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  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 . 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: firstname.lastname@example.org (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 . 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 . 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 . Current pharmacological treatments fail to control the course of about half the cases of bipolar disorder . 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 . A further long-term beneﬁt of psychological adjunctive therapy is that, compared to conventional therapy, it is less costly and more effective . 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  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 . 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 . 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 . 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 . 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  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)  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)  and Misadjustment Scale (IS) . In all of these scales, lower scores indicate better outcomes. These tools are described in detail elsewhere . 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. . 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 . 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  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 , 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 , 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 , 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 , 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 . 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 , 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. References  Amador XF, Friedman JH, Kasapis C, Yale SA, Flaum M, Gorman JM. Suicidal behavior in schizophrenia and its relationship to awareness of illness. Am J Psychiatry 1996;153:1185–8.  American Psychiatric Association. Diagnostic and Statistical manual of mental disorders, Fourth Edition, Washington D.C.: American Psychiatric Association; 1994.  Ball JR, Mitchell PB, Corry JC, Skillecorn A, Smith M, Malhi GS. A randomized controlled trial of cognitive therapy for bipolar disorder: focus on long-term change. J Clin Psychiatry 2006;67:277–86.  Beck AT, Rush AJ, Shaw BF, Emery G. Cognitive therapy of depression. New York: Guilford Press; 1979. ˜ a E, Lorenzo MC. Tratamientos psicolo´gicos eﬁcaces para el trastorno  Becon bipolar. Psicothema 2001;13:511–22.  Beltman MW, Voshaar RC, Speckens AE. Cognitive-behavioural therapy for depression in people with a somatic disease: meta-analysis of randomised controlled trials. Br J Psychiatry 2010;197:11–9.  Bertelsen M, Jeppesen P, Petersen L, Ohlenschlaeger J, le Quach P, Christensen TO, et al. Five-year follow-up of a randomized multicenter trial of intensive early intervention vs standard treatment for patients with a ﬁrst episode of psychotic illness. The OPUS Trial. Arch Gen Psychiatry 2008;65:762–71.  Colom F, Vieta E. A perspective on the use of psychoeducation, cognitivebehavioral therapy and interpersonal therapy for bipolar patients. Bipolar Disord 2004;6:480–6.  Colom F, Vieta E, Martı´nez-Ara´n A, Garcı´a-Garcı´a M, Reinares M, Torrent C, ˜ ola de una escala de evaluacio´n de la manı´a: validez y et al. Versio´n espan ﬁabilidad de la Escala de Young. Med Clin 2002;119:366–71.  Colom F, Vieta E, Sa´nchez-Moreno J, Palomino-Otiniano R, Reinares M, Goikolea JM, et al. Group psychoeducation for stabilised bipolar disorders: 5-year outcome of a randomized clinical trial. Br J Psychiatry 2009;194:260–5.  De Dios C, Ezquiaga E, Garcı´a A, Soler B, Vieta E. Time spent with symptoms in a cohort of bipolar disorder outpatients in Spain: a prospective 18-month follow-up study. J Affect Disord 2010;125:74–81.  Echeburu´a E, Corral P, Ferna´ndez-Montalvo J. Escala de Inadaptacio´n: propiedades psicome´tricas en contextos clı´nicos. Ana´lisis y Modiﬁcacio´n de Conducta 2000;26:325–40.  First MB, Spitzer RL, Gibbon M, Williams JBW. Structured clinical interview for DSM-IV-TR Axis I disorders, research revision. Patient Edition (SCID-I/P). Biometrics Research. New York: New York State Psychiatric Institute; 2002.  Gazalle FK, Hallal PC, Andreazza AC, Frey BN, Kauer-Sant’Anna M, Weyne F, et al. Manic symptoms and quality of life in bipolar disorder. Psychiatry Res 2007;153:33–8. ˜ o y evaluacio´n de un  Gonza´lez-Isasi A, Echeburu´a E, Gonza´lez-Pinto A. Disen programa de intervencio´n psicolo´gica para pacientes con trastorno bipolar refractarios a tratamiento: un estudio piloto. Ana´lisis y Modiﬁcacio´n de Conducta 2003;29:649–71. ˜ ez B, Aizpuru F, Gonza´lez Gonza´lez-Isasi A, Echeburu´a E, Mosquera F, Iba´n Pinto A. Long-term efﬁcacy of a psychological intervention program for patients with refractory bipolar disorder: a pilot study. Psychiatry Res 2010;176:161–5. ˜ ana JM, Gonza´lez-Pinto A. How effective  Gonza´lez-Isasi A, Echeburu´a E, Limin is a psychological intervention program for patients with refractory disorder? A randomized controlled trial. J Affect Disord 2010;126:80–7. ˜ ana JM, Gonza´lez-Pinto A. Predictors of  Gonza´lez-Isasi A, Echeburu´a E, Limin good outcome in patients with refractory bipolar disorder following a drug or a drug and cognitive-behavioral treatment. Compr Psychiatry 2012;53: 224–9.  Gonza´lez-Pinto A, Lalaguna B, Mosquera F, Pe´rez de Heredia JL, Gutie´rrez M, Ezcurra J, et al. Use of olanzapine in dysphoric mania. J Affect Disord 2001;66:247–53.  Gonza´lez-Pinto A, Tohen M, Lalaguna B, Pe´rez-Heredia JL, Ferna´ndez-Corres B, Gutie´rrez M, et al. Treatment of bipolar I rapid cycling patients during dysphoric mania with olanzapine. J Clin Psychopharmacol 2002;22: 450–4.  Gonza´lez-Pinto A, Gonza´lez C, Enjuto S, Ferna´ndez de Corres B, Lo´pez P, Palomo J, et al. Psychoeducation and cognitive-behavioral therapy in bipolar disorder: an update. Acta Psychiatr Scand 2004;109:83–90.  Gonza´lez-Pinto A, Mosquera F, Alonso M, Lo´pez P, Ramı´rez F, Vieta E, et al. Suicidal risk in bipolar I disorder patients and adherence to long-term lithium treatment. Bipolar Disord 2006;8:618–24.  Gonza´lez-Pinto A, Dardennes R, de Ze´licourt M, Lo´pez P, Oliveros RG, Vieta E, et al. In-patient care costs of patients with bipolar I disorder: a comparison between two European centers. J Affect Disord 2009;121:152–5.  Judd LL, Akiskal HS, Schettler PJ, Endicott J, Maser J, Solomon DA, et al. The long-term natural history of the weekly symptomatic status of bipolar I disorder. Arch Gen Psychiatry 2002;59:530–7.  Judd LL, Schettler PJ, Akiskal HS, Coryell W, Leon AC, Maser JD, et al. Residual symptom recovery from major affective episodes in bipolar disorders and rapid episode relapse/recurrence. Arch Gen Psychiatry 2008;65: 386–394.  Lam D. What can we conclude from studies on psychotherapy in bipolar disorder? Invited commentary on. . . Cognitive-behavioral therapy for severe and recurrent bipolar disorders. Br J Psychiatry 2006;188: 321–2.  Lam DH, Jones S, Hayward P, Bright J. Cognitive therapy for bipolar disorder: a therapist’s guide to concepts. Methods and Practice. New York: John Wiley & Sons; 1999.  Lam DH, Watkins ER, Hayward P, Bright J, Wright K, Kerr N, et al. A randomized controlled study of cognitive therapy for relapse prevention for bipolar affective disorder: outcome of the ﬁrst year. Arch Gen Psychiatry 2003;60:145–52.  Lam DH, Hayward P, Watkins ER, Wright K, Sham P. Relapse prevention in patients with bipolar disorder: cognitive therapy outcome after 2 years. Am J Psychiatry 2005;162:324–9.  Linszen D, Dingemans P, Lenior M. Early intervention and a ﬁve-year follow-up in young adults with a short duration of untreated psychosis: ethical implications. Schizophr Res 2001;51:55–61.  Lo´pez P, Mosquera F, de Leo´n J, Gutie´rrez M, Ezcurra J, Ramı´rez F, et al. Suicide attempts in bipolar patients. J Clin Psychiatry 2001;62:963–6.  Mansell W, Colom F, Scott J. The nature and treatment of depression in bipolar disorder: a review and implications for future psychological investigation. Clin Psychol Rev 2005;25:1076–100.  Meyer TD, Hautzinger M. Cognitive behaviour therapy for bipolar disorders; relapse rates for treatment period and 2-year follow-up. Psychol Med 2012;42:1429–39.  Miklowitz DJ, Otto MW, Frank E, Reilly-Harrington NA, Wisniewski SR, Kogan JN, et al. Psychosocial treatments for bipolar depression: a 1-year randomized trial from the Systematic Treatment Enhancement Program. Arch Gen Psychiatry 2007;64:419–26.  Miklowitz DJ, Otto MW, Frank E, Reilly-Harrington NA, Kogan JN, Sachs GS, et al. Intensive psychosocial intervention enhances functioning in patients with bipolar depression: results from a 9-month controlled trial. Am J Psychiatry 2007;164:1340–7.  Piccinni A, Catena M, Del Debbio A, Marazziti D, Monje C, Schiavi E, et al. Health-related quality of life and functioning in remitted bipolar I outpatients. Compr Psychiatry 2007;48:323–8.  Scott J, Paykel E, Morriss R, Bentall R, Kinderman P, Johnson T, et al. Cognitivebehavioral therapy for severe and recurrent bipolar disorders: randomized controlled trial. Br J Psychiatry 2006;188:313–20.  Scott J, Colom F, Popova E, Benabarre A, Cruz N, Valenti M, et al. Long-term mental health resource utilization and cost of care following group psychoeducation or unstructured group support for bipolar disorders: a cost-beneﬁt analysis. J Clin Psychiatry 2009;70:378–86.  Spielberger CD, Gorsuch RL, Lushene RE. The state trait anxiety inventory. Palo ˜ ol Alto (California): Consulting Psychologist Press; 1970 [Traducido al espan por N. Seisdedos y publicado por TEA Ediciones].  Stahl S. Psicofarmacologı´a esencial de la depresio´n y del trastorno bipolar. Barcelona: Ariel; 2002. A. Gonza´lez Isasi et al. / European Psychiatry 29 (2014) 134–141  Tolin DF. Is cognitive-behavioural therapy more effective than other therapies?: a meta-analytic review. Clin Psychol Rev 2010;30: 710–20. ˜ ola del  Va´zquez C, Sanz J. Fiabilidad y valores normativos de la versio´n espan Inventario para la Depresio´n de Beck de 1978. Clı´nica y Salud 1997;8: 403–22.  Vieta E, Pacchiarotti I, Valentı´ M, Berk M, Scott J, Colom F. A critical update on psychological interventions for bipolar disorders. Curr Psychiatry Rep 2009;11:494–502. 141  Yatham LN, Bowden CL, Calabrese JR. The impact of polarity of subsyndromal symptoms in bipolar maintenance studies. Symposium IV: the burden of bipolar disorder; medical illness, suicide and cognitive impairment. Bipolar Disord 2005;7:113.  Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry 1978;1:429–35.  Zaretsky A, Lancee W, Miller C, Harris A, Parikh SV. Is cognitive-behavioral therapy more effective than psychoeducation in bipolar disorder? Can J Psychiatry 2008;53:441–8.