Improving Negative Symptoms of Psychosis In Real-world Environments
Phase: NA
Conditions: Schizophrenia
Sponsor: University of California, San Diego

Improving Negative Symptoms of Psychosis In Real-world Environments 
    
NCT02170051 
 
 
PROTOCOL APPROVED OCTOBER 19, 2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Phase II of the project (22.5 months) will include a pilot RCT comparing combined CBSST-CCT to goal-
focused supportive contact (SC), an active control group. 64 participants (16 from each of 4 community 
locations) will be recruited, and the interventions will be delivered in a group format on-site by masters-level 
research therapists. The locations will include a large board and care facility, a clubhouse, and two 
psychosocial rehabilitation centers (see letters of support). Participants with schizophrenia and moderate-to-
severe negative symptoms will be randomized to condition after completing baseline assessments, and will 
then be treated for 4.5 months and followed longitudinally for 6 months after treatment. Assessments will be 
administered at baseline, midway through treatment, post-intervention, and 6 month follow-up. The 6-month 
follow-up recognizes the need to determine enduring effects, as well as findings that differences between CBT 
and control conditions are often greater at follow-up than at post-treatment (Sensky et al., 2000; Granholm et 
al., 2007b; Gould et al., 2001). The last-enrolled participants will finish their 6-month follow-up assessments 
during quarter 2 of year 3. During the last 2 quarters of the project, we will (1) conduct our data analyses, (2) 
write manuscripts, and (3) prepare an R01 application for a larger scale study of CBSST-CCT.  
 
Figure 3. Timeline of the proposed study 
Year 1 
Year 2 
Year 3 
Q1 
Q2 
Q3 
Q4 
Q1 
Q2 
Q3 
Q4 
Q1 
Q2 
Q3 
Q4 
-Hire and train staff 
-Focus groups (patients, 
family members, clinicians) 
-Develop combined 
CBSST-CCT manual 
-Practice group (4.5 mos) 
Recruit, enroll, randomize, and deliver 
intervention to first 16 participants  
(4.5 months tx + 6 months f/u) 
 
 
Recruit, enroll, randomize, and deliver 
intervention to second 16 participants  
(4.5 months tx + 6 months f/u) 
 
 
Recruit, enroll, randomize, and deliver 
intervention to third 16 participants  
(4.5 months tx + 6 months f/u) 
 
 
Recruit, enroll, randomize, and deliver 
intervention to fourth 16 participants  
(4.5 months tx + 6 months f/u) 
-Data analysis 
-Manuscript writing 
-R01 preparation 
 
3.3. Participants. Inclusion/exclusion criteria were designed to select 64 participants with schizophrenia with 
moderate-to-severe negative symptoms (Buchanan, 2007), enriched for predominantly primary negative 
symptoms but allowing for untreated secondary negative symptoms. Selecting for moderate-to-severe negative 
symptoms will minimize the likelihood that negative symptom improvement is secondary to improvement in 
positive symptoms or depression, and will capture those negative symptoms that lead to functional disability 
and are currently an unmet treatment need (Buchanan, 2007). The NIMH-MATRICS Consensus Statement on 
Negative Symptoms (Kirkpatrick et al., 2006) has recommended this approach. Inclusion criteria: (1) 
Voluntary informed consent to participate; (2) Age 18 to 65; (3) DSM-IV diagnosis of schizophrenia or 
schizoaffective disorder based on MINI/SCID; (4) Moderate-to-severe negative symptoms on the Clinical 
Assessment Interview for Negative Symptoms (CAINS total score >19); (5) ≥ 6th grade reading level on the 
Wide Range Achievement Test-4 Reading subtest (needed for reading treatment manual); (6) Stable on 
medications; no changes within 3 months prior to enrollment. Exclusion criteria: (1) Prior CBT, SST, or CCT 
in the past 5 years; (2) Severe positive symptoms on the Positive and Negative Syndrome Scale (PANSS 
Delusions, Disorganization, Hallucinations, or Suspiciousness >5); (3) Severe depression on the Calgary 
Depression Scale for Schizophrenia (CDSS >8); (4) Ocular damage/disease/surgery/medications that affect 
pupil dilation; (5) DSM-IV alcohol or substance dependence diagnosis in past 6 months based on the MINI or 
SCID; (6) Level of care required interferes with outpatient therapy (e.g., hospitalized; severe medical illness). 
 
3.4. Feasibility of recruitment and retention. Subjects will be recruited from a large board and care facility 
(Broadway Home), a clubhouse (The Meeting Place), and two psychosocial rehabilitation and recovery 
programs in San Diego (Project Enable and Areta Crowell). All four locations have the numbers of service 
users needed to recruit a group of 16 individuals, and all have the space to run groups on-site (please see 
letters of support). (We also have a back-up location, the Psychosocial Rehabilitation and Recovery Center, 
directed by Dr. Granholm at the VA San Diego Healthcare System.) In our prior CBSST trials, we achieved a 
79% consent rate of patients with schizophrenia. In two ongoing trials, we have enrolled 242 patients with 
schizophrenia from the proposed recruitment locations and 42% had at least moderate-to-severe negative 
symptoms at baseline, demonstrating that we can enroll patients with negative symptoms into psychosocial 
intervention studies. In addition, we will enhance feasibility by providing all interventions on-site, particularly 
important with negative symptom cohorts. Monetary incentives (only for assessments, not therapy sessions) 
will also facilitate enrollment and retention, and we have found that a strong intervention focus on real-world 

goals (e.g., relationships, independence, finances, work/school) promotes enrollment and retention. We will 
optimize follow-up with regular patient contact in treatment, mailings to confirm whereabouts (e.g., birthday and 
holiday cards), and consent to contact at least one person likely to know subject whereabouts. These methods 
have resulted in low drop-out rates in prior trials (<10% drop-out at 4.5 months, 20% drop-out at 18 months). 
 
3.5. Procedures and Design Considerations. To ensure that participants meet study criteria, we will use the 
Mini International Neuropsychiatric Interview (MINI; Sheehan et al., 1998) or Structured Clinical Interview for 
DSM-IV (SCID; First et al., 1997), followed by a consensus diagnosis with an experienced clinician, using all 
available records and the structured interview. To reduce participant burden, participants who have undergone 
a SCID or MINI interview by a trained, reliable interviewer as part of other research participation within the past 
year will not have to repeat the interview. We will also obtain demographic data, medical/pharmacologic 
history, and alcohol/substance history. We will use the Schedule for the Deficit Syndrome (Kirkpatrick et al., 
1989) to characterize the sample into deficit and nondeficit groups for exploratory analyses. Following informed 
consent and baseline assessment, randomization via computer-generated randomization scheme 
(www.randomization.com) will be used to assign participants to one of the two conditions. Assessors will be 
blind to randomization status. Assessments will be administered at baseline, midway through treatment (2.25 
months), post-treatment (4.5 months), and 6-month follow-up (10.5 months). Thus, participants will be enrolled 
in the study for 10.5 months. Participants will not be compensated for their time receiving therapy, but they will 
be compensated for their time at all four assessments. Participants will be paid $30 for participating in each (~3 
hr) assessment, plus a $20 bonus for completing all four assessments. Two masters-level therapists will 
provide both interventions at two locations each so as not to confound therapist effects with location effects. All 
participants will continue to receive their current treatments, including pharmacotherapy, with their current 
providers throughout the study. We will ensure that patients enrolled in either treatment condition in this project 
do not receive other CBT, SST, or cognitive remediation/training interventions during study participation, but 
will not restrict any other types of services or medications. We will not try to influence pharmacotherapy, but 
will track medications at each assessment and these data will be used to explore differences in outcomes. We 
will attempt to obtain follow-up data on all participants, regardless of whether or not they complete treatment. 
Design Considerations. The main strengths of the proposed study are its importance, innovation, design, and 
feasibility. The study design will answer the questions of interest with adequate power and will be feasible to 
complete (n=16 needed at each location), given the ample number of potential participants available at each 
location (see letters of support). Importantly, the four locations are all part of the San Diego County mental 
health system, and all assessors, therapists, and study staff will be the same across the four locations, 
therefore, this is not a multi-site trial with the potential for site effects. We are intentionally selecting 
participants with a high negative symptom burden and identified treatment locations enriched for lower-
functioning patients with more severe negative symptoms. For the control condition, we considered using 
“treatment as usual,” but opted for an active comparison condition that wouldn’t confound specific with 
nonspecific therapeutic factors. We also considered comparing CBSST-CCT with standard CBSST or CCT, but 
concluded that this design would not be appropriate for a pilot project, in which the central question is, “does 
the bundled intervention work?” Multiple treatment arms (CBSST-CCT vs. CBSST vs. CCT vs. SC) would not 
be feasible in a pilot study and we have already established the efficacy of CCT and CBSST relative to control 
groups. This is not a dismantling study, and at this stage we believe it is less important to determine whether 
one of the components of CBSST-CCT is more effective. The bundling of CBT, SST, and CCT components 
that target the multiple deficits linked to negative symptoms and poor functioning in schizophrenia (e.g., 
defeatist attitudes; social competence; problem solving; cognitive impairments) is potentially more effective. 
We will be able to compare the effects of CBSST-CCT to historical effects of CBSST and CCT alone, which 
have been studied in >250 people with schizophrenia. We elected to have two masters-level therapists 
deliver both interventions at each location, which will equate treatment conditions and locations for 
nonspecific therapist characteristics, a common procedure in psychosocial clinical trials. With this procedure, it 
will be important to actively monitor the nature of clinician interactions with consumers to ensure CBSST-CCT 
interventions are not delivered in SC. We are confident that we can prevent treatment contamination because 
CBSST-CCT will be manual-driven and rated for fidelity, and we will record sessions in both conditions to 
carefully monitor and address any contamination that might arise. We have experience with this approach to 
monitoring fidelity to different interventions from our prior CBSST and CCT trials. Finally, we chose masters-
level therapists, because few doctoral-level therapists are available in community mental health systems.  
 

3.5.1. Experimental condition: CBSST-CCT. 
Our combined intervention will be a seamless 
integration of CBSST and CCT, each described 
here. Please see Appendix 1 and 2 for copies 
of the CBSST and CCT manuals.  
CBSST (Granholm et al., 2002; 2005; McQuaid 
et al., 2000) integrates CBT and SST to target 
the different factors contributing to negative 
symptoms and poor functioning in our model of 
functional outcome (Figure 4). The CBSST 
manual includes a patient workbook describing 
the skills and homework assignments. The CBT 
components are based on established CBT 
techniques (Beck et al., 1979; Beck, 1995) and 
techniques developed specifically for patients 
with schizophrenia (Kingdon & Turkington, 
1994; Beck & Rector, 2000). The SST components are based partly on an SST intervention available from 
Psychiatric Rehabilitation Consultants (Liberman, 1991) and Bellack, Muser et al. (2004). Cognitive therapy is 
combined with role-play practice of communication skills and problem-solving training. CBSST, therefore, 
targets the multidimensional deficits that contribute to negative symptoms and disability in patients with 
schizophrenia. CBSST is a group therapy intervention delivered in three, 6-session modules (see Table 1) for a 
total of 18 group therapy sessions, but participants cycle through the sequence of three modules twice, for a 
total of 36 sessions (we have successfully delivered CBSST both weekly for 9 months and twice-weekly for 4.5 
months). Repeating the modules in this way provides skills practice consistent with behavioral learning 
principles to compensate for cognitive impairment. This is not simply rote repetition, as skills are applied to 
different thoughts, problems, and social situations in patients’ lives during repetition of the modules, and 
repetition promotes mastery and self-efficacy. Each group therapy session is two hours, with a lunch or snack 
break mid-way. CBSST will be modified to strengthen its impact on negative symptoms for the 
proposed project in several ways: (1) Most importantly, all modules will focus more extensively on 
challenging defeatist performance beliefs hypothesized to be associated with negative symptoms (see Table 
1); (2) Therapy will be provided on-site and motivational interviewing techniques (e.g., four squares discussion 
of what is good and not so good about coming to group or working on goals) are added to the initial session of 
each module to promote treatment engagement; (3) Affect expression and recognition is targeted more 
extensively in behavioral role plays in the social skills training module; (4) Behavioral activation activities (e.g., 
scheduling pleasant activities; behavioral day scheduling) are added to the problem solving module.  
 
CCT (Twamley, 2008, 2011, 2012) is a 12-week, manualized, low-tech, group-based compensatory cognitive 
training intervention designed to target 4 cognitive domains: (1) prospective memory, (2) attention and 
vigilance, (3) learning and memory, and (4) executive functioning. These domains were selected based on 
their degree of impairment in schizophrenia-spectrum disorders, relevance for psychosocial functioning, and 
potential modifiability (Green et al., 2000; McGurk & Meltzer, 2000; Spaulding et al., 1999). Our goal was to 
take advantage of intact abilities in schizophrenia, such as habit learning (Clare et al., 1993; Keri et al., 2005) 
and imagery (Thakkar & Park, 2012) to bolster impaired functions. Because habit learning is also highly 
resistant to forgetting (Bayley et al., 2005), we aimed to help participants form new habits in attention, learning, 
and problem-solving to automate tasks and reduce the active cognitive effort usually demanded for effective 
performance. CCT does not use computers, and strategies taught do not “train to the test” or use any of the 
outcome measures during training. Selected strategies taught in each domain are presented in Table 2. The 
CCT treatment manual has been distributed to over 250 clinicians and has been used with first episode 
schizophrenia participants, clients in supported employment and supported education settings, and has been 
adapted for other disease populations (brain injury, mild cognitive impairment, multiple sclerosis, Parkinson’s 
disease, compulsive hoarding, and substance use disorders). CCT improves negative symptoms and can also 
enhance CBSST by enhancing attention to CBSST content, learning of content, and memory for content. 
 
Table 1. CBSST Module Goals and Corresponding Manual Content 
CBSST Thought Challenging Module Goals 
Session/Homework Content 
Address symptoms and challenge defeatist beliefs 
that interfere with real-world skills execution 
Thought challenging skills to challenge defeatist performance beliefs, 
including expectancies (“It won’t be fun”), self-efficacy beliefs (“I always fail”), 
and atypical beliefs (“Spirits will harm me”) 
Model of Functional Outcome in Schizophrenia
Functional 
Capacity
Community 
Contexts &
Opportunities
SocialSupport/ 
Hindrances, 
Institutional 
Hindrances, 
Resources 
Neurocognitive 
Functioning
Daily 
Functioning
Negative 
Symptoms
Anhedonia, 
Amotivation, 
Apathy, Blunted 
Affect
Cognitions
Defeatist 
Performance 
Beliefs, Social 
Disinterest
Figure 4. Empirically-driven model of functional outcome. 

Planning to engage in effortful goal-directed behaviors and use the skills they 
have 
Introduce the general concepts of CBT, including the 
relationship between thoughts, actions and feelings, 
automatic thoughts, thought challenging by 
examining evidence for beliefs, and mistakes in 
thinking  
Discussion, thought records, and homework involving identifying (a) thoughts, 
(b) relationships between thoughts, feelings and behaviors, and (c) mistakes 
in thinking (e.g., jumping to conclusions; mind reading; all-or-none thinking) 
Behavioral experiments to gather evidence to evaluate beliefs 
CBT techniques to help patients examine the logic of beliefs and generate 
more adaptive alternatives to mistakes in thinking 
Help participants learn and remember to use their 
CBT skills 
Mnemonic aids are provided (e.g., wallet cards describing skills). Example: to 
foster thought challenging, we use the acronym, “3C’s: Catch it, Check it, 
Change it,” where “it” is a maladaptive thought 
CBSST Social Skills Training Module Goals 
Session/Homework Content 
Improve communication skills and psychosocial 
interactions (e.g., asking someone for support) via 
behavioral role plays 
Role plays focused on interacting with roommates, friends and family, making 
new friends, and effectively interacting with case managers, other service 
providers, and support persons 
Improve expression of positive and negative 
feelings, making requests, comfortable sharing of 
feelings, and communicating assertively 
Role plays emphasize non-verbal affect expression and recognition of affect 
in others (e.g., group members are asked to change facial expressions and 
label and comment on affect expression in others performing role plays)  
Improving everyday activities and psychosocial functioning are common role 
play topics (e.g., asking a roommate to change their behavior; asking 
someone to go to the movies; assertive interactions) 
Improve self-efficacy and defeatist performance 
beliefs 
Self-efficacy and performance beliefs are elicited before and after role plays 
(0-10 ratings of how successful you think you will be/were) to challenge 
defeatist beliefs about communication abilities 
CBSST Solving Problems Module Goals 
Session/Homework Content 
Improve basic problem-solving skills 
Skills are taught 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 
Help participants develop plans to solve real-world 
problems and improve illness self-management 
Use skills to address living situations, finances, use of public transportation, 
finding a job, enrolling in school, coping with symptoms and stress, 
remembering to take medications, and hygiene/health 
Improve negative symptoms  
Planning and scheduling pleasant activities; behavioral activation techniques 
Develop confidence in effective problem-solving 
Challenge defeatist beliefs by eliciting ratings of expected success or failure 
before executing a plan and review evidence about success after executing a 
plan 
 
Table 2. Cognitive Domains Targeted in CCT and Corresponding Manual Content 
Cognitive Domain 
Strategies taught and practiced to improve cognition and functioning 
Prospective Memory 
Calendar use; to-do lists; prioritizing tasks; linking tasks by using planned cues; automatic places; 
using routines to automate tasks 
Attention/Vigilance 
Eye contact, paraphrasing, asking questions during conversations; self-talk during tasks; taking 
breaks to refocus 
Learning/Memory 
Taking notes; association; chunking; categorization; acronyms; visual imagery; overlearning 
Executive Functioning 
Six step problem solving method; self-talk and self-monitoring while solving problems; hypothesis 
testing using pro and con evidence; set shifting; set maintenance 
 
Defeatist Beliefs and Rationale for the Combined Treatment Approach. It is well-known that 
neurocognitive deficits are associated with poor functional outcome in schizophrenia (Green, 1996; Green et 
al., 2004; Milev et al., 2005; Kurtz et al., 2005), but this relationship is at least partially mediated by several 
factors, including negative symptoms. Neurocognitive abilities and learning opportunities determine functional 
skill capacity on performance-based measures, but several personal factors determine whether skills are 
actually performed (e.g., attitudes/expectations, motivation, anhedonia, moods, insight; Bowie et al., 2006; 
Grant & Beck, 2009; Horan et al., 2010; Wiersma et al., 2000; Robinson et al., 2004; Twamley et al., 2002). In 
particular, the premise that expectations and performance beliefs can influence symptoms and functional 
outcome is a key component of the cognitive model that guides CBT interventions for schizophrenia. Several 
researchers (Avery et al., 2009; Grant & Beck; 2009; Horan et al., 2010; Rector et al., 2005) have found that 
defeatist beliefs (e.g., “Why bother, I always fail,” “It’s not worth the effort”) and effort contribute to negative 
symptoms and poor functioning in schizophrenia. Rector et al. (2005) proposed that dysfunctional attitudes 
about the personal costs of applying energy can lead to passivity and avoidance of activities that require effort, 
as a defense against anticipated failure and negative evaluations by others. This avoidance and lack of effort 
manifests as diminished motivation (avolition-apathy), loss of pleasure (anhedonia-asociality), impoverished 
speech (alogia), and blunted affect. Defeatist beliefs and low expectations for success are associated with 
neurocognitive impairment (Grant & Beck, 2009), possibly because neurocognitive impairment can lead to 
discouraging failure experiences that lead to low success expectancies. Pathophysiological processes 
associated with cognitive impairment in schizophrenia can also lead to impaired striatum-mediated reward 

prediction, which may reduce drive-motivated behavior by disrupting the process of generating accurate 
expectations of success (Barch & Dowd, 2010). In social learning and self-efficacy theories of motivation in 
healthy individuals (Bandura, 1986; 1997), self-competency beliefs are central to motivation to engage in goal-
directed activities and willingness to expend effort when tasks become more difficult. People who expect to 
succeed are more willing to try new tasks, choose harder tasks, and expend more effort (Wingfield & Eccles, 
2000; Bandura, 1997). Social learning theory and the CBT model applied to schizophrenia, therefore, suggest 
that defeatist beliefs may lead to disengagement from effortful social and community functioning activities as a 
defense against anticipated failure and negative evaluations by others, which manifests as negative symptoms 
and poor functioning. Table 3 shows how CBSST and CCT will be integrated in order to increase the focus on 
reduction of defeatist beliefs and negative symptoms, as well as increase attention, learning, memory, and 
executive functioning to reduce negative symptom severity and maximize benefit from CBSST. 
 
Table 3. Proposed Integration of CBSST and CCT by Content Area 
CBSST Thought Challenging Module  
Planned Integration of CCT Content 
Address symptoms and challenge defeatist beliefs that 
interfere with real-world skills execution 
All throughout: Use attention, learning, and memory strategies to 
aid in learning and retaining CBSST content 
Use experiential exercises to prove to participants that when they 
try harder, they do better 
Introduce the general concepts of CBT, including the 
relationship between thoughts, actions and feelings, 
automatic thoughts, thought challenging by examining 
evidence for beliefs, and mistakes in thinking  
Introduce the types of cognitive problems that are common in 
mental illness 
Help participants learn and remember to use their CBT 
skills 
Teach and reinforce prospective memory skills to improve 
attendance, homework completion, and remembering to use skills 
CBSST Social Skills Training Module  
 
Improve communication skills and psychosocial 
interactions (e.g., asking someone for support) via 
behavioral role plays 
Teach and reinforce conversational attention skills (e.g., listening 
actively, eliminating distractions, asking questions, and 
paraphrasing [LEAP]) to improve cognitive aspects of 
communication and social communication 
Improve expression of positive and negative feelings, 
making requests, comfortable sharing of feelings, and 
communicating assertively 
Improve self-efficacy and defeatist performance beliefs 
CBSST Solving Problems Module  
 
Improve basic problem-solving skills 
Teach cognitive flexibility and planning strategies in addition to 
problem-solving (CBSST and CCT use a very similar problem-
solving strategy already) 
Help participants develop plans to solve real-world 
problems and improve illness self-management 
Reinforce cognitive flexibility strategies to help participants realize 
when they should try a different strategy to achieve their goals 
Behavioral activation to improve negative symptoms  
Use planning skills to plan and execute pleasurable activities and 
social activities 
Develop confidence in effective problem-solving 
Use repetition and practice of executive skills to increase 
confidence 
 
3.5.2. Control Condition: Goal-focused Supportive Contact (SC). We propose to use a robust control 
condition, SC, a group therapy intervention that provides the same frequency and amount of therapist and 
other group member contact as CBSST-CCT. Thirty-six twice-weekly SC sessions (4.5 months) will be 
delivered, and each group therapy session is two hours, with a lunch or snack break mid-way. The SC 
intervention will have a primary focus on setting and achieving recovery goals (e.g., living, learning, working 
and socializing). As in the CBSST section above, focusing on personalized recovery goals is included to 
enhance motivation for treatment and reduce drop-out in this population with high negative symptoms. 
Sessions will be semi-structured and consist of check-in about symptoms and potential crisis management, 
followed by a flexible discussion about setting and working toward recovery goals. Sessions will typically 
include components of psychoeducation, empathy, and non-directive reinforcement of health, coping, and 
symptom management behaviors, that grow out of group discussions, with only minimal therapist guidance. 
Participants will be asked to think about how the discussions had bearing on their individual goals, and will be 
encouraged to ask for the advice of other participants in achieving specific goals, but no specific training will be 
provided in cognitive-behavioral coping strategies, social skills, problem solving, or cognitive strategies.  
 
3.5.3 Treatment Fidelity. Recordings of CBSST-CCT sessions will be rated using items from the Cognitive 
Therapy Rating Scale for Psychosis (CTS-Psy; Haddock et al., 2001), the SST Fidelity scale (Bellack, Mueser 
et al., 2004), and the Cognitive Training Fidelity Scale (Twamley, unpublished). A random 20% of CBSST-CCT 
sessions will be rated by Dr. Dimitri Perivoliotis, who has delivered CBSST and CCT and will not be involved in 
participant assessments. Monthly fidelity ratings will be fed back to therapists during supervision to improve 
fidelity. SC sessions will also be rated to ensure that SC groups do not receive training in CBSST or CCT skills. 
 

3.6. Measures. Assessments (see Table 4) will be administered at baseline, midway through treatment (2.25 
months), post-treatment, and 6-month follow-up. Assessors will be blind to treatment condition. We have 
systematic procedures in place to counsel patients not to reveal their treatment assignment, which has 
maintained the blind in prior trials (Granholm et al., 2005). Assessors will receive extensive training using 
videotaped and practice interviews and will not complete assessments until achieving at least .80 inter-rater 
reliability. We will also check for rater drift every 90 days. We achieved high inter-rater reliability in other 
studies (e.g., ICC=.88 for PANSS total; .87 for positive symptoms; .83 for SANS total; .86 for MASC). 
 
Table 4. Assessments and Timeline 
Domain 
Measure 
Baseline 
Midway  
Post 
6-mo f/u 
Diagnostic assessment  
Diagnosis 
SCID or MINI 
X 
 
 
 
Deficit Syndrome 
Schedule for the Deficit Syndrome 
X 
 
 
 
Reading level 
Wide Range Achievement Test-4 Reading 
X 
 
 
 
Symptoms (primary outcome is negative symptoms)  
Negative symptoms 
Clinical Assessment Interview for Negative Sx 
X 
X 
X 
X 
Positive symptoms 
PANSS positive subscale  
X 
X 
X 
X 
Depressive symptoms 
Calgary Depression Scale for Schizophrenia (CDSS) 
X 
X 
X 
X 
Functioning  
Perf.-based functional capacity 
UCSD Performance-Based Skills Assessment – Brief  
X 
X 
X 
X 
Perf.-based social competence  
Maryland Assessment of Social Competence 
X 
X 
X 
X 
Rehabilitation goals/milestones 
Psychosocial Rehabilitation (PSR) Toolkit 
X 
X 
X 
X 
Self-reported living skills 
Specific Levels of Functioning Scale (SLOF) 
X 
X 
X 
X 
Neurocognition 
MATRICS Consensus Cognitive Battery  
X 
X 
X 
X 
CBSST-CCT Content Knowledge  
Comprehensive Modules Test (CMT) 
X 
X 
X 
X 
Defeatist Attitudes  
Defeatist Performance Attitudes Scale (DPAS) 
X 
X 
X 
X 
Effort Allocation – Pupillometry  
Pupil response, digit span recall  
6th-digit dilation amplitude 
X 
X 
X 
X 
Pupil response to SOA task 
10-letter array dilation amplitude 
X 
X 
X 
X 
 
Diagnostic assessment (at baseline only) will ensure diagnosis and further characterize the participants. The 
Structured Clinical Interview for DSM-IV (SCID; First et al., 1997) or the Mini International Neuropsychiatric 
Interview (MINI; Sheehan et al., 1998) will be used to establish diagnoses of schizophrenia or schizoaffective 
disorder. To reduce participant burden, participants who have undergone a SCID or MINI interview by a 
trained, reliable interviewer as part of other research participation within the past year will not have to repeat 
the interview. The Schedule for the Deficit Syndrome (SDS; Kirkpatrick et al., 1989) will characterize the 
participants as meeting/not meeting deficit syndrome criteria for potential moderator analyses. The Wide 
Range Achievement Test-4 (Wilkinson & Robertson, 2006) Reading subtest will ensure that participants have a 
reading level (6th grade or higher) sufficient for reading the treatment manual, per the inclusion criteria.  
 
Negative symptom severity will be measured with the Clinical Assessment Interview for Negative Symptoms 
(CAINS; Horan, Kring et al., 2011; Kring et al., 2013), a new, state-of-the-art instrument developed by an 
NIMH-funded consensus committee, addressing problems with previous measures (e.g., PANSS, SANS). We 
selected the CAINS because it was developed to better capture experiential deficits (e.g., motivation, interest, 
desire for social affiliation, anhedonia), which were the negative symptoms that changed most in our prior 
clinical trials, and experiential negative symptoms are most linked to defeatist attitudes (Grant & Beck, 2009; 
Green et al., 2012; Horan et al., 2010). The CAINS also relies less on behavioral or performance deficits to 
rate negative symptom severity, which minimizes overlap with functioning measures. The 13 CAINS items (9 
interview items and 4 objectively rated items) are rated 0 (no impairment) to 4 (severe deficit) measuring 
Expression of emotions and speech and Motivation/Pleasure across social, vocational and recreational life 
domains. It has demonstrated good inter-rater reliability (ICCs=.77-.93), test-retest stability (r=.69), and 
convergent validity (with both negative symptom measures and real-world functioning), and discriminant 
validity. It is not confounded with depression, cognition, or medication side effects. The mean score in the 
standardization sample was 19, so we will use 19 as a cutoff score for study inclusion. Positive symptom 
severity will be measured with the Positive and Negative Syndrome Scale (PANSS; Kay et al., 1987) positive 
subscale, a gold-standard measure in the field. Depressive symptom severity will be assessed with the 
Calgary Depression Scale for Schizophrenia (CDSS; Addington et al., 1990), which was especially designed to 
capture depressive symptoms in schizophrenia without confounding cognitive, negative, and extrapyramidal 
symptoms. The CDSS is a 9-item scale derived from the Hamilton Depression Rating Scale and the Present 

State Examination with demonstrated reliability (ICC=.89) and validity (Addington et al, 1992, 1994). A cut 
score of >9 best predicts a diagnosis of major depression in people with schizophrenia (Kim et al., 2006). 
 
Functioning will be measured with a combination of performance based measures, self-report measures, and 
objectively rated measures. Performance-based functional capacity will be assessed with the UCSD 
Performance-Based Skills Assessment – Brief (UPSA-B; Mausbach et al., 2007), comprised of Finance and 
Communication subscales, which has been shown to predict independent living status. For the communication 
subtest, participants take part in role plays using a telephone (e.g., to make an emergency call; calling to 
reschedule a doctor’s appointment). For the finances subtest, participants count change, read a utility bill, and 
write a check to pay the bill. Social competence will be measured with the Maryland Assessment of Social 
Competence (MASC; Bellack et al., 1994), a role-play based measure of social skill and ability to resolve 
interpersonal problems through conversation. The MASC takes about 15-20 minutes to administer and 
consists of three 3-minute role-play communication scenarios (1 conversation initiation and 2 assertion), during 
which the participant 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. Videotaped role-plays are coded by blinded raters on dimensions of verbal content, nonverbal 
communication behavior, and an overall effectiveness score, which will be the primary MASC variable. 
Functional status (milestones) will be measured using the Psychosocial Rehabilitation (PSR) Toolkit (Arns et 
al., 2001), which assesses status and progress toward rehabilitation goals in the domains of work, education, 
finance, and residence. Objective information is collected on employment, educational activity, residential 
situation, and financial status. The measure requires no subject testing burden, because research staff 
complete the PSR Toolkit (with participant release of information). Participant status in each domain is rated on 
a progressive scale, ranging from the absence of meaningful functioning in the domain to fully independent 
functioning (e.g., Employment: 1=no employment, 2=non-paid work, 3=sheltered workshops…11=independent 
competitive employment). Finally, we will administer the Specific Levels of Functioning Scale (SLOF; 
Schneider and Struening, 1983), which was found to be the best rating scale in the recent NIMH-funded 
Validation of Everyday Real-World Outcomes (VALERO) study (Harvey et al., 2011).  
 
Neurocognition will be assessed with the MATRICS Consensus Cognitive Battery (MCCB; Nuechterlein et al., 
2008), an NIMH-funded consensus battery designed for multiple repeat testing of neurocognitive abilities 
relevant in schizophrenia. The MCCB was designed for use as an outcome measure in clinical trials and was 
developed through systematic selection and psychometric evaluation of the tests involved (Nuechterlein et al., 
2008; Kern et al., 2008; Green et al., 2008). It measures speed of processing, attention/vigilance, working 
memory, verbal learning, visual learning, reasoning and problem solving, and social cognition. The specific 
tests in the battery include: Category Fluency, BACS Symbol Coding, Trail Making Test (Part A), Continuous 
Performance Test (Identical Pairs Version), University of Maryland Letter-Number Span, Wechsler Memory 
Scale-III Spatial Span, Hopkins Verbal Learning Test-Revised, Brief Visual Memory Test-Revised, NAB Mazes, 
and MSCEIT: Managing Emotions. In line with the suggestions of the MATRICS Neurocognition Committee 
and the MATRICS-NIMH advice to the FDA, we will use the composite score for the entire battery.  
 
CBSST-CCT Content Knowledge will be measured with the Comprehensive Modules Test (CMT). The CMT 
was originally developed at UCLA for use with SST modules (Liberman, 1991) and was modified to assess 
skills trained in CBSST. Interviewers ask questions about content trained (e.g., “What are the 3C’s?”), as well 
as the application of skills in vignettes. Questions with vignettes were developed to assess mastery of thought 
challenging, communication, and problem-solving skills. The CMT total score will be used. 
Defeatist Performance Attitudes will be measured with the Defeatist Performance Attitudes Scale (DPAS), a 
15-item self-report subscale derived from factor analysis of the commonly-used 40-item Dysfunctional Attitude 
scale (DAS; Cane et al., 1986; Weissman, 1978). The DPAS indexes defeatist beliefs 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”) 
on a Likert scale. We have extensive experience with the DPAS: we (Quinlan, Granholm & Roesch, 2009), like 
others (Green et al., 2012; Horan et al., 2010) replicated the findings by Grant and Beck (2009) that defeatist 
performance beliefs mediate the relationship between neurocognitive impairment and negative symptoms in 
schizophrenia (see Figure 4), including both Diminished Expression (Affective Flattening+Alogia) and 
Diminished Motivation (Avolition+Asociality) factors.  
 
Task Effort (Pupillometry). In the proposed project, pupil size will be recorded during performance of two 
cognitive tasks, a digit span recall task and a span of apprehension (SOA) task, because we have linked 
diminished pupillary responses (effort) on these tasks to more severe negative symptoms and defeatist 

attitudes (Gallegos et al., 2009, Granholm et al., 2007a). On the digit span recall task, pupil responses will be 
recorded for up to 15 seconds on trials with fixed, randomly-determined spans of 3 (low load), 6 (moderate load), 
and 9 (high load) digits presented (four trials per span length) aurally at the rate of one digit per 1.5 seconds, 
while the subject views a gray dot on a white background. Pupillary response (average diameter for one second) 
at the last digit in the 6 digit condition showed the strongest relationships with both defeatist attitudes and 
negative symptoms in our prior study, so we will use this amplitude (change relative to baseline). On the partial-
report SOA task, subjects will be told that either a "T" or an "F" will be presented on the computer screen in a 
group of other letters (70 msec exposure) and they must push one of two response buttons corresponding to 
the correct target. The target stimulus will be embedded in arrays containing either 2 (3-letter condition) or 9 
(10-letter condition) distractor letterspace. 40 trials of each array-size condition will be presented in 
counterbalanced blocks. Peak dilation (change relative to baseline) in the 10-letter array condition, which was 
related to negative symptoms in our prior research, will be used as the primary dependent measure. Phasic 
change pupil responses are not affected by medications (Granholm et al., 1997, 2004, Ahern & Beatty, 1979). 
Dr. Granholm has published extensively on pupillary response (Granholm et al., 1997; 2004; 2007; 2009; 
Granholm & Steinhauer, 2004; Fish & Granholm, 2008), which has been used for over 80 years as an 
objective, reliable, and sensitive psychophysiological index of effortful processing resource allocation to tasks. 
Blood collection and storage. Blood samples (10 mls) will be drawn and stored for future gene expression 
analysis to identify predictive markers of CBSST-CCT outcome. Collected blood will be prepared for RNA 
extraction by sequestering and preserving the peripheral blood mononuclear cells by passing the sample 
through a Leukolock™ filter (Ambion, Inc.) and then saturating the filter with RNAlater (Ambion, Inc.). 
Saturated filters can be stored for extended periods of time for later analysis. Quality-assured total RNA 
samples will be stored at -80C for later microarray analysis in collaboration with our colleagues, Drs. Ming 
Tsuang, William Kremen, and Stephen Glatt. Drs. Tsuang and Kremen will donate blood drawing supplies, 
personnel, and freezer space for this project (see letter of support from Drs. Tsuang and Kremen). 
 
3.7. General Statistical Approach. Data acquired in this project will be managed by a junior statistician, Peter 
Link, and analyzed with assistance from Dr. Shah Golshan. Primary analyses will be based on a linear mixed-
effects model for continuous data (Hedeker et al., 1991; 1997; Laird, 1982) and will be performed using HLM 
6.06. HLM is an intent-to-treat method that uses all available data, obviating the need for imputation of missing 
data. Our randomization procedure is expected to control patient and treatment variables that might be 
associated with outcome, but if there are any baseline differences between groups, we will control for them 
statistically. All hypothesis tests will be two-sided with alpha set at .05. We will control Type I error by reducing 
measures to one key variable or a total or composite score when possible and will use Bonferroni correction for 
secondary outcomes in a domain family and secondary analyses. 
 
Hypothesis 1 (feasibility): 64 subjects at 4 community locations will be enrolled and retained (>80%) in a pilot 
RCT. (Inferential statistics not needed to determine whether enrollment and retention goals are met.) 
 Hypothesis 2 (efficacy): Compared to participants in SC, those in CBSST-CCT will show significantly greater 
reduction in negative symptom severity (primary outcome) and greater improvements in cognition and 
functioning (secondary outcomes) from baseline to post-treatment. Effect sizes for these outcomes will be 
greater than historical effect sizes (.42-.47) based on our previous studies of similar participants.  
Hypothesis 2 will be tested with HLM. Baseline to follow-up effect sizes will also be computed The primary 
mixed-model analysis will include a random intercept, a random effect for assessment time (baseline, midway, 
post-treatment, 6-month follow-up), with treatment group (CBSST-CCT vs. SC), and all interactions as 
predictors of the primary outcome measure, CAINS total. Model diagnostics will be used to determine the 
suitability of an autoregressive error component and nonlinear effects for assessment time. Using Bonferroni-
correction within an outcome domain, secondary analyses will use the same mixed-model to examine the 
secondary outcome variables in the functioning domain and the other secondary outcome variables in Table 4, 
with the exception of the PSR ToolKit Global Indicator, which is not a continuous variable. A Chi square test 
will be used to determine if the treatment groups differ significantly in the proportion of participants who 
achieve improvements in objective indicators of real-life functioning goals on the PSR ToolKit indicator. Power 
analysis: The purpose of our pilot RCT is to examine feasibility and generate effect sizes to establish 
benchmarks for future studies, not to complete an adequately powered efficacy study. With a sample size of 
64, we will have .50 power to detect an effect size of .5 and .80 power to detect an effect size of 1.0 and for 
negative symptoms (Spybrook et al., Optimal Design, 2011).