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

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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: angie.berutti@gmail.com

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.

KEY WORDS: bipolar disorder; family history; mood disorder; comorbidity;

impulsivity.

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

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

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

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

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

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

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

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).

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

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.

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

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)

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)

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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.

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.

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.

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.