1. Elsevier Editorial System(tm) for Journal of Affective Disorders
Manuscript Draft
Manuscript Number: JAD-D-14-00969R4
Title: Risk Factors for Suicide in Bipolar I Disorder in Two Prospectively Studied Cohorts
Article Type: Research Paper
Keywords: Bipolar Disorder, Suicide, Risk Factors, Suicide Attempts
Corresponding Author: Prof. William Coryell,
Corresponding Author's Institution: Univeristy of Iowa College of Medicine
First Author: William Coryell
Order of Authors: William Coryell; Abby Kriener; Brandon Butcher; John Nurnberger; Francis
McMahon; Wade Berrettini; Jess Fiedorowicz
Abstract: Background - These analyses were undertaken to determine whether similar risk factors for
suicide emerged across two prospectively studied cohorts of individuals with bipolar I disorder.
Methods - The NIMH Collaborative Study of Depression (CDS) recruited 288 patients with bipolar I
disorder from 1978-1981 as they sought treatment. Subjects were followed semiannually and then
annually for up to 30 years. The Bipolar Genomics studies identified individuals through clinical
referrals and advertisement. Clinical follow-up did not occur but personal identifiers of 1748 were
matched with National Death Index (NDI) records. Kaplan-Meier survival analyses tested ten potential
risk factors.ResultsThe CDS and Genomic follow-ups encompassed 12,667 and 4,529 person-years,
respectively. Suicides/100 person-years were 0.26 and 0.055. The demographic or clinical variables
that predicted suicide differed considerably in the two cohorts. The odds ratio for suicide for those
with any history of suicide attempt was 2.3 and 2.8, respectively, and was the third highest odds ratio
of the tested risk factors in both studies. Limitations - 1. In one of the two cohorts, matching to the NDI
was the only means available to ascertain death and cause of death. 2. In one of the two cohorts,
depressive symptom ratings were, in most cases, applied to those of a past major depressive episode.
Conclusions - Differences in the sources of participants in studies of suicide risk may result in marked
differences across studies in both rates of suicide and in risk factors. A history of suicide attempt is a
relatively robust risk factor across samples.

2. Risk Factors for Suicide in Bipolar I Disorder in Two Prospectively Studied Cohorts
Running Title: Risks for Suicide in Bipolar I Disorder
William Coryell1
: Corresponding Author
Abby Kriener1
Brandon Butcher1
John Nurnberger2
Francis McMahon3
Wade Berrettini4
Jess Fiedorowicz1
1
University of Iowa Carver College of Medicine, Department of Psychiatry
2
Indiana University, Department of Psychiatry
3
Johns Hopkins University, Department of Psychiatry
4
University of Pennsylvania, Department of Psychiatry
Corresponding Author: William Coryell
University of Iowa, Carver College of Medicine
Department of Psychiatry Research
500 Newton Road, Suite 2-205 MEB
Iowa City, IA 52242-1900
Phone: 319-353-4434 Fax: 319-353-3003
Email: william-coryell@uiowa.edu
*Cover Letter

3. Acknowledgements
The authors have no conflicts of interest to report.
This study was funded by NIMH grants R01MH025416-33 and R01MH059548-09, and
American Foundation for Suicide Prevention #0006-2008B.
Acknowledgement

4. Conflict of interest
All authors declare no conflict of interest that could influence their work.
*Conflict of Interest

5. Contributors
W.C. conceived of the analysis, interpreted the data and wrote the manuscript. B.D.B. assisted
in data analysis and R.Y. performed laboratory assessments. C.C. designed the study from
which these results were derived and oversaw recruitment and all data collection. R.Y., B.D.B.,
T.L.B., L.N.D., J.S., and C.C. gave comments for the manuscript.
*Contributors
Click here to download Contributors: Contributors.docx

6. Role of funding source
This study was supported by a grant from the National Institute of Mental Health. This agency
had no vote in study design, acquisition or interpretation of data, or writing the report.
*Role of the Funding Source

7. Highlights of Risk Factors for Suicide in Bipolar I Disorder in Two Prospectively Studied
Cohorts
 Risk factors for suicide and bipolar I disorder can vary markedly depending on the
sources of subjects and the methods of follow-up.
 The most consistently observed risk factor for suicide in bipolar I disorder is a history of
suicide attempt.
 In neither study was a suicide attempt with high lethality or intent a stronger predictor of
suicide than a history of any attempt.
*Highlights (for review)
Click here to download Highlights (for review): Highlights.docx Click here to view linked References

8. For the resubmission the following items were addressed:
1. Citations and references changed to follow journal style.
2. Changed margins in Abstract from 1”x1.25” to 1”x1”
3. Changed spacing from Double-spaced to single spaced on all documents
4. Made font type and size consistent in all documents, including tables: (Arial, 11)
5. Aligned References section
6. References style changed to JAD Format
I have added a paragraph at the beginning of the Discussion section to summarize what
is new and different in this submission.--W Coryell
*Response to Reviewers

9. ABSTRACT
Background
These analyses were undertaken to determine whether similar risk factors for suicide
emerged across two prospectively studied cohorts of individuals with bipolar I disorder.
Methods
The NIMH Collaborative Study of Depression (CDS) recruited 288 patients with bipolar I
disorder from 1978-1981 as they sought treatment. Subjects were followed semiannually
and then annually for up to 30 years. The Bipolar Genomics studies identified individuals
through clinical referrals and advertisement. Clinical follow-up did not occur but personal
identifiers of 1748 were matched with National Death Index (NDI) records. Kaplan-Meier
survival analyses tested ten potential risk factors.
Results
The CDS and Genomic follow-ups encompassed 12,667 and 4,529 person-years,
respectively. Suicides/100 person-years were 0.26 and 0.055. The demographic or
clinical variables that predicted suicide differed considerably in the two cohorts. The
odds ratio for suicide for those with any history of suicide attempt was 2.3 and 2.8,
respectively, and was the third highest odds ratio of the tested risk factors in both
studies.
Limitations
1. In one of the two cohorts, matching to the NDI was the only means available to
ascertain death and cause of death.
2. In one of the two cohorts, depressive symptom ratings were, in most cases, applied to
those of a past major depressive episode.
Conclusions
Differences in the sources of participants in studies of suicide risk may result in marked
differences across studies in both rates of suicide and in risk factors. A history of suicide
attempt is a relatively robust risk factor across samples.
Key Words: Bipolar Disorder, Suicide, Risk Factors, Suicide Attempts
*Manuscript
Click here to view linked References

10. 1
Introduction
The bipolar disorders carry with them markedly elevated risks for suicide. A review of 27 studies
showed a median suicide rate of 0.47 per 100 person years (Tondo et al., 2003) A more recent
review added seven studies that had a median rate of 0.17 per 100 person years (Pompili et al.,
2013). The 13 reports that provided standardized mortality ratios (SMR), yielded a median value
of 22.4 (Tondo, et al. 2003). Suicide thus may be 22-fold more likely among individuals with
bipolar disorder than it is among age- and sex-matched individuals from the general population.
However, the large majority of the listed studies began follow-up when the individuals with
bipolar disorder were in the midst of an acute episode. Because the periods immediately
following episodes, particularly those that require hospitalization, are ones of considerably
higher risk, studies without lengthy follow-up periods are likely to substantially overestimate
lifetime likelihoods of suicide. Moreover, regardless of follow-up length, individuals with
psychiatric disorders who, at any point, require hospitalization are at higher risks for suicide than
those who do not (Brown et al., 2000).
Individuals with major depressive disorder are, of course, also at increased risk for suicide but
the results of some studies have indicated that rates are higher for those with bipolar disorder
(Tondo et al., 2007). In caring for patients with any mood disorder, clinicians are frequently
required to consider near- and far-term risks for suicide. These estimations bear on such
decisions as the timing of hospitalizations and discharges, the degree of home supervision to
recommend, and the selection of treatments such as electroconvulsive therapy. Prospective
studies, those that uniformly inquire at the beginning of the follow-up period into the presence or
absence of a specified list of clinical and demographic features, offer a distinct advantage in the
search for reproducible risk factors. In contrast, those that rely on reviews of medical records
are limited by variance in whether a given factor was assessed and how it was defined. Yet,
prospective studies of suicide risk factors in bipolar disorder per se are rare. The most recent
systematic review of risk factors in bipolar illness (Hawton et al., 2005) listed only two published
reports that tested an array of possible risk factors assessed through structured interviews
administered at baseline (Angst et al., 2002; Coryell et al., 2003). At least four prospective
studies have appeared since that review but two followed the patients for only two years
(Dennehy et al., 2011; Marangell et al., 2006), while the other two follow-ups lasted only four
(Khalsa et al., 2008) and five (Gonzalez-Pinto et al., 2006) years.
Another weakness lies in the differing methods for calculating mortality outcomes. The CDS
followed up on each prospectively observed death with interviews of family members and with
the acquisition of death certificates. Those lost to followup before 1990, after a mean period of
10 years, were matched against NDI records. This was not repeated subsequently, though, and
mortality outcomes were undetermined for those lost to followup after 1990, or those lost to
followup before this date that died later. On the other hand, the ascertainment of deaths in the
genomic cohort, while up to date, was entirely dependent on NDI matching. Fortunately, the
accuracy of the NDI appears to be high, with a sensitivity to death ranging from 87.0% to 97.9%
and the accuracy of cause of death being 96.0% (Cowper et al., 2002).
With these issues in mind we undertook an analysis of two large and prospectively followed
cohorts of bipolar I disorder. One derived from subjects recruited to participate in any of the
several waves of the Bipolar Genomic Consortium (Dick et al., 2003). The other focused on
those probands from the NIMH Collaborative Depression Study (CDS) (Coryell, et al. 2003) who
met Research Diagnostic Criteria (RDC) (Spitzer et al., 1978) for bipolar I disorder or
schizoaffective mania, mainly affective type, at intake or later during a long-term, high-intensity
follow-up. (Fiedorowicz et al. 2011)

11. 2
Aims of the Study
To determine risk factors for suicide in bipolar I disorder that are robust across cohorts.

12. 3
Methods
Between 1989 and 2009, the academic centers participating in the Bipolar Genomic Consortium
used advertisement and clinical referral to recruit individuals who met DSM-III-R or DSM-IV
criteria for a lifetime diagnosis of bipolar I disorder. Trained raters administered the Diagnostic
Interview for Genetic Studies (DIGS) (Nurnberger et al., 1994) and study psychiatrists based a
best estimate diagnosis on the results. Those centers that had used an informed consent
narrative that permitted the use of personal identifying information outside of that center
(University of Iowa, University of Pennsylvania, Indiana University and Johns Hopkins
University) provided the names, addresses, marital status and birthdates to the first author (WC)
who then collated the information for screening by the National Death Index (NDI).
The NIMH CDS recruited patients who met RDC for MDD, bipolar disorder or schizoaffective
disorder as they sought treatment at any of five tertiary care academic centers: Harvard
University, Columbia University, Washington University, Rush Presbyterian School of Medicine
and the University of Iowa. Diagnostic determinations were based on information from the
Schedule for Affective Disorders and Schizophrenia (SADS) (Endicott and Spitzer 1978). This
information, in turn, was derived from direct interview by professional raters, from medical
records and from family members. This analysis is limited to those whose index episode
included a major depressive phase.
Subjects were reassessed at six-month intervals for the first five years and then annually for up
to 30 years. When follow-up efforts revealed that a patient had died, raters interviewed
immediate family members whenever possible to learn the circumstances surrounding the death
and its causes. In 1990, the CDS submitted personal identifying information to the NDI for all
subjects who had been lost to follow-up. The additional deaths and their causes were then
added to the data.
In both the Genomic study and the CDS study all subjects provided informed consent before
participation. Tested risk factors were selected on the basis of the literature concerning suicide
in depressive disorders generally. The analysis excluded most symptom-based measures
because participants in the Genomics studies reported the symptoms that had been present
during their worst episodes and these episodes might have occurred years previously. It did
include hopelessness, though, because this was the only symptom determined to be a risk
factor for suicide in the previously noted systematic review(Hawton, et al. 2005).
Only variables assessed at the baseline interview were tested as risk factors. Marital status was
treated as a dichotomy of divorced or separated versus all other marital states at the time of
study entry. The DSM diagnoses of drug abuse and dependence were lumped but only alcohol
dependence was considered in the Genomic cohort because the RDC did not separate alcohol
abuse and dependence. In both cohorts a positive response to the question, “Have you ever
attempted to kill yourself?” constituted a history of suicide attempt. Both the DIGS and SADS
rate the lethality of the most serious suicide attempt on a six-point scale. For this analysis, a
high lethality attempt required a rating of five or six. Ratings for the intent underlying the most
serious suicide attempt were made on a three-point scale in the DIGS and a six-point scale in
the RDC. Here, a rating of three or more in either instrument indicated a high-intent attempt. In
both cohorts, the presence or absence of the delusional subtype of a major depressive episode
referred to the most severe episode.
Statistical analyses used SPSS, version 21. Simple group comparisons of continuous variables
used student’s t-tests and those of categories used chi-square tests. The analyses of baseline
risk factors for eventual suicide considered each separately and used Kaplan-Meier estimators

13. 4
for categorical independent variables and Cox-regression for continuous independent variables.
All p-values were two-tailed for continuous independent variables. The limited number of
suicides precluded the assessment of interactions between risk variable.
Results
The two cohorts differed considerably by size, by dates of recruitment and by follow-up length,
though not by the demographic variables of age, sex and marital status (Table 1). The CDS
sample experienced 64 deaths of which 12 (18.8 %) were judged to be suicides (Table 2). In the
Genomic cohort, 66 died and of those 7 (10.6 %) died by suicide, a proportion not significantly
different from that of the CDS sample (χ2
=1.7, df = 1, p = 0.19). However, the numbers of
suicides per 100 person-years were 0.26 and 0.055, respectively, a nearly five-fold difference
(χ2
= 16.8, df = 1, p = <0.0001). The two hazard curves illustrate the difference in risks for
suicide over time (Figure 1).
Of the risk factors tested in the Genomic cohort, the proportions divorced or separated were
significantly higher for those who later died by suicide than for the remaining subjects (Table 3).
In the CDS cohort, those who committed suicide were significantly more likely to be male, to
have expressed prominent feelings of hopelessness, or to have made any suicide attempt
(Table 4). Though the strongest risk factor in the CDS was being male, this was somewhat
protective in the Genomic study cohort.
The determination of cause of death in the Genomic cohort depended entirely on NDI records
and cause of death was therefore not as certain as in the CDS cohort. Nine subjects were listed
as having died from unnatural causes other than suicide and the addition of these deaths as
possible suicides did not substantially alter results. Being divorced or separated remained the
only significant risk factor (OR=3.1, CI= 1.2, 8.4, p= 0.01) and a trend existed for the presence
of alcoholism (OR= 2.5, CI= 0.9, 6.5, p= 0.06). We tested whether this group was largely
contaminated by actual suicide by considering the same set of risk factors. None reached
significance as predictors of non-suicide unnatural death.
Odds ratios for those with or without a history of suicide attempts were similar in the two cohorts
and, when risk factors were sorted by odds ratios, a history of suicide attempt ranked third in
both. Also in both cohorts, a history of a high lethality attempt had an OR of 1.4, less than the
ORs for any suicide attempt.

14. 5
Discussion
When considered in light of the prevalence of a morbidity associated with bipolar disorder the
number prospective follow-ups of completed suicide are surprisingly few (Angst et al., 2002;
Coryell et al., 2003; Dennehy et al., 2011; Gonzalez-Pinto et al., 2006; Khalsa et al., 2008;
Marangell et al., 2006;). Only two of these have exceeded five years in duration (Angst et al.,
2002; Coryell et al., 2003). Moreover, no report has directly compared findings in two separate
cohorts. These results are therefore unique in revealing risk factors that are robust in their
consistency across differing cohorts and methodologies.
Results showed marked differences in risks for suicide and in the features that appeared most
important as risk factors. The contrasting risks for eventual suicide highlight the importance of
sampling. For 90.6% of the CDS subjects with bipolar I disorder, follow-up began shortly after
an admission and many of these had occurred because of suicidal threats or behaviors. In
contrast, 14.2% of the Genomic sample had never been admitted and, for the 85.8% that had,
the admission was in the past in 97.2% of the cases. Notably, though, the rate of suicide per
100,000 person-years (55) in the Genomic studies, though much lower than that for the CDS
subjects, was still five-fold higher than the rate of 10 to 12 usually cited for the overall US
population.
Sampling differences between the two follow-ups was also reflected in the observation that the
early slope of the hazard curve for suicide was much steeper in the first five years than it was
later in the CDS follow-up (Figure 1). The hazard slope of the Genomic sample was relatively
unchanging throughout. The differences between studies in survival curves for the first five
years is likely to reflect the fact that the CDS sample was comprised largely of inpatients at the
beginning of follow-up and that risks for suicide following such periods are particularly high.
Those risk factors for suicide that reached significance did not overlap in the two samples. For
some features this may have resulted from differences in the accuracy with which they were
assessed. Feelings of hopelessness, in particular, were much more easily quantified in the CDS
sample because it was being assessed in the current episode. However, demographic factors
such as being divorced or male sex are not so liable to differences in recency, but these
variables also performed quite differently in the two samples.
Despite marked contrasts in significant risk factors, a history of suicide attempts was in the top
three factors when they were ranked by odds ratios. This gives emphasis to the frequent
observation that a history of attempts is the most consistently identified risk factor in studies of
suicide both across samples and across diagnoses (Coryell and Young 2005).
The risk factor findings identified in the CDS sample are remarkably well supported by the
results of a meta-analysis of 13 studies of suicide in bipolar disorder samples (Hawton, et al.
2005). As in the CDS sample, the 3 factors shown to be predictive were male sex,
hopelessness, and history of suicide attempts.
Strengths underlying the data presented here include the fact that both follow-ups were
prospective in design and that both began observation with the use of thorough structured
interviews to assess symptoms and demographics. Both were lengthy relative to many of the
follow-up studies of suicide in the literature. Very few prospective studies of suicide risk factors
have dealt with the issue of suicide among subjects lost to followup and this is likely to have
affected results. The use of NDI matching for both samples can be viewed as strength.
Limitations

15. 6
Structured interviews, and therefore assessments of symptom-based suicide risk factors,
differed in the two studies. Consequently, it cannot be determined whether differences in the
strengths of particular risk factors resulted from differences inherent in the two cohorts or from
differences in how the factors were assessed. The contrasting methodologies probably also
accounted for some of the differences in findings. Assessments in the CDS were done when
symptoms were active but were assessed retrospectively in the genomics study. Appraisals of
such factors as hopelessness, suicidal thoughts, and psychotic features were probably more
accurate in the CDS and this may account for the higher odds ratios for suicide associated with
these items in the CDS data.
Another weakness lies in the differing methods for calculating mortality outcomes. The CDS
followed up on each prospectively observed death with interviews of family members and with
the acquisition of death certificates. Those lost to followup before 1990, after a mean period of
10 years, were matched against NDI records. This was not repeated subsequently, though, and
mortality outcomes were undetermined for those lost to followup after 1990, or those lost to
followup before this date that died later. On the other hand, the ascertainment of deaths in the
genomic cohort, while up to date, was entirely dependent on NDI matching. Fortunately, the
accuracy of the NDI appears to be high, with a sensitivity to death ranging from 87.0% to 97.9%
and the accuracy of cause of death being 96.0% (Cowper et al., 2002).
Information from death certificates may underestimate suicide rates as well. In a followup with
50,546 Swedish conscripts, a review of death certificates together with forensic, pathological,
and toxicological data yielded 208 suicides of which 13 (6.2%) had died by other causes
according to death certificates (Allebeck et al., 1991).
Conclusions
Despite these limitations, this comparison of suicide outcomes in two differing cohorts serves to
underscore the tenuousness of conclusions that can be drawn from a single study. At the same
time, the results here reinforce the importance of a previous suicide attempt as a risk factor that
is most likely to hold across samples.

16. 7
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17. 8
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18. Table 1. Follow-up of Two Bipolar I Samples
Bipolar Genomics CDS
Source of Subjects Individuals
Recruited by
Referral and
Advertisement
Patients
Currently
Seeking
Treatment (91%
Inpatient)
n 1748 288
Date Range of recruitment 1989-2009 1978-1981
Follow-up length
mean (SD) years 7.3 (4.5) 15.9 (8.6)
total person-years 12,667 4529
number (%) female 1154 (66.0) 154 (53.5)
mean (SD) age at intake 42.2 (13.0) 36.7 (13.1)
Marital status, number (%)
single 563 (32.2) 117 (40.6)
separated/divorced 520 (29.7) 65 (22.6)
married 581 (34.9) 92 (31.9)
other 85 (4.9) 14 (4.9)
Alcoholism 652 (36.8) 80 (2738)
Any suicide attempt 802 (47.3) 95 (33.0)
Drug abuse 241 (16.6) 22 (7.6)
Any high lethality attempt 143 (18.1) 26 (9.0)
Any high intent attempt 410 (52.4) 25 (8.7)
Hopelessness 1397 (87) 182 (63)
Delusional depression 287 (22.3) 146 (50.7)
Suicidal thoughts in worst episode 1075 (67.5) 114 (39.6)
Table 1

19. Table 2. Suicide Rates
Bipolar
Genomics
CDS
Number of suicides 7 12
Number of deaths 66 64
Suicides/deaths x 100 10.6 18.7
Suicides/100-person-yrs .055* 0.26
*Rate in US in 2009 = .012
Table 2

20. Table 3. Possible Risk Factors for Suicide: Genomics Study
Odds Ratio CI p
Divorced or separated 13.3 1.6,
111.1
0.002
Alcoholism 4.2 0.8, 21.9 0.06
Any suicide attempt 2.8 0.5, 14.4 0.20
Drug abuse 2.0 0.4, 10.5 0.39
Any high lethality attempt 1.1 0.1, 10.3 0.91
Any high intent attempt 0.9 0.1, 6.5 0.93
Hopelessness 0.9 0.1, 7.2 0.89
Male sex 0.8 0.2, 4.1 0.76
Delusional depression 0.3 0.0, 4.7 0.19
Suicidal thoughts in worst
episode
0.6 0.1, 2.8 0.54
Table 3

21. Table 4. Possible Risk Factors for Suicide: CDS
Odds Ratio CI p
Male sex 6.1 1.3, 28.5 0.02
Hopelessness 4.1 1.2, 14.1 0.02
Any suicide attempt 2.3 1.2, 4.4 0.01
Suicidal thoughts 2.2 0.7, 7.1 0.18
Divorced separated 1.8 0.5, 6.1 0.36
Delusional depression 1.8 0.5, 6.0 0.10
Any high intent attempt 1.6 0.2, 10.3 0.33
Any high lethality attempt 1.4 0.2, 9.4 0.71
Drug abuse 0.45 0.02, 7.89 0.98
Alcoholism 0.5 0.1, 2.4 0.20
Table 4

22. Figure 1. Suicide Risk in Bipolar I Disorder: Bipolar Genomics vs. CDS
Figure 1