The purpose of this study is to test the feasibility of a modification of CET (Cognitive
Enhancement Therapy) to address symptomatic and functional difficulties associated with
Clinical High Risk for Psychosis (CHR).
Cognition for Learning and for Understanding Everyday Social Situations (CLUES) is designed
to improve cognitive functioning (e.g., memory, attention, planning, etc.) in order to
improve school, work, and social functioning. CLUES includes the following:
1. Computerized cognitive remediation ("exercises") to improve cognition.
2. Social-cognitive skills group designed to teach participants to act wisely in social
3. Individual coaching sessions designed to enhance translation of skills learned from
computer exercises and the group into real life.
CLUES is based on Hogarty and Greenwald's Cognitive Enhancement Therapy (CET), which was
designed for treating individuals with schizophrenia. Research on CET for individuals with
schizophrenia has found that CET appears to have helped participants improve cognition and
social and work functioning.
This study will investigate the feasibility of CLUES for young people who are showing signs
of clinical risk for psychosis.
Part 1: Preliminary open label trial of CLUES (n=8) to examine preliminary evidence of
target engagement (change in cognition and social cognition), to refine assessment and
recruitment approaches, to further optimize the treatment manual, and to ascertain
feasibility and tolerability.
Part 2: Preliminary randomized controlled trial of CLUES vs supportive therapy (ST) +
computer games to explore preliminary evidence of efficacy of CLUES vs. the control
Psychotic disorders such as schizophrenia (SZ) are among the most disabling conditions in
all of medicine. These disorders typically begin in adolescence or young adulthood, and are
preceded by premorbid impairments in cognitive and social function dating from early
childhood; these deficits worsen in adolescence and are accompanied by sub-threshold
positive and negative symptoms (the prodromal, or clinical high risk state, CHR) before
onset of the first psychotic episode. Recent staging models have operationalized approaches
to defining early and late phases of CHR; Early CHR (stage 1a) is characterized by cognitive
impairments and sub-threshold negative symptoms, while late CHR (stage 1b) is associated
with sub-threshold positive and disorganized symptoms as well as further cognitive and
functional declines. The emergence of cognitive and functional decline in Individuals at CHR
who convert to psychosis highlights the importance of early intervention.
Impairments in cognition are present in children who later go on to develop SZ. Impairments
in cognition are key rate-limiting factors to functional recovery from psychotic disorders
and include deficits in psychomotor speed, memory, attention, reasoning, and social
cognition. The latter include deficits in perspective-taking, emotion perception and
regulation, clearly linked to functional outcome in SZ. Perspective-taking (ability to
understand the thoughts, feelings, and intentions of others) and emotion regulation (ability
to have cognitive control over emotional stimuli) are critical for healthy social
development; their impairment is a major contributor to social and functional disability.
There is compelling evidence from recent meta-analyses that psychosocial approaches to
cognitive remediation are effective in SZ. We have shown that a psychosocial cognitive
rehabilitation known as Cognitive Enhancement Therapy (CET) substantially improves both
social cognition and employment rates among patients with early course SZ. The effects were
durable at 1 year following end of treatment.
CET is a comprehensive, developmental approach to address social and non-social cognitive
deficits in SZ; it seeks to facilitate the development of adult social-cognitive milestones
(e.g., perspective-taking, social context appraisal) by shifting thinking from reliance on
effortful, serial processing to a "gistful" and spontaneous abstraction of social themes
(details about CET in section C.2.6). CET targets social-cognitive impairments in
perspective-taking and emotion regulation through computerized training in basic
neurocognitive processes, and the use of social-cognitive rehabilitation groups. The
efficacy of CET for remediating social-cognitive impairments in perspective-taking and
emotion regulation in SZ presumably reflects an underlying change in fronto-temporal brain
function and connectivity during the course of treatment, made possible by the plasticity of
the human brain. CET may also protect against gray matter loss, and even support
fronto-temporal gray matter growth in service of social-cognitive enhancement in SZ.
In this study, we plan to modify CET for individuals at CHR. We will develop a manual for
CLUES and systematically test the acceptability, tolerability, adherence and preliminary
proof of target engagement (part 1), and preliminary efficacy in a proof of concept open
label trial (part 2). An important recent initiative in treatment development is to ensure
informed, data-driven decisions early in clinical trials, i.e. to identify therapeutic
targets, obtain evidence of target engagement and a proof of concept of efficacy prior to
proceeding to expensive clinical trials. To pursue this goal, we will evaluate CET effects
on cognition and social cognition in part 1 before efficacy testing in part 2.
This study will be organized in two parts:
Part 1: Preliminary open-label CLUES group (n=8) to verify target engagement (using
cognition and social cognition measures), to evaluate feasibility and tolerability, and to
iteratively refine the manual.
Part 2: Small, randomized trial comparing CLUES (2 groups, n=15 each to a control condition
(psychotherapy + an active computer-based program, Sporcle, with simple/ non-demanding
computer games).CLUES Interventions in this part will be optimized based on part 1 results.
1) Individualized assessment: The intervention begins with a comprehensive assessment of
neurocognition and social cognition, as well as cognitive style. This informs development of
an individualized coaching plan targeting the individual's areas of difficulty. The
individualized coaching plan sets CET apart from other more standardized cognitive
remediation approaches. 2) Neurocognitive remediation sessions. Weekly CET cognitive
remediation sessions involve working with a partner (peer) and is facilitated by a
clinician. This provides a unique opportunity for participants to complete "bottom up"
cognitive exercises designed to improve processing speed, attention, memory and problem
solving while also learning to negotiate the social tasks involved in working with a partner
(e.g., making appropriate small talk, paying attention and keeping score while a partner
engages in the tasks, providing encouragement when a partner struggles, and/or managing
feelings that come up when the participant struggles more than their partner). 3) Social
cognitive group: Participants take part in weekly social cognitive groups concurrently with
neurocognitive training and individual sessions. This group is designed to help participants
learn strategies for applying skills to improve non-social and social cognition and provide
in vivo learning experiences to foster the development of social wisdom and interpersonal
success. A broad, theoretically-driven array of social-cognitive abilities are targeted in
the social cognitive groups, which range from abstracting the "gist" or main point in social
interactions to perspective taking, social context appraisal, and emotion management.
Participants actively engage in the social cognitive groups by responding to unrehearsed
social exchanges, presenting homework, participating in cognitive exercises that focus on
experiential learning, providing feedback to peers, and chairing homework sessions. 4)
Individual coaching: Weekly individual coaching sessions provide opportunities for the
intervention to be further tailored to the participants' specific goals, cognitive
difficulties and cognitive style. Coaching sessions help the participant to develop a
training plan, digest information and skills learned in social cognitive group and in the
neurocognitive training sessions, and figure out how to apply them to make progress toward
Control treatment (Part 2 only):
During part 1, all participants will take part in CLUES. During part 2, we will conduct a
small randomized trial in which participants will be randomized to CLUES or the control
intervention (n=15 each). The control intervention will consist of weekly supportive
personal therapy plus 2 hours/ week of participation in Sporcle, a web-based, publicly
available active computer-based, generic, quiz-type program. Sporcle provides quizzes on
subject areas from geography to basic arithmetic to pop-culture. Sporcle includes games such
as identifying popular logos, naming as many pictured fruits and vegetables as possible, and
listing state capitols. Based on online user data and on level of difficulty, relatively
easy exercises are chosen (averaging approximately 70% accuracy (i.e. 70% of quiz items
correctly answered, on average). Games are presented to participants on "prescription cards"
each week, with an aim of participating in 2 hours per week (equivalent to 1 hour of
lumosity plus 1 hour per week paired computer training.
In ST, patients meet individually with a therapist to learn and practice a variety of
stress-reduction and illness management techniques. The ST approach is designed to be
sensitive to the patient's stage of development and divided into 2 phases. The first, basic
phase (0-3 months) focuses on psychoeducation about risk for psychosis (to be developed
during phase 1), the role of stress in the disorder, and symptom exacerbation, and
introduces basic coping strategies to minimize and/or avoid stress in one's life.The second,
phase (4-6 months) advances to a personalized approach to the identification of early cues
of distress and the application of healthy coping strategies to enhance adjustment. By
tailoring the treatment to the patient's stage of recovery, Patients meet weekly with a
therapist, although more frequent sessions are available if needed. We will seek to match
the number of sessions or hours of treatment between CLUES and ST.
Participants will be assessed at: 1) Baseline, 2) 3 months into the program, 3) at the time
of completion of the program (6 months), and 4) 3 months following completion of CLUES, in
the part 2 trial only (Table 1). All these assessments will be administered during part 1 to
assess acceptability, applicability to the CHR population and assessment burden;
Observations will then be used to optimize assessment battery for part 2.
Broad criteria for clinical high risk for psychosis including meeting for SIPS clinical
high risk syndrome or any two of the following:
- Trait risk: Having a first degree relative with a psychotic disorder, or a
schizotypal disorder in the patient
- Positive symptoms: One or more of the attenuated SOPS Positive or Disorganized items
scoring mild (3), moderate (4) or severe (5) but not at a psychotic level; these may
include one or more Basic Symptoms (Klosterkotter et al 2001).
- Negative symptoms: Two or more of the SOPS negative symptoms rated at least moderate
- Cognition: executive cognitive impairment (at least 1.0 standard deviation deficit
relative to age-expected norms on at least 30% of the measures
- Functioning: GAF decline > 30% over the last 2 years, sustained for > 1 mo.
- History of meeting full criteria for psychotic disorder
- Significant neurological or medical disorders that may produce cognitive impairment
(e.g., seizure disorder, traumatic brain injury)
- More than 6 months (lifetime) of exposure to antipsychotic treatment
- A recent (within the past 3 months) history of substance abuse or dependence
- IQ < 80
- Failure to achieve at least a 6th grade reading level
- Persistent suicidal or homicidal behavior