GUEST EDITORIAL

Is Psychiatry Ignoring Suicide?

The Case for Clozapine
Mark Sinyor, MSc, MD* and Gary Remington, MD, PhD, FRCPCÞþ

p to 10% of patients with schizophrenia will ultimately die of suicide.1 Unfortunately, specific
U treatments targeting suicide have proven elusive. Clozapine is the first and only medication
indicated for the treatment of suicide according to the US Food and Drug Administration,2 and it has
been argued that the underuse of clozapine for suicide prevention represents a significant failure of
implementation of evidence-based medicine in psychiatry.3 Widespread reluctance to use clozapine
can chiefly be attributed to the increased risk of death secondary to agranulocytosis, which was high
before the modern advent of careful and mandatory hematologic monitoring.4 Although some guide-
lines suggest that clozapine could be used early in the treatment of schizophrenia when there is a high
risk of suicide, clozapine is generally positioned as a third-line agent and is routinely initiated even later
in real-world clinical settings.5 This fact deserves redress because the present underuse of clozapine may
well represent the best available example of a systematic failure on the part of psychiatry to pursue
treatments that directly target suicide mortality.
Analyses of large databases of clozapine users have found mortality from agranulocytosis to
occur in 0.01% to 0.03% of patients.5 Increased risk of agranulocytosis and related mortality is most
pronounced in the first year of treatment; thereafter, the risk is low and comparable to other anti-
psychotics during subsequent years.5 In contrast, the risk of completed suicide in the year after a first
episode of psychosis has been calculated as 0.31%,6 with a 10-year cumulative risk of 2.05%.6
Another study of patients with confirmed schizophrenia found a cumulative 10-year suicide risk of
4.1%, again with suicides occurring more frequently in the first year of follow-up.7 The risk of
suicide in the first year after diagnosis of schizophrenia, therefore, appears to be at least 10-fold
higher than the risk of dying from agranulocytosis in the first year of clozapine treatment. Finally,
a recent nationwide study in Denmark found that the cumulative incidence of suicide in the first
36 years after psychiatric contact was 6.6% and 4.9% in men and women with schizophrenia,
respectively.8
To properly estimate risk, we must also examine the evidence for clozapine as an antisuicide
agent. Numerous studies have provided indirect evidence that clozapine prevents suicide,2 although
well-designed, prospective trials powered to detect differences in completed suicide are lacking. An
11-year follow-up study of patients with schizophrenia in Finland found that the rate of suicide for
clozapine was 0.08% per person-year compared with a mean rate of 0.25% for other second generation
antipsychotics (ie, olanzapine, risperidone, and quetiapine).9 Similarly, Hennen and Baldessarini10
conducted a meta-analysis and established that the risk ratio for completed suicide was 2.9 favoring
clozapine compared with other treatments.
For the sake of argument, let us make several conservative estimates. Based on the aforemen-
tioned data, it is reasonable to estimate the risk of suicide in the first year of schizophrenia to be
approximately 0.3% and the risk of agranulocytosis to be 0.03% (the highest danger estimate). Let
us also assume that clozapine treatment reduces the number of suicides by only 20%, again a con-
servative estimate given that one would predict approximately 67% fewer suicides based on the studies
by Nordentoft et al9 and Hennen and Baldessarini.10 In this scenario, 1 year of clozapine treatment
would prevent twice as many suicides as the number of deaths it would cause by agranulocytosis,
with a relative risk reduction of 10% and an absolute reduction of 3 suicides per 10,000.
Let us now make the much less conservative, but still plausible, assumptions that the 10-year
risk of suicide after diagnosis of schizophrenia is 4.0%, the 10-year risk of death from agranulo-
cytosis on clozapine is 0.02%, and clozapine treatment reduces the number of suicides by 50%
compared with other antipsychotics. In this scenario, 10 years of clozapine treatment would prevent
100 times as many suicides as the number of deaths it would cause by agranulocytosis, with a
relative risk reduction of 49.5% and an absolute reduction of 198 suicides per 10,000. Keeping in

From the *Department of Psychiatry, Sunnybrook Health Sciences Centre, and †Schizophrenia Head, Brain and Behaviour
Program, Department of Psychiatry, University of Toronto; and ‡Medication Clinic, Schizophrenia Program, Centre for
Addiction and Mental Health, Toronto, Ontario, Canada.
Reprints: Mark Sinyor, MSc, MD, Department of Psychiatry, Sunnybrook Health Sciences Centre, University of Toronto,
2075 Bayview Ave, Toronto, Ontario, Canada M4N 3M5 (e-mail: mark.sinyor@utoronto.ca).
Copyright * 2012 by Lippincott Williams & Wilkins
ISSN: 0271-0749
DOI: 10.1097/JCP.0b013e31825501f b

Journal of Clinical Psychopharmacology & Volume 32, Number 3, June 2012 www.psychopharmacology.com 307

Copyright © 2012 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Guest Editorial Journal of Clinical Psychopharmacology
mind that there are no other specific treatments for suicide in
schizophrenia at present, even verification of the more con-
servative calculation would have profound clinical
ramifications.
These data beg the question, why are all patients with
schizophrenia not prescribed clozapine? Of course, it is not such
a straightforward question in that other factors must also be taken
into consideration. Over and above methodological challenges
to studies examining clozapine for suicide, there are numerous
other reasons why clozapine is used infrequently. These include
increased risk for weight gain/metabolic sequelae,11 as well as
rare but potentially life-threatening adverse effects other than
agranulocytosis such as paralytic ileus, seizures, myocarditis,
and cardiomyopathy. High costs, the need for routine hemato-
logic monitoring, and the relative absence of specialty clinics
streamlined for clozapine administration and monitoring are also
significant hurdles. However, these factors do not adequately ex-
plain why researchers and clinicians alike are not pursuing the use
of clozapine as an antisuicide agent more vigorously. Large-
scale pragmatic trials examining the treatment of schizophrenia
have already demonstrated that clozapine is equivalent or su-
perior in effectiveness to other antipsychotics on measures of
morbidity in schizophrenia.12,13 Furthermore, a recently pub-
lished 11-year population-based cohort study has reported that
clozapine, compared with both conventional and other atypical
antipsychotics, carried the lowest risk of all-cause mortality, a
finding that extended beyond suicide.9 It should be noted that
there are no prospective randomized controlled trials defini-
tively showing that clozapine prevents completed suicide. How-
ever, there is clearly ample evidence to support more vigorous
and systematic examination of clozapine’s potential advantages
for mortality both from suicide and other causes as well. Re-
searchers and funding agencies need to make difficult choices
about priorities. Unfortunately mortality which is rightly a topic
of obsession for most specialties in medicine has been largely
ignored in psychiatry. What is most worrying is not that so few
patients are taking clozapine but rather that so few in the
psychiatric community are paying attention to the question of
whether they should be.
AUTHOR DISCLOSURE INFORMATION
Dr Sinyor has received a research grant from the Physi-
cians’ Services Incorporated Foundation. Dr Remington has re-
ceived research grants from Neurocrine Biosciences, Novartis,
308 www.psychopharmacology.com
Copyright © 2012 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
& Volume 32, Number 3, June 2012
and Medicure Inc; acted as a consultant for Roche and Labor-
atorios Farmacéuticos Rovi; and received speaker’s fees from
Novartis.
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* 2012 Lippincott Williams & Wilkins