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

Suicidal behavior in patients with psychotic disordersrepresents a seriously undertreated life-threateningcondition. The International Suicide Prevention Trial(InterSePT) is the first large-scale, prospective studydesigned to evaluate the potential of antipsychoticmedications to reduce suicidal behaviors in patientswith schizophrenia or schizoaffective disorder who areknown to be at high risk for suicide. The unique chal-lenges to study design and the solutions identified forthe InterSePT study are described. These challengesincluded defining suicidal behavior in patients withpsychosis, endpoint selection, determination of ana-lytic strategy, and development of scales to assess sui-cidal behavior. Given the life-threatening nature ofsuicidal behavior, ethical considerations required thatthe design minimize suicide attempts and deaths.While the study focused primarily on treatment of sui-cide, opportunities were used to collect data in relatedareas of interest, including suicide risk factors, otherefficacy measures (e.g., Positive and NegativeSyndrome Scale, Covi Anxiety Scale, CalgaryDepression Scale), adverse events, pharmacoeconom-ics, and pharmacogenetics. Because of the complexityof the design issues, a steering committee, suicide mon-itoring board, and publication committee were estab-lished to assist with their managementKeywords: Suicide, suicidal behavior, schizophre-nia, schizoaffective disorder, study design, clozapine,olanzapine.Schizophrenia Bulletin, 30(3):577-586, 2004.Bleuler referred to the suicidal drive as "the most seriousof schizophrenic symptoms" (Bleuler 1911, p. 488).Indeed, it is estimated that schizophrenia patients have a50 percent lifetime risk of attempting suicide. Annualdeath rates from suicide in this population have beenreported to be 0.4 percent to 0.8 percent, with a lifetimerisk of 10 percent (Nyman and Jonsson 1986; Axelssonand Lagerkvist-Briggs 1992; Meltzer and Fatemi 1995).Although suicidal behavior is well documented in psy-chotic patients, the magnitude of the problem is not gener-ally understood, risk factors are not well established orwidely recognized, and little information on the treatmentof suicidal patients is available. Consequently, a patient'ssuicide risk is seldom assessed in clinical practice. Inaddition, detection of suicide risk factors and preventionof suicide are particularly difficult because of the uniqueissues presented by patients with psychotic disorders.These patients are frequently beset with thought disorder,delusions, hallucinations, lack of insight, and negativesymptoms, all of which interfere with their ability to com-municate with their caregivers. Overall, suicidal behaviorin patients with schizophrenia and related disorders repre-sents a major public health problem that has not been ade-quately addressed by the medical community (Singh1998).Existing data suggest that, for the most part, pharma-cotherapy for schizophrenia has not affected the rate ofsuicide among patients with psychotic disorders. Studieswith conventional antipsychotic medications have shownincreased (Beisser and Blanchette 1961; Hussar 1962),decreased (Johnson et al. 1983), or unchanged (Kline1959; Cohen et al. 1964; Planansky and Johnston 1971)rates of suicide in schizophrenia, and demonstrated that