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he clinical management of patients with affective disorders requires an estimate of their risk for suicide, but the
empirical basis for such estimates is tenuous. Of the three
applicable study designs, one uses vital statistics to describe the demographic characteristics of those in the
general population who commit suicide. This approach
can test only a few risk factors, and the results do not generalize to clinical samples because a substantial proportion of those who commit suicide do so without seeking
help for a psychiatric disorder. A second approach identifies diagnostically mixed patient groups, most often made
up of patients who have threatened or attempted suicide,
and compares those who subsequently complete suicide
to those who do not. The diagnostic heterogeneity characteristic of these groups seriously limits conclusions. Many
psychiatric disorders substantially increase the risk for
eventual suicide, and the factors that predispose an individual to suicide in one illness may be unimportant in another. For example, recent loss and lack of social support
are much more likely to precede suicide among alcoholics
than they are among individuals who have primary depressive disorder (1, 2).
A third design, the follow-up of cohorts with specific
disorders, is more likely to identify risk factors peculiar to
748
The dexamethasone suppression test (DST) offers a clinically practical means for detecting such hyperactivity and
may therefore serve to estimate suicide risk. In the procedure used in the majority of studies, 1 mg of dexamethasone is administered orally at 11:00 p.m., and plasma cortisol levels are determined from blood samples drawn the
following day at 8:00 a.m. and 4:00 p.m. A value from either
sample exceeding 5 g/dl indicates failure to suppress cortisol and is considered evidence for HPA-axis hyperactivity.
Some studies have, in fact, found that patients with abnormal DST results were more likely to have recently
made a suicide attempt (1114) or were more likely to
make future attempts (11, 15). Numerous authors have
failed to find such relationships, though (1620). There
have been far fewer efforts to test HPA-axis disturbance as
a predictor of completed suicide, but the results have been
much more consistent.
Carroll et al. (21) identified five suicides from among 250
melancholic patients who had undergone the DST and
noted that all had been nonsuppressors of cortisol,
whereas this was true of only one-half of the remaining
melancholic patients. Coryell and Schlesser (22) learned
of four suicides from among 205 inpatients with primary
unipolar depression who had undergone the DST while
hospitalized. All of these, but less then half (45.8%) of the
remaining patients, had been nonsuppressors. Finally,
Norman et al. (23) drew from a large sample of depressed
inpatients with DST results and matched the 13 who subsequently committed suicide both to other patients who
had attempted suicide before admission and to patients
who had not attempted suicide. Again, approximately
one-half (54%) of those who later committed suicide were
nonsuppressors at 4:00 p.m., compared with 28% of those
who had not attempted suicide and only 8% of those with
a previous attempt.
These studies of completed suicide did not test the relative value of other clinical predictors. This leaves the possibility that DST results served as a proxy for features such
as delusions, overall symptom severity, hopelessness, or a
history of mania. Moreover, the observation periods were
limited. Carroll et al. (21) did not describe the length of follow-up, and the other two studies averaged less than 3
years of observation (23, 24).
The earlier report from this center concerning serious
suicide attempts and DST results (15) described patients
who entered the National Institute of Mental Health Collaborative Study of the Affective DisordersClinical
Branch, a long-term follow-up of patients who met Research Diagnostic Criteria (RDC) (25) for major depressive
disorder, mania, or schizoaffective disorder. Although the
baseline assessment for the Collaborative Depression
Study included only demographic and clinical variables, a
large proportion of those who entered the study as inpatients at the University of Iowa center underwent a 1-mg
DST as part of their routine clinical assessment. Follow-up
has continued since the original report on suicide atAm J Psychiatry 158:5, May 2001
tempts, and a number of suicides have occurred in the interval. This study examines the relationship between DST
results and these suicides. Because all subjects underwent
structured phenomenological assessments at baseline,
the relative importance of clinical predictors can also be
examined.
Method
Subjects
Between 1978 and 1981, inclusive, patients who sought treatment as inpatients or outpatients for conditions that met RDC for
major depressive disorder, mania, or schizoaffective disorder
were recruited into the Collaborative Depression Study. Participants were age 18 or older, white, and English speaking. The current analysis was restricted to inpatients recruited at the University of Iowa center.
Procedures
All subjects provided written informed consent after being
given a complete description of the study. Diagnoses were based
on the full Schedule for Affective Disorders and Schizophrenia
(SADS) (26), which combined information from direct interviews
and medical records. Follow-up interviews, structured by the
Longitudinal Interval Follow-Up Evaluation (27), took place at 6month intervals for the next 5 years and annually thereafter. The
protocol did not determine or influence treatment, but ongoing
somatotherapies were methodically monitored and quantified, as
described elsewhere (28).
DSTs were not part of the Collaborative Depression Study protocol. The patients described in this report received them in one
of two ways. A formal research protocol, described elsewhere (29),
included the DST and overlapped with the period of intake for the
Collaborative Depression Study. Other patients received the DST
because it was ordered by the treating physician, as was often
done during the period of intake for the collaborative study. In either case, the patient took 1 mg of dexamethasone orally at 11:00
p.m. and provided blood samples the next day at 8:00 a.m. and/or
4:00 p.m. Cortisol levels were determined by a competitive protein-binding assay (30). A cortisol value greater then 5 g/dl in either postdexamethasone sample indicated nonsuppression of
cortisol. For the patients assessed in the protocol of Schlesser et
al. (29), the designation as suppressor or nonsuppressor, but not
the actual postdexamethasone cortisol value, remained available
for this analysis. The results are therefore limited to this categorical grouping.
In most cases, raters learned of suicides as they attempted to
reach the patient for the next follow-up interview. In all cases of
death, raters sought to obtain descriptions of the circumstances
from informants, from the death certificate, and from pertinent
medical records. They then made a judgment of whether the
death was due to suicide. Raters were not formally blinded to the
DST results, and the cortisol values from tests ordered outside of
the Schlesser et al. (29) protocol were recorded in the hospital
charts. These results were not, however, among the variables assessed by raters in the Collaborative Depression Study.
Statistical Analysis
Three potential predictors of suicidemale sex, living alone,
and the presence of a suicide attempt during the index illness episode before intakewere selected on the basis of the previously
described literature review. The presence of hopelessness in the
week preceding intake was also considered because it has been a
particularly robust predictor of suicide in diagnostically mixed
samples (31, 32). Hopelessness was considered present if the
749
Suppressors
(N=46)
Mean SD
10.9
36.4
5.4
14.5
9.8
35.3
5.4
14.0
Female gender
Clinical characteristics
Delusions
Current diagnosisa
Major depressive disorder
Bipolar II major depressive
disorder
Bipolar I major depressive
disorderb
Schizoaffective disorder,
depressed type
Alcoholism, past or present
Drug dependence,
past or present
Nonsuppressors
(N=32)
Mean
SD
33
71.7
19
59.4
10.9
21.9
37
80.4
22
68.8
15.2
6.3
4.3
25.0
1
13
2.2
28.3
1
9
3.1
28.1
4.3
3.1
Results
Of the 246 probands who entered the Collaborative Depression Study at the Iowa site, 83 underwent a DST within
1 week of admission. Excluding the 13 patients known to
have died during follow-up, 61 (87.1%) completed at least
2 years of follow-up, and 44 (62.9%) completed at least 15
years. Some follow-up information was available for 78
patients. These 78 differed from the remaining 151 patients followed at the Iowa site in three of the baseline variables listed in Table 1 and Table 2: those who received a
DST were less likely to have psychotic features (N=12
[15.4%] versus N=41 [27.2%]) (2=4.0, df=1, p<0.05), less
likely to have bipolar I disorder (N=10 [12.8%] versus N=56
[37.1%]) (2=13.6, df=1, p=0.0002), and more likely to have
made a serious suicide attempt (N=16 [20.5%] versus N=12
[7.9%]) (2=7.6, df=1, p<0.006). The underrepresentation
750
Discussion
These results support the view, based largely on postmortem evidence, that HPA-axis hyperactivity is a characteristic of patients with major depressive disorder who
commit suicide. Although this finding has obvious relevance to the possible pathogenesis of serious suicidal behavior in major depressive disorder, it also has practical
significance. None of the variables selected from the literature as likely risk factors were significantly predictive in this
cohort. Even the most intuitively compelling of thesea
serious suicide attempt earlier in the index episodewas
not significantly more frequent among the patients who
eventually committed suicide. In contrast, HPA-axis hyperactivity at baseline increased the odds of an eventual suicide 14-fold.
Am J Psychiatry 158:5, May 2001
Analysis
SE
26
52
3
5
11.5
9.6
17.4
10.8
9.7
4.6
39
39
4
4
10.3
10.3
14.1
11.7
7.1
5.6
16
62
0
8
0.0
12.9
0.0
15.4
0.0
5.2
22
56
1
7
4.5
12.5
4.6
15.9
4.4
5.8
35
42
4
3
11.4
7.1
11.9
8.9
5.6
4.9
16
62
3
5
18.8
8.1
21.4
10.1
11.0
4.5
59
9
10
6
1
1
10.2
11.1
10.0
11.5
12.5
25.0
4.4
11.7
21.6
12
66
0
8
0.0
12.1
0.0
15.0
0.0
5.1
32
46
7
1
21.9
2.2
26.8
2.9
9.3
2.9
Log-Rank 2
0.11
df
1
p
0.74
0.04
0.85
1.85
0.17
0.94
0.33
0.53
0.47
1.34
0.25
0.01
0.99
1.57
0.21
7.87
0.005
FIGURE 1. Cumulative Probabilities of Suicide Among Depressed Patients by Baseline Dexamethasone Suppression
Test Resultsa
30
Nonsuppressors (N=32)
Suppressors (N=46)
25
20
15
10
5
0
Intake
The fact that suppressors and nonsuppressors had cumulative probabilities of suicide that continued to diverge
across 15 years of follow-up indicates that the suicide risk
implied by a positive DST result is an enduring one. The
simplest view of this finding presumes that the propensity
to HPA-axis hyperactivity during a given major depressive
episode is a characteristic of an individuals lifetime illness. Although the few efforts to study the stability of DST
results over time have shown only modest test-retest reliability (24, 36), high correlations have been demonstrated
between postdexamethasone cortisol levels obtained during separate hospitalizations (24).
Risk Estimate
Predictor
Sex
Male
Female
Age at intake relative to median of 32 years
At or below
Above
Living alone
Yes
No
Feelings of hopelessness
Yes
No
Hamilton Depression Rating Scale score
relative to median score of 27
Below
At or above
Serious suicide attempt in index episode
Yes
No
Polarity
Nonbipolar
Bipolar II
Bipolar I
Delusional
Yes
No
DST result
Nonsuppression
Suppression
9 10 11 12 13 14 15
these disorders, even in the context of a superimposed depressive disorder, may not have the same predictive value
as they do in primary depressive disorder. This possibility
could not be assessed in the current study group, given its
limited size and composition. Thus, the use of DST results
to quantify risk for eventual suicide should, pending contrary evidence, be confined to patients for whom major depressive disorder has been the dominant illness over time.
751
The inclusion criteria used in the Collaborative Depression Study are also relevant to generalizability. No African
Americans were included, and the patients studied at the
Iowa center were otherwise more culturally homogenous
than patient samples in many other settings. More research will be necessary to determine whether these findings can be applied in diverse populations.
The DST is subject to a number of confounds that could
not be rigorously controlled in this data set. These include
a variety of medications and medical illnesses. Although
the DST was generally not administered in circumstances
thought to invalidate the results, the presence or absence
of these factors was not adequately documented in these
data. Such factors as plasma level variability (37, 38) and
the stress associated with hospital admission (39) have
also been thought to influence DST results, but it has not
been clearly shown that the control of these variables improves the diagnostic performance of the DST. In as much
as such variables are confounds, their influence would
tend to produce false negative results, and this was clearly
not the outcome here.
Evidence for an association between nonsuppression of
cortisol and suicide risk seems strong. That HPA-axis hyperactivity is a far more robust predictor than other clinical variables clearly needs independent replication. Given
the widespread use of the DST in the early 1980s, there are
many potential cohorts that could be followed to further
test this finding.
These findings also underscore the importance of the
HPA axis in the pathophysiology of suicide. Although the
serotonin system has been the major focus of biological
research on suicide (40, 41), there is now substantial evidence that HPA-axis abnormalities may underlie serotonin abnormalities in the genesis of suicidal behavior (42).
Further attention to the interplay between these systems
in suicidal behavior is clearly warranted. Whichever system eventually proves to be the more etiologically fundamental, it appears that, at present, HPA-axis hyperactivity
is the more clinically accessible, and therefore more clinically useful, of the two.
Received June 16, 2000; revisions received Oct. 12 and Nov. 20,
2000; accepted Nov. 28, 2000. From the Department of Psychiatry,
University of Iowa College of Medicine; and Dallas Neuropsychiatry
Associates, Dallas, Tex. Address reprint requests to Dr. Coryell, Department of Psychiatry, University of Iowa College of Medicine, 2-205
MEB, Iowa City, IA 52242-1000.
Supported in part by NIMH grants MH-51324 and MH-25416.
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