Association between family history of mood disorders and clinical characteristics of bipolar...
Transcript of Association between family history of mood disorders and clinical characteristics of bipolar...
![Page 1: Association between family history of mood disorders and clinical characteristics of bipolar disorder: Results from the Brazilian bipolar research network](https://reader035.fdocuments.in/reader035/viewer/2022081814/575096bc1a28abbf6bcd37c0/html5/thumbnails/1.jpg)
Author's Accepted Manuscript
Association Between Family History of MoodDisorders and Clinical Characteristics of Bipo-lar Disorder: Results from the Brazilian Bipo-lar Research Network
Mariangeles Berutti, Fabiano G. Nery, RodrigoSato, Angela Scippa, Flavio Kapczinski, BenyLafer
PII: S0165-0327(14)00094-9DOI: http://dx.doi.org/10.1016/j.jad.2014.02.045Reference: JAD6612
To appear in: Journal of Affective Disorders
Received date: 15 February 2014Accepted date: 28 February 2014
Cite this article as: Mariangeles Berutti, Fabiano G. Nery, Rodrigo Sato, AngelaScippa, Flavio Kapczinski, Beny Lafer, Association Between Family History ofMood Disorders and Clinical Characteristics of Bipolar Disorder: Results fromthe Brazilian Bipolar Research Network, Journal of Affective Disorders, http://dx.doi.org/10.1016/j.jad.2014.02.045
This is a PDF file of an unedited manuscript that has been accepted forpublication. As a service to our customers we are providing this early version ofthe manuscript. The manuscript will undergo copyediting, typesetting, andreview of the resulting galley proof before it is published in its final citable form.Please note that during the production process errors may be discovered whichcould affect the content, and all legal disclaimers that apply to the journalpertain.
www.elsevier.com/locate/jad
![Page 2: Association between family history of mood disorders and clinical characteristics of bipolar disorder: Results from the Brazilian bipolar research network](https://reader035.fdocuments.in/reader035/viewer/2022081814/575096bc1a28abbf6bcd37c0/html5/thumbnails/2.jpg)
Title: Association Between Family History of Mood Disorders and Clinical
Characteristics of Bipolar Disorder: Results from the Brazilian Bipolar Research
Network
Authors: Mariangeles Berutti,1 Fabiano G. Nery,1,2 Rodrigo Sato1, Angela Scippa,3
Flavio Kapczinski,4 Beny Lafer1
Authors’ affiliations:
1Bipolar Disorder Program (PROMAN), Department of Psychiatry, University of São
Paulo Medical School, São Paulo, Brazil
2Department of Psychiatry & Behavioral Neuroscience, University of Cincinnati
College of Medicine, Cincinnati, USA
3Center for Treatment of Affective Disorders (CETHA), Department of Psychiatry,
Federal University of Bahia, Salvador, Brazil
4Bipolar Disorder Program (PROTAHBI), Department of Psychiatry, Federal
University of Rio Grande do Sul, Porto Alegre, Brazil
Location of work: University of Sao Paulo Medical School. Rua Dr. Ovidio Pires de
Campos, 785. Cerqueira Cesar. Sao Paulo/SP. Brazil. ZIP code: 05403-010. Phone
(fax): 55 (11) 3069.7928.
Correspondence: Mariangeles Berutti, Institute & Department of Psychiatry
University of Sao Paulo Medical School. Rua Dr. Ovidio Pires de Campos, 785.
Cerqueira Cesar. Sao Paulo/SP. Brazil. ZIP code : 05403-010. Phone (fax): 55 (11)
3069.7928. E-mail: [email protected]
![Page 3: Association between family history of mood disorders and clinical characteristics of bipolar disorder: Results from the Brazilian bipolar research network](https://reader035.fdocuments.in/reader035/viewer/2022081814/575096bc1a28abbf6bcd37c0/html5/thumbnails/3.jpg)
ABSTRACT:
Objectives: To compare clinical characteristics of bipolar disorder (BD) in patients
with and without a family history of mood disorders (FHMD) in a large sample from
the Brazilian Research Network of Bipolar Disorders.
Methods: Four-hundred eighty-eight DSM-IV BD patients participating in the
Brazilian Research Network of Bipolar Disorders were included. Participants were
divided between those with FHMD (n=230) and without FHMD (n=258). We
compared these two groups on demographic and clinical variables and performed a
logistic regression to identify which variables were most strongly associated with
positive family history of mood disorders.
Results: BD patients with FHMD presented with significantly higher lifetime
prevalence of any anxiety disorder, obsessive-compulsive disorder, social phobia,
substance abuse, and were more likely to present history of suicide attempts, family
history of suicide attempts and suicide, and more psychiatric hospitalizations than BD
patients without FHMD. Logistic regression showed that the variables most strongly
associated with a positive FHMD were any comorbid anxiety disorder, comorbid
substance abuse, and family history of suicide.
Limitations: Cross-sectional study and verification of FHMD by indirect information
Conclusion: BD patients with FHMD differ from BD patients without FHMD in rates
of comorbid anxiety disorder and substance abuse, number of hospitalizations and
suicide attempts. As FHMD is routinely assessed in clinical practice, these findings
may help to identify patients at risk for particular manifestations of BD and may point
to a common, genetically determined neurobiological substrate that increases the risk
of conditions such as comorbidities and suicidality in BD patients.
![Page 4: Association between family history of mood disorders and clinical characteristics of bipolar disorder: Results from the Brazilian bipolar research network](https://reader035.fdocuments.in/reader035/viewer/2022081814/575096bc1a28abbf6bcd37c0/html5/thumbnails/4.jpg)
KEY WORDS: bipolar disorder; family history; mood disorder; comorbidity;
impulsivity.
![Page 5: Association between family history of mood disorders and clinical characteristics of bipolar disorder: Results from the Brazilian bipolar research network](https://reader035.fdocuments.in/reader035/viewer/2022081814/575096bc1a28abbf6bcd37c0/html5/thumbnails/5.jpg)
1. Introduction
Bipolar disorder (BD) in general affects up to 4.5% of the population, and BD
type I in particular affects 1.0% of the population causing significant suffering for
patients and their families due to the severe, recurrent and disabling nature of the
disease (Merikangas et al., 2007; Goodwin and Jamison, 2007; Phillips and Kupfer,
2013). BD is highly heritable (Smoller and Finn, 2003; Barnett and Smoller, 2009).
The disease risk in first-degree relatives of BD patients is approximately ten times
higher than for the general population (Barnett and Smoller, 2009). Relatives of BD
patients are also at increased risk for mood disorders in general. The risk for major
depressive disorder (MDD) among relatives of BD patients is three times higher than
among relatives of healthy controls (Smoller and Finn, 2003; Barnett and Smoller,
2009). Not only does BD diagnosis aggregate in families but some clinical
characteristics of the disease do as well, including early age at onset, psychotic
symptoms, comorbid panic disorder, alcohol use disorders, rapid cycling, and suicidal
thoughts (Rice et al., 1987; Leboyer et al., 1998; O’Mahony et al., 2002; Schulze et
al., 2006; Bellivier 2006; Saunders et al., 2008; Hua et al., 2011). In clinical settings,
these increased risks translate into a common situation for a BD patient in which one
or more parents or siblings also suffer from BD or from MDD. Because of the high
heritability of mood disorders in general, and of BD in particular, it is assumed that
such families have a high genetic loading for mood disorders. However, whether this
high genetic loading translates into a more severe disease in patients from such
families is poorly understood.
One way to investigate this question is to compare BD patients with a positive
FHMD to those BD patients whose family history is negative for mood disorders. In
![Page 6: Association between family history of mood disorders and clinical characteristics of bipolar disorder: Results from the Brazilian bipolar research network](https://reader035.fdocuments.in/reader035/viewer/2022081814/575096bc1a28abbf6bcd37c0/html5/thumbnails/6.jpg)
MDD patients, having a positive FHMD is associated with a younger age at disease
onset, long duration of episodes, increased suicidality, female gender, and higher
neuroticism (Nierenberg et al., 2007; Husain et al., 2009; Holma et al., 2011). In BD,
three studies reported that a positive FHMD was associated with early disease onset,
increased number of episodes, suicidality, and more hospitalizations (Mrad et al.,
2007), and increased rates of comorbid anxiety disorders (Mantere et al., 2012;
Serretti et al., 2013). On the other hand, FHMD was not associated with comorbid
Axis I conditions, manic or depressive symptoms severity, or number of manic or
depressive episodes in a 1-year follow up period (McElroy et al., 2001; Nolen et al.,
2004).
The aim of this study was to investigate associations between clinical
correlates of disease and FHMD among BD patients with high genetic loading for
mood disorders. We compared BD patients with and without FHMD among first- and
second-degree relatives on several clinical characteristics of the disease that could
indicate greater disease severity. Our hypothesis was that BD patients from families
with positive FHMD would present with more severe disease than patients without a
family history of mood disorder. As FHMD is easily and routinely investigated in
clinical practice, findings of this study can potentially help clinicians to understand
and identify characteristics associated with more severe disease courses.
2. Methods
Patients
The sample was comprised of 488 consecutive BD outpatients from three
research centers participating in the Brazilian Research Network for Bipolar
![Page 7: Association between family history of mood disorders and clinical characteristics of bipolar disorder: Results from the Brazilian bipolar research network](https://reader035.fdocuments.in/reader035/viewer/2022081814/575096bc1a28abbf6bcd37c0/html5/thumbnails/7.jpg)
Disorders. Center 1: Bipolar Disorder Program (PROMAN), Department of
Psychiatry, University of São Paulo Medical School; Center 2: Bipolar Disorder
Program (PROTAHBI), Department of Psychiatry, Federal University of Rio Grande
do Sul; and Center 3: Center for Treatment of Affective Disorders (CETHA),
Department of Psychiatry, Federal University of Bahia. Inclusion criteria included age
over 18 years and a DSM-IV BD diagnosis. The study protocol was approved by the
local Ethics Committee of each institution and all patients gave written informed
consent to participate in the study. All study procedures were carried out according to
the Declaration of Helsinki.
Psychiatric assessments
Diagnostic assessments were all conducted by research-trained, board-
certified psychiatrists, using the Structured Clinical Interview for DSM-IV Disorders
(SCID), versions for patients (First et al., 2002). The 17-item Hamilton Depression
Rating Scale (HAMD-17) (Hamilton, 1960) and the Young Mania Rating Scale
(YMRS) (Young et al., 1978) were administered to assess severity of depressive and
manic symptoms, respectively. Demographic and clinical characteristics of the
disease, including age of onset, rapid cycling, hospitalizations, suicide attempts,
family history of mood disorders or substance use disorders were obtained using the
same standardized protocol and information from the SCID. Patients were classified
as euthymic when they did not meet criteria for any mood episode in the last 2 months
and also had a HAMD-17 score and YMRS score lower than 7 in the week before the
assessment. They were classified as non-euthymic if they were in a full mood episode
or had subsyndromal symptoms. FHMD was evaluated using a standardized
questionnaire to assess presence or absence of mood disorders (major depressive
disorder or bipolar disorder) in first- and second-degree relatives. Presence was
![Page 8: Association between family history of mood disorders and clinical characteristics of bipolar disorder: Results from the Brazilian bipolar research network](https://reader035.fdocuments.in/reader035/viewer/2022081814/575096bc1a28abbf6bcd37c0/html5/thumbnails/8.jpg)
defined as the presence of a lifetime clinical diagnosis of major depressive disorder or
bipolar disorder by a psychiatrist.
Statistical analysis
Participants were divided into two groups: BD patients with and without
FHMD. Demographic and clinical characteristics of these two groups were compared
using exact X2 tests for cross-tabulated categorical data and Mann-Whitney U test or
T test for ordinal and interval scale data. A stepwise binary logistic regression
analysis was then conducted to compare the existence of clinical features in BD
patients with positive or negative FHMD. For the regression analyses, we included
only variables with significant associations in the univariate analyses. The
corresponding chi-square values, odds ratios, and 95% confidence intervals (CIs) are
reported. Significance was set at p = 0.05 (two-tailed). SPSS (SPSS, Inc., Chicago,
IL) version 14.0 was used to perform all the analyses.
3. Results
Four hundred eighty-eight BD patients participated in the study. Of those, 140
(28.7%) were male and 348 (71.3%) were female. Mean age ± standard deviation
(S.D.) was 40.6 ± 11.4 years, ranging from 18 to 74 years old. Four hundred and
thirty-nine (90%) patients were classified with BD type I, 36 (7.4%) with BD type II
and 13 (2.7%) with BD not otherwise specified (NOS).
Two hundred and thirty BD patients reported the presence of a clinical
diagnosis of a mood disorder in at least one first- or second-degree relative (positive
FHMD) and 258 BD patients did not present any history of mood disorders among
![Page 9: Association between family history of mood disorders and clinical characteristics of bipolar disorder: Results from the Brazilian bipolar research network](https://reader035.fdocuments.in/reader035/viewer/2022081814/575096bc1a28abbf6bcd37c0/html5/thumbnails/9.jpg)
first- and second-degree relatives (negative FHMD). For first-episode psychosis, three
patients had missing data; for family history of substance use disorder, three patients
had missing data; and for rapid cycling, four patients had missing data. Analyses were
repeated without these missing data and results did not change.
BD patients with positive FHMD presented with significantly higher lifetime
prevalences of any anxiety disorder (p<0.001), obsessive-compulsive disorder
(p=0.002), social phobia (p=0.02), and substance abuse (p=0.02) than BD patients
with negative FHMD. BD patients with positive FHMD were also more likely to
make at least one lifetime suicide attempt (p=0.01), to have a positive family history
of either completed suicide (p=0.02) or suicide attempts (p=0.03), and to have more
psychiatric hospitalizations (p= 0.03) than BD patients with negative FHMD. Results
from the univariate analyses are displayed in Table 1.
Insert Table 1 about here
Stepwise binary logistic regression showed that the variables most strongly
associated with a positive FHMD among BD patients were in decreasing order of risk:
any comorbid anxiety disorder, comorbid substance abuse and family history of
suicide. The results of the logistic regression are shown in Table 2.
Insert Table 2 about here
4. Discussion
![Page 10: Association between family history of mood disorders and clinical characteristics of bipolar disorder: Results from the Brazilian bipolar research network](https://reader035.fdocuments.in/reader035/viewer/2022081814/575096bc1a28abbf6bcd37c0/html5/thumbnails/10.jpg)
This study compared demographic characteristics and clinical correlates in BD
patients with and without FHMD. We found an association between positive FHMD
and history of suicide attempts, family history of suicide, comorbid anxiety and
substance use disorders, and more hospitalizations in BD patients.
Half of our population reported having positive FHMD among first- and
second-degree relatives, consistent with some (Dilsaver et al., 2006; Mrad et al.,
2007; Mantere et al., 2012) but not all (McElroy et al., 2011) studies in BD
populations. In the McElroy et al. (2011) study, FHMD was assessed only among
first-degree relatives of patients, which may have contributed to a narrower diagnostic
frequency.
In the univariate analysis, a positive FHMD was associated with both a
personal history of suicide attempts and family history of suicide. Other studies have
also found associations between family history of psychiatric disorders in general and
mood disorders in particular and suicide behavior in BD patients (Slama et al., 2004;
Mantere et al., 2012 ; Pawlak et al., 2013) and in MDD patients (Nierenberg et al.,
2007; Holma et al., 2011). The increased risk for suicide attempts and for family
history of suicidality among BD patients that have positive FHMD may be an
expression of the higher occurrence of mood disorders in these families. For instance,
BD carries a greater risk for suicide compared with other psychiatric illnesses.
Approximately 15% of the BD population commits suicide and 50% of BD patients
make a suicide attempt at least once in their lifetimes (Abreu et al, 2009; Pompilli et
al., 2013). However, evidence suggests that suicidal behaviors have heritability
independent from mood disorders (Leverich et al., 2003; Lopez et al., 2001; Tsai et
al., 2002; Manchia et al., 2013). Suicide attempts are familial and possibly influenced
by genetic factors (Glowinski et al., 2001; Sani et al., 2011). It is also noteworthy that
![Page 11: Association between family history of mood disorders and clinical characteristics of bipolar disorder: Results from the Brazilian bipolar research network](https://reader035.fdocuments.in/reader035/viewer/2022081814/575096bc1a28abbf6bcd37c0/html5/thumbnails/11.jpg)
not only genetic contribution but also family environment might contribute to increase
risk for suicide in BD, as negative life events and an absence of social support have
been linked to suicide attempts in BD (Leverich et al., 2003). Indeed, at least in
youths with BD, suicidal ideation has been associated with poorer family
environment, as suggested by greater conflicts with parents, less adaptability to stress,
and more recent stressful family events (Goldstein et al., 2009).
Another important finding in our study was the association between FHMD
and comorbid anxiety disorders in general, or with comorbid social phobia or
comorbid obsessive-compulsive disorder in particular. It should be noted that after
multivariate analysis, only comorbid anxiety disorders in general was associated with
FHMD. Mantere et al (2012) presented similar findings, where BD (type I and II)
patients with FHMD, alcoholism, or any major psychiatric disorders among first-
degree relatives had an odds ratio of 4.8 (p=0.001) for having an anxiety disorder.
However, other studies have failed to find such associations (McElroy et al., 2011;
Nolen et al., 2004).
BD is highly comorbid with anxiety disorders (McElroy et al., 2011; Goldberg
and Fawcett, 2012). The presence of comorbid anxiety in BD patients has also been
associated with several markers of clinical severity, including earlier age of onset,
greater number of depressive episodes, higher prevalence of attempted suicide,
alcohol and substance abuse, poorer role functioning, and less favorable response to
lithium treatment (Young et al., 1993; Otto et al., 2006; Goes et al., 2012). It has been
hypothesized that several areas of overlap might exist between these disorders that
may stem from common genetic etiology. On the other hand, some studies have
suggested that BD patients with comorbid anxiety disorders were more likely to have
been exposed to childhood environmental risk factors for psychopathology, including
![Page 12: Association between family history of mood disorders and clinical characteristics of bipolar disorder: Results from the Brazilian bipolar research network](https://reader035.fdocuments.in/reader035/viewer/2022081814/575096bc1a28abbf6bcd37c0/html5/thumbnails/12.jpg)
parental loss and vulnerable family environment, than BD patients without comorbid
anxiety disorders (Sala et al., 2012; Quarantini et al., 2010; Daruy-Filho et al, 2011).
Having a positive FHMD was also associated with an increased risk for
comorbid substance use disorders among BD patients, in both the univariate and
multivariate analyses. BD is also highly comorbid with substance use disorders. Rates
of substance use disorder can be as high as 41% in BD (Levin and Hennessy, 2004;
McElroy et al., 2001). Comorbid substance use disorders lead to a more pernicious
and difficult to treat illness course, including delayed recovery from mood episodes,
lower remission rates, greater number of mixed episodes, faster relapses, and
increased prevalence of suicide attempts (Dalton et al., 2003; Krishnan 2005; Sublette
et al., 2009). It is interesting to note that a recent study found that risk for BD is
associated with risk for alcohol use disorders and anxiety disorders in 61 bipolar
families (Carmiol et al., 2013). The association between BD and alcohol use disorders
among family members remained significant even after controlling for anxiety
disorders, which suggests that unique and shared genetic factors influence the risk for
the comorbidity between BD and alcohol use disorders.
Is it possible that impulsivity is a common neurobiological factor linking
patients with FHMD to family history of suicide, comorbid anxiety disorders and
comorbid substance use? In fact, higher impulsivity is common in suicide attempters,
whether or not they have BD (Baca-Garcia et al., 2005; Swann et al., 2005) and in
subjects with family history of suicide (Roy, 2006; Sarchiapone et al., 2009).
Substance use disorder patients (Moeller et al., 2001; Clark et al., 2006) and BD
subjects with comorbid alcohol and substance misuse have higher impulsivity than
BD subjects without these comorbidities (Holmes et al., 1994; Swann et al., 2004;
Nery et al., 2013).
![Page 13: Association between family history of mood disorders and clinical characteristics of bipolar disorder: Results from the Brazilian bipolar research network](https://reader035.fdocuments.in/reader035/viewer/2022081814/575096bc1a28abbf6bcd37c0/html5/thumbnails/13.jpg)
Higher impulsivity is also found in patients with anxiety disorders (Perugi et
al., 2011; Del Carlo et al., 2012), and BD patients with comorbid anxiety disorders
have higher impulsivity than BD patients without anxiety disorders (Taylor et al.,
2008; Bellani et al., 2012). Finally, BD patients have higher trait impulsivity than
non-BD comparison groups (Moeller et al., 2001; Peluso et al., 2007; Swann et al.,
2009; Nery et al., 2013). It is also interesting to note that increased impulsivity is
present among unaffected relatives of BD patients (Lombardo et al., 2012; Almeida et
al, 2011; Henna et al., 2013), suggesting that, at least to some extent, impulsivity is
also familial. Impulsivity is moderately heritable, suggesting that genes may modulate
behaviors that involve impulse control (Bezdjian et al., 2011; Bevilacqua and
Goldman, 2013). Therefore, we speculate whether families of BD probands with high
genetic loading for mood disorders may also be characterized by high impulsivity,
which in turn would put their family members with BD at increased risk for suicide,
anxiety or addiction. A study comparing trait impulsivity in BD patients with and
without FHMD would be adequate to address this hypothesis.
Our study has specific limitations. It is a cross-sectional study, and inferences
about causal relationships cannot be made. A substantial subset of our sample was in
a current mood episode. If a larger proportion of BD patients had been in complete
disease remission, there may have been lower prevalence rates of psychiatric
comorbidities, as having such a sample may avoid overestimating comorbid diagnoses
by eliminating overlapping acute symptoms that influence memory recall of
information. Another important limitation was that patients were asked if they have
any first- or second-degree relative with a diagnosis or who have received treatment
for a mood disorder; there was no reliable instrument used to confirm diagnosis in
relatives. Another limitation was that the three research groups were from university
![Page 14: Association between family history of mood disorders and clinical characteristics of bipolar disorder: Results from the Brazilian bipolar research network](https://reader035.fdocuments.in/reader035/viewer/2022081814/575096bc1a28abbf6bcd37c0/html5/thumbnails/14.jpg)
hospitals, therefore it is a sample with patients attending tertiary level of attention,
which may limit the generalizability of our findings.
On the other hand, our study also has considerable strengths. It is one of the
first studies to specifically investigate the association between high genetic loading
for mood disorders and clinical characteristics of BD. Family history of mood
disorders, as a proxy for high genetic loading is easily and routinely assessed in
clinical practice, and associations between these variables may help the clinician to
identify patients at risk for more severe manifestations of BD.
In conclusion, we found that BD patients with positive FHMD in first- and
second-degree relatives are at increased risk for comorbid anxiety disorders, comorbid
substance use disorders, and have more family history of suicide. They also have
more hospitalizations and more suicide attempts than BD patients without FHMD. As
family history of mood disorders is easily and routinely assessed in clinical practice,
these findings may help clinicians to identify patients at risk for more severe
manifestations of BD. Moreover, as FHMD may function as a proxy for high genetic
loading for mood disorders, these associations may point to a common
neurobiological substrate that is genetically transmitted and increases the risk of BD
patients to develop more severe forms of disease.
![Page 15: Association between family history of mood disorders and clinical characteristics of bipolar disorder: Results from the Brazilian bipolar research network](https://reader035.fdocuments.in/reader035/viewer/2022081814/575096bc1a28abbf6bcd37c0/html5/thumbnails/15.jpg)
Table 1: Demographic and clinical characteristics of bipolar disorder patients with
and without family history of mood disorders.
Characteristics Positive
FHMD
(n=230)
Negative
FHMD
(n=258)
p-value
Age (mean±S.D.), in years 40.6±11.4 40.6±11.5 0.83
Male, n (%) 64 (27.8) 76 (29.5) 0.69
BD subtype
BD type I 201 (87.4) 238 (92.2) 0.2
BD type II 21 (9.1) 15 (5.8)
BD NOS 8 (3.5) 5 (1.9)
Rapid cycling, n (%) 53 (23.1) 40 (15.7) 0.11
Current mood state
Euthymic, n (%) 64 (27.8) 76 (29.5) 0.11
Psychosis in first episode 95 (41.7) 121 (47.1) 0.15
Lifetime psychosis 167 (72.6) 187 (72.5) 0.98
Substance misuse during first episode 27 (11.7) 23 (8.9) 0.38
Rapid cycling 53 (23.1) 40 (15.7) 0.11
Lifetime psychiatric hospitalization 150 (65.2) 191 (74) 0.03
Lifetime history of suicide attempts, n (%) 111 (48.3) 96 (37.2) 0.01
Family history of suicide 59 (25.7) 44 (17.1) 0.02
Family history of suicide attempts 53 (23) 41 (15.9) 0.05
Family history of substance use disorder 114 (50.0) 112 (43.6) 0.17
Comorbid alcohol abuse/dependence 59 (25.7) 51 (19.8) 0.12
![Page 16: Association between family history of mood disorders and clinical characteristics of bipolar disorder: Results from the Brazilian bipolar research network](https://reader035.fdocuments.in/reader035/viewer/2022081814/575096bc1a28abbf6bcd37c0/html5/thumbnails/16.jpg)
Comorbid substance abuse/dependence 49 (21.3) 32 (12.4) 0.02
Comorbid any anxiety disorder 136 (59.1) 110 (42.6) <0.001
Comorbid panic disorder 36 (15.7) 37 (14.3) 0.68
Comorbid agoraphobia 33 (14.3) 23 (8.9) 0.06
Comorbid social phobia 48 (20.9) 33 (12.8) 0.02
Comorbid specific phobia 63 (27.4) 55 (21.3) 0.12
Comorbid obsessive compulsive disorder 40 (17.4) 21 (8.1) 0.002
Comorbid generalized anxiety disorder 32 (13.9) 25 (9.7) 0.15
Comorbid eating disorder 24 (10.4) 18 (7) 0.17
BD (bipolar disorder); FHMD (family history of mood disorders); S.D. (standard
deviation)
![Page 17: Association between family history of mood disorders and clinical characteristics of bipolar disorder: Results from the Brazilian bipolar research network](https://reader035.fdocuments.in/reader035/viewer/2022081814/575096bc1a28abbf6bcd37c0/html5/thumbnails/17.jpg)
Table 2: Logistic regression analysis of variables associated with positive family
history of mood disorder among Brazilian bipolar disorder patients.
Variables Odds ratio 95% CI P value
Comorbid any anxiety disorder 2.14 1.38-3.31 0.001
Comorbid substance abuse/dependence 1.89 1.13-3.16 0.015
Family history of suicide 1.69 1.07-2.69 0.026
CI (confidence interval)
![Page 18: Association between family history of mood disorders and clinical characteristics of bipolar disorder: Results from the Brazilian bipolar research network](https://reader035.fdocuments.in/reader035/viewer/2022081814/575096bc1a28abbf6bcd37c0/html5/thumbnails/18.jpg)
References
Abreu, L. N., Lafer, B., Baca-Garcia, E., & Oquendo, M. A. (2009). Suicidal
ideation and suicide attempts in bipolar disorder type I: an update for the clinician.
Rev. Bras. Psiquiatr. , 31 (3), 271-280.
Almeida, K. M., Nery, F. G., Moreno, R. A., Gorenstein, C., & Lafer, B.
(2011). Personality traits in bipolar disorder type I: a sib-pair analysis. Bipolar
Disord., 13 (7-8), 662-669.
Baca-Garcia, E., Diaz-Sastre, C., García Resa, E., Blasco, H., Braquehais
Conesa, D., Oquendo, M. A., et al. (2005). Suicide attempts and impulsivity. Eur
Arch. Psychiatry Clin. Neurosci., 255 (2), 152-156.
Barnett, J. H., & Smoller, J. W. (2009). The genetics of bipolar disorder.
Neuroscience, 164 (1), 331-343.
Bellani, M., Hatch, J. P., Nicoletti, M. A., Ertola, A. E., Zunta-Soares, G.,
Swann, A. C., et al. (2012). Does anxiety increase impulsivity in patients with bipolar
disorder or major depressive disorder? J. Psychiatr. Res., 46 (5), 616-621.
Bellivier, F. (2006). Evolution of bipolar disorder. Encephale , 32 Pt 2, S506--
S510.
Bevilacqua, L., & Goldman, D. (2013). Genetics of impulsive behaviour.
Philos. Trans. R. Soc. Lond. B. Biol. Sci., 368 (1615), 20120380.
Bezdjian S, Baker LA, Tuvblad C. (2011) Genetic and environmental
influences on impulsivity: a meta-analysis of twin, family and adoption studies. Clin.
Psychol. Rev. (7):1209-23
![Page 19: Association between family history of mood disorders and clinical characteristics of bipolar disorder: Results from the Brazilian bipolar research network](https://reader035.fdocuments.in/reader035/viewer/2022081814/575096bc1a28abbf6bcd37c0/html5/thumbnails/19.jpg)
Carmiol, N., Peralta, J.M., Almasy, L., Contreras, J., Pacheco, A., Escamilla,
M.A., Knowles, E.E., Raventós, H., Glahm, D.C. (2013). Shared genetic factors
influence risk for bipolar disorder and alcohol use disorders. Eur. Psychiatr. 13
.2013.10.001. [Epub ahead of print]
Clark, L., Sarna, A., & Goodwin, G. M. (2005). Impairment of executive
function but not memory in first-degree relatives of patients with bipolar I disorder
and in euthymic patients with unipolar depression. Am. J. Psychiatry , 162 (10), 1980-
1982.
Dalton, E. J., Cate-Carter, T. D., Mundo, E., Parikh, S. V., & Kennedy, J. L.
(2003). Suicide risk in bipolar patients: the role of co-morbid substance use disorders.
Bipolar Disord., 5 (1), 58-61.
Daruy-Filho, L., Brietzke, E., Lafer, B., & Grassi-Oliveira, R. (2011).
Childhood maltreatment and clinical outcomes of bipolar disorder. Acta Psychiatr.
Scand., 124 (6), 427-434.
Del Carlo, A., Benvenuti, M., Fornaro, M., Toni, C., Rizzato, S., Swann, A.
C., et al. (2012). Different measures of impulsivity in patients with anxiety disorders:
a case control study. Psychiatry Res., 197 (3), 231-236.
Dilsaver, S. C., Akiskal, H. S., Akiskal, K. K., & Benazzi, F. (2006). Dose-
response relationship between number of comorbid anxiety disorders in adolescent
bipolar/unipolar disorders, and psychosis, suicidality, substance abuse and familiality.
J Affect. Disord., 96 (3), 249-258.
First MB, Pincus HA. (2002) The DSM-IV Text Revision: rationale and
potential impact on clinical practice. Psychiatr. Serv., 53(3):288-292.
![Page 20: Association between family history of mood disorders and clinical characteristics of bipolar disorder: Results from the Brazilian bipolar research network](https://reader035.fdocuments.in/reader035/viewer/2022081814/575096bc1a28abbf6bcd37c0/html5/thumbnails/20.jpg)
Glowinski, A. L., Bucholz, K. K., Nelson, E. C., Fu, Q., Madden, P. A., Reich,
W., et al. (2001). Suicide attempts in an adolescent female twin sample. J Am Acad
Child Adolesc. Psychiatry, 40 (11), 1300-1307.
Goes, F. S., McCusker, M. G., Bienvenu, O. J., Mackinnon, D. F.,
Mondimore, F. M., Schweizer, B., et al. (2012). Co-morbid anxiety disorders in
bipolar disorder and major depression: familial aggregation and clinical
characteristics of co-morbid panic disorder, social phobia, specific phobia and
obsessive-compulsive disorder. Psychol. Med., 42 (7), 1449-1459.
Goldberg, D., & Fawcett, J. (2012). The importance of anxiety in both major
depression and bipolar disorder. Depress. Anxiety., 29 (6), 471-478.
Goldstein, T. R., Birmaher, B., Axelson, D., Goldstein, B. I., Gill, M. K.,
Esposito-Smythers, C., et al. (2009). Family environment and suicidal ideation among
bipolar youth. Arch. Suicide Res., 13 (4), 378-388.
Goodwin FK, Jamison KR. Manic-depressive illness. Bipolar disorders and
recurrent depression. 2nd ed. New York: Oxford University Press, 2007.
Hamilton M. (1960) A rating scale for depression. J. Neurol. Neurosurg.
Psychiatry., 23:56-62.
Henna, E., Hatch, J. P., Nicoletti, M., Swann, A. C., Zunta-Soares, G., &
Soares, J. C. (2013). Is impulsivity a common trait in bipolar and unipolar disorders?
Bipolar Disord., 15 (2), 223-227.
Holma, K. M., Melartin, T. K., Holma, I. A., Paunio, T., & Isometsä, E. T.
(2011). Family history of psychiatric disorders and the outcome of psychiatric
![Page 21: Association between family history of mood disorders and clinical characteristics of bipolar disorder: Results from the Brazilian bipolar research network](https://reader035.fdocuments.in/reader035/viewer/2022081814/575096bc1a28abbf6bcd37c0/html5/thumbnails/21.jpg)
patients with DSM-IV major depressive disorder. J. Affect. Disord., 131 (1-3), 251-
259.
Holmes, H., Ziemba, J., Evans, T., & Williams, C. A. (1994). Nursing model
of psychoeducation for the seriously mentally ill patient. Issues Ment. Health Nurs.,
15 (1), 85-104.
Hua LL, Wilens TE, Martelon M, Wong P, Wozniak J, Biederman J.(2011).
Psychosocial functioning, familiality, and psychiatric comorbidity in bipolar youth
with and without psychotic features. J. Clin. Psychiatry., 72(3):397-405
Husain MM, Rush AJ, Wisniewski SR, McClintock SM, Fava M, Nierenberg
AA, Davis L, Balasubramani GK, Young E, Albala AA, Trivedi MH. (2009) Family
history of depression and therapeutic outcome: findings from STAR*D. J. Clin.
Psychiatry., 70(2):185-95
Krishnan, K. R. (2005). Psychiatric and medical comorbidities of bipolar
disorder. Psychosom Med., 67 (1), 1-8.
Leboyer, M., Bellivier, F., McKeon, P., Albus, M., Borrman, M., Perez-Diaz,
F., et al. (1998). Age at onset and gender resemblance in bipolar siblings. Psychiatry
Res., 81 (2), 125-131.
Leverich, G. S., Altshuler, L. L., Frye, M. A., Suppes, T., Keck, J. P.,
McElroy, S. L., et al. (2003). Factors associated with suicide attempts in 648 patients
with bipolar disorder in the Stanley Foundation Bipolar Network. J. Clin. Psychiatry.,
64 (5), 506-515.
Levin, F. R., & Hennessy, G. (2004). Bipolar disorder and substance abuse.
Biol. Psychiatry, 56 (10), 738-748.
![Page 22: Association between family history of mood disorders and clinical characteristics of bipolar disorder: Results from the Brazilian bipolar research network](https://reader035.fdocuments.in/reader035/viewer/2022081814/575096bc1a28abbf6bcd37c0/html5/thumbnails/22.jpg)
Lombardo, L. E., Bearden, C. E., Barrett, J., Brumbaugh, M. S., Pittman, B.,
Frangou, S., et al. (2012). Trait impulsivity as an endophenotype for bipolar I
disorder. Bipolar Disord., 14 (5), 565-570.
López, P., Mosquera, F., de León, J., Gutiérrez, M., Ezcurra, J., Ramírez, F., et
al. (2001). Suicide attempts in bipolar patients. J. Clin. Psychiatry, 62 (12), 963-966.
Manchia, M., Hajek, T., O'Donovan, C., Deiana, V., Chillotti, C., Ruzickova,
M., et al. (2013). Genetic risk of suicidal behavior in bipolar spectrum disorder:
analysis of 737 pedigrees. Bipolar Disord., 15 (5), 496-506.
Mantere, O., Suominen, K., Valtonen, H. M., Arvilommi, P., Leppämäki, S.,
Paunio, T., et al. (2012). Concomitants of family histories of mood disorders and
alcoholism in a clinical cohort of patients with bipolar I and II disorder. J. Nerv.
Ment.Dis., 200 (5), 388-394.
McElroy, S. L., Altshuler, L. L., Suppes, T., Keck, J. P., Frye, M. A.,
Denicoff, K. D., et al. (2001). Axis I psychiatric comorbidity and its relationship to
historical illness variables in 288 patients with bipolar disorder. Am. J. Psychiatry.,
158 (3), 420-426.
McElroy, S. L., Frye, M. A., Hellemann, G., Altshuler, L., Leverich, G. S.,
Suppes, T., et al. (2011). Prevalence and correlates of eating disorders in 875 patients
with bipolar disorder. J. Affect. Disord., 128 (3), 191-198.
Merikangas, K. R., Akiskal, H. S., Angst, J., Greenberg, P. E., Hirschfeld, R.
M., Petukhova, M., et al. (2007). Lifetime and 12-month prevalence of bipolar
spectrum disorder in the National Comorbidity Survey replication. Arch. Gen.
Psychiatry, 64 (5), 543-552.
![Page 23: Association between family history of mood disorders and clinical characteristics of bipolar disorder: Results from the Brazilian bipolar research network](https://reader035.fdocuments.in/reader035/viewer/2022081814/575096bc1a28abbf6bcd37c0/html5/thumbnails/23.jpg)
Moeller, F. G., Barratt, E. S., Dougherty, D. M., Schmitz, J. M., & Swann, A.
C. (2001). Psychiatric aspects of impulsivity. Am. J. Psychiatry, 158 (11), 1783-1793.
Mrad, A., Mechri, A., Rouissi, K., Khiari, G., & Gaha, L. (2007). [Clinical
characteristics of bipolar I patients according to their family history of affective
disorders]. Encephale, 33 (5), 762-767.
Nery, F. G., Hatch, J. P., Monkul, E. S., Matsuo, K., Zunta-Soares, G. B.,
Bowden, C. L., et al. (2013). Trait impulsivity is increased in bipolar disorder patients
with comorbid alcohol use disorders. Psychopathology, 46 (3), 145-152.
Nierenberg, A. A., Trivedi, M. H., Fava, M., Biggs, M. M., Shores-Wilson,
K., Wisniewski, S. R., et al. (2007). Family history of mood disorder and
characteristics of major depressive disorder: a STAR*D (sequenced treatment
alternatives to relieve depression) study. J. Psychiatr. Res, 41 (3-4), 214-221.
Nolen, W. A., Luckenbaugh, D. A., Altshuler, L. L., Suppes, T., McElroy, S.
L., Frye, M. A., et al. (2004). Correlates of 1-year prospective outcome in bipolar
disorder: results from the Stanley Foundation Bipolar Network. Am. J. Psychiatry,
161 (8), 1447-1454.
O'Mahony, E., Corvin, A., O'Connell, R., Comerford, C., Larsen, B., Jones,
R., et al. (2002). Sibling pairs with affective disorders: resemblance of demographic
and clinical features. Psychol. Med., 32 (1), 55-61.
Otto, M. W., Simon, N. M., Wisniewski, S. R., Miklowitz, D. J., Kogan, J. N.,
Reilly-Harrington, N. A., et al. (2006). Prospective 12-month course of bipolar
disorder in out-patients with and without comorbid anxiety disorders. Br. J.
Psychiatry, 189, 20-25.
![Page 24: Association between family history of mood disorders and clinical characteristics of bipolar disorder: Results from the Brazilian bipolar research network](https://reader035.fdocuments.in/reader035/viewer/2022081814/575096bc1a28abbf6bcd37c0/html5/thumbnails/24.jpg)
Pawlak, J., Dmitrzak-W?glarz, M., Skibi?ska, M., Szczepankiewicz, A.,
Leszczy?ska-Rodziewicz, A., Rajewska-Rager, A., et al. (2013). Suicide attempts and
clinical risk factors in patients with bipolar and unipolar affective disorders. Gen.
Hosp. Psychiatry, 35 (4), 427-432.
Peluso, M. A., Hatch, J. P., Glahn, D. C., Monkul, E. S., Sanches, M., Najt, P.,
et al. (2007). Trait impulsivity in patients with mood disorders. J. Affect. Disord., 100
(1-3), 227-231.
Perugi, G., Del Carlo, A., Benvenuti, M., Fornaro, M., Toni, C., Akiskal, K.,
et al. (2011). Impulsivity in anxiety disorder patients: is it related to comorbid
cyclothymia? J. Affect. Disord., 133 (3), 600-606.
Phillips ML, Kupfer DJ. (2013) Bipolar disorder diagnosis: challenges and
future directions. Lancet, 381(9878):1663-1671
Pompili, M., Gonda, X., Serafini, G., Innamorati, M., Sher, L., Amore, M., et
al. (2013). Epidemiology of suicide in bipolar disorders: a systematic review of the
literature. Bipolar Disord., 15 (5), 457-490.
Quarantini, L. C., Netto, L. R., Andrade-Nascimento, M., Almeida, A. G.-d.,
Sampaio, A. S., Miranda-Scippa, A., et al. (2009). [Comorbid mood and anxiety
disorders in victims of violence with posttraumatic stress disorder]. Rev. Bras.
Psiquiatr., 31 Suppl 2, S66--S76.
Rice, J., Reich, T., Andreasen, N. C., Endicott, J., Van Eerdewegh, M.,
Fishman, R., et al. (1987). The familial transmission of bipolar illness. Arch. Gen.
Psychiatry, 44 (5), 441-447.
![Page 25: Association between family history of mood disorders and clinical characteristics of bipolar disorder: Results from the Brazilian bipolar research network](https://reader035.fdocuments.in/reader035/viewer/2022081814/575096bc1a28abbf6bcd37c0/html5/thumbnails/25.jpg)
Roy, A. (2006). Family history of suicide and impulsivity. Arch. Suicide Res.,
10 (4), 347-352.
Sala, R., Goldstein, B. I., Morcillo, C., Liu, S.-M., Castellanos, M., & Blanco,
C. (2012). Course of comorbid anxiety disorders among adults with bipolar disorder
in the U.S. population. J. Psychiatr. Res., 46 (7), 865-872.
Sani, G., Tondo, L., Koukopoulos, A., Reginaldi, D., Kotzalidis, G. D.,
Koukopoulos, A. E., et al. (2011). Suicide in a large population of former psychiatric
inpatients. Psychiatry Clin. Neurosci., 65 (3), 286-295.
Sarchiapone, M., Carli, V., Janiri, L., Marchetti, M., Cesaro, C., & Roy, A.
(2009). Family history of suicide and personality. Arch. Suicide Res., 13 (2), 178-184.
Saunders, E. H., Scott, L. J., McInnis, M. G., & Burmeister, M. (2008).
Familiality and diagnostic patterns of subphenotypes in the National Institutes of
Mental Health bipolar sample. Am. J. Med. Genet. B Neuropsychiatr. Genet., 147B
(1), 18-26.
Schulze, T. G., Hedeker, D., Zandi, P., Rietschel, M., & McMahon, F. J.
(2006). What is familial about familial bipolar disorder? Resemblance among
relatives across a broad spectrum of phenotypic characteristics. Arch. Gen.
Psychiatry, 63 (12), 1368-1376.
Serretti, A., Chiesa, A., Calati, R., Linotte, S., Sentissi, O., Papageorgiou, K.,
et al. (2013). Influence of family history of major depression, bipolar disorder, and
suicide on clinical features in patients with major depression and bipolar disorder.
Eur. Arch. Psychiatry Clin. Neurosci., 263 (2), 93-103.
![Page 26: Association between family history of mood disorders and clinical characteristics of bipolar disorder: Results from the Brazilian bipolar research network](https://reader035.fdocuments.in/reader035/viewer/2022081814/575096bc1a28abbf6bcd37c0/html5/thumbnails/26.jpg)
Slama, F., Bellivier, F., Henry, C., Rousseva, A., Etain, B., Rouillon, F., et al.
(2004). Bipolar patients with suicidal behavior: toward the identification of a clinical
subgroup. J. Clin. Psychiatry, 65 (8), 1035-1039.
Smoller, J. W., & Finn, C. T. (2003). Family, twin, and adoption studies of
bipolar disorder. Am. J. Med. Genet. C Semin. Med. Genet., 123C (1), 48-58.
Sublette, M.E., Carballo, J. J., Moreno, C., Galfalvy, H. C., Brent, D. A.,
Birmaher, B., et al. (2009). Substance use disorders and suicide attempts in bipolar
subtypes. J. Psychiatr. Res., 43 (3), 230-238.
Swann, A. C., Dougherty, D. M., Pazzaglia, P. J., Pham, M., & Moeller, F. G.
(2004). Impulsivity: a link between bipolar disorder and substance abuse. Bipolar
Disord., 6 (3), 204-212.
Swann, A. C., Dougherty, D. M., Pazzaglia, P. J., Pham, M., Steinberg, J. L.,
& Moeller, F. G. (2005). Increased impulsivity associated with severity of suicide
attempt history in patients with bipolar disorder. Am. J. Psychiatry, 162 (9), 1680-
1687.
Swann, A. C., Lijffijt, M., Lane, S. D., Steinberg, J. L., & Moeller, F. G.
(2009). Increased trait-like impulsivity and course of illness in bipolar disorder.
Bipolar Disord., 11 (3), 280-288.
Taylor, C. T., Hirshfeld-Becker, D. R., Ostacher, M. J., Chow, C. W., LeBeau,
R. T., Pollack, M. H., et al. (2008). Anxiety is associated with impulsivity in bipolar
disorder. J. Anxiety Disord., 22 (5), 868-876.
Tsai, S.-Y. M., Kuo, C.-J., Chen, C.-C., & Lee, H.-C. (2002). Risk factors for
completed suicide in bipolar disorder. J. Clin. Psychiatry, 63 (6), 469-476.
![Page 27: Association between family history of mood disorders and clinical characteristics of bipolar disorder: Results from the Brazilian bipolar research network](https://reader035.fdocuments.in/reader035/viewer/2022081814/575096bc1a28abbf6bcd37c0/html5/thumbnails/27.jpg)
Young, L. T., Cooke, R. G., Robb, J. C., Levitt, A. J., & Joffe, R. T. (1993).
Anxious and non-anxious bipolar disorder. J. Affect. Disord., 29 (1), 49-52.
![Page 28: Association between family history of mood disorders and clinical characteristics of bipolar disorder: Results from the Brazilian bipolar research network](https://reader035.fdocuments.in/reader035/viewer/2022081814/575096bc1a28abbf6bcd37c0/html5/thumbnails/28.jpg)
Acknowledgements: This research was partly supported by a generous private
donation from the family of Thompson Motta (to PROMAN). Flavio Kapczinski is
supported by INCT-TM, CNPq, and CAPES. Angela Miranda-Scippa is supported by
CNPq. Beny Lafer is supported by State and Federal research grants from FAPESP,
CNPq and CAPES.
![Page 29: Association between family history of mood disorders and clinical characteristics of bipolar disorder: Results from the Brazilian bipolar research network](https://reader035.fdocuments.in/reader035/viewer/2022081814/575096bc1a28abbf6bcd37c0/html5/thumbnails/29.jpg)
Conflict of Interest: Fabiano Nery held a temporary position as an associate medical
advisor in Eli Lilly and Company from June 2012 to May 2013. Flavio Kapczinski is
a consultant for Eli Lilly and Lundbeck. Angela Scippa is a speaker for Abbott. The
other authors do not have any commercial associations that might pose a conflict of
interest in connection with this manuscript.
![Page 30: Association between family history of mood disorders and clinical characteristics of bipolar disorder: Results from the Brazilian bipolar research network](https://reader035.fdocuments.in/reader035/viewer/2022081814/575096bc1a28abbf6bcd37c0/html5/thumbnails/30.jpg)
Contributors: Authors Beny Lafer, Angela Miranda-Scippa, and Flavio Kapczinski
designed the study and wrote the protocol. Authors Fabiano G. Nery and Rodrigo
Sato collected data and organized the database. Authors Mariangeles Berutti and
Fabiano G. Nery managed the literature searches, undertook the statistical analysis,
and wrote the first draft of the manuscript. All authors contributed to and have
approved the final manuscript.
![Page 31: Association between family history of mood disorders and clinical characteristics of bipolar disorder: Results from the Brazilian bipolar research network](https://reader035.fdocuments.in/reader035/viewer/2022081814/575096bc1a28abbf6bcd37c0/html5/thumbnails/31.jpg)
Role of the Funding Source: The funding parties that supported this study had no
participation in the study design, the collection, analysis, and interpretation of data,
and in the writing of the report, or in the decision to submit the paper for publication.