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Wk 9 Assignment 1

Assignment 1: “Captain of the Ship” Project – Schizophrenia Spectrum and Other Psychotic Disorders

In earlier weeks, you were introduced to the concept of the “captain of the ship.” In this Assignment, you become the “captain of the ship” once again as you provide treatment recommendations and identify medical management, community support resources, and follow-up plans for a client with a schizophrenia spectrum/other psychotic disorder.

To prepare for this Assignment:

Select an adult or older adult client with a schizophrenia spectrum and other psychotic disorder you have seen in your practicum.

In 3–4 pages, write a treatment plan for your client in which you do the following:

Describe the HPI and clinical impression for the client.
Recommend psychopharmacologic treatments and describe specific and therapeutic endpoints for your psychopharmacologic agent. (This should relate to HPI and clinical impression.)
Recommend psychotherapy choices (individual, family, and group) and specific therapeutic endpoints for your choices.
Identify medical management needs, including primary care needs, specific to this client.
Identify community support resources (housing, socioeconomic needs, etc.) and community agencies that are available to assist the client.
Recommend a plan for follow-up intensity and frequency and collaboration with other providers.
LINK:

Randomized Clinical Trial of Cognitive Behavioral Social Skills Training
for Schizophrenia: Improvement in Functioning and Experiential

Negative Symptom

Eric Granholm and Jason Holden
Veterans Affairs San Diego Healthcare System and University

of California, San Diego

Peter C. Link
Veterans Affairs San Diego Healthcare System

John R. McQuai

Veterans Affairs San Francisco Medical Center and University of California, San Francisco

Objective: Identifying treatments to improve functioning and reduce negative symptoms in consumers
with schizophrenia is of high public health significance. Method: In this randomized clinical trial,
participants with schizophrenia or schizoaffective disorder (N � 149) were randomly assigned to
cognitive behavioral social skills training (CBSST) or an active goal-focused supportive contact (GFSC)
control condition. CBSST combined cognitive behavior therapy with social skills training and problem-
solving training to improve functioning and negative symptoms. GFSC was weekly supportive group
therapy focused on setting and achieving functioning goals. Blind raters assessed functioning (primary
outcome: Independent Living Skills Survey [ILSS]), CBSST skill knowledge, positive and negative
symptoms, depression, and defeatist performance attitudes. Results: In mixed-effects regression models
in intent-to-treat analyses, CBSST skill knowledge, functioning, amotivation/asociality negative symp-
toms, and defeatist performance attitudes improved significantly more in CBSST relative to GFSC. In
both treatment groups, comparable improvements were also found for positive symptoms and a
performance-based measure of social competence. Conclusions: The results suggest CBSST is an
effective treatment to improve functioning and experiential negative symptoms in consumers with
schizophrenia, and both CBSST and supportive group therapy actively focused on setting and achieving
functioning goals can improve social competence and reduce positive symptoms.

Keywords: cognitive behavioral social skills training, schizophrenia, negative symptoms, functioning,
group therapy

Schizophrenia affects approximately 1% of the world popu-
lation and leads to profound disability in quality of life and
everyday functioning, including impairment in independent liv-

ing, education, working, and socializing (Harvey et al., 2012;
Harvey & Strassnig, 2012). Negative symptoms of schizophre-
nia account for much of the poor functional outcome in schizo-
phrenia and represent an unmet treatment need in a large
proportion of patients (Kirkpatrick, Fenton, Carpenter, &
Marder, 2006). More than 20% of consumers with schizophre-
nia are estimated to have clinically relevant persistent negative
symptoms in need of treatment (Buchanan, 2007). Identifying
treatments to reduce negative symptoms and improve function-
ing in consumers with schizophrenia is of high public health
significance.

Modest improvements in functioning and negative symptoms in
consumers with schizophrenia have been found in clinical trials of
cognitive behavior therapy (CBT) and social skills training (SST). In
a meta-analysis (Wykes, Steel, Everitt, & Tarrier, 2008) of 33 clinical
trials of CBT for schizophrenia, the effect size for functioning (d �
0.38) and negative symptom (d � 0.44) outcomes were comparable to
the effect size for positive symptoms (d � 0.37). It should be noted
that these treatment effects were attenuated in trials with higher design
quality (Wykes et al., 2008). Numerous clinical trials of SST have
also found medium effects for community functioning (d � 0.52) and
modest effects for negative symptoms (d � 0.40; Benton & Schroe-
der, 1990; Kurtz & Mueser, 2008).

This article was published Online First June 9, 2014.
Eric Granholm and Jason Holden, Veterans Affairs San Diego Health-

care System and Department of Psychiatry, University of California, San
Diego; Peter C. Link, Veterans Affairs San Diego Healthcare System; John
R. McQuaid, Veterans Affairs San Francisco Medical Center and Depart-
ment of Psychiatry, University of California, San Francisco.

Research reported in this publication was supported by the Department
of Veterans Affairs, Veterans Health Administration, Office of Research
and Development, Rehabilitation Research and Development Service and
by the National Institute of Mental Health of the National Institutes of
Health (Grants RO1MH071410 and P30MH66248). The content is solely
the responsibility of the authors and does not necessarily represent the
official views of the National Institutes of Health. We thank the partici-
pants who volunteered for this study (Trial Registry: ClinicalTrials.gov
#NCT 00338975).

Correspondence concerning this article should be addressed to Eric
Granholm, Veterans Administration San Diego Healthcare System (116B),
3350 La Jolla Village Drive, San Diego, CA 92161. E-mail: egranholm@
ucsd.edu

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Journal of Consulting and Clinical Psychology © 2014 American Psychological Association
2014, Vol. 82, No. 6,

1173

–1185 0022-006X/14/$12.00 http://dx.doi.org/10.1037/a0037098

1173

http://ClinicalTrials.gov

mailto:egranholm@ucsd.edu

http://dx.doi.org/10.1037/a0037098

Given the potential efficacy of CBT and SST for schizophre-
nia, a group therapy intervention was developed combining
these two treatments called cognitive behavioral social skills
training (CBSST; Granholm, McQuaid, Auslander, & McClure,
2004; McQuaid et al., 2000). CBSST is a recovery-oriented psy-
chosocial rehabilitation intervention that targets functioning and
negative symptoms in schizophrenia. By adding CBT to SST,
therapists can use SST to train new skills, and thoughts that
interfere with skilled performance in the real world (e.g., low
self-efficacy, defeatist performance attitudes) can be addressed in
cognitive therapy. Several researchers have found that defeatist
attitudes (e.g., “Why try—I always fail”) are associated with poor
functioning and negative symptoms, especially experiential (amo-
tivation/asociality) negative symptoms (Grant & Beck, 2009;
Green, Hellemann, Horan, Lee, & Wynn, 2012; Horan et al.,
2010). Self-efficacy beliefs are central to motivation to engage in
goal-directed activities and willingness to continue to expend
effort when tasks become more difficult (Avery, Startup, &
Calabria, 2009; Grant & Beck, 2009), and self-efficacy is related
to negative symptoms and social functioning in consumers with
schizophrenia (Cardenas et al., 2013; Hill & Startup, 2013; Yanos,
Primavera, & Knight, 2001). Rector, Beck, and Stolar (2005)
proposed that dysfunctional attitudes about the personal costs of
applying energy toward goal-directed tasks could, as a defense
against anticipated failure and negative evaluations by others, lead
to passivity and avoidance of activities that require effort. By
addressing self-efficacy and defeatist attitudes, therefore, consum-
ers may increase motivation for social engagement and successful
skill performance in the community. Consistent with this hypoth-
esis, Grant, Huh, Perivoliotis, Stolar, and Beck (2012) found that
a CBT intervention designed in part to address defeatist perfor-
mance attitudes in schizophrenia reduced avolition–apathy nega-
tive symptoms and improved functioning (as measured by the
Global Assessment of Functioning Scale; American Psychiatric
Association, 2000) to a greater extent than standard treatment.
Investigators in another open CBT trial also found significant
improvement in both dysfunctional attitudes and negative symp-
toms in a sample of consumers with psychotic disorders who had
not been taking antipsychotic medication (Morrison et al., 2012).

However, some studies have not found a direct relationship
between self-efficacy and functioning in schizophrenia. For exam-
ple, the relationship between self-efficacy and functional outcome
has been found to be mediated or moderated by other factors, such
as negative symptoms (Pratt, Mueser, Smith, & Lu, 2005) and
illness insight (Kurtz, Olfson, & Rose, 2013). In addition, the SST
components of CBSST involve observational learning, practice of
specific skills, reinforcement, and corrective feedback. Change in
functioning in CBSST may stem from behavioral activation of
practiced skills, rather than change in defeatist attitudes and self-
efficacy.

In a prior CBSST clinical trial (Granholm et al., 2005; Gran-
holm et al., 2007), 76 middle-aged and older consumers (M age �
54 years) with schizophrenia or schizoaffective disorder were
randomized to treatment as usual (TAU) or CBSST. Participants in
CBSST showed significantly greater CBSST skill mastery and
functioning relative to participants in TAU, and these improve-
ments were maintained at 1-year follow-up (Granholm et al.,
2007). This trial showed that CBSST was more effective than TAU
but did not control for nonspecific therapist contact. In a subse-

quent trial (Granholm, Holden, Link, McQuaid, & Jeste, 2013),
CBSST was compared with an active psychosocial control condi-
tion, goal-focused supportive contact (GFSC), in 64 middle-aged
and older consumers (M age � 55 years) with schizophrenia or
schizoaffective disorder. GFSC is an enhanced supportive contact
intervention focused on helping consumers set and work toward
functioning goals in a support group that provides the same
amount of therapist and group contact as CBSST. Participants in
CBSST showed significantly greater CBSST skill mastery and
functioning relative to participants in the active GFSC control
condition. Significant comparable reductions in experiential (amo-
tivation/asociality) negative symptoms were also found in both
CBSST and GFSC. Defeatist attitudes did not change significantly
in treatment, but greater improvement in defeatist attitudes was
associated with greater improvement in functioning in CBSST.

Both of these prior CBSST trials were focused on middle-aged
and older consumers (age �50) who had been ill for three decades
on average. The efficacy of CBSST, therefore, has not been tested
in a nongeriatric, more representative sample. The present study
was a randomized clinical trial comparing CBSST with GFSC in
consumers with schizophrenia or schizoaffective disorder who
were ages 18 – 65. Longer duration of illness and older age have
been associated with poorer outcome in CBT for psychosis (Drury,
Birchwood, Cochrane, & Macmillan, 1996; Morrison et al., 2004;
2012). Similarly, in the meta-analysis by Kurtz and Mueser (2008),
older samples showed less improvement on performance-based
functional capacity measures, and a trend association (p � .065)
was found between older age and less improvement in negative
symptoms. Lower self-efficacy has also been found to be corre-
lated with longer duration of illness and greater number of hospi-
talizations in consumers with schizophrenia (McDermott, 1995).
Therefore, defeatist attitudes and experiential negative symptoms
may be more likely to improve in the nongeriatric sample in the
present trial. It was hypothesized that functional outcome, negative
symptoms, and defeatist attitudes would improve to a significantly
greater extent in CBSST than in GFSC.

Method

Design

All study procedures were approved by the institutional review
board of the University of California, San Diego, and Veterans
Affairs San Diego Healthcare System. After providing informed
consent and completing baseline assessments, eligible participants
were randomly assigned to one of two treatment conditions:
CBSST or GFSC. An independent statistician allocated partici-
pants to treatments according to a computer-generated randomiza-
tion list. The study coordinator, who was not involved in any
assessments or treatments, contacted the statistician to ascertain
treatment assignment. Participants were then treated for 9 months
and followed for 12 months after treatment, with baseline, 4.5-
month (mid-treatment), 9-month (end-of-treatment), 15-month
(mid-follow-up), and 21-month (1 year posttreatment) follow-up
assessments. Assessors were blinded to treatment allocation, and
therapists and the study coordinator, who were aware of treatment
allocation, did not complete any outcome assessments. Treatment
took place in a separate building from that used for assessments,
and participants were counseled by the study coordinator not to

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1174 GRANHOLM, HOLDEN, LINK, AND MCQUAID

reveal any information about their treatment groups or the content
of therapy to the assessors before each assessment visit. Partici-
pants received compensation ($50) for completing assessment
visits but not for attending treatment sessions. Transportation was
provided to assessment visits, if necessary, but not to therapy
sessions.

Participants

Participants were recruited through flyers and brochures posted
and handed out by a study recruiter at a variety of community
settings throughout San Diego County, including residential facil-
ities (board & care/assisted living homes), clubhouses/drop-in
settings, outpatient psychiatry clinics, and other treatment settings
in the University of California San Diego Health System, San
Diego County Mental Health System, and Veterans Affairs San
Diego Healthcare System. Inclusion criteria were (a) age � 18
years, (b) diagnosis of schizophrenia (N � 117) or schizoaffective
disorder (N � 32) based on the Structured Clinical Interview for
the DSM–IV (SCID; First, Spitzer, Gibbon, & Williams, 1996) and
available medical record review, and (c) capacity to provide in-
formed consent. At baseline, all but four consumers reported
taking antipsychotic medications, 72 also reported antidepressant
medications, and 41 reported mood stabilizers. The minimal ex-
clusion criteria consisted of (a) prior exposure to CBT or SST
during the previous 5 years, and (b) level of care required at
baseline that would interfere with participation in outpatient ther-
apy groups or assessments (e.g., disabling medical problems, or
current hospitalization for medical, psychiatric, or substance abuse
problems).

Interventions

Treatment conditions were matched for amount of therapist
contact and the same therapists delivered both interventions. Par-
ticipants in both treatment conditions were offered a total of 36
weekly group therapy sessions (9 months) during a treatment
phase, which was followed by monthly booster sessions during the
follow-up period (12 sessions). In both conditions, group therapy
sessions were 2 hr, with a lunch or snack break mid-way. Group
sessions were facilitated by two masters- or doctoral-level thera-
pists with at least 2 years of CBT experience. Two of us (E.G. and
J.M.) provided training and weekly supervision, including review
of session videotapes. Participants in both treatment groups
(CBSST and GFSC) were also offered individual 30 –50 min
goal-setting sessions with one of their two group therapists at
baseline and every 3 months thereafter.

Individual goal-setting sessions. In these individual sessions,
two recovery-oriented (living, learning, working, or socializing)
functioning goals were set, progress toward goal achievement was
tracked, and therapists provided supportive encouragement. Func-
tional goal achievement was the primary focus of both group
interventions (CBSST and GFSC). These individual sessions were
added to both treatment arms to allow additional time for person-
alized goal setting and breaking long-term goals down into short-
term goals and specific, attainable goal steps.

Cognitive behavioral social skills training (CBSST).
CBSST (Granholm et al., 2004; 2005; 2007; 2013; Granholm,
McQuaid, McClure, Pedrelli, & Jeste, 2002; McQuaid et al.,

2000), as provided in the current study, was a group therapy
intervention delivered in three, 6-session modules that were in-
tended to be completed twice, for a total of 36 weekly sessions (9
months) during the treatment phase. CBSST booster sessions did
not follow a manualized sequence of skill training as was followed
in the treatment phase. Rather, therapists guided participants in
selecting any of the skills trained during the treatment phase to
address concerns and functioning goals. The CBSST treatment
manual included a participant workbook that described the skills
and included homework assignment forms.

The three CBSST modules were the Cognitive Skills Module,
Social Skills Module, and Problem-Solving Skills Module. Train-
ing thought-challenging skills was the exclusive focus of the
Cognitive Skills Module, but thought challenging was also used
throughout the other two modules (e.g., to address defeatist atti-
tudes and other thoughts that could be obstacles to skill learning or
goal achievement). Cognitive interventions were not strongly for-
mulation or schema based; rather, cognitive therapy components
focused on the practice of simplified thought-challenging skills
and behavioral experiment activities. Thought-challenging skills
were used to address symptoms and challenge defeatist beliefs that
interfere with functioning behaviors, including expectancies (“It
won’t be fun”), self-efficacy beliefs (“I always fail”), and anom-
alous/delusional beliefs (“Spirits will harm me”). Group members
were introduced to the general concepts of CBT, including the
relationship among thoughts, actions and feelings (generic cogni-
tive model), automatic thoughts, thought challenging through be-
havioral experiments and examining evidence for beliefs, and
mistakes in thinking. The primary thought-challenging skill trained
was the “3C’s: Catch It, Check It, Change It” (“It” is an unhelpful
thought).

The primary goal of the Social Skills Module was to improve
communication skills through behavioral role plays, including
active listening, expressing positive and negative feelings, and
making positive requests. Important role plays included assertive
interactions with coworkers, friends, and family; making new
friends; and effectively interacting with case managers, doctors,
and other support persons.

Basic problem-solving skills were trained in the Problem-
Solving Skills Module using the acronym, SCALE: Specify the
problem, Consider all possible solutions, Assess the best solution,
Lay out a plan, and Execute and Evaluate the outcome. The focus
was on developing specific, feasible plans to solve real-world
problems, including scheduling pleasant activities, improving liv-
ing situations, handling finances, using public transportation, find-
ing a volunteer or paid job, and enrolling in classes.

Goal-focused supportive contact (GFSC). The GFSC inter-
vention was an enhanced supportive contact control condition with
a primary focus, like CBSST, on setting and achieving functioning
goals (e.g., living, learning, working, and socializing). Sessions
were semistructured and consisted of check-in about distress and
potential crisis management, followed by a flexible group discus-
sion about setting and working toward functioning goals. Sessions
typically included components of psychoeducation, empathy, and
nondirective reinforcement of health, coping, and symptom man-
agement behaviors, which grew out of group discussions, with
minimal therapist guidance. Booster sessions employed the same
approach as that used in the treatment phase.

1175CBSST FOR SCHIZOPHRENIA

Treatment Fidelity

Twenty-four randomly selected sessions (12 from each group,
stratified by module for the CBSST group) were rated for fidelity
using the Cognitive Therapy Rating Scale for Psychosis (CTS–
Psy; Haddock et al., 2001) and the Social Skills Group Observa-
tion Checklist (SSGOC; Bellack, Mueser, Gingerich, & Agresta,
2004). Only six items related to role play practice were rated from
the SSGOC (established a rationale, discussed and modeled steps,
engaged client in a role play, provided positive feedback, provided
suggestions for improvement, and reinforced small steps in re-
peated role plays; all rated 0, for absent, or 1, for present), because
the remaining items overlapped with nonspecific therapist items
(e.g., understanding, interpersonal effectiveness) and session-
structure items (e.g., agenda setting, homework) that were also
rated on the CTS–Psy. The CTS–Psy total score was significantly
greater in CBSST (M � 40.4, SD � 4.0) relative to GFSC (M �
19.7, SD � 1.8), t(22) � 13.14, p � .001. The total CTS–Psy score
for CBSST, but not for GFSC, was above the cutoff for competent
CBT for psychosis (�30) used in previous clinical trials (e.g.,
Turkington, Kingdon, & Turner, 2002). CTS–Psy ratings of CBT-
specific skills were significantly greater for CBSST than for GFSC
(sum of Agenda, Feedback, Collaboration, Guided Discovery,
Focus on Key Cognitions, Choices of CBT Interventions, Quality
of Interventions, and Homework items: CBSST M � 28.4, SD �
3.9; GFSC M � 7.9, SD � 1.6; t(22) � 13.29, p � .001), whereas
ratings of nonspecific therapy skills did not differ significantly
between CBSST and GFSC (sum of Understanding and Interper-
sonal Effectiveness items: CBSST M � 11.94, SD � 0.2; GFSC
M � 11.86, SD � 0.4; t(22) � 0.65, p � .52). The mean rating on
the six SSGOC role play items was 4.0 (SD � 1.2) for the CBSST
Social Skills Module and 0.0 for the other CBSST modules and
GFSC. This is not surprising, given that role play practice is only
intended to be included in the CBSST Social Skills Module.
Therefore, the two interventions, which were delivered by the
same therapists, had similar nonspecific supportive therapy com-
ponents, but high-fidelity CBT and SST interventions were only
present in CBSST.

Outcome Measures

Independent Living Skills Survey (ILSS). The primary out-
come measure was self-reported functioning on the ILSS (Wallace,
Liberman, Tauber, & Wallace, 2000). The ILSS is a 51-item,
self-report measure that was administered in an interview format to
assess multiple domains of functioning (appearance and clothing,
personal hygiene, care of possessions and living space, food prep-
aration, health maintenance, transportation, money management,
leisure and recreational activities, job seeking, and job mainte-
nance). According to standard scoring procedures, items were
scored 0 (not performed), 1 (performed), or “not able to demon-
strate” (e.g., for food preparation items when meals were provided
by assisted living staff), and the average of available items was
computed for each domain (domain scores were not computed if
more than half the items were missing or scored “not able to
demonstrate”). Consistent with our prior study (Granholm et al.,
2005), a composite score was computed as the average of scores on
five relevant functional domains (appearance and clothing, per-
sonal hygiene, health maintenance, transportation, and leisure and
community activities; range � 0 –1). Other domain scores could

not be computed due to many “not able to demonstrate” item
scores for the majority of participants who were unemployed,
receiving disability income that was managed by others, and living
in board-and-care settings where cleaning and cooking services
were provided. The ILSS was administered at all assessment
points.

Comprehensive Module Test (CMT). The CMT was used as
a proximal measure of skills acquisition to assess knowledge of the
specific content in the three CBSST modules. The CMT was
included as an intervention check on whether consumers learned
the CBSST skills, not a test of whether the intervention improved
outcomes better than GFSC. The CMT was originally developed at
University of California, Los Angeles, for use with SST modules
(Liberman, 1994). Content questions (e.g., “What are the 3Cs?”)
and vignettes requiring appropriate use of skills were developed to
assess mastery of communication (max � 11), problem-solving
(max � 11) and thought-challenging (max � 11) skills. The CMT
total score (max � 33) was used in analyses. The CMT was
administered at all assessment points.

Maryland Assessment of Social Competence (MASC). The
MASC (Bellack & Meuser, 1993; Bellack, Sayers, Mueser, &
Bennett, 1994) was used as a performance-based measure of social
skill capacity. The MASC is a structured behavioral role play
assessment that measures the ability to resolve interpersonal prob-
lems through conversation scenarios (initiating a conversation;
assertive requests), during which the consumer interacts with a live
confederate who plays a role (e.g., boss) in a problem-oriented
situation (e.g., asking for a work shift change). The measure has
three parallel sets of scenarios for multiple administrations. Vid-
eotaped role plays are coded by blinded raters on dimensions of
verbal content, nonverbal communication behavior, and an overall
effectiveness score, which was the primary MASC variable. The
MASC was not administered at mid-treatment or mid-follow-up
assessments.

Psychosocial Rehabilitation Toolkit (PSR Toolkit). The
PSR Toolkit; described by Arns, Rogers, Cook, and Mowbray
(2001), was used to collect objective functional milestone infor-
mation on a consumer’s employment, educational activity, psychi-
atric hospitalizations, and residential situation. This measure does
not rely on self-report, because research staff obtain employment
status records (e.g., time cards; pay stubs), educational transcripts,
and hospital discharge summaries; visit residential settings to
determine level of services; and talk with psychiatrists, residential
staff, case managers, and/or family members to obtain objective
information. At each assessment point, milestone variables were
(a) unemployed (coded as 0) versus employed (any paid or unpaid
job or sheltered workshop coded as 1); (b) no education activities
(coded as 0) versus any educational engagement (coded as 1) and
any psychiatric hospitalization (coded as 1) versus none (coded as
0), and (c) assisted (coded as 0) versus unassisted living (coded as
1). The PSR Toolkit was not administered at mid-treatment or
mid-follow-up assessments.

Positive and Negative Syndrome Scale (PANSS), Scale for
the Assessment of Negative Symptoms (SANS), and Beck De-
pression Inventory–2nd edition (BDI–II). The PANSS (Kay,
Fiszbein, & Opler, 1987), SANS (Andreasen, 1982), and BDI–II
(Beck, Steer, & Brown, 1996) were administered to assess clinical
symptoms. Based on factor analytic studies of the SANS
(Blanchard & Cohen, 2006; Peralta & Cuesta, 1999; Sayers, Cur-

1176 GRANHOLM, HOLDEN, LINK, AND MCQUAID

ran, & Mueser, 1996), two negative symptom factors were derived:
Diminished Expression, defined as the average of Affective Flat-
tening and Alogia global ratings (Items 8 and 13); and Diminished
Motivation, defined as the average of Avolition–Apathy and
Anhedonia–Asociality global ratings (Items 17 and 22). All symp-
tom measures were administered at all assessment points.

Defeatist Performance Attitude Scale (DPAS). Finally,
DPAS is a 15-item self-report subscale derived from factor anal-
ysis of the commonly used Dysfunctional Attitude Scale (Form A;
Cane, Olinger, Gotlib, & Kuiper, 1986; Weissman, 1980; Weiss-
man & Beck, 1978). The DPAS indexes endorsement of defeatist
attitudes about one’s ability to perform goal-directed tasks (e.g.,
“If you cannot do something well, there is little point in doing it at
all”; “If I fail at my work, then I am a failure as a person”; “People
will probably think less of me if I make mistakes and fail”). Items
are rated on a 1–7 Likert scale and higher total scores (range �
15–105) indicate more severe defeatist performance attitudes.

Reliability. Assessors received training using videotape and
practice interviews and did not complete assessments until achiev-
ing at least .80 interrater reliability. Interrater reliability (interclass
correlation) was .88 for PANSS total, .87 for PANSS positive, .83
for SANS total, and .86 for the MASC effectiveness score.

Statistical Analyses

In intent-to-treat (ITT) analyses, all participants who completed
baseline assessments were randomized and included in the analy-
ses. Mixed-effects regression modeling (utilizing HLM Version
6.08; Raudenbush, Bryk, & Congdon, 2008) was used. Growth
curve models predicting each Level-1 outcome variable (ILSS
Composite, MASC Effectiveness, SANS Diminished Motivation,
SANS Diminished Expression, PANSS Positive, PANSS Total,
BDI–II Total) were estimated using time (in months centered at
baseline), as a Level-1 predictor and group (coded CBSST � 0.5,
GFSC � – 0.5), number of therapy sessions attended (centered at
the median), and the Group � Sessions interaction, as Level-2
predictors of both the slope and intercept parameters. Hierarchical
logistic models using a Bernoulli Level-1 sampling model and
logit link function were used for PSR ToolKit binary variables.
Effect sizes at end of treatment and 21-month follow-up were
estimated by computing the treatment group difference for HLM
model-predicted values for each outcome variable for hypothetical
participants with a median number of sessions attended and divid-
ing by the baseline assessment pooled standard deviation for the
outcome. Finally, chi-square tests were used to examine group
differences in rates of achievement of functioning milestones on
binary PSR ToolKit variables.

Results

Sample

The flow of participants through the 21-month protocol is
shown in Figure 1. Sixty-three percent (N � 94) of participants
were reassessed at mid-treatment, 54% (N � 81) at end of treat-
ment, 38% (N � 57) at mid-follow-up, and 38% (N � 57) at final
follow-up, and 70% (N � 104) of participants had more than one
assessment (median number of assessments � 3). The groups did
not differ significantly in dropout rates at any assessment point.

Dropouts at 21 months did not differ significantly from partici-
pants with a 21-month follow-up assessment on baseline ILSS,
t(146) � 1.28, p � .203; PANSS Positive Symptom Scale,
t(146) � 0.17, p � .863; SANS Diminished Motivation, t(145) �
0.29, p � .771; SANS Diminished Expression, t(145) � 0.76, p �
.446; MASC, t(135) � 0.82, p � .413; or DPAS, t(145) � 0.37,
p � .712 scores. The CBSST and GFSC treatment groups did not
differ significantly with regard to any demographic characteristic
(Table 1) or any outcome variable at baseline (Table 2).

Outcomes

Table 2 shows descriptive statistics for each outcome variable
for each treatment group at each assessment point, and results from
the mixed-effects regression models are presented in Table 3.
Statistically significant Group � Time interactions were found for
the primary functioning outcome (ILSS), as well as for SANS
Diminished Motivation, DPAS, and CMT, indicating significantly
greater improvements over time for functioning, experiential neg-
ative symptoms, defeatist attitudes, and CBSST skill knowledge in
CBSST relative to GFSC (see Figure 2). For these outcomes, effect
sizes for the difference between model-estimated means of the two
treatment groups at 21 months ranged from medium to very large
(SANS Diminished Motivation � .72; ILSS � 1.00; DPAS �
0.90; CMT � 1.40; Table 3). The effect of time, but not the
Group � Time interaction, was marginally significant for the
MASC and significant for the PANSS Positive Subscale, indicat-
ing marginally significant improvements in social competence and
significant improvement in positive symptoms over time, regard-
less of group membership (see Figure 3).

Given our hypothesis that duration of illness might impact
defeatist belief severity, duration of illness was included as a
covariate in the mixed-effects regression model for DPAS but was
not a significant predictor of the intercept (� � 0.09, t � 0.79, p �
.430, 95% confidence interval [CI] [– 0.14, 0.32]) or slope (� �
– 0.01, t � �1.38, p � .170, 95% CI [– 0.02, 0.00]). The number
of older patients was very small (N � 11 over age 55; N � 0 over
65) in this sample, however, so this may not be an adequate test of
the potential impact of duration of illness.

Objective Functioning Milestones

Hierarchical logistic regression models showed a statistically
significant Group � Time interaction for education (� � 0.18, t �
1.98, p � .05, odds ratio [OR] � 1.19, 95% CI [1.00, 1.42]),
indicating significantly greater engagement in educational activi-
ties over time in CBSST than in GFSC, but not for living situation
(� � – 0.01, t � �0.30, p � .764, OR � 0.99, 95% CI [0.90,
1.09]), employment (� � 0.01, t � 0.11, p � .915, OR � 1.01,
95% CI [0.91, 1.12]), or psychiatric hospitalizations (� � 0.04, t �
0.68, p � .499, OR � 1.04, 95% CI [0.94, 1.15]). A significantly
greater proportion of participants were engaged in educational
activities at end of treatment in CBSST relative to GFSC
(CBSST � 19%; GFSC � 4%; �2 � 4.56, p � .033), but the
proportion of participants living independently (CBSST � 33%;
GFSC � 24%; �2 � 0.78, p � .378), working in paid or volunteer
jobs (CBSST � 36%; GFSC � 22%; �2 � 1.90, p � .168), and
hospitalized (CBSST � 22%; GFSC � 27%; �2 � 0.21, df �1,
p � .645) did not differ significantly between the treatment

1177CBSST FOR SCHIZOPHRENIA

groups. Groups did not differ significantly at baseline on any of
these milestones.

Treatment Adherence
The treatment groups did not differ significantly with regard to the

mean number of sessions attended (36 possible) during the treatment
phase (CBSST M � 12.2, SD � 10.6, range � 0 –34; GFSC: M �
15.6, SD � 12.9, range � 0 –36), t(147) � 1.74, p � .083. Partici-
pants generally did not take advantage of booster sessions (64% did
not attend any of the 12 sessions), but groups did not differ signifi-

cantly with regard to the mean number of booster sessions attended
(CBSST M � 2.2, SD � 3.7, range � 0 –12; GFSC: M � 2.8, SD �
4.5, range � 0 –12), t(147) � 0.86, p � .392.

To examine the effects of treatment engagement and dose of
intervention, we included in all statistical models reported the number
of sessions attended (plus two-way interactions with group and time,
and the three-way interaction) as a predictor of outcome. All of these
effects involving number of sessions were nonsignificant except for
the effect of number of sessions attended on the CMT outcome (� �
0.05, t � 2.12, p � .036), and in model with ILSS as the outcome, the

Figure 1. Flow of consumers with schizophrenia through the 21-month randomized clinical trial comparing
cognitive behavioral social skills training (CBSST) with an active goal-focused supportive contact (GFSC)
control treatment. All participants who completed baseline assessments were randomized and included in
analyses. CBT � cognitive behavior therapy; SST � social skills training.

1178 GRANHOLM, HOLDEN, LINK, AND MCQUAID

Group � Number of Sessions � Time interaction was significant
(� � �0.0003, t � �3.80, p � .001). The correlation between
number of sessions attended and ILSS trajectory (slope across assess-
ment points) was significant for GFSC (r � .27, p � .046) but not for
CBSST (r � �.14, p � .356), with greater attendance associated with
greater improvement in functioning in GFSC but not in CBSST. In
addition, general hypothesis testing in HLM was used to compare
ILSS scores of participants with low attendance (eight sessions) and
high attendance (24 sessions). At 21 months, model-estimated ILSS
scores for participants in CBSST with low (.753) and high (.728)
session attendance did not differ significantly, �2(1) � 1.23, p � .267,
d � �0.25, but did differ significantly between participants with low
(.631) and high (.690) session attendance in GFSC, �2(1) � 10.39,

p � .002, d � 0.58. In addition, the effect size for the treatment group
difference (CBSST v. GFSC) in model-estimated ILSS scores was
small to medium and not significant for participants with high atten-
dance, �2(1) � 2.57, p � .105, d � 0.38, but was large and significant
for participants with low attendance, �2(1) � 17.26, p � .001, d �
1.21.

Discussion

The results indicated that CBSST is an effective psychosocial
intervention to improve functioning in consumers with schizophre-
nia. Functioning trajectories over time were significantly more
positive in CBSST than in GFSC. Rates of achieving functioning

Table 1
Baseline Participant Characteristics

Variable

GFSC (N � 76) CBSST (N � 73) Statistical analysis

N % M SD N % M SD �2 t df p

Male 53 70 46 63 0.76 1 .385
White 44 58 41 56 0.05 1 .831
Age (years) 41.6 9.2 41.1 10.4 0.33 147 .742
Education (years) 12.3 1.8 12.3 2.0 0.04 147 .967
Duration of illness (years) 21.4 10.6 21.3 11.5 0.05 147 .961
PANSS Total 73.3 20.0 71.5 16.6 0.59 146 .556

Note. GFSC � goal-focused supportive contact; CBSST � cognitive behavioral social skills training; PANSS � Positive and Negative Syndrome Scale.

Table 2
Descriptive Statistics for Available Data on All Outcome Measures at Each Assessment Point for Each Treatment Group

Measure/group

Baseline 4 months
End of

treatment
6-month
follow-up

12-month
follow-up

N M (SD) N M (SD) N M (SD) N M (SD) N M (SD)

ILSS
CBSST 72 0.73 (0.10) 41 0.74 (0.10) 35 0.72 (0.10) 23 0.73 (0.12) 24 0.71 (0.11)
GFSC 76 0.70 (0.10) 50 0.71 (0.11) 44 0.71 (0.10) 31 0.69 (0.12) 31 0.69 (0.11)

MASC
CBSST 63 3.4 (1.0) — — 35 3.8 (0.9) — — 24 3.5 (0.8)
GFSC 74 3.2 (1.2) — — 42 3.4 (1.1) — — 28 3.3 (1.0)

CMT
CBSST 72 5.8 (3.0) 42 8.1 (4.4) 36 10.4 (5.7) 24 11.8 (5.1) 24 11.1 (6.4)
GFSC 76 5.6 (3.5) 52 5.8 (4.0) 44 6.5 (3.9) 33 5.6 (2.8) 31 5.7 (3.3)

SANS Dim. Motivation
CBSST 71 2.26 (1.11) 39 2.33 (1.14) 36 2.06 (1.06) 24 2.02 (1.12) 25 1.74 (0.81)
GFSC 76 2.11 (1.17) 49 2.11 (1.16) 45 2.29 (0.91) 33 2.26 (1.31) 31 2.27 (1.15)

SANS Dim. Expression
CBSST 71 1.82 (1.13) 39 1.87 (1.15) 36 1.92 (1.05) 24 1.85 (1.03) 25 1.82 (0.96)
GFSC 76 1.80 (1.15) 49 1.99 (1.04) 45 1.89 (1.12) 33 2.02 (1.00) 31 2.00 (0.96)

PANSS Positive
CBSST 72 19.4 (5.5) 42 19.4 (5.2) 36 16.6 (4.1) 24 18.4 (6.3) 25 15.0 (4.7)
GFSC 76 20.2 (6.7) 52 19.8 (6.0) 45 18.7 (5.8) 33 18.7 (5.8) 31 17.2 (5.1)

BDI–II
CBSST 72 17.4 (9.7) 42 17.1 (11.2) 36 14.0 (10.2) 24 15.8 (11.0) 25 12.6 (9.3)
GFSC 75 17.2 (11.5) 52 16.7 (13.6) 45 13.8 (10.4) 33 15.6 (15.1) 31 17.3 (12.0)

DPAS
CBSST 71 51.1 (17.2) 42 51.6 (15.7) 36 49.8 (14.6) 24 46.2 (16.9) 25 44.2 (13.3)
GFSC 76 56.0 (17.2) 52 56.2 (19.4) 45 54.1 (18.3) 33 54.3 (17.9) 32 54.8 (17.7)

Note. Groups did not differ significantly at baseline on any outcome measure. CBSST � cognitive behavioral social skills training; GFSC � goal-focused
supportive contact; ILSS � Independent Living Skills Survey; MASC � Maryland Assessment of Social Competence (MASC not administered at
mid-treatment or mid-follow-up); CMT � Comprehensive Modules Test; SANS Dim. Motivation/Dim. Expression � Scale for Assessment of Negative
Symptoms Diminished Motivation/Diminished Expression factors; PANSS � Positive and Negative Syndrome Scale; BDI–II � Beck Depression
Inventory–II; DPAS � Defeatist Performance Attitude Scale.

1179CBSST FOR SCHIZOPHRENIA

milestones, which are very difficult to impact through available
treatments, were also better in CBSST, especially for educational
engagement. These findings replicated the results of two prior
CBSST clinical trials with older adults (Granholm et al., 2005,
2007, 2013) and extended the evidence for better functional out-
come to a more representative sample of consumers with schizo-
phrenia. These benefits of CBSST cannot be attributed to nonspe-
cific therapist factors alone. Functioning outcomes improved to a
greater extent in CBSST than in GFSC, suggesting specific CBT
and SST interventions were more potent interventions than goal
setting and supportive contact alone. Taken together, the findings

from three CBSST clinical trials suggest that CBSST should be
offered over supportive goal-setting interventions to geriatric and
nongeriatric consumers with schizophrenia.

Experiential negative symptoms and defeatist performance atti-
tudes also improved to a significantly greater extent in CBSST
relative to GFSC. These findings are consistent with the results of
another open CBT trial that showed significant improvement in
both dysfunctional attitudes and negative symptoms in a sample of
consumers with psychotic disorders who had not been taking
antipsychotic medication (Morrison et al., 2012). Granholm et al.
(2013) also found that participants with more severe defeatist

Table 3
Results of Mixed-Effects Random Regression Modeling for All Outcomes

Outcome measure/
predictor variable � 95% CI t p

Treatment end 21-month follow-up

ILSS (primary outcome)
Intercept 0.717 [0.702, 0.733] 90.10 �.001
Group 0.022 [�0.009, 0.053] 1.36 .177
Time �0.001 [�0.002, 0.000] �1.38 .171
Group � Time 0.004 [0.002, 0.006] 2.62 .010 .55 1.00

MASC
Intercept 3.36 [3.17, 3.55] 34.92 �.001
Group 0.23 [�0.14, 0.61] 1.21 .229
Time 0.01 [�0.00, 0.03] 1.85 .065
Group � Time �0.01 [�0.04, 0.02] �0.55 .582 .14 .04

CMT
Intercept 6.06 [5.54, 6.59] 22.72 �.001
Group 0.69 [�0.36, 1.73] 1.29 .201
Time 0.11 [0.04, 0.19] 2.97 .004
Group � Time 0.19 [0.04, 0.34] 2.42 .017 .72 1.40

SANS Diminished Motivation
Intercept 2.20 [2.04, 2.37] 25.96 �.001
Group 0.18 [�0.16, 0.51] 1.03 .304
Time 0.01 [�0.01, 0.02] 0.53 .596
Group � Time �0.05 [�0.09, �0.01] �2.39 .018 .22 .72

SANS Diminished Expression
Intercept 1.82 [1.65, 2.00] 20.56 �.001
Group 0.03 [�0.32, 0.38] 0.18 .862
Time 0.02 [0.00, 0.04] 2.00 .047
Group � Time �0.01 [�0.05, 0.03] �0.28 .782 .02 .08

PANSS Positive
Intercept 19.59 [18.71, 20.46] 43.74 �.001
Group �0.50 [�2.25, 1.26] �0.56 .578
Time �0.13 [�0.21, �0.04] �2.84 .006
Group � Time �0.09 [�0.26, 0.08] �1.02 .312 .21 .39

BDI�II
Intercept 17.26 [15.50, 19.03] 19.16 �.001
Group 0.06 [�3.47, 3.60] 0.04 .972
Time �0.14 [�0.32, 0.03] �1.64 .102
Group � Time �0.17 [�0.51, 0.17] �0.97 .332 .14 .33

DPAS
Intercept 53.85 [51.28, 56.41] 41.19 �.001
Group �4.34 [�9.46, 0.79] �1.66 .099
Time �0.20 [�0.42, 0.02] �1.82 .070
Group � Time �0.54 [�0.97, �0.10] �2.42 .017 .53 .90

Note. All models included number of sessions attended (plus all two-way interactions with group and time and the three-way interaction) as a predictor
of outcome, but all effects involving number of sessions were nonsignificant, except the Group � Session � Time interaction in the Independent Living
Skills Survey (ILSS) model, � � �0.0003, t � �3.80, p � .001, and the effect of number of sessions attended in the Comprehensive Modules Test (CMT)
model: � � 0.05, t � 2.12, p � .036. Effect sizes (d) were estimated by computing the treatment group difference for HLM (hierarchical linear modeling)
model-predicted values for each outcome variable for hypothetical participants with a median number of sessions attended and dividing by the baseline
assessment pooled standard deviation. CI � confidence interval; MASC � Maryland Assessment of Social Competence; SANS � Scale for Assessment
of Negative Symptoms; PANSS � Positive and Negative Syndrome Scale; BDI–II � Beck Depression Inventory–II; DPAS � Defeatist Performance
Attitude Scale.T

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1180 GRANHOLM, HOLDEN, LINK, AND MCQUAID

attitudes at baseline were more likely to show improved function-
ing and that change in defeatist attitudes during treatment pre-
dicted better functional outcome 9 months after treatment. Given
that defeatist performance attitudes have been associated with
functional outcome and experiential negative symptoms (Grant &
Beck, 2009; Horan et al., 2010; Green et al., 2012), it is possible
that reductions in defeatist attitudes in CBT interventions contrib-
uted to improvements in these outcomes. However, this is only the
first clinical trial to demonstrate significantly greater improvement
in experiential negative symptoms in CBSST relative to an active
control condition, so it may be premature to recommend CBSST
for negative symptoms, until this finding is replicated.

Unlike the present clinical trial, a previous trial of CBSST for
older consumers with schizophrenia (Granholm et al., 2013), did
not find significantly greater improvement in negative symptoms
or defeatist attitudes in CBSST relative to GFSC. Several factors
may have contributed to these conflicting findings. First, experi-
ential negative symptoms and defeatist attitudes may be more rigid
and resistant to change in older consumers who have experienced
decades of illness-related failures, stigma, and negative evalua-
tions by others. In support of this possibility, longer duration of
illness and older age have been associated with poorer outcome in
CBT for psychosis trials (Drury et al., 1996; Morrison et al., 2004,
2012), and longer duration of illness was associated with lower

CBSST
GFSC

0 4 9 15 21

Time in Months

0.660

0.680

0.700

0.720

IL
S

S
C

om
po

si
te

0.740

CBSST
GFSC
0 4 9 15 21
Time in Months

2.00

2.20

2.40

2.60

S
A

N
S

D
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he
d

M
ot

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CBSST
GFSC
0 4 9 15 21
Time in Months

6.00

7.00

8.00

9.00

10.00

C
M

T
To

ta
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CBSST
GFSC
0 4 9 15 21
Time in Months

44.00

48.00

52.00

56.00
D

P
A

S
To

ta
l

Figure 2. Trajectories across assessment points from baseline to 21-month follow-up are shown for hypothet-
ical participants with a median number (12) of therapy sessions attended in cognitive behavioral social skills
training (CBSST) and goal-focused supportive contact (GFSC). Trajectories were estimated from mixed-effects
regression models that showed significant Group � Time interactions for functioning (Independent Living Skills
Survey [ILSS], p � .010), negative symptoms (Scale for Assessment of Negative Symptoms [SANS] Dimin-
ished Motivation Factor, p � .018), dysfunctional attitudes (Defeatist Performance Attitude Scale [DPAS], p �
.017) and CBSST skills acquisition (Comprehensive Modules Test [CMT], p � .017). Improvement is indicated
by increasing scores for ILSS and CMT and decreasing scores for the DPAS and SANS.T

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1181CBSST FOR SCHIZOPHRENIA

self-efficacy in one study (McDermott, 1995). However, the pres-
ent sample had been ill for two decades on average, so consumers
in this study had significant exposure to factors that might impact
severity of defeatist attitudes, and we did not find significant
associations between duration of illness and severity of defeatist
attitudes in the present sample. Second, a factor analytic study of
the Dysfunctional Attitudes Scale (DAS) Form A in older
(age �60) adults with nonpsychotic depression did not find strong
support for a similar defeatist performance attitude (or “perfec-
tionism”) factor of the DAS, suggesting questionable validity of
the DPAS measure in older psychiatric samples (Floyd, Scogin, &
Chaplin, 2004). A Defeatist Performance Attitude Scale (DPAS)
measure with items more relevant to older consumers (e.g., items
on health and loss of independence, rather than achievement) may
be needed to adequately test cognitive mediation in CBT studies
with older consumers. Finally, it is possible that the SST compo-
nents and improvement in social skills in CBSST contributed to
improvements in functioning and negative symptoms to a greater
extent than reduction in defeatist beliefs. Self-efficacy and self-
defeatist beliefs might be modified in CBSST but this may not be
necessary to improve outcome. Improvements may stem from
behavioral activation of practiced skills.

Thus, there is some evidence that functioning and negative
symptom outcomes in CBT are mediated by reduction in defeatist
attitudes, but this will require further study with larger samples
(perhaps combining samples from multiple trials) to increase
power to examine defeatist beliefs in the context of other potential
mediators and moderators (e.g., age, duration of illness, gender,
insight, neurocognitive impairment). Nonetheless, the findings of
this study and other recent research (Granholm et al., 2013; Grant
& Beck, 2009; Green et al., 2012; Horan et al., 2012) suggest that

cognitive therapy interventions targeting defeatist beliefs may help
improve functioning and negative symptom outcomes in some
consumers with schizophrenia.

It is notable that both treatments showed improvements in social
competence and positive symptoms. This suggests that an active
psychosocial intervention that includes at least supportive contact
and systematic recovery-oriented goal setting can be beneficial to
consumers with schizophrenia for reducing positive symptom dis-
tress and increasing competence in social interactions to some
extent (e.g., through interactions with peers in group). Other re-
searchers have pointed out the benefits of supportive contact
interventions to consumers with schizophrenia (Penn et al., 2004).
Despite the benefits found for GFSC, it is important to note that
functioning, negative symptoms, and defeatist attitudes all im-
proved to a greater extent in CBSST than in GFSC, suggesting the
specific CBT and SST interventions were more potent than sup-
portive goal-setting interventions in improving these outcomes.

Given the cost and burden of delivering psychosocial interven-
tions, it is important to identify the minimal therapy dosage needed
to improve outcomes. On average, participants received only 12 of
the 36 CBSST sessions offered and did not actively engage in
booster sessions. Nonetheless, negative symptom and functioning
outcomes were still superior in CBSST relative to GFSC, and the
number of sessions attended was not significantly associated with
outcome in CBSST, suggesting additional exposure may not result
in additional gains. Morrison et al. (2004) also found that the
number of sessions delivered was not associated with symptom
outcome in a CBT for psychosis effectiveness trial conducted in a
community mental health setting. These findings may indicate that
less exposure to the CBSST content is a sufficient dosage for
benefit. However, additional research is needed to determine the

CBSST
GFSC
0 4 9 15 21
Time in Months

16.00

17.00

18.00

19.00

P
A
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S
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os
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ve
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GFSC

0 4 9 15 21
Time in Months

3.30

3.40

3.50

3.60

3.70

M
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S
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ec
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Figure 3. Trajectories across assessment points from baseline to 21-month follow-up are shown for hypothet-
ical participants with a median number (12) of therapy sessions attended in cognitive behavioral social skills
training (CBSST) and goal-focused supportive contact (GFSC). Trajectories were estimated from mixed-effects
regression models that showed a significant time effect for positive symptoms (Positive and Negative Syndrome
Scale [PANSS] Positive Subscale, p � .006) and a marginally significant time effect for social competence
(Maryland Assessment of Social Competence [MASC], p � .065). Improvement is indicated by decreasing
scores for the PANSS and increasing scores for the MASC.

1182 GRANHOLM, HOLDEN, LINK, AND MCQUAID

adequate dosage of treatment, because participants were not ran-
domized to longer and shorter treatments, so participant charac-
teristics (e.g., motivation, neurocognitive impairment, illness se-
verity) may have contributed to number of sessions delivered. It
will be important to randomize participants to high- and low-
intensity interventions in future trials to identify the optimal num-
ber of sessions needed to impact functional outcome in psychos-
ocial rehabilitation interventions.

In contrast to CBSST, in GFSC, additional treatment was sig-
nificantly associated with better functional outcome. This differ-
ence in dose effects between conditions might be related to the
skills training approach of CBSST. In skills-based interventions,
participants learn and use skills that can be applied in the absence
of a therapist, but when skills are not trained, extended contact
with a supportive therapist may be required for meaningful gains.
Once consumers learn skills in CBSST, they can continue to use
them to work on functioning goals, even if they drop out of
treatment. In contrast, once consumers drop out of GFSC, they no
longer have the support of the therapist to work on goals. The skills
are the active ingredients in CBSST, whereas the therapist and
other group members are the primary active ingredients in GFSC.
A greater dose of treatment, therefore, leads to greater exposure to
the active ingredient in GFSC, but even if consumers dropout in
CBSST, they can continue to use the skills they learned to improve
functioning and negative symptoms.

Treatment retention in this trial (54%) was much lower than in
previous CBSST trials (75%– 86%; Granholm et al., 2005, 2013).
It is possible that sampling differences contributed to the high
dropout rate, in that the lengthy, repeating nature of the CBSST
modules might be more appropriate for an older, more chronically
ill population and might be more disliked by nongeriatric consum-
ers, leading them to drop out. Dropout rates, however, did not
differ significantly between GFSC and CBSST, so repeating the
CBSST modules may not be the cause of dropout in this nonge-
riatric sample. It is possible that challenges related to the limited
public transportation system and long travel distances in San
Diego County contributed to differences in dropout rates between
CBSST clinical trials, because transportation was provided to
therapy in previous trials with good retention but not in the present
trial. Mueser et al. (2010) also suggested that transportation chal-
lenges impacted attendance in a multisite trial of SST for consum-
ers with serious mental illness, because they found greater atten-
dance (90% vs. 66%) at sites with better access to transportation.
In future research, modifications like using a shorter, less-
redundant intervention and providing transportation might help
engage and retain consumers in interventions like CBSST, espe-
cially in areas with limited public transportation.

This study had several limitations. As noted earlier, this clinical
trial had a high dropout rate, which limits interpretation of results,
because group differences found might reflect a selective bias in
who remained in the study. Several steps were taken to address this
and increase confidence in the results. First, the mixed-effects
regression analyses used do not require complete data and allow
for a larger number of participants to be included than would be
possible with traditional analysis-of-variance-based designs,
which increases both power and generalizability. Second, several
analyses were conducted to identify possible biases introduced by
drop-out rates. The two treatment groups did not differ signifi-
cantly in drop-out rates, and participants who dropped out did not

differ significantly from those retained on any of the key outcome
variables at baseline. These analyses provided no evidence that
drop-out rates introduced a systematic bias into the sample.

Another important limitation was that the primary outcome
measure was a self-report measure of functioning, and the validity
of patient-reported outcomes has been questioned in this popula-
tion (Bowie et al., 2007; Sabbag et al., 2012). However, significant
change was also found on at least one objective functioning
milestone (educational activities), which provided some additional
support for greater improvement in functioning in CBSST. The
study also cannot answer the question of whether CBSST should
be offered over CBT or SST. The relative efficacy of these
interventions bundled into CBSST is an area requiring additional
research. Finally, the present trial did not inform which patients
should be offered CBSST. More research is needed to identify
which consumers are more likely to benefit.

Despite these limitations, identifying treatments to improve
functioning and reduce negative symptoms in consumers with
schizophrenia is of high public health significance, and the results
of this randomized clinical trial indicated that CBSST is an effec-
tive psychosocial intervention to improve these outcomes in some
consumers with schizophrenia.

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Received May 28, 2013
Revision received April 7, 2014

Accepted April 16, 2014 �

1185CBSST FOR SCHIZOPHRENIA

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http://dx.doi.org/10.1037/1040-3590.8.3.269

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http://dx.doi.org/10.1176/appi.ps.52.4.493

Randomized Clinical Trial of Cognitive Behavioral Social Skills Training for Schizophrenia: Impr …

Method
Design
Participants
Interventions
Individual goal-setting sessions
Cognitive behavioral social skills training (CBSST)
Goal-focused supportive contact (GFSC)
Treatment Fidelity
Outcome Measures
Independent Living Skills Survey (ILSS)
Comprehensive Module Test (CMT)
Maryland Assessment of Social Competence (MASC)
Psychosocial Rehabilitation Toolkit (PSR Toolkit)
Positive and Negative Syndrome Scale (PANSS), Scale for the Assessment of Negative Symptoms (SAN …)
Defeatist Performance Attitude Scale (DPAS)
Reliability
Statistical Analyses
Results
Sample
Outcomes
Objective Functioning Milestones
Treatment Adherence
Discussion
References

Neurocognitive Functions in Schizophrenia: A Systematic Review
of the Effects of Typical and Atypical Antipsychotic Drug

Cyntia Diógenes Ferreira,
Maria Genecleide Dias de Souza,
and Bernardino Fernández-Calvo

Federal University of Paraíb

João Paulo Machado-de-Sousa
and Jaime Eduardo Cecilio Hallak

University of São Paulo

Nelson Torro-Alves
Federal University of Paraíba

Schizophrenia is characterized by, in addition to positive and negative symptoms,
impaired cognitive functioning. In this article, we conducted a systematic review of
studies that directly compared the effects of typical and atypical antipsychotics o

neurocognitive functions. Twenty-three articles published between 2000 and 2015 wer

included in the review. In general, atypical antipsychotics had a broader range of effec

on neurocognitive functions, with improvements in working memory, executive func-
tions, memory, and verbal fluenc

Few articles reported no differences between typica

and atypical medication or an advantage of typical medication. However, it is importan

to highlight that differences between the 2 classes of medication may not be attributable
solely to the antipsychotics but to confounding factors including, for example, the
concurrent use of anticholinergics to alleviate extrapyramidal symptoms, which can
impair cognition. This review may help provide a better understanding of treatments
addressing the maintenance or recovery of neurocognitive functions in patients with
schizophrenia, which may have important benefits to the patients’ quality of life

Keywords: schizophrenia, cognition, antipsychotics

Impaired neurocognitive functioning is com-
mon in schizophrenia (Keefe & Fenton, 2007),
with reported deficits in attention (Coleman et
al., 2009), processing speed (Dickinson, Ram-
sey, & Gold, 2007; Knowles, David, &
Reichenberg, 2010), working memory (Levaux
et al., 2009), intelligence (Kremen, Seidman,
Faraone, & Tsuang, 2001), verbal fluency (Bho-

jraj et al., 2009), and executive functions (Wo-
brock et al., 2009). Some studies have sug-
gested that neurocognitive dysfunction is
present even before the first psychotic episode
(Albus et al., 2006), lasting throughout the dis-
ease independently from the evolution of psy-
chotic symptoms (O’Leary et al., 2000). The
neurocognitive decline has impacts on patients’
quality of life, affecting their autonomy, psy-
chosocial skills, and employment prospects
(Lam, Raine, & Lee, 2014

The history of antipsychotic drugs began in
the 1950s with the discovery of the effects of
chlorpromazine, which belongs to the chemical
class of phenothiazines. Chlorpromazine was
initially used to tranquilize patients in the pre-
operatory period, and then some clinical studies
revealed its effects in restoring the quality of
life of psychiatric patients. Later on, a new class
of drugs was introduced, the butyrophenones,
mainly represented by the haloperidol. These
antipsychotic drugs were known as neuroleptics

Cyntia Diógenes Ferreira, Maria Genecleide Dias de
Souza, and Bernardino Fernández-Calvo, Department of
Psychology, Federal University of Paraíba, João Pessoa,
Paraíba, Brazil; João Paulo Machado-de-Sousa and Jaime
Eduardo Cecilio Hallak, Department of Neuroscience an

Behavior, Ribeirão Preto Medical School, University of São
Paulo, Ribeirão Preto, São Paulo, Brazil; Nelson Torro-
Alves, Department of Psychology, Federal University of
Paraíba, João Pessoa, Paraíba, Brazil.

Correspondence concerning this article should be ad-
dressed to Cyntia Diógenes Ferreira, Department of Psy-
chology–Bloc IV, Federal University of Paraíba–Campus I,
Cidade Universitária–João Pessoa–PB, Brazil CEP 58059-
900. E-mail: cyntiadiogenes@gmail.com

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Psychology & Neuroscience © 2016 American Psychological Association
2016, Vol. 9, No. 1,

–31 1983-3288/16/$12.00 http://dx.doi.org/10.1037/pne0000045

mailto:cyntiadiogenes@gmail.com

http://dx.doi.org/10.1037/pne0000045

because of their neurologic side effects, the
so-called extrapyramidal effects (Lehmann &
Ban, 1997; Miyamoto, Duncan, Marx, &
Lieberman, 2005).

In the following decades, many advances re-
vealed the mechanisms of antipsychotic drugs,
which mainly acted on the dopaminergic sys-
tem, more specifically on the D2 receptors of
dopamine (Kapur & Mamo, 2003). According
to the dopaminergic theory of schizophrenia,
the excessive activation of D2 receptors in the
nucleus accumbens would produce positive
symptoms (e.g., delusions and hallucinations),
whereas the negative symptoms (e.g., blunted
affect and cognitive deficits) would result from
a reduced activity in dopaminergic receptors in
the prefrontal cortex. Therefore, the ideal anti-
psychotic would reduce dopaminergic activity
in the nucleus accumbens and enhance the ac-
tivity in the prefrontal cortex, acting on both
positive and negative symptoms (Kapur, 2004).

The antagonistic action on dopamine recep-
tors is responsible for the therapeutic effect of
antipsychotic drugs, a mechanism with impor-
tant side effects, for example, on the dopami-
nergic pathway from substantia nigra to dorsal
striatum (caudate-putamen in the basal nuclei),
which is part of the extrapyramidal system. The
extrapyramidal effects are responsible for motor
deficits such as bradykinesia and acathisia,
characterizing the parkinsonian syndrome
(Johnstone, Frith, Crow, Carney, & Price,
1978). The induction of extrapyramidal effects
is a key feature of typical antipsychotics (“neu-
roleptics”); however, an atypical profile was
observed after the advent of clozapine. In par-
ticular, it was observed that clozapine reduced
both positive and negative symptoms without
producing extrapyramidal side effects (Maia-
de-Oliveira et al., 2012). This difference estab-
lished two classes of antipsychotics—typical
(first generation) and atypical (second genera-
tion).

The complex relationship between alterations
in dopaminergic transmission and some mental
disorders, such as schizophrenia, indicate that
more research in necessary to understand the
mechanisms of action of dopamine in primary
cognitive domains. According to some studies,
the action of dopamine in the prefrontal cortex
follows an inverted U dose–response curve, in
which an increase or decrease in relation to an

optimum level results in cognitive impairments
(Veselinović et al., 2013).

Atypical antipsychotics may, in addition to
acting on the dopaminergic system, act on se-
rotonergic pathways (Meltzer & Massey, 2011).
When administered in clinically effective doses,
these drugs may block serotonin (5-HT) 2A;
directly or indirectly stimulate 5-HT1A recep-
tors; and, to a lesser extent, reduce the neu-
rotransmission mediated by the dopamine re-
ceptor D2. This is in contrast to the effects of
typical antipsychotics, which are mainly antag-
onists of D2 and D3 dopamine receptors, with
little antagonism over 5-HT2A receptors. This
different effect on 5-HT receptors may contrib-
ute to significant differences in efficacy and
tolerance between typical and atypical antipsy-
chotics (Meltzer, 2013; Meltzer & Massey,
2011).

Currently, there is evidence that atypical
antipsychotics have greater benefits for neu-
rocognitive function compared with typical
antipsychotics (Bilder et al., 2002). Such re-
sults have been observed with the administra-
tion of olanzapine (Sharma, Hughes, Soni, &
Kumari, 2003), clozapine (Keefe, Silva, Per-
kins, & Lieberman, 1999), risperidone (Lee,
Chou, Li, Wan, & Yen, 2007), and quetiapine
and ziprasidone (Johnsen, Jørgensen, Kroken,
& Løberg, 2013). However, despite the wide-
spread use of these drugs in clinical practice,
there are limited data comparing their overa

efficacy in reducing the different symptoms
of schizophrenia. Nevertheless, some studies
have found contradictory results (Crespo-
Facorro et al., 2009; Thornton, Van Snellen-
berg, Sepehry, & Honer, 2006).

The quality of schizophrenia treatment with
antipsychotics may be evidenced by improve-
ment in symptoms and cognitive functioning.
Estimates of the dose–response relationship for
its effectiveness and adverse events requires
careful study of the drug, mainly by conducting
randomized controlled trials (Owen et al.,
2002). The compilation of different research
results contributes to defining schizophrenia
treatment guidelines in psychiatric clinical prac-
tice, with the specification of antipsychotics,
dose intervals, efficacy of pharmacological
treatment, and other therapeutic interventions
(Dixon, Perkins, & Calmes, 2009; Lehman et
al., 2004).

13ANTIPSYCHOTIC DRUGS IN SCHIZOPHRENIA

T
hi

s
do
cu
m
en
t
is
co

py
ri

gh
te
d
by
th
e
A
m
er
ic
an
P
sy
ch
ol
og
ic
al
A
ss
oc
ia
ti
on
or
on
e
of
it
s
al
li
ed
pu
bl
is
he
rs
.
T
hi
s
ar
ti
cl
e

is
in

te
nd
ed
so
le
ly
fo
r
th
e
pe
rs
on
al
us
e
of
th
e
in
di
vi
du
al
us
er
an
d
is
no
t
to

be
di

ss
em
in
at
ed
br
oa
dl
y.

The World Federation of Societies of Biolog-
ical Psychiatry (WFSBP) task force has sought
to establish a consensus on key recommenda-
tions for the treatment of schizophrenia in psy-
chiatric practice through a systematic review of
the available evidence (Falkai et al., 2005). It
has found that the doses must be adjusted ac-
cording to antipsychotic tolerability in order to
rapidly achieve the therapeutic range (Falkai et
al., 2005). Several studies of the diverse atypi-
cal antipsychotics have sought to identify the
minimum effective dose for each, but discrep-
ancies still exist (e.g., Citrome & Volavka,
2002; Leucht et al., 2014). Davis and Chen
(2004) reviewed studies comparing two or more
doses of antipsychotics in patients with schizo-
phrenia or schizoaffective disorder, with the
purpose of calculating the dose–response curve
for both typical and atypical medications. For
haloperidol, they found that the effective dose
was close to the maximum dose (3.3–10 mg).
For olanzapine, the maximum effective dose
can be greater than 16 mg, with 6 mg being 33%
less effective compared with higher doses. It
was also found that 4 mg of risperidone was the
most efficient dose, whereas a dosage of 2 mg
daily was 50% less effective than were higher
doses. These results demonstrate the importance
of evaluating doses used in the studies.

In summary, there is general agreement in the
literature on the cognitive impairments related
to schizophrenia, but there are conflicting re-
sults concerning the effects of different antipsy-
chotic drugs on cognition. Here, we review
studies that directly compared the effects of
typical and atypical antipsychotics on neuro-
cognitive functions in patients with schizophre-
nia.

Method

Using the terms typical and atypical antipsy-
chotic and cognition and schizophrenia, we
conducted a systematic search for empirical re-
search articles published between 2000 and
2015 and indexed in PubMed, LILACS, Sci-
ELO, and Science Direct. As a complementary
strategy, we also screened the reference lists of
the articles found for further relevant publica-
tions. The inclusion criteria for the review were
(a) comparison of the effects of typical and atypical
antipsychotic drugs on neurocognitive functions in
schizophrenia through empirical studies, (b) admin-

istration of neuropsychological tests, and (c) use of
human participants. Literature reviews, meta-
analysis studies, theses, dissertations, and neuroim-
aging studies were not included. The systematic re-
view employed the guidelines of the PRISMA
(Preferred Reporting Items for Systematic Reviews
and Meta-Analyses; http://www.prisma-statement
.org/) initiative for literature searches and data
reporting in quantitative and qualitative system-
atic reviews. The initial selection was based on
the articles’ titles and abstracts and followed by
reading and evaluating the full articles accord-
ing to the inclusion criteria. We found a total of
23 studies that compared the effects of typical
and atypical antipsychotics on neurocognitive
functions.

Results

Figure 1 is a flow diagram of our systematic
review. In general, most articles were published
from 2003 to 2009. In comparison with typical
antipsychotics, atypical drugs were associated
with better performances in neuropsychological
tests, with only four studies reporting no differ-
ences between typical and atypical antipsychot-
ics (Davidson et al., 2009; Keefe et al., 2007;
Rémillard, Pourcher, & Cohen, 2008; Wittorf,
Sickinger, Wiedemann, & Klingberg, 2008).
These findings suggest that atypical antipsy-
chotics are more efficient in maintaining or im-
proving neurocognitive functions in schizophre-
nia patients. The most frequently investigated
atypical drugs were risperidone (n � 16), olan-
zapine (n � 13), quetiapine (n � 7), and clo-
zapine (n � 6).

Across studies, there was broad diversity in
the methods employed to assess the neurocog-
nitive functions in schizophrenia. However, the
main neuropsychological instruments used were
the Wisconsin Card Sorting Test (n � 13),
Wechsler Adult Intelligence Scale (n � 12),
Trail Making Test (n � 11) and the Wechsler
Memory Scale—Revised (n � 9), all of which
are involved in the assessment of executive
functions, intelligence, visual attention and task
switching, and memory.

The findings by Han et al. (2015) suggest that
long-term treatment with antipsychotic cloza-
pine caused worse performance in immediate
memory (composed of list learning and story
memory tasks) and delayed memory (composed
of list recall, story recall, figure recall and list

14 FERREIRA ET AL.

http://www.prisma-statement.org/

recognition tasks) than for those individua

taking typical drugs. However, individuals tak-
ing clozapine showed better language perfor-
mance than did those taking risperidone. Mül-
ler, Werheid, Hammerstein, Jungmann, and
Becker (2005) observed an advantage of indi-
viduals taking atypical drugs in the task of or-
dering digits, which requires working memory.
Also, Morrens, Hulstijn, and Sabbe (2008) in-
vestigated the effects of antipsychotics on psy-
chomotor speed and found that of individuals
taking typical drugs induced higher psychomo-
tor deceleration in a copy task. Krakowski and
Czobor (2011) found that general cognitive in-
dex was greater for patients taking olanzapine
than for those taking clozapine or haloperidol.
Beninger et al. (2003) observed that individuals
taking typical and atypical antipsychotics had
distinct effects on nondeclarative memory and
that patients taking typical medication had a
better performance in decision-making (as mea-
sured by the Iowa Gambling Task), whereas
patients taking atypical medication were better
at probabilistic classification learning.

Treatment with atypical antipsychotics, in
comparison to typical antipsychotics, was gen-
erally associated with gains in cognitive func-

tioning, as observed by Harvey, Rabinowitz,
Eerdekens, and Davidson (2005) with risperi-
done. In a similar way, Keefe et al. (2004

)

reported improvements in cognitive perfor-
mance after 12 weeks of treatment with atypical
antipsychotics in schizophrenia, whereas the re-
sults were modest with the administration of
haloperidol. In a subsequent study, Purdon et al.
(2000) showed that, in the initial stages of
schizophrenia, olanzapine and quetiapine led to
benefits in processing speed. In addition, Keefe,
Young, et al. (2006) observed that patients able
to remain in treatment for the entire 52 wee

benefited more from olanzapine or risperidone
treatment than haloperidol treatment.

Guo et al. (2011) observed neurocognitive
benefits with the use of olanzapine and haloper-
idol after 12, 24, 52, and 104 weeks of treat-
ment, with an advantage of olanzapine in the
12th and 24th weeks; even so, they found no
significant differences between groups of pa-
tients treated with haloperidol, olanzapine, and
risperidone with regard to the composite score
of the neurocognitive tests. However, when in-
dividual scores were analyzed, they verified that
olanzapine and risperidone improved perfor-
mance on the domains of executive function,

Figure 1. Flow diagram of the surveyed studies investigating the effects of typical and
atypical antipsychotic drugs.

15ANTIPSYCHOTIC DRUGS IN SCHIZOPHRENIA

learning/memory, processing speed, attention/
vigilance, verbal working memory, and motor
functions, whereas haloperidol-treated patients
improved only on the domain of learning/
memory compared to the baseline. Risperidone
improved the performance in all those domains
in addition to visuospatial memory.

In studies assessing the use of combined
drugs, Hori et al. (2006) observed that “nonstan-
dard” use of antipsychotics (defined as antipsy-
chotic polypharmacy or dosage �1,000 mg/day
of chlorpromazine equivalents) is associated
with cognitive function. Patients taking atypical
antipsychotics showed better performance on
visual memory, delayed recall, and executive
function than did those taking typical drugs.

The antipsychotic olanzapine demonstrates a
large improvement in cognitive functions eval-
uated in some studies. Purdon et al. (2000)
found that patients produced better procedural
learning measures when treated with olanzapine
than with haloperidol or risperidone, especially
after 6 months of treatment. Cuesta, Peralta, and
Zarzuela (2001) found a small advantage of
olanzapine over risperidone in attentional func-
tions, verbal memory, and executive functions
in patients with chronic schizophrenia.

Lee et al. (2007) highlighted the good results
obtained with risperidone compared to haloper-
idol in verbal learning and working memory.
Harvey et al. (2004) described an improvement
in cognitive functions in patients who switched
from typical or atypical drugs (olanzapine or
risperidone) to ziprasidone.

Purdon, Malla, Labelle, and Lit (2001) ob-
served that quetiapine, in comparison with hal-
operidol, was associated with improvements in
verbal fluency, reasoning, immediate memory,
executive functions, and visuomotor tracking.
Similarly, Velligan et al. (2002) found an ad-
vantage of quetiapine over haloperidol on exec-
utive functions, attention, and verbal memory.

On the other hand, some studies showed sim-
ilar effects for the two classes of antipsychotics.
Davidson et al. (2009) found no differences
between haloperidol and second-generation an-
tipsychotic drugs (amisulpride, olanzapine, que-
tiapine, and ziprazidone) on the cognitive per-
formance of patients with schizophreniform
disorder or first-episode schizophrenia. Keefe et
al. (2007) found no significant differences be-
tween typical (i.e., perphenazine) and atypical
(i.e., olanzapine, quetiapine, and risperidon

antipsychotics administered. Wittorf et al.
(2008) observed improvements in memory, at-
tention, and executive functions in both patients
using typical antipsychotics and those using
atypical antipsychotics, with no differences be-
tween the drug classes. In addition, Rémillard et
al. (2008) found no improvement in neurocog-
nitive performance in groups treated with ris-
peridone and haloperidol over a 12-month fol-
low-up. However, risperidone was more
effective than haloperidol to reduce psychiatric
symptoms.

Suzuki and Gen (2012), in a study conducted
with long-acting antipsychotics, found that
switching from haloperidol decanoate depot to
risperidone long-acting injection improved cog-
nitive functions including memory, executive
function, motor processing function, and atten-
tion. This is an important finding considering
that risperidone is less likely than haloperidol to
cause extrapyramidal symptoms and that in
their study it allowed them to reduce the anti-
parkinsonian medication. Main findings and
characteristics of the studies included in the
systematic review are presented in Table 1.

With regard to the study design and conduct
of the clinical trials, we found that 10 studies
used the double-blind randomization procedure
to investigate the treatment with typical and
atypical antipsychotics. Ten studies defined
groups on the basis of the medication already
taken by the participants or that would be pre-
scribed by the professionals. In four studies,
participants were randomly distributed between
groups, but the double-blind procedure was not
used (see Table 1).

Discussion

We reviewed empirical studies comparing
the effects of typical and atypical antipsychotics
on neurocognitive functions in patients with
schizophrenia. In general terms, we observed
that atypical antipsychotics have a broader
range of effects on neurocognition in compari-
son with typical drugs, which in turn were as-
sociated with improvements in executive func-
tions, as revealed by some studies (Cuesta et al.,
2001; Keefe, Young, et al., 2006; Purdon et al.,
2001).

Atypical antipsychotics were generally more
efficient than was haloperidol (Guo et al., 2011;
Harvey et al., 2004) or combined use (polyp-

16 FERREIRA ET AL.

T
ab

le
1

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t
A

)

(t
a
b
le

co
n
ti

n
u
es

)

17ANTIPSYCHOTIC DRUGS IN SCHIZOPHRENIA

T
ab
le
1

(c
o
n
ti

n
u
ed

)
S
tu
dy
S
am
pl
e
C
ha
ra
ct
er
is
ti
cs
of
th
e
m
ai
n
sa
m
pl
e
T
yp
ic
al
dr
ug
s
A
ty
pi
ca
l
dr
ug
s
S
tu
dy
de
si
gn
N
eu
ro
co
gn
it
iv
e
fu
nc
ti
on
s
A
ss
es
sm
en
t
to
ol
s
R
es
ul
ts
T
yp
ic
al
�
at
yp
ic
al
A
ty
pi
ca
l
�
ty
pi
ca
l

H
an

et
al
.
(2

01
5)

N
�

57
7

(n
�

41
8

pa
ti
en
ts
w
it
h
sc
hi
zo
ph
re

ni
a,

n
�

15
9

he
al

th
y

co
nt
ro
ls
).
C
hr
on
ic
pa
ti
en
ts
N
ot
sp
ec
ifi
ed
(n
�

11
2)

C
lo
za
pi
ne
(n

�
21

5)
,
ri
sp
er
id
on
e
(n
�

91
)

T
ra
ns
ve
rs
al

Im
m

ed
ia

te
m

em
or

y,
vi

su
os

pa
ti

al
–

co
ns

tr
uc

ti
on

al
,

la
ng

ua
ge

,
at

te
nt

io
n,

de
la

ye
d

m
em
or
y

R
B

A
N

S
Im

m
ed

ia
te

an
d
de
la
ye
d
m
em
or
y

pe
rf

or
m

an
ce

th
an

th
os

e
ta

ki
ng

cl
oz

ap
in
e
C
lo
za
pi

ne
sh

ow
ed

be
tt

er
la

ng
ua

ge
pe

rf
or

m
an

e
th

an
th

os
e

ta
ki

ng
ri

sp
er
id
on
e

H
ar

ve
y

et
al
.
(2

00
4)

n
�

27
0

(p
at
ie
nt
s
w
it
h
sc
hi
zo
ph
re
ni

a
or

sc
hi

zo
af

fe
ct

iv
e

di
so

rd
er

th
at

ch
an

ge
d

th
e
m
ed

ic
at

io
n

to
zi

pr
as

id
on
e)
N
on
cr
it
ic
al
pa
ti
en
ts
N
ot
sp
ec
ifi
ed
(n
�

10
8)

.
Z

ip
ra

si
do

ne
,
ol
an
za
pi
ne
(n
�
10
4)
,
ri
sp
er
id
on
e
(n
�

58
)

T
ra
ns
ve
rs
al
L
ea

rn
in

g
an
d
m
em
or

y,
at

te
nt
io
n
an
d

vi
gi

la
nc

e,
ex

ec
ut
iv
e
fu
nc
ti
on
,
ve
rb
al
fl
ue
nc
y,

vi
su

m
ot

or
sp

ee
d

R
A
V
L
T
,

S
pa

ti
al

W
or

ki
ng
M
em
or
y
te
st

,
C

P
T

-I
P

,
D

S
D

T
,
T
M
T
(A
an
d
B
),

F
A

S
(a

ni
m

al
s,

ve
ge

ta
bl

es
,

fr
ui

ts
),

W
C
S
T

S
ig

ni
fi

ca
nt

im
pr

ov
em

en
ts
w
it

h
bo

th
ty

pe
s

of
m

ed
ic

at
io
n
in
ex
ec
ut
iv
e
fu
nc
ti

on
(W

C
S

T
)

Z
ip

ra
si

do
ne

:
L

ea
rn

in
g
an
d
m
em
or
y

(R
A

V
L

T
),

at
te
nt
io

n
(d

is
tr

ac
ti

on
co

nd
it

io
n–

D
S

D
T

),
vi

su
om
ot
or
sp
ee

d
(T

M
T

),
ve

rb
al
fl
ue

nc
y

H
ar
ve
y
et
al
.
(2

00
5)

n
�

53
3

(p
at
ie
nt
s
w
it
h
sc
hi
zo
ph
re
ni

a)
F

ir
st

-e
pi

so
de

sc
hi
zo
ph
re
ni

a
H

al
op

er
id

l
(n

�
25

0)
R

is
pe

ri
do

ne
(n
�
25

)
L

on
gi

tu
di

na
l

(b
as

el
in

e
an

d
3

m
on

th
)

V
is

uo
m

ot
or
sp
ee

d,
m

em
or
y,
vi

gi
la

nc
e,

ex
ec
ut
iv
e
fu
nc
ti
on
,
ve
rb

l
fl

ue
nc

y,
ps

yc
ho

m
ot
or
sp
ee
d
an
d
at
te
nt
io
n
W
M
S
-R
–v
is
ua
l
re
pr
od
uc
ti
on

su
bt

es
t,

R
A
V
L
T
,

C
P

T
–

IP
–d

ig
it

ve
rs

io
n,
ve
rb

al
fl

ue
nc

y
ex

am
in

at
io

ns
,

W
A

IS
-R

,
W
C
S
T
S
ig
ni
fi
ca
nt
im
pr
ov
em
en
ts
w
it
h
bo
th
ty
pe
s
of
m
ed
ic
at
io
n
in
V
is
uo
m
ot
or
sp
ee

d
(W

M
S

-R
)

an
d
vi
gi
la
nc

e
(C

on
ti

nu
ou

s
P

er
fo

rm
an

ce
T

es
t)

M
em
or
y
an
d
ve
rb

al
le

ar
ni

ng
(R

A
V

L
T

),
ex

ec
ut
iv
e
fu
nc
ti
on
(W
C
S
T
)

H
or

i
et

al
.
(2
00

6)
n

�
15

9
(n

�
67

pa
ti
en
ts
w
it

h
ch

ro
ni

c
sc

hi
zo
ph
re
ni
a,
n
�

92
co

nt
ro

ls
)

C
hr
on
ic
an
d

no
nc

ri
ti

ca
l
pa
ti
en
ts
C
hl
or
pr
om
az
in
e
an
d

si
m

il
ar

(n
�

23
)

N
ot
sp
ec
ifi
ed
(n
�

22
)

T
ra
ns
ve
rs
al
M
em
or
y,

in
te

ll
ig

en
ce

(I
Q

),
ex
ec
ut
iv
e
fu
nc
ti
on

,
sp

at
ia

l
ab

il
it

y,
ps
yc
ho
m
ot
or
sp
ee
d
W
M
S
-R
,
W

A
IS

–
R

,
W
C
S
T
,
T
M

T
–A

dv
an

ce
d

V
is
ua
l
m
em
or
y

(W
M

S
-R

),
de

la
ye

d
re

ca
ll

(W
M
S
-R
),
ex
ec
ut
iv
e
fu
nc
ti
on
(W
C
S
T
)

18 FERREIRA ET AL.

T
ab
le
1
(c
o
n
ti
n
u
ed
)
S
tu
dy
S
am
pl
e
C
ha
ra
ct
er
is
ti
cs
of
th
e
m
ai
n
sa
m
pl
e
T
yp
ic
al
dr
ug
s
A
ty
pi
ca
l
dr
ug
s
S
tu
dy
de
si
gn
N
eu
ro
co
gn
it
iv
e
fu
nc
ti
on
s
A
ss
es
sm
en
t
to
ol
s
R
es
ul
ts
T
yp
ic
al
�
at
yp
ic
al
A
ty
pi
ca
l
�
ty
pi
ca
l

K
ee

fe
et

al
.
(2
00

7)
n

�
14

60
(p

at
ie
nt
s
w
it
h
sc
hi
zo
ph
re
ni
a)
C
hr
on
ic
pa
ti
en
ts

P
er

ph
en

az
in

e
(n
�
25

7)
O

la
nz
ap
in
e
(n

�
33

0)
,

qu
et
ia
pi
ne
(n
�
32

9)
,

ri
sp
er
id
on
e
(n
�

33
3)

,
zi

pr
as
id
on
e
(n
�
18
3)
L
on
gi
tu
di
na
l
(b
as
el
in
e
an
d

12
m

ot
hs

)
P
ro
ce
ss
in
g
sp
ee

d,
re

as
on

in
g,

w
or

ki
ng
m
em
or
y,
ve
rb
al
m
em
or
y,
vi
gi
la

nc
e

C
O

W
A
T
,
C
P
T
–

P
,

W
A
IS
-R

–
di

gi
t
sy
m
bo
l
te
st
,
W
C
S
T
,
W
A

IS
.

N
o
si
gn

ifi
ca

nt
di

ff
er
en
ce

s
be

w
ee

n
tr

ea
tm
en
ts
K
ee
fe
et
al
.
(2
00

4)
N

�
16

7
(p

at
ie
nt
s
w
it

h
fi

rs
t

ep
is

od
e

of
sc

hi
zo
ph
re
ni
a,
sc
hi
zo
af
fe
ct
iv
e
di
so
rd
er
,
an
d
sc
hi
zo
ph
re
ni
fo
rm
di
so
rd

er
)

F
ir
st
-e
pi
so
de
sc
hi
zo
ph
re
ni
a
H
al
op
er
id
ol
(n
�

78
)

O
la
nz
ap
in
e
(n
�

89
)

L
on
gi
tu
di
na
l
(b
as
el
in
e
an
d

12
w

ee
ks

)

V
er

ba
l

fl
ue
nc
y,
at
te
nt
io

n,
m

em
or
y
an

d
le

ar
ni

ng
,

vi
su

om
ot

or
sp
ee
d,
w
or
ki
ng
m
em
or
y,
m
ot
or
sp
ee
d,
ex
ec
ut
iv
e
fu
nc
ti

on
s,

di
si

nh
ib

it
io

n,
de

si
gn
fl
ue
nc
y,
m
em
or
y
an
d
vi
su

al
or

ie
nt
at
io

n,
la

te
ra

li
ty

C
P

T
-I

P
,

C
V

L
T
,
W
A
IS

-R
di

gi
t-

sy
m
bo
l
te
st
,
D

ot
T

es
t

of
V

is
uo

sp
at

ia
l

W
or
ki
ng
M
em
or
y,

L
et

te
r-

N
um

be
r

S
eq

ue
nc
in
g
T
es

t,
F

in
ge

r
O

sc
il

la
ti

n
T

es
t,
W
C
S
T

–
64

-c
ar

d,
T

M
T
(A
an
d
B

),
va

ri
ab

le
–

in
te

rv
al

de
la
ye
d

al
te

rn
at

io
n

ta
sk

,
ob

je
ct

al
te
rn
at
io
n
ta
sk
,
S

C
W

T
,

R
uf

f
F

ig
ur

al
F

lu
en

cy
T

es
t,
W
M

S
R

S
ig
ni
fi
ca
nt
im
pr
ov
em
en
ts

(n
on

w
ei

gh
te
d
sc
or
es

)
w

it
h

bo
th

ty
pe
s
of
m
ed
ic
at
io
n

in
ve

rb
al
fl
ue
nc
y,
m
ot

or
fu

nc
ti
on
,
w
or
ki
ng
m
em
or
y,
ve
rb
al
m
em
or

y,
an

d
vi
gi
la
nc
e

C
om

po
si

te
sc

or
es

of
ve

rb
al
fl
ue
nc
y,
m
ot
or
fu
nc
ti
on
,
w
or
ki
ng
m
em
or
y,
ve
rb
al
m
em
or
y,
an
d
vi
gi
la
nc
e
(t
a
b
le
co
n
ti
n
u
es
)

19ANTIPSYCHOTIC DRUGS IN SCHIZOPHRENIA

fe
,

S
ei

dm
an

,
et

al
.
(2
00

6)
N

�
26

3
(p

at
ie
nt
s
w
it
h
fi
rs
t
ep
is
od
e
of
sc
hi
zo
ph
re
ni
a,
sc
hi
zo
af
fe
ct
iv
e
di
so
rd
er
,
an
d
sc
hi
zo
ph
re
ni
fo
rm
di
so
rd
er
)
F
ir
st
-e
pi
so
de
sc
hi
zo
ph
re
ni
a
H
al
op
er
id
ol
O
la
nz
ap
in
e
L
on
gi
tu
di
na
l
(b
as
el
in
e
an
d

12
,

24
,

52
,

10
4

w
ee

ks
)

A
tt
en
ti

on
an

d
vi
gi
la
nc
e,
pr
oc
es
si
ng
sp
ee
d,
m
ot
or
fu
nc
ti
on
,
ve
rb
al
m
em
or
y
an
d
le
ar
ni
ng
,
ve
rb
al
fl
ue
nc

y,
w

or
ki

ng
m

em
or
y,
an
d
vi
su
os
pa
ti

al
w

or
ki
ng
m
em
or
y
C
P
T
-I
P
,
W
A
IS
–
R
–d
ig
it
sy
m
bo
l
te
st

,
fi

ng
er

ta
pp

in
g,
C
V
L
T
,
C

at
eg

or
y

In
st

an
ce

s
an

d
C

on
tr

ol
le

d
O

ra
l

A
ss
oc
ia
ti
on

,
L

et
te

r-
N

m
be

r
S

pa
n,

W
C
S
T
–
64
-c
ar
d,
T
M
T
(A
an
d
B
),
va
ri
ab
le
–
in
te
rv
al
de
la
ye
d
al
te
rn
at
io
n,

ob
je

ct
al

te
rn

at
io

n,
S

C
W
T
,
R
uf

f
de

si
gn
fl
ue
nc
y
te
st
,
W
M
S
R
,
B
en

to
n

L
in

e
O

ri
en

ta
ti

on
T

es
t
S
ig
ni
fi
ca
nt
im
pr
ov
em
en
ts
w
it
h
bo
th
ty
pe
s
of
m
ed
ic
at
io
n
in
th
e

co
m

po
si
te
sc

or
e

of
ne

ur
oc

og
ni

ti
ve

te
st

s
D

ig
it

S
ym

bo
l
an
d

C
on

ti
nu

ou
s

P
er
fo
rm
an
ce
T
es

t
in

th
e

12
th

w
ee

k
of

tr
ea

tm
en

t,
w

ei
gh

te
d

sc
or

e
in
th
e
12
th
an
d

24
th

w
ee
ks
K
ee
fe
,

Y
ou

ng
,
et
al
.
(2

00
6)

N
�

41
4

(p
at
ie
nt
s
w
it
h
sc
hi
zo
ph
re
ni

a)
P

at
ie
nt
s

in
ea

rl
y-

st
ag

e
sc
hi
zo
ph
re
ni
a
H
al
op
er
id
ol
(n
�

97
)

O
la
nz
ap
in
e
(n
�

15
9)

,
ri
sp
er
id
on
e
(n
�
15
8)
L
on
gi
tu
di
na
l
(b
as
el
in
e
an
d
12
m
ot
hs
)

E
xe

cu
ti

ve
fu

nc
ti
on
,
le
ar
ni
ng
an
d
m
em
or
y,
pr
oc
es
si
ng
sp
ee
d,
at
te
nt
io

n-
vi

gi
la
nc
e,
ve
rb
al
w
or
ki
ng
m
em
or

y,
ve

rb
al
fl
ue
nc
y,
m
ot
or
fu
nc
ti
on
,
an
d
vi
su

os
pa

ti
al

ab
il

it
y

R
A
V
L
T
,
W
C
S
T
–
64
-c
ar

d,
R

C
F
T
,
W
A

S
,

C
P

T
-D

S
,
V
er
ba
l

F
lu

en
cy

,
C

O
W

A
T

,
G

ro
ov

ed
P

eg
bo
ar
d

(t
ot

al
nu

m
be

r
of

pe
gs

)
P
at
ie
nt

s
ab

le
to

re
m

ai
n

in
tr

ea
tm
en
t
fo
r
th
e
en
ti

re
52

w
ee

ks
be

ne
fi

te
d
m
or

e
fr

om
ol

an
za
pi
ne

or
ri

sp
er
id
on
e
th

an
ha

lo
pe

ri
do
l

20 FERREIRA ET AL.

K
ra

ko
w

sk
i

&
C

zo
bo

r
(2

01
1)
.
N
�

82
(p

at
ie
nt
s
w
it
h
sc
hi
zo
ph
re
ni
a

or
sc

hi
zo

af
fe

ct
iv

e
di
so
rd
er
)
N
on
cr
it
ic
al
pa
ti
en
ts
H
al
op
er
id
ol
(n
�
22
)
C
lo
za
pi
ne
(n

�
30

),
ol

an
za
pi
ne
(n
�

30
)

L
on
gi
tu
di
na
l
(b
as
el
in
e
an
d
12
w
ee
ks
)

P
sy

ch
om

ot
or
fu
nc
ti
on

,
ge

ne
ra

l
ex

ec
ut
iv
e
fu
nc
ti
on
,
vi
su
al
an
d
ve
rb
al
m
em
or
y,
vi
su
os
pa
ti

al
ab

il
it
y
W
C
S
T

–
ca

te
go

ri
es

co
m

pl
et

ed
,

T
M

T
-B

,
W
M
S

-R
–l

og
ic

al
m
em
or
y
an

d
fi

gu
ra

l
m
em
or

y,
M

M
S
E

G
en

er
al

co
gn
it
iv
e
in

de
x

w
as

gr
ea

te
r

w
it

h
ol

an
za
pi
ne
th
an
w
it

h
cl

oz
ap

in
e

or
ha

lo
pe
ri
do

.
C

lo
za

pi
ne

:
la

ng
ua
ge
pe
rf
or
m
an

ce
th

an
ri

sp
er
id
on

e
L

ee
et

al
.
(2
00

7)
N

�
16

3
(n

�
68

pa
ti
en
ts
w
it
h
sc
hi
zo
ph
re
ni
a
an
d
n
�

95
co

nt
ro
ls
)
N
on
cr
it
ic
al
pa
ti
en
ts
H
al
op
er
id
ol
(n
�

10
)

R
is

pe
ri
do
ne
(n
�
10
)
L
on
gi
tu
di
na
l
(b
as
el
in
e
an
d

1,
2,

4,
an

d
8

w
ee
ks
)
E
xe
cu
ti
ve
fu
nc
ti
on
,
w
or
ki
ng
m
em
or
y,
an
d
vi
su
os
pa
ti
al
sp
ee
d
W
C
S
T
,
M

az
e

pa
ra

di
gm

s
fo

r
co

gn
it

iv
e
fu
nc
ti
on
pe
rf
or
m
an
ce
W
or
ki
ng
m
em
or
y
an
d
vi
su
os
pa
ti
al
sp
ee

d
(M

az
e
pa
ra
di
gm
s)

M
or

re
ns

et
al
.
(2

00
8)

N
�

12
1

(n
�

96
pa

ti
en
ts
w
it
h
sc
hi
zo
ph
re
ni

a,
n

�
25
co
nt
ro
ls
)
C
hr
on
ic
pa
ti
en
ts

B
ro

m
pe

ri
do
l
(n

�
2)

,
fl

up
en

ti
xo

l
(n

�
1)

,
ha

lo
pe
ri
do
l
(n
�
11

),
pi

m
oz

id
e
(n
�

2)
,

zu
cl

op
en

th
ix

ol
(n

�
5)

R
is
pe
ri
do
ne
(n
�

26
),

ol
an
za
pi
ne
(n

�
24

),
ar
ip
ip
ra
zo
le
(n
�
1)

,
am

is
ul
pr
id
e
(n

�
8)

,
qu

et
ia

pi
ne
(n
�
5)
,
cl
oz
ap
in
e
(n
�
11
).
T
ra
ns
ve
rs
al
P
ro
ce
ss
in
g
sp
ee

d,
ve

rb
al
m
em
or
y,
w
or
ki
ng
m
em
or
y,
ex
ec
ut
iv
e
fu
nc
ti
on
,
an
d

ps
yc

ho
m

ot
ri

ci
ty

S
D
S
T
,
C
V
L
T
,
L
et
te
r-
N
um
be
r
S
eq
ue
nc
in
g
ta
sk
,
W
C
S
T
,
C
P
T
-I
P
,

fi
gu

re
-c

op
yi

ng
ta

sk
s

P
sy
ch
om
ot
or

m
ea

su
re

s
(fi

gu
re

–
co

py
in

g
ta

sk
s)

M
ül

le
r

et
al
.
(2
00
5)

.
N

�
70

(n
�

43
pa

ti
en
ts
w
it
h
sc
hi
zo
ph
re
ni
a,
n

�
27

co
nt
ro
ls
)
N
on
cr
it
ic
al
pa
ti
en
ts
F
lu

pe
nt

ix
ol

(n
�

14
),

ha
lo
pe
ri

do
l

(n
�

7)
,

pi
m

oz
id

e
(n
�
1)

,
le

vo
m

ep
ro

m
az
in
e
(n
�
1)
C
lo
za
pi
ne
(n
�
10
),
ol
an
za
pi
ne
(n
�

8)
,

ri
sp
er
id
on
e
(n
�
4)
,

am
is

ul
pr

id
e
(n
�

3)
,

qu
et
ia
pi
ne
(n
�
2)
.
T
ra
ns
ve
rs
al
W
or
ki
ng
m
em
or
y
an
d
ex
ec
ut
iv
e
fu
nc
ti
on
s

M
C

S
T
,
M
W
T

-A
,

ve
rb
al
fl
ue
nc

y,
di

gi
t

or
de

ri
ng

sp
an

ta
sk
W
or
ki
ng
m
em
or
y

(d
ig

it
or

de
ri

ng
sp

an
ta

sk
)

(t
a
b
le
co
n
ti
n
u
es
)

21ANTIPSYCHOTIC DRUGS IN SCHIZOPHRENIA

P
ur

do
n

et
al
.
(2

00
0)

N
�

65
(p

at
ie
nt
s
w
it
h
sc
hi
zo
ph
re

ni
a–

in
it

ia
l
st
ag
e)
P
at
ie
nt
s
in
ea
rl
y-
st
ag
e
sc
hi
zo
ph
re
ni
a
H
al
op
er
id
ol
(n
�
23
)
R
is
pe
ri
do
ne
(n
�
21
),
ol
an
za
pi
ne
(n
�
21
)
L
on
gi
tu
di
na
l
(b
as
el
in
e
an

d
6,

30
,

an
d

54
w

ee
ks
)

M
ot

or
sk

il
ls

,
at
te
nt
io
n,
ve
rb
al
an

d
no

nv
er

ba
l
fl
ue
nc
y,

re
as

on
in

g,
ex

ec
ut
iv
e
fu
nc
ti
on

s,
an

d
im

m
ed
ia
te

re
ca

G
ro

ov
ed

P
eg

bo
ar

d
T

es
t
an
d
th
e

F
in

ge
r

T
ap

pi
ng

T
es

t,
V

er
ba
l
an

d
N

on
ve

rb
al
S
pa
n
te

st
s,

W
M
S
-R
,
C
O
W
A
T
,
W
A
IS

-R
,

D
es

ig
n

F
lu
en
cy
T
es

,
H

oo
pe

r
V

is
ua

l
O

rg
an

iz
at

io
n
T
es

t,
R

C
F
T
O
la
nz
ap
in
e:
G
en
er
al

in
de

x
of

co
gn
it
iv

e
do

m
ai

ns
,
no
nv
er
ba
l
fl
ue
nc
y
an
d
re
as
on
in
g

(H
oo

pe
r

V
is
ua
l

O
rg

an
iz

at
io
n
T
es
t)
P
ur
do
n
et
al
.
(2

00
1)

N
�

25
(p

at
ie
nt
s
w
it
h
sc
hi
zo
ph
re
ni
a)
N
on
cr
it
ic
al
pa
ti
en
ts
H
al
op
er
id
ol
(n
�

12
)

Q
ue

ti
ap

in
e
(n
�

13
)

L
on
gi
tu
di
na
l
(b
as
el
in
e
an
d

8
an

d
54

w
ee
ks
)
M
ot

or
ab

il
it
y,
at
te
nt
io
n,
ve
rb
al
fl
ue
nc
y
an
d
re
as
on
in
g,
vi
su
os
pa
ti
al
in
te
ll
ig
en
ce
,
ex
ec
ut
iv
e
fu
nc
ti
on
an
d
vi
su
om
ot

or
tr

ac
ki

ng
,

im
m

ed
ia

te
re

ca
ll
F
in
ge
r
T
ap
pi
ng
T
es

t,
G

ro
ov
ed
P
eg
bo
ar
d
T
es

t,
W

M
S
-R
,
C
O
W
A
T
,
de
si

gn
fl

ue
nc

y,
V

is
ua
l
O
rg
an
iz
at
io
n
T
es

t,
C

om
pl

ex
F

ig
ur

e
C

op
y

T
es

t,
T

M
T

(B
),

W
A
IS
-R
–
di
gi
t
sy
m
bo
l
te
st
,
W
C
S
T
,
R
A
V
L
T
,
W
M
S
-R
–v
is
ua
l
re
pr
od
uc
ti
on
te
st
,
R

ey
an

d
T

ay
lo

r
C

om
pl
ex
F
ig
ur

e
Im

m
ed
ia
te

R
ec

al
l
T
es
t
V
er
ba
l
fl
ue
nc
y
an
d
re
as
on
in

g,
im

m
ed
ia
te
re
ca

ll
,

ex
ec
ut
iv
e
fu
nc
ti
on
an
d
vi
su
om
ot
or

tr
ac

ki
ng

22 FERREIRA ET AL.

00
3)

n
�

39
(p

at
ie
nt
s
w
it
h
sc
hi
zo
ph
re
ni
a)
P
at
ie
nt
s
in
ea
rl
y-
st
ag
e
sc
hi
zo
ph
re
ni
a
H
al
op
er
id
ol
(n
�

9)
R

is
pe
ri
do
ne
(n

�
13

),
ol
an
za
pi
ne
(n
�

11
)

L
on
gi
tu
di
na
l
(b
as
el
in
e
54
w
ee
ks
)
P
ro

ce
du

ra
l
le
ar
ni
ng

T
ow

er
of

T
or

on
to

te
st
S
ig
ni
fi
ca
nt
im
pr
ov
em
en
ts

in
pe

rf
or
m
an

ce
w

it
h
bo
th
ty
pe
s
of
m
ed
ic
at
io
n

af
te

r
6

w
ee

ks
of

tr
ea
tm
en

t
O

la
nz
ap
in

e
(a

ft
er

6
m
on
th
s
of
tr
ea
tm
en

t)
R

ém
il

la
rd

et
al
.
(2
00
8)
N
�

46
(n

�
28

pa
ti
en
ts
w
it
h
sc
hi
zo
ph
re
ni
a,
n
�

18
co

nt
ro
ls
)
N
on
cr
it
ic
al
pa
ti
en
ts
H
al
op
er
id
ol
(n
�

14
)

R
is
pe
ri
do
ne
(n
�
14
)
L
on
gi
tu
di
na
l
(b
as
el
in
e,

3,
6,

an
d

12 m
on

th
s)
V
er
ba
l
m
em
or
y,
pr
oc
es
si
ng
sp
ee
d
C
V
L
T

,
d2

C
an

ce
ll

at
io
n
T
es
t
N
o
si
gn
ifi
ca
nt
di
ff
er
en
ce
s
be

tw
ee

n
tr
ea
tm
en
ts

S
uz

uk
i,

&
G

en
(2

01
2)

N
�

20
(p

at
ie
nt
s
w
it
h
sc
hi
zo
ph
re
ni
a)
N
on
cr
it
ic
al
pa
ti
en
ts
H
al
op
er
id
ol

de
ca

no
at

e
de

po
t

(n
�
10
)
R
is
pe
ri
do
ne

lo
ng

–
ac

ti
ng

in
je

ct
io

n
(n

�
10
)
L
on
gi
tu
di
na
l
(b
as
el
in
e
an
d

24
w

ee
ks
)
E
xe
cu
ti
ve
fu
nc
ti
on
,
ve
rb
al
m
em
or

y
fu

nc
ti

on
.

an
d
at
te
nt
io
n
W
C
S
T

(K
ei

o
V

er
si

on
),

S
T

M
-C

O
M

E
T

M
em
or
y,
ex
ec
ut
iv
e
fu
nc
ti
on
,
m
ot
or
pr

oc
es

si
ng

fu
nc
ti
on
,
an
d
at
te
nt

V
el

li
ga

n
et
al
.
(2
00

2)
n

�
58

(p
at
ie
nt
s
w
it
h
sc
hi
zo
ph
re
ni

a)
.

N
on
cr
it
ic
al
pa
ti
en
ts

.
H

al
op
er
id
ol
(n
�
15

)
Q

ue
ti

ap
in

e
(3

00
m

g-
n

�
17

,
60

0m
g-

n
�

26
)

L
on
gi
tu
di
na
l
(b
as
el
in
e
an
d
24
w
ee
ks
).
E
xe
cu
ti
ve
fu
nc
ti
on
s,
m
em
or
y,
at
te
nt
io
n.
S
C
W
T
,
H

op
ki

ns
V

er
ba

l
L

ea
rn
in
g,
S
ym

bo
l-

di
gi

t
su

bs
ti

tu
ti

on
,
T
M
T
(A

e
B

),
P

ar
ag

ra
ph

re
ca

ll
(v

er
ba
l
m
em
or

y)
,

V
er
ba
l
fl
ue
nc
y,
P
at
te
rn
m
em

or
y.

Q
ua

ti
ap
in
e

(6
00

m
g)

:
E

xe
cu

ti
ve
fu
nc
ti
on

(v
er

ba
l
fl
ue

nc
y)

,
at
te
nt
io
n

(S
tr

oo
p

C
ol

or
–

W
or

d)
an

d
ve

rb
al
m
em
or
y

(p
ar

ag
ra

ph
re
ca
ll
)

23ANTIPSYCHOTIC DRUGS IN SCHIZOPHRENIA

W
it

to
rf

et
al
.
(2
00
8)
N
�

12
2

(n
�

82
pa

ti
en
ts
w
it
h
sc
hi
zo
ph
re
ni
a,
n

�
40

co
nt
ro
ls
)
N
on
cr
it
ic
al
pa
ti
en
ts
P
er
ph
en
az
in
e
(n

�
6)

,
pe

ra
zi

ne
(n
�
6)
,
fl

up
he

na
zi
ne
(n
�
1)
,
fl
up
en
ti
xo

l
�

cl
or

pr
ot

hi
xe

n
(n
�
1)
,
ha
lo
pe
ri
do
l
�
fl
up
he
na
zi
ne
(n
�

1)
,

pe
ra

zi
ne

�
pr

om
et

ha
zi

e
�

br
om

pe
ri
do
l
(n
�
1)
O
la
nz
ap
in
e
(n
�
14
),
cl
oz
ap
in
e
(n

�
12

),
ri

sp
er
id
on
e
�
cl
oz
ap
in
e
(n
�
2)
,
ri
sp
er
id
on
e
(n
�
1)
,
am
is
ul
pr
id
e
(n
�
1)
,
su
lp
ir
id
e
(n
�
1)
,
ol
an
za
pi

ne
�

am
is
ul
pr
id
e
(n
�
1)
,
cl
oz
ap
in
e
�
ri
sp
er
id
on
e

�
ol

an
za
pi
ne
(n
�
1)
L
on
gi
tu
di
na
l
(b
as
el
in
e
an
d
6
m
on
th
s)
M
em
or
y,
at
te
nt
io

n,
ex

ec
ut
iv
e
fu
nc
ti
on
W
C
S
T
,
C
P
T

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24 FERREIRA ET AL.

harmacy) of typical drugs (Hori et al., 2006) in
the remediation of cognitive deficits in schizo-
phrenia. However, in some cases such an ad-
vantage was not evident. Keefe, Seidman, et al.
(2006) found that lower doses of haloperidol
produced better effects on cognitive symptoms
than did the administration of olanzapine.
Thornton et al. (2006), in a review article, re-
ported no significant differences between typi-
cal and atypical antipsychotics on long-term
memory, whereas Crespo-Facorro et al. (2009)
found no differences between the effects of
haloperidol and those of atypical drugs (olan-
zapine and risperidone) on neurocognition.

We observed that the studies reviewed had
huge differences in sample size, ranging from
20 to 1,432 participants. When it came to larger
samples (above 100 participants), we identified
a relatively consistent pattern of the effects of
typical and atypical antipsychotics on cognition.
In general, both classes of antipsychotics pro-
duced positive effects on visuomotor processing
speed and vigilance (Harvey et al., 2005), ex-
ecutive functions (Harvey et al., 2004; Suzuki &
Gen, 2012), and other neurocognitive functions
(Davidson et al., 2009; Guo et al., 2011; Purdon
et al., 2000). In addition, atypical antipsychotics
had a tendency to produce better effects on
cognitive functions. Harvey et al. (2005) con-
ducted a study with 506 patients and verified
that patients under typical (haloperidol) and
atypical (risperidone) treatment presented better
episodic memory, vigilance, and visuomotor
speed. However, only the group under atypical
treatment presented a better performance in ex-
ecutive functions and verbal fluency. In con-
trast, Han et al. (2015) found that individuals
taking clozapine showed worse immediate and
delayed memory performance than did those
taking typical antipsychotics.

Among the studies with large samples, Keefe
et al. (2007) and Davidson et al. (2009) found
no differences between first- and second-
generation antipsychotics. Keefe et al. (2007)
showed that both typical (perphenazine) and
atypical (olanzapine, quetiapine, risperidone,
and ziprasidone) antipsychotics produced simi-
lar positive effects on neurocognitive functions.
According to the authors, this result may be
related to the fact that perphenazine is a mod-
erate typical antipsychotic, producing minor
sedative effects and extrapyramidal symptoms,
a different pattern than observed with first-

generation antipsychotics such as haloperidol.
Anticholinergic drugs are usually employed to
attenuate extrapyramidal symptoms, but they
also impair cognitive functions. Considering
this fact, it is reasonable to suppose that small
quantities of anticholinergic were administered
concurrently with perphenazine, which may ex-
plain the better cognitive performance obtained
with typical treatment. Although perphenazine
is not considered an atypical antipsychotic, one
of its metabolites has relatively high affinity
with serotonin 2A receptors, which may confer
some atypical properties. Furthermore, Keefe et
al. (2007) adopted inclusion criteria (e.g., al-
lowing comorbidity, use of other medications,
and substance abuse) that made the comparison
with more-controlled studies difficult. Despite
the fact that groups were not homogeneous, the
study has some aspects similar to “real-world”
conditions, and their results may be broadly
applied. Similarly, Davidson et al. (2009) found
no differences between the treatment with low
doses of haloperidol and second-generation an-
tipsychotics. In accordance with the previous
point, the authors argued that lower doses of
haloperidol are probably associated with the
decrease of extrapyramidal symptoms and the
use of anticholinergic medications.

In the literature, many studies have indi-
cated that higher doses of first-generation an-
tipsychotics can impair cognition. For exam-
ple, Knowles et al. (2010), in a meta-analysis
study, examined the influence of potential
variables on processing speed and other spe-
cific cognitive functions in schizophrenia.
They found that processing speed is signifi-
cantly affected by several moderating factors,
such as IQ differences between case and compar-
ison subjects concerning the dosage of the anti-
psychotic medication. For the case of chlorprom-
azine, they found a strong relationship between
dosage and performance in the symbol-coding
task, in which the smaller the daily doses of chlor-
promazine, the lower the coding-task effect size.
When they grouped the four studies with the high-
est and the lowest doses values, they found an
effect size of �2.04 and �1.24, respectively, in
comparison with healthy controls. In such a
case, one cannot rule out the possibility that, for
the patients who received more chlorpromazine,
the concurrent-use higher dosages of anticho-
linergic medication may have contributed to the
worse cognitive performance. Cognitive bene-

25ANTIPSYCHOTIC DRUGS IN SCHIZOPHRENIA

fits of the atypical antipsychotic may be supe-
rior for some domains of cognition and require
less use of anticholinergic drugs, which impair
memory, for treatment of extrapyramidal side
effects (Meltzer, 2013), but even in studies
showing an advantage of atypical over typical
antipsychotics one cannot be sure of the mag-
nitude of the impairment produced by the con-
current use of antiparkinsonian medication. For
example, Suzuki and Gen (2012) found that the
switching from haloperidol decanoate depot to
risperidone long-acting injection (RLAI) im-
proved cognitive function, including memory,
executive function, motor processing function,
and attention. In the study, they also observed a
significant reduction in the antiparkinsonian
medication (biperiden) taken by the group sub-
mitted to RLAI compared to the control group.
Therefore, the authors concluded that “it is im-
possible to rule out the possibility that the con-
comitant use of anti-Parkinson’s medication
may have masked changes in cognitive func-
tions” (p. 475). In fact, this problem has been
related in many works in literature (Leucht et
al., 2009).

An important characteristic to be stressed
in the selected studies is the variation in the
morbidity time of schizophrenia. Some stud-
ies involve assessments from the first episode
of schizophrenia (Davidson et al., 2009; Har-
vey et al., 2005; Keefe et al., 2004 and Keefe,
Seidman, et al., 2006), which provide impor-
tant information on neurocognitive deficits
not associated with side effects of treatment
with antipsychotics. Among such studies,
only Davidson et al. (2009) reported no dif-
ferences between treatment with haloperidol
and atypical antipsychotics in the symptom-
atic improvement of patients with schizophre-
nia. Some of these studies reported that both
typical and atypical antipsychotics promote
improvements in neurocognitive function,
with atypical antipsychotics tending to favor
some specific cognitive functions, such as
memory, verbal learning, and executive func-
tion (Harvey et al., 2005); verbal fluency,
motor function, and vigilance (Keefe et al.,
2004); and processing speed and attention
(Keefe, Seidman, et al., 2006).

In a different manner, other studies have
evaluated chronic schizophrenia patients
(Cuesta et al., 2001; Han et al., 2015; Hori et al.,
2006; Keefe et al., 2007; Morrens et al., 2008).

Most of these studies indicated an advantage for
atypical antipsychotics on neurocognitive func-
tion (Cuesta et al., 2001; Han et al., 2015; Hori
et al., 2006; Morrens et al., 2008). Only Keefe
et al. (2007) found no differences among classes
of antipsychotics on neurocognitive function in
patients with chronic schizophrenia, which may
be associated with the use of a typical antipsy-
chotic (perphenazine) with characteristics simi-
lar to those for atypical drugs (see earlier).
Lieberman et al. (2005) reported variations in
efficacy and tolerability of antipsychotic medi-
cations in chronic patients, and they also found
substantial limitations in the effectiveness of
typical and atypical antipsychotics. Olanzapine
appeared to be more effective than the other
drugs studied; however, there were no signifi-
cant differences between perphenazine and
other atypical drugs. This variation in duration
of illness chronicity makes a direct comparison
between studies difficult, because there is no
well-established evidence on the progression
pattern of impairment in schizophrenia, which
can be caused by the use of long-term medica-
tion and/or by the underlying disease process
(Keefe, 2008).

In order to understand the effect of different
antipsychotics on cognition, recent studies have
been conducted with healthy participants. For
example, Veselinović et al. (2013), in a single-
blind, randomized, placebo-controlled study,
analyzed the subchronic effect of antidopamin-
ergic treatment. They found that after a 7-day
intervention, young healthy participants pre-
sented impairments in processing speed, atten-
tion, and learning when compared to healthy
controls receiving the placebo. Differences be-
tween first- (haloperidol and reserpine) and sec-
ond-generation (aripiprazole) antipsychotics
were not observed, but seven of the 18 patients
(38.9%) submitted to the haloperidol group in-
terrupted the study ahead of schedule, probably
due to the side effects associated with the med-
ication.

In the present review, when we analyzed
the studies with smaller sample sizes, only
Wittorf et al. (2008) and Rémillard et al.
(2008) did not find significant differences be-
tween typical and atypical drugs. According
to Wittorf et al. (2008), this may be due to
factors related to the sample, because they
tested patients in the stabilization phase and
excluded those who had to withdraw before

26 FERREIRA ET AL.

follow-up. Thus, their results may apply only
to patients who were able to recover from the
disease. In addition, the sample comprised
only first-episode cases.

Concerning the design of the clinical trials,
we observed that most of the studies with large
samples used the randomized double-blind pro-
cedure (Harvey et al., 2005; Guo et al., 2011;
Keefe et al., 2007, 2004), which contributes to
making the study more reliable and reducing
research bias.

Finally, it is important to indicate some
limitations of the present review. The first one
concerns the heterogeneity of the neuropsy-
chological tests used and the cognitive func-
tions investigated. Some studies addressed
broad neurocognitive domains such as intel-
ligence, whereas others focused on specific
functions such as working memory. Such
characteristics of the review make difficult or
prevent an adequate analysis of the same cog-
nitive function throughout the studies. A sug-
gestion for future works is to carry out a
review on the same cognitive function as-
sessed by similar neurocognitive tests. Like-
wise, a meta-analysis may focus on the effect
size concerning the impairment of a certain
cognitive function, similar to the studies by
Dickinson et al. (2007) and Knowles et al.
(2010) in regard to the analysis of processing
speed and other specific cognitive functions
in schizophrenia.

Another limitation concerns the exclusion of
neuroimaging studies that could contain rele-
vant evidence about the effects of different an-
tipsychotics on cognition. The inclusion of
those studies, however, would have made any
synthesis still more complicated by the inclu-
sion of additional variables, and it is our opinion
that this should be the subject of another review.
It is worth noting, however, that the keywords
chosen allowed us to gather representative
works in the literature that have directly com-
pared the effects of typical and atypical antip-
sychotics on neurocognitive functions in pa-
tients with schizophrenia.

Our review showed that most empirical stud-
ies indicated advantages of atypical over typical
antipsychotics, especially regarding cognitive
functions such as working memory, reasoning,
attention, and verbal fluency. However, it is
important to highlight that many studies indi-
cated that the decrease in the dosage or an

adjustment in the type of first-generation anti-
psychotic (e.g., perphenazine) may reduce ex-
trapyramidal symptoms and the subsequent use
of anticholinergics, thereby attenuating the cog-
nitive impairments associated with their admin-
istration. Those findings indicate that more re-
search is needed to disentangle the negative
effect produced on cognition by anticholin-
ergics from other variables, such as the kind of
antipsychotic prescribed.

Another important variable that may hinder
comparison studies is the duration of antipsy-
chotic treatment along with the follow-up eval-
uation time. In some longitudinal studies, pa-
tients were evaluated a few weeks after starting
treatment with certain medications, for exam-
ple, between 1 and 8 weeks (Lee et al., 2007). In
other cases, patients were followed up for a
longer time interval, such as in Keefe, Seidman,
et al. (2006), where patients were evaluated at
12, 24, 52, and 104 weeks after the beginning of
treatment.

Table 1 shows that the majority of studies
(73.9%) used a longitudinal design for evaluat-
ing neurocognitive function. The advantages
and disadvantages of transverse or longitudinal
designs must be considered in each case. In
longitudinal studies, there is a higher dropout
rate of patients and learning can influence the
results during short retest intervals (Rund,
1998). Cross-sectional studies may have greater
sample heterogeneity regarding the stages of the
disease, chronicity, medications used, and their
association with neuroleptics and anticholin-
ergics, representing potential confounding vari-
ables.

Despite the promising results, future re-
search is required to assess the advantages
and disadvantages of atypical drugs in the
long term. Further systematic reviews should
investigate specific cognitive functions such
as working memory, attention, or verbal flu-
ency, which would contribute to more-
accurate results. Similarly, additional empir-
ical analyses may focus on the effects of
antipsychotics on specific neurocognitive
functions or social cognition, for example.
This line of investigation is of great impor-
tance because of its potential contributions to
establishing effective pharmacological treat-
ments that allow the maintenance or recovery
of neurocognitive functions in schizophrenia,
increasing the quality of life of patients.

27ANTIPSYCHOTIC DRUGS IN SCHIZOPHRENIA

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Received July 13, 2015
Revision received February 8, 2016

Accepted February 12, 2016 �

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31ANTIPSYCHOTIC DRUGS IN SCHIZOPHRENIA

http://dx.doi.org/10.1177/0269881105057002

http://dx.doi.org/10.1016/S0920-9964%2801%2900268-7

http://dx.doi.org/10.1177/0269881112466183

http://dx.doi.org/10.1016/j.acn.2007.12.005

http://dx.doi.org/10.1080/15622970701849986

Neurocognitive Functions in Schizophrenia: A Systematic Review of the Effects of Typical and Aty …

Method
Results
Discussion
References

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