Acta Psychiatr Scand 2014: 130: 364373 2014 John Wiley & Sons A/S.

4 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
All rights reserved ACTA PSYCHIATRICA SCANDINAVICA
DOI: 10.1111/acps.12272

Bipolar disorder in the elderly: a cohort

study comparing older and younger patients
Nivoli AMA, Murru A, Pacchiarotti I, Valenti M, Rosa AR,
Hidalgo D, Virdis V, Strejilevich S, Vieta E, Colom F. Bipolar disorder
in the elderly: a cohort study comparing older and younger patients.
Objective: The purpose of this study was to analyze dierences in
clinical and socio-demographic characteristics between older and
younger bipolar outpatients paying special attention to depressive
symptoms in a large, naturalistic cohort.
Method: Five hundred and ninety-three DSM-IV-TR bipolar
outpatients were enrolled. Clinical characteristics were assessed
according to DSM-IV-TR (SCID-I). Subjects were categorized into two
groups according to current age (older OBD: age > 65 years; younger-
YBD: age < 65 years).
Results: About 80% of patients were younger (N = 470), and a fth
were older (N = 123), with a mean age of 77.30 years in OBD. Older
patients were more likely to be married, not qualied, bipolar II, with
depressive polarity of rst episode, higher age at illness onset, higher
age at rst hospitalization. They were more likely to present with
depressive predominant polarity, with lifetime history of catatonic,
psychotic and melancholic features, age at illness onset >40 years, as
well as suering from more medical comorbidities when compared to
younger bipolars.
Conclusion: The clinical presentation of bipolar disorder in late life
would be dened more frequently by melancholic depressive features
and a predominantly depressive polarity. These results suggest that
treatment strategies for elderly bipolar patients should focus in the
prevention of depressive episodes.
A. M. A. Nivoli1,2, A. Murru1,
I. Pacchiarotti1, M. Valenti1,
A. R. Rosa3,4, D. Hidalgo5,
V. Virdis6, S. Strejilevich7,
E. Vieta1, F. Colom1
1
Bipolar Disorders Unit, Institute of Neurosciences,
Hospital Clinic, University of Barcelona, IDIBAPS,
CIBERSAM, Barcelona, Catalonia, Spain, 2Department
of Neuroscience, Institute of Psychiatry, University of
Sassari, Sassari, Italy, 3Laboratory of Molecular
Psychiatry, Centro de Pesquisas Experimentais, Hospital
de Clnicas de Porto Alegre, INCT for Translational
Medicine, Porto Alegre, 4Centro Universitario La Salle,
Canoas, RS, Brazil, 5Hospital Clinic, Barcelona,
Catalonia, Spain, 6Geriatric Unit, Civil Hospital, Sassari,
Italy and 7Bipolar Disorder Program, Neurosciences
Institute, Favaloro University & Institute of Cognitive
Neurology (INECO), Buenos Aires, Argentina
Key words: bipolar disorder; elderly; predominant
polarity; melancholic features
Eduard Vieta, Bipolar Disorders Unit, Institute of
Neuroscience, Hospital Clinic, Villarroel 170, 9-0,
Barcelona 08036, Catalonia, Spain.
E-mail: evieta@clinic.ub.es
Accepted for publication March 7, 2014

Signicant outcomes
A depressive predominant polarity characterizes the course of the illness in older patients and sup-
ports the hypothesis of bipolar disorder (BD) in the elderly as a dierent entity with a specic clinical
presentation when compared to younger populations.
Specic depressive symptoms signicantly discriminated older and younger bipolar patients. Bipolar
depression in elderly presented more frequently with melancholic features, while younger patients
were characterized by atypical depression.
Age at illness onset >40 years was a signicant predictor of BD in the elderly, providing a new
insight into the relevant debate about the early- and late-onset BD as two distinct entities.

Limitations
The older adult patients in this study may represent a survivor cohort of older individuals with bipo-
lar disorder. Individuals who reside in non-community settings as well as individuals who died pre-
maturely are not included in our sample.
Retrospective assessment of historical illness variables of older patients inherent to time frame before
attending our Bipolar Unit may be aected by memory recall errors.
Suicide completions earlier in life may render the present older adults a survivor cohort.

364

Introduction
Bipolar disorder (BD) in old age is a growing
public health problem. Between 4% and 17% of
older patients in psychiatric settings would suer
a BD (1, 2). In selected populations, the preva-
lence rates for older BD are higher than for the
general population (9.7% in nursing homes, 8
10% in inpatient settings) (3, 4). BD in late life
is a clinically heterogeneous condition, perhaps
more so than in early life. This heterogeneity
presumably reects the combined inuences of
genetic vulnerabilities and the interplay of physi-
cal and psychosocial factors across the life span.
Data from literature suggested that older people
with BD may have a dierent clinical pattern
compared to younger (5, 6). Studies that directly
compared younger and older bipolar patients
found few dierences (3). The most consistent
nding was that older patients were more likely
to be women, and there was some evidence sup-
porting the lower frequency and milder severity
of mania in the elderly (7), even if other studies
have found no substantial dierences in (8).
Older patients with BD presented more often
with depressive episodes, less days of bipolar
symptoms, and a number of comorbid condi-
tions including substance/alcohol use, anxiety,
eating disorders, and medical comorbidities (9
11). Among inpatients, the ones who were older
at rst psychiatric hospitalization (>50 years)
presented with less psychotic mania and more
severe psychotic depression. Among outpatients,
no statistical dierence was found between
patients with late and early rst outpatient con-
tact (12).
Data regarding late-life mania (13, 14) have
emphasized a number of ndings including the
high prevalence of cognitive dysfunction (4, 15,
16), abnormalities on structural neuroimaging
(17), potential genetic susceptibility (18), and the
association between these disorders and neurologic
disorders, especially cerebrovascular disease (5).
However, most studies examined age-related char-
acteristics of depression without specically
addressing bipolar depression (19). One study (20)
reported increased psychotic symptoms in older
patients with BD II, with atypical depressive fea-
tures being less common in late life.
In general, the current literature provided con-
icting information on age-related BD symptom
presentation (2, 21), and the majority of studies
have focused on hospitalized manic patients.
Moreover, many studies are hindered by small
sample sizes, and older outpatients are often
under-represented (3). Reports on dierences in
Bipolar disorder in the elderly
the clinical presentation of BD among older and
younger patients are so far inconclusive, requesting
additional rigorous studies in larger samples.
Studying such dimensions has important impli-
cations for intervention and prevention strategies
in geriatric research and clinical care. This under-
standing is crucial to better approach a population
that carries signicant morbidity, mortality, eco-
nomic burden, and poor responses to standard
treatment. Moreover, in older adults, BD depres-
sion appears to be particularly malignant, being
associated with substantial medical comorbidi-
ty, early impairment, premature mortality, and
reduced quality of life (3, 22, 23).
Aims of the study
Taking into consideration this gap in scientic
knowledge, the purpose of our study was to deter-
mine dierences in clinical and socio-demographic
characteristics between older and younger bipolar
outpatients in a large, representative naturalistic
bipolar disorder cohort. Special attention to
depressive symptoms was placed, concerning both
current and lifetime depressive features.
Material and methods
Five hundred and ninety-three DSM-IV-TR bipo-
lar outpatients were enrolled in a naturalistic
cohort study at the outpatient Bipolar Disorders
Unit, Hospital Clinic, University of Barcelona.
Entry criteria required subjects to be diagnosed
with DSM-IV-TR criteria for BD (type I, II, NOS),
aged >18 years. Current mood symptoms (at the
time of assessment) were rated and classied on the
basis of DSM-IV criteria (also for melancholic,
psychotic, and atypical depressive symptoms).
Lifetime assessment of mood episodes and symp-
toms during the naturalistic follow-up at the Barce-
lona Bipolar Disorder Unit was extracted from
clinical records and past mental state examinations
systematically collected. Mood symptoms and epi-
sodes before patients recruitment at Barcelona
Unit were based on the evaluation of previous
medical records and interviews with the patient
and family members. This study is a systematic fol-
low-up, as described in previous paper (24) with
some variables coming from a prospective assess-
ment (longitudinal, naturalistic follow-up at the
Barcelona Bipolar Unit) and others having been
collected retrospectively. For retrospective vari-
ables, including past treatments, age at onset, pre-
vious hospitalization, medical comorbidities, a
very accurate data collection was performed:
clinical information was conrmed by means of
365
Nivoli et al.
structured interviews, and clinical features were
evaluated using specic rating scales, and compre-
hensive interviews administered by psychiatrists
and psychologists, adequately trained to enhance
inter-rater reliability. The history of illness was
gathered by clinical les, lifetime computerized
medical recordswhich registered any treatment/
hospitalization of patients in any medical center
throughout the public setting of our countrycor-
responding to the last 5 years and additional infor-
mation from previous non-computerized clinical
records. Cognitive impairment was assessed by
trained neuropsychologists thought specic exami-
nation, but only severe general cognitive impair-
ment was registered for this study. Informed
consent was signed, and condentiality was pre-
served. Psychiatric diagnoses were conrmed by
structured interviews (SCID-I) (25). All available
data were cross-referred. Predominant polarity
was dened as 2/3 of the total number of episodes
being of the same polarity (depressive or manic/
hypomanic), as plentifully described elsewhere
(26). Patients were treated accordingly with the
Barcelona Bipolar Disorders Unit treatment algo-
rithms and good clinical practice for BD (27).
Statistical analyses
Subjects were categorized according to age (older
OBD: age > 65 years; younger-YBD: age < 65
years) (28). Data were analyzed with Students
t-tests/ANOVA and Pearson chi-square/Fishers
exact test in contingency tables (chi-squared) (Bon-
ferroni corrections). Mean dierences in quantita-
tive variables with a non-normal distribution were
assessed with MannWhitney U-test for two inde-
pendent groups. Signicance was set at P < 0.05
(two-tailed). A further analysis was undertaken
according to age at illness onset (early-onset
EOBD: <40 years; late-onset LOBD: >40 years)
(29) and to predominant polarity (manic/hypo-
manic-MPP vs. depressive-DPP) (26). There is not
an unequivocal denition of late and early onset of
the illness, and the scientic community lacks to
provide a worldwide agreement. The choice of the
age of 40 years referred to an admixture analysis
used to determine the best-tting model for
observed ages at onset of 368 consecutively admit-
ted patients (29). The results obtained by authors
have been compared with those of other models.
The mean ages estimated in this model allowed to
identify three age-at-onset subgroups: early
(17.4 years, SD = 2.3), intermediate (25.1 years,
SD = 6.2), and late age at onset (40.4 years,
SD = 11.3). Another group conrmed these
analyses in a bigger sample of 1082 bipolar
366
patients (30) and shows that patients from
these subgroups diered in clinical phenotypes. A
multiple regression model was applied to detect
the variables associated with the age (outcome, as
a continuous variable, to detect every possible
correlation of clinical variables across age). Multi-
collinearity and extreme cases were excluded, and
normality of residuals was checked (histograms
and PP plots). Power analyses indicated that the
sample size provided enough power (>80%) to
detect a statistically signicant dierence between
the two groups in the range of 1520% (current
age as dependent variable). Statistical analyses
were performed using the Statistical Package for
Social Sciences (SPSS, 18.0 version for Windows;
IBM Corporation, Armonk, NY, USA).
Results
The sample was composed by 593 bipolar patients
consecutively enrolled at the Barcelona Bipolar
Disorder Unit, 267 men (45%) and 326 women
(55%). In our sample of 593 bipolar patients,
about 40% of patients was of so-called dicult-to-
treat patients (n = 238, 40.13%), meaning that
they come from all over Spain to be attended at
the Bipolar Unit of Barcelona, and 59.78%
(n = 355) come directly from our catchment area:
it means that they are not dicult-to-treat
patients, but they can be dened as belonging to
bipolar patients general population. Distribution
of socio-demographic variables and clinical char-
acteristics by current age is showed in Table 1.
OBD were more likely to be diagnosed with a BD
II (41.5% vs. 25.5%, v2 = 12.018, P = 0.001),
while in the YBD group, BD I was more frequent.
Onset episode in OBD was signicantly more
likely to be depressive (79.3% vs. 68%) with higher
age at illness onset (40.05 years, SD = 16.16;
P < 0.001), while a manic/hypomanic episode was
more likely to characterize illness onset in the
YBD (32.6% vs. 20.4%) with earlier age at onset
(25.21 years, SD = 8.75; P < 0.001). OBD were
more likely to present with a depressive predomi-
nant polarity (30.9% vs. 22.3%, v2 = 3.898,
P = 0.048), while a manic/hypomanic predomi-
nant polarity of the course was signicantly dis-
played by younger (21.3% vs. 10.6%, v2 = 7.246,
P = 0.007). OBD had their rst hospitalization at
a mean age of 51.53, signicantly older than YBD
(29.39 years, P > 0.001). BD in elderly presents
more frequently with lifetime history of catatonic
(9.1% vs. 3.1%, v2 = 0.096, P = 0.047) and melan-
cholic features (56.3% vs. 31.1%, v2 = 21.093,
P < 0.001) and psychotic symptoms. YBD had
lifetime history of atypical depression (23.4% vs.
 Bipolar disorder in the elderly

Table 1. Key demographic and clinical variables (categorical and quantitative) in patients aged <65 years compared with patients aged >65 years in the total sample (n = 593)

Current age < 65 years Current age > 65 years

(n = 470) (n = 123)

N % N % Statistic (v) P

Gender
Male 220 46.8 47 38.2 2.911 0.088
Female 250 53.2 66 71.8
Marital status
Never married 215 47.0 14 11.6 50.330 <0.001
Married 242 53.0 107 88.4
Educational level
Qualified 252 56.0 31 27.2 30.193 <0.001
Not qualified 198 44.0 83 72.8
Cohabitation
Cohabiter 377 80.2 86 69.9 6.058 0.048
Not cohabiter 59 12.6 23 18.7
Working activity
Worker 16 3.6 5 4.4 0.175 0.676
Not worker 434 96.4 109 95.6
Personal autonomy
Good 354 84.3 77 78.6 1.857 0.173
Bad 66 15.7 21 21.4
Adherence to treatment
Good 283 66.9 74 73.3 1.521 0.127
Bad 140 33.1 27 26.7
DSM-IV diagnosis
Bipolar type I 332 70.6 67 54.5 12.018 0.001
Bipolar type II 120 25.5 51 41.5
Bipolar NOS 18 3.8 5 4.1
Presence of predominant polarity*
Yes 205 80.1 51 19.9 0.162 0.687
No 210 78.7 57 21.3
Manic/hypopredominant polarity 100 21.3 13 10.6 7.246 0.007
Depressive predominant polarity 105 22.3 38 30.9 3.898 0.048
Predominant polarity at first episode
Manic/hypomanic 136 32.6 21 20.4 5.350 0.021
Depressive 289 68.0 82 79.3
Illness onset >40 years 37 8.4 60 52.2 120.740 <0.001
Psychotic symptoms (lifetime) 252 58.3 62 54.4 0.575 0.448
Psychotic symptoms (first episode) 137 32.8 31 28.7 0.654 0.419
Presence of stressful life events 240 62.3 65 67.0 0.728 0.394
Seasonality 124 30.2 36 33.0 0.330 0.566
Rapid cycling 92 21.5 24 21.6 0.001 0.977
Catatonic features 13 3.4 9 9.1 0.096 0.047
Melancholic features 119 31.1 54 56.3 21.093 <0.001
Atypical depressive symptoms 86 23.4 12 12.8 5.037 0.025
Delusions (lifetime) 365 90.8 96 97.0 4.121 0.042
Family history of affective disorder 280 64.7 55 50.9 6.920 0.009
Family history of suicide 67 15.7 16 15.7 0.000 0.999
Suicide ideation 288 71.1 67 66.3 0.880 0.348
Suicide attempts 131 31.2 30 29.1 0.165 0.684
Alcohol abuse 44 9.4 14 11.4 0.451 0.502

Current age < 65 years Current age > 65 years

(n = 470) (n = 123)
Statistic
Mean SD Mean SD (Students t-test) P

Age (current) 46.14 10.09 77.30 25.37 13.348 <0.001

Age at illness onset 25.21 8.75 40.05 16.16 9.497 <0.001
Age at first hospitalization 29.39 10.44 51.53 16.03 10.511 <0.001

367
Nivoli et al.

Table 1. (Continued)

Current age < 65 years Current age > 65 years

(n = 470) (n = 123) Statistic
(MannWhitney
Mean SD Mean SD U-test) P

Total hospitalizations (n) 1.84 2.16 2.15 2.99 21952.0 0.817

Total episodes (n) 14.62 17.30 19.85 26.27 25009.5 0.239
Affective episodes (n)
Manic 2.54 3.78 2.27 4.08 18029.5 0.037
Hypomanic 4.55 7.73 7.11 12.11 21358.0 0.082
Depressive 6.98 8.86 10.72 15.16 25295.0 0.061
Mixed 0.76 1.88 0.53 1.55 17625.0 0.383
Suicide attempts (n) 0.77 2.25 0.50 1.04 16379.5 0.468

*Percentages are referred to predominant polarity Yes or No.

Range 74.1182.7.

12.8%, v2 = 5.037, P = 0.025), a signicantly present with melancholic features compared to

higher frequency of family history of aective dis-
order (64.7% vs. 50.9%, v2 = 6.920, P = 0.009)
and a higher number of manic episodes
(P = 0.037; Table 1). Several medical comorbidi-
ties were detected in our sample, being mostly pres-
ent in the older group (Table 2).
A further analysis was performed by grouping
patients on the basis of depressive predominant
polarity (Table 3). Among patients with depressive
predominant polarity (n = 143), almost a half of
older patients (45.9%) had the illness onset after
40 years compared to 11.3% of younger patients
(19.405, P < 0.001). Older predominantly
depressed bipolar patients were more likely to
younger predominantly depressed patients (62.5%
vs. 38.2%, v2 = 5.623, P = 0.018).
When all predictors were entered together in a
multivariate analysis, including diagnosis, to adjust
for this variable when looking at age-related dier-
ences, the amount of variation in our outcome that
was accounted for all predictors (R2-value) was
34.8% (P < 0.001) (Table 4). If the eect of all
other predictors was held constant, a signicant
positive contribution to the outcome was given by
illness onset >40 years (b = 0.177; P = 0.001), age
at illness onset (b = 0.151, P = 0.014), and age
at rst hospitalization (b = 0.212; P < 0.001),
presence of cognitive impairment (b = 0.077;

Table 2. Medical comorbidity in the total sample (n = 593) by age

Current age < 65 years Current age > 65 years

(n = 470) (n = 123)
Statistic
N % N % (v) P

Coronary heart disease 1 0.8 6 10.2 8.999* 0.006

Chronic heart failure 3 2.5 7 12.1 6.586* 0.016
Acute myocardial infarction 3 2.5 5 8.6 3.311* 0.117
Arterial Hypertension 25 21.2 16 27.1 0.778 0.378
Atherosclerosis 1 0.8 5 8.5 6.987* 0.016
Deep venous insufficiency 0 0 3 5.2 6.209* 0.035
Dyslipidemia 9 7.6 7 11.5 0.732 0.392
Obesity 1 0.8 3 5.2 3.275* 0.105
Diabetes mellitus type I 1 0.9 1 1.3 0.246 1.000
Diabetes mellitus type II 10 8.5 13 21.0 5.692 0.017
Vascular dementia 0 0 4 6.6 7.915* 0.013
Alzheimers disease 0 0 4 6.6 8.327* 0.011
General cognitive impairment 0 0 5 8.8 10.655* 0.003
Parkinsons disease 1 0.8 3 5.2 3.275* 0.105
Ischemic cerebrovascular disease 1 0.8 5 8.8 7.363* 0.014
Epilepsy 3 2.5 1 1.7 0.117* 1.000
Pulmonary chronic disease 4 3.4 9 15 7.817* 0.011
Osteoporosis 1 0.9 6 10.2 8.911* 0.006
Cancer 3 2.6 11 19.6 14.853* <0.001
Chronic renal failure 0 0 5 8.6 10.383* 0.004
Motors side effects 0 0 4 7.4 8.874* 0.009

*Fishers exact test (significance two-tailed).

Motor side effects for which patient attended at emergency service.

368
 Bipolar disorder in the elderly

Table 3. Main age-related differences in clinical and socio-demographic characteristic (categorical and quantitative) in patients with depressive predominant polarity (n = 143)

Current age < 65 years Current age > 65 years

(n = 105) (n = 38)

N % N % Statistic (v) P

Gender
Male 42 40.0 14 36.8 0.117 0.733
Marital status
Never married 32 32.0 7 18.4 2.504 0.114
Married 68 68.0 31 81.6
Educational level
Qualified 58 58.0 10 27.8 9.761 0.002
Not qualified 42 42.0 26 72.2
Working activity
Not worker 97 97.0 34 94.4 0.488 0.485
DSM-IV diagnosis
Bipolar type I 67 65.0 19 51.4 2.953 0.086
Bipolar type II 36 35.0 18 48.6
Predominant polarity at first episode
Manic/hypomanic 10 10.1 2 6.3 0.431 0.511
Depressive 89 89.9 30 93.8
Illness onset >40 years 11 11.3 17 45.9 19.405 <0.001
Psychotic symptoms (lifetime) 46 47.9 20 55.6 0.611 0.434
Catatonic features 2 2.2 3 9.4 3.019 0.086
Melancholic features 34 38.2 20 62.5 5.623 0.018
Atypical depressive symptoms 19 22.6 7 21.9 0.007 0.932
Psychotic depression 22 26.2 8 30.8 0.210 0.647
Family history of affective disorder 67 70.5 18 54.5 2.804 0.094
Suicide ideation 66 69.5 19 59.4 1.103 0.294

Current age < 65 years Current age > 65 years

(n = 105) (n = 38)
Statistic
Mean SD Mean SD (Students t-test) P

Age (current) 48.4 9.3 80.8 43.9 4.055 <0.001

Age at illness onset 27.7 8.7 38.1 15.2 21.621 <0.001
Age at first hospitalization 32.4 10.6 49.3 14.8 4.236 <0.001

Current age < 65 years Current age > 65 years

(n = 105) (n = 38)
Statistic
Mean SD Mean SD (MannWhitney U-test) P

Total hospitalizations (n) 1.4 1.9 1.4 1.4 1.748 0.587

Total episodes (n) 11.4 14.5 14.5 20.3 1.868 0.613
Affective episodes (n)
Manic 1.1 1.4 0.8 1.1 1.459 0.376
Hypomanic 2.1 4.3 3.0 5.2 1.567 0.210
Depressive 7.3 10.0 10.7 15.3 2.299 0.162
Mixed 0.8 1.8 0.4 0.8 1.248 0.186
Suicide attempts (n) 0.8 1.5 0.4 0.7 1.061 0.489

P = 0.035), melancholic features (b = 0.1137; of 593 bipolar outpatients, with special attention
P < 0.001), and other medical illnesses, such as to depressive symptoms (both current and life-
Type II diabetes mellitus (b = 0.157; P = 0.041), time).
Alzheimers disease (b = 0.654; P < 0.001), and There were three main key ndings in the pres-
coronary heart disease (b = 0.460; P = 0.34). ent study which we considered as important contri-
butions to an understudied, even if gradually
growing, area of knowledge: i) several socio-demo-
Discussion
graphic and clinical dierences between older and
The purpose of this study was to determine dier- younger outpatients, ii) a specic predominant
ences in clinical and socio-demographic character- polarity dierentiated the two groups, and iii) spe-
istics between older and younger bipolar cic depressive symptoms signicantly discrimi-
outpatients, enrolled in a naturalistic cohort study nated older and younger bipolar patients.

369
Nivoli et al.

Table 4. Multiple regression model of current age in the total sample (n = 593)

Variable B Std error b t Sig 95% CI

Constant 0.372 0.062 5.999 < 0.001 0.494 0.250

DSM-IV diagnosis (bipolar I vs. II) 0.048 0.032 0.054 1.493 0.136 0.015 0.111
Depressive polarity of first episode 0.019 0.035 0.020 0.550 0.582 0.087 0.049
Depressive predominant polarity 0.029 0.033 0.030 0.858 0.391 0.037 0.094
Melancholic features 0.128 0.033 0.137 3.913 < 0.001 0.064 0.192
Catatonic features 0.046 0.063 0.026 0.741 0.459 0.077 0.169
Family history of affective disorders 0.001 0.030 0.001 0.017 0.987 0.060 0.059
Illness onset >40 years old 0.195 0.061 0.177 3.197 0.001 0.075 0.316
Age at illness onset 0.005 0.002 0.151 2.475 0.014 0.001 0.009
Age at first hospitalization 0.008 0.002 0.212 4.824 < 0.001 0.005 0.011
Coronary heart disease 0.460 0.216 0.121 2.127 0.034 0.035 0.884
Chronic heart failure 0.131 0.133 0.041 0.988 0.324 0.393 0.130
Atherosclerosis 0.210 0.232 0.051 0.905 0.366 0.666 0.246
Diabetes mellitus type II 0.157 0.076 0.071 2.048 0.041 0.006 0.307
Alzheimers disease 0.654 0.174 0.131 3.761 < 0.001 0.312 0.995
Vascular dementia 0.180 0.182 0.036 0.989 0.323 0.178 0.538
Parkinsons disease 0.118 0.180 0.024 0.657 0.511 0.235 0.472
Ischemic cerebrovascular disease 0.238 0.160 0.058 1.492 0.136 0.075 0.552
Cancer 0.155 0.106 0.056 1.467 0.143 0.053 0.362
Cognitive impairment 0.347 0.164 0.077 2.113 0.035 0.024 0.669

Dependent variable: Current age. All predictors entered in one block (hierarchical method).
Model summary: R = 0.590; R2 = 348; DurbinWatson test = 0.676; ANOVA: F = 16.255; Sig, P < 0.001.
Bold values denote statistical significance.

multivariate analyses for BD in the elderly. This

Socio-demographic and general clinical differences
Our data showed that older patients were more
likely to be married and not qualied compared to
younger ones, but both were signicantly more
likely not to be employed. These results were
similar to data by Al Jurdi et al. (2) where signi-
cantly higher percentages of older participants
(STEP-BD) were married (51.6%) compared to
younger, conrmed in a more recent study (4). It is
important to specify that some results about socio-
demographic features can be related to the socio-
economic environment where the study has been
conducted, limiting the interpretation of their clini-
cal relevance, and need further evaluation. The
authors found patients not to dier on bipolar sub-
type, while in our sample, OBD subjects were more
likely to be diagnosed with a BD II disorder, while
YBD were more frequently BD I. The rst episode
of the illness in older patients was signicantly
more likely to be depressive with a later onset
(around 40 years) and with the rst hospitalization
signicantly later compared to younger patients.
On the other hand, the younger patients presented
with manic/hypomanic rst episode at earlier age
(around 25 years) and with the rst hospitalization
signicantly earlier. Our analysis did not show any
further information or dierence when analyses
were performed by grouping older patients by cur-
rent age and measuring intragroup dierences on
the basis of the age at illness onset (cuto point
40 years). On the other hand, age at illness
onset >40 years was a signicant predictor in our
result should not be interpreted as to suggest that a
later age at onset confers greater longevity in peo-
ple with BD. It simply has got a statistical signi-
cance in being associated with older bipolar
patients. Our data provided additional support to
the hypothesis of using age at onset to identify
more homogeneous groups of individuals with BD,
which may represent dierent subtypes of BD (13,
16, 31). In our sample, OBD presented more fre-
quently with catatonic features and psychotic
symptoms compared with YBD, conrming previ-
ous data (20). YBD were characterized by a signi-
cant presence of family history of aective disorder
compared to older patients, and this was somewhat
inconsistent with Depp and Jestes nding (3) that
noticed that family history of psychiatric disorder
was more frequent among older patients. This
inconsistence may be interpreted on the basis of the
fact that the majority of data revised by Depp and
Jeste derived from studies of inpatient and institu-
tionalized psychiatric populations, which reected
a higher severity of illness and more neurobiologi-
cal underpinnings than the outpatients recruited in
our study. On the other hand, our sample of old
outpatients may be much more representative of
the general population of older bipolar patients
who seek treatment in the clinical practice, and our
data conrm previous nding about the high fam-
ily history of psychiatric disorders in younger
patients (12). The prevalence of medical comorbidi-
ty in older patients detected in our sample was in
line with previous reports in the same setting (32).

370

Predominant polarity
The presence of depressive predominant polarity
in older patients compared to the manic/hypo-
manic predominant polarity in younger patients is
perhaps the main contribution of our study. These
data support previous ndings which suggested a
prevalence of depression in the elderly and mania
in younger bipolar patients (3). Anyway, our
results add a new concept. The fact that a specic
predominant polarity was dierently distributed in
the two age-related groups gives us information
about the specic course of the illness and may be
a further support to the hypothesis proposed by
some authors of BD in the elderly as a dierent
entity with a specic clinical presentation when
compared to BD in younger populations. This is
not an absolute statement whose aim is to conrm
this hypothesis, but a new suggestion for motivat-
ing further studies on age-related dierences in
predominant polarity. Predominant polarity, con-
ceptualized by Colom et al. (26), and conrmed in
dierent samples (33, 34), identies a valid prog-
nostic parameter with diagnostic and therapeutic
implications. As suggested by the literature,
Depressive Polarity has been found to be strongly
associated with depressive or mixed onset of BD,
lifetime history of attempted suicide and a higher
mean number of suicide attempts as well as ear-
lier age of onset, longer duration of illness and
higher number electroconvulsive treatment, longer
latency-to-BD diagnosis, more Axis-II comorbidi-
ty, mixed states, being married, and female gender
(24, 26, 32, 34). All together these ndings led us to
conrm that subtyping bipolar patients by pre-
dominant polarity yields predictive associations
and may contribute to improve planning of clinical
care and to biological studies of BD. Our nding
conrmed the importance of this concept as a sig-
nicant course specier and added new informa-
tion in the eld of geriatric psychiatry. The
treatment implications include the necessary focus
in preventing depression using medications with
low polarity index, as dened by Popovic et al.
(35); those medications are more suitable for
patients with predominant depressive episodes;
moreover, drugs with a lower risk for interactions
and a benign cognitive prole should also be given
preference.
Specific depressive symptoms
In our sample, BD in elderly presented more fre-
quently with melancholic features, while younger
patients were characterized by atypical depression.
Melancholic features kept being a signicant
Bipolar disorder in the elderly
predictor for elderly in the multivariate analysis.
Melancholic depression has been associated in pre-
vious studies with more severe symptomatology,
family history of depression, greater biological
underpinnings, more evidence of neurobiological
abnormalities, concomitant evidence of biological
dysfunction particularly involving the hypotha-
lamicpituitaryadrenal axis and poor response to
placebo (3640). Some data suggested that melan-
cholic depression is reported to be more common
in severe, psychotic depression, and in old age both
inpatients (41) and outpatients (42). In this study
on unipolar and bipolar II outpatients, Benazzi
found that the group of patients with melancholic
depression dierentiated from the atypical group
as the following: higher age, higher age at onset,
fewer women, more unipolar cases, fewer bipolar
II cases, lower functioning, more depression, and
more psychotic features. Our ndings conrmed
these data but are at odds with some previous nd-
ings: in a recent study in patients with BD I by Al
Jurdi et al. (2), no dierences between older and
younger adults regarding depression were found. It
is not clear whether melancholic depression is a
distinct depressive subtype or rather represents a
point on a continuum of severity of depression
(43), and this could be particularly true for bipolar
depression, where melancholic and atypical fea-
tures should not be understood necessarily in a
strict DSM way as two opposite ways of depres-
sion, as one does not exclude the other when it
comes to bipolar presentation (38). On the other
hand, atypical depression seemed to characterize
the depressed symptomatology of younger bipolar
patients in our sample. It has already been proved
that atypical features are present in 40% of bipolar
patients and associated with lower age at onset
(44).
Our ndings did not necessarily support to the
hypothesis of a melancholic/atypical dichotomy; it
may well be that aging helps the progressive me-
lancholization of bipolar depression by impacting
on mood reactivity and energy. Taken together,
these observations could be interpreted as late-life
BD deserves specic attention.
A number of methodological limitations need to
be considered when interpreting these ndings. A
limitation may include the last-resort nature of the
Barcelona Bipolar Program at Hospital Clinic,
which implies a percentage of so-called dicult-to-
treat patients. However, over 60% of our sample
did come directly from our catchment area and are
more representative of the standard bipolar popu-
lation that the dicult-to-treat patients. Anyway,
in our analyses, we did not dierentiate patients on
the basis of the geographic area (local vs. patients
371
Nivoli et al.
from all over Spain). The older adult patients in
this study may represent a survivor cohort of
older individuals with BD. Individuals who reside
in non-community settings as well as individuals
who died prematurely are obviously not included
in our elderly sample. Cognitive impairment was
assessed by trained neuropsychologists thought
specic examination, but only severe general cog-
nitive impairment was registered for this study.
Data from previous studies are controversial, and
further studies are needed to better understand the
overlapping with dementia and mild cognitive
impairment in bipolar patients. Anyway, the pres-
ent study is not specically aimed the understand-
ing of this topic. Instead, we have focused in
detecting some dierences in the clinical presenta-
tion of depression within a sample of bipolar
patients across life spam. The fact that older
patients show also general severe cognitive impair-
ment, in a very small percentage (8.8%) in our
sample, does not invalidate our observation about
clinical presentation of depression in older bipolar
patients. It is important to mention that patients
with the diagnosis of depression due to a general
medical condition were excluded, a diagnosis
which is given when depressed mood or anhedonia
occurs in patients already diagnosed with a medi-
cal illness that is associated with depression. This
sample consists of patients with the diagnosis of
BD following the DSM-IV criteria. Treatment of
BD and/or depressive symptoms in the elderly is
one of the major challenges for clinicians due to its
heterogeneous clinical presentation, its high com-
orbidity, and the degree of illness-related disability
in this specic age frame. Anyway, it was not the
aim of the present study to provide readers with
specic treatment recommendations for older
bipolar patients. The analysis of what medication
would be better than another in this specic
patients population would deserve a very complex
discussion, and it would constitute another article
per se.
We believe that our report is an important addi-
tion to the literature in late-life BD with a number
of methodological strengths, including the use of a
relatively large representative sample of outpa-
tients, current DSM diagnostic assessment, higher
age stratication compared with previous studies
(>65 years old and mean age of 77.3 years), long-
lasting naturalistic follow-up of the illness course.
This is the rst study that specically analyzed the
presence of depressive symptoms by applying a
conceptualized specier of course such as predomi-
nant polarity. Furthermore, this study results from
a cross-sectional analysis of a prospective natural-
istic follow-up (24, 44, 45). The long time frame of
372
this study (mean duration 10.4 years) provides a
large number of clinical evaluations with high
diagnostic accuracy and the absence of bias associ-
ated with recalling historical data for most vari-
ables: single time-point assessment of patients in
previous retrospective studies may lead to the
unreliability of patients recall and heterogeneity in
diagnoses. Patients are well known and carefully
diagnosed during this naturalistic follow-up, with
excellent reliability.
The present study showed a number of age-
related dierences in clinical and socio-demo-
graphic between older and younger bipolar
outpatients. The most original nding is about the
clinical presentation of BD in late life. Older bipo-
lar patients presented with a depressive predomi-
nant polarity of the course and with melancholic
depressive features more frequently than their
younger counterpart.
This is the rst study that specically reports a
signicant relationship between age and predomi-
nant polarity, with potential clinical implications
in diagnosis and treatment. Therapy should priori-
tize the prevention of depressive episodes. Further-
more, our data emphasize the importance of
melancholic depression in older bipolar patients,
help to better dene a specic subgroup population
of BD in the elderly, and provide community-
based priorities for future psychiatric research.
Our study oers intriguing ndings for further
testing and contributes to our understanding of
patients with late-life BD and their underlying
pathophysiology.
References
1. Sajatovic M, Chen P. Geriatric bipolar disorder. Psychiatr
Clin North Am 2011;34:319333.
2. Al Jurdi RK, Schulberg HC, Greenberg RL et al. Charac-
teristics associated with inpatient versus outpatient status
in older adults with bipolar disorder. J Geriatr Psychiatry
Neurol 2012;25:6268.
3. Depp CA, Jeste DV. Bipolar disorder in older adults: a crit-
ical review. Bipolar Disord 2004;6:343367.
4. Sheeran T, Greenberg RL, Davan LA et al. A descriptive
study of older bipolar disorder residents living in New
York Citys adult congregate facilities. Bipolar Disord
2012;14:756763.
5. Besga A, Martinez-Cengotitabengoa M, Gonzalez-Ortega I
et al. The role of white matter damage in late onset bipolar
disorder. Maturitas 2011;70:160163.
6. DellOsso B, Buoli M, Bortolussi S et al. Patterns of Axis
I comorbidity in relation to age in patients with Bipolar
Disorder: a cross-sectional analysis. J Aect Disord
2011;130:318322.
7. Oostervink F, Boomsma MM, Nolen WA et al. Bipolar dis-
order in the elderly: dierent eects of age and of age of
onset. J Aect Disord 2009;116:176183.
8. Benedetti A, Scarpellini P, Casamassima F, Lattanzi L,
Liberti M, Musetti L, Cassano GB. Bipolar disorder in late

life: clinical characteristics in a sample of older adults
admitted for manic episode. Clin Pract Epidemiol Ment
Health 2008;4:22.
9. Dols A, Rhebergen D, Beekman A, Kupka R, Sajatovic M,
Stek ML. Psychiatric and medical comorbidities: results
from a bipolar elderly cohort study. Am J Geriatr Psychia-
try 2014; doi: 10.1016/j.jagp.2013.12.176 [Epub ahead of
print].
10. Kemp DE, Sylvia LG, Calabrese JR et al. General medical
burden in bipolar disorder: ndings from the LiTMUS
comparative eectiveness trial. Acta Psychiatr Scand
2014;129:2434.
11. Goldstein BI, Herrmann N, Shulman KI. Comorbidity in
bipolar disorder among the elderly: results from an epide-
miological community sample. Am J Psychiatry
2006;163:319321.
12. Kessing LV. Diagnostic subtypes of bipolar disorder in
older versus younger adults. Bipolar Disord 2006;8:5664.
13. Leboyer M, Henry C, Paillere-Martinot ML et al. Age at
onset in bipolar aective disorders: a review. Bipolar Dis-
ord 2005;7:111118.
14. Sajatovic M, Blow FC, Ignacio RV et al. New-onset bipo-
lar disorder in later life. Am J Geriatr Psychiatry
2005;13:282289.
15. Schouws SNTM, Stek ML, Comijs HC et al. Cognitive
decline in elderly bipolar disorder patients: a follow-up
study. Bipolar Disord 2012;14:749755.
16. Martino DJ, Strejilevich SA, Manes F. Neurocognitive
functioning in early-onset and late-onset older patients
with euthymic bipolar disorder. Int J Geriatr Psychiatry
2013;28:142148.
17. Zanetti MV, Cordeiro Q, Busatto GF. Late onset bipolar
disorder associated with white matter hyperintensities: a
pathophysiological hypothesis. Prog Neuropsychophar-
macol Biol Psychiatry 2007;31:551556.
18. Faraone SV, Glatt SJ, Su J et al. Three potential suscepti-
bility loci shown by a genome-wide scan for regions inu-
encing the age at onset of mania. Am J Psychiatry
2004;161:625630.
19. Husain MM, Rush AJ, Sackeim HA et al. Age-related char-
acteristics of depression: a preliminary STAR*D report.
Am J Geriatr Psychiatry 2005;13:852860.
20. Benazzi F. Bipolar II depression in late life: prevalence and
clinical features in 525 depressed outpatients. J Aect
Disord 2001;66:1318.
21. Montes JM, Alegria A, Garcia-Lopez A et al. Understand-
ing bipolar disorder in late life: clinical and treatment cor-
relates of a sample of elderly outpatients. J Nerv Ment Dis
2013;201:674679.
22. Ciulla L, Lopes Nogueira E, Da Silva Filho IG et al. Sui-
cide risk in the elderly: data from Brazilian public health
care program. J Aect Disord 2014;152154:513516.
23. Kapczinski F, Vieta E, Andreazza AC et al. Allostatic load
in bipolar disorder: implications for pathophysiology and
treatment. Neurosci Biobehav Rev 2008;32:675692.
24. Nivoli AM, Pacchiarotti I, Rosa AR et al. Gender
dierences in a cohort study of 604 bipolar patients: the
role of predominant polarity. J Aect Disord 2011;133:
443449.
25. First MB, Spitzer RL, Gibbon M et al. Structured clinical
interview for DSM-IV-TR axis I disorders, research
version, non-patient edition. New York: Biometrics
Research, New York State Psychiatric Institute, 2002.
Bipolar disorder in the elderly
26. Colom F, Vieta E, Daban C et al. Clinical and therapeutic
implications of predominant polarity in bipolar disorder.
J Aect Disord 2006;93:1317.
27. Vieta E. Pros and cons of specialised care in bipolar disor-
der: an international perspective. Br J Psychiatry 2013;
202:170171.
28. Alexopoulos GS. Depression in the elderly. Lancet
2005;365:19611970.
29. Bellivier F, Golmard J-L, Rietschel M et al. Age at onset
in bipolar I aective disorder: further evidence for three
subgroups. Am J Psychiatry 2003;160:9991001.
30. Azorin JM, Bellivier F, Kaladjian A et al. Characteristics
and proles of bipolar I patients according to age-at-
onset: ndings from an admixture analysis. J Aect Dis-
ord 2013;150:9931000.
31. Chu D, Gildengers AG, Houck PR et al. Does age at
onset have clinical signicance in older adults with
bipolar disorder? Int J Geriatr Psychiatry 2010;25:1266
1271.
32. Lala SV, Sajatovic M. Medical and psychiatric comorbidi-
ties among elderly individuals with bipolar disorder: a
literature review. J Geriatr Psychiatry Neurol 2012;25:
2025.
33. Rosa AR, Andreazza AC, Kunz M et al. Predominant
polarity in bipolar disorder: diagnostic implications.
J Aect Disord 2008;107:4551.
34. Mazzarini L, Pacchiarotti I, Colom F et al. Predominant
polarity and temperament in bipolar and unipolar aec-
tive disorders. J Aect Disord 2009;119:2833.
35. Popovic D, Reinares M, Goikolea JM et al. Polarity index
of pharmacological agents used for maintenance treatment
of bipolar disorder. Eur Neuropsychopharmacol 2012;
22:339346.
36. Rej S, Butters MA, Aizenstein HJ et al. Neuroimaging
and neurocognitive abnormalities associated with bipolar
disorder in old age. Int J Geriatr Psychiatry 2014;29:
421427.
37. Lloyd J, Moore PB, Cousins DA et al. White matter lesions
in euthymic patients with bipolar disorder. Acta Psychiatr
Scand 2009;120:481491.
38. Colom F, Vieta E. The road to DSM-V. Bipolar disorder
episode and course speciers. Psychopathology 2009;
42:209218.
39. Baldessarini RJ, Undurraga J, Vazquez GH et al. Predomi-
nant recurrence polarity among 928 adult international
bipolar I disorder patients. Acta Psychiatr Scand 2012;
125:293302.
40. Cowen PJ. Classication of depressive disorders. Curr Top
Behav Neurosci 2013;14:313.
41. Parker G, Roy K, Wilhelm K. The nature of bipolar
depression: implications for the denition of melancholia.
J Aect Disord 2000;59:217224.
42. Benazzi F. Psychomotor changes in melancholic and atypi-
cal depression: unipolar and bipolar-II subtypes. Psychia-
try Res 2002;112:211220.
43. Kendler KS. The diagnostic validity of melancholic major
depression in a population based sample of female twins.
Arch Gen Psychiatry 1997;54:299304.
44. Vieta E. Bipolar units and programmes: are they really
needed? World Psychiatry 2011;10:152.
45. Vieta E. Tertiarism in psychiatry: the Barcelona Clinic
Bipolar Disorder Programme. Rev Psiquiatr Salud Ment
2011;4:14.
373
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