviewer to the patient's treatment condition, and sent documents that would be reviewed by blinded raters to a central medical monitor. In addition, to ensure that all relevant potential endpoints were collected, monitors reviewed each

patient's clinical records, including all reported adverse events and serious adverse events, for any incident that might have represented an overt or covert self-injurious act that met criteria for a potential endpoint. Such cases, not already identified by the site, were flagged for review. Only cases of self-evidently nonserious self-inflicted injury were excluded from additional followup. Extensive data on all cases of potential suicide, suicide attempt, or hospitalization for imminent risk of suicide were translated when necessary and sent to a medical reviewer to ensure that they had been adequately blinded. This package of material included background information; information on the index event; any associated hospitalization or rescue intervention; all relevant, obtainable medical records pertaining to the event; recent ratings on depression and suicidal behavior that had been completed by the blinded psychiatrist; and records on drug compliance. Dr. Cox reviewed this material to make certain that any mention of the patient's treatment and any signs or symptoms that might reveal the patient's treatment (e.g., drooling, regularly reported white blood cell counts, excessive drowsiness, hypotension) were eliminated from the case descriptions. Once this review was complete, the information was submitted to the SMB members who individually reviewed the cases to determine whether the incidents met criteria for an endpoint. If there was disagreement among them, they discussed the findings on a conference call and developed a consensus rating. This included classification of each self-damaging act as either a suicidal gesture or a suicide attempt. To establish concurrent reliability for the SMB decisions, material on each potential endpoint was forwarded in parallel to the on-site blinded psychiatrist. This psychiatrist reviewed this material and made an independent determination of whether criteria for an endpoint were met.

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Clinical Assessments
To provide secondary data that would supplement the characterization of the patients and the effects of treating them with clozapine or olanzapine, ancillary data were collected. These included data to assess suicidal ideation, depression, anxiety, psychosis, extrapyramidal symptoms, overall functioning, safety, and health economics. In addition, information was collected on cognition and insight for subsets of patients who participated in this trial. Because no prior prospective studies had examined treatment effects on suicidal behavior in psychotic patients, little work had been done to develop scales to assess symptoms of suicidality in patients with psychotic disorders. As a consequence, several new scales were created in preparation for this study. The Beck Suicide Scale

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Figure 1. Primary Endpoint Data Flow for Type I Events1

Information on Potential Suicide Events

PEP

Legend
SMB = Suicide Monitoring Board PEP = Potential Endpoint Package
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Principal Investigator
PEP

Ingenix Medical Monitor

Database
1

SEF = Suicide Event Form-SMB

Blinded psychiatrist has no role in determining primary type I events.

(Beck et al. 1979) was used as a model for the InterSePT Scale for Suicidal Thinking (ISST), which was used as one measure of suicidality in this study. This scale was developed for use with a semistructured interview to standardize the collection of information on suicidality used to rate this scale and a global scale of suicidality (see next paragraph). This standardization was especially important for a large multicultural study in which individual approaches to rating suicidality might otherwise vary widely across centers, countries, and languages. The long duration of the trial also resulted in changes in raters and increased the need for standardization of the rating process so that ratings would be valid over time. Furthermore, individual items on the suicide scale had to be adapted to be relevant for psychotic patients and ratings had to be anchored to reflect the needs of a pharmacological trial. A global assessment of suicidality was created for this study to provide an index to assess an expert's assessment of suicidal behavior that would help confirm the validity of the ISST. This global scale (the Clinical Global Impression of Suicidality) included two assessments of the patient's suicidality. One rating assessed (on a 5-point scale) the most severe level of suicidality experienced by the patient during the previous 7 days. The second rating assessed (on a 7-point scale) how much the patient's suicidality had changed from baseline. Development of these scales is described in Lindenmayer et al. (2003).

Trial Duration
No data relevant to the evaluation of a schizophrenic population at high risk for suicide were identified in the published literature. Consequently, it was difficult to identify a basis for determining the appropriate duration of treatment for this study. Based on a review of the available epidemiologic data and treatment outcomes of suicidality in patients with schizophrenia (Rennie 1939; Winokur and Tsuang 1975; Cohen et al. 1990), a 2-year duration of clinical observation was selected as short enough to make the study logistically and economically feasible but long enough to capture a sufficient number of endpoints to identify clinically meaningful treatment differences between clozapine and olanzapine.

Sample Size
The sample size was calculated based on the rate of occurrence of type 1 events. It was hypothesized that the percentages of event-free subjects during the 2-year treatment phase in the clozapine and olanzapine treatment groups would be 55 percent and 45 percent, respectively. Using a two-sided log-rank test with a significance level of 0.05 and a statistical power of 80 percent, it was determined that, if the treatment hypothesis held, a total of 381 patients with at least one type 1 event (or a total of 762 subjects) would be needed to differen-

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tiate the two treatments (Freedman 1982). With allowance for an estimated overall dropout rate of 15 percent, it was concluded that approximately 900 subjects (450 subjects in each group) would need to be randomized.

Statistical Analyses
Primary efficacy analyses for this study were performed on the intent-to-treat population, which included all randomized patients, whether or not the patients received any treatment and whether or not the treatment designated in the protocol was taken. Safety analyses were completed on a "safety population," which consisted of all randomized patients who took at least one dose of study medication. The primary efficacy variables were defined as the time (in days, after randomization) to the first occurrence of any of the primary outcome events described above (see "Selection of Study Objective and Endpoints"). Because (1) patients could experience multiple events, (2) the two types of events were not identical, and (3) the time to an event could be censored for patients with no events, the primary statistical analysis of these variables was based on the approach of Wei, Lin, and Weissfeld (Wei et al. 1989), commonly known as the WLW method. This analysis is a semiparametric method used to analyze multivariate failure time data. This method models the marginal distribution with a Cox proportional hazards model. For the primary analysis, pooled country was included as the strata variable and treatment group as the only covariate. Countries with a small number of patients (<50) randomized were pooled with those from another participating country based on similarity in their prevailing medical practice patterns. The WLW method provided estimates of treatment effects for the two types of events (type I and type IT) and the robustness of the covariance matrix. Based on the FDA's suggestion, these two estimates were combined for an overall estimate of treatment effect and its pooled standard error by giving equal weight (0.5) to each estimate. By use of these estimates of the combined treatment effect and the corresponding robust standard error, a single twosided test of the null hypothesis of no treatment effect on either event type at a 5 percent level of significance was performed. In addition to the primary analysis described above, several predefined secondary analyses of these two event types for suicidal behavior were performed. The treatment effects, adjusted for covariates, were estimated using the following covariates in the Cox proportional hazards model: treatment, sex, and the following measurements at baseline: age group (at three levels: <32 years, 3344 years, and >45 years), number of lifetime suicide attempts, Clinical Global Impression Severity of Suicidality (CGI-SS; Lindenmayer et al. 2003) score (5point scale) by the blinded psychiatrist, total score (total of items 1-8 and 10-12) of the ISST (Lindenmayer et al. 2003) by the blinded psychiatrist, total score of the

Patient Management and Rescue Interventions

A foremost concern of this study was patient safety, including reduction of suicide attempts and prevention of deaths from suicide. Every effort was made to support this goal. To this end, patients in both treatment groups were seen by an unblinded health care professional weekly for the first 26 weeks and biweekly thereafter. During this visit, the health care professional was required to ask at least two questions to assess each patient's level of suicidal ideation. If a patient's suicidal ideation, depression, or psychosis worsened during the course of the study, the treating psychiatrist was directed by the protocol to take whatever clinical measures were necessary to reduce these symptoms and prevent an event from occurring. Concomitant medications (all types, including adding other antipsychotics), electroconvulsive therapy, hospitalization, psychotherapy, and all other appropriate means were allowed. It was recommended that all possible therapeutic interventions be implemented before a patient's participation in the trial was terminated. In support of this approach, treatment algorithms for patients with worsening of psychosis or suicidal behavior were provided to treating clinicians.

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Dropouts
Given previous experience in treatment studies of patients with schizophrenia (Tran et al. 1997), it was expected that a large number of patients would drop out from the study and potentially be lost to followup before completing 2 years of observation. A large dropout rate would have biased the estimated treatment effect, if the dropouts were nonrandom. In particular, if the rate and time to dropout were related to the treatment assignments, the results would be difficult to interpret. To get as complete a picture of patient response as possible, every effort was made to follow patients and assess clinical outcome for the entire 2-year period of involvement. To facilitate this, patients were allowed to reenter the study, if they desired. In addition, a limited amount of information assessing primary clinical response was obtained in as many dropouts as could be found and who would agree to provide it.

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Calgary Depression Scale (CDS; Addington et al. 1994), diagnosis, substance (drug or alcohol) abuse, total score of the Extrapyramidal Symptoms Rating Scale (items 1-55; Chouinard et al. 1980), total score of the positive components of Lindenmayer's five-factor model of schizophrenia (Lindenmayer et al. 1994), hopelessness score (item 2 of the CDS), and total score of the Covi Anxiety Scale (Covi et al. 1981).

the study blind. The CRO was responsible for communication among sites, blinded raters, the steering committee, and the SMB and for maintaining a "firewall" that would prevent unblinding of blinded raters and the study sponsor. The data base was maintained by the CRO and transferred to the sponsor only after all data were cleaned, coded, and locked for the final analyses.

Supervising Committees
Two supervisory committees in addition to the SMB were formed to facilitate the activities of the InterSePT study. An international group of expert advisors was brought together as a steering committee to provide oversight for the clinical and scientific aspects of the study. The InterSePT Steering Committee consisted of five independent experts on schizophrenia (none of whom participated as investigators in the trial), a medical representative from the study sponsor, and an independent statistician. This committee was created to address key issues that arose during the study and to advise on and approve all amendments to trial design and study conduct during the study. They were also responsible for reviewing site performance, reviewing interim analysis reports, and, if necessary, recommending study termination for reasons of safety. In addition, they approved the conventions developed by the SMB for assessing endpoints related to suicide attempts and hospitalizations to prevent suicide. Because of the unique and clinically important nature of the data being collected in this trial, a publication committee was created at the time the trial was initiated. This group, consisting of leaders from the study sponsor and leading academic experts in schizophrenia and suicidality from across the world, was responsible for identifying potential publications that might be generated from this trial and ensuring that they were completed in a scientifically consistent and efficient process so that they would be maximally informative to the medical community. A detailed charter for this publication committee was developed from the outset to maximize the publication committee's focus and effectiveness.

Conclusions
Suicide is the major cause of death in schizophrenia and accounts for approximately 10 percent of deaths among psychiatric patients (Nyman and Jonsson 1986; Axelsson and Lagerkvist-Briggs 1992; Meltzer and Fatemi 1995). It is a human tragedy not only for its victims but also for the estimated six or seven immediate survivors of each victim (Singh 1998). The InterSePT study was conducted in an effort to lessen this tragedy. This is the first study of its kind to prospectively evaluate effects of clozapine or any other antipsychotic medication on suicidal behavior. A primary challenge was to detect differences in long-term outcome among the treatment groups on a number of endpoint measures (e.g., suicide attempts), while simultaneously using all means necessary to prevent this unacceptable clinical outcome. Because of its many challenges, successful completion of the InterSePT study required a unique partnership among academicians, regulatory authorities, health care providers, patients and their caregivers, and the organization sponsoring this trial. This need for collaboration was identified well before the study was initiated and continued after its conclusion. Overall, this close interaction among participants from industry, academicians, and clinicians represents a model for conduct of complex clinical studies. The study design resolved a number of complex issues and methodological challenges, and data resulting from it promise to significantly increase our knowledge of suicidal behavior in schizophrenia. Even so, it is likely to generate more questions than it answers in this highly complex field and will hopefully spark interest in conducting similar trials that will identify other effective therapies for suicidal behavior.

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Logistical Management
A clinical research organization (CRO) (Ingenix Pharmaceutical Services) was employed to manage the logistical aspects of the InterSePT study. Its role was especially important because of the complexities of the endpoint evaluation process. All operational activities were performed by the CRO from the outset of the study. In addition, this group played a crucial role in maintaining

References
Addington, D.; Addington, J.; and Maticka-Tindale, E. Specificity of the Calgary Depression Scale for schizophrenics. Schizophrenia Research, 11:239-244, 1994. American Psychiatric Association. DSMIV: Diagnostic

and Statistical Manual of Mental Disorders. 4th ed.

Washington, DC: APA, 1994.

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Axelsson, R., and Lagerkvist-Briggs, M. Factors predicting suicide in psychotic patients. European Archives of Psychiatry and Clinical Neuroscience, 241:259-266, 1992. Beck, A.T.; Kovacs, M.; and Weissman, A. Assessment of suicidal intention: The Scale for Suicide Ideation. Journal of Consulting and Clinical Psychology, 2:343-352, 1979. Beisser, A.R., and Blanchette, J.E. A study of suicides in a mental hospital. Diseases of the Nervous System, 22:365-369, 1961. Bleuler, F. Dementia Praecox or the Group of Schizophrenias. (1911) Translated by J. Zinkin. New York, NY: International Universities Press, 1950. Chouinard, G.; Ross-Chouinard, A.; Annable, L.; and Jones, B.D. Extrapyramidal symptom rating scale. Canadian Journal of Neurological Science, 7(3):233, 1980. Cohen, L.J.; Test, M.A.; and Brown, R.L. Suicide and schizophrenia: Data from a prospective community treatment study. American Journal of Psychiatry, 147:602-607, 1990. Cohen, S.; Leonard, C.V.; Farberow, N.L.; Schneidman, E.S. Tranquilizers and suicide in the schizophrenic patient. Archives of General Psychiatry, 11:312-321, 1964. Covi, L.; Rickels, K.; and Lipman, O.S. Effects of psychotropic agents on depression. Psychopharmacology Bulletin, 100-101,1981. Freedman, L.S. Tables of the number of patients required in clinical trials using the log rank test. Statistics in Medicine, 1:121-129, 1982. Hussar, A.E. Effect of tranquilizers on medical morbidity and mortality in a mental hospital. Journal of the American Medical Association, 179:682-686, 1962. Johnson, D.A.; Pasterski, G.; Ludlow, J.M.; Street, K.; and Taylor, R.D. The discontinuance of maintenance neuroleptic therapy in chronic schizophrenic patients: Drug and social consequences. Ada Psychiatrica Scandinavica, 67:339-352, 1983. Khan, A.; Khan, S.R.; Leventhal, R.M.; and Brown, W.A. Symptom reduction and suicide risk among patients treated with placebo in antipsychotic clinical trials: An analysis of the Food and Drug Administration data base. American Journal of Psychiatry, 158:1449-1454, 2001. Kline, N.S. Psychopharmaceuticals: Effects and sideeffects. Bulletin of the WHO, 21:397^*10, 1959. Lindenmayer, J.P.; Bernstein-Hyman, R.; and Grochowski, S. A new five-factor model of schizophrenia. Psychiatric Quarterly, 65:299-322, 1994.

Lindenmayer, J.P.; Czobor, P.; Alphs, L.D.; Nathan, A.M.; Anand, R.; Islam, Z.; Chou, J.C.; and the InterSePT Study Group. The InterSePT scale for suicidal thinking: Reliability and validity. Schizophrenia Research, 63:161-170,2003. Margolese, H.C.; Chouinard, G.; Larach, V.W.; and Beauclair, L. Relationship between antipsychotic-induced akathisia and tardive dyskinesia and suicidality in schizophrenia: Impact of clozapine and olanzapine. Ada Psychiatrica Belgica, 101:128-144, 2001. Meltzer, H.Y. Suicide and schizophrenia: Clozapine and the InterSePT study. International Clozaril/Leponex Suicide Prevention Trial. Journal of Clinical Psychiatry, 60(Suppl. 12):47-50, 1999. Meltzer, H.Y., and Fatemi, H. Suicide in schizophrenia: The effect of clozapine. Clinical Neuropharmacology, 18:S18-S24, 1995. Meltzer, H.Y., and Okayli, G. Reduction of suicidality during clozapine treatment of neuroleptic-resistant schizophrenia: Impact on risk-benefit assessment. American Journal of Psychiatry, 152(2): 183-190, 1995. Meltzer, H.Y.; Alphs, L.; Altamura, C ; Anand, R.; Bertoldi, A.; Bourgeois, M.; Green, A.I.; Islam, M.Z.; Kane, J.; Krishnan, R.; Lindenmayer, J.-R; and Potkin, S. Reduced suicidality in schizophrenia and schizoaffective disorder with clozapine: Report of the International Suicide Prevention Trial (InterSePT). Archives of General Psychiatry, 60:82-91, 2003. Erratum in Archives of General Psychiatry, 60(7):735, 2003. Munro, J.; O'Sullivan, D.; Andrews, C ; Arana, A.; Mortimer, A.; and Kerwin, R. Active monitoring of 12,760 clozapine recipients in the U.K. and Ireland. British Journal of Psychiatry, 175:576-580, 1999. Nyman, A., and Jonsson, H. Patterns of self-destructive behavior in schizophrenia. Ada Psychiatrica Scandinavica, 73:252-262, 1986. Palmer, D.D.; Hunter, I.D.; and Wyatt, R.J. Do antipsychotic medications decrease the risk of suicide in patients with schizophrenia? Journal of Clinical Psychiatry, 60(Suppl. 2): 100-103, 1999. Planansky, K., and Johnston, R. The occurrence and characteristics of suicidal preoccupation and acts in schizophrenia. Ada Psychiatrica Scandinavica, 47:473-483, 1971. Reid, W.H.; Mason, M.; and Hogan, T. Suicide prevention effects associated with clozapine therapy in schizophrenia and schizoaffective disorder. Psychiatric Services, 49:1029-1033, 1998. Rennie, T. Follow-up study of five hundred patients with schizophrenia to 1923. Archives of Neurology and Psychiatry, 41:877-891, 1939.

Downloaded from schizophreniabulletin.oxfordjournals.org by guest on August 8, 2011

585

Schizophrenia Bulletin, Vol. 30, No. 3, 2004

L. Alphs et al.

Sernyak, M.J.; Desia, R.; Stolar, M.; and Rosenheck, R. Impact of clozapine on completed suicide. American Journal of Psychiatry, 158:931-937, 2001. Singh, B.S. Suicide: The public health crisis of our

Acknowledgments
Appreciation is expressed for the work of John Messina, Richard Hartman, Mojtaba Noursalehi, and Frederick Young for their support and thoughtful contributions to the design of this study and its write-up and also to the InterSePT Study Group for their participation in the conduct of this work.

time. Australian

and New Zealand Journal of

Medicine, 28:295-300, 1998. Stephens, J.H.; Richard, P.; and McHugh, P.R. Suicide in patients hospitalized for schizophrenia: 1913-1940. Journal of Nervous and Mental Disease, 187:10-14, 1999. Tran, P.V.; Hamilton, S.H.; Kuntz, A.J.; Potvin, J.H.; Andersen, S.W.; Beasley, C , Jr.; and Tollefson, G.D. Double-blind comparison of olanzapine versus risperidone in the treatment of schizophrenia and other psy-

The Authors
Larry Alphs, M.D., PhD., is Executive Director, Pfizer Global Research and Development, Ann Arbor, MI. Ravi Anand, M.D., is Consultant, Basle, Switzerland. M. Zahur Islam, Ph.D., is Director, Novartis Pharmaceuticals, East Hanover, NJ. Herbert Y. Meltzer, M.D., is Professor, Vanderbilt University, Nashville, TN. John M. Kane, M.D., is Director, Psychiatric Research, Long Island Jewish-Hillside Medical Center, Glen Oaks, NY. Ranga Krishnan, M.D., is Professor and Chairman, Department of Psychiatry, Duke University, Durham, NC. Alan I. Green, M.D., is Professor and Chairman, Department of Psychiatry, Dartmouth University, Hanover, NH. Steven Potkin, M.D., is Professor, Department of Psychiatry, University of California, Irvine, CA. Guy Chouinard, M.D., M.Sc., FRCR is at McGill University, Montreal, Canada. JeanPierre lindenmayer, MD., is Clinical Professor of Psychiatry, Manhattan Psychiatric Center-Nathan Kline Institute for Psychiatric Research, Wards Island, NY. Rob Kerwin, M.D., is at Kings College, Institute of Psychiatry, London, England.

chotic disorders. Journal of Psychopharmacology, 17:407^*18, 1997.

Clinical

Walker, A.M.; Lanza, L.L.; Arellano, F.; and Rothman, K.J. Mortality in current and former users of clozapine. Epidemiology, 8:671-677, 1997. Wei, L.J.; Lin, D.Y.; and Weissfeld, L. Regression analysis of multivariate incomplete failure time data by modeling marginal distributions. Journal of the

Downloaded from schizophreniabulletin.oxfordjournals.org by guest on August 8, 2011

American Statistical Association, 84:1065-1073, 1989. Winokur, G., and Tsuang, M. The Iowa 500: Suicide in mania, depression, and schizophrenia. American
Journal of Psychiatry, 6:650-651, 1975.

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