The Long-Term Effectiveness of Psychoeducation for

Bipolar Disorders in Mental Health Services. A 4-Year

Follow-Up Study Running title: 4-Year Outcome of
Psychoeducation
Chiara Buizza1*, Valentina Candini2, Clarissa Ferrari3, Alberto Ghilardi1, Francesco M.
Saviotti4, CESARE TURRINA1, Gianluigi Nobili4, Margherita Sabaudo5, Giovanni De
Girolamo2

1
Department of Clinical and Experimental Sciences, University of Brescia, Italy, 2Unità
Operativa di Psichiatria Epidemiologica e Valutativa, Centro San Giovanni di Dio
Fatebenefratelli (IRCCS), Italy, 3Centro San Giovanni di Dio Fatebenefratelli (IRCCS),

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Italy, 4Local Social Health Agency Garda, Italy, 5Department of Mental Health and
Addictions, Civil Hospital of Brescia, Italy

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Submitted to Journal:
Frontiers in Psychiatry

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Specialty Section:

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Mood and Anxiety Disorders

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ISSN:

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1664-0640

Article type:
Original Research Article

Received on:
03 Sep 2019

Accepted on:
06 Nov 2019

Provisional PDF published on:

06 Nov 2019

Frontiers website link:

www.frontiersin.org

Citation:
Buizza C, Candini V, Ferrari C, Ghilardi A, Saviotti FM, Turrina C, Nobili G, Sabaudo M and
De_girolamo G(2019) The Long-Term Effectiveness of Psychoeducation for Bipolar Disorders in Mental
Health Services. A 4-Year Follow-Up Study Running title: 4-Year Outcome of Psychoeducation. Front.
Psychiatry 10:873. doi:10.3389/fpsyt.2019.00873

Copyright statement:
© 2019 Buizza, Candini, Ferrari, Ghilardi, Saviotti, Turrina, Nobili, Sabaudo and De_girolamo. This is
an open-access article distributed under the terms of the Creative Commons Attribution License (CC
BY). The use, distribution and reproduction in other forums is permitted, provided the original
author(s) or licensor are credited and that the original publication in this journal is cited, in
accordance with accepted academic practice. No use, distribution or reproduction is permitted
which does not comply with these terms.
This Provisional PDF corresponds to the article as it appeared upon acceptance, after peer-review. Fully formatted PDF
and full text (HTML) versions will be made available soon.

Frontiers in Psychiatry | www.frontiersin.org

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1 The Long-Term Effectiveness of Psychoeducation for Bipolar

2 Disorders in Mental Health Services. A 4-Year Follow-Up Study
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5 Running title: 4-Year Outcome of Psychoeducation
6
7 Chiara Buizza1*°, Valentina Candini2°, Clarissa Ferrari3, Alberto Ghilardi1, Francesco Maria Saviotti4,
8 Cesare Turrina1, Gianluigi Nobili4, Margherita Sabaudo5, Giovanni de Girolamo2
9
10 Affiliations
1
11 Chiara Buizza, Department of Clinical and Experimental Sciences, University of Brescia, Italy.
2
12 Valentina Candini, Psychiatric Epidemiology and Evaluation Unit, IRCCS Istituto Centro San
13 Giovanni di Dio Fatebenefratelli, Brescia, Italy.
3
14 Clarissa Ferrari, Service of Statistics, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli,
15 Brescia, Italy.
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16 Alberto Ghilardi, Department of Clinical and Experimental Sciences, University of Brescia, Italy.
4
17 Francesco Maria Saviotti, Department of Mental Health, ASST Garda, Italy.
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18 Cesare Turrina, Department of Clinical and Experimental Sciences, University of Brescia, Italy.
4
19 Gianluigi Nobili, Department of Mental Health, ASST Garda, Italy.
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20 Margherita Sabaudo, Department of Mental Health, ASST Spedali Civili, Brescia, Italy.
2
21 Giovanni de Girolamo, Psychiatric Epidemiology and Evaluation Unit, IRCCS Istituto Centro San
22 Giovanni di Dio Fatebenefratelli, Brescia, Italy.
23

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24 °These authors contributed equally to this work.
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26

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Trial registration: ISRCTN17827459

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Word count: 3.386
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Correspondence:
Dr. Chiara Buizza*

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Department of Clinical and Experimental Sciences, University of Brescia, Viale Europa 11, Brescia,
Italy
Phone +39 030 3717149
Email: chiara.buizza@unibs.it

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1 ABSTRACT
2 Aims: The aims of the present study were to assess: the effectiveness of psychoeducation in
3 MHSs in terms of time to first hospitalization during 4-year follow-up; the number and the
4 days of hospitalizations, and the number of people hospitalized at 4-year follow-up; variables
5 associated with better outcome in BD patients. Methods: This is a controlled study involving
6 an experimental group (N=57) and a control group (N=52). The treatment phase consisting of
7 21 weeks, in which all participants received TAU, while the experimental group received
8 additional psychoeducation. Results: The survival analysis showed significant differences in
9 terms of time to first hospitalization of up to 4-year follow-up: the patients in the
10 psychoeducation group showed a longer time free from hospitalizations than the control
11 group. Concerning the predictors of time to first hospitalization, the only factor that showed a
12 trend to statistical significance was psychoeducation. Conclusions: This is one of few studies
13 assessing the long-term effectiveness of psychoeducation in a naturalistic setting. The data
14 confirm that psychoeducation can impact illness course, in terms of longer time free from
15 hospitalizations.
16
17 Key words: psychoeducation, effectiveness, follow-up, hospitalizations, integrated treatment,
18 Bipolar Disorder.
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20

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1 1. INTRODUCTION
2 Bipolar Disorder (BD) is a chronic and recurrent mental disorder, which often causes severe
3 disability among people who suffer from it. Even though medication is needed, the role of
4 psychosocial factors both in the onset and in the progression of BD has become progressively
5 evident and has led to the development of several psychosocial approaches as adjunctive treatment
6 to pharmacological therapies. Among the several psychological treatments, psychoeducation has
7 shown its efficacy, so that recent reviews of evidence-based guidelines for the clinical management
8 of BD state that ‘all patients with BD should be offered group or individual psychoeducation’
9 (Connolly and Thase, 2011; Podawiltz, 2012). Many studies have confirmed that psychoeducation
10 is effective in helping people with BD detect early signs and implement behavioural measures to
11 prevent full-blown episodes, which are frequently associated with high morbidity and more
12 hospitalizations (Swartz and Swanson, 2014; Bond and Anderson, 2015; Miziou et al., 2015;
13 Salcedo et al., 2016; Oud et al., 2016). Moreover, Chatterton and colleagues (2017) in their meta-
14 analysis showed that psychoeducation is very effective to improve medication adherence. A current
15 review, aimed to assess the literature on the efficacy of several types of psychoeducation
16 (individual, group, family, internet-based), showed that group and family psychoeducation are the
17 most efficacious; in contrast, the individual and internet psychoeducation need further study (Soo et
18 al., 2018).
19 Although to date the benefits of group psychoeducation in the management of BD are well known,
20 the evidence that the positive effects of psychoeducation persist over time is still weak; moreover,
21 there are few studies about effectiveness of psychoeducation provided in ordinary Mental Health

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22 Services, as it was investigated in the present study. Meyer and Hautzinger (2012) have shown, for

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23 example, that there were no differences in relapse between treatment conditions over 2-year follow-

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24 up, pointing out that some shared aspects, such as information or regular mood monitoring, might

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25 explicate the effects of psychological treatment for BD.
26 In a previous study we evaluated the effectiveness of psychoeducation at 1-year follow-up (Candini
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et al., 2013) comparing two groups: one group attended psychoeducation and one group was in a

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waiting list (control group).

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The results showed that the number of patients hospitalized during the 1-year follow-up, the mean

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30 number of hospitalizations per patient, and the mean number of hospitalization days were
31 significantly lower for psychoeducation patients.
32 In this study we want to evaluate the outcomes of psychoeducation at 4-year follow-up, in order to
33 assess the long-term effectiveness of psychoeducation over time. Furthermore, we wanted to see if
34 there are variables that can predict who will better respond to psychoeducation. In fact, there are
35 still two key questions that need to be addressed: how to predict who will most benefit from
36 psychoeducation, and therefore to which patients to recommend it.
37
38 2. MATERIALS AND METHODS
39 2.1 Study design
40 This controlled study involved two groups of outpatients: patients in the experimental group
41 received treatment as usual (TAU), consisting of one monthly visit with the treating psychiatrist and
42 pharmacological treatment specific for BD, and additional psychoeducation according to Colom and
43 Vieta’s model (Colom and Vieta, 2006); patients in the control group received only TAU. During
44 the 4-year follow-up all participants continued to receive TAU; the experimental group did not
45 receive boosting sessions of psychoeducation.
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47 2.2 Participants
48 One hundred and twenty-seven outpatients with BD, aged 18-65 years, were involved in this study.
49 Eighteen were excluded: 13 not meeting inclusion criteria and 5 declined to participate.
50 The study is a pragmatic trial conducted under routine conditions and so randomization was not
51 possible. Two DMHs (DMH-A and DMH-B) located in Brescia, a northern Italian town, were
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1 involved: patients were selected and evaluated at both DMHs. Psychoeducation was implemented
2 only at DMH-A; DMH-B, where psychoeducation was never implemented for organizational
3 reasons, represented the control group (Candini et al., 2013). Furthermore, during the 4-year follow-
4 up 13 (28.8%) patients dropped out of treatment at DMH-B; since the size of the control sample
5 became too small for a proper comparison, we randomly selected 20 additional patients meeting
6 inclusion criteria from the DMH-B electronic registry to be added to the original control sample;
7 these patients underwent the same evaluation of the original sample (see below).
8 Inclusion criteria were: diagnosis of BD type I or II; being euthymic for at least 3 months;
9 information about illness course during ≥18 months prior to start of psychoeducation (collected
10 from the medical record and from the psychiatrist); willingness to continue current medication; and
11 written informed consent to participate in group psychoeducation. Exclusion criteria included: all
12 DSM-IV Axis I disorders; mental retardation (IQ <70); current substance use such as alcohol,
13 cannabis, cocaine, etc (except for tobacco smoking); organic brain damage, or deafness. Patients
14 undergoing any structured form of psychological treatment were also excluded.
15 The study was approved by Ethical Committee of the Saint John of God, Fatebenefratelli of Brescia
16 (N° 96/2009/I). All procedures performed in this study were in accordance with the 1964 Helsinki
17 declaration and its later amendments or comparable ethical standards. All participants have
18 written/wrote informed consent to participate in group psychoeducation.
19
20 2.3 Psychoeducation group
21 Group psychoeducation was performed according to Colom and Vieta’s model, consisting of 21

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22 weekly sessions of 90 minutes, each aiming at improving four main areas: illness awareness,

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23 treatment adherence, early detection of warning signs of a probable episode and lifestyle regularity

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24 (Colom and Vieta, 2006). The psychoeducation was delivered in groups of 8-12 participants,

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25 conducted by two clinical psychologists, who had previously attended a training psychoeducation
26 course directly held by Francesc Colom. Patients missing more than five sessions were excluded
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results.

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from the group, to avoid the potential for insufficient treatment ‘dosages’ in cases producing nil

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30 2.4 Standardised assessment
31 Before inclusion in the study, all patients in both groups were assessed through the following tools:
32 the Structured Clinical Interview for DSM-IV Axis I (SCID-I) to confirm Bipolar Disorder
33 diagnosis; the Young Mania Rating Scale (YMRS), and the Hamilton Rating Scale for Depression
34 (HAM-D-17) in order to assess euthymia. The cut-offs of HAM-D-17 <8 and YMRS <6 were
35 identified by previous studies (Colom et al., 2009). There were no differences between the two
36 groups in the mean level of mood symptoms at the baseline. The average of the HAM-D-17 total
37 score was 4.64 (SD=3.5) for the psychoeducation group and 5.14 (SD=3.1) for the control group
38 (U=817: p=0.344). The average of the YMRS total score was 3.7 (SD=3.3) for the psychoeducation
39 group and 3.8 (SD=3.3) for the control group (U=1207: p=0.830).
40 Personality disorders were detected through the clinician's diagnosis in medical records. Finally,
41 socio-demographic, clinical and treatment-related information were collected through the Patient
42 Schedule.
43
44 2.5 Main outcome measurements
45 The main aims of this study were: (a) to assess the number and the days of hospitalizations, and the
46 number of people hospitalized at 4-year follow-up; (b) to assess the effectiveness of
47 psychoeducation in ordinary mental health services in terms of time to first hospitalization during
48 the 4-year follow-up; (c) to identify possible variables associated with better outcome over time
49 with BD patients who attended group psychoeducation, and to understand who benefitted from
50 psychoeducation. All data concerning hospitalization were collected from the Lombardy Region’s
51 electronic Mental Health Information System, which saves mandatory information concerning all

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1 hospital admissions to all General Hospital Psychiatric Units (GHPUs). As a result, we ensured that
2 all information concerning hospitalization were accurate and reliable.
3
4 2.6 Statistical analysis
5 Sample characteristics were provided in terms of descriptive statistics including frequencies,
6 percentages (for qualitative variables), mean and standard deviation (for quantitative variables).
7 Differences between psychoeducation and control groups were tested with a Chi-square test for
8 categorical variables and by T-test for Gaussian distributed quantitative variables (or non-parametric
9 Mann-Whitney test for non-Gaussian variables). Normality assumption was tested with a Shapiro-
10 Wilk test as well as Kolmogorov-Smirnov test (data not shown). All tests were two-tailed and the
11 probability of a type I error was set at p = 0.05.
12 The Kaplan-Meier (KM) survival analysis was used to analyse the hospitalization-free curves at 4-
13 year follow-up time. Differences of KM-curves between the two groups were evaluated by Log-
14 rank test. Cox proportional-hazards regression model were performed to analyse the dependency of
15 time to first hospitalization on predictor variables (Laine and Reyes, 2014). All analysis were
16 conducted according to an ‘intention-to-treat’ model, including all patients who started but did not
17 complete psychoeducation (drop-outs). Analysis were performed by using SPSS 23.0 and by
18 survival package of R: A language and environmental for statistical computing (version 3.4.1, R
19 Development Core Team, 2015).
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21 2. RESULTS

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22 3.1 Patients’ recruitment and drop-out

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23 Overall, 109 euthymic outpatients were recruited: 57 patients were enrolled in the experimental

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24 group and 52 in the control group. In the psychoeducation group, 46 individuals out of 57 (80.7%)

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25 completed psychoeducation program, attending a mean of 19.3 sessions (SD=0.9). Eleven
26 participants (19.3%) withdrew from the group for various reasons: manic recurrence (1 patient),
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depressive recurrence (1 patient), mixed recurrence (2 patients), conflicting schedules (3 patients),

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or disagreement with the biological approach underlying the cause of BD (4 patients). In all cases,

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drop out participants attended a mean of 10.4 sessions (SD=

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31 5.3).
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33 3.2 Samples’ socio-demographic characteristics
34 The samples’ characteristics at baseline are reported in table 1, both groups were comparable
35 regarding socio-demographic and clinical characteristics. Despite 20 patients added to the control
36 group, these results show that the features of new patients did not diverge from those of the patients
37 in the original control group; indeed the sociodemographic and clinical characteristics of the new
38 control group did not differ significantly from those of the experimental group.
39
40 Table 1
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42 3.3 Number of people hospitalized during the 4-year follow-up
43 No significant differences between-group (χ2=3.09, p=0.109) were observed during the 4-year
44 follow-up: 23 (44.2%) individuals out of 52 in the control group were hospitalized and 16 (28.1%)
45 out of 57 in the psychoeducation group.
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47 3.4 Number of hospitalizations during the 4-year follow-up
48 During the 4-year follow-up, the psychoeducation group had a mean number of 0.5 (SD=0.97)
49 hospital admissions versus 0.9 (SD=1.40) observed among controls (U=1732; p=0.076).
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51 3.5 Number of hospitalization days during the 4-year follow-up
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1 During the 4-year follow-up the psychoeducation group reported a mean of 9.3 (SD=20.08)
2 hospitalization days as compared to 16.8 (SD=27.23) in the control group (U=1735; p=0.074).
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4 3.6 Hospital admissions and days of hospitalization among completers during the 4-year
5 follow-up
6 In addition to the ‘intention-to-treat’ analysis, including all patients who started but did not
7 conclude psychoeducation, we assessed the effectiveness of psychoeducation among completers
8 (89.9% of the sample). During the 4-year follow-up, no significant differences between-group in the
9 number of people hospitalized were detected: 23 out of 52 control participants had been
10 hospitalized versus 12 out of 46 in the completer psychoeducation group (Chi-square =3.50;
11 p=0.074). However, we observed a reduction in the mean number of hospitalizations in the group
12 completing the psychoeducation programme, as compared to the control group (0.3 versus 0.9;
13 U=14339, p=0.043) and in mean days of hospitalization (6.9 versus 16.8; U=1441, p=0.042).
14
15 3.7 Time to hospitalization at 4-year follow-up
16 Figure 1 shows the survival analysis for patients’ time to first hospitalization. The two groups’ event
17 curves differed significantly in terms of time to hospitalization in the ITT analysis (log rank=3.9,
18 p<.047). The completers’ event curves are shown in figure 2. The between-group differences were
19 also significant in this instance (log rank =4.3, p<.037). In both cases, the patients in the
20 psychoeducation group showed a longer time free from hospitalizations than the control group.
21 However, it should be noticed that the difference between the two groups during 4-year follow-up is

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22 mainly due to the difference found at the 1-year follow-up. In fact, in the following years (2-4

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23 years) the differences between the two groups tend to decrease: this finding is well noticeable

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24 looking at figures 3 and 4.

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26 Figures 1, 2, 3, 4
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3.8 Predictors of time to first hospitalization

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No socio-demographic or clinical variables were associated with a shorter/longer time to first

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30 hospitalization (with hazard ratios -HR's- close to one; table 2). The only factor that showed a trend
31 to statistical significance with longer time to first hospitalization was ‘psychoeducation’: patients
32 who attended psychoeducation had a longer time to first hospitalization than patients in the control
33 group (HR=0.53; 95% CI: 0.28-1.01).
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35 Table 2
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37 3. DISCUSSION
38 To our knowledge, this is one of the few studies which has tested the long-term effectiveness of
39 psychological interventions for BD with a long follow-up (Colom et al., 2009; González et al.,
40 2014). Furthermore, it is important to emphasize that in this study psychoeducation was provided in
41 a naturalistic setting of mental health services’ daily activities.
42 Our study confirms that group psychoeducation conferred a long-lasting prophylactic effect, in
43 terms of longer time free from hospitalizations, as shown in the survival curves.
44 However, further analysis show that differences between the two groups during the 4 years decrease
45 significantly after the first-year follow-up. This result suggests that it might be useful to implement
46 boosting sessions after the end of the psychoeducation, in order to prolong the period of time free
47 from hospitalization. The boosting sessions may help patients remember protective lifestyles and
48 risk factors for BD, and encourage a rigorous monitoring of prodromes, in order to prevent relapse.
49 It is interesting to observe that the number of hospitalizations and days of hospitalization among
50 patients who completed psychoeducation was also significantly lower than in the control group.
51 This indicates that patients who completed psychoeducation were more able to recognize prodromes

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1 early, avoiding the most severe recurrences, which require hospitalization: even when
2 hospitalization was necessary, it was shorter. In contrast, according to ITT analysis, the differences
3 between the groups were not statistically significant, probably due to the insufficient 'dose' of
4 treatment among non-completers. In any event, even the ITT analysis show that those who started
5 psychoeducation had a number of hospitalizations and days of hospitalization lower than the control
6 group. Although this difference did not reach statistical significance, it may be considered clinically
7 relevant, in particular with regard to the number of days of hospitalization, which in the
8 psychoeducation group was almost half of the control group. As a comparison, it is very doubtful
9 that any mood stabilizer may confer any degree of protection from recurrences during 4 years
10 following the discontinuation of medication.
11 Our results showed how this time-limited single intervention brought about a major improvement in
12 BD outcome over the long term (in our case 4 years). Therefore, group psychoeducation can
13 enhance behavioral and life style changes that seem to be maintained over time, although some
14 patients might need boosting sessions, as other studies suggested (Colom et al., 2009; Lam et al.,
15 2005; Ball et al., 2006).
16 The positive effects of psychoeducation would seem possible because this type of psychosocial
17 treatment cannot be considered simple information. Psychoeducation produces a process of
18 awareness on illness, that is necessary for an effective management of BD (Colom et al., 2009).
19 Indeed, psychoeducation include educational and psychosocial targets that need the use of
20 educational techniques to promote a long-lasting behavioral change in BD patients. For this reason,
21 it is reasonable to assume that its effects are maintained over time. This assumption is confirmed by

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22 a recent meta-analysis showing that the greater improvements in mania symptoms and in social

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23 functioning at long-term follow-up relative to the short term may be indicative of increased

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24 effectiveness of psychoeducation over time (Chatterton et al., 2017).

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26 4.1 Impacts of psychoeducation
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Psychoeducation is considered very important for people suffering from BD and their relatives

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(Gex-Fabry et al., 2015), both due to its primary efficacy for recurrence prevention and its

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secondary benefit associated with improved perceived social support, better awareness of BD, better

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30 attitude towards drugs and access to services. This has been demonstrated in a recent qualitative
31 research on patients’ subjective experiences of a group psychoeducation intervention for people
32 with BD, aimed at understanding the feasibility, acceptability and impact of psychoeducation (Poole
33 et al., 2015). It is possible that these secondary outcomes are determined by certain informal aspects
34 of group setting, e.g. patients who benefited from learning from others, feeling less socially
35 isolated. Meeting other people with BD normalized their illness experience, delivered a feeling of
36 community. All these aspects contribute to the most important goal in the treatment of every patient
37 with a chronic disorder (such as BD), i.e. the improvement of the perceived quality of life.
38 Moreover, thanks to psychoeducation patients become more knowledgeable about medication and
39 treatment options, improving treatment adherence. In fact, they may become more aware of the
40 importance of drug treatment to prevent relapses. This leads them to take medication more regularly
41 (Chatterton et al., 2017). Other important effects of psychoeducation include promotion of a more
42 regular lifestyle and the early detection of prodromal signs, fundamental factors to improve the
43 course and prognosis of BD (Perry et al., 1999; Colom et al., 2005; Colom et al., 2009; Frank et al.,
44 2005).
45 Finally, the greater mood stabilization produced by psychoeducation is a significant achievement in
46 view of recent discoveries about neuroprogression in BD. Through the reduction of recurrences,
47 psychoeducation could contrast the neuroprogression of BD, reducing brain changes and cognitive
48 impairment (Passos et al., 2016).
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50 4.2 Clinical implications: who benefits from psychoeducation?
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1 Recent studies suggested the usefulness of psychoeducation for relapse prevention only in a
2 selected subgroup of early stage patients (Miller et al., 2004; Scott et al, 2007; de Barros et al.,
3 2013; Morriss et al., 2016). Although it seems logical that psychoeducation should be offered to
4 patients as soon as possible, our results suggest that this intervention can have a wider range of
5 action. In our study, important variables usually associated with a worse course of BD, such as
6 psychotic symptoms, suicide attempts, Axis II comorbidity, early age of onset did not produce any
7 significant differences on the effectiveness of psychoeducation. Moreover, it is very important to
8 consider that the secondary effects of psychoeducation above mentioned, which go beyond the
9 prevention of relapses, produce a significant improvement in the patients’ quality of life
10 (Faridhosseini et al., 2017), probably due to a higher levels of self-efficacy (Abraham et al., 2014).
11 From these considerations, we suggest that psychoeducation should be offered to all patients with
12 BD and not only those at an early stage of the disease. As stated in the recent evidence-based
13 guidelines for the clinical management of BD (revised third edition recommendations from the
14 British Association for Psychopharmacology), psychoeducation should always be the preferred
15 psychological intervention for people suffering from BD (Goodwin et al., 2016).
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17 4.3 Limitations
18 This study has some limitations. The most important is its limited generalisability, caused by lack of
19 randomisation and by the small number of participants involved. Moreover, the primary outcome of
20 this study was recurrences with hospitalization, but no information was available on mood
21 instability like hypomanic or moderate depressive that did not require hospitalization, but which are

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22 equally important from a clinical point of view. More, as the participants were not followed-up, but

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23 rather their hospitalisation data used, it was also not possible to know what other psychological

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24 interventions they may have done over the 4-year period. Furthermore, most patients suffered by

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25 BD I, so we cannot be sure that similar results in terms of psychoeducation effectiveness can be also
26 extended to patients with BD II. Finally, no data on the polarity of recurrences were also available,
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(Simhandl et al., 2015).

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30 4. CONCLUSIONS
31 The results of this study show that patients who participated in psychoeducation had a longer time
32 to first hospitalization, after 4 years, compared to patients who received TAU only. However, since
33 the effectiveness of psychoeducation tends to decrease over time, it may be useful to add boosting
34 sessions after the end of psychoeducation, in order to prolong the period of time free from
35 hospitalization.
36 Moreover, this study shows that there were not socio-demographic or clinical variables associated
37 with time to first hospitalization, but the only factor related to a longer time free from
38 hospitalizations was the attendance to psychoeducation.
39 These data confirm that combining pharmacological plus an evidence-based adjunctive
40 psychosocial intervention, such as group psychoeducation, is currently the most efficacy way to
41 improve BD outcomes. Although many studies have stated that psychoeducation should be applied
42 as early as possible, our study shows that psychoeducation can have a wider range of action and be
43 also useful for patients with a longer history of illness. For this reason, psychoeducation should be
44 offered to all patients with BD in Mental Health Services.
45
46
47 Acknowledgments
48 Thanks are due to Maida Belluati, Silvia Bonomi, Veronica Bonzi, Maria Teresa Caldera Angelo
49 Campana, Andrea Cesareni, Valentina Cocchi, Paola Corsini, Claudia Dal Brun, Alessandra
50 Donnarumma, Roberta Ermentini, Graziano Fezzardi, Emanuela Gualazzini, Arianna Landi,
51 Cristiano Marchese, Daniela Milito, Paola Palumbo, Laura Parlavecchio, Raffaella Saracco,

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1 Giuseppe Seggioli, Joyce Severino, Fabio Teti, Gianpaolo Valenti, Luciana Vavassori, and Amneris
2 Zanini for their generous help in the overall organization and conduct of the project. We are also
3 grateful to all patients who collaborated and shared their experiences with us.
4
5 Conflict of Interest
6 The authors declare that they have no competing interests. This project was funded by the
7 Lombardy Region ‘Progetti Innovativi per la Salute Mentale’ (TR15).
8
9 Author Contributions Statement
10 CB has managed the literature searches, designed the study, conducted the psychoeducation groups,
11 wrote the protocol and the manuscript, and managed the analysis.
12 VC has designed the study, conducted the psychoeducation groups, wrote the protocol and the
13 manuscript.
14 CF has performed data analysis, wrote the statistical analysis section and contributed to the writing
15 of results and gave her final approval of the version to be published.
16 AG managed the literature search, wrote the protocol and the manuscript, and gave his final
17 approval of the version to be published
18 FMS has selected patients and helped organize the study at the Desenzano DMH. He was involved
19 in manuscript revision, and gave his final approval of the current version.
20 CT has selected patients and helped organize the study at the Brescia DMH. He was involved in
21 manuscript revision, and gave his final approval of the current version.

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22 GN has selected patients and helped organize the study at the Desenzano DMH. He was involved in

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23 manuscript revision, and gave his final approval of the current version.

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24 MS has selected patients and helped organize the study at the Desenzano DMH. He was involved in

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25 manuscript revision, and gave his final approval of the current version.
26 GDG he started the project and applied for funding, managed the literature search, designed the
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study, wrote the protocol and the manuscript, coordinated the study, and gave his final approval of

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the current version.

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All authors read and approved the final manuscript.

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32 Contribution to the Field Statement
33 Bipolar Disorder (BD) is a chronic and recurrent mental disorder, which often causes severe
34 disability among people who suffer from it. Although the pharmacological therapy is needed, the
35 role of psychosocial factors has become increasingly evident and has led to the development of
36 different psychological approaches as adjunctive treatment to medicament. Among the several
37 psychological treatments, psychoeducation has shown its efficacy. However, the evidence that the
38 positive effects of psychoeducation persist over time is still weak, and mostly there are few studies
39 about effectiveness of psychoeducation provided in ordinary Mental Health Services. This study is
40 one of the few that has assessed the long-term effectiveness of psychoeducation in a naturalistic
41 setting of Mental Health Services’ daily activities. This study shows that the effect of
42 psychoeducation seems to decrease over time. Moreover, this study suggests that this intervention
43 can have a wider range of action. For this reason the psychoeducation should be offered to patients
44 as soon as possible as indeed all the evidence-based guidelines for the clinical management of BD.
45
46
47 REFERENCES
48
49 Abraham K., Miller C.J., Birgenheir D.G., Lai Z., and Kilbourne A. (2014) Self-Efficacy and
50 Quality of Life Among People With Bipolar Disorder. J. Nerv. Ment. Dis. 202(8), 583-588. doi:
51 10.1097/NMD.0000000000000165
 10

1
2 Ball J.R., Mitchell P.B., Corry J.C., Skillecorn A., Smith M., and Malhi G.S. (2006). A
3 randomized controlled trial of cognitive therapy for bipolar disorder: focus on long-term
4 change. J. Clin. Psychiatry. 67(2), 277-286.
5
6 Bond K., and Anderson I.M. (2015). Psychoeducation for relapse prevention in bipolar disorder:
7 a systematic review of efficacy in randomized controlled trials. Bipolar. Disord. 17, 349-362.
8 doi: 10.1111/bdi.12287
9
10 Candini V., Buizza C., Ferrari C., Caldera M.T., Ermentini R., Ghilardi A., et al. (2013). Is
11 structured group psychoeducation for bipolar patients effective in ordinary mental health
12 services? A controlled trial in Italy. J. Affect. Disord. 151(1), 149-155. doi:
13 10.1016/j.jad.2013.05.069
14
15 Chatterton M.L., Stockings E., Berk M., Barendregt J.J., Carter R., and Mihalopoulos C. (2017).
16 Psychosocial therapies for the adjunctive treatment of bipolar disorder in adults: network meta-
17 analysis. Br. J. Psychiatry. 210(5), 333-341. doi: 10.1192/bjp.bp.116.195321
18
19 Colom F., Vieta E., Sánchez-Moreno J., Martínez-Arán A., Reinares M., Goikolea J.M., et al.
20 (2005). Stabilizing the stabilizer: group psychoeducation enhances the stability of serum lithium
21 levels. Bipolar. Disord. 7 Suppl 5, 32-36. do 10.1111/j.1399-5618.2005.00249.x

l
22

a
23 Colom F., Vieta E., Sánchez-Moreno J., Palomino-Otiniano R., Reinares M., Goikolea J.M., et

n
24 al. (2009). Group psychoeducation for stabilised bipolar disorders: 5-year outcome of a

sio
25 randomised clinical trial. Br. J. Psychiatry. 194, 260-265. doi: 10.1192/bjp.bp.107.040485
26
27
28
29

o i
Colom F., and Vieta E. (2006). Manuale di psicoeducazione per il disturbo bipolare (2006)

v
Roma: Giovanni Fioriti Editore.

r
P
30 Connolly K.R., and Thase M.E. (2011). The clinical management of bipolar disorder: a review
31 of evidence-based guidelines. Prim. Care. Companion. CNS. Disord. 13;4. doi:
32 10.4088/PCC.10r01097
33
34 de Barros Pellegrinelli K., de O Costa L., Silval K.I., Dias V.V., Roso M.C., Bandeira M., et al.
35 (2013). Efficacy of psychoeducation on symptomatic and functional recovery in bipolar
36 disorder. Acta. Psychiatr. Scand. 127(2), 153-158. doi: 10.1111/acps.12007
37
38 Faridhosseini F., Baniasadi M., Fayyazi Bordbar M.R., Pourgholami M., Ahrari S., and
39 Asgharipour N. (2017). Effectiveness of Psychoeducational Group Training on Quality of Life
40 and Recurrence of Patients with Bipolar Disorder. Iran. J. Psychiatry. 12(1), 21-28.
41
42 Frank E., Kupfer D.J., Thase M.E., Mallinger A.G., Swartz H.A., Fagiolini A.M., et al. (2005).
43 Two-year outcomes for interpersonal and social rhythm therapy in individuals with bipolar I
44 disorder. Arch. Gen. Psychiatry. 62(9), 996-1004.
45
46 Gex-Fabry M., Cuénoud S., Stauffer-Corminboeuf M.J., Aillon N., Perroud N., and Aubry J.M.
47 (2015). Group Psychoeducation for Relatives of Persons With Bipolar Disorder: Perceived
48 Benefits for Participants and Patients. J. Nerv. Ment. Dis. 203(9), 730-734. doi:
49 10.1097/NMD.0000000000000355
50

10
 11

1 González Isasi A., Echeburúa E., Limiñana J.M., and González-Pinto A. (2014).
2 Psychoeducation and cognitive-behavioral therapy for patients with refractory bipolar disorder:
3 A 5-year controlled clinical trial. Eur. Psychiat. 29(3), 134-141. doi:
4 10.1016/j.eurpsy.2012.11.002
5
6 Goodwin G.M., Haddad P.M., Ferrier I.N., Aronson J.K., Barnes T.R.H., Cipriani A., et al.
7 (2016). Evidence-based guidelines for treating bipolar disorder: Revised third edition
8 recommendations from the British Association for Psychopharmacology. J. Psychopharmacol.
9 30(6), 495-553. doi: 10.1177/0269881116636545
10
11 Laine T., and Reyes E.M. (2014). Tutorial: Survival Estimation for Cox Regression Models with
12 Time-Varying Coefficients Using SAS and R. J. Stat. Softw. 61. doi: 10.18637/jss.v061.c01
13
14 Lam D., Donaldson C., Brown Y., and Malliaris Y. (2005). Burden and marital and sexual
15 satisfaction in the partners of bipolar patients. Bipolar. Disord. 7(5), 431-440. doi:
16 10.1111/j.1399-5618.2005.00240.x
17
18 Meyer T.D., and Hautzinger M. (2012). Cognitive behaviour therapy and supportive therapy for
19 bipolar disorders: relapse rates for treatment period and 2-year follow-up. Psychol. Med. 42,
20 1429-1439. doi: 10.1017/S0033291711002522
21

l
22 Miller I.W., Solomon D.A., Ryan C.E., and Keitner G.I. (2004). Does adjunctive family therapy

a
23 enhance recovery from bipolar I mood episodes? J. Affect. Disord. 82(3), 431-436. doi:

n
24 10.1016/j.jad.2004.01.010

sio
25
26 Miziou S., Tsitsipa E., Moysidou S., Karavelas V., Dimelis D., and Polyzoidou V. (2015).
27
28
29

o i
Psychosocial treatment and interventions for bipolar disorder: a systematic review. Ann. Gen.

v
Psychiatry. 14: 19. doi: 10.1186/s12991-015-0057-z

r
P
30 Morriss R., Lobban F., Riste L., Davies L., Holland F., Long R., et al. (2016). Clinical
31 effectiveness and acceptability of structured group psychoeducation versus optimised
32 unstructured peer support for patients with remitted bipolar disorder (PARADES): a pragmatic,
33 multicentre, observer-blind, randomised controlled superiority trial. Lancet. Psychiatry. 3(11),
34 1029-1038. doi: 10.1016/S2215-0366(16)30302-9
35
36 Oud M., Mayo-Wilson E., Braidwood R., Schulte P., Jones S.H., Morriss R., et al. (2016).
37 Psychological interventions for adults with bipolar disorder: systematic review and meta-
38 analysis. Br. J. Psychiatry. 208, 213-222. doi: 10.1192/bjp.bp.114.157123.
39
40 Passos I.C., Mwangi B., Vieta E., Berk M., and Kapczinski F. (2016). Areas of controversy in
41 neuroprogression in bipolar disorder. Acta. Psychiatr. Scand. 134(2), 91-103. doi:
42 10.1111/acps.12581
43
44 Perry A., Tarrier N., Morriss R., McCarthy E., and Limb K. (1999). Randomised controlled
45 trial of efficacy of teaching patients with bipolar disorder to identify early symptoms of relapse
46 and obtain treatment. BMJ. 318(7177), 149-153. doi: 10.1136/bmj.318.7177.149
47
48 Podawiltz A. (2012). A review of current bipolar disorder treatment guidelines. J. Clin.
49 Psychiatry. 73(3). doi: 10.4088/JCP.10060tx2cc
50
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1 Poole R., Smith D., and Simpson S. (2015). Patients’ perspectives of the feasibility,
2 acceptability and impact of a group-based psychoeducation programme for bipolar disorder: a
3 qualitative analysis. BMC. Psychiatry. 15, 184. doi: 10.1186/s12888-015-0556-0
4
5 Reinares M., Moreno J.S., and Fountoulakis K.N. (2014). Psychosocial interventions in bipolar
6 disorder: what, for whom, and when. J. Affect. Disord. 156, 46-55. doi:
7 10.1016/j.jad.2013.12.017
8
9 Salcedo S., Gold A.K., Sheikh S., Marcus P.H., Nierenberg A.A., Deckersbach T., et al. (2016).
10 Empirically supported psychosocial interventions for bipolar disorder: Current state of the
11 research. J. Affect. Disord. 201, 203-214. doi: 10.1016/j.jad.2016.05.018
12
13 Scott J., Colom F., and Vieta E. (2007). A meta-analysis of relapse rates with adjunctive
14 psychological therapies compared to usual psychiatric treatment for bipolar disorders. Int. J.
15 Neuropsychopharmacol. 10(1), 123-129. doi: 10.1017/S1461145706006900
16
17 Simhandl C., Radua J., König B., and Amann B.L. (2015). The prevalence and effect of life
18 events in 222 bipolar I and II patients: A prospective, naturalistic 4 year follow-up study. J.
19 Affect. Disord. 170, 166-171. doi: 10.1016/j.jad.2014.08.043
20
21 Soo S.A., Zhang Z.W., Khong S.J., Low J.E.W., Thambyrajah V.S., Alhabsyi S.H.B.T., et al.

l
22 (2018). Randomized Controlled Trials of Psychoeducation Modalities in the Management of

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23 Bipolar Disorder: A Systematic Review. J. Clin. Psychiatry. 79(3). doi: 10.4088/JCP.17r11750.

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25 Swartz H.A., and Swanson J. (2014). Psychotherapy for Bipolar Disorder in Adults: A Review
26 of the Evidence. Focus. (Am. Psychiatr. Publ.). 12(3), 251-266. doi:
27
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30 Figure 1. Survival curves for hospitalization at 4-year follow-up (log rank=3.9, p=.047) (Intention to
31 treat analysis)
32
33 Figure 2. Survival curves for hospitalization at 4-year follow-up (log rank =4.3, p=.037)
34 (Completers)
35
36 Figure 3. Survival curves for hospitalization at 1-year follow-up (log rank=4.34, p=.037) (Intention
37 to treat analysis)
38
39 Figure 4. Survival curves for hospitalization at 1-year follow-up (log rank=0.65 p=.419) (Intention to
40 treat analysis)
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1 Table 1. Sociodemographic and clinical characteristics of study participants

Characteristics Psychoeducation Control Statistical p-value

group group test
(n=57) (n=52)
Male gender, n (%) 27 (47.4) 27 (51.9) .00a .94
Mean age (sd) 41.5 (9.1) 41.7 (10.1) -.12b .90
Mean education, years (sd) 11.8 (3.5) 10.6 (3.5) 1.7b .07
In employment, n (%) 28 (49.1) 30 (57.6) .80a .37
Marital status, married, n (%) 22 (38.6) 21 (40.3) .03a .84
Diagnostic subtype, bipolar I, n (%) 55 (96.5) 49 (94.2) .31a .57
Rapid cycling*, yes, n (%) 3 (5.2) 0 (0.0) 2.7a .09
Presence of psychotic symptoms*, n (%) 51 (89.4) 39 (78.0) 2.6a .10
Presence of attempted suicide*, n (%) 12 (21.0) 11 (21.1) .00a .94
Mean age of onset, years (sd) 29.0 (8.5) 27.8 (8.2) .75b .45
Mean age of first contact with Mental Health 32.6 (8.7) 31.8 (9.0) .44b .65
Services, years (sd)
Number of previous hospitalizations#, 0.4 (0.7) 0.3 (0.7) 1.3c .34
mean (sd)
Personality disorders, n (%) 10 (17.5) 15 (28.8) 2.3a .12
a
2 Chi-squared test; df = 1
b
3 t-test
c
4 Mann-Whitney
5 *Lifetime history

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6 In the 18 months before the start of psychoeducation
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2 Table 2. Predictors of time to remission
3 Cox proportional-hazards regression (univariate) models output (completers/[ITT])
4
Predictors of remission time Hazard Ratio HR 95% CI of HR p-value

Gender, female versus male 0.81 0.43-1.53 .513

Age, years 0.99 0.96–1.03 .742
Education, years 1.01 0.92–1.10 .826
Employed, yes versus no 0.76 0.40–1.43 .394
Marital status, yes versus no 0.78 0.40–1.52 .469
Diagnostic subtype, Bipolar I, yes versus no 21.9 0.05–930.69 .317
Personality Disorder, yes versus no 0.76 0.38–1.54 .454
Age of onset, years 1.01 0.98–1.05 .504
Duration of illness, years 0.98 0.94–1.02 .324
Study group, psychoeducation versus control 0.53 0.28 -1.01 .052
5

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