European Psychiatry 33 (2016) 9–17
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Original article
A randomized trial to assess the efficacy of a psychoeducational intervention on caregiver burden in schizophrenia M. Martı´n-Carrasco a,b,h, P. Ferna´ndez-Catalina c, A.I. Domı´nguez-Pancho´n d, ˜ oz-Hermoso b, M. Gonc¸alves-Pereira e,f, E. Gonza´lez-Fraile a,*, P. Mun g,h J. Ballesteros , the EDUCA-III group a
Institute of Psychiatric Research, Bilbao, Spain Padre Menni Psychiatric Centre, Pamplona, Spain c Psychosocial Rehabilitation Resource (Sisters Hospitallers), Madrid, Spain d Aita-Menni Hospital, Arrasate-Mondrago´n, Spain e Clı´nica Psiquia´trica de S. Jose´ (Sisters Hospitallers), Lisboa, Portugal f CEDOC, NOVA Medical School, Faculdade de Cieˆncias Me´dicas, Universidade NOVA de Lisboa, Lisboa, Portugal g University of the Basque Country, UPV/EHU, Leioa, Spain h CIBER Mental Health, Spain b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 27 August 2015 Received in revised form 23 December 2015 Accepted 3 January 2016 Available online 4 February 2016
Background: Patient’s relatives usually care for patients with schizophrenia, and as informal caregivers they experience negative consequences. The aim of the EDUCA-III trial is to test the efficacy of a psychoeducational intervention program (PIP) versus standard care to reduce the caregiver burden at post-intervention (4 months), and at follow-up (8 months). Method: A two-arm, evaluator blind, multicentre, randomized controlled trial. The PIP group had 12 weekly group sessions. The control intervention group had the usual support and standard care. Primary outcomes were change scores since baseline on the Zarit Burden Interview (ZBI) and the Involvement Evaluation Questionnaire (IEQ). Results: One hundred and nine caregivers were randomized to PIP and 114 to control condition from 23 research sites. The decrease of ZBI scores was significantly higher on the PIP arm at 4 months (mean difference [MD] = 4.33; 95% CI 7.96, 0.71), and at 8 months (MD = 4.46; 95% CI 7.79, 1.13). There were no significant decreases in the IEQ scores (MD at 4 months = 2.80; 95% CI 6.27, 0.67; MD at 8 months = 2.85; 95% CI 6.51, 0.81). Conclusions: The PIP condition seems to reduce caregiver burden. Trial registration: ISRCTN32545295. ß 2016 Elsevier Masson SAS. All rights reserved.
Keywords: Schizophrenia Caregivers Mental health Randomized controlled trial
1. Introduction Schizophrenia is an incapacitating, long-lasting psychiatric disorder which has serious consequences for both the patient and caregivers [1]. During the asylum period, families were usually excluded from care. However, the process of deinstitutionalization and the development of community psychiatry in the 1960s and 1970s changed the pattern of care of many severe psychiatric patients, placing in the family the burden of care. Usually a family
* Corresponding author. Instituto de Investigaciones Psiquia´tricas, C/Egan ˜ a 10, 48010 Bilbao, Spain. Tel.: +34 94 443 4927; fax: +34 94 443 7131. E-mail address: [email protected] (E. Gonza´lez-Fraile). http://dx.doi.org/10.1016/j.eurpsy.2016.01.003 0924-9338/ß 2016 Elsevier Masson SAS. All rights reserved.
member, known as the primary or main caregiver, assumed most of the care [2]. This main caregiver become responsible of the patient care, helping them to solve tasks related with different areas of care; for instance his/her physical and emotional support (i.e. adherence to treatment), socio-economic aspects (i.e. social integration, occupational issues), or activities of daily life (ADLs) [3]. Caring for a person with schizophrenia can lead to substantial physical and psychological burden, including negative physical and emotional effects as well as costs in terms of time and use of economical resources [4]. This complex situation has been defined as ‘‘caregiver burden’’: a negative psychological state experienced by informal caregivers produced by physical, psychological/emotional, social, economic difficulties derived from the care of patients [5,6].
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Although positive experiences also appear [7], between 83 to 95% of relatives or friends of patients with schizophrenia might experience significant burden that may reduce the quality of care provided, endangering both patients and caregivers alike [8,9]. It is therefore important that a comprehensive treatment of schizophrenia include interventions intended for reducing the negative impact of the illness on caregivers. However, with some exceptions [10], most research supporting the efficacy of family interventions has focused on patient outcomes, and only marginally has considered the situation of the caregiver as an adequate target for intervention [11]. Accordingly, the NICE guideline highlights lack of evidence on interventions specifically targeting caregiver burden in schizophrenia [12]. The EDUCA-III trial, presented here, is a multicentre randomized controlled trial designed to assess the effect of a psychoeducational intervention program (PIP) on caregiver’s burden and other relevant mental health outcomes. The PIP was administered in a group format and focused on the didactically and skilful communication of key information to the caregiver within the framework of a cognitive-behavioural approach [13].
the patient should have been diagnosed at least 2 years before trial recruitment and was receiving appropriate outpatient clinical care. The following were considered exclusion criteria: caregivers without time to attend the weekly sessions of PIP training; caregivers currently receiving, or having recently received (last year), any standardized psychoeducational intervention similar to the one administered in the trial; the patient cared for had an hospitalization in the month before randomization, or was on residential care; the patient presented mental retardation, dementia or any other organic cognitive disorder. On the other hand, the following criteria for ending the trial before completion were established:
To assess the efficacy of a PIP versus standard care on the reduction of caregiver burden at the end of trial (4 months since baseline), and to assess the maintenance of the therapeutic effect at follow-up (8 months since baseline).
caregiver decision; change from outpatient to inpatient status or residential care for the patient being cared for; patient being discharged from the original health care service; protocol deviations as assessed by the central research committee.
2. Methods
2.3. Interventions
2.1. Hypothesis and design
The caregivers allocated to the control group received the usual support from the outpatient psychiatric service where the patients were treated, and had periodical interviews and information about the situation and clinical course of the patient. The caregivers allocated to the intervention group received the same usual support plus the PIP. The PIP was developed by a group of psychiatric, psychologist and mental health experts with practical knowledge in patient and caregiver interventions. It is based on the principles of the psychoeducational program developed in REACHII study [14] for dementia caregivers, subsequently adapted to the characteristics of caregivers of people with schizophrenia. Underlying the PIP is a behavioural-cognitive approach to provide caregivers with education, skills to manage troublesome behaviors, social support, cognitive strategies for reframing negative emotional responses, and strategies for enhancing healthy behaviors and managing stress. The PIP was administered over 12 weekly group sessions lasting 90–120 mins each. To avoid fatigue or inattention there was a time-break of 15 mins at the middle of each session. On the PIP sessions the caregiver received standardized information about the clinical course of schizophrenia and was trained on cognitive and behavioural skills. These included general caregiving abilities, communication skills, the ability to seek and enjoy pleasant events, to seek support, as well as relaxation techniques. The PIP required active participation from caregivers (i.e. role playing, applying new skills to conflict, etcetera). It applied cognitivebehavioural techniques focused on identifying and challenging negative beliefs and developing a new style to deal with caregiving demands. All sessions had the same formal structure:
1.1. Aims of the trial
The main hypothesis of the trial was that caregivers allocated to a PIP would present lower subjective burden at postintervention endpoint (4 months), and at further follow-up (8 months) than caregivers allocated to control condition. A secondary hypothesis was that caregivers allocated to PIP would also present better mental health according to self-reported indicators at endpoint and follow-up than caregivers allocated to control condition. The design was a two-arm, evaluator blind, international, multicentre, randomized controlled trial. All research sites had 2 investigators: one trained in the application of the PIP, and other– blinded to the allocated intervention–who assessed the caregiver outcomes. Throughout the trial, a central research committee oversight the correct management of trial procedures and adherence to protocol. The trial protocol was approved by appropriate Institutional Review Boards of Spain and Portugal (Ethical and Scientific Research Committees of Navarra, Spain; and Sisters Hospitallers, Portugal). All participants (caregivers and patients) signed an informed consent form prior to randomization and trial inclusion. 2.2. Participants, inclusion and exclusion criteria Dyads of patients diagnosed with schizophrenia or schizoaffective disorder (DSM-IV criteria) and family primary caregivers were recruited from 21 outpatient psychiatric centres in Spain and from 3 outpatient psychiatric centres in Portugal. Persons caring for a relative were eligible for the trial if they met the following inclusion criteria: males or females (18+ years) currently caring for a relative with a diagnosis of schizophrenia or schizoaffective disorder; the caregiver should not be professionally paid (i.e., he/she should be an informal caregiver) and spend a minimum of 4 h/ week caring for the patient;
an introduction to review the progress of the homework tasks; information about the topic to be deal with; exercises to practice the new knowledge or skills. The PIP was applied by mental health professionals (psychologist or psychiatrist) trained in the program by the same researchers who developed it. We provided a manual for the therapist and a
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Table 1 Contents of the Psychoeducational Intervention Program (PIP). Session
Content
Topics developed
1
Knowing mental illness I
2
Knowing mental illness II
3
Treatment
4
Take care of oneself
5
Stress & well-being
6
Importance of thinking
7
To do pleasant activities
8
Assertive communication
9
Behaviour problems
10
Solving problems
11
Approaching demanding situations
12
Knowledge of support & helping services
Motivation for sharing the program Information about mental illness Understanding causes, prognosis, relapse How to deal with an emergency Integral treatment resources How to deal with treatment withdrawal Effect of burden in the caregiver Learning to take care of oneself Tension, emotion & stress Management skills Relaxation by breathing Identifying beliefs & changing negative beliefs Muscular relaxation Identifying & planning pleasant activities Muscular relaxation How to talk with the patient How to talk with the health services Relaxation by mental distraction ABC of behaviour How to manage behaviour problems To make a plan to change behaviour Relaxation by mental distraction Importance of emotion Methods to solve problems Relaxation by imaginery Identifying & acting Suggestions of experts & professionals Relaxation by imaginery Assistance, health services & laws About the future Wrapping summary and program evaluation by the caregivers
manual for the caregiver to follow and apply the PIP throughout the trial. The whole intervention is available online (http://www. fundacion-iip.org/IIP/). Table 1 presents the contents of the PIP by session. 2.4. Outcome assessment The trial included three evaluations conducted at visit #1 (baseline), visit #2 (postintervention, 4 months since trial inception), and visit #3 (follow-up, 8 months since trial inception). All outcomes were based on self-reported scales applied and assessed by a researcher blind to intervention allocation. 2.5. Primary outcome measures Change scores since baseline to postintervention endpoint and follow-up in the caregiver burden assessed by the Zarit Burden Interview (ZBI) [5] and the Involvement Evaluation Questionnaire (IEQ) [15]. The ZBI includes 22 statements recorded in a 0–4 Likert scale (total score range 0 to 88), that rates the subjective component of burden. Although it has been mainly used in dementia rather than in schizophrenia caregivers [16], we thought the ZBI was an appropriate outcome assessment [4]. Its sensibility to change has been reported in dementia [17] but also in schizophrenia caregivers [18,19]. The ZBI has been translated and validated in Spanish [20] and Portuguese [21]. The IEQ is now recognized as one of the leading caregiving measures in severe mental illness [9]. It includes a 31-item core module questionnaire recorded in a 0–4 Likert scale that rates the consequences of caregiving experienced in the previous 4 weeks, including the negative impact on caregivers. Beyond its total score (computed from 27 of the 31 items), the IEQ includes four subscales: worrying (6 items), urging (8 items), tension (9 items) and supervision (6 items) [9,22]. For both the ZBI and the IEQ, higher scores mean higher burden, thus negative score changes mean better outcomes.
The IEQ has been translated and validated in Spanish [15] and Portuguese [23]. 2.6. Secondary outcome measures Change scores since baseline to postintervention endpoint and follow-up on the caregiver mental health rated by the General Health Questionnaire, 28 items (GHQ-28) [24], and the Center for Epidemiologic Studies Depression Scale (CES-D) [25]. The GHQ-28 includes 4 subscales with 7-item each. Items present a 0–3 Likert scale giving a total subscale range from 0 to 21, and a total score range of 0 to 84. Higher score means higher level of psychological distress, thus negative score changes mean better outcomes. The underlying domains for the subscales are somatic symptoms, anxiety and insomnia, social dysfunction, and severe depression. The GHQ-28 has been validated in Spanish [26] and Portuguese [27]. The CES-D is a 20-item questionnaire that rates depressive feelings and related behaviours during the past week. Items present a 0–3 Likert scale. Higher score means higher level of depressive symptoms, thus negative score changes mean better outcomes. There are Spanish and Portuguese versions of CES-D [28,29]. 2.7. Sample size We assumed the comparison between groups would present a moderate effect size favouring the PIP over the control group in the ZBI scale (standardised mean difference = 0.40). With such estimate and a baseline ZBI score of 55 with SD of 15, 200 caregivers randomized in 1:1 ratio would be needed to attain 85% power with a level of 5%. 2.8. Randomization The randomization was done centrally. The sequence generation for each research site was obtained by block randomisation
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using block sizes of 1 to 4. The R package ‘‘blockrand’’ was used [30]. None of the site investigators participated or had access to the randomization process. The randomisation sequence was known only by the investigator responsible for developing the PIP. The investigator who applied and assessed the caregiver self-reported outcomes at visits #1 to #3 was blind to the intervention allocation throughout the trial length. 2.9. Statistical methods Means and SDs describe continuous variables. Frequencies and percentages describe categorical variables. Main results were analyzed by between-group differences in the change scores since baseline at visits #2 and #3 for the primary and secondary outcomes. Two analyses were performed. A complete case analyses (CC) that included caregivers providing full information at the corresponding times. Results are reported by mean differences, SDs and/or 95% confidence intervals (CI), and standardised effect sizes (SMD). We used the usual Cohen’s cut-off points to interpret SMD estimates: values 0.2 for a small effect, values 0.5 for a medium effect, and values 0.8 for a large effect [31]. To allow for the attrition rates throughout the trial length, we also analysed the data using a mixed linear model for repeated measures (MLM) assuming missing at random (MAR) at visits #2 and #3 [32]. We assessed the effect of the intervention by testing the interaction term of intervention by visit. We compared the full model including the main factors (intervention, visit) and their interaction with the nested and reduced model excluding the interaction.
In addition to the main analysis, a subgroup analysis within the experimental group was conducted to find clinical and sociodemographic variables associated to the reduction on the caregiver burden. The a priori selected variables were the ZBI and GHQ-28 scores at baseline; the number of PIP sessions attended by the caregivers; the diagnosis of the person cared for, the gender, age, educational level, and marital status of the caregiver; the time the caregiver was providing care as well as the weekly hours dedicated; and the external help provided. After simple and multiple regression analysis, a backward stepwise linear regression analysis was performed (P-value to retain of 0.10) to obtain the most parsimonious model able to explain the variability in the change of ZBI scores since baseline to end of trial at 8 months. We run the analyses with Stata v13 (StataCorp, College Station, TX, 2013) and R v3.0.2 (R Foundation for Statistical Computing, Vienna, Austria, 2013).
3. Results 3.1. Recruitment and losses to follow-up The trial recruited 223 caregivers (109 randomized to PIP and 114 to control condition) from March to May 2012. The last visit took place along the period September 2012–January 2013. Fig. 1 shows the trial flowchart. Data from 21 research sites from Spain and 2 from Portugal were included in the analyses. The median recruitment by research site was 9 caregivers (range 5 to 19).
Fig. 1. Trial flowchart.
M. Martı´n-Carrasco et al. / European Psychiatry 33 (2016) 9–17
The mean elapsed time between baseline and visit #2 was 4.5 months (SD = 1.2). The mean elapsed time between baseline and visit #3 was 8.6 months (SD = 1.3). In the PIP group, 21 caregivers (19.3%) were lost to follow-up at visit #2. The corresponding figure in the control group was 11 (9.6%). The difference was not significant (Fisher exact test, P = 0.39). At visit #3, 4 additional caregivers in the PIP group were lost to follow-up (4.5%). The corresponding figure in the control group was 5 (4.8%). The difference was not significant (Fisher exact test, P = 0.43). The patients being cared for were predominantly male (71 [65%] and 89 [78%] in the PIP and control arm respectively), and had a mean age of 38.7 years (SD = 11.1) in the PIP group and 39.3 years (SD = 9.1) in the control group. Most patients presented a diagnosis of schizophrenia (92 patients [84%] in the PIP group and 100 patients [88%] in the control group), with 17 patients (16%) in the PIP group, and 14 patients (12%) in the control group with a diagnosis of schizoaffective disorder. Table 2 presents the baseline characteristics of the caregivers by intervention. Overall, caregivers were
Table 2 Sociodemographic and baseline clinical data for caregivers. Variables Sex, n (%) Male Female Age (y), mean (SD) Educational level, n (%) Without degree Primary Secondary (high school) College, university Marital status, n (%) Single Married Separated, divorced Widow/er Work situation, n (%) Working Unemployed Housewife Retired Disabled Relationship to patient, n (%) Father/mother Spouse/partner Brother/sister Son/daughter Other Time providing care (y), mean (SD) Hours dedicated/w, mean (SD) External help provided, n (%) Yes No Diagnosis, n (%) Schizophrenia Schizoaffective ZBI score, mean (SD) IEQ score, mean (SD) IEQ total score IEQ tension IEQ supervision IEQ worries IEQ urging CES-D score, mean (SD) GHQ-28 score, mean (SD) GHQ-28 total score GHQ-28 somatic symptoms GHQ-28 anxiety & insomnia GHQ-28 social dysfunction Ghq-28 severe depression
PIP (N = 109)
Control (N = 114)
22 (20.2) 87 (79.8) 59.2 (11.4)
31 (27.2) 83 (72.8) 61.1 (11.6)
7 (6.4) 38 (34.9) 34 (31.2) 30 (27.5)
12 48 39 15
13 59 18 19
(11.9) (54.1) (16.5) (17.4)
7 (6.1) 79 (69.3) 14 (12.3) 14 (12.3)
41 (37.6) 8 (0.7) 33 (30.3) 27 (24.8) 0 (0.0)
30 (26.3) 14 (12.3) 36 (31.6) 32 (28.1) 2 (1.7)
78 (71.6) 7 (6.4) 18 (16.5) 2 (1.8) 4 (3.7) 14.2 (9.8) 5.3 (1.4)
87 (76.3) 6 (5.3) 20 (17.5) 0 (0.0) 1 (0.1) 15.5 (10.1) 5.2 (1.4)
55 (50.5) 54 (49.5)
56 (49.1) 58 (50.9)
32.3 (16.5)
31.8 (15.8)
30.5 (16.3) 6.6 (5.2) 3.5 (4.6) 12.0 (5.9) 10.2 (6.3) 15.2 (10.3)
29.0 (15.5) 6.3 (4.8) 3.0 (4.0) 11.6 (5.7) 9.7 (6.5) 16.3 (10.3)
24.4 (10.7) 6.3 (3.6) 7.7 (4.2) 7.8 (2.1) 2.6 (3.4)
25.8 (12.4) 6.6 (4.1) 7.9 (4.5) 7.8 (2.7) 3.4 (3.9)
(10.5) (42.1) (34.2) (13.2)
ZBI: Zarit Burden Interview; IEQ: Involvement evaluation Questionnaire; CES-D: Center for Epidemiologic Studies-Depression Scale; GHQ-28: General Health Questionnaire-28 items.
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predominantly married women caring for their child, with a mean age of 60 years, had a low to medium educational level, and presented a mean caring exposure of 15 years. The current caring load was 5 h per week and half the recruited carers had external help. 3.2. Primary outcomes Table 3 shows the ZBI and the IEQ differences among interventions through time. The CC analysis for the ZBI showed a significant effect favouring the PIP with a moderate effect size at 4 and 8 months since trial inception (SMD = 0.35 and 0.40). The MLM analysis assuming MAR showed a significant interaction of intervention arm by time (P = 0.006) in favour of the PIP. The CC analysis for the IEQ showed a non-significant effect favouring the PIP with a small effect size (SMD = 0.23). The MLM analysis did not show a significant interaction of intervention arm by time (P = 0.12). Of the IEQ subscales, the tension domain showed the bigger effect at 4 and 8 months since trial inception (SMD = 0.26 and 0.25) without attaining significance at the 5% level (MLM analysis, P = 0.08). The MLM analyses for the rest of IEQ subscales do not show a significant difference of efficacy over time by intervention arm (IEQ supervision, P = 0.33; IEQ worries, P = 0.27; IEQ motivation, P = 0.42). 3.3. Secondary outcomes Table 3 also shows the CES-D and GHQ-28 differences among interventions. For the CES-D the CC analysis showed a significant effect favouring the PIP with a small size at 4 and 8 months (SMD = 0.34 and 0.21 respectively). The MLM analysis showed a significant interaction of intervention arm by time (P = 0.023) in favour of the PIP. For the GHQ-28 the CC analysis showed a significant effect for its total score favouring the PIP with a small size at 4 but not at 8 months (SMD = 0.30 and 0.18 respectively). The MLM analysis showed a non-significant interaction of intervention arm by time (P = 0.11). Most of the GHQ-28 subscales did not show a significant interaction of intervention arm by time (somatic symptoms P = 0.19; anxiety & insomnia P = 0.17; severe depression P = 0.67). On the contrary the social dysfunction subscale showed a significant interaction favouring the PIP (P = 0.005). However it seems to be mainly explained by the moderate effect size attained at 4 months (SMD = 0.46) that disappeared at 8 months (SMD = 0.11). None of the patients required inpatient or residential care throughout the trial length. 3.4. Subgroup analysis within the experimental group Table 4 shows the results of the linear regression analyses performed. Only 2 variables, the ZBI score at baseline and the provision of external help (professional support or economical benefits) are significantly associated with the improvement in ZBI scores at end of trial. The ZBI at baseline is positively associated with the reduction on burden what means that those caregivers experiencing more burden at baseline will be also those who will improve more by the end of trial. Conversely, the provision of external help is negatively associated with burden reduction. Those caregivers with external help present 5 points less in the ZBI change scores than caregivers without external support (95% CI: 0.25 to 10 points less).
4. Discussion The main results of this study, those related with primary outcomes, support a moderate efficacy of a PIP administered in a
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Table 3 Efficacy outcomes (change scores from baseline). Complete case analyses and mixed linear model for repeated measures. Visit 2 (4 months since baseline) Outcomes
Zarit Total Score, mean (SD)
Visit 3 (8 months since baseline)
Control
Mean difference
SMD
PIP
Control
Mean difference
SMD
(N = 86)
(N = 97)
(95% CI)
(95% CI)
(N = 82)
(N = 91)
(95% CI)
(95% CI)
4.33
0.35
4.60 (12.68)
0.27 (12.07)
( 7.96 to 4.52 (11.58)
IEQ Tension
1.16 (4.19)
IEQ Worries IEQ Urging
0.77 (3.54) 1.42 (5.02) 1.43 (4.97)
1.72 (12.13)
0.09 (5.34) 0.56 (2.84) 0.29 (5.46) 0.94 (4.98) 0.36 (9.60)
0.71)
2.8 ( 6.27 1.26 ( 2.67 0.21 ( 1.14 1.13 ( 2.67 0.49 ( 1.95 3.22
( 0.64 to
to 0.67) to 0.16) to 0.72) to 0.41) to 0.96)
2.86 (9.17)
GHQ-28, mean (SD) GHQ-28 Total Score GHQ-28 Somatic Symptoms
4.59 (11.00) 0.89 (3.88)
0.02 (3.88)
( 5.99 to 3.35 ( 6.59 to 0.87
GHQ-28 Anxiety & Insomnia
1.84 (4.57)
0.73 (3.71)
( 2.01 to 0.26) 1.1
GHQ-28 Social Dysfunction
1.60 (3.32)
0.15 (2.96)
GHQ-28 Severe Depression
0.26 (2.49)
0.34 (3.79)
( 0.53 0.26 ( 0.55 0.07 ( 0.36 0.28 ( 0.57 0.1 ( 0.39 0.34
1.21 (11 09)
0.06)
0.23
CES-D Total Score, mean (SD)
1.25 (11.20)
5.67 (10.97)
5.46 (12.09)
2.60 (12.18)
1.48 (3.69)
0.48 (4.19)
to 0.06) to 0.03) 1.05 (3.39)
0.41 (3.08)
to 0.22) 1.37 (5.58)
0.66 (5.81)
to 0.01) 2.05 (5.01)
1.12 (5.27)
to 0.19) 0.73 (7.77)
3.00 (12.32)
0.87 (11.14)
0.59 (4.56)
( 0.51 to 0.07) 0.27
( 2.31 to 0.10) 1.45 ( 2.36 to 0.08
0.10)
0.53)
( 0.86 to 1.03)
( 0.63 to 0.3 ( 0.59 to 0.22
0.4
( 7.79 to
2.38 (7.77)
0.46)
4.46
0.05)
1.13)
2.85 ( 6.51 1 ( 2.19 0.64 ( 1.62 0.71 ( 2.43 0.93 ( 2.48 1.65
0.006
( 0.70 to
0.10)
0.23 to 0.81) to 0.20) to 0.33) to 1.01) to 0.62)
( 0.53 0.25 ( 0.55 0.2 ( 0.50 0.12 ( 0.42 0.18 ( 0.48 0.21
0.118 to 0.06) 0.081 to 0.05) 0.328 to 0.10) 0.27 to 0.17) 0.416 to 0.12) 0.023
0.33 (4.11)
( 4.01 to 0.72) 2.13 ( 5.64 to 1.38) 0.92
( 0.51 to 0.09) 0.18 ( 0.48 to 0.12) 0.21
0.193
1.24 (4.60)
0.70 (4.16)
( 2.22 to 0.38) 0.54
( 0.51 to 0.09) 0.13
0.169
( 0.56 to 0.02) 0.46
0.64 (3.16)
0.30 (3.02)
( 1.85 to 0.77) 0.34
( 0.42 to 0.18) 0.11
0.005
( 0.75 to 0.02
0.53 (2.81)
0.20 (3.84)
( 1.27 to 0.58) 0.33
( 0.41 to 0.19) 0.1
0.67
( 1.35 to 0.68)
( 0.40 to 0.20)
0.01)
0.17)
( 0.27 to 0.31)
0.109
PIP: Psychoeducational Intervention Program; SMD: Standardized Mean Difference; IEQ: Involvement Evaluation Questionnaire; CES-D: Center for Epidemiologic Studies–Depression Scale; GHQ-28: General Health Questionnaire Scaled (28 items). a P-values for the interaction of intervention by time from the mixed linear mixed model for repeated measures.
M. Martı´n-Carrasco et al. / European Psychiatry 33 (2016) 9–17
IEQ, mean (SD) IEQ Total Score
IEQ Supervision
P-valuesa
PIP
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Table 4 Associations among change scores since baseline of the Zarit Burden Inventory and baseline clinical and sociodemographic variables. Results from linear regressions. Baseline variables
Coefficient (95% CI) Univariate regression
Coefficient (95% CI) Multiple regression
Coefficient (95% CI) Stepwise regression
ZBI at baseline GHQ-28 at baseline Intervention sessions attended Diagnosis Schizophrenia Schizoaffective Sex Male Female Age Educational level Primary Secondary (high school) College, university Marital status Single Married Separated, divorced Widow/er Time providing care Hours dedicated External help provided No Yes
0.34 (0.21 to 0.47)*** 0.24 (0.02 to 0.47)* 0.42 ( 0.55 to 1.39)
0.32 (0.15 to 0.50)*** 0.04 ( 0.22 to 0.30) 0.03 ( 0.95 to 1.01)
0.37 (0.23 to 0.50)***
Reference level 2.77 ( 9.87 to 4.33)
Reference level 1.79 ( 8.61 to 5.02)
Reference level 1.27 ( 5.60 to 8.14) 0.09 ( 0.13 to 0.31)
Reference level 2.17 ( 9.39 to 5.05) 0.14 ( 0.12 to 0.41)
Reference level 0.80 ( 4.78 to 6.38) 4.17 ( 2.10 to 10.4)
Reference level 1.79 ( 4.12 to 7.70) 2.79 ( 4.33 to 9.90)
Reference 2.82 ( 11.8 to 6.12) 3.94 ( 14.0 to 6.12) 6.54 ( 16.6 to 3.52) 0.001 ( 0.02 to 0.02) 0.56 ( 1.27 to 2.39)
Reference 1.91 ( 10.8 to 6.99) 5.54 ( 15.2 to 4.13) 8.21 ( 19.2 to 2.76) 0.03 ( 0.02 to 0.02) 1.10 ( 0.97 to 3.18)
Reference level 3.30 ( 8.66 to 2.07)
Reference level 5.33 ( 10.5 to
0.12) *
Reference level 5.04 ( 9.82 to
0.25) *
ZBI: Zarit Burden Inventory; GHQ-28: General Health Questionnaire-28 items. * P-value < 0.05; ** P-value < 0.01; *** P-value < 0.001.
group format to reduce the subjective burden associated with caregiving tasks in caregivers of patients with schizophrenia or schizoaffective disorder. The ZBI reduction at postintervention presents a moderate effect in favour of the intervention group (SMD: 0.35; 95% CI: 0.64 to 0.06) and the improvement is maintained at follow-up (SMD: 0.40; 95% CI: 0.70 to 0.10), with a significant interaction of treatment by time (P = 0.006). The same trend of caregiver burden reduction over time was found with the IEQ tension domain that overlaps with the burden domain of the ZBI (SMD at end of trial: 0.26; 95% CI: 0.55 to 0 03; SMD at follow-up: 0.25; 95% CI: 0.55 to 0.05). However, this trend did not attain statistical significance (P = 0.118). Part of the discrepancy observed between the results of both scales could be explained by the different constructs they measure. Whereas the ZBI focus is on the perceived and thus subjective component of burden, the IEQ rates also objective and behavioural domains of burden [33]. Accordingly, the efficacy of the PIP intervention might be explained by reducing the subjective component of burden. As far as secondary outcomes are concerned, our results also suggest that the PIP intervention is useful to reduce depressive symptoms over time as measured by the CES-D (P = 0.023), but not according to the GHQ-28 (P = 0.109). As before, this discrepancy could be explained because both scales measure different depression domains. Whereas the GHQ depression items assess severe and likely unchangeable symptoms, the CES-D items include other dominions more changeable with the PIP training (i.e. motor and physiological symptoms). Focusing on the caregivers who had the PIP intervention, those more likely to reduce the burden would be the ones with higher levels of burden at the beginning of the intervention. On the other hand, caregivers with external help do not seem to reduce the burden as much as caregivers who had no access to external resources (mainly professional support by paid caregivers, or economic benefits for caring). Probably, they represent caregiver clusters with different demands on caring related with severity of the disease.
4.1. Limitations and strengths of the research Our trial present several limitations that could overestimate the efficacy of the PIP intervention. According to the risk of bias, the most important relates to the blinding and concealment of subjects to interventions, and also to ascertainment bias throughout the trial. In studies like the EDUCA-III with interventions that are hard, if not impossible, to mask and blind to both the patient and professionals, selection and performance bias cannot be excluded. In this trial, ascertainment bias was managed by blinding assessment evaluators. Also, in this trial selection bias seems unlikely since no violations to the random assignment were detected. However, we cannot guarantee that information crosscontamination between groups did not happened over the trial, and that knowing the assignment to intervention or control, has not biased the self-perception of caregivers to the questions posed in the assessment scales. Thus performance bias cannot be ruled out completely and, if present, could have lead to an overestimation of the results. On the other hand, attrition bias seems unlike since there are not recorded different dropouts and causes of attrition between-groups, either at end of trial, or at follow-up. Even if we cannot rule out the possibility of overestimating the efficacy of the PIP assessed in this trial because of the risk of bias previously discussed, our results on the moderate positive effect of the PIP seem to agree with previous studies. We have found six studies with similar design (randomized assignment to interventions), intervention (psychoeducational intervention including both stress management and coping), and aims (efficacy trials) [18,34–38] and included in a recent systematic review and metaanalysis [39]. We have combined the primary outcomes of those studies, and found that our main result on the postintervention burden efficacy of the PIP is smaller than the weighted combination result ( 0.35 versus 0.78), but, nevertheless, fits well within the 95% CI of the pooled studies ( 1.37 to 0.20). Therefore, we think our overall results support the effectiveness of a psychoeducational intervention to reduce caregiver burden in schizophrenia. However we need also to stress that the effects so far reported
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for our primary outcomes are moderate according to the effect sizes obtained. Because of being a multicentre trial including research sites from two countries (Portugal and Spain), the findings of our trial could present better generalisability, and possibly external validity, than single centre studies. Current guidelines on schizophrenia treatment, stress the need for family interventions with goals aimed at the adoption of adaptive copying styles (how to handle psychological reactions to the experience of the illness in a relative, how to improve or acquire the abilities to manage stress and communicate with the other, how to manage the appropriate health resources over the illness periods) [40]. In this sense, the PIP reported in this trial fits such requirements and presents a moderate effect size with clinical relevance. 5. Conclusions An analysis of 223 informal caregivers of patients with schizophrenia or schizoaffective disorder showed the efficacy of a PIP administered in a group format to reduce the subjective burden and depression associated with caregiving tasks. These results were maintained at follow-up at 8 months. Caregivers presenting higher levels of burden at the beginning of the intervention and those who do not have access to external help were more likely to improve in the burden as consequence of the PIP intervention. Disclosure of interest The authors declare that they have no competing interest. Acknowledgements The EDUCA-III trial was funded by a research grant from Instituto de Salud Carlos III, Spain (PI10/01049). The role of the funding source was limited to economic support. It was not involved in the study process, preparation or submission of the manuscript. The EDUCA-III research sites and the researchers involved are: Jesu´s Moraza, Arkaitz De La Cruz, Vicente Hueso (Hospital de Dı´a y CRPS Beasain- Hospital Aita Menni, Mondrago´n); Asuncio´n Lizarazu, Marı´a Blanca Ferna´ndez de Corres, Paz Lander, Nuria Grive´, Isabel Alonso, Marixa Larreina, Elvira Castellano (Hospital Psiquia´trico de A´lava, Vitoria); Rosario Beguiristain, Pablo Malo (CSM Bombero Etxaniz, Bilbao); Rocı´o del Pino, Zita Blanco, Janire Garay (Universidad de Deusto); Juan Carlos Irurzun, Karmele Iribar, Karmele Zarraga (CSM Donostia Amara, San Sebastia´n); Marta Arrieta, Rosario Bengochea, Silvia Pe´rez, Mariola Palacios (CRPS Santander y CRPS Torrelavega- Centro Hospitalario Padre Menni); Luis Alberto Cuellar, Rebeca Lo´pez (Centro Hospitalario Benito Menni, Valladolid); Mireia Gonza´lez, Mireia Segarra (Hospital Sagrat Cor, Martorell); Mo´nica Guasch, Inma Esteve (Hospital Mare` de Deu de La Merce´, Barcelona); Jaime Gra´cio, Susana Pestana, Filipa Nunes (Clı´nica Psiquia´trica de Sa˜o Jose´, Lisboa, Portugal); Catarina Vidigal, Rita Ribeiro (Casa de Sau´de da Idanha, Belas, Portugal); Patrı´cia Godinho, Mariana Gil (Casa de Sau´de do Bom Jesus, Braga, Portugal); Marı´a Carmen Hurtado, Marı´a Nieves Tapiador, Ana Carolina Martı´nez (CD -EASC Villaverde, Madrid); Manuela Guimo´n, Rau´l Gonza´lez, Jose´ Marı´a Pinedo, Vero´nica Robles, Marta Mora, Paola Ferna´ndez (CD-EASC-CRPS-CRL Vallecas, Madrid); Rocı´o Ferna´ndez, Carolina Mogollo´n (CRPS Badajoz); Ana Fuentes, Beatriz Rodrı´guez, Marı´a Mora (CD San Miguel -EASC Salamanca- EASC Chamartı´n, Madrid); Urbano Barrientos, Carlos Rebolleda, Eva Ojalvo, Lourdes Soladana (CRPS-CD-EASC Aranjuez, Madrid); Laura Romero, Roberto Martı´n, Marı´a Amores, Vanesa
Rodrı´guez, Sara Gonza´lez (CRPS-CD-EASC Retiro, Madrid); Marı´a A´ngeles Polo, Virginia Lo´pez (Centro Inicia, Santander); Oriol Imbernon, Blanca Perise´, Marı´a Rosario Herna´ndo, Ana Bele´n Lardies (Benito Menni CASM, Sant Boi; Unidad Polivalente de Salud Mental de Hospitalet, L´Hospitalet de Llobregat). References [1] Whiteford HA, Degenhardt L, Rehm J, Baxter AJ, Ferrari AJ, Erskine HE, et al. Global burden of disease attributable to mental and substance use disorders: findings from the Global Burden of Disease Study 2010. Lancet 2013;382(9904):1576–86. [2] Thornicroft G, Tansella M. The balanced care model: the case for both hospitaland community-based mental healthcare. Br J Psychiatry 2013;202(4):246–8. [3] Magliano L, Fadden G, Madianos M, de Almeida JM, Held T, Guarneri M, et al. Burden on the families of patients with schizophrenia: results of the BIOMED I study. Soc Psychiatry Psychiatr Epidemiol 1998;33(9):405–12. [4] Awad AG, Voruganti L. 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Psychol Aging 2003;18:375–84. [15] van Wijngaarden B, Schene AH, Koeter M, Va´zquez-Barquero JL, Knudsen HC, Lasalvia A, et al. Caregiving in schizophrenia: development, internal consistency and reliability of the Involvement Evaluation Questionnaire - European version: EPSILON study 4. Br J Psychiatr 2000;(Suppl. 39):s21–7. [16] Gonc¸alves-Pereira M, Zarit SH. The Zarit Burden Interview in Portugal: validity and recommendations in dementia and palliative care. Acta Med Port 2014;27(2):163–5. [17] Chien WT, Lee YM. A disease management program for families of persons in Hong Kong with dementia. Psychiatr Serv 2008;59(4):433–6. [18] Navidian A, Kermansaravi F, Rigi SN. The effectiveness of a group psychoeducational program on family caregiver burden of patients with mental disorders. BMC Research Notes 2012;5(399). [19] Tanrıverdi D, Ekinci M. The effect psychoeducation intervention has on the caregiving burden of caregivers for schizophrenic patients in Turkey. Int J Nurs Pract 2012;18(3):281–8. [20] Martin-Carrasco M, Otermin P, Pe´rez-Camo V, Pujol J, Agu¨era L, Martı´n MJ, et al. EDUCA study: psychometric properties of the Spanish version of the Zarit Caregiver Burden Scale. Aging Ment Health 2010;14(6):705–11. [21] Gonc¸alves-Pereira M, Carmo I, Da-Silva JA, Papoila AL, Mateos R, Zarit SH. Caregiving experiences and knowledge about dementia in Portuguese clinical outpatient settings. Int Psychogeriatr 2010;22:277–80. [22] Schene AH, van Wijngaarden B, Koeter MW. Family caregiving in schizophrenia: domains and distress. Schizophr Bull 1998;24:609–18. [23] Gonc¸alves-Pereira M, van Wijngaarden B, Xavier M, Papoila AL, Caldas-deAlmeida JM, Schene AH. Caregiving in severe mental illness: the psychometric properties of the Involvement Evaluation Questionnaire in Portugal. Ann Gen Psychiatry 2012;11:8. http://dx.doi.org/10.1186/1744-859X-11-8. [24] Goldberg DP, Hillier VF. A scaled version of the General Health Questionnaire. 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M. Martı´n-Carrasco et al. / European Psychiatry 33 (2016) 9–17 [28] Pe´rez-Sola JS, Puigdemont V, Pe´rez-Blanco D, Figueres J, Alvarez ME. Estudio de validacio´n del Center for Epidemiologic Studies-Depression (CES-D) en tras˜ ola. Actas Luso Esp Neurol Psiquiatr Cien tornos afectivos en poblacio´n Espan Afin 1997;25:243–9. [29] Gonc¸alves B, Fagulha T. The Portuguese version of the Center for Epidemiologic Studies Depression Scale (CES-D). Eur J Psychol Assess 2004;20: 339–48. [30] Blockrand: randomization for block random clinical trials [Internet]. CRAN. Rproject.org; 2013 [http://CRAN.Rproject.org/package=blockrand, cited 2013 Mar 25]. [31] Cohen J. Statistical Power Analysis for the Behavioral Sciences, 2nd ed., Hillsdale, NJ: Erlbaum; 1988. [32] Pinheiro JC, Bates DM. Mixed-effects models in S and S-PLUS. New York: Springer; 2004. [33] Vella S-L, Pai N. The measurement of burden of care in serious mental illness: a qualitative review. Aust N Z J Psychiatry 2012;47(3):222–34. [34] Chien W-T, Chan S, Thompson DR. Effects of a mutual support group for families of Chinese people with schizophrenia: 18-month follow-up. Br J Psychiatry 2006;189:41–9. [35] Magliano L, Fiorillo A, Malangone C, De Rosa C, Maj M. Patient functioning and family burden in a controlled, real-world trial of family psychoeducation for schizophrenia. Psychiatr Serv 2006;57:1784–91. [36] Chien W-T, Wong K-F. A family psychoeducation group program for Chinese people with schizophrenia in Hong Kong. Psychiatr Serv 2007;58:1003–6. [37] Koolaee AK, Etemadi A. The outcome of family interventions for the mothers of schizophrenia patients in Iran. Int J Soc Psychiatr 2010;56:634–46. [38] Sharif F, Shaygan M, Mani A. Effect of a psycho-educational intervention for family members on caregiver burdens and psychiatric symptoms in patients with schizophrenia in Shiraz, Iran. BMC Psychiatry 2012;12(48). [39] Yesufu-Udechuku A, Harrison B, Mayo-Wilson E, Young N, Woodhams P, Shiers D, et al. Interventions to improve the experience of caring for people with severe mental illness: systematic review and meta-analysis. Br J Psychiatry 2015;206(4):268–74. [40] Kuipers E, Yesufu-Udechuku A, Taylor C, Kendall T. Management of psychosis and schizophrenia in adults: summary of updated NICE guidance. Br Med J 348:g1173. http://dx.doi.org/10.1136/bmj.g1173.
Manuel Martin-Carrasco, MD PhD. Affiliation: Psychiatric Research Institute. Ma Josefa Recio Foundation, Bilbao, Spain. Position: Director of the Psychiatric Research Institute (Maria Josefa Recio Foundation, Bilbao). Associate Professor of the Faculty of Medicine of the University of Navarra (Pamplona, Spain). Research interests: Care of people with dementia and their relatives, severe mental illness, and psychometry.
Paola Ferna´ndez-Catalina, MPsychol. Affiliation: Psychosocial Rehabilitacio´n Program of Sisters Hospitalliers, Madrid, Spain. Position: Director of residential and out-patient mental health services in Madrid. Research interests: Psychotherapy interventions, psychosocial rehabilitation of patients with mental disease and with family intervention.
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Ana I. Domı´nguez-Pancho´n, MPsychol. Affiliation: Aita Menni Hospital, Gipuzkoa, Spain. Psychiatric Research Institute. Ma Josefa Recio Foundation, Bilbao, Spain. Position: Clinical psychologist at Aita Menni Hospital in Mondrago´n (Basque Country). Associate Professor at Deusto University. Research interests: Psychometric assessment of caregiver burden and development of new psychoeducational program interventions.
M. Gonc¸alves-Pereira, MD, PhD. Affiliation: Clı´nica Psiquia´trica de S. Jose´ (Sisters Hospitallers), Lisboa, Portugal. CEDOC, NOVA Medical School, Faculdade de Cieˆncias Me´dicas, Universidade NOVA de Lisboa, Lisboa, Portugal. Position: Professor of Medical Psychology at NOVA Medical School (Faculdade de Cieˆncias Me´dicas, Universidade Nova de Lisboa). Research interests: Geriatric psychiatry and family interventions.
Eduardo Gonza´lez-Fraile, MPsychol, PhD. Affiliation: Psychiatric Research Institute. Ma Josefa Recio Foundation, Bilbao, Spain. Associated Professor at International University of La Rioja (UNIR). Position: PhD Psychologist. Research interests: Psychoeducational interventions, informal caregiver, statistical methods, meta-analyses and risk of bias.
˜ oz-Hermoso, BPsychol. Paula Mun Affiliation: Clı´nica Psiquiatrica Padre Menni, Pamplona, Spain. Position: Clinical psychologist at Clı´nica Psiquiatrica Padre Menni in Pamplona (Spain). Research interests: Assessment and intervention of burden in caregivers. Mental health and family interventions.
Javier Ballesteros, MD, PhD. Affiliation: University of the Basque Country, UPV/EHU. Psychiatric Research Institute. Ma Josefa Recio Foundation, Bilbao, Spain. Position: Professor in the Department of Neuroscience– Psychiatry, at the University of the Basque Country, UPV/EHU. Research interests: Methodological and practical issues on evidence based psychiatry: efficacy of pharmacological and non-pharmacological interventions on mental health problems, assessment of outcomes with patientrelated-outcomes, risk of bias, handling of likely publication biases, systematic reviews and meta-analysis.
Contents lists available at ScienceDirect
European Psychiatry journal homepage: http://www.europsy-journal.com
Original article
A randomized trial to assess the efficacy of a psychoeducational intervention on caregiver burden in schizophrenia M. Martı´n-Carrasco a,b,h, P. Ferna´ndez-Catalina c, A.I. Domı´nguez-Pancho´n d, ˜ oz-Hermoso b, M. Gonc¸alves-Pereira e,f, E. Gonza´lez-Fraile a,*, P. Mun g,h J. Ballesteros , the EDUCA-III group a
Institute of Psychiatric Research, Bilbao, Spain Padre Menni Psychiatric Centre, Pamplona, Spain c Psychosocial Rehabilitation Resource (Sisters Hospitallers), Madrid, Spain d Aita-Menni Hospital, Arrasate-Mondrago´n, Spain e Clı´nica Psiquia´trica de S. Jose´ (Sisters Hospitallers), Lisboa, Portugal f CEDOC, NOVA Medical School, Faculdade de Cieˆncias Me´dicas, Universidade NOVA de Lisboa, Lisboa, Portugal g University of the Basque Country, UPV/EHU, Leioa, Spain h CIBER Mental Health, Spain b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 27 August 2015 Received in revised form 23 December 2015 Accepted 3 January 2016 Available online 4 February 2016
Background: Patient’s relatives usually care for patients with schizophrenia, and as informal caregivers they experience negative consequences. The aim of the EDUCA-III trial is to test the efficacy of a psychoeducational intervention program (PIP) versus standard care to reduce the caregiver burden at post-intervention (4 months), and at follow-up (8 months). Method: A two-arm, evaluator blind, multicentre, randomized controlled trial. The PIP group had 12 weekly group sessions. The control intervention group had the usual support and standard care. Primary outcomes were change scores since baseline on the Zarit Burden Interview (ZBI) and the Involvement Evaluation Questionnaire (IEQ). Results: One hundred and nine caregivers were randomized to PIP and 114 to control condition from 23 research sites. The decrease of ZBI scores was significantly higher on the PIP arm at 4 months (mean difference [MD] = 4.33; 95% CI 7.96, 0.71), and at 8 months (MD = 4.46; 95% CI 7.79, 1.13). There were no significant decreases in the IEQ scores (MD at 4 months = 2.80; 95% CI 6.27, 0.67; MD at 8 months = 2.85; 95% CI 6.51, 0.81). Conclusions: The PIP condition seems to reduce caregiver burden. Trial registration: ISRCTN32545295. ß 2016 Elsevier Masson SAS. All rights reserved.
Keywords: Schizophrenia Caregivers Mental health Randomized controlled trial
1. Introduction Schizophrenia is an incapacitating, long-lasting psychiatric disorder which has serious consequences for both the patient and caregivers [1]. During the asylum period, families were usually excluded from care. However, the process of deinstitutionalization and the development of community psychiatry in the 1960s and 1970s changed the pattern of care of many severe psychiatric patients, placing in the family the burden of care. Usually a family
* Corresponding author. Instituto de Investigaciones Psiquia´tricas, C/Egan ˜ a 10, 48010 Bilbao, Spain. Tel.: +34 94 443 4927; fax: +34 94 443 7131. E-mail address: [email protected] (E. Gonza´lez-Fraile). http://dx.doi.org/10.1016/j.eurpsy.2016.01.003 0924-9338/ß 2016 Elsevier Masson SAS. All rights reserved.
member, known as the primary or main caregiver, assumed most of the care [2]. This main caregiver become responsible of the patient care, helping them to solve tasks related with different areas of care; for instance his/her physical and emotional support (i.e. adherence to treatment), socio-economic aspects (i.e. social integration, occupational issues), or activities of daily life (ADLs) [3]. Caring for a person with schizophrenia can lead to substantial physical and psychological burden, including negative physical and emotional effects as well as costs in terms of time and use of economical resources [4]. This complex situation has been defined as ‘‘caregiver burden’’: a negative psychological state experienced by informal caregivers produced by physical, psychological/emotional, social, economic difficulties derived from the care of patients [5,6].
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Although positive experiences also appear [7], between 83 to 95% of relatives or friends of patients with schizophrenia might experience significant burden that may reduce the quality of care provided, endangering both patients and caregivers alike [8,9]. It is therefore important that a comprehensive treatment of schizophrenia include interventions intended for reducing the negative impact of the illness on caregivers. However, with some exceptions [10], most research supporting the efficacy of family interventions has focused on patient outcomes, and only marginally has considered the situation of the caregiver as an adequate target for intervention [11]. Accordingly, the NICE guideline highlights lack of evidence on interventions specifically targeting caregiver burden in schizophrenia [12]. The EDUCA-III trial, presented here, is a multicentre randomized controlled trial designed to assess the effect of a psychoeducational intervention program (PIP) on caregiver’s burden and other relevant mental health outcomes. The PIP was administered in a group format and focused on the didactically and skilful communication of key information to the caregiver within the framework of a cognitive-behavioural approach [13].
the patient should have been diagnosed at least 2 years before trial recruitment and was receiving appropriate outpatient clinical care. The following were considered exclusion criteria: caregivers without time to attend the weekly sessions of PIP training; caregivers currently receiving, or having recently received (last year), any standardized psychoeducational intervention similar to the one administered in the trial; the patient cared for had an hospitalization in the month before randomization, or was on residential care; the patient presented mental retardation, dementia or any other organic cognitive disorder. On the other hand, the following criteria for ending the trial before completion were established:
To assess the efficacy of a PIP versus standard care on the reduction of caregiver burden at the end of trial (4 months since baseline), and to assess the maintenance of the therapeutic effect at follow-up (8 months since baseline).
caregiver decision; change from outpatient to inpatient status or residential care for the patient being cared for; patient being discharged from the original health care service; protocol deviations as assessed by the central research committee.
2. Methods
2.3. Interventions
2.1. Hypothesis and design
The caregivers allocated to the control group received the usual support from the outpatient psychiatric service where the patients were treated, and had periodical interviews and information about the situation and clinical course of the patient. The caregivers allocated to the intervention group received the same usual support plus the PIP. The PIP was developed by a group of psychiatric, psychologist and mental health experts with practical knowledge in patient and caregiver interventions. It is based on the principles of the psychoeducational program developed in REACHII study [14] for dementia caregivers, subsequently adapted to the characteristics of caregivers of people with schizophrenia. Underlying the PIP is a behavioural-cognitive approach to provide caregivers with education, skills to manage troublesome behaviors, social support, cognitive strategies for reframing negative emotional responses, and strategies for enhancing healthy behaviors and managing stress. The PIP was administered over 12 weekly group sessions lasting 90–120 mins each. To avoid fatigue or inattention there was a time-break of 15 mins at the middle of each session. On the PIP sessions the caregiver received standardized information about the clinical course of schizophrenia and was trained on cognitive and behavioural skills. These included general caregiving abilities, communication skills, the ability to seek and enjoy pleasant events, to seek support, as well as relaxation techniques. The PIP required active participation from caregivers (i.e. role playing, applying new skills to conflict, etcetera). It applied cognitivebehavioural techniques focused on identifying and challenging negative beliefs and developing a new style to deal with caregiving demands. All sessions had the same formal structure:
1.1. Aims of the trial
The main hypothesis of the trial was that caregivers allocated to a PIP would present lower subjective burden at postintervention endpoint (4 months), and at further follow-up (8 months) than caregivers allocated to control condition. A secondary hypothesis was that caregivers allocated to PIP would also present better mental health according to self-reported indicators at endpoint and follow-up than caregivers allocated to control condition. The design was a two-arm, evaluator blind, international, multicentre, randomized controlled trial. All research sites had 2 investigators: one trained in the application of the PIP, and other– blinded to the allocated intervention–who assessed the caregiver outcomes. Throughout the trial, a central research committee oversight the correct management of trial procedures and adherence to protocol. The trial protocol was approved by appropriate Institutional Review Boards of Spain and Portugal (Ethical and Scientific Research Committees of Navarra, Spain; and Sisters Hospitallers, Portugal). All participants (caregivers and patients) signed an informed consent form prior to randomization and trial inclusion. 2.2. Participants, inclusion and exclusion criteria Dyads of patients diagnosed with schizophrenia or schizoaffective disorder (DSM-IV criteria) and family primary caregivers were recruited from 21 outpatient psychiatric centres in Spain and from 3 outpatient psychiatric centres in Portugal. Persons caring for a relative were eligible for the trial if they met the following inclusion criteria: males or females (18+ years) currently caring for a relative with a diagnosis of schizophrenia or schizoaffective disorder; the caregiver should not be professionally paid (i.e., he/she should be an informal caregiver) and spend a minimum of 4 h/ week caring for the patient;
an introduction to review the progress of the homework tasks; information about the topic to be deal with; exercises to practice the new knowledge or skills. The PIP was applied by mental health professionals (psychologist or psychiatrist) trained in the program by the same researchers who developed it. We provided a manual for the therapist and a
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Table 1 Contents of the Psychoeducational Intervention Program (PIP). Session
Content
Topics developed
1
Knowing mental illness I
2
Knowing mental illness II
3
Treatment
4
Take care of oneself
5
Stress & well-being
6
Importance of thinking
7
To do pleasant activities
8
Assertive communication
9
Behaviour problems
10
Solving problems
11
Approaching demanding situations
12
Knowledge of support & helping services
Motivation for sharing the program Information about mental illness Understanding causes, prognosis, relapse How to deal with an emergency Integral treatment resources How to deal with treatment withdrawal Effect of burden in the caregiver Learning to take care of oneself Tension, emotion & stress Management skills Relaxation by breathing Identifying beliefs & changing negative beliefs Muscular relaxation Identifying & planning pleasant activities Muscular relaxation How to talk with the patient How to talk with the health services Relaxation by mental distraction ABC of behaviour How to manage behaviour problems To make a plan to change behaviour Relaxation by mental distraction Importance of emotion Methods to solve problems Relaxation by imaginery Identifying & acting Suggestions of experts & professionals Relaxation by imaginery Assistance, health services & laws About the future Wrapping summary and program evaluation by the caregivers
manual for the caregiver to follow and apply the PIP throughout the trial. The whole intervention is available online (http://www. fundacion-iip.org/IIP/). Table 1 presents the contents of the PIP by session. 2.4. Outcome assessment The trial included three evaluations conducted at visit #1 (baseline), visit #2 (postintervention, 4 months since trial inception), and visit #3 (follow-up, 8 months since trial inception). All outcomes were based on self-reported scales applied and assessed by a researcher blind to intervention allocation. 2.5. Primary outcome measures Change scores since baseline to postintervention endpoint and follow-up in the caregiver burden assessed by the Zarit Burden Interview (ZBI) [5] and the Involvement Evaluation Questionnaire (IEQ) [15]. The ZBI includes 22 statements recorded in a 0–4 Likert scale (total score range 0 to 88), that rates the subjective component of burden. Although it has been mainly used in dementia rather than in schizophrenia caregivers [16], we thought the ZBI was an appropriate outcome assessment [4]. Its sensibility to change has been reported in dementia [17] but also in schizophrenia caregivers [18,19]. The ZBI has been translated and validated in Spanish [20] and Portuguese [21]. The IEQ is now recognized as one of the leading caregiving measures in severe mental illness [9]. It includes a 31-item core module questionnaire recorded in a 0–4 Likert scale that rates the consequences of caregiving experienced in the previous 4 weeks, including the negative impact on caregivers. Beyond its total score (computed from 27 of the 31 items), the IEQ includes four subscales: worrying (6 items), urging (8 items), tension (9 items) and supervision (6 items) [9,22]. For both the ZBI and the IEQ, higher scores mean higher burden, thus negative score changes mean better outcomes.
The IEQ has been translated and validated in Spanish [15] and Portuguese [23]. 2.6. Secondary outcome measures Change scores since baseline to postintervention endpoint and follow-up on the caregiver mental health rated by the General Health Questionnaire, 28 items (GHQ-28) [24], and the Center for Epidemiologic Studies Depression Scale (CES-D) [25]. The GHQ-28 includes 4 subscales with 7-item each. Items present a 0–3 Likert scale giving a total subscale range from 0 to 21, and a total score range of 0 to 84. Higher score means higher level of psychological distress, thus negative score changes mean better outcomes. The underlying domains for the subscales are somatic symptoms, anxiety and insomnia, social dysfunction, and severe depression. The GHQ-28 has been validated in Spanish [26] and Portuguese [27]. The CES-D is a 20-item questionnaire that rates depressive feelings and related behaviours during the past week. Items present a 0–3 Likert scale. Higher score means higher level of depressive symptoms, thus negative score changes mean better outcomes. There are Spanish and Portuguese versions of CES-D [28,29]. 2.7. Sample size We assumed the comparison between groups would present a moderate effect size favouring the PIP over the control group in the ZBI scale (standardised mean difference = 0.40). With such estimate and a baseline ZBI score of 55 with SD of 15, 200 caregivers randomized in 1:1 ratio would be needed to attain 85% power with a level of 5%. 2.8. Randomization The randomization was done centrally. The sequence generation for each research site was obtained by block randomisation
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using block sizes of 1 to 4. The R package ‘‘blockrand’’ was used [30]. None of the site investigators participated or had access to the randomization process. The randomisation sequence was known only by the investigator responsible for developing the PIP. The investigator who applied and assessed the caregiver self-reported outcomes at visits #1 to #3 was blind to the intervention allocation throughout the trial length. 2.9. Statistical methods Means and SDs describe continuous variables. Frequencies and percentages describe categorical variables. Main results were analyzed by between-group differences in the change scores since baseline at visits #2 and #3 for the primary and secondary outcomes. Two analyses were performed. A complete case analyses (CC) that included caregivers providing full information at the corresponding times. Results are reported by mean differences, SDs and/or 95% confidence intervals (CI), and standardised effect sizes (SMD). We used the usual Cohen’s cut-off points to interpret SMD estimates: values 0.2 for a small effect, values 0.5 for a medium effect, and values 0.8 for a large effect [31]. To allow for the attrition rates throughout the trial length, we also analysed the data using a mixed linear model for repeated measures (MLM) assuming missing at random (MAR) at visits #2 and #3 [32]. We assessed the effect of the intervention by testing the interaction term of intervention by visit. We compared the full model including the main factors (intervention, visit) and their interaction with the nested and reduced model excluding the interaction.
In addition to the main analysis, a subgroup analysis within the experimental group was conducted to find clinical and sociodemographic variables associated to the reduction on the caregiver burden. The a priori selected variables were the ZBI and GHQ-28 scores at baseline; the number of PIP sessions attended by the caregivers; the diagnosis of the person cared for, the gender, age, educational level, and marital status of the caregiver; the time the caregiver was providing care as well as the weekly hours dedicated; and the external help provided. After simple and multiple regression analysis, a backward stepwise linear regression analysis was performed (P-value to retain of 0.10) to obtain the most parsimonious model able to explain the variability in the change of ZBI scores since baseline to end of trial at 8 months. We run the analyses with Stata v13 (StataCorp, College Station, TX, 2013) and R v3.0.2 (R Foundation for Statistical Computing, Vienna, Austria, 2013).
3. Results 3.1. Recruitment and losses to follow-up The trial recruited 223 caregivers (109 randomized to PIP and 114 to control condition) from March to May 2012. The last visit took place along the period September 2012–January 2013. Fig. 1 shows the trial flowchart. Data from 21 research sites from Spain and 2 from Portugal were included in the analyses. The median recruitment by research site was 9 caregivers (range 5 to 19).
Fig. 1. Trial flowchart.
M. Martı´n-Carrasco et al. / European Psychiatry 33 (2016) 9–17
The mean elapsed time between baseline and visit #2 was 4.5 months (SD = 1.2). The mean elapsed time between baseline and visit #3 was 8.6 months (SD = 1.3). In the PIP group, 21 caregivers (19.3%) were lost to follow-up at visit #2. The corresponding figure in the control group was 11 (9.6%). The difference was not significant (Fisher exact test, P = 0.39). At visit #3, 4 additional caregivers in the PIP group were lost to follow-up (4.5%). The corresponding figure in the control group was 5 (4.8%). The difference was not significant (Fisher exact test, P = 0.43). The patients being cared for were predominantly male (71 [65%] and 89 [78%] in the PIP and control arm respectively), and had a mean age of 38.7 years (SD = 11.1) in the PIP group and 39.3 years (SD = 9.1) in the control group. Most patients presented a diagnosis of schizophrenia (92 patients [84%] in the PIP group and 100 patients [88%] in the control group), with 17 patients (16%) in the PIP group, and 14 patients (12%) in the control group with a diagnosis of schizoaffective disorder. Table 2 presents the baseline characteristics of the caregivers by intervention. Overall, caregivers were
Table 2 Sociodemographic and baseline clinical data for caregivers. Variables Sex, n (%) Male Female Age (y), mean (SD) Educational level, n (%) Without degree Primary Secondary (high school) College, university Marital status, n (%) Single Married Separated, divorced Widow/er Work situation, n (%) Working Unemployed Housewife Retired Disabled Relationship to patient, n (%) Father/mother Spouse/partner Brother/sister Son/daughter Other Time providing care (y), mean (SD) Hours dedicated/w, mean (SD) External help provided, n (%) Yes No Diagnosis, n (%) Schizophrenia Schizoaffective ZBI score, mean (SD) IEQ score, mean (SD) IEQ total score IEQ tension IEQ supervision IEQ worries IEQ urging CES-D score, mean (SD) GHQ-28 score, mean (SD) GHQ-28 total score GHQ-28 somatic symptoms GHQ-28 anxiety & insomnia GHQ-28 social dysfunction Ghq-28 severe depression
PIP (N = 109)
Control (N = 114)
22 (20.2) 87 (79.8) 59.2 (11.4)
31 (27.2) 83 (72.8) 61.1 (11.6)
7 (6.4) 38 (34.9) 34 (31.2) 30 (27.5)
12 48 39 15
13 59 18 19
(11.9) (54.1) (16.5) (17.4)
7 (6.1) 79 (69.3) 14 (12.3) 14 (12.3)
41 (37.6) 8 (0.7) 33 (30.3) 27 (24.8) 0 (0.0)
30 (26.3) 14 (12.3) 36 (31.6) 32 (28.1) 2 (1.7)
78 (71.6) 7 (6.4) 18 (16.5) 2 (1.8) 4 (3.7) 14.2 (9.8) 5.3 (1.4)
87 (76.3) 6 (5.3) 20 (17.5) 0 (0.0) 1 (0.1) 15.5 (10.1) 5.2 (1.4)
55 (50.5) 54 (49.5)
56 (49.1) 58 (50.9)
32.3 (16.5)
31.8 (15.8)
30.5 (16.3) 6.6 (5.2) 3.5 (4.6) 12.0 (5.9) 10.2 (6.3) 15.2 (10.3)
29.0 (15.5) 6.3 (4.8) 3.0 (4.0) 11.6 (5.7) 9.7 (6.5) 16.3 (10.3)
24.4 (10.7) 6.3 (3.6) 7.7 (4.2) 7.8 (2.1) 2.6 (3.4)
25.8 (12.4) 6.6 (4.1) 7.9 (4.5) 7.8 (2.7) 3.4 (3.9)
(10.5) (42.1) (34.2) (13.2)
ZBI: Zarit Burden Interview; IEQ: Involvement evaluation Questionnaire; CES-D: Center for Epidemiologic Studies-Depression Scale; GHQ-28: General Health Questionnaire-28 items.
13
predominantly married women caring for their child, with a mean age of 60 years, had a low to medium educational level, and presented a mean caring exposure of 15 years. The current caring load was 5 h per week and half the recruited carers had external help. 3.2. Primary outcomes Table 3 shows the ZBI and the IEQ differences among interventions through time. The CC analysis for the ZBI showed a significant effect favouring the PIP with a moderate effect size at 4 and 8 months since trial inception (SMD = 0.35 and 0.40). The MLM analysis assuming MAR showed a significant interaction of intervention arm by time (P = 0.006) in favour of the PIP. The CC analysis for the IEQ showed a non-significant effect favouring the PIP with a small effect size (SMD = 0.23). The MLM analysis did not show a significant interaction of intervention arm by time (P = 0.12). Of the IEQ subscales, the tension domain showed the bigger effect at 4 and 8 months since trial inception (SMD = 0.26 and 0.25) without attaining significance at the 5% level (MLM analysis, P = 0.08). The MLM analyses for the rest of IEQ subscales do not show a significant difference of efficacy over time by intervention arm (IEQ supervision, P = 0.33; IEQ worries, P = 0.27; IEQ motivation, P = 0.42). 3.3. Secondary outcomes Table 3 also shows the CES-D and GHQ-28 differences among interventions. For the CES-D the CC analysis showed a significant effect favouring the PIP with a small size at 4 and 8 months (SMD = 0.34 and 0.21 respectively). The MLM analysis showed a significant interaction of intervention arm by time (P = 0.023) in favour of the PIP. For the GHQ-28 the CC analysis showed a significant effect for its total score favouring the PIP with a small size at 4 but not at 8 months (SMD = 0.30 and 0.18 respectively). The MLM analysis showed a non-significant interaction of intervention arm by time (P = 0.11). Most of the GHQ-28 subscales did not show a significant interaction of intervention arm by time (somatic symptoms P = 0.19; anxiety & insomnia P = 0.17; severe depression P = 0.67). On the contrary the social dysfunction subscale showed a significant interaction favouring the PIP (P = 0.005). However it seems to be mainly explained by the moderate effect size attained at 4 months (SMD = 0.46) that disappeared at 8 months (SMD = 0.11). None of the patients required inpatient or residential care throughout the trial length. 3.4. Subgroup analysis within the experimental group Table 4 shows the results of the linear regression analyses performed. Only 2 variables, the ZBI score at baseline and the provision of external help (professional support or economical benefits) are significantly associated with the improvement in ZBI scores at end of trial. The ZBI at baseline is positively associated with the reduction on burden what means that those caregivers experiencing more burden at baseline will be also those who will improve more by the end of trial. Conversely, the provision of external help is negatively associated with burden reduction. Those caregivers with external help present 5 points less in the ZBI change scores than caregivers without external support (95% CI: 0.25 to 10 points less).
4. Discussion The main results of this study, those related with primary outcomes, support a moderate efficacy of a PIP administered in a
14
Table 3 Efficacy outcomes (change scores from baseline). Complete case analyses and mixed linear model for repeated measures. Visit 2 (4 months since baseline) Outcomes
Zarit Total Score, mean (SD)
Visit 3 (8 months since baseline)
Control
Mean difference
SMD
PIP
Control
Mean difference
SMD
(N = 86)
(N = 97)
(95% CI)
(95% CI)
(N = 82)
(N = 91)
(95% CI)
(95% CI)
4.33
0.35
4.60 (12.68)
0.27 (12.07)
( 7.96 to 4.52 (11.58)
IEQ Tension
1.16 (4.19)
IEQ Worries IEQ Urging
0.77 (3.54) 1.42 (5.02) 1.43 (4.97)
1.72 (12.13)
0.09 (5.34) 0.56 (2.84) 0.29 (5.46) 0.94 (4.98) 0.36 (9.60)
0.71)
2.8 ( 6.27 1.26 ( 2.67 0.21 ( 1.14 1.13 ( 2.67 0.49 ( 1.95 3.22
( 0.64 to
to 0.67) to 0.16) to 0.72) to 0.41) to 0.96)
2.86 (9.17)
GHQ-28, mean (SD) GHQ-28 Total Score GHQ-28 Somatic Symptoms
4.59 (11.00) 0.89 (3.88)
0.02 (3.88)
( 5.99 to 3.35 ( 6.59 to 0.87
GHQ-28 Anxiety & Insomnia
1.84 (4.57)
0.73 (3.71)
( 2.01 to 0.26) 1.1
GHQ-28 Social Dysfunction
1.60 (3.32)
0.15 (2.96)
GHQ-28 Severe Depression
0.26 (2.49)
0.34 (3.79)
( 0.53 0.26 ( 0.55 0.07 ( 0.36 0.28 ( 0.57 0.1 ( 0.39 0.34
1.21 (11 09)
0.06)
0.23
CES-D Total Score, mean (SD)
1.25 (11.20)
5.67 (10.97)
5.46 (12.09)
2.60 (12.18)
1.48 (3.69)
0.48 (4.19)
to 0.06) to 0.03) 1.05 (3.39)
0.41 (3.08)
to 0.22) 1.37 (5.58)
0.66 (5.81)
to 0.01) 2.05 (5.01)
1.12 (5.27)
to 0.19) 0.73 (7.77)
3.00 (12.32)
0.87 (11.14)
0.59 (4.56)
( 0.51 to 0.07) 0.27
( 2.31 to 0.10) 1.45 ( 2.36 to 0.08
0.10)
0.53)
( 0.86 to 1.03)
( 0.63 to 0.3 ( 0.59 to 0.22
0.4
( 7.79 to
2.38 (7.77)
0.46)
4.46
0.05)
1.13)
2.85 ( 6.51 1 ( 2.19 0.64 ( 1.62 0.71 ( 2.43 0.93 ( 2.48 1.65
0.006
( 0.70 to
0.10)
0.23 to 0.81) to 0.20) to 0.33) to 1.01) to 0.62)
( 0.53 0.25 ( 0.55 0.2 ( 0.50 0.12 ( 0.42 0.18 ( 0.48 0.21
0.118 to 0.06) 0.081 to 0.05) 0.328 to 0.10) 0.27 to 0.17) 0.416 to 0.12) 0.023
0.33 (4.11)
( 4.01 to 0.72) 2.13 ( 5.64 to 1.38) 0.92
( 0.51 to 0.09) 0.18 ( 0.48 to 0.12) 0.21
0.193
1.24 (4.60)
0.70 (4.16)
( 2.22 to 0.38) 0.54
( 0.51 to 0.09) 0.13
0.169
( 0.56 to 0.02) 0.46
0.64 (3.16)
0.30 (3.02)
( 1.85 to 0.77) 0.34
( 0.42 to 0.18) 0.11
0.005
( 0.75 to 0.02
0.53 (2.81)
0.20 (3.84)
( 1.27 to 0.58) 0.33
( 0.41 to 0.19) 0.1
0.67
( 1.35 to 0.68)
( 0.40 to 0.20)
0.01)
0.17)
( 0.27 to 0.31)
0.109
PIP: Psychoeducational Intervention Program; SMD: Standardized Mean Difference; IEQ: Involvement Evaluation Questionnaire; CES-D: Center for Epidemiologic Studies–Depression Scale; GHQ-28: General Health Questionnaire Scaled (28 items). a P-values for the interaction of intervention by time from the mixed linear mixed model for repeated measures.
M. Martı´n-Carrasco et al. / European Psychiatry 33 (2016) 9–17
IEQ, mean (SD) IEQ Total Score
IEQ Supervision
P-valuesa
PIP
M. Martı´n-Carrasco et al. / European Psychiatry 33 (2016) 9–17
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Table 4 Associations among change scores since baseline of the Zarit Burden Inventory and baseline clinical and sociodemographic variables. Results from linear regressions. Baseline variables
Coefficient (95% CI) Univariate regression
Coefficient (95% CI) Multiple regression
Coefficient (95% CI) Stepwise regression
ZBI at baseline GHQ-28 at baseline Intervention sessions attended Diagnosis Schizophrenia Schizoaffective Sex Male Female Age Educational level Primary Secondary (high school) College, university Marital status Single Married Separated, divorced Widow/er Time providing care Hours dedicated External help provided No Yes
0.34 (0.21 to 0.47)*** 0.24 (0.02 to 0.47)* 0.42 ( 0.55 to 1.39)
0.32 (0.15 to 0.50)*** 0.04 ( 0.22 to 0.30) 0.03 ( 0.95 to 1.01)
0.37 (0.23 to 0.50)***
Reference level 2.77 ( 9.87 to 4.33)
Reference level 1.79 ( 8.61 to 5.02)
Reference level 1.27 ( 5.60 to 8.14) 0.09 ( 0.13 to 0.31)
Reference level 2.17 ( 9.39 to 5.05) 0.14 ( 0.12 to 0.41)
Reference level 0.80 ( 4.78 to 6.38) 4.17 ( 2.10 to 10.4)
Reference level 1.79 ( 4.12 to 7.70) 2.79 ( 4.33 to 9.90)
Reference 2.82 ( 11.8 to 6.12) 3.94 ( 14.0 to 6.12) 6.54 ( 16.6 to 3.52) 0.001 ( 0.02 to 0.02) 0.56 ( 1.27 to 2.39)
Reference 1.91 ( 10.8 to 6.99) 5.54 ( 15.2 to 4.13) 8.21 ( 19.2 to 2.76) 0.03 ( 0.02 to 0.02) 1.10 ( 0.97 to 3.18)
Reference level 3.30 ( 8.66 to 2.07)
Reference level 5.33 ( 10.5 to
0.12) *
Reference level 5.04 ( 9.82 to
0.25) *
ZBI: Zarit Burden Inventory; GHQ-28: General Health Questionnaire-28 items. * P-value < 0.05; ** P-value < 0.01; *** P-value < 0.001.
group format to reduce the subjective burden associated with caregiving tasks in caregivers of patients with schizophrenia or schizoaffective disorder. The ZBI reduction at postintervention presents a moderate effect in favour of the intervention group (SMD: 0.35; 95% CI: 0.64 to 0.06) and the improvement is maintained at follow-up (SMD: 0.40; 95% CI: 0.70 to 0.10), with a significant interaction of treatment by time (P = 0.006). The same trend of caregiver burden reduction over time was found with the IEQ tension domain that overlaps with the burden domain of the ZBI (SMD at end of trial: 0.26; 95% CI: 0.55 to 0 03; SMD at follow-up: 0.25; 95% CI: 0.55 to 0.05). However, this trend did not attain statistical significance (P = 0.118). Part of the discrepancy observed between the results of both scales could be explained by the different constructs they measure. Whereas the ZBI focus is on the perceived and thus subjective component of burden, the IEQ rates also objective and behavioural domains of burden [33]. Accordingly, the efficacy of the PIP intervention might be explained by reducing the subjective component of burden. As far as secondary outcomes are concerned, our results also suggest that the PIP intervention is useful to reduce depressive symptoms over time as measured by the CES-D (P = 0.023), but not according to the GHQ-28 (P = 0.109). As before, this discrepancy could be explained because both scales measure different depression domains. Whereas the GHQ depression items assess severe and likely unchangeable symptoms, the CES-D items include other dominions more changeable with the PIP training (i.e. motor and physiological symptoms). Focusing on the caregivers who had the PIP intervention, those more likely to reduce the burden would be the ones with higher levels of burden at the beginning of the intervention. On the other hand, caregivers with external help do not seem to reduce the burden as much as caregivers who had no access to external resources (mainly professional support by paid caregivers, or economic benefits for caring). Probably, they represent caregiver clusters with different demands on caring related with severity of the disease.
4.1. Limitations and strengths of the research Our trial present several limitations that could overestimate the efficacy of the PIP intervention. According to the risk of bias, the most important relates to the blinding and concealment of subjects to interventions, and also to ascertainment bias throughout the trial. In studies like the EDUCA-III with interventions that are hard, if not impossible, to mask and blind to both the patient and professionals, selection and performance bias cannot be excluded. In this trial, ascertainment bias was managed by blinding assessment evaluators. Also, in this trial selection bias seems unlikely since no violations to the random assignment were detected. However, we cannot guarantee that information crosscontamination between groups did not happened over the trial, and that knowing the assignment to intervention or control, has not biased the self-perception of caregivers to the questions posed in the assessment scales. Thus performance bias cannot be ruled out completely and, if present, could have lead to an overestimation of the results. On the other hand, attrition bias seems unlike since there are not recorded different dropouts and causes of attrition between-groups, either at end of trial, or at follow-up. Even if we cannot rule out the possibility of overestimating the efficacy of the PIP assessed in this trial because of the risk of bias previously discussed, our results on the moderate positive effect of the PIP seem to agree with previous studies. We have found six studies with similar design (randomized assignment to interventions), intervention (psychoeducational intervention including both stress management and coping), and aims (efficacy trials) [18,34–38] and included in a recent systematic review and metaanalysis [39]. We have combined the primary outcomes of those studies, and found that our main result on the postintervention burden efficacy of the PIP is smaller than the weighted combination result ( 0.35 versus 0.78), but, nevertheless, fits well within the 95% CI of the pooled studies ( 1.37 to 0.20). Therefore, we think our overall results support the effectiveness of a psychoeducational intervention to reduce caregiver burden in schizophrenia. However we need also to stress that the effects so far reported
M. Martı´n-Carrasco et al. / European Psychiatry 33 (2016) 9–17
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for our primary outcomes are moderate according to the effect sizes obtained. Because of being a multicentre trial including research sites from two countries (Portugal and Spain), the findings of our trial could present better generalisability, and possibly external validity, than single centre studies. Current guidelines on schizophrenia treatment, stress the need for family interventions with goals aimed at the adoption of adaptive copying styles (how to handle psychological reactions to the experience of the illness in a relative, how to improve or acquire the abilities to manage stress and communicate with the other, how to manage the appropriate health resources over the illness periods) [40]. In this sense, the PIP reported in this trial fits such requirements and presents a moderate effect size with clinical relevance. 5. Conclusions An analysis of 223 informal caregivers of patients with schizophrenia or schizoaffective disorder showed the efficacy of a PIP administered in a group format to reduce the subjective burden and depression associated with caregiving tasks. These results were maintained at follow-up at 8 months. Caregivers presenting higher levels of burden at the beginning of the intervention and those who do not have access to external help were more likely to improve in the burden as consequence of the PIP intervention. Disclosure of interest The authors declare that they have no competing interest. Acknowledgements The EDUCA-III trial was funded by a research grant from Instituto de Salud Carlos III, Spain (PI10/01049). The role of the funding source was limited to economic support. It was not involved in the study process, preparation or submission of the manuscript. The EDUCA-III research sites and the researchers involved are: Jesu´s Moraza, Arkaitz De La Cruz, Vicente Hueso (Hospital de Dı´a y CRPS Beasain- Hospital Aita Menni, Mondrago´n); Asuncio´n Lizarazu, Marı´a Blanca Ferna´ndez de Corres, Paz Lander, Nuria Grive´, Isabel Alonso, Marixa Larreina, Elvira Castellano (Hospital Psiquia´trico de A´lava, Vitoria); Rosario Beguiristain, Pablo Malo (CSM Bombero Etxaniz, Bilbao); Rocı´o del Pino, Zita Blanco, Janire Garay (Universidad de Deusto); Juan Carlos Irurzun, Karmele Iribar, Karmele Zarraga (CSM Donostia Amara, San Sebastia´n); Marta Arrieta, Rosario Bengochea, Silvia Pe´rez, Mariola Palacios (CRPS Santander y CRPS Torrelavega- Centro Hospitalario Padre Menni); Luis Alberto Cuellar, Rebeca Lo´pez (Centro Hospitalario Benito Menni, Valladolid); Mireia Gonza´lez, Mireia Segarra (Hospital Sagrat Cor, Martorell); Mo´nica Guasch, Inma Esteve (Hospital Mare` de Deu de La Merce´, Barcelona); Jaime Gra´cio, Susana Pestana, Filipa Nunes (Clı´nica Psiquia´trica de Sa˜o Jose´, Lisboa, Portugal); Catarina Vidigal, Rita Ribeiro (Casa de Sau´de da Idanha, Belas, Portugal); Patrı´cia Godinho, Mariana Gil (Casa de Sau´de do Bom Jesus, Braga, Portugal); Marı´a Carmen Hurtado, Marı´a Nieves Tapiador, Ana Carolina Martı´nez (CD -EASC Villaverde, Madrid); Manuela Guimo´n, Rau´l Gonza´lez, Jose´ Marı´a Pinedo, Vero´nica Robles, Marta Mora, Paola Ferna´ndez (CD-EASC-CRPS-CRL Vallecas, Madrid); Rocı´o Ferna´ndez, Carolina Mogollo´n (CRPS Badajoz); Ana Fuentes, Beatriz Rodrı´guez, Marı´a Mora (CD San Miguel -EASC Salamanca- EASC Chamartı´n, Madrid); Urbano Barrientos, Carlos Rebolleda, Eva Ojalvo, Lourdes Soladana (CRPS-CD-EASC Aranjuez, Madrid); Laura Romero, Roberto Martı´n, Marı´a Amores, Vanesa
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Manuel Martin-Carrasco, MD PhD. Affiliation: Psychiatric Research Institute. Ma Josefa Recio Foundation, Bilbao, Spain. Position: Director of the Psychiatric Research Institute (Maria Josefa Recio Foundation, Bilbao). Associate Professor of the Faculty of Medicine of the University of Navarra (Pamplona, Spain). Research interests: Care of people with dementia and their relatives, severe mental illness, and psychometry.
Paola Ferna´ndez-Catalina, MPsychol. Affiliation: Psychosocial Rehabilitacio´n Program of Sisters Hospitalliers, Madrid, Spain. Position: Director of residential and out-patient mental health services in Madrid. Research interests: Psychotherapy interventions, psychosocial rehabilitation of patients with mental disease and with family intervention.
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Ana I. Domı´nguez-Pancho´n, MPsychol. Affiliation: Aita Menni Hospital, Gipuzkoa, Spain. Psychiatric Research Institute. Ma Josefa Recio Foundation, Bilbao, Spain. Position: Clinical psychologist at Aita Menni Hospital in Mondrago´n (Basque Country). Associate Professor at Deusto University. Research interests: Psychometric assessment of caregiver burden and development of new psychoeducational program interventions.
M. Gonc¸alves-Pereira, MD, PhD. Affiliation: Clı´nica Psiquia´trica de S. Jose´ (Sisters Hospitallers), Lisboa, Portugal. CEDOC, NOVA Medical School, Faculdade de Cieˆncias Me´dicas, Universidade NOVA de Lisboa, Lisboa, Portugal. Position: Professor of Medical Psychology at NOVA Medical School (Faculdade de Cieˆncias Me´dicas, Universidade Nova de Lisboa). Research interests: Geriatric psychiatry and family interventions.
Eduardo Gonza´lez-Fraile, MPsychol, PhD. Affiliation: Psychiatric Research Institute. Ma Josefa Recio Foundation, Bilbao, Spain. Associated Professor at International University of La Rioja (UNIR). Position: PhD Psychologist. Research interests: Psychoeducational interventions, informal caregiver, statistical methods, meta-analyses and risk of bias.
˜ oz-Hermoso, BPsychol. Paula Mun Affiliation: Clı´nica Psiquiatrica Padre Menni, Pamplona, Spain. Position: Clinical psychologist at Clı´nica Psiquiatrica Padre Menni in Pamplona (Spain). Research interests: Assessment and intervention of burden in caregivers. Mental health and family interventions.
Javier Ballesteros, MD, PhD. Affiliation: University of the Basque Country, UPV/EHU. Psychiatric Research Institute. Ma Josefa Recio Foundation, Bilbao, Spain. Position: Professor in the Department of Neuroscience– Psychiatry, at the University of the Basque Country, UPV/EHU. Research interests: Methodological and practical issues on evidence based psychiatry: efficacy of pharmacological and non-pharmacological interventions on mental health problems, assessment of outcomes with patientrelated-outcomes, risk of bias, handling of likely publication biases, systematic reviews and meta-analysis.
