Psychiatry Research 287 (2020) 112914

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Psychiatry Research
journal homepage: www.elsevier.com/locate/psychres

Short communication

A randomized controlled trial of social skills training for patients with T

treatment-resistant schizophrenia with predominantly negative symptoms
⁎
Monica Kayoa,¥, , Silvia Scemesa,¥, Mariangela Gentil Savoiaa, Alice Bichuettea,
Ana Claudia Abreua, Emily Pereira da Silvaa, Patricia Bariaa, Victoria Piovaccaria,
Beatriz Petrecheb, Rodrigo Affonseca Bressanb, Ary Gadelhab, Helio Elkisa
a
Departamento e Instituto de Psiquiatria, Hospital das Clínicas (HCFMUSP), Faculdade de Medicina, Universidade de São Paulo, Rua Dr. Ovidio Pires de Campos 785, 3rd
floor, São Paulo, SP 05403-010, Brazil
b
Department of Psychiatry, Universidade Federal de São Paulo, SP, Brazil

A R T I C LE I N FO A B S T R A C T

Keywords: We conducted a randomized controlled trial to assess the effectiveness of social skills training (SST) in improving
Behavior therapy negative symptoms in patients with treatment-resistant schizophrenia with predominantly negative symptoms.
Social functioning Patients were randomized to receive SST (n = 29) or to a control group (n = 33), in a 20-week program with
Psychosocial therapy weekly group sessions. Patients were assessed at baseline, post-treatment (20 weeks) and 6-month follow-up
with the Positive and Negative Syndrome Scale. There was no significant improvement in the negative symptoms
in either group, at any timepoint. Caution is warranted to interpret the results due to small sample size.

1. Introduction
Social skills training (SST) has been shown to be more efficacious
for negative symptoms in patients with schizophrenia than treatment as
usual (Turner et al., 2018).
However, to the best of our knowledge, there are no studies which
have investigated the efficacy of SST in patients with treatment-re-
sistant schizophrenia (TRS), especially those with predominantly ne-
gative symptoms, a condition which is highly prevalent and has a worse
outcome (Haro et al., 2018).
(Elkis and Buckley, 2016; Howes et al., 2017) and current clozapine use
for at least six months (Lally et al., 2016). They were also required to
score 16 or more on the negative subscale of the Positive and Negative
Syndrome Scale (PANSS) (Kay et al., 1987).
Exclusion criteria were having less than five years of schooling, a
psychiatric hospitalization in the last three months, a history of sub-
stance abuse or dependence, traumatic brain injury or intellectual dis-
ability as a primary disorder.
2.2. Study design

2. Methods This is a randomized, controlled, assessor-blind trial with two arms:

2.1. Participants
Patients with a diagnosis of schizophrenia based on DSM-IV-TR
criteria (American Psychiatric Association, 2000) were included. They
were aged between 18 and 60 years and were outpatients of the Schi-
zophrenia Research Program at the Instituto de Psiquiatria at Uni-
versidade de São Paulo (PROJESQ) or the Schizophrenia Program at the
Universidade Federal de São Paulo (PROESQ).
TRS was defined as persistence of psychotic symptoms after at least
two adequate trials with two different antipsychotics at effective doses
social skills training (SST) and a control group (CG).
The study was approved by the Institutional Review Boards of the
University of São Paulo General Hospital (Protocol no 0761/08) and
UNIFESP (CEP 1976/10). All participants gave written informed con-
sent. The trial was registered at ClinicalTrials.gov (NCT00791882) and
was conducted following the recommendations of the latest version of
the Declaration of Helsinki (World Medical Association, 2013). The
study spanned from February 2010 to February 2012.

⁎
Corresponding author.
E-mail addresses: monica.kayo@gmail.com (M. Kayo), helkis@usp.br (H. Elkis).
¥
Both authors contributed equally to this work.

https://doi.org/10.1016/j.psychres.2020.112914
Received 21 January 2020; Received in revised form 9 March 2020; Accepted 10 March 2020
0165-1781/ © 2020 Published by Elsevier B.V.
M. Kayo, et al. Psychiatry Research 287 (2020) 112914

2.3. Procedures
Patients attended 20 sessions over 20 weeks. Each session lasted
60 min and included six to nine participants. The same psychotherapist
led the SST sessions at the two sites. The sessions followed a manual
based on the method proposed by Bellack (Bellack et al., 2004).
The SST sessions consisted of relaxation exercises, homework re-
view, role-playing activities, feedback from the patients and homework
assignment. Before leaving, the patients were asked to identify situa-
tions in their lives in which they could practice their homework.
Sessions 18 and 19 were dedicated to goal setting.
The CG was conducted by nurse specialists in mental health and had
the same duration and number of participants per session as the SST.
The sessions included reading about the social skills practiced in the
SST group, but no role-playing activities, homework or goal setting.
Control group therapists were instructed not to give the patients di-
rections, but to listen and redirect questions to the group.
Participants were assessed at baseline, after 20 weeks and after six
months, using the PANSS (Kay et al., 1987), the Clinical Global Im-
pression (CGI) (Guy, 1976) and the Social Skills Inventory (SSI)
(Del Prette and Dell Prette, 2013).
The SSI is a 38-item, self-reported questionnaire. Each item de-
scribes an interactive social situation and a possible reaction to it.
Subjects are asked to estimate how often they react to that specific si-
tuation. Scores range from zero (never or rarely) to four (always or
almost always). Some items have a negative meaning, i.e., the higher
the score, the lower the skill. In those cases, the score is inverted. Based
on factor analysis, the 38 items of the SSI are clustered into 5 factors (F)
(Del Prette and Dell Prette, 2013). A computer program generated the
SSI scores.
2.4. Outcomes
The primary outcome was the change in PANSS negative subscale
score between pretreatment and the follow-up assessments at 20-weeks
and six-months.
Package for Social Science (SPSS) version 25 and the Comprehensive
Metanalysis program version 2.0 were used for calculations.
3. Results
3.1. Sample
Seventy-one patients were assessed for eligibility with 62 rando-
mized to the SST group (N = 29) or control group (CG, N = 33).
Twenty-eight patients in the SST group and 18 in the CG completed
the intervention phase, and 24 in the SST group and 16 in CG com-
pleted the 6-month follow-up. Dropouts were not assessed.
3.2. Baseline characteristics
Subjects were predominantly male (70.9%) and single (88.7%).
There were no differences between groups regarding demographic
variables such as ethnicity, age, duration of illness (mean 16.3 years in
both), age of onset, number of previous hospitalizations, or years of
schooling. According to the CGI, patients could be considered moder-
ately ill, either in the SST group (mean of 4.10, SD 0.78) or the CG
(mean 4.34, SD 0.90). In terms of total PANSS score, patients were
considered also moderately ill, with a mean total PANSS of 71.90
(10.83) in SST group and 70.4 (13.8) in the CG (Leucht et al., 2005).
There was a predominance of negative symptoms (mean 25.5 [4.6] in
SST group and 25.13 [6.34] in CG) over positive symptoms (mean 14.8
[5.1] and 25.13 [6.34] in SST and CG, respectively). All patients were
taking clozapine, with doses ranging from 300 to 850 mg, and remained
stable during the study. Patients in the SST group were receiving sig-
nificantly higher daily doses of clozapine (mean 606.25 mg) than the
CG (mean 530.30 mg) (p = 0.03). The IQ in both groups was lower
than those observed in the general population (mean 78.00 [12.56] in
SST group and 75.40 [13.30] in CG), and in people with schizophrenia
(Fioravanti et al., 2012).
3.3. Comparison between groups at different timepoints

2.5. Statistical analysis 3.3.1. Mixed model analysis

Baseline patient characteristics were compared between groups
using Pearson's chi-square and Student's t-tests. Between-group differ-
ences were compared longitudinally using linear mixed models at
baseline, post-treatment and follow-up. Cohen's d was calculated as
follows: mean of the social skill training (SST) group minus mean of the
control group (CG) divided by the pooled standard deviation.and was
interpreted in the usual manner (0.2 indicates small effect size; 0.4–0.6
moderate effect and values higher than 0.8 a large effect size)
(Cohen, 1988). The level of significance was 5%. The Statistical
A longitudinal linear mixed model was used to compare outcome
variables at the three timepoints. No interactions were found between
any factors. Clozapine doses and IQ were entered as covariates in the
linear analysis
3.3.2. Effect size analysis
No improvement was observed in the primary outcome. The only
symptom that improved significantly, achieving a moderate effect size,
was control of aggressiveness (item F5). This effect was sustained long
term (Table 1).

Table 1
Effect sizes at baseline, post-treatment and follow-up for the Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression (CGI) and Social Skills
Inventory (SSI) and its factors (F1 to F5).
Baseline Post-Treatment Follow- up

d CI 95% d CI 95% d CI 95%

PANSS Positive 0.268 −0.245 0.781 0.275 −0.334 0.883 0.208 −0.457 0.872
PANSS Negative 0.064 −0.447 0.575 0.339 −0.271 0.949 0.327 −0.340 0.994
PANSS General 0.016 −0.495 0.527 0.244 −0.363 0.852 0.250 −0.415 0.914
PANSS Total 0.119 −0.392 0.631 0.349 −0.261 0.959 0.183 −0.481 0.846
CGI 0.285 −0.228 0.799 0.222 −0.406 0.850 0.087 −0.582 0.755
SSI Total 0.264 −0.253 0.781 0.176 −0.403 0.755 0.041 −0.585 0.667
SSI F1 0.372 −0.148 0.892 0.181 −0.398 0.760 0.158 −0.470 0.785
SSI F2 0.235 −0.282 0.752 0.245 −0.335 0.825 0.188 −0.439 0.816
SSI F3 0.037 −0.478 0.552 0.105 −0.473 0.683 0.216 −0.412 0.844
SSI F4 0.030 −0.485 0.545 0.189 −0.390 0.768 0.042 −0.584 0.668
SSI F5 0.112 −0.403 0.628 0.445 −0.140 1.030 0.682 0.037 1.327

2
M. Kayo, et al.
4. Discussion
The present study showed no greater efficacy of SST, as compar-
edwith a neutral activity, for treatment of negative symptoms in pa-
tients with TRS with predominantly negative symptoms.
Our sample had a high mean negative score of 25.5 (SST) and 25.13
(CG) and can be classified as “TRS- negative symptom domain”, with at
least two negative symptoms at moderate or greater severity, or at least
one symptom with a severe rating (Howes et al., 2017).
Despite being used on patients with mood disorders (Castanho de
Almeida Rocca et al., 2008), the SSI was originally conceived to eval-
uate social skills in a normal population (Del Prette and Dell
Prette, 2013; Scemes et al., 2016) and is not yet validated for schizo-
phrenia.
The importance of complementing the clinic-based SST sessions
with real-life practice (Glynn et al., 2002), as well as involving in-
digenous supporters (Tauber et al., 2000), is well known. Although such
features were not contemplated in our study, the homework assignment
and role-playing activities based on real-life situations suggested by the
participants tried to mitigate this limitation.
Our study has several further limitations: small sample size, a higher
dropout rate in the control group, as well as lack of monitoring of
treatment adherence and clozapine plasma level dosing (Howes et al.,
2017).
Lastly, the lack of indigenous supporters or monitored real-life
practice possibly resulted in suboptimal implementation of the SST.
Our findings suggest that SST is not efficacious for improvement of
negative symptoms in patients with TRS with predominantly negative
symptoms, but caution is required to interpret these results due to the
study's limitations.
Funding
This study received financial support from the Fundação de Amparo
à Pesquisa do Estado de São Paulo (FAPESP, São Paulo Research
Foundation grant 2009/ 13934–6) and from the Schizophrenia Program
of the Instituto de Psiquiatria at Universidade São Paulo (PROJESQ) .
CRediT authorship contribution statement
Monica Kayo: Investigation, Formal analysis, Writing - original
draft, Writing - review & editing. Silvia Scemes: Conceptualization,
Investigation, Methodology. Mariangela Gentil Savoia: Supervision.
Alice Bichuette: Investigation, Data curation, Writing - review &
editing. Ana Claudia Abreu: Investigation, Data curation, Writing -
review & editing. Emily Pereira da Silva: Investigation, Data curation,
Writing - review & editing. Patricia Baria: Investigation, Data curation,
Writing - review & editing. Victoria Piovaccari: Investigation, Data
curation, Writing - review & editing. Beatriz Petreche: Investigation,
Data curation, Writing - review & editing. Rodrigo Affonseca Bressan:
Supervision, Writing - review & editing. Ary Gadelha: Supervision,
Writing - review & editing. Helio Elkis: Conceptualization, Formal
analysis, Methodology, Supervision, Writing - review & editing.
Declaration of Competing Interest
Helio Elkis has received research grants from FAPESP, Janssen, and
Roche and honoraria for travel support, advisory board participation, or
speaking from Aché, Daiichi-Sankyo, Cristalia, Janssen, Roche and
Teva. Ary Gadelha was speaker of Daiichi-Sankyo, Janssen, Aché,
Cristália and Lundbeck and member of advisory boards of Daiichi-
Sankyo and Janssen. Rodrigo Affonseca Bressan reports grants, personal
Psychiatry Research 287 (2020) 112914
fees and non-financial support from Janssen, and personal fees from
Pfizer and Aché outside the scope of this study. Monica Kayo has acted
as a consultant for pharmaceutical companies in other therapeutic
areas, non-related to this study: Bayer, Gilead, Moksha 8, Takeda, Teva,
Ultragenyx, União Química and Zambon. The other authors declared
that did not have any potential conflicts of interest to declare.
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