Adaptation of Cognitive Enhancement Therapy for Persons at Clinical High Risk for Psychosis

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.

Overview:

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.

Interventions:

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
personal goals.

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.

Inclusion Criteria:

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
in severity

- 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.

Exclusion Criteria:

- 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