Understanding How Cognitive Remediation Works

Unemployment is a major burden for people with severe mental illness (SMI) such as
schizophrenia, with competitive work rates typically between 10-20%. Over the past two
decades, supported employment (SE) has been shown to improve competitive work in persons with
SMI, and it is now considered an evidence-based practice (EBP). However, there is a need to
improve the effectiveness of SE, as 30-60% of consumers work little or not at all, and jobs
are often brief and end unsuccessfully. Cognitive remediation, when combined with vocational
rehabilitation, has shown promise for improving work outcomes, including in consumers in SE.
The most extensively studied approach is the Thinking Skills for Work (TSW) program,
developed by this research group, which incorporates computer-based cognitive exercises to
restore cognitive skills and teaching compensatory strategies by a Cognitive Specialist who
is integrated into the vocational rehabilitation team. Five randomized controlled trials
(RCTs), two conducted in SE programs (including one previously conducted by this research
group), have shown that adding the TSW program to vocational (SE) services improves work and
cognitive outcomes compared to vocational (SE) services alone.

The proposed study takes the next bold step of "dismantling" the TSW program to evaluate
whether the cognitive practice exercises component is critical to improving outcomes in SE,
or whether a more streamlined and efficient version of the program that focuses only on
teaching compensatory skills is sufficient. The study will also yield important information
about whether some consumers benefit from computer cognitive exercises, but not others,
permitting the TSW program to be individually tailored to consumers' personal needs.

In preparation for the proposed study we developed, standardized, and pilot tested a variant
of the TSW program, the Cognitive Skills for Work (CSW) program, that teaches compensatory
skills for managing cognitive difficulties but omits computer cognitive exercises, resulting
in a program that is approximately one-half the intensity of the original TSW program. A
small ongoing pilot study indicated that consumers in SE could be readily engaged and
retained in the CSW program and obtain work, supporting the feasibility of this streamlined
version of TSW. The proposed research will be an RCT conducted at two high fidelity SE
programs, comparing the effects of the TSW and CSW programs in consumers enrolled in SE.

The following hypotheses will be tested:

Primary Hypothesis: Participants in TSW will have better competitive work outcomes than those
in the CSW program. This hypothesis is based on the fact that virtually all cognitive
remediation research on SMI has included cognitive exercises designed to restore cognitive
skills, such as the computer-based cognitive exercises in TSW, with some programs also
teaching compensatory strategies. If the null hypothesis is not rejected, and TSW is found to
be not significantly more effective than CSW, then dissemination efforts can focus on the
more efficient CSW.

Secondary Hypothesis: Participants in TSW will improve more in cognitive functioning than
those in CSW. This hypothesis is based on the same rationale as Hypothesis #1.

Exploratory Analyses: In addition to evaluating whether the TSW and CSW programs differ
overall in their impact on vocational and cognitive outcomes, we will explore whether
consumer characteristics can be identified that predict a differential response to either
program. For example, it is possible that consumers with more severe cognitive impairment
will respond better to the full TSW program, whereas those with less severe impairment may
benefit equally well from the more efficient CSW program.

The proposed research has high potential impact for improving the outcomes of SE, an
established EBP for increasing competitive work in SMI, but whose effectiveness is limited by
the extent of consumers' cognitive impairment. Maximizing the efficiency of the TSW program,
a cognitive remediation program shown to improve work outcomes in two RCTs of SE programs, by
determining whether a more streamlined version of the program that requires about one-half
the time to implement (the CSW program) is equally effective, could reduce the costs of
disseminating and implementing the program, making it accessible to more consumers. This
study could also help identify which consumers benefit most from the cognitive exercises
component of TSW, thereby facilitating tailoring of the program to the individual's personal
needs. Ultimately, this research could play a critical role in making the dream of
competitive work a reality for many consumers with SMI.

In addition, a supplementary study, commencing in September 2015, will assess a promising
biomarker for understanding the mechanisms underlying the effects of cognitive remediation,
brain-derived neurotrophic factor (BDNF), in new enrollees in the parent R01 study. BDNF is a
widely distributed protein throughout the central nervous system that promotes neuronal
growth and is associated with a broad range of cognitive functions. Limited research suggests
that cognitive remediation increases serum BDNF levels, including one study of schizophrenia
and another study of Parkinson's disease. This supplemental study will provide a test of
whether computerized cognitive training contributes to increased BDNF levels, and whether
increases in BDNF are associated with improved cognitive functioning. The supplement will
take advantage of the ongoing parent R01 study of the TSW program by measuring BDNF levels at
baseline, following delivery of computerized cognitive training/teaching coping skills (6-8
months after baseline), and at two follow-ups (16 and 24 months after baseline) in a
diagnostically heterogeneous sample of 38 consumers with impaired cognitive functioning. This
supplement will complement the aims of the parent R01 by shedding light on possible
mechanisms related to how TSW works and for whom, thereby informing efforts to refine and
improve the program, as well as targeting individuals who fail to benefit.

The supplementary study will test the following hypotheses:

Primary Hypothesis: Participants in TSW will show greater increases in BDNF levels from
baseline to post-training than participants in CSW. This hypothesis is based on the
expectation that the computerized cognitive training exercises in TSW will lead to greater
improvements in cognitive functioning than training in compensatory strategies only in CSW,
with increases in BDNF levels associated with improved cognitive performance. We also expect
that greater increases in BDNF for the TSW group will be maintained at the 16- and 24 month
follow-up assessments.

Secondary Hypotheses: 1.) Greater improvements in cognitive functioning from baseline to the
post-training and follow-up assessments in TSW than CSW will be associated with stronger
increases in BDNF levels over the same assessment points. This hypothesis tests whether
greater gains in BDNF levels for TSW mediate the long-term and sustained improvements in
cognitive functioning for this program compare to CSW. 2.) Lower baseline BDNF levels will be
associated with less gain in cognitive functioning for TSW. This hypothesis tests whether
baseline BDNF levels moderate the effectiveness of TSW on improving cognitive functioning,
with lower BDNF levels predicting less benefit. BDNF could both be found to be both a
mediator and a moderator of the effects of cognitive remediation on improving cognitive
functioning.

The supplement will take place at the same sites as the parent R01: Thresholds Inc. in
Chicago, and the Mental Health Center of Greater Manchester, NH. Inclusion and exclusion
criteria for the supplemental sub-study are identical to those for parent R01 study. As
before, pregnancy is not a rule out for participation in the BDNF supplement study.
Phlebotomists associated with each site will draw one tablespoon of blood from clients at
each assessment timepoint, therefore, a total of up to four (4) tablespoons of blood might be
drawn from each client over the course of the study. Drawing BDNF specimens over the full
24-month course of the study will permit researchers to address several important questions
regarding the role of BDNF in contributing to neurocognitive functioning, both in response to
cognitive remediation as well as how it interacts with cognitive challenging environmental
demands—work.

Inclusion Criteria:

- Chronic mental disorder

- Minimum age 18.

- Unemployed

- Wants employment

- Must be a recipient of services at one of two participating agencies

- Fluent in English.

- Cognitively impaired, as defined by 1.0 SD below normative scores in memory or
executive functioning

- Willing and legally able to provide informed consent to participate in study. Subjects
with court appointed legal guardians will be included.

Exclusion Criteria:

-History of neurological conditions that impair cognition