Journal of Affective Disorders 87 (2005) 11 16

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Research report

Gender, suicidality and bipolar mixed states in adolescents

Steven C. Dilsavera,b,T, Franco Benazzic,d, Zoltan Rihmere,
Kareen K. Akiskalf,g, Hagop S. Akiskalf,g,h
a
Community Mental Health Clinic, Rio Grande City, TX, USA
Merced Department of Mental Health, P.O. Box 839, Merced, CA, USA
c
E Hecker Outpatient Center, Ravenna, Italy
d
Department of Psychiatry, National Health Service, Forli, Italy
e
National Institute for Psychiatry and Neurology, Budapest, Hungary
f
National Union of Depressive and Manic-Depressive Associations, Rennes, France
g
International Mood Disorders Program, La Jolla, CA, USA
h
San Diego Veterans Administration Medical Center, USA
b

Received 5 December 2004; accepted 10 February 2005

Available online 6 June 2005

Abstract
Background: The purpose of this study was to determine the relationship between mixed states and suicidality among
adolescent outpatients presenting with a DSM-IV defined major depressive episode (MDE).
Methods: Two-hundred and forty-seven adolescents meeting the criteria for MDE were screened for the presence of concurrent,
intra-MDE hypomania/mania (i.e., mixed states). All patients were asked whether they had current suicidal ideation or had
recently attempted any self-destructive physical act associated with the thought of dying (i.e., a suicide attempt). The data were
subjected to analysis using univariate logistic regression.
Results: One hundred of the 247 (40.5%) adolescents were bipolar type I or type II. Of these, 82% were in mixed states. Of the
patients with suicidal ideation, 62.8% were girls, and of those with histories of a suicide attempt, 69.4% were girls. Girls had
more than twice the risk of having suicidal ideation (OR = 2.2, p = 0.004) and nearly 3 times the risk of having histories of a
suicide attempt than boys (OR = 2.87, p b 0.0001). Being in a mixed state per se did not predict either suicidal ideation or a
suicide attempt among all of the 247 patients. However, mixed states apparently independently contributed to the risk of (nonfatal) suicidal behavior among girls only. Of the mixed states, girls had nearly 4 times the risk of having made a suicide attempt
compared with those without mixed states (OR = 3.9, p = 0.003). Age, presence of psychotic features and family history of mood
disorder had little or no bearing on suicidality.
Limitations: Correlational chart review study, no data collection on Axis I and Axis II comorbidity and adverse life-events.
Conclusions: This report of greater suicidality in adolescent girls in a mixed state parallels the well-known adult literature of
high frequency of mixed states in women. The findings are of relevance to the controversy of antidepressants and suicidality in

T Corresponding author. Merced Department of Mental Health, P.O. Box 839, Merced, California, USA. Tel.: +1 209 722 4953; fax: +1 209
381 7511.
E-mail address: StevenDilsaver@aol.com (S.C. Dilsaver).
0165-0327/$ - see front matter D 2005 Published by Elsevier B.V.
doi:10.1016/j.jad.2005.02.003

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S.C. Dilsaver et al. / Journal of Affective Disorders 87 (2005) 1116

juvenile depressives in that they identify a vulnerable group. In line with earlier suggestions by the senior author [Akiskal, H.S.,
1995. Developmental pathways to bipolarity: are juvenile-onset depressions pre-bipolar? J. Am. Acad. Child Adolesc. Psych.
34, 754763], our data highlight the public health importance of the wider recognition of bipolar mixed states in juvenile
patients masquerading as unipolar depression. Finally, it appears to us that it is the failure of our formal nosology on mixed
statesrather than the antidepressants per sewhich is the root problem in this controversy.
D 2005 Published by Elsevier B.V.
Keywords: Adolescents; Affective disorders; Bipolar disorder; Depression; Mania; Mixed states; Suicidality; Suicide

1. Introduction
There is now growing literature on early-onset
adolescent mania and its treatment (Carlson and
Strober, 1978; Akiskal et al., 1985; Geller et al.,
2002; Kafantaris et al., 2004). This literature indicates
that mixed states are not an uncommon phenomenon
among manic adolescent patients. Recently, we
reported that of adolescents with major depressive
episode (MDE), 40% were bipolar, among which
most were in a mixed state (Dilsaver et al., in press).
In adults, mixed states (i.e., dysphoric or mixed
mania) are more often than not female, and suicidality
and hopelessness are prevalent clinical features
(Akiskal et al., 1998). Recent reports suggest that
compared to pure depressive episode, depressive and
mixed state/agitated depression also increases the risk
of suicidal behavior (Benazzi, 2003a; Maj et al., 2003;
Akiskal et al., 2005). We therefore sought to examine
the relationship of gender, mixed state and suicidality
among adolescent patients with major depressive
episode (MDE).

2. Methods
The patients are all adolescents between the ages of
12 and 17 years, who presented in a public sector
outpatient clinic for the destitute. The threshold for
referral is moderate to severe impairment in multiple
domains. The age of 12 years includes, by convention,
adolescence in the psychiatric pediatric literature.
The racial composition of the community was 99%
Hispanic and 1% other. This is significant. Hispanic
families characteristically dedicate all of the resources
at their disposal to the avoidance of hospitalization.
Consequently, many patients in this database would
have required hospitalization if of another culture.

However, the mobilization of nuclear and extended

family almost always renders this avoidable. Further,
hospitalization was not an available option for our
patients except under the most extreme of circumstances. This is in part due to the fact that hospital
resources for adolescents could require transport to a
state facility four hours removed from home. Allowing such an event would be foreign to the traditional
Hispanic family.
All patients were free from psychotropic medication at the time of the initial clinical assessment. All of
the patients were evaluated in and through the process
of delivering ordinary, routine clinical services by the
first author rather than carrying out the dictates of a
research protocol. Accordingly, informed consent was
not required.
All interviews were also conducted by the first
author (SCD). Each patient received a structured
screen for the presence of MDE and concurrent
hypomania/mania using the apposite modules from
the Structured Clinical Interview for DSM-IV-Patient
Version (SCID, First et al., 1997). A patient with
delusions, hallucinations or formal thought disorder
was classified as having psychotic features. Family
history of major depressive disorder (MDD) or of
either bipolar I or II disorder (BPD) among firstdegree relatives was obtained by live interview or
interview by proxy using the apposite modules in the
SCID. Rendering a diagnosis by proxy demanded that
the relative in question unequivocally met the full
criteria for MDD or BPD. Data on other Axis I and II
disorders were not collected.
Patients were placed in one of four categories. The
first included all those meeting DSM-IV criteria for
bipolar I disorder, depressed. The second included
patients meeting the criteria for bipolar II, depressed.
The third included all patients categorized as being
mixed. The fourth included patients meeting the

S.C. Dilsaver et al. / Journal of Affective Disorders 87 (2005) 1116

criteria for MDE but who never had an episode of

hypomania or mania.
DSM-IV (American Psychiatric Association,
1994) does not have a distinct category for a
syndrome defined by the presence of MDE and
hypomania. In DSM-IV, a mixed state is operationally defined as a syndrome in which a patient meets
the full criteria for MDE (except for the duration
criterion of two weeks) and mania. In the present
database, all patients meeting the full criteria for
MDE (including the duration criterion) and either
hypomania or mania for at least a continuous week
were categorized as simply being in a mixed state.
This is in keeping with a warning in the Introduction
to the DSM-IV that the manual is not to serve as a
substitute for clinical judgment. Therefore, effort was
not made to determine whether those patients
categorized as being bmixedQ were in a hypomanic
or manic mixed state. Drawing such a distinction
would not have had treatment implications, and efforts
to do so would have constituted an academic exercise
inappropriate to the setting in which this work was
conducted. In particular, the fact that adolescents
parents avoided hospitalization somewhat confounded
the BP-I versus BP-II distinction, which was originally
made on the basis of need for hospitalization (Dunner
et al., 1976).
The diagnostic approach to mixed state employed
in this study is somewhat different from that of the
two of the present authors (Benazzi, 2003a,b; Akiskal
and Benazzi, 2003) and that of Sato et al. (2003):
Their position, sensitive to the void in the DSM-IV,
have advanced the concept of the bdepressive mixed
state.Q A depressive mixed state is the mixture of a
MDE and hypomanic symptoms that does not
necessarily meet the full criteria for hypomania (i.e.,
MDE with two or three intra-episodic features of
hypomania). These symptoms, by definition do not
include elevated mood and increased self-esteem.
However, in the present study, all of the patients
categorized as being mixed included those meeting
the DSM-IV criteria for mixed state or the full-criteria
for hypomania during MDE.
A suicide attempt was operationally defined as any
physically self-destructive act of a patient associated
with the idea of terminating ones life. This act did not
need to be serious from a medical perspective. The
thought of the act being associated with the possibility

13

of death sufficed to categorize the act as a suicide

attempt.
2.1. Statistics
All measures of variance in sample means refer to
the standard deviation of the mean (S.D.). Relative
risk (odds unadjusted for by gender, age and other
possible confounding variables) is presented for
descriptive purposes only. Univariate logistic regression was used to determine whether the relationship
between gender and suicidality was significant. It was
also used to determine whether being in a mixed state,
as opposed to being non-mixed, and suicidality were
related. Statistical analyses were performed using
STATA 8.2 statistical software [Stata Corporation,
College Station, Texas, 2003]. Since the data were
obtained through chart review without a priori
hypotheses, we conservatively set the level of
significance for p V 0.05, two-tailed.

3. Results
Two-hundred and forty-seven (n = 247) adolescents
met the formal criteria for MDE. The demographic
and diagnostic features of the sample are summarized
in Table 1.
One hundred (40.5%) met criteria for bipolar
disorder. Eighty-two percent of the bipolar patients,
46 boys and 36 girls, were in a mixed state. Thus,
Table 1
Variables
% of sample which are girls
Mean age of all patients (S.D.)
% who were bipolar I depressed
% who were bipolar II depressed
% meeting the criteria for MDD (bunipolar disorderQ)
% with an index episode of mixed state
% of all patients with psychotic features
% of all patients with current suicidal ideation
% of all patients with recent histories of physically
self-destructive acts
% of all subjects with a family history of bipolar
disorder
% of all subjects with a family history of major
depressive disorder
% of all subjects with a family history of bipolar
disorder and/or major depressive disorder

56.2
14.7 (1.5)
4.4
2.8
59.5
33.1
40.0
66.3
47.7
19.0
23.0
42.0

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S.C. Dilsaver et al. / Journal of Affective Disorders 87 (2005) 1116

boys and girls constituted 56.1% and 43.9% of the

mixed patients, respectively. As reported elsewhere
(Benazzi, 2003a,b), males were more likely to be in a
mixed state than females.
Fifty-five of the mixed patients (67.1%) currently
had suicidal ideation. This included 31 (86.1%) girls
and 24 (52.2%) boys. Thus, the risk of a mixed girl
having suicidal ideation, relative to a boy, was 1.65.
Forty-two mixed patients (51.2%) had recent histories
of suicide attempts. This included 29 girls (80.6%)
and 13 (28.3%) boys. Thus, the relative risk of a girl
having a suicide attempt was 2.8.
Ninety-seven (65.9%) of the 147 non-mixed
patients had suicidal ideation. This included 69
(71.1%) girls and 28 (28.8%) boys. Thus, the relative
risk of a non-mixed girl having suicidal ideation to
that of a non-mixed boy was 2.5. Sixty-eight (46.3%)
of the 147 non-mixed patients had histories of suicide
attempts. This included 50 (51.5%) girls and 18
(26.4%) boys. Thus, the relative risk of a non-mixed
girl having a suicide attempt to a non-mixed boy was
2.7.
Twenty-seven of the 46 mixed boys (58.7%) and
18 of the 36 mixed girls (50.0%), had psychotic
features. Forty of the mixed patients (48.8%) had
family histories of MDD and/or BPD. Eighteen of the
36 girls (50.0%) had a family history of MDD and/or
BPD as did 22 of the 46 (47.8%) mixed boys. Twentysix of the 82 mixed patients (31.7%) had a family
history of BPD. These included 13 (36.1%) girls and
13 (50.0%) boys.
Sixteen of the 50 non-mixed boys (32.0%) and 34
of the 97 non-mixed girls (35.0%), had psychotic
features. Fifty-five of the non-mixed patients (37.3%)
had family histories of MDD and/or BPD. Thirtythree of the 97 non-mixed girls (34.0%) had a family
history of MDD and/or BPD as did 22 of the 50
(44.0%) of the non-mixed boys. Nineteen of the 147
non-mixed patients (12.9%) had a family history of
BPD. These included 10 (10.3%) girls and 9 (18.0.%)
boys.
Of all the patients with suicidal ideation, 62.8%
were girls. Univariate logistic regression of females
versus suicidal ideation disclosed an odds ratio of 2.2
(95% CI = 1.23.7, p = 0.004). This suggests that girls
had more than twice the risk of having suicidal
ideation than did boys. Of the patients with histories
of suicide attempts 69.4% were girls. The univariate

logistic regression model disclosed an odds ratio of

2.87 (95% CI = 1.74.8, p b 0.0001). This suggests
that girls had about a three fold greater risk of a
suicide attempt than did boys.
Univariate logistic regression of suicidal ideation
versus mixed state revealed an odds ratio of 1.0 (95%
CI = 0.51.8, p = 0.87). Univariate logistic regression
of suicide attempts versus mixed state disclosed an
odds ratio of 1.2 (95% CI = 0.72.0, p = 0.45). Thus,
merely being in a mixed state was not a risk factor for
either having suicidal ideation or a history of
attempted suicide.
Univariate logistic regression of suicidal ideation
versus the mixed state within the female sample
disclosed an odds ratio of 2.6. This suggests that the
mixed girls had 2.6 times the risk of non-mixed girls
of having suicidal ideation. However, due to sample
size, this finding missed significance (95% CI = 0.94
7.5, p = 0.063). Univariate logistic regression of
suicide attempts versus mixed state within the female
subsample disclosed an odds ratio of 3.9. Thus, girls
in a mixed state were nearly four times more likely to
have a suicide attempt than the non-mixed girls (95%
CI = 1.59.7, p = 0.003).
Given the differences between mixed and nonmixed girls, one can ask bDoes the presence of
psychosis, family history or age of the proband
mediate the elevated risks?Q Univariate logistic
regression of suicidal ideation or attempts versus the
presence of psychotic features, family history of MDD
and/or bipolar disorder, family history of bipolar
disorder and age did not disclose evidence that these
variables were causally related to the results.
Univariate logistic regression of suicidal ideation
versus age disclosed an odds ratio of 4.4 (95%
CI = 0.721.0, p = 0.099). Univariate logistic regression analysis revealed a significant relationship
between age and suicide attempts within the entire
sample (OR = 15.5, 95% CI = 2.981.0, p = 0.001):
The bolderQ adolescents were more likely to have a
suicide attempt.

4. Discussion
Being in a mixed state did not confer increased risk
of having either suicidal ideation or a recent suicide
attempt among the 247 patients. The univariate

S.C. Dilsaver et al. / Journal of Affective Disorders 87 (2005) 1116

logistic regression model indicated that girls in mixed

states were at twice the risk of having suicidal
ideation, though this missed significance. However,
they were at 4 times the risk of having a recent suicide
attempt. The latter finding was highly significant.
Importantly, the statistical model indicated that the
presence of psychotic features, family history of mood
disorder and age were not confounding variables.
Thus, the results suggest that being in a mixed state
independently increased the risk of a girl having a
suicide attempt. No such relationship existed among
boys.
It is well known that suicide attempts are much
more common among females, but because males use
significantly more violent/lethal methods, they are
markedly overrepresented among suicide victims
(Hawton and van Heeringen, 2000; Isometsa and
Lonnqvist, 1998; Beautrais, 2003). Moreover, since
5678% of suicides (again, significantly more males
than females) die by their first suicide attempt
(Isometsa and Lonnqvist, 1998), it is possible that
for this reason, males are underrepresented in specific
samples of patients with past suicide attempts. In
other words, considering this presentation bias, and
given the fact that mixed state is a risk factor for
suicide, it is possible that among males, mixed
affective episode increases mainly the risk of completed, rather than attempted suicide. This suggestion
could be supported by our finding, i.e. the rates of
prior suicide attempts versus current suicidal ideation
in mixed girls, in non-mixed girls and in non-mixed
boys are similar (80.6% versus 86.1%, 51.5% versus
71.1%, and 26.4% versus 28.8%), but in contrast to
this, in mixed boys, the rate of past suicide attempts is
substantially lower than the rate of suicidal ideation
(28.8% versus 52.2%). However, gender differences
of the other suicide risk factors, not investigated in
this study, such as comorbid anxiety disorders and
history of sexual abuse (Wunderlich et al., 2001;
Beautrais, 2003) that have been shown to be much
more common among female than male adolescent
suicide attempters, could also explain this gender
difference.
We (Dilsaver et al., 1994, 1997; Akiskal et al.,
1998) and others (Strakowski et al., 1996; Goldberg et
al., 1998) reported that being in a mixed mania and
mixed/agitated depression (Benazzi, 2003a; Maj et al.,
2003; Akiskal et al., 2005) was associated with an

15

increased risk of suicidal ideation in adults. However,

gender differences in suicidality were not detected in
the foregoing analyses.
The rate of suicide attempts was remarkably high
in this study. This stems in part from the operational
definition of a suicide attempt. It included any
physically self-destructive act mentally linked with
the thought of dying without regard for the medical
seriousness of the event. This is the first study that
has, to the best of our knowledge, employed this
operational definition.
This is also the first study of the relationship of
the mixed state to suicidality among adolescent girls.
The data, as they now stand, indicate that it is
critical to assess all adolescents in mixed states for
suicidal ideation and histories of self-destructive acts
linked with the wish to die. Efforts to replicate our
main finding of adolescent girls with mixed states
being at an increased risk for suicide attempts
relative to their male counterparts (who seem to be
at an elevated risk of committed suicide) are needed.
The factors accounting for such a difference (i.e.,
anxiety disorder comorbidity, history of sexual
abuse, impulsivity, etc.) could prove clinically and
theoretically important. At the public health level,
this finding is important because it identifies a
depressive subgroup vulnerable to suicidal acts. It
is relevant from a practical viewpoint, since worsening of depression (including auto- and heteroaggressive behaviors) under antidepressant monotherapy has been observed very frequently in
pediatric bipolar patients (Faedda et al., 2004; Wilens
et al., 2003). We further submit it has something to
do with the recently enforced black-box warning of
the FDA (2004) for possible suicidality in juvenile
depressives receiving antidepressants. At least one
large study (N24,000 patients) has found no evidence
for suicide attempts in antidepressant-treated MDD
adolescents (Voluck et al., 2004). We submit that in
the rare event such attempts do occur, they may be
accounted for by a formulation of the senior author
in 1995 (Akiskal, 1995), and recently shown by us
(Dilsaver et al., in press), namely that juvenile
depressions very often are mixed bipolar in nature.
Thus, we submit that antidepressants are not at the
root of the problemrather it is the inadequate
characterization of bipolar mixed states in our formal
diagnostic system.

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