CLUES (Cognition for Learning and for Understanding Everyday Social Situations): An 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.