European Psychiatry 33 (2016) 9–17

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. Martı́n-Carrasco a,b,h, P. Fernández-Catalina c, A.I. Domı́nguez-Panchón d,
M. Gonçalves-Pereira e,f, E. González-Fraile a,*, P. Muñoz-Hermoso b,
J. Ballesteros g,h, the EDUCA-III group
a
Institute of Psychiatric Research, Bilbao, Spain
b
Padre Menni Psychiatric Centre, Pamplona, Spain
c
Psychosocial Rehabilitation Resource (Sisters Hospitallers), Madrid, Spain
d
Aita-Menni Hospital, Arrasate-Mondragón, Spain
e
Clı´nica Psiquiátrica de S. José (Sisters Hospitallers), Lisboa, Portugal
f
CEDOC, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisboa, Portugal
g
University of the Basque Country, UPV/EHU, Leioa, Spain
h
CIBER Mental Health, Spain

A R T I C L E I N F O A B S T R A C T

Article history: Background: Patient’s relatives usually care for patients with schizophrenia, and as informal caregivers
Received 27 August 2015 they experience negative consequences. The aim of the EDUCA-III trial is to test the efficacy of a
Received in revised form 23 December 2015 psychoeducational intervention program (PIP) versus standard care to reduce the caregiver burden at
Accepted 3 January 2016
post-intervention (4 months), and at follow-up (8 months).
Available online
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.
Keywords:
Primary outcomes were change scores since baseline on the Zarit Burden Interview (ZBI) and the
Schizophrenia
Caregivers
Involvement Evaluation Questionnaire (IEQ).
Mental health Results: One hundred and nine caregivers were randomized to PIP and 114 to control condition from
Randomized controlled trial 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.

1. Introduction member, known as the primary or main caregiver, assumed most

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 Psiquiátricas, C/Egaña 10,
48010 Bilbao, Spain. Tel.: +34 94 443 4927; fax: +34 94 443 7131.
E-mail address: iip@fundacion-iip.org (E. González-Fraile).
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, occu-
pational 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].

http://dx.doi.org/10.1016/j.eurpsy.2016.01.003
0924-9338/ß 2016 Elsevier Masson SAS. All rights reserved.
10 M. Martı´n-Carrasco et al. / European Psychiatry 33 (2016) 9–17
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 schizophre-
nia 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 schizophre-
nia [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].
1.1. Aims of the trial
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).
2. Methods
2.1. Hypothesis and design
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 schizoaf-
fective 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;
 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:
 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 commit-
tee.
2.3. Interventions
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 REACH-
II 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 beha-
viors, 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 informa-
tion 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 cognitive-
behavioural 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:
 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 psychi-
atrist) trained in the program by the same researchers who
developed it. We provided a manual for the therapist and a
 M. Martı´n-Carrasco et al. / European Psychiatry 33 (2016) 9–17 11

Table 1
Contents of the Psychoeducational Intervention Program (PIP).

Session Content Topics developed

1 Knowing mental illness I Motivation for sharing the program

Information about mental illness
2 Knowing mental illness II Understanding causes, prognosis, relapse
How to deal with an emergency
3 Treatment Integral treatment resources
How to deal with treatment withdrawal
4 Take care of oneself Effect of burden in the caregiver
Learning to take care of oneself
5 Stress & well-being Tension, emotion & stress
Management skills
Relaxation by breathing
6 Importance of thinking Identifying beliefs & changing negative beliefs
Muscular relaxation
7 To do pleasant activities Identifying & planning pleasant activities
Muscular relaxation
8 Assertive communication How to talk with the patient
How to talk with the health services
Relaxation by mental distraction
9 Behaviour problems ABC of behaviour
How to manage behaviour problems
To make a plan to change behaviour
Relaxation by mental distraction
10 Solving problems Importance of emotion
Methods to solve problems
Relaxation by imaginery
11 Approaching demanding situations Identifying & acting
Suggestions of experts & professionals
Relaxation by imaginery
12 Knowledge of support & helping services 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 IEQ has been translated and validated in Spanish [15] and
the trial. The whole intervention is available online (http://www. Portuguese [23].
fundacion-iip.org/IIP/). Table 1 presents the contents of the PIP
by session. 2.6. Secondary outcome measures

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.
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 genera-
tion for each research site was obtained by block randomisation
12 M. Martı´n-Carrasco et al. / European Psychiatry 33 (2016) 9–17
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 interac-
tion with the nested and reduced model excluding the interaction.
Fig. 1. Trial flowchart.
In addition to the main analysis, a subgroup analysis within the
experimental group was conducted to find clinical and sociode-
mographic 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 regres-
sion 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).
 M. Martı´n-Carrasco et al. / European Psychiatry 33 (2016) 9–17 13

The mean elapsed time between baseline and visit #2 was predominantly married women caring for their child, with a mean
4.5 months (SD = 1.2). The mean elapsed time between baseline age of 60 years, had a low to medium educational level, and
and visit #3 was 8.6 months (SD = 1.3). In the PIP group, presented a mean caring exposure of 15 years. The current
21 caregivers (19.3%) were lost to follow-up at visit #2. The caring load was 5 h per week and half the recruited carers had
corresponding figure in the control group was 11 (9.6%). The external help.
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 3.2. Primary outcomes
(4.5%). The corresponding figure in the control group was 5 (4.8%).
The difference was not significant (Fisher exact test, P = 0.43). Table 3 shows the ZBI and the IEQ differences among
The patients being cared for were predominantly male (71 [65%] interventions through time. The CC analysis for the ZBI showed
and 89 [78%] in the PIP and control arm respectively), and had a a significant effect favouring the PIP with a moderate effect size at
mean age of 38.7 years (SD = 11.1) in the PIP group and 39.3 years 4 and 8 months since trial inception (SMD = 0.35 and 0.40). The
(SD = 9.1) in the control group. Most patients presented a diagnosis MLM analysis assuming MAR showed a significant interaction of
of schizophrenia (92 patients [84%] in the PIP group and 100 patients intervention arm by time (P = 0.006) in favour of the PIP. The CC
[88%] in the control group), with 17 patients (16%) in the PIP group, analysis for the IEQ showed a non-significant effect favouring the
and 14 patients (12%) in the control group with a diagnosis of PIP with a small effect size (SMD = 0.23). The MLM analysis did
schizoaffective disorder. Table 2 presents the baseline characte- not show a significant interaction of intervention arm by time
ristics of the caregivers by intervention. Overall, caregivers were (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
Table 2 analysis, P = 0.08). The MLM analyses for the rest of IEQ subscales
Sociodemographic and baseline clinical data for caregivers.
do not show a significant difference of efficacy over time by
Variables PIP (N = 109) Control (N = 114) intervention arm (IEQ supervision, P = 0.33; IEQ worries, P = 0.27;
Sex, n (%) IEQ motivation, P = 0.42).
Male 22 (20.2) 31 (27.2)
Female 87 (79.8) 83 (72.8) 3.3. Secondary outcomes
Age (y), mean (SD) 59.2 (11.4) 61.1 (11.6)
Educational level, n (%)
Without degree 7 (6.4) 12 (10.5)
Table 3 also shows the CES-D and GHQ-28 differences among
Primary 38 (34.9) 48 (42.1) interventions. For the CES-D the CC analysis showed a significant
Secondary (high school) 34 (31.2) 39 (34.2) effect favouring the PIP with a small size at 4 and 8 months
College, university 30 (27.5) 15 (13.2) (SMD = 0.34 and 0.21 respectively). The MLM analysis showed a
Marital status, n (%)
significant interaction of intervention arm by time (P = 0.023) in
Single 13 (11.9) 7 (6.1)
Married 59 (54.1) 79 (69.3) favour of the PIP. For the GHQ-28 the CC analysis showed a
Separated, divorced 18 (16.5) 14 (12.3) significant effect for its total score favouring the PIP with a small
Widow/er 19 (17.4) 14 (12.3) size at 4 but not at 8 months (SMD = 0.30 and 0.18 respective-
Work situation, n (%) ly). The MLM analysis showed a non-significant interaction of
Working 41 (37.6) 30 (26.3)
intervention arm by time (P = 0.11). Most of the GHQ-28 subscales
Unemployed 8 (0.7) 14 (12.3)
Housewife 33 (30.3) 36 (31.6) did not show a significant interaction of intervention arm by time
Retired 27 (24.8) 32 (28.1) (somatic symptoms P = 0.19; anxiety & insomnia P = 0.17; severe
Disabled 0 (0.0) 2 (1.7) depression P = 0.67). On the contrary the social dysfunction
Relationship to patient, n (%)
subscale showed a significant interaction favouring the PIP
Father/mother 78 (71.6) 87 (76.3)
Spouse/partner 7 (6.4) 6 (5.3) (P = 0.005). However it seems to be mainly explained by the
Brother/sister 18 (16.5) 20 (17.5) moderate effect size attained at 4 months (SMD = 0.46) that
Son/daughter 2 (1.8) 0 (0.0) disappeared at 8 months (SMD = 0.11). None of the patients
Other 4 (3.7) 1 (0.1) required inpatient or residential care throughout the trial length.
Time providing care (y), mean (SD) 14.2 (9.8) 15.5 (10.1)
Hours dedicated/w, mean (SD) 5.3 (1.4) 5.2 (1.4)
External help provided, n (%) 3.4. Subgroup analysis within the experimental group
Yes 55 (50.5) 56 (49.1)
No 54 (49.5) 58 (50.9) Table 4 shows the results of the linear regression analyses
Diagnosis, n (%)
performed. Only 2 variables, the ZBI score at baseline and the
Schizophrenia
Schizoaffective provision of external help (professional support or economical
ZBI score, mean (SD) 32.3 (16.5) 31.8 (15.8) benefits) are significantly associated with the improvement in ZBI
IEQ score, mean (SD) scores at end of trial. The ZBI at baseline is positively associated
IEQ total score 30.5 (16.3) 29.0 (15.5) with the reduction on burden what means that those caregivers
IEQ tension 6.6 (5.2) 6.3 (4.8)
experiencing more burden at baseline will be also those who will
IEQ supervision 3.5 (4.6) 3.0 (4.0)
IEQ worries 12.0 (5.9) 11.6 (5.7) improve more by the end of trial. Conversely, the provision of
IEQ urging 10.2 (6.3) 9.7 (6.5) external help is negatively associated with burden reduction.
CES-D score, mean (SD) 15.2 (10.3) 16.3 (10.3) Those caregivers with external help present 5 points less in the ZBI
GHQ-28 score, mean (SD)
change scores than caregivers without external support (95% CI:
GHQ-28 total score 24.4 (10.7) 25.8 (12.4)
GHQ-28 somatic symptoms 6.3 (3.6) 6.6 (4.1)
0.25 to 10 points less).
GHQ-28 anxiety & insomnia 7.7 (4.2) 7.9 (4.5)
GHQ-28 social dysfunction 7.8 (2.1) 7.8 (2.7)
Ghq-28 severe depression 2.6 (3.4) 3.4 (3.9) 4. Discussion
ZBI: Zarit Burden Interview; IEQ: Involvement evaluation Questionnaire; CES-D:
Center for Epidemiologic Studies-Depression Scale; GHQ-28: General Health The main results of this study, those related with primary
Questionnaire-28 items. 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) Visit 3 (8 months since baseline)

Outcomes PIP Control Mean difference SMD PIP Control Mean difference SMD P-valuesa
(N = 86) (N = 97) (95% CI) (95% CI) (N = 82) (N = 91) (95% CI) (95% CI)

Zarit Total Score, 4.60 (12.68) 0.27 (12.07) 4.33 0.35 5.67 (10.97) 1.21 (11 09) 4.46 0.4 0.006
mean (SD)
( 7.96 to 0.71) ( 0.64 to 0.06) ( 7.79 to 1.13) ( 0.70 to 0.10)

M. Martı´n-Carrasco et al. / European Psychiatry 33 (2016) 9–17

IEQ, mean (SD) 4.52 (11.58) 1.72 (12.13) 2.8 0.23 5.46 (12.09) 2.60 (12.18) 2.85 0.23 0.118
IEQ Total Score
( 6.27 to 0.67) ( 0.53 to 0.06) ( 6.51 to 0.81) ( 0.53 to 0.06)
IEQ Tension 1.16 (4.19) 0.09 (5.34) 1.26 0.26 1.48 (3.69) 0.48 (4.19) 1 0.25 0.081
( 2.67 to 0.16) ( 0.55 to 0.03) ( 2.19 to 0.20) ( 0.55 to 0.05)
IEQ Supervision 0.77 (3.54) 0.56 (2.84) 0.21 0.07 1.05 (3.39) 0.41 (3.08) 0.64 0.2 0.328
( 1.14 to 0.72) ( 0.36 to 0.22) ( 1.62 to 0.33) ( 0.50 to 0.10)
IEQ Worries 1.42 (5.02) 0.29 (5.46) 1.13 0.28 1.37 (5.58) 0.66 (5.81) 0.71 0.12 0.27
( 2.67 to 0.41) ( 0.57 to 0.01) ( 2.43 to 1.01) ( 0.42 to 0.17)
IEQ Urging 1.43 (4.97) 0.94 (4.98) 0.49 0.1 2.05 (5.01) 1.12 (5.27) 0.93 0.18 0.416
( 1.95 to 0.96) ( 0.39 to 0.19) ( 2.48 to 0.62) ( 0.48 to 0.12)
CES-D Total Score, 2.86 (9.17) 0.36 (9.60) 3.22 0.34 2.38 (7.77) 0.73 (7.77) 1.65 0.21 0.023
mean (SD)
( 5.99 to 0.46) ( 0.63 to 0.05) ( 4.01 to 0.72) ( 0.51 to 0.09)
GHQ-28, mean (SD) 4.59 (11.00) 1.25 (11.20) 3.35 0.3 3.00 (12.32) 0.87 (11.14) 2.13 0.18 0.109
GHQ-28 Total Score ( 6.59 to 0.10) ( 0.59 to 0.01) ( 5.64 to 1.38) ( 0.48 to 0.12)
GHQ-28 Somatic 0.89 (3.88) 0.02 (3.88) 0.87 0.22 0.59 (4.56) 0.33 (4.11) 0.92 0.21 0.193
Symptoms
( 2.01 to 0.26) ( 0.51 to 0.07) ( 2.22 to 0.38) ( 0.51 to 0.09)
GHQ-28 Anxiety & 1.84 (4.57) 0.73 (3.71) 1.1 0.27 1.24 (4.60) 0.70 (4.16) 0.54 0.13 0.169
Insomnia
( 2.31 to 0.10) ( 0.56 to 0.02) ( 1.85 to 0.77) ( 0.42 to 0.18)
GHQ-28 Social 1.60 (3.32) 0.15 (2.96) 1.45 0.46 0.64 (3.16) 0.30 (3.02) 0.34 0.11 0.005
Dysfunction
( 2.36 to 0.53) ( 0.75 to 0.17) ( 1.27 to 0.58) ( 0.41 to 0.19)
GHQ-28 Severe 0.26 (2.49) 0.34 (3.79) 0.08 0.02 0.53 (2.81) 0.20 (3.84) 0.33 0.1 0.67
Depression
( 0.86 to 1.03) ( 0.27 to 0.31) ( 1.35 to 0.68) ( 0.40 to 0.20)

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 15

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) Coefficient (95% CI) Coefficient (95% CI)
Univariate regression Multiple regression Stepwise regression

ZBI at baseline 0.34 (0.21 to 0.47)*** 0.32 (0.15 to 0.50)*** 0.37 (0.23 to 0.50)***
GHQ-28 at baseline 0.24 (0.02 to 0.47)* 0.04 ( 0.22 to 0.30)
Intervention sessions attended 0.42 ( 0.55 to 1.39) 0.03 ( 0.95 to 1.01)
Diagnosis
Schizophrenia Reference level Reference level
Schizoaffective 2.77 ( 9.87 to 4.33) 1.79 ( 8.61 to 5.02)
Sex
Male Reference level Reference level
Female 1.27 ( 5.60 to 8.14) 2.17 ( 9.39 to 5.05)
Age 0.09 ( 0.13 to 0.31) 0.14 ( 0.12 to 0.41)
Educational level
Primary Reference level Reference level
Secondary (high school) 0.80 ( 4.78 to 6.38) 1.79 ( 4.12 to 7.70)
College, university 4.17 ( 2.10 to 10.4) 2.79 ( 4.33 to 9.90)
Marital status
Single Reference Reference
Married 2.82 ( 11.8 to 6.12) 1.91 ( 10.8 to 6.99)
Separated, divorced 3.94 ( 14.0 to 6.12) 5.54 ( 15.2 to 4.13)
Widow/er 6.54 ( 16.6 to 3.52) 8.21 ( 19.2 to 2.76)
Time providing care 0.001 ( 0.02 to 0.02) 0.03 ( 0.02 to 0.02)
Hours dedicated 0.56 ( 1.27 to 2.39) 1.10 ( 0.97 to 3.18)
External help provided
No Reference level Reference level Reference level
Yes 3.30 ( 8.66 to 2.07) 5.33 ( 10.5 to 0.12) * 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 cross-
contamination 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 overestima-
tion 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 inter-
ventions), intervention (psychoeducational intervention including
both stress management and coping), and aims (efficacy trials)
[18,34–38] and included in a recent systematic review and meta-
analysis [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 combina-
tion 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 psychoe-
ducational intervention to reduce caregiver burden in schizophre-
nia. However we need also to stress that the effects so far reported
16 M. Martı´n-Carrasco et al. / European Psychiatry 33 (2016) 9–17
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:
Jesús Moraza, Arkaitz De La Cruz, Vicente Hueso (Hospital de Dı́a y
CRPS Beasain- Hospital Aita Menni, Mondragón); Asunción
Lizarazu, Marı́a Blanca Fernández de Corres, Paz Lander, Nuria
Grivé, Isabel Alonso, Marixa Larreina, Elvira Castellano (Hospital
Psiquiátrico de Álava, Vitoria); Rosario Beguiristain, Pablo Malo
(CSM Bombero Etxaniz, Bilbao); Rocı́o del Pino, Zita Blanco, Janire
Garay (Universidad de Deusto); Juan Carlos Irurzun, Karmele Iribar,
Karmele Zarraga (CSM Donostia Amara, San Sebastián); Marta
Arrieta, Rosario Bengochea, Silvia Pérez, Mariola Palacios (CRPS
Santander y CRPS Torrelavega- Centro Hospitalario Padre Menni);
Luis Alberto Cuellar, Rebeca López (Centro Hospitalario Benito
Menni, Valladolid); Mireia González, Mireia Segarra (Hospital
Sagrat Cor, Martorell); Mónica Guasch, Inma Esteve (Hospital Marè
de Deu de La Mercé, Barcelona); Jaime Grácio, Susana Pestana,
Filipa Nunes (Clı́nica Psiquiátrica de São José, Lisboa, Portugal);
Catarina Vidigal, Rita Ribeiro (Casa de Saúde da Idanha, Belas,
Portugal); Patrı́cia Godinho, Mariana Gil (Casa de Saúde do Bom
Jesus, Braga, Portugal); Marı́a Carmen Hurtado, Marı́a Nieves
Tapiador, Ana Carolina Martı́nez (CD -EASC Villaverde, Madrid);
Manuela Guimón, Raúl González, José Marı́a Pinedo, Verónica
Robles, Marta Mora, Paola Fernández (CD-EASC-CRPS-CRL Vallecas,
Madrid); Rocı́o Fernández, Carolina Mogollón (CRPS Badajoz); Ana
Fuentes, Beatriz Rodrı́guez, Marı́a Mora (CD San Miguel -EASC
Salamanca- EASC Chamartı́n, Madrid); Urbano Barrientos, Carlos
Rebolleda, Eva Ojalvo, Lourdes Soladana (CRPS-CD-EASC Aranjuez,
Madrid); Laura Romero, Roberto Martı́n, Marı́a Amores, Vanesa
Rodrı́guez, Sara González (CRPS-CD-EASC Retiro, Madrid); Marı́a
Ángeles Polo, Virginia López (Centro Inicia, Santander); Oriol
Imbernon, Blanca Perisé, Marı́a Rosario Hernándo, Ana Belén
Lardies (Benito Menni CASM, Sant Boi; Unidad Polivalente de Salud
Mental de Hospitalet, ĹHospitalet 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 hospital-
and 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. The burden of schizophrenia on caregivers: a review.
Pharmacoeconomics 2008;26:149–62.
[5] Zarit SH, Reever KE, Bach-Peterson J. Relatives of the impaired elderly: corre-
lates and feelings of burden. Gerontologist 1980;20:649–55.
[6] Grad J, Sainsbury P. Mental illness and the family. Lancet 1963;9(1):544–7.
[7] Szmukler G. From family ‘‘burden’’ to caregiving. Psychiatr Bull 1996;20:
449–51.
[8] Perlick DA, Ra R, Kaczynski R, Swartz MS, Canive JM, Lieberman JA. Compo-
nents and correlates of family burden in schizophrenia. Psychiatr Serv
2006;57:1117–25.
[9] van Wijngaarden B, Schene AH, Koeter M, Becker T, Knapp M, Knudsen HC,
et al. People with schizophrenia in five countries: conceptual similarities and
intercultural differences in family caregiving. Schizophr Bull 2003;29:573–86.
[10] Magliano L, Fiorillo A, Fadden G, Gair F, Economou M, Kallert T, et al. Effec-
tiveness of a psychoeducational intervention for families of patients with
schizophrenia: preliminary results of a study funded by the European Com-
mission. World Psychiatry 2005;4(1):45–9.
[11] Sin J, Norman I. Psychoeducational interventions for family members of people
with schizophrenia: a mixed-method systematic review. J Clin Psychiatry
2013;74(12):1145–62.
[12] National Institute for Clinical Excellence. Schizophrenia: Core interventions in
the treatment and management of schizophrenia in primary and secondary
care (update version). London: National Collaborating Centre for Mental
Health; 2010.
[13] Baüml J, Froböse T, Kraemer S, Rentrop M, Pitschel-Walz G, Psychoeducation:.
a basic psychotherapeutic intervention for patients with schizophrenia and
their families. Schizophr Bull 2006;32(Suppl. 1):S1–9.
[14] Wisniewski SR, Belle SH, Coon DW, et al. The Resources for Enhancing
Alzheimer’s Caregiver Health (REACH): project design and baseline characte-
ristics. Psychol Aging 2003;18:375–84.
[15] van Wijngaarden B, Schene AH, Koeter M, Vázquez-Barquero JL, Knudsen HC,
Lasalvia A, et al. Caregiving in schizophrenia: development, internal consis-
tency and reliability of the Involvement Evaluation Questionnaire - European
version: EPSILON study 4. Br J Psychiatr 2000;(Suppl. 39):s21–7.
[16] Gonçalves-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 psycho-
educational 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, Pérez-Camo V, Pujol J, Agüera L, Martı́n 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] Gonçalves-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 schizophre-
nia: domains and distress. Schizophr Bull 1998;24:609–18.
[23] Gonçalves-Pereira M, van Wijngaarden B, Xavier M, Papoila AL, Caldas-de-
Almeida 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.
Psychol Med 1979;9:139–45.
[25] Radloff LS. The CES-D scale: a self-report depression scale for research in the
general population. Appl Psychol Measure 1977;1:385–401.
[26] Lobo A, Pérez-Echeverrı́a MJ, Artal J. Validity of the scaled version of the
General Health Questionnaire (GHQ-28) in a Spanish population. Psychol Med
1986;16:135–40.
[27] Pais-Ribeiro JL, Antunes S. Contribution to the study of adaptation of the
28 items General Health Questionnaire (GHQ 28) into Portuguese. Revista
Portuguesa de Psicossomatica 2003;5:37–45.
 M. Martı´n-Carrasco et al. / European Psychiatry 33 (2016) 9–17 17

[28] Pérez-Sola JS, Puigdemont V, Pérez-Blanco D, Figueres J, Alvarez ME. Estudio de Ana I. Domı́nguez-Panchón, MPsychol.
validación del Center for Epidemiologic Studies-Depression (CES-D) en tras- Affiliation: Aita Menni Hospital, Gipuzkoa, Spain. Psy-
tornos afectivos en población Española. Actas Luso Esp Neurol Psiquiatr Cien chiatric Research Institute.
Afin 1997;25:243–9. Ma Josefa Recio Foundation, Bilbao, Spain.
[29] Gonçalves B, Fagulha T. The Portuguese version of the Center for Epidemiologic Position: Clinical psychologist at Aita Menni Hospital in
Studies Depression Scale (CES-D). Eur J Psychol Assess 2004;20: Mondragón (Basque Country). Associate Professor at
339–48. Deusto University.
[30] Blockrand: randomization for block random clinical trials [Internet]. CRAN. Research interests: Psychometric assessment of care-
Rproject.org; 2013 [http://CRAN.Rproject.org/package=blockrand, cited giver burden and development of new psychoeducatio-
2013 Mar 25]. nal program interventions.
[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 M. Gonçalves-Pereira, MD, PhD.
qualitative review. Aust N Z J Psychiatry 2012;47(3):222–34. Affiliation: Clı́nica Psiquiátrica de S. José (Sisters Hospi-
[34] Chien W-T, Chan S, Thompson DR. Effects of a mutual support group for tallers), Lisboa, Portugal. CEDOC, NOVA Medical School,
families of Chinese people with schizophrenia: 18-month follow-up. Br J Faculdade de Ciências Médicas, Universidade NOVA de
Psychiatry 2006;189:41–9. Lisboa, Lisboa, Portugal.
[35] Magliano L, Fiorillo A, Malangone C, De Rosa C, Maj M. Patient functioning and Position: Professor of Medical Psychology at NOVA
family burden in a controlled, real-world trial of family psychoeducation for Medical School (Faculdade de Ciências Médicas, Univer-
schizophrenia. Psychiatr Serv 2006;57:1784–91. sidade Nova de Lisboa).
[36] Chien W-T, Wong K-F. A family psychoeducation group program for Chinese Research interests: Geriatric psychiatry and family
people with schizophrenia in Hong Kong. Psychiatr Serv 2007;58:1003–6. interventions.
[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). Eduardo González-Fraile, MPsychol, PhD.
[39] Yesufu-Udechuku A, Harrison B, Mayo-Wilson E, Young N, Woodhams P, Affiliation: Psychiatric Research Institute.
Shiers D, et al. Interventions to improve the experience of caring for people Ma Josefa Recio Foundation, Bilbao, Spain. Associated
with severe mental illness: systematic review and meta-analysis. Br J Psychi- Professor at International University of La Rioja (UNIR).
atry 2015;206(4):268–74. Position: PhD Psychologist.
[40] Kuipers E, Yesufu-Udechuku A, Taylor C, Kendall T. Management of psychosis Research interests: Psychoeducational interventions,
and schizophrenia in adults: summary of updated NICE guidance. Br Med J informal caregiver, statistical methods, meta-analyses
348:g1173. http://dx.doi.org/10.1136/bmj.g1173. and risk of bias.

Manuel Martin-Carrasco, MD PhD.

Affiliation: Psychiatric Research Institute.
Ma Josefa Recio Foundation, Bilbao, Spain. Paula Muñoz-Hermoso, BPsychol.
Position: Director of the Psychiatric Research Institute Affiliation: Clı́nica Psiquiatrica Padre Menni, Pamplona,
(Maria Josefa Recio Foundation, Bilbao). Associate Pro- Spain.
fessor of the Faculty of Medicine of the University of Position: Clinical psychologist at Clı́nica Psiquiatrica
Navarra (Pamplona, Spain). Padre Menni in Pamplona (Spain).
Research interests: Care of people with dementia and Research interests: Assessment and intervention of bur-
their relatives, severe mental illness, and psychometry. den in caregivers. Mental health and family interven-
tions.

Paola Fernández-Catalina, MPsychol.

Affiliation: Psychosocial Rehabilitación Program of Sis-
ters Hospitalliers, Madrid, Spain.
Position: Director of residential and out-patient mental
health services in Madrid.
Research interests: Psychotherapy interventions, psy-
chosocial rehabilitation of patients with mental disease
and with family intervention.
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 pharmacolog-
ical and non-pharmacological interventions on mental
health problems, assessment of outcomes with patient-
related-outcomes, risk of bias, handling of likely publi-
cation biases, systematic reviews and meta-analysis.