1. CO-1 Suicidal Behavior in Schizophrenia and Schizoaffective Disorder Herbert Y. Meltzer, MD Bixler Professor of Psychiatry and Pharmacology Vanderbilt University C

2. CO-2 Overview of Presentation  Suicidal behavior in schizophrenia and schizoaffective disorder  Suicidal behavior as a separate domain from psychosis  Pre-InterSePT evidence for Clozaril ® effects on suicidal behavior C

3. CO-3 Suicidal Behavior in Schizophrenia “Patients with dementia praecox often need hospitalization to prevent aggression against others and suicide.” Emil Kraepelin, 1897 “The suicidal drive is clearly the most serious of schizophrenic symptoms.” Eugen Bleuler, 1911 C

4. CO-4 The Spectrum of Suicidal Behavior  20% to 40% of patients with schizophrenia and schizoaffective disorder attempt suicide §  4% to 13% die by suicide ||  Annual number of suicides in US for schizophrenia is 3,600 ¶ Suicidal thoughts Suicide plans Suicide attempts Suicide Communicated behavior Observed behavior §Roy et al, 1984; Landmark et al, 1987; Heila et al, 1998; Harkavy-Friedman et al, 1999. ||Tsuang, 1978; Heila et al, 1997; Osby et al, 2000; ¶US Surgeon General. C

5. CO-5 Suicidal Behavior as a Domain Separate From Psychosis C

6. CO-6 Suicidal Behavior Is a Separate Domain from Psychosis Successful treatment of positive symptoms does not eliminate the risk of suicide attempts or completion. Lifetime and current suicidal behavior not significantly different between neuroleptic- resistant and neuroleptic-responsive patients. § C §Meltzer, 1997.

7. CO-7 Schizophrenia and Schizoaffective Disorder Lifetime Suicidal Ideation and Attempts N = Meltzer et al, Case Western Reserve MHCRC, unpublished data. 164 4 4 87 9 9 148 27 C

8. CO-8 No Significant Correlation Between Psychopathology and Suicidal Behavior (N = 390) Psychopathology Measures Rho P value HAM-Depression Total0.418.0001 BPRS-Anxiety/Depression0.349.0001 BPRS-Positive Symptoms0.086.09 BPRS-Negative Symptoms–0.005.9 Quality of Life Scale –0.009.8 Global Assessment of Function Scale–0.052.2 Meltzer and Okayli, 1995 and unpublished data. C

9. CO-9 The Burden of Suicidal Behavior Psychosocial  Physical and mental disability  Disruption of personal and family life Financial  Average cost for suicide attempt in US, mostly due to cost of hospitalization: $33,000 § §Palmer et al, 1995. C

10. CO-10 Pre-InterSePT Evidence for Clozaril ® Effects on Suicidal Behavior C

11. CO-11 Reduction of Suicidal Behavior During Clozaril ® Treatment §  Compared suicidal behavior 2 yr before and 2 to 5 yr on Clozaril  N = 88:73 schizophrenia 15 schizoaffective disorder  Retrospective and prospective information from patients, informants, medical records  Clozaril monotherapy, weekly monitoring, assessment, and psychosocial treatment program §Meltzer and Okayli, 1995. C

12. CO-12 Treatment With Clozaril ® Affects Suicidal Behavior § §Meltzer and Okayli, 1995. 4777N =9710117350 NoneIdeationUnintended self harm Low probability of success High probability of success 53% 88% 10% 8% 1% 11% 19% 3% 6% 0 Suicide attempts C

13. CO-13 Registry Data for the Effect of Clozaril ® on Suicidal Behavior  US Clozaril Registry (2 studies, 1994 to 1998) reported that Clozaril reduced the rate of completed suicide compared with treatment as usual §  Reviews of data from treatment registries (Texas and UK) also showed that treatment with Clozaril reduced the rate of completed suicide || §Meltzer and Okayli, 1995; Reid et al, 1998. ||Reid et al, 1998; Munro et al, 1999. C

14. CO-14 Epidemiologic Evidence for Anti-Suicidal Effects of Clozaril ® Prior to InterSePT Walker et al, 1997

15. CO-15 Study Objectives  Determine death due to all causes associated with Clozaril ® use  Subjects: patients in the Clozaril National Registry (CNR) from 1991 until end of 1993 – Patients age 10 to 54 yrs – 67,072 current and former Clozaril users § – 85,399 patient-years of exposure to Clozaril §Maximum duration of Clozaril use was < 4 years.

16. CO-16 Study Methods  Clozaril ® users were grouped into – “current”(0 - 14 days since last WBC record) – “recent”(15 - 106 days) – “past”(> 107 days)  Mortality data from the CNR were matched with National Death Index and Social Security Administration Death Master Files CNR = Clozaril National Registry.

17. CO-17 Deaths Due to Suicide as a Function of Clozaril ® Exposure Walker et al, 1997.

18. CO-18 Standardized Mortality Ratios for Current and Recent Exposure CurrentCIRecentCI All causes0.460.37-0.591.691.28-2.25 Suicide0.170.10-0.301.110.62-1.99 Current Clozaril ® users had a 54% lower risk of death from any cause than past Clozaril users The risk of death by suicide was reduced by 83% Suicide accounted for 19% of all deaths Walker et al, 1997.

19. CO-19 Conclusion of Walker et al Study  Clozaril ® reduced the risk of completed suicide  Data are consistent with previous findings  The reduced suicide rate was the largest contributor to the lower overall mortality rate in the Clozaril current-user group  The beneficial effect of Clozaril on suicide did not persist after it was discontinued

20. CO-20 Overall Considerations (1)  Attempted suicide is an important public health issue, occurring in 20% to 40% of patients with schizophrenia and schizoaffective disorder  Attempted suicide is a major burden on patients, families, and society  Suicidal behavior is a separate domain from psychosis  Extensive previous research suggested that Clozaril ® reduces suicidal behavior C

21. CO-21 Overall Considerations (2)  InterSePT (International Suicide Prevention Trial) was designed to provide a controlled, prospective test of the hypothesis that Clozaril reduces the risk of suicidal behavior  Innovative design of an extremely important public health problem in a very high-risk population