[ The suicide rate of persons in the population at large is 11
per 100,000 per year.]
Dr. Khan's finding raises serious ethical questions about clinical trials in
psychiatry:
Are patients assigned to placebo exposed to increased mortality risk?
Or, as the article points out, some observers" have suggested that psychotropics
may themselves increase the risk of suicide."
Dr. Khan further suggested that "The high rates of suicide among patients
studied might suggest an "iceberg effect" in the general population. The numbers
that come to light under the close scrutiny of the clinical trial situation
indicate the extent to which attempted and completed suicides are concealed or
mislabeled in the community."
ALLIANCE FOR HUMAN RESEARCH PROTECTION (AHRP)
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Contact: Vera Hassner Sharav
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August 2002 . Volume 30 . Number 8
News
Analysis of large database
Antisuicidal Effect Of Psychotropics Remains Uncertain
'We have to ask if medication is the only way' to approach the prevention of
suicide.
Carl Sherman
Contributing Writer
BOCA RATON, FLA. - Psychotropic therapy did not appear to have a marked impact
on suicide risk, examination of a large database indicated-in fact, no class of
medication had much more or less effect than placebo, Dr. Arif Khan said at a
meeting of the New Clinical Drug Evaluation Unit sponsored by the National
Institute of Mental Health.
Overall, attempted and completed suicides among patients with diverse
psychiatric conditions are substantially more frequent than had been expected,
the analysis suggested.
"Given that suicide is such a complex behavior ... we have to ask if medication
is the only way to [approach] it," said Dr. Khan of Northwest Clinical Research
Center, Bellevue, Wash.
The conventional response to suicidality in psychiatry is pharmacotherapy. The
assumption that this will be beneficial "is never challenged much," Dr. Khan
said, and raises ethical questions about clinical trials, such as whether
patients assigned to placebo may be exposed to increased mortality risk. Some
observers, on the other hand, have suggested that psychotropics may themselves
increase the risk of suicide.
In fact, the only biologic treatments for which there are many data on this
score are ECT and lithium, which have been shown to reduce suicidal ity. More
limited data support a similar effect for clozapine.
Dr. Khan reported an analysis of clinical trial data for drugs approved by the
Food and Drug Administration between 1985 and 2000. This included suicide and
attempted suicide rates for more than 71,604 patients treated with the atypical
antipsychotics risperidone, olanzapine, and quetiapine; all the selective
serotonin reuptake inhibitors; nefazodone, mirtazapine, and bupropion; the
benzodiazepine alprazolam; and the anticonvulsant valproate.
One striking finding was the elevated rate of completed suicides for patients
during these trials. Compared with the rate of 11/100,000 persons per year for
the population at large, the rates of completed suicide were 752/100,000 persons
per year for those in antipsychotic trials; 718 in antidepressant trials; 425 in
trials of medication for social anxiety disorder; 136 for panic disorder; and
105 for obsessive-compulsive disorder.
This was particularly surprising in light of the attempt, in most clinical
trials, to exclude patients who are actively suicidal, Dr. Khan said.
Figures on attempted suicide found similarly increased risk. The figures implied
that 5% of patients who enroll in antipsychotic trials will attempt suicide in
the following year; 3.7% of those in antidepressant trials will make an attempt;
and 1.2% of those in trials of medication for anxiety disorders will attempt
suicide.
Suicide rates were higher, in the trials taken as a whole, for patients who were
assigned to placebo than to the investigational drug (1,750/100,000 persons per
year vs. 710/100,000 persons per year). But because participants were exposed to
placebo for far less time than to the drugs (a mean of 33 days vs. 148 days),
this could not be assumed to indicate an antisuicidal effect of medication, he
said.
In the case of trials for depression and anxiety disorders, suicide rates were
in fact higher among those who received the investigational drug than placebo,
Dr. Khan said.
The high rates of suicide among patients studied might suggest an "iceberg
effect" in the general population. The numbers that come to light under the
close scrutiny of the clinical trial situation indicate the extent to which
attempted and completed suicides are concealed or mislabeled in the community,
Dr. Khan speculated.
Highlights of Six Specific DSM-V Research Agenda
1. Basic Nomenclature Issues of DSM-V
The most diffuse of the research agendas, this section consists of six
independent subsections on issues of nomenclature:
How to define "mental disorder." DSM has never contained a detailed
definition that is useful as a criterion for deciding what is, or is not, a
mental disorder.
A useful definition should be developed.
Validity. DSM-V should possibly include a rating of the quality of
information and quantity of information available to support different
diagnostic systems.
Dimensionality vs. categories. Like the classification systems of many
other branches of medicine, the DSM-IV system is categorical. A dimensional
system would better represent variations in psychiatric symptomology, although
it is premature to assume that DSM-V would be largely dimensional. However,
research could provide valuable information about the usefulness of a
dimensional system.
Reducing gaps between DSM-V and ICD-11. APA's goal has always been to
link DSM with the World Health Organization's International Statistical
Classification of Diseases and Related Health Problems. However, differences
still interfere with the compatibility of the two systems. Reconciliation is
recommended; in the future, the decision may be made to create a single,
unified, worldwide system for diagnosing mental disorders.
Cross-cultural use of DSM-V. Diverse populations have diverse norms of
functioning. To foster cross-cultural applicability of DSM constructs, norms,
and guidelines, research should identify cultural variants in symptom definition
and manifestation, and anthropologic approaches to different cultural models of
mental illness.
Use of DSM-V in nonpsychiatric settings. Primary care providers now also
use the manual that was developed for use by psychiatrists. The study group
identified a need to define diagnostic criteria in ways that can be applied
outside the traditional psychiatric interview. Research is needed to develop
tools for this, including lab tests and diagnosis, and psychological testing and
diagnosis using standardized, computer-scored symptom-rating scales.
2. Neuroscience Research Agenda to Guide Development of a
Pathophysiologically Based Classification System
The DSM classification system should evolve from symptomatic to etiologic,
perhaps eventually becoming a multiaxial diagnostic system based on genotype,
neurobiologic indicators, behavioral phenotype, environmental modifiers, and
therapeutics. While this will probably not be reflected in DSM-V, neuroscience
research over the next 10-20 years will have a profound impact on the existing
diagnostic system.
3. Advances in Developmental Science
This agenda focuses on the deficiencies of the DSM-IV in relation to
diagnosing children. Because the individual is a product of nested environments,
from childhood to adulthood research should focus on discovering the links
between childhood and adult disorders, and include epidemiologic, neuroscience,
and genetic studies of children. Early childhood diagnosis at preschool age
should also be the focus of research.
4. Personality Disorders and Relational Disorders
This agenda focuses on what many clinicians believe are the most
unsatisfactory sections of the DSM-IV. It suggests creating a new dimensional
model of diagnosing personality disorders instead of the current categorical
classification system, which many feel fails to address the real-life complexity
of these disorders.
Furthermore, the agenda suggests consideration of possibly introducing
relational disorders with diagnostic criteria.
5. Mental Disorders and Disability
This agenda recommends separating the constructs of psychiatric symptoms and
functional impairment in order to enable research into the factors that explain
the varying degrees of disability that are observed across patients, given the
same level of symptom severity.
Removing the impairment criteria from psychiatric diagnosing also will encourage
early intervention for those at risk of future morbidity.
6. Culture and Psychiatric Diagnosis
DSM-IV criteria are meant to apply to all patients regardless of age, sex, or
culture. However, different cultural backgrounds are tied to different
expression of symptoms, and a generic set of criteria does not do justice to
cultural diversity.
Research requires a truly integrative approach that investigates the expression
of disorders, treatment response, and diagnostic criteria across the full
population spectrum.
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