APPENDIX 2: SUMMARY OF THE LITERATURE

CLOZARIL^®^ (clozapine) and SUICIDIAL BEHAVIOR

+----------------+-----------------------------------------------------+
| ##### Do       | Advisory Committee Briefing Document -- Appendix 2  |
| cument type: { |                                                     |
| #document-type |                                                     |
|  .Firstpageinf |                                                     |
| o .unnumbered} |                                                     |
+----------------+-----------------------------------------------------+
| ##### Docume   | Final                                               |
| nt status: {#d |                                                     |
| ocument-status |                                                     |
|  .Firstpageinf |                                                     |
| o .unnumbered} |                                                     |
+----------------+-----------------------------------------------------+
| #####          | October 1, 2002                                     |
| Release date:  |                                                     |
| {#release-date |                                                     |
|  .Firstpageinf |                                                     |
| o .unnumbered} |                                                     |
+----------------+-----------------------------------------------------+
| ##### Number   | 15                                                  |
|  of pages: {#n |                                                     |
| umber-of-pages |                                                     |
|  .Firstpageinf |                                                     |
| o .unnumbered} |                                                     |
+----------------+-----------------------------------------------------+

AVAILABLE FOR PUBLIC DISCLOSURE WITHOUT REDACTION

**Search Strategies**

The *Medline* (1966 to date), *Biosis* (1993 to date), *Embase* (1974 to
date), *Psycinfo* (1887 to 03 October 2001), *Derwent Drug File* (1983
to 2001), and *Sandoz Medical Document* (1966 to date) databases were
searched using the following searches: clozapine/Clozaril^®^ /Leponex^®^
and suicide. After review of the content of these searches, 58 articles
were requested, obtained, and reviewed. In addition, an independent
internet search was performed using Pubmed, a service of the National
Library of Medicine, using the search terms clozapine and suicide and
clozaril and suicide. From this search, an additional four papers were
identified, requested, obtained, and reviewed. In reviewing all of the
publications obtained, an additional eight papers, which were identified
from the reference lists of these publications, were obtained and
reviewed for relevance. In summary, 70 articles were obtained and
reviewed. Of these 70 articles, 34 were considered to be pertinent to
this submission.

Of 34 publications pertinent to the effects of Clozaril on suicidality,
none were double-blind. They were categorized as population studies (6),
non-population studies (5), case reports/observational data (6), and
review articles (17) and summarized in Table 1 and in the narrative
below.

**POPULATION STUDIES**

**1. Walker AM, Lanza LL, Arellana A, et al. Mortality in current and
former users of clozapine. Epidemiology 8; 1997: 671-677.**

Summarizing a comprehensive, retrospective review of clozapine's effect
on mortality, Walker et al compared rates of various causes of death in
67,072 current and former clozapine users in the United States from 1991
to the end of 1993. This study linked data from the National Registry of
Clozapine Recipients to the National Death Index and Social Security
Administration Death Master Files. To reduce the number of patients in
the cohort whose indication was Parkinson's disease rather than
schizophrenia, a detailed analysis concentrated on the age range from 10
through 54 years. Effects of current, recent, and past clozapine
exposure on mortality in this population of schizophrenics were
compared. During the 3-year study period there were 396 deaths in this
age group. Almost one-third of the deaths were from external causes,
including suicides, accidents and homicides. Suicide accounted for 19%
of all deaths. Relative to the incidence of suicide during past
clozapine use, there was a substantial deficit of suicides during the
period of current clozapine exposure. The rate ratio of suicide in
current clozapine users compared with past exposure was 0.17 (95% CI:
0.10-0.30). The authors concluded that clozapine treatment appears to
reduce mortality in severe schizophrenics, mostly by decreasing suicide
rates.

**2. Reid WH, Mason M, Hogan T. Suicide prevention effects associated
with clozapine therapy in schizophrenia and schizoaffective disorder.
Psychiatric Services 1998;49: 1029-1033.**

This retrospective study examined annual suicide rates over a 2-year
period (1993-1995) among an annual average of 30,130 patients with
schizophrenia and schizoaffective disorder who had received services
from the Texas Department of Mental Health and Mental Retardation.
Eighty-six percent (86%) of the patients were between the ages of 18 and
59, and 13% were 60 years of age or older. Suicide rates among a
subgroup of 1,367 patients treated with clozapine were evaluated over a
6-year period (1991-1996). Patients included in this cohort had been
receiving clozapine for at least 30 days and had not discontinued the
drug for more than 14 days. Patients for whom clozapine had been
prescribed, but for whom no information about the duration of treatment
or drug discontinuation was available, were also included. Only one
suicide occurred in this subgroup of clozapine-treated patients during
the 6-year study period. Given an average of 1,310 patients continuously
receiving clozapine each year, the annual suicide rate for
clozapine-treated patients was 12.74 per 100,000, substantially lower
than the rate of 63.1 patients per 100,000 calculated for the average
annual total study population of 30,130 schizophrenic and
schizoaffective patients. This study suggests that clozapine therapy was
associated with a lower suicide rate compared with therapy with other
antipsychotic drugs.

**3. Munro J, O'Sullivan D, Andrews C, Arana A, Mortimer A, Kerwin R.
Active monitoring of 12,760 clozapine recipients in the UK and Ireland.
Br J Psychiatry 1999;175:576-580.**

########  

To quantify the risk factors for agranulocytosis in treatment-resistant
schizophrenics receiving clozapine treatment, a retrospective analysis
was performed using data from 12,760 subjects in the UK and Ireland.
These data were collected by the Clozapine Patient Monitoring Service
\[CPMS\] for the period from January 1990 to April 1997. The duration of
clozapine treatment ranged from 1 day to 7.6 years, with a mean dose
(after 12 weeks of treatment) of 388 mg/day (mean maximum dose of
462 mg/day). Results of the analysis showed that the cumulative
incidence of agranulocytosis was only 0.73%, and this condition was
reversible in all but two cases. Only 13 deaths were confirmed suicides.
Literature on suicide and schizophrenia were reviewed. Studies
presenting the expected number of suicides in the national population
were compared with the suicides in the UK cohort. This cohort of
clozapine-treated patients experienced a suicide risk one-fourth the
rate expected for schizophrenics in the general population. The authors
acknowledged growing evidence of an anti-suicidal effect of clozapine.

**4. Sajatovic M, Bingham R, Garver D, et al. An assessment of clinical
practice of clozapine therapy for veterans. Psychiatric Services
2000;51:669-671.**

This retrospective study analyzed treatment outcomes of schizophrenic
patients receiving clozapine treatment within the US Department of
Veterans Affairs system, using a subset of data obtained from the
National Clozapine Coordinating Center. Data were evaluated for 2996
patients (mean age 44.8 10.2 years) treated with clozapine over a 5-year
period. Patient psychopathology was evaluated using the Brief
Psychiatric Rating Scale (BPRS), and involuntary movements were rated
using the Abnormal Involuntary Movement Scale (AIMS). Before clozapine
treatment, 42.3% of the patients had a history of suicide attempts, with
5% having attempted suicide during the month before starting clozapine
treatment. After treatment only two suicides were observed during the
study period (0.1%). Results of the analysis showed a significant
improvement (*P*\<0.001) in all of the BPRS subscales and improvement in
the AIMS score in these clozapine-treated patients. The authors conclude
that treating patients who have a high degree of aggressiveness and
suicidality with clozapine may be particularly beneficial.

**5. Modaj I, Hirschmann S, Rava A, et al. Sudden death in patients
receiving clozapine treatment: a preliminary investigation. J Clin
Psychopharmacology 2000;20:325-327.**

Using a database from one mental health center in Israel, this
retrospective study analyzed the rates of sudden death, suicide, and
disease-related death over a period of 6 years and 8 months from
1991-1997 in schizophrenic patients who received clozapine (n= 561) and
non-clozapine treatment (n=4918). During this period, there were a total
of 10 deaths in the clozapine treated group (1.8%) and 105 deaths in the
non-clozapine treated group (2.1%). There were significantly more sudden
deaths in the clozapine group (6/561; 1.1%) than in the non-clozapine
treated group (14/4918; 0.3%) (*P*\<0.01); however, 2  of the 6 deaths
occurred after cessation of clozapine treatment. In contrast, there were
significantly fewer disease-related deaths in the clozapine group
(2/561; 0.4% vs 86/4918, 1.7%) (*P*\<0.05). The difference in suicide
rate was not significantly different between groups (2/561
clozapine-treated patients; 0.36% vs 5/4918; 0.10% in the non-clozapine
treated patients). The authors suggest that interpretation of these data
should be made with caution in light of the limited number of deaths.

**6. Sernyak MJ, Desia R, Stolar M, Rosenheck R. Impact of clozapine on
completed suicide. Am J Psychiatry 2001; 158:931-937.**

This retrospective study evaluated clozapine's effect on the rate of
death due to suicide. Data for this study in the US were obtained from
the discharge abstracts of 45,917 Veteran's Administration patients who
had psychiatric hospitalizations of at least 1 day during the fiscal
years 1992 through 1995, for which the primary discharge diagnosis was
schizophrenia. Of these 45,917 patients, 1,415 had received clozapine
treatment for the first time while hospitalized during the study period.
Of the remaining 44,502 patients, 2,830 were selected as a control
group. Propensity scoring was employed to maximize the comparability of
the clozapine and control groups. However, patients with any duration of
exposure to clozapine were included in the clozapine treatment group
without regard to their treatment status at the time of death or their
duration of clozapine treatment. Patients who were exposed to clozapine
for any length of time had a statistically significant lower overall
age-and age-adjusted mortality rate than did those with no clozapine
exposure. No data for the exact duration of treatment at the time of
death was provided. There was no significant difference in the rates of
suicide between the clozapine-treated (10 suicides/1415
clozapine-treated patients; 0.71%) and nonclozapine-treated patients (23
suicides/2380 non-clozapine-treated patients; 0.97%). This study
supports the effect of clozapine on reducing mortality, but does not
provide evidence for a reduction in suicidality with clozapine
treatment.

NONPOPULATION STUDIES

1\. Meltzer HY and Okayli G. Reduction of suicidality during clozapine
treatment of neuroleptic-resistant schizophrenia: impact on risk-benefit
assessment. Am J

Psychiatry 1995;152:183-190.

This retrospective mirror-image study at a multi-site, single center in
the US compared the suicidality of neuroleptic-resistant and
neuroleptic-responsive patients who were diagnosed with chronic
schizophrenia or schizoaffective disorder. It further examined whether
clozapine treatment decreased suicidality in neuroleptic-resistant
patients compared with their pre-clozapine treatment rate. Prior
episodes of suicidality were assessed in a total of 183
neuroleptic-resistant and 237 neuroleptic-responsive patients with
schizophrenia or schizoaffective disorder. There was no significant
difference between these two groups in prior suicidality episodes at
baseline. After initiating clozapine treatment during an index
hospitalization, suicidality was assessed at weekly intervals during
hospitalization and at 6 weeks, 3 and 6 months after hospitalization,
and every 6 months thereafter for a mean follow-up period of 3.5 years.
The results for suicide were compared with those results obtained from a
review of treatment for the 2 years prior to the initiation of clozapine
treatment. In the 88 patients who received clozapine for at least 6
months, there was a marked reduction in suicidality compared to the
prior history of these same patients. The percentage of patients with
suicidality decreased from 47% at baseline to 12% during the follow-up
period. There were 22 suicide attempts in the 2 years prior to the
initiation of clozapine therapy and only 3 suicide attempts, with low
probability for lethality, during the 2 years of follow-up while
patients continued to receive clozapine treatment. This represents an
86% decrease in suicide attempts and a concomitant reduction in the
lethal potential of the suicide attempts. The results of this study
suggest that the use of clozapine reduces suicidality.

**2. Littrell KH, Herth KA, Hinte LE.** **The experience of hope in
adults with schizophrenia. Psychiatric Rehabilitation Journal
1996;19:61-65.**

This prospective longitudinal study assessed the effects of psychosocial
treatment and clozapine therapy on the level of hope in patients with
refractory schizophrenia and a history of suicide attempts. This study
was conducted in 44 adults with schizophrenia at a single center in the
US. Its primary focus was on a subgroup of 14 individuals who had made
previous suicide attempts. Twelve of the 14 subjects were male. The mean
age of the 14 patients was 33 years, and the average dose of clozapine
was 550 mg/day. Previous suicide attempts ranged from 1 to 6, with a
mean of 2 attempts since diagnosis of disease. The Herth Hope Index
(HHI) was used to assess the overall level of hope, the Brief
Psychiatric Rating Scale (BPRS) was used to measure psychopathology, and
the Social Adjustment Scale-Patient Version (SAS-PT) was used to
evaluate reintegration. These measures were administered to the subjects
before any psychosocial or clozapine treatment and reassessed monthly,
with analyses performed after 6 and 12 months of treatment. Results of
the study showed that levels of hope increased significantly between
baseline and after 12 months of treatment (*P*\<0.001). None of the
participants attempted suicide or were rehospitalized during the
12-month study period. Subjects also displayed an improvement in
psychopathology and social functioning. The main findings of this study
were improvement in psychopathology, reintegration, and reduction in
suicide attempts compared to baseline in adult schizophrenia patients
receiving a combination of clozapine and psychosocial therapy and the
correlation of these outcomes to levels of hope.

**3. Botsis AJ, Giotakos O, Lazaridis P, Petrovas G, Stefanis CN.
Clozapine efficacy on suicidal behavior across two main psychiatric
disorders.**

> **Eur Neuropsychopharmacol 1997;7(suppl 2):S202.**

This prospective study conducted at a single center in Greece examined
the effects of clozapine treatment on depression and suicidal behavior
in 10 psychiatric inpatients (6   schizophrenics and 4 major depressives
with psychotic features). All 10 patients had been treated with high
doses of typical neuroleptics (and high doses of antidepressants in the
four major depressives) for at least 4 weeks. Clozapine was then
administered for 4 weeks  (450 mg/day). The patients were evaluated by
the BPRS, Modified Overt Aggression Scale, and Montgomery-Asberg
Depression Scale during their drug-free period, at the end of treatment
with classical neuroleptics, after 4 weeks of clozapine treatment, and
again at the end of the third month of their follow-up. The patient's
clinical symptoms showed improvement after 10 days of clozapine
treatment, and their suicidal behaviour and general psychopathology were
diminished after 3 weeks of clozapine treatment. The authors concluded
that clozapine may be efficacious in reducing suicidality.

4\. Spivak B, Roitman S, Vered Y, et al. Diminished suicidal and
aggressive behavior, high plasma norepinephrine levels, and serum
triglyceride levels in chronic neuroleptic-resistant schizophrenic
patients maintained on clozapine.

> Clin Neuropharmacol 1998;21:245-250.

This retrospective, mirror-image study conducted at a single center in
Israel evaluated the effects of clozapine on impulsiveness and
aggression (including suicidality) and prospectively examined its effect
on serum lipids, serotonin (5-HT), and norepinephine (NE) levels. The
patient population consisted of 30 neuroleptic-resistant chronic
schizophrenic patients (19 men and 11 women) who were maintained on
clozapine (mean dose SD of 295.0 165.3 mg/day) for 1 year and a control
group of 20 chronic schizophrenic patients (10 men and 10 women) who
were maintained on typical antipsychotic agents for 1 year.
Aggressiveness and impulsiveness was assessed by the Overt Aggression
Scale (OAS) and Impulsivity Scale (IS). In addition, a retrospective
evaluation of aggressive behavior during the period preceding the last
year of antipsychotic treatment (time point when patients in both groups
had been maintained on typical antipsychotics) was performed. Suicidal
attempts or suicidal behavior during the year preceding clozapine or
typical antipsychotic treatments were categorized as present or absent.
The results of the study showed that the clozapine-treated patients had
significantly less impulsiveness (IS score) and aggressiveness (OAS
score) than the control group (*P*\<0.05). None of the clozapine-treated
patients had attempted suicide during the 1 year of clozapine treatment
compared with 5 patients in the control group (Fisher\'s exact test,
*P*\<0.05). Results of the laboratory test analyses showed that the
clozapine group had significantly higher triglyceride levels and
platelet-poor plasma concentrations of norepinephrine than the control
group. Platelet-poor plasma 5-HT levels were similar in both groups, as
were cholesterol and LDL levels. The major finding of this study was the
demonstration of lower levels of suicidality, impulsiveness, and
aggressiveness in chronic schizophrenic patients maintained on clozapine
for 1 year compared with patients treated for the same period with
typical antipsychotics.

**5. Ciapparelli A, Dell'Osso L, Pini S, Chiavacci MC, Fenzi M, Cassano
GB. Clozapine for treatment-refractory schizophrenia, schizoaffective
disorder, and psychotic bipolar disorder: a 24-month naturalistic study.
J Clin Psychiatry 2000;61:329-334.**

This prospective study conducted in Italy evaluated the response to
clozapine over a 24-month period in patients who had schizophrenia,
schizoaffective disorder, or psychotic bipolar disorder. This study was
conducted in 91 adult psychotics: 31 schizophrenics, 26 with
schizoaffective disorders, and 34 with psychotic bipolar disorder.
Sixty-three of the 91 patients were male. The mean age of the three
groups ranged from 32.2 to 36.5 years. The mean dose of clozapine at
endpoint was 236, 237 and 160 mg/day for the schizophrenic,
schizoaffective, and psychotic bipolar patients, respectively. At
baseline, 26 of the 91 patients had made a suicide attempt or had had
suicidal ideation. Patients were treated with clozapine for 24 months in
combination with other neuroleptics and other medications as appropriate
(i.e., anticonvulsants, antidepressants, lithium, etc.). The severity of
psychopathology was assessed using the BPRS-Expanded version (BPRS-E) at
baseline, and after 1, 6, 12, and 24 months of clozapine treatment.
Patients were also evaluated at baseline and after 12 and 24 months
using the CGI-Severity of Illness Scale (CGI-S). Suicidal ideation was
also assessed at baseline by the interviewer on the basis of clinical
judgment. The presence of suicidal ideation at baseline correlated with
a lower BPRS total score after 24 months. When the analyses were
restricted to patients with suicidal ideation at baseline, a significant
reduction in the BPRS-E suicide item score was found at 24 months
*P*\<0.27). There was a significant and persistent clinical improvement
(reduction in BPRS total scores and CGI-S scores) in all patients at 24
months with clozapine treatment. Improvement was significantly greater
among patients with schizoaffective disorder and bipolar disorder than
those with schizophrenia. The authors concluded that the results of this
study showed clozapine to be effective in reducing suicidality after 24
months of treatment in patients with suicidal ideation and gave further
support for the use of clozapine for lowering suicide risk in patients
with schizophrenia and in those with severe mood disorders.

**CASE REPORTS/OBSERVATIONAL DATA**

Four case reports were identified from the literature. Three of these 4
patients were female. Subject age was provided for three of the cases
and ranged from 34 to 44 years old. Two of the patients were
schizophrenic and 2 had bipolar disorders. Remission or reduction of
suicideal ideation or suicide attempts was observed in 3 of the 4 cases
after treatment with Clozaril. Clozaril treatment duration in two of
these cases was 12 months (325 mg/day) and 3.5 weeks (125 mg/day).
(VangalaVR, Brown ES, Suppes T. Clozapine associated with decreased
suicidality in bipolar disorder: a case report. Bipolar Disorders
1999;2:123-124.; Privitera MR, Lamberti JS, Maharaj K. Clozapine in a
bipolar depressed patient. Am J Psychiatry 1993;150:986.) For the third
case, only the daily dose was provided (450 mg). (Martin, LM, Pablos EG,
Andres RMS. Reduccion del riesgo de suicidio en una paciente
esquizofrenica tratada con clozapina. An Psiquiatria \[Madrid\]
1997;13:390-391.) In the fourth case report, the patient received 400 mg
of Clozaril/day for 6 weeks, at which point the patient committed
suicide. (Tamam L, Ozpoyraz N. Suicide during clozapine treatment: a
case report. Isr J Psychiatry Relat Sci 2001;38:127-132.) This patient
had no history of suicidal ideation and had shown improvement in
clinical symptoms after initiating Clozaril treatment.

Two additional observational retrospective reports from Canada and Italy
were identified from the literature. In the Canadian report, no suicides
were observed in continuous users (n=11 patients) of Clozaril (3-year
treatment duration), and 2 suicides were observed in 11 patients who had
taken Clozaril for 1 and 9 days, respectively, and discontinued therapy;
therefore, these were considered unrelated to Clozaril. (Dickson RA,
Dalby JT, Williams R, Warden SJ, et al. Hospital days in
clozapine-treated patients. Can J Psychiatry 1998;43, 945-948.) In the
Italian report, a reduction in suicidality with Clozaril treatment was
reported: 2 suicides vs 22 in the total population of 103 patients
examined. (Altamura AC, Bignotti S, Tura GB, et al. Suicidal behaviour
in schizophrenia: a retrospective study. European Neuropsychopharmacol
1999;9(Suppl. 5):S271.) The authors concluded that clozapine has a
possible role in reducing suicide or suicidal ideation.

**REVIEW PAPERS**

A literature search identified 17 papers that reviewed previously
published data on suicidality and clozapine. Reprints of these papers
were obtained and reviewed and found to contain no data or references
that have not been presented above.

CONCLUSION

Between 1991 and 2001, reports of 11 studies of the effects of clozapine
on suicidality in patients with schizophrenia or schizoaffective
disorder were identified. Of theses, 6 were population studies and 5
were non-population studies. In addition, 4 case study reports and
2 observational reports were identified. Eight studies used
retrospective analyses with a total clozapine-treated patient population
of 86,327, and 3 were prospective studies with a total clozapine-treated
population of 145 patients. None of the studies were double-blind
comparisons of two or more treatments. Across all studies, the majority
of patients were between the ages of 18 and 60. Where the published
literature described the clozapine dosage received by these patients,
the mean dosage by study ranged from 236 mg/day to 550 mg/day. This is
in accord with standard medical practice for the treatment of
schizophrenia. Analysis of these data from 11 geographically diverse
locations, as well as the anecdotal evidence from 4 individual case
reports and 2 observational reports provide strong evidence supporting
the efficacy of clozapine in reducing suicidality and suicide in
patients with schizophrenia and schizoaffective disorder.

**REFERENCES**

**POPULATION STUDIES**

Modaj I, Hirschmann S, Rava A, et al. Sudden death in patients receiving
clozapine treatment: a preliminary investigation. J Clin
Psychopharmacology 2000;20(3):325-327.

Munro J, O'Sullivan D, Andrews C, Arana A, Mortimer A, Kerwin R. Active
monitoring of 12,760 clozapine recipients in the UK and Ireland. Br J
Psychiatry 1999;175:576-580.

Reid WH, Mason M, Hogan T. Suicide prevention effects associated with
clozapinetherapy in schizophrenia and schizoaffective disorder.
Psychiatric Services 1998; 49 (8):1029-1033.

Sajatovic M, Bingham R, Garver D, et al. An assessment of clinical
practice of clozapine therapy for veterans. Psychiatric Services
2000;51:669-671.

Sernyak MJ, Desia R, Stolar M, Rosenheck R. Impact of clozapine on
completed suicide. Am J

Psychiatry 2001; 158:931-937.

Walker AM, Lanza LL, Arellana A, et al. Mortality in current and former
users of clozapine. Epidemiology 8; 1997: 671-677.

NONPOPULATION STUDIES

Botsis AJ, Giotakos O, Lazaridis P, Petrovas G, Stefanis CN. Clozapine
efficacy on suicidal behavior across two main psychiatric disorders. Eur
Neuropsychopharmacol 1997;7(suppl 2):S202.

Ciapparelli A, Dell'Osso L, Pini S, Chiavacci MC, Fenzi M, Cassano GB.
Clozapine for treatment-refractory schizophrenia, schizoaffective
disorder, and psychotic bipolar disorder: a 24-month naturalistic study.
J Clin Psychiatry 2000;61:329-334.

Littrell KH, Herth KA, Hinte LE. The experience of hope in adults with
schizophrenia. Psychiatric Rehabilitation Journal 1996;19:61-65.

Meltzer HY and Okayli G. Reduction of suicidality during clozapine
treatment of neuroleptic-resistant schizophrenia: impact on risk-benefit
assessment. Am J Psychiatry 1995;152:183-190.

Spivak B, Roitman S, Vered Y, et al. Diminished suicidal and aggressive
behavior, high plasma norepinephrine levels, and serum triglyceride
levels in chronic neuroleptic-resistant schizophrenic patients
maintained on clozapine. Clin Neuropharmacol 1998;21:245-250.

**CASE REPORTS/OBSERVATIONAL DATA**

Altamura AC, Bignotti S, Tura GB, et al. Suicidal behaviour in
schizophrenia: a retrospective study. European Neuropsychopharmacol
1999;9(Suppl. 5):S271.

Dickson RA, Dalby JT, Williams R, Warden SJ, et al. Hospital days in
clozapine-treated patients. Can J Psychiatry 1998;43, 945-948.

Martin, LM, Pablos EG, Andres RMS. Reduccion del riesgo de suicidio en
una paciente esquizofrenica tratada con clozapina. An Psiquiatria
(Madrid) 1997;13:390-391.

Privitera MR, Lamberti JS, Maharaj K. Clozapine in a bipolar depressed
patient. Am J Psychiatry 1993;150:986.

Tamam L, Ozpoyraz N. Suicide during clozapine treatment: a case report.
Isr J Psychiatry Relat Sci 2001;38:127-132.

VangalaVR, Brown ES, Suppes T. Clozapine associated with decreased
suicidality in bipolar disorder: a case report. Bipolar Disorders
1999;2:123-124.

**REVIEW PAPERS**

Baldessarini RJ, Jamison KR. Effects of medical interventions on
suicidal behavior. J Clin Psychiatry 1999;60(suppl 2):117-122.

Collaborative Working Group on Clinical Trial Evaluations. Atypical
antipsychotics for treatment of depression in schizophrenia and
affective disorders. J Clin Psychiatry 1998;59(suppl 12):41-45.

Conley RR. Optimizing treatment with clozapine. J Clin Psychiatry
1998;59(suppl 3):44-48.

Keck PE Jr, Strakowski SM, McElroy SL. The efficacy of atypical
antipsychotics in the treatment of depressive symptoms, hostility, and
suicidality in patients with schizophrenia. J Clin Psychiatry
2000;61(suppl 3):4-9.

Meltzer HY. Treatment of sucidality in schizophrenia. Ann NY Acad
Sciences 2001; 932:44-60.

Meltzer HY. Suicide in schizophrenia: risk factors and clozapine
treatment. J Clin Psychiatry 1998;59(suppl 3):15-20.

Meltzer HY. Treatment-resistant schizophrenia -- the role of clozapine.
Curr Med Res Opinion 1997;14:1-20.

Meltzer HY. Multiple-outcome criteria in schizophrenia: an overview of
outcome with clozapine. Eur Psychiatry 1995;10(suppl 1):19s-25s.

Meltzer HY, Anand R, Alphs L. Reducing suicide risk in schizophrenia --
focus on the role of clozapine. CNS Drugs 2000;14:355-365.

Meltzer HY, Fatemi H. Suicide in schizophrenia: the effect of clozapine.
Clin Neuropharmacol 1995;18(suppl 3):S18-S24.

Miller AL, Glinski J. Youth suicidal behavior: assessment and
intervention. J Clin Psychology, 2000;56:1131-1152.

Nielsen B. The influence of antipsychotic on suicidal behavour in
schizophrenic patients.. Nord J Psychiatry 1997:51(Suppl 40):39-47.

Pavlovsky P. Suicide in schizophrenics. C S Psychiat 1996;92:373-377.

Remington GJ, Addington D, Collins EJ, et al. Clozapine: Current status
and role in the pharmacotherapy of schizophrenia. Can J
Psychiatry;1996;41:161-166.

Siris SG. Suicide and schizophrenia. J Psychopharmacol 2001;15:127-135.

Stockmeier CA, Meltzer HY. Biologic studies of suicide in schizophrenia.
Clin Neuropharmacol 1995:18(Suppl 3):S9-S17.

Wagstaff AJ, Bryson HM. Clozapine, A review of its pharmacological
properties and therapeutic use in patients with schizophrenia who are
unresponsive to or intolerant of classical antipsychotic agents. CNS
Drugs 1995;4:370-400.

+------+-----+---------+----------+-------+-----+-------+------------+
| **   |     |         |          |       |     |       |            |
| Tabl |     |         |          |       |     |       |            |
| e 1. |     |         |          |       |     |       |            |
| Clo  |     |         |          |       |     |       |            |
| zari |     |         |          |       |     |       |            |
| l^®^ |     |         |          |       |     |       |            |
| Publ |     |         |          |       |     |       |            |
| icat |     |         |          |       |     |       |            |
| ions |     |         |          |       |     |       |            |
| S    |     |         |          |       |     |       |            |
| umma |     |         |          |       |     |       |            |
| ry** |     |         |          |       |     |       |            |
+======+=====+=========+==========+=======+=====+=======+============+
| **A  | **  | **D     | **Po     | **    | **C | *     | **Suicide  |
| utho | Sam | esign** | pulation | Cloza | loz | *Refe | R          |
| r/Ye | ple |         | C        | pine: | api | rence | ate/Effect |
| ar** | S   |         | haracter | Trea  | ne: | Gr    | on         |
|      | ize |         | istics** | tment | D   | oup/T | Sui        |
|      | (n  |         |          | durat | ose | ime** | cidality** |
|      | )** |         |          | ion** | /da |       |            |
|      |     |         |          |       | y** |       |            |
+------+-----+---------+----------+-------+-----+-------+------------+
| **PO |     |         |          |       |     |       |            |
| PULA |     |         |          |       |     |       |            |
| TION |     |         |          |       |     |       |            |
| S    |     |         |          |       |     |       |            |
| TUDI |     |         |          |       |     |       |            |
| ES** |     |         |          |       |     |       |            |
+------+-----+---------+----------+-------+-----+-------+------------+
| Wa   | Clo | US;     | Patients | Range | Not | R     | Suicides:  |
| lker | zap | retros  | enrolled | of    | pr  | ecent | 24         |
| 1997 | ine | pective | in US    | mean  | ovi | and   | current/18 |
|      | -tr | a       | Clozaril | obs   | ded | past  | recent/33  |
|      | eat | nalysis | National | erved |     | cloz  | past       |
|      | ed: | of      | Registry | da    |     | apine | users;     |
|      | 67, | p       | from     | ys/su |     | users | suicid     |
|      | 072 | atients | 1991 to  | bject |     | com   | es/100,000 |
|      |     | treated | 1993.    |       |     | pared | pe         |
|      |     | 199     | Po       | **    |     | to    | rson-yrs=3 |
|      |     | 1-1993; | pulation | Curre |     | cu    | 9/246/222. |
|      |     | e       | analyzed | nt**: |     | rrent | Suicide    |
|      |     | xamined | by age   |       |     | users | rate ratio |
|      |     | mo      | groups   | 4     |     |       | = 0.17 for |
|      |     | rtality | of 10-54 | 7-339 |     |       | current    |
|      |     | rates   | and      |       |     |       | clozapine  |
|      |     |         | 55-94    | *     |     |       | users      |
|      |     |         | years    | *Rece |     |       | compared   |
|      |     |         |          | nt**: |     |       | w/ past    |
|      |     |         |          |       |     |       | users.     |
|      |     |         |          | 7-43  |     |       |            |
|      |     |         |          |       |     |       |            |
|      |     |         |          | **Pa  |     |       |            |
|      |     |         |          | st:** |     |       |            |
|      |     |         |          | 9     |     |       |            |
|      |     |         |          | 9-114 |     |       |            |
+------+-----+---------+----------+-------+-----+-------+------------+
| Reid | Tot | US      | Schizo   | At    | No  | 3     | Suicides:  |
| 1998 | al: | (Texas  | phrenic/ | least | m   | 0,130 | 1/1310     |
|      |     | state   | schizo-a | 30    | ean | schi  | cloz-trt;  |
|      | 30, | psyc    | ffective | days  | d   | zophr | 38/30,130  |
|      | 130 | hiatric | pts;     | exp   | ose | enic/ | total pop; |
|      |     | facil   | examined | osure | pr  |       | 5-fold     |
|      | Clo | ities); | annual   |       | ovi | schiz | decrease   |
|      | zap | retros  | suicide  |       | ded | oaffe | in suicide |
|      | ine | pective | rates    |       |     | ctive | rate in    |
|      | -tr | a       | for 2    |       |     | pat   | cl         |
|      | eat | nalysis | years    |       |     | ients | oz-treated |
|      | ed: |         | (        |       |     |       | patients   |
|      | 1   |         | 1993-95) |       |     |       |            |
|      | 310 |         | of       |       |     |       |            |
|      |     |         | 30,130   |       |     |       |            |
|      |     |         | pts.     |       |     |       |            |
|      |     |         | Subgroup |       |     |       |            |
|      |     |         | of 1,367 |       |     |       |            |
|      |     |         | c        |       |     |       |            |
|      |     |         | lozapine |       |     |       |            |
|      |     |         | treated  |       |     |       |            |
|      |     |         | pts      |       |     |       |            |
|      |     |         | e        |       |     |       |            |
|      |     |         | valuated |       |     |       |            |
|      |     |         | over     |       |     |       |            |
|      |     |         | 6-yr     |       |     |       |            |
|      |     |         | period   |       |     |       |            |
|      |     |         | (        |       |     |       |            |
|      |     |         | 1991-96) |       |     |       |            |
|      |     |         | .        |       |     |       |            |
+------+-----+---------+----------+-------+-----+-------+------------+
| M    | Clo | UK and  | Tre      | 1 day | M   | NA    | 13/12,188  |
| unro | zap | I       | atment-r | --    | ean |       | clozapine  |
| 1999 | ine | reland; | esistant | 7.6   | d   |       | treated    |
|      | -tr | retros  | schiz    | years | ose |       | patients;  |
|      | eat | pective | ophrenic |       | 388 |       | decreased  |
|      | ed: | a       | patients |       | mg/ |       | suicide    |
|      | 12, | nalysis |          |       | day |       | risk       |
|      | 760 | of      |          |       | (m  |       | compared   |
|      |     | clo     |          |       | ean |       | with rate  |
|      |     | zapine- |          |       | max |       | in         |
|      |     | treated |          |       | d   |       | sch        |
|      |     | (1990   |          |       | ose |       | izophrenic |
|      |     | -1998); |          |       | 462 |       | patients   |
|      |     | Aim:    |          |       | m   |       | in UK      |
|      |     | quantif |          |       | g/d |       |            |
|      |     | ication |          |       | ay) |       |            |
|      |     | of risk |          |       |     |       |            |
|      |     | factors |          |       |     |       |            |
|      |     | for     |          |       |     |       |            |
|      |     | a       |          |       |     |       |            |
|      |     | granulo |          |       |     |       |            |
|      |     | cytosis |          |       |     |       |            |
+------+-----+---------+----------+-------+-----+-------+------------+

+------+-----+---------+----------+-------+-----+-------+------------+
| **A  | **  | **D     | **Po     | **    | **C | *     | **Suicide  |
| utho | Sam | esign** | pulation | Cloza | loz | *Refe | R          |
| r/Ye | ple |         | C        | pine: | api | rence | ate/Effect |
| ar** | S   |         | haracter | Trea  | ne: | Gr    | on         |
|      | ize |         | istics** | tment | D   | oup/T | Sui        |
|      | (n  |         |          | durat | ose | ime** | cidality** |
|      | )** |         |          | ion** | /da |       |            |
|      |     |         |          |       | y** |       |            |
+------+-----+---------+----------+-------+-----+-------+------------+
| S    | C   | US; VA  | Schiz    | Not   | Not | NA    | Suicide    |
| ajat | loz | da      | ophrenic | pro   | pr  |       | rate 0.1%  |
| ovic | api | tabase, | cloz-trt | vided | ovi |       | after      |
| 2000 | ne: | 5-y     | patients |       | ded |       | clozapine  |
|      | 2   | period, | in US VA |       |     |       | treatment  |
|      | 996 | retros  | system;  |       |     |       | (2         |
|      |     | pective | mean     |       |     |       | suicides); |
|      |     | study;  | age:     |       |     |       | sig.       |
|      |     | c       | 44.8     |       |     |       | Decrease   |
|      |     | ompared | years    |       |     |       | compared   |
|      |     | e       |          |       |     |       | with       |
|      |     | ndpoint |          |       |     |       | before     |
|      |     | to      |          |       |     |       | trt; Sig.  |
|      |     | b       |          |       |     |       | i          |
|      |     | aseline |          |       |     |       | mprovement |
|      |     | BPRS    |          |       |     |       | on BPRS    |
|      |     | and     |          |       |     |       |            |
|      |     | AIMS    |          |       |     |       |            |
|      |     | scores  |          |       |     |       |            |
+------+-----+---------+----------+-------+-----+-------+------------+
| M    | C   | Israel; | Schiz    | Not   | Not | Non   | 2/561      |
| odaj | loz | retros  | ophrenic | pro   | pr  | -cloz | clozapin   |
| 2000 | api | pective | patients | vided | ovi | apine | e-treated; |
|      | ne: | a       | in one   |       | ded | tr    | 5/4918     |
|      | 5   | nalysis | mental   |       |     | eated | non        |
|      | 61; | 199     | health   |       |     | (     | -clozapine |
|      |     | 1-1997; | center   |       |     | other | treated;   |
|      | non | d       |          |       |     | ag    | No sig     |
|      | -cl | atabase |          |       |     | ents) | difference |
|      | oza | of one  |          |       |     |       | in suicide |
|      | pin | mental  |          |       |     |       | rate       |
|      | e-: | health  |          |       |     |       | between    |
|      | 4   | center  |          |       |     |       | the two    |
|      | 918 |         |          |       |     |       | groups     |
+------+-----+---------+----------+-------+-----+-------+------------+
| Ser  | To  | US; VA  | Schiz    | 28%   | Not | Wi    | Suicides:  |
| nyak | tal | da      | ophrenic | rec   | pr  | thout | long-term  |
| 2001 | s   | tabase; | p        | eived | ovi | r     | cl         |
|      | amp | retros  | atients: | cloz  | ded | ecord | oz=5/1018; |
|      | le: | pective | mean     | apine |     | of    | short-term |
|      | 4   | an      | age:     |       |     | any   | c          |
|      | 5,9 | alysis: | cloz     | \<1   |     | cloz  | loz=5/397; |
|      | 17; | 199     | trt=43.0 | year, |     | apine | non-cloz   |
|      |     | 2-1995; | yr,      |       |     | trea  | trt:       |
|      | Clo | e       | noncloz  | 72%   |     | tment | 23/2,380;  |
|      | zap | xamined | tr       | re    |     |       | No sig.    |
|      | ine | overall | t=43.6yr | ceive |     |       | d          |
|      | -tr | mo      |          | dcloz |     |       | ifferences |
|      | eat | rtality |          | apine |     |       | in suicide |
|      | ed: | and     |          |       |     |       | rate       |
|      | 14  | cause-s |          | [\    |     |       | between    |
|      | 15; | pecific |          | >]{.u |     |       | clozapine  |
|      |     | mo      |          | nderl |     |       | trt and    |
|      | n   | rtality |          | ine}1 |     |       | non        |
|      | onc |         |          | year  |     |       | -clozapine |
|      | loz |         |          |       |     |       | trt pts;   |
|      | -tr |         |          |       |     |       |            |
|      | eat |         |          |       |     |       |            |
|      | ed: |         |          |       |     |       |            |
|      | 2   |         |          |       |     |       |            |
|      | 380 |         |          |       |     |       |            |
+------+-----+---------+----------+-------+-----+-------+------------+
| **N  |     |         |          |       |     |       |            |
| ONPO |     |         |          |       |     |       |            |
| PULA |     |         |          |       |     |       |            |
| TION |     |         |          |       |     |       |            |
| S    |     |         |          |       |     |       |            |
| TUDI |     |         |          |       |     |       |            |
| ES** |     |         |          |       |     |       |            |
+------+-----+---------+----------+-------+-----+-------+------------+
| Mel  | To  | US;     | schiz    | 2     | M   | N     | 3/88; Sig. |
| tzer | tal | 198     | ophrenic | -year | ean | eurol | Decreased  |
| 1995 | p   | 6-1993; | or       | dur   | do  | eptic | s          |
|      | op: | mirror  | schizoa  | ation | se: | --    | uicidality |
| and  | 4   | -image, | ffective | of    | 500 | respo | by 86.4%   |
| 199  | 20; | retrosp | p        | cloz  | mg/ | nsive | in         |
| 8^1^ |     | ective. | atients; | apine | day | pati  | clo        |
|      | n   | E       |          | trea  |     | ents; | zapine-trt |
|      | eur | xamined |          | tment |     | pre-  | patients   |
|      | ole | suic    |          |       |     | vs    | compared   |
|      | pti | idality |          |       |     | post- | w/ before  |
|      | c-r |         |          |       |     | trt   | clozapine  |
|      | esi |         |          |       |     | of    | treatment  |
|      | st. |         |          |       |     | n     |            |
|      | c   |         |          |       |     | eurol |            |
|      | loz |         |          |       |     | eptic |            |
|      | t   |         |          |       |     | resi  |            |
|      | rt: |         |          |       |     | stant |            |
|      | 1   |         |          |       |     | pat   |            |
|      | 83; |         |          |       |     | ients |            |
|      |     |         |          |       |     |       |            |
|      | cl  |         |          |       |     |       |            |
|      | oz- |         |          |       |     |       |            |
|      | trt |         |          |       |     |       |            |
|      | [   |         |          |       |     |       |            |
|      | \>] |         |          |       |     |       |            |
|      | {.u |         |          |       |     |       |            |
|      | nde |         |          |       |     |       |            |
|      | rli |         |          |       |     |       |            |
|      | ne} |         |          |       |     |       |            |
|      | 6   |         |          |       |     |       |            |
|      | m   |         |          |       |     |       |            |
|      | ont |         |          |       |     |       |            |
|      | hs: |         |          |       |     |       |            |
|      | 88  |         |          |       |     |       |            |
+------+-----+---------+----------+-------+-----+-------+------------+

+------+-----+---------+----------+-------+-----+-------+------------+
| **A  | **  | **D     | **Po     | **    | **C | *     | **Suicide  |
| utho | Sam | esign** | pulation | Cloza | loz | *Refe | R          |
| r/Ye | ple |         | C        | pine: | api | rence | ate/Effect |
| ar** | S   |         | haracter | Trea  | ne: | Gr    | on         |
|      | ize |         | istics** | tment | D   | oup/T | Sui        |
|      | (n  |         |          | durat | ose | ime** | cidality** |
|      | )** |         |          | ion** | /da |       |            |
|      |     |         |          |       | y** |       |            |
+------+-----+---------+----------+-------+-----+-------+------------+
| Litt | To  | US;     | Schiz    | 12    | M   | Com   | Reduced    |
| rell | tal | prosp   | ophrenic | m     | ean | pared | suicide    |
| 1996 | clo | ective, | patients | onths | do  | r     | attempts   |
|      | zap | open    |          |       | se: | ating | to 0       |
|      | ine | --label |          |       | 550 | scale | during a   |
|      | -tr | study;  |          |       | mg/ | re    | 12-month   |
|      | eat | e       |          |       | day | sults | study      |
|      | ed: | xamined |          |       |     | after | period,    |
|      | 44; | levels  |          |       |     | 6 and | increased  |
|      |     | of hope |          |       |     | 12    | hope       |
|      | sub | (HHI)   |          |       |     | m     | levels;    |
|      | set | suicide |          |       |     | onths | improved   |
|      | w   | at      |          |       |     | of    | general    |
|      | ith | tempts, |          |       |     | cloz  | clinical   |
|      | pr  | BPRS,   |          |       |     | apine | psych      |
|      | evi | and     |          |       |     | trea  | opathology |
|      | ous | reinte  |          |       |     | tment | and        |
|      | s   | gration |          |       |     | with  | rei        |
|      | uic | (       |          |       |     | bas   | ntegration |
|      | ide | SAS-Pt) |          |       |     | eline |            |
|      | att |         |          |       |     | s     |            |
|      | emp |         |          |       |     | cores |            |
|      | ts: |         |          |       |     |       |            |
|      | 14  |         |          |       |     |       |            |
+------+-----+---------+----------+-------+-----+-------+------------+
| Bo   | 10  | Greece; | Schizo   | 4     | Da  | Trea  | Reduced    |
| tsis | cl  | prosp   | phrenics | weeks | ily | tment | suicidal   |
| 1997 | oza | ective, | and      |       | d   | p     | behavior   |
|      | pin | open    | major    |       | ose | eriod | and        |
|      | e-t | label.  | de       |       | of  | w/    | general    |
|      | rea | E       | pressive |       | up  | std   | clinical   |
|      | ted | xamined | in-      |       | to  | ne    | psych      |
|      |     | s       | patients |       | 450 | urole | opathology |
|      |     | uicidal |          |       | mg/ | ptics |            |
|      |     | b       |          |       | day | b     |            |
|      |     | ehavior |          |       |     | efore |            |
|      |     | and     |          |       |     | cloz  |            |
|      |     | p       |          |       |     | apine |            |
|      |     | sychopa |          |       |     | trea  |            |
|      |     | thology |          |       |     | tment |            |
+------+-----+---------+----------+-------+-----+-------+------------+
| Sp   | 30  | Israel; | Neuro    | 1     | M   | Ch    | Suicides:  |
| ivak | clo | retros  | leptic-r | year  | ean | ronic | 0/30       |
| 1998 | zap | pective | esistant |       | d   | sc    | clozapine  |
|      | ine | mirro   | schiz    |       | ose | hizop | trt; 5/30  |
|      | -tr | r-image | ophrenic |       | of  | hreni | control    |
|      | eat | a       | patients |       | 295 | csw/1 | group;     |
|      | ed; | nalysis | c        |       | mg/ | year  | sig.       |
|      |     | of      | lozapine |       | day | trea  | decreased  |
|      | 30  | impuls  | t        |       |     | tment | suicide    |
|      | std | ive/agg | reatment |       |     | w     | rate in    |
|      | ant | ressive | for 1    |       |     | /clas | clozapine  |
|      | ips | b       | year;    |       |     | sical | treated    |
|      | y-c | ehavior | mean age |       |     | anti  | patients.  |
|      | hot | and     | 36.9     |       |     | psych |            |
|      | ics | suic    | year     |       |     | otics |            |
|      |     | idality |          |       |     |       |            |
+------+-----+---------+----------+-------+-----+-------+------------+
| Cia  | 91  | Italy;  | Tre      | 24    | 2   | Compa | Inpatients |
| ppar | t   | prosp   | atment-r | m     | 36, | rison | with       |
| elli | rt- | ective, | esistant | onths | 2   | of    | suicidal   |
| 2000 | res | ope     | p        |       | 37, | cloz  | ideation   |
|      | ist | n-label | sychotic |       | and | apine | at         |
|      | ant | study;  | p        |       | 160 | trea  | baseline,  |
|      | ps  | com     | atients; |       | m   | tment | there was  |
|      | ych | parison | range in |       | g/d | in    | a          |
|      | oti | of      | mean age |       | for | the   | s          |
|      | cs: | cl      | 3        |       | sch | three | ignificant |
|      | 31  | ozapine | 2.2-36.5 |       | izo | types | reduction  |
|      | sch | tr      | year for |       | -ph | of    | in the     |
|      | izo | eatment | three    |       | ren | pat   | BPRS-E     |
|      | -ph | in the  | groups   |       | ic, | ients | suicide    |
|      | ren | three   |          |       |     |       | item score |
|      | ic; | types   |          |       | sc  |       | at 24      |
|      | 26  | of      |          |       | hiz |       | months of  |
|      | sc  | psy     |          |       | o-a |       | clozapine  |
|      | hiz | chotics |          |       | ffe |       | treatment. |
|      | o-a |         |          |       | cti |       |            |
|      | ffe |         |          |       | ve, |       |            |
|      | cti |         |          |       | b   |       |            |
|      | ve; |         |          |       | ipo |       |            |
|      |     |         |          |       | lar |       |            |
|      | 34  |         |          |       | p   |       |            |
|      | b   |         |          |       | ts, |       |            |
|      | ipo |         |          |       | res |       |            |
|      | lar |         |          |       | pec |       |            |
|      |     |         |          |       | tiv |       |            |
|      |     |         |          |       | ely |       |            |
+------+-----+---------+----------+-------+-----+-------+------------+

+------+-----+---------+----------+-------+-----+------+------------+
| **A  | **  | **D     | **Po     | **    | **C | **R  | **Suicide  |
| utho | Sam | esign** | pulation | Cloza | loz | efer | R          |
| r/Ye | ple |         | C        | pine: | api | ence | ate/Effect |
| ar** | S   |         | haracter | Trea  | ne: | Grou | on         |
|      | ize |         | istics** | tment | D   | p/Ti | Sui        |
|      | (n  |         |          | durat | ose | me** | cidality** |
|      | )** |         |          | ion** | /da |      |            |
|      |     |         |          |       | y** |      |            |
+------+-----+---------+----------+-------+-----+------+------------+
| **   |     |         |          |       |     |      |            |
| CASE |     |         |          |       |     |      |            |
| R    |     |         |          |       |     |      |            |
| EPOR |     |         |          |       |     |      |            |
| TS/O |     |         |          |       |     |      |            |
| BSER |     |         |          |       |     |      |            |
| VATI |     |         |          |       |     |      |            |
| ONAL |     |         |          |       |     |      |            |
| DA   |     |         |          |       |     |      |            |
| TA** |     |         |          |       |     |      |            |
+------+-----+---------+----------+-------+-----+------+------------+
| P    | 1   | US      | 4        | 3.5   | 125 | NA   | S          |
| rivi |     |         | 4-yr-old | weeks | mg  |      | ubstantial |
| tera |     |         | bipolar  |       |     |      | decrease   |
| 1993 |     |         | female   |       |     |      |            |
+------+-----+---------+----------+-------+-----+------+------------+
| Ma   | 1   | Spain   | 1        |       | 450 | NA   | S          |
| rtin |     |         | 7-yr-old |       | mg  |      | ubstantial |
|      |     |         | female   |       |     |      | decrease   |
| 1997 |     |         |          |       |     |      |            |
+------+-----+---------+----------+-------+-----+------+------------+
| Dic  | 26  | Ca      | Tre      | Conti | Not | T    | 2 suicides |
| kson |     | nadian; | atment-r | nuous | pr  | hree | in group   |
| 1998 |     | retros  | esistant | u     | ovi | gr   | of 11      |
|      |     | pective | schiz    | sers: | ded | oups | dis        |
|      |     | review  | ophrenic | 3     |     | comp | continued; |
|      |     |         | p        | years |     | ared | occurred   |
|      |     |         | atients; |       |     | with | after      |
|      |     |         | Groups:  |       |     | each | dis        |
|      |     |         | c        |       |     | o    | continuing |
|      |     |         | lozapine |       |     | ther | treatment, |
|      |     |         | co       |       |     |      | treatment  |
|      |     |         | ntinuous |       |     |      | durations  |
|      |     |         | use (11  |       |     |      | of 1 and 9 |
|      |     |         | pts),    |       |     |      | days (not  |
|      |     |         | int      |       |     |      | considered |
|      |     |         | errupted |       |     |      | clozapin   |
|      |     |         | use (4   |       |     |      | e-related) |
|      |     |         | pts),    |       |     |      |            |
|      |     |         | disc     |       |     |      |            |
|      |     |         | ontinued |       |     |      |            |
|      |     |         | (11      |       |     |      |            |
|      |     |         | pts);    |       |     |      |            |
|      |     |         | mean     |       |     |      |            |
|      |     |         | age:     |       |     |      |            |
|      |     |         | 3        |       |     |      |            |
|      |     |         | 1.8 year |       |     |      |            |
+------+-----+---------+----------+-------+-----+------+------------+
| Alta | 103 | I       | Schizo   | Not   | Not | NA   | Suicides:  |
| mura |     | talian, | phrenic/ | pro   | pr  |      | 2 with     |
| 1999 |     | retros  | schizoa  | vided | ovi |      | clo        |
|      |     | pective | ffective |       | ded |      | zapine-trt |
|      |     | review  | p        |       |     |      | (no        |
|      |     |         | atients; |       |     |      | d          |
|      |     |         | 68 males |       |     |      | enominator |
|      |     |         | and 35   |       |     |      | provided); |
|      |     |         | females  |       |     |      | 22         |
|      |     |         |          |       |     |      | suicides   |
|      |     |         |          |       |     |      | in total   |
|      |     |         |          |       |     |      | pop of     |
|      |     |         |          |       |     |      | 103; cloz  |
|      |     |         |          |       |     |      | associated |
|      |     |         |          |       |     |      | with       |
|      |     |         |          |       |     |      | reduction  |
|      |     |         |          |       |     |      | in         |
|      |     |         |          |       |     |      | s          |
|      |     |         |          |       |     |      | uicidality |
+------+-----+---------+----------+-------+-----+------+------------+
| Van  | 1   | US      | 3        | 12    | 325 | NA   | S          |
| gala |     |         | 4-yr-old | m     | mg  |      | ubstantial |
| 1999 |     |         | female   | onths |     |      | decrease   |
+------+-----+---------+----------+-------+-----+------+------------+
| T    | 1   | Turkey  | 3        | 6     | 400 | NA   | Suicide    |
| amam |     |         | 6-yr-old | weeks | mg  |      | death      |
| 2001 |     |         | male     |       |     |      |            |
+------+-----+---------+----------+-------+-----+------+------------+
| **RE |     |         |          |       |     |      |            |
| VIEW |     |         |          |       |     |      |            |
| PAPE |     |         |          |       |     |      |            |
| RS** |     |         |          |       |     |      |            |
+------+-----+---------+----------+-------+-----+------+------------+
| A    |     |         |          |       |     |      |            |
| li   |     |         |          |       |     |      |            |
| tera |     |         |          |       |     |      |            |
| ture |     |         |          |       |     |      |            |
| se   |     |         |          |       |     |      |            |
| arch |     |         |          |       |     |      |            |
| id   |     |         |          |       |     |      |            |
| enti |     |         |          |       |     |      |            |
| fied |     |         |          |       |     |      |            |
| 17   |     |         |          |       |     |      |            |
| Re   |     |         |          |       |     |      |            |
| view |     |         |          |       |     |      |            |
| Pa   |     |         |          |       |     |      |            |
| pers |     |         |          |       |     |      |            |
| that |     |         |          |       |     |      |            |
| were |     |         |          |       |     |      |            |
| obta |     |         |          |       |     |      |            |
| ined |     |         |          |       |     |      |            |
| and  |     |         |          |       |     |      |            |
| r    |     |         |          |       |     |      |            |
| evie |     |         |          |       |     |      |            |
| wed. |     |         |          |       |     |      |            |
| No   |     |         |          |       |     |      |            |
| ad   |     |         |          |       |     |      |            |
| diti |     |         |          |       |     |      |            |
| onal |     |         |          |       |     |      |            |
| p    |     |         |          |       |     |      |            |
| erti |     |         |          |       |     |      |            |
| nent |     |         |          |       |     |      |            |
| re   |     |         |          |       |     |      |            |
| fere |     |         |          |       |     |      |            |
| nces |     |         |          |       |     |      |            |
| to   |     |         |          |       |     |      |            |
| Cloz |     |         |          |       |     |      |            |
| aril |     |         |          |       |     |      |            |
| and  |     |         |          |       |     |      |            |
| sui  |     |         |          |       |     |      |            |
| cide |     |         |          |       |     |      |            |
| were |     |         |          |       |     |      |            |
| obse |     |         |          |       |     |      |            |
| rved |     |         |          |       |     |      |            |
| o    |     |         |          |       |     |      |            |
| ther |     |         |          |       |     |      |            |
| than |     |         |          |       |     |      |            |
| the  |     |         |          |       |     |      |            |
| ones |     |         |          |       |     |      |            |
| su   |     |         |          |       |     |      |            |
| mmar |     |         |          |       |     |      |            |
| ized |     |         |          |       |     |      |            |
| a    |     |         |          |       |     |      |            |
| bove |     |         |          |       |     |      |            |
| in   |     |         |          |       |     |      |            |
| this |     |         |          |       |     |      |            |
| Ta   |     |         |          |       |     |      |            |
| ble. |     |         |          |       |     |      |            |
+------+-----+---------+----------+-------+-----+------+------------+

^1^ The Meltzer 1998 publication only discusses the 88-patient
clozapine-treated cohort whose data were presented in the Meltzer 1995
publication.