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European Psychiatry 29 (2014) 134–141
Available online at
www.sciencedirect.com
Original article
Psychoeducation and cognitive-behavioral therapy for patients with refractory
bipolar disorder: A 5-year controlled clinical trial
˜ ana c, A. Gonza´lez-Pinto d
A. Gonza´lez Isasi a,*, E. Echeburu´a b, J.M. Limin
a
Psychiatry Department, Hospital Universitario Insular, Las Palmas de Gran Canaria, Spain
Faculty of Psychology, University of the Basque Country, CIBERSAM, San Sebastia´n, Spain
c
Unidad de Investigacio´n, Complejo Hospitalario Universitario Insular Materno-Infantil, Las Palmas de Gran Canaria, Spain
d
CIBERSAM, Department of Psychiatry, Santiago Apo´stol Hospital, EHU/UPV, Vitoria, Spain
b
A R T I C L E I N F O
A B S T R A C T
Article history:
Received 18 September 2012
Received in revised form 29 October 2012
Accepted 4 November 2012
Available online 28 December 2012
Objective: The aim of this research, which represents an additional and longer follow-up to a previous
trial, was to evaluate a 5-year follow-up study of a combined treatment (pharmacological + psychoeducational and cognitive-behavioral therapy) as compared with a standard pharmacological treatment
in patients with refractory bipolar disorder.
Method: Forty patients were randomly assigned to either an Experimental group–under combined
treatment — or a Control group — under pharmacological treatment. Data were analyzed by analysis of
variance (ANOVA), with repeated measures at different evaluation time points.
Results: Between-group differences were significant at all evaluation time points after treatment.
Experimental group had less hospitalization events than Control group in the 12-month evaluation
(P = 0.015). The Experimental group showed lower depression and anxiety in the 6-month (P = 0.006;
P = 0.019), 12-month (P = 0.001; P < 0.001) and 5-year (P < 0.001, P < 0.001) evaluation time points.
Significant differences emerged in mania and misadjustment already in the post-treatment evaluation
(P = 0.009; P < 0.001) and were sustained throughout the study (6-month: P = 0.006, P < 0.001; 12month: P < 0.001, P < 0.001; 5-year: P = 0.004, P < 0.001). After 5-year follow-up, 88.9% of patients in
the Control group and 20% of patients in the Experimental group showed persistent affective symptoms
and/or difficulties in social-occupational functioning.
Conclusions: A combined therapy is long-term effective for patients with refractory bipolar disorder.
Suggestions for future research are commented.
Published by Elsevier Masson SAS.
Keywords:
Refractory bipolar disorder
Combined therapy
Pharmacological treatment
Psychoeducation
Cognitive-behavioral model
Long-term follow-up
1. Introduction
Patients with a refractory bipolar disorder (resistant to
treatment and with a history of unfavorable progression)
frequently have a poor prognosis; they usually present with
residual symptoms [25,31], rapid cycling [20] and suicide attempts
[19,22], despite receiving appropriate treatment with mood
stabilizers. Furthermore, even without presentation of rapid
cycling, these patients may suffer frequent relapses and experience
severe difficulties in their social-occupational functioning. This
situation is significantly associated with elevated total healthcare
costs [23].
Refractory bipolar disorder is a rather frequent finding in
patients with this disorder. In a recent study, patients followed-up
* Corresponding author. Hospital Universitario Insular de Gran Canaria, Servicio
de Psiquiatrı´a, Avenida Marı´tima s/n, 35016 Las Palmas, Las Palmas de Gran Canaria,
Spain. Tel.: +34 92 84 41 50 2; fax: +34 92 84 41 55 5.
E-mail address: anagonis@hotmail.com (A. Gonza´lez Isasi).
0924-9338/$ – see front matter . Published by Elsevier Masson SAS.
http://dx.doi.org/10.1016/j.eurpsy.2012.11.002
for 18 months after resolution of their episodes, remained
symptomatic for one third of the follow-up period and were three
times more days depressed than manic or hypomanic [11]. Other
studies reported that up to 40% of patients with bipolar disorders
continued to show subsyndromal symptoms after recovery
[24,44]. In this context, euthymic patients were found to progress
better and to report higher quality of life than patients with
subsyndromal symptoms [32]. In an earlier study, we found that
receiving combined therapy, experiencing fewer previous hospitalizations and having higher self-esteem were the most influencing factors for a favorable progression of refractory bipolar disorder
[18].
Current pharmacological treatments fail to control the course of
about half the cases of bipolar disorder [40]. Recent reviews of
studies based on psychoeducational and cognitive-behavioral
therapy for bipolar disorder [21,43] evidenced that both psychoeducation and cognitive-behavioral therapy were most effective
treatments for preventing recurrence in patients under pharmacological therapy [5,8,21].
A. Gonza´lez Isasi et al. / European Psychiatry 29 (2014) 134–141
In a recent study, a group of patients receiving standard
treatment for bipolar disorder was compared with a group
additionally receiving psychoeducation as an adjunctive therapy,
for a 5-year follow-up period. Patients receiving adjunctive
psychoeducation therapy experienced fewer recurrence episodes
and shorter periods with acute symptoms, and needed shorter
hospital stay [10]. A further long-term benefit of psychological
adjunctive therapy is that, compared to conventional therapy, it is
less costly and more effective [38].
In the last few years, structured psychological therapies that
combine both types of procedure (psychoeducation and cognitivebehavioral therapy) are being increasingly adopted [28,34,35,37].
While psychoeducation has proven effective on bipolar disorder
[10] both for preventing manic and depressive episodes, studies
reported that cognitive-behavioral therapy is especially useful in
the treatment and prevention of depression [6,41]. Thus, combining both therapies was expected to be especially helpful. Studies on
other severe mental diseases like schizophrenia, suggested that
enhancing patients’ insight into the disease through psychoeducation without providing clues to reduce depressive symptoms could
entail certain risk [1]. However, in a long-term study, participants
who received cognitive-behavioral therapy in addition to psychoeducation experienced 50% fewer days of depressed mood over
the course of 1 year and less antidepressant increases as compared
with the group of psychoeducation alone [46].
Earlier we reported the results of a pilot study on this issue,
though with a reduced number of patients [15,16]. More
recently, we presented a study on the evaluation of short-term
and medium-term (1 year) efficacy of a psychological intervention program that combined psychoeducation with cognitivebehavioral therapy, applied as a complement to pharmacological
therapy with a group-based approach, for patients with
refractory bipolar disorder [17]. We also proposed that
incorporating such a psychological program to standard clinical
practice in Mental Health Centers of our Community could help
reducing the burden and associated costs of these patients on the
Health Services.
However, no evidence of the long-term effectiveness of such a
program is available, an important issue in view of the chronic
nature of this type of mental disease. Some researchers reported
that the effectiveness of psychological interventions decreased
over the time [7,30], while others demonstrated persistent efficacy
[10].
The main aim of this study was to evaluate the effectiveness of a
psychological program for patients with refractory bipolar
disorder, taking into account global affective symptoms and
adaptation to daily life as therapeutic failure/success, in a 5-year
follow-up study. We also examined, as a secondary aim, specific
clinical differences regarding anxiety, depression, mania, misadjustment and recent hospitalizations, between a group of
patients receiving standard treatment for bipolar disorder and a
group additionally receiving psychoeducation and cognitivebehavioral therapy as an adjunctive therapy.
135
patient meeting the DSM-IV-TR [2] criteria for type I bipolar
disorder for at least 2 years;
history of severe or unfavorable progression of the disease
despite adequate pharmacological treatment, defined as two or
more relapse events in the preceding year, suicide attempts,
persistent affective symptoms (for a period of at least 3 months)
despite appropriate drug treatment (Beck’s Depression Index
[BDI]score > 7; Young Mania Rating Scale [YMRS] score > 6) or
severe difficulties in social-occupational functioning (Misadjustment Scale [IS]score > 14);
patient euthymic or with subsyndromal symptoms at the
beginning of the study (BDI > 7; YMRS > 6);
patient not receiving psychotherapy (individual or groupbased);
age between 18 and 65 years.
Patients with poor medication adherence, according to the
doctor or relatives’ report, were excluded.
Forty patients were recruited for this study. All of them
completed the treatment during the follow-up period except for
two control patients who died during the first year (one by suicide
and one by heart attack); none of them met the criteria to diagnose
a depressive or hypomanic or manic episode at the beginning of the
study. All patients gave their informed consent to participate in
this randomized clinical trial. This research was approved by the
Hospital’s Ethics Committee.
2.2. Study design
The sample size was calculated for 5% confidence level, 90%
power, 0.75 success proportion in the experimental group, 0.20
success proportion in the control group, and 15% approximate
failure; the resulting sample size was approximately 20 subjects
per group.
Subjects were randomly assigned to either the Experimental or
the Control group. Subjects in the Experimental group received
psychotherapy in addition to conventional drug treatment, while
those in the Control group only received conventional drug
treatment. Patients in the Control group did not receive
psychotherapy during the 5 years of the study.
Independent measures corresponding to each subject were
evaluated at five different time points: immediately before
treatment (baseline), immediately after the termination of the
treatment (post-treatment), in a follow-up visit 6 months after the
termination of treatment (6 months), in a follow-up visit 12
months after the termination of treatment (12 months) and in a
follow-up visit 5 years after the termination of treatment (5 years).
The researchers in charge of evaluating the subjects were
blinded to their treatment.
This study was designed for between-group comparison of the
proportions of patients with persistent affective symptoms and/or
severe difficulties in their social-occupational functioning during
the follow-up period, and for analyzing the number of hospitalization events as well as possible improvements in daily functioning and anxiety in both groups of patients.
2. Method
2.3. Assessment measures
2.1. Participants
Participants were outpatients diagnosed with refractory bipolar
disorder in the Grand Canary healthcare area, who were managed
at the Center for Mental Health of Las Palmas, during 2005 and
2006. All of these patients were under pharmacological treatment,
prescribed on an individual basis, mainly consisting of a mood
stabilizer (predominantly lithium); some of them also received
antipsychotics and/or benzodiazepines. Inclusion criteria were:
Patients underwent a semi-structured individual interview
(Structured Clinical Interview for DSM-IV-TR Axis DisordersPatient Version; SCID-P) [13] at the beginning of the study, aimed
at confirming the diagnosis of a bipolar disorder I or II, according to
the DSM-IV-TR criteria. During the interview, subjects were asked
to describe their symptoms, the history of their disorder, the
treatments they had received and the degree to which they
perceived their disorder to be disabling for daily life.
136
A. Gonza´lez Isasi et al. / European Psychiatry 29 (2014) 134–141
During each evaluation visit, the researcher (blinded to
patients’ treatment) administered the following questionnaires:
Beck’s Depression Index (BDI) [4,42], Young Mania Rating Scale
(YMRS) [2,9,45], State Trait Anxiety Inventory (STAI-S) [39] and
Misadjustment Scale (IS) [12]. In all of these scales, lower scores
indicate better outcomes. These tools are described in detail
elsewhere [15].
2.4. Treatment groups
2.4.1. Experimental group (pharmacological treatment plus
psychotherapy)
Patients assigned to this group participated in a psychological
intervention program in addition to their conventional pharmacological treatment. The psychological program consisted of an initial
psychoeducation session about their disorder, followed by an
explanation of the relationship between thoughts, activities,
physical feelings and mood, and about identifying and monitoring
early warning symptoms in order to deal with them. Subsequently,
they were trained in the use of anxiety-control techniques
(relaxation and breathing, self-instructions and cognitive distraction), sleep hygiene habits and planning gratifying activities. Later
on, they were trained in detecting distorted thoughts and using the
process of cognitive restructuring. Finally, for the purpose of
consolidating the treatment and in an attempt to prevent relapse,
participants were trained in problem solving and improvement of
self-esteem. In addition, a program of social skills (assertiveness,
non-verbal communication, conversational skills, giving and
receiving compliments, giving and receiving criticism and asking
for favors) was introduced from the second session on, and was
part of every therapy session until the end of the treatment. The
objectives of the psychological intervention program were to
enhance patients’ understanding of their disorder, to reduce the
number of hospitalizations, to reduce their levels of anxiety, to
improve their repertoire of social skills and assertiveness control,
to help them controlling their mood by shifting thoughts and
getting involved in enjoyable activities, to enhance their selfesteem and to improve their adaptation to daily life by learning
problem-solving strategies.
The cognitive therapy used in this research was based on the
therapist’s guide manual included in Lam et al. [27]. This
psychological intervention program — based on a cognitivebehavioral model — consisted of 20 weekly sessions of 1.5 hours
each, led by a clinical psychologist assisted by psychiatric nurses.
Patients in the Experimental group underwent psychotherapy in
two subgroups of 10 subjects each.
Two weeks elapsed between patients’ consent and the
beginning of the psychological intervention program. As mentioned, all patients in this group were under individualized
psychoactive drug(s) treatment (mood stabilizers, antipsychotics
and/or benzodiazepines) adjusted by a psychiatrist.
2.4.2. Control group (pharmacological treatment)
Patients assigned to the control group only received an
individualized psychoactive drug(s) treatment (mood stabilizers,
antipsychotics and/or benzodiazepines) adjusted by a psychiatrist.
Patients regularly visited their psychiatrist approximately once in
a month, although a psychiatrist was available to provide support
when necessary.
2.5. Statistical analysis
In a first analysis, the baseline characteristics of both groups
were compared.
Analysis of the results of STAI-S was based on numerical scores,
while the results of BDI, YMRS and IS were analyzed both
numerically and categorically for the purpose of comparing the
proportion of subjects with persistent depression or mania
symptoms (BDI score > 7; YMRS score > 6) and/or severe difficulties in social-occupational functioning (IS score > 14) in both
groups, during the follow-up period. The number of recent
hospitalizations, i.e. admissions to hospital during the previous
6 months, was established before every evaluation session.
Continuous variables were expressed as mean with standard
deviation/typical error or range values. Variables were compared
both within- and between-groups at different evaluation time
points by using ANOVA, including one or two factors, both with
repeated measures. Categorical variables were expressed as
number of cases and proportions and were compared between
groups, at different evaluation time points, by using the Pearson’s
Chi2 test.
Effect size analysis, based on the Cohen’s d (continuous
variables) and Chuprov’s T-square (proportions) tests, was used
to estimate clinical differences.
3. Results
3.1. Descriptive characteristics at baseline
Table 1 shows the descriptive characteristics at baseline for
both groups. As expected for a study with a random-design, no
significant between-group differences were found in terms of:
proportion of males and females, number of prior hospitalization
events, number of recent hospitalization events, use of lithium or
other mood stabilizers, adherence measured by the clinician in
charge of the patient, and results of the questionnaires. Thus, the
results of subsequent repeated measures analysis were expected to
be unbiased. Patients’ mean age was 41 years ( 10.76). Seventyfive percent of patients in each group had persistent affective
symptoms (depression rather than mania symptoms) and/or severe
difficulties in social-occupational functioning. The rest of patients had
experienced two or more relapse events during the previous year.
3.2. Between-group differences in persistent affective symptoms and/
or difficulties in social-occupational functioning
Fig. 1 shows the percentage of patients with persistent affective
symptoms (BDI > 7; YMRS > 6) and/or difficulties in socialoccupational functioning (IS > 14) in the Experimental and Control
group at different evaluation time points:
in the post-treatment evaluation, 80% of Control patients and
45% of Experimental patients showed these symptoms (difference reached statistical significance X2 = 5.227, P = 0.022,
T2 = 0.131);
in the 6-month evaluation, 80% of Control patients and 40% of
Experimental patients were affected (difference also significant
X2 = 6.667, P = 0.010, T2 = 0.167);
in the 12-month evaluation, 83.3% of Control patients and only
30% of Experimental patients were affected (difference significant X2 = 10.90, P = 0.001, T2 = 0.287);
in the 5-year evaluation, 88.9% of Control patients and only 20%
of Experimental patients showed symptoms (difference also
significant X2 = 18.034, P = 0.001, T2 = 0.475).
3.3. Between-group differences in main variables throughout the
study
Table 2 shows the differences between Experimental and
Control groups in terms of the measured variables, at the different
evaluation time points: in the post-treatment evaluation, the
A. Gonza´lez Isasi et al. / European Psychiatry 29 (2014) 134–141
137
Table 1
Description of sample and baseline characteristics.
Total
Experimental group
(n = 20)
Control group
(n = 20)
21 (52.5)
19 (47.5)
11 (55.0)
9 (45.0)
10 (50.0)
10 (50.0)
Age
41.30 (10.76)
43.35 (11.48)
39.25 (9.85)
Age of onsetd
30.05 (10.82)
29.75 (11.5)
30.35 (9.5)
Duration of disorder
13.68 (5–25)
13.35 (6–25)
No. previous episodesc
10.75 (2–18)
11.10 (2–17)
Gender
Maleb
Femaleb
d
c
No. prior hospitalizations
c
Statisticsa
P value
0.10
0.752
–1.21
0.233
0.18
0.858
14.01 (5–24)
0.46
0.649
10.40 (3–18)
0.40
0.693
–0.23
0.822
1.53
0.134
–1.39
0.172
2.18 (0–20)
2.30 (0–20)
2.05 (0–20)
No. recent hospitalizationsc
0.25 (0–3)
0.10 (0–1)
0.40 (0–3)
Scales at baseline
STAI-Sd
19.05 (10.34)
21.30 (11.57)
16.80 (8.66)
Beck Depression
7b
> 7b
14 (35.0)
26 (65.0)
8 (40.0)
12 (60.0)
6 (30.0)
14 (70.0)
0.44
0.507
Mania Rating Scale
6b
> 6b
36 (90.0)
4 (10.0)
17 (85.0)
3 (15.0)
19 (95.0)
1 (5.0)
1.11
0.292
Misadjustment Scale
14b
> 14b
22 (55.0)
18 (45.0)
9 (45.0)
11 (55.0)
13 (65.0)
7 (35.0)
1.62
0.204
Persistent affective symptoms and/or severe misadjustment
With symptomsb
Without symptomsb
30 (75.0)
10 (25.0)
15 (75.0)
5 (25.0)
15 (75.0)
5 (25.0)
0.00
1.000
a
b
c
d
Due to the sample size, the Chi2 test and the t Student test were used for comparisons between categorical and numerical variables.
n (%).
Mean (range).
Mean (standard deviation).
number of recent hospitalizations tended to be higher for Control
than for Experimental patients (t = 2.03, P = 0.056); by the 12month evaluation, this difference reached statistical significance
(t = 2.71, P = 0.015) thus evidencing that patients in the Experimental group needed less hospitalizations than those in the
Control group; in the 5-year evaluation, the number of hospitalizations was higher for the Control group, though not significantly
(t = 1.68, P = 0.109).
Anxiety and depression related symptoms followed a similar
trend, with Control patients showing worse outcome. Although
differences were not significant in the post-treatment evaluation
(STAI-S: t = 1.92, P = 0.062; BDI: t = 1.54, P = 0.131), they reached
significance in the 6-month (STAI-S: t = 2.46, P = 0.019; BDI:
t = 2.91, P = 0.015), 12-month (STAI-S: t = 6.50, P < 0.001; BDI:
t = 3.81, P = 0.001) and 5-year evaluations (STAI-S: t = 8.46,
P < 0.001; BDI: t = 6.71, P < 0.001).
Mania and misadjustment symptoms were milder in Experimental than in Control patients at all evaluation time points: posttreatment (YMRS: t = –0.72, P = 0.009; IS: t = 5.67, P < 0.001); 6month (YMRS: t = 3.10, P = 0.006; IS: t = 7.01, P < 0.001); 12-month
(YMRS: t = 4.49, P < 0.001; IS: t = 11.98, P < 0.001); and 5-year
(YMRS: t = 3.28, P = 0.004; IS: t = 7.88, P < 0.001).
3.4. Within-group differences in main variables throughout the study
Fig. 1. Percentage of patients with persistent affective symptoms and/or with
important maladaptation.
Table 3 shows within-group differences in the measured
variables. Observations were compared at the indicated evaluation
time points.
No significant differences were found in the number of
hospitalization events throughout the study for the Experimental
group, while it increased significantly for the Control group
(F = 6.881, P = 0.018).
Symptoms of anxiety, depression and misadjustment showed
similar patterns, namely they decreased significantly for the
Experimental group (STAI-S: F = 23.586, P < 0.001; BDI: F = 33.329,
P < 0.001; IS: F = 49.530, P < 0.001) and increased significantly for
the Control group (STAI-S: F = 22.45, P < 0.001; BDI: F = 7.056,
P = 0.017; IS: F = 49.530, P = 0.001) throughout the study.
Mania symptoms increased significantly for the Control group
(YMRS: F = 12.321, P = 0.003), while remained unchanged for the
Experimental group (YMRS: F = 3.124, P = 0.093).
138
Table 2
Between-group differences at the different evaluation time points.
Values
Pretreatment
Post-treatment
6 months
12 months
5 years
Mean (sd)
t (P value)c
Mean (sd)
t (P value)c
Mean (sd)
t (P value)c
Mean (sd)
t (P value)c
Mean (sd)
t (P value)c
No. recent hospitalizations
Control group
Experimental group
0.40 (0.82)
0.10 (0.31)
1.53 (0.139)
0.25 (0.55)
0.00 (0.00)
2.03 (0.056)
0.30 (0.66)
0.05 (0.22)
1.61 (0.121)
0.39 (0.61)
0.00 (0.00)
2.71 (0.015a)
1.06 (2.24)
0.02 (0.49)
1.68 (0.109)
d = –0.62
Anxiety (STAI-S)
Control group
Experimental group
Beck Depression (BDI)
Control group
Experimental group
Mania Scale (YMRS)
Control group
Experimental group
d = –0.64
b
c
d = –0.62
22.35 (12.24)
1.92 (0.062)
16.00 (11.93)
d = –0.53
26.35 (13.94)
2.46 (0.019a)
16.50 (11.27)
d = –0.78
32.78 (11.97)
6.50 (< 0.001b)
8.85 (10.72)
d = –2.10
28.44 (8.92)
8.80 (5.05)
11.25 (9.06)
0.07 (0.942)
11.05 (8.11)
d = –0.02
12.70 (10.28)
1.54 (0.131)
8.60 (5.95)
d = –0.50
14.85 (10.16)
2.91 (0.006a)
6.80 (7.03)
d = –0.94
13.72 (10.47)
3.81 (0.001b)
3.80 (4.87)
d = –1.29
17.61 (6.75)
4.30 (5.46)
1.85 (2.70)
2.50 (3.01)
3.75 (4.68)
0.65 (1.27)
–0.72 (0.477)
12.70 (7.95)
15.10 (7.17)
–1.00 (0.323)
d = 0.32
a
d = –0.91
16.80 (8.66)
–1.39 (0.172)
21.30 (11.57)
d = 0.55
d = 0.22
Misadjustment Scale
Control group
Experimental group
d = –0.49
P < 0.05.
P < 0.001.
Bonferroni correction for multiples comparisons.
2.85 (0.009a)
5.40 (6.92)
0.55 (1.10)
d = –1.04
14.85 (6.22)
4.65 (5.11)
5.67 (< 0.001b)
d = –1.80
3.10 (0.006a)
d = –1.21
15.50 (6.04)
3.45 (4.75)
7.01 (< 0.001b)
d = –2.23
6.39 (5.83)
0.20 (0.52)
4.49 (< 0.001b)
d = –1.95
17.22 (4.809)
11.98 (< 0.001b)
1.90 (2.65)
d = –4.11
8.46 (< 0.001b)
d = –2.71
6.71 (< 0.001b)
d = –2.18
10.39 (11.40)
3.28 (0.004a)
1.45 (1.99)
d = –1.33
19.00 (7.14)
4.40 (3.48)
7.88 (< 0.001b)
d = –2.72
A. Gonza´lez Isasi et al. / European Psychiatry 29 (2014) 134–141
Scales
A. Gonza´lez Isasi et al. / European Psychiatry 29 (2014) 134–141
139
Table 3
Within-group differences throughout the study.
Control group
Experimental group
Scales
Pre
Post
6M
12 M
5Y
F (P value)
Pre
Post
6M
12 M
5Y
F (P value)
No. prior hospitalizations
Anxiety (STAI-S)
Beck Depression (BDI)
Mania Scale (Young)
Misadjustment Scale
2.06
16.80
11.25
1.85
12.70
2.28
22.35
12.70
3.75
14.85
2.61
26.35
14.85
5.40
15.50
3.00
32.78
13.72
6.39
17.22
4.06
28.44
17.61
10.39
19.00
6.881 (0.018a)
22.45 (< 0.001b)
7.056 (0.017a)
12.321 (0.003a)
15.620 (0.001a)
2.30
21.30
11.05
2.50
15.10
2.30
16.00
8.60
0.65
4.65
2.35
16.50
6.80
0.55
3.45
2.35
8.85
3.80
0.20
1.90
2.50
8.80
4.30
1.45
4.40
6.86 (0.144)
23.589 (< 0.001b)
33.329 (< 0.001b)
3.124 (0.093)
49.530 (< 0.001b)
a
b
P < 0.05.
P < 0.001.
4. Discussion
As far as we know, this is the first study to show such long-term
maintained efficacy of a combined pharmacological plus psychoeducation and cognitive-behavioral therapy program in subjects
with refractory bipolar disorder. Patients with refractory bipolar
disorders, who present persistent and significant affective
symptoms (depression rather than mania symptoms) despite
appropriate pharmacological treatment generate the highest
burden on the healthcare system, while showing the worst
outcomes in terms of disease progression and chronicity [14,36].
Inclusion of euthymic patients and patients with subsyndromal
symptoms was based on the reality of daily clinical practice [32].
Up-to-date, well-controlled studies including patients with bipolar
disorders with a history of unfavorable progression are rather
scarce. We postulate that the present research study contributes to
evaluate the possible benefits of a combined therapy and to study
the progression of refractory disorders in patients under standard
therapy. Thus, it offers a good ecological validity.
The psychological program applied in this study was based on
psychoeducation and cognitive-behavioral therapy, some of the
most studied therapeutic approaches in this field [21,34,35]. Longterm randomized controlled trials published up-to-date, either
included psychoeducation only [10] or follow-up periods shorter
than 5 years [3,29]. We decided to use group therapy because it
facilitated the application of the therapy and reduced its associated
costs.
Combined treatment proved better than pharmacological
treatment in relieving mania, depression and anxiety symptoms
after 6 months and in producing better adjustment to everyday life
upon termination of treatment. These benefits were maintained
after 5 years. During these 5 years, patients did not receive any other
psychological treatment or support. Furthermore, although the
number of hospitalization events increased significantly for the
Control group, it remained unchanged for the Experimental group
throughout the 5-year follow-up period. No subjects failed to
comply with the treatment or were lost to follow-up, except for two
control patients who died in the first year (one by suicide and one by
a heart attack). The reason why no participant left the group and no
study patient lost to follow-up was probably related to an active
commitment of therapist to patients. Thus, psychological therapy,
applied as a complement to pharmacological therapy, seemed to be
attractive to patients, effective in producing good results and
efficient for application due to its short duration and group-based
format. The standard treatment consisted of medication prescription without psychological intervention, which may have contributed to the marked differences between groups, thus supporting the
efficacy of a psychological treatment in terms of improving the
evolution of bipolar disorders. Psychological treatment helps
patients to learn how to better manage their illness.
Up-to-date evidence supports the view that pharmacological
treatments available are necessary though not sufficient to treat
refractory bipolar disorders successfully. The few published studies
conducted with patients with bipolar disorders with a history of
unfavorable progression [26,34,35], showed that combined therapy
reduced the number of episodes, hospitalizations and symptoms,
and improved social functional capacity. Such improvements were
sustained during 1-year follow-up [3,28]. Our results agree with
these studies, and further evidence a new aspect: not only is the
improvement sustained, but also the evidence of positive effects
increased in several areas over the time.
In contrast with our results, Scott et al., in 2006 [37], found no
differences in patients with a refractory bipolar disorder, who were
treated with psychotherapy. However, their sample comprised a
combination of acute patients and patients in remission;
moreover, some of them were not under pharmacological
treatment. It is our view that patients should not be in the manic
or hypomanic phase at the time psychotherapy is applied, because
this therapy might be ineffective in that situation; furthermore, the
pharmacological treatment should be prescribed according to
clinical guidelines by psychiatrists with expertise in the management of these difficult-to-treat patients. Lam et al., 2005 [29],
found that cognitive therapy had no significant effect in reducing
relapse over an 18-month study period and that additional booster
sessions were necessary. Our psychological intervention program
included psychoeducation, anxiety-control techniques, cognitive
restructuring, activities planning, a social skill program, a problemsolving program and a self-esteem improvement program. In turn,
Meyer and Hautzinger, in 2012 [33], did not find any differences in
relapse rates over a 24-month study between cognitive-behavior
therapy (CBT) and supportive therapy (ST) of equal intensity and
frequency, suggesting that certain shared characteristics (e.g.
information, systematic mood monitoring) might explain the
effects of psychosocial treatment for bipolar disorder. Changes
over time were observed in some variables, they were not
differentially associated with CBT or ST. Their results also suggest
that a higher number of prior episodes, a lower number of therapy
sessions and a diagnosis of bipolar II disorder are associated with a
shorter time before relapse.
In our earlier pilot study conducted with a reduced population
sample [16], we found significant differences between the group
under combined treatment and the group under pharmacological
treatment in the 12-month evaluation but not in earlier evaluations. That treatment included some psychoeducation although
not in a structured fashion. More recently, we reported differences
already in the post-treatment evaluation, which were even larger
in the 6-month and 12-month evaluations [17]. Such difference in
the outcome of both studies may be accounted for by the intensity
of the applied psychological treatment (13 sessions in the first
study, 20 in the later one) and the size of the sample (20 subjects in
the first study, 40 subjects in the later one). In this study, we found
the program to be still effective by the 5-year evaluation. Thus,
unlike other studies [29], our results support the view that the
benefits of a psychological treatment do not dissipate over time.
Anyway, there are some limitations in this study. It would have
been interesting to have more information (for example, the
140
A. Gonza´lez Isasi et al. / European Psychiatry 29 (2014) 134–141
recurrences or time to recurrence) about the whole sample in the
period between the 12-month and 5-year assessments. These
measures would have offered a more comprehensive idea of the
trajectory of the clinical course of the illness. Further research
should take this limitation into account.
We postulate that this study evidences the long-term benefits
of a psychological treatment and opens new research lines. Further
studies with larger sample sizes, where additional variables are
evaluated, such as the number of days admitted to hospital or the
adherence to medication, are needed. Additionally, research lines
focused on the evaluation of the different components of the
psychological program (psychoeducation and cognitive-behavioral therapy) or comparing psychoeducation alone with more
structured psychological programs, would be helpful and enriching. A further step to this issue would address the effectiveness of
psychological programs applied to patients’ relatives/caretakers.
Disclosure of interest
The authors declare that they have no conflicts of interest
concerning this article.
Acknowledgements
The work presented in the manuscript ‘‘Psychoeducation and
cognitive-behavioral therapy for patients with refractory bipolar
disorder: A 5-year controlled clinical trial’’ by the authors Ana
˜ ana and Ana
Gonza´lez Isasi, Enrique Echeburu´a, Jose´ Marı´a Limin
Gonza´lez-Pinto, has been entirely funded by the Servicio Canario
de Salud. Therefore, the funding source is the same public
institution where the work has been performed.
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