Treatment to Enhance Cognition in Bipolar Disorder

Cognitive dysfunction is increasingly recognized as a major feature of bipolar disorder
(BD), present by illness onset, persistent into euthymia, and associated with functional
outcome. Deficits are qualitatively similar to those seen in schizophrenia (SZ), and may be
quantitatively similar in some patient groups, e.g. in patients with a history of psychosis.
Despite strong associations between cognitive impairment and functional outcomes in BD,
treatment for these symptoms at present is inadequate. Pharmacotherapies do little to
address cognitive symptoms, and may even worsen them. Psychosocial cognitive remediation
(CR) treatments have been developed to target these symptoms and their functional
correlates, and have shown early promise in patients with SZ in improving both
neurocognition and community functioning. However, despite the overlap of neurocognitive
deficits between patients with SZ and BD, no studies to date have extended
neuroscience-based CR to patients with BD. The present study aims to assess the efficacy of
CR treatment in patients with BD with a history of psychosis using a 70-hour CR paradigm
compared to a dose-matched computer-based control. It is hypothesized that patients in the
CR group will exhibit improvements in cognitive and community functioning compared to
controls, which will persist during a 6-month durability phase. Additionally, putative
mechanisms of functional change will be examined, including mediator effects of cognitive
and clinical change on community functioning. 130 patients with BD with a history of
psychosis recruited from the Psychotic Disorders Programs at McLean Hospital will be
randomized into either the CR or computer control group. CR will be administered using the
BrainWorks program, neuroscience-based training programs that have shown early promise in
patients with SZ. Participants will be assessed on measures of clinical, cognitive, and
community functioning at baseline, following the 70-hour treatment or control phase, and
again 6 months later. Participants may opt to participate in an fMRI study at pre- and
post-treatment; resting state, task-based and functional connectivity, and diffusion tensor
imaging data will be collected to evaluate preliminary evidence of neurobiological changes
after training versus control. Additionally, participants may opt in to participation in two
tasks of reward sensitivity including the Probabilistic Reward task and Richard's Delay
Discounting. These tasks are administered pre- and post-treatment to evaluate the role of
reward in treatment response as well as the potential for CR to modulate reward processing.
This project is in keeping with the NIH's stated strategic priorities for improving mental
health outcomes in patients and strengthening the impact of National Institute of Mental
Health (NIMH)-supported research on public health, with specific recommendations for broad
implementation of effective psychosocial interventions.

Inclusion Criteria:

- Clinical diagnosis of BD with psychosis

- PANSS < 75; PANSS Psychosis item scores = 3 or under; YMRS = 6 or under

- Age between 18 and 50

- Within 10 years of illness onset

- Legal and mental competency of the participant

Exclusion Criteria:

- Age under 18 or over 50

- PANSS >75; PANSS Psychosis item scores >3; YMRS > 6

- Legal or mental incompetence (legal incompetence defined by any guardianship
(including of person or treatment guardianship); mental incompetence defined by
failure of the informed consent survey)

- Psychiatric inpatient status at time of enrollment

- Delirium secondary to medical illness

- Psychotic or mood disorder due to general medical or neurological illness

- History of head trauma

- History of seizure disorder or photo-sensitive seizures

- Use of anticholinergic medication, clozapine or olanzapine at baseline

- Rapid-cycling bipolar disorder

- Diagnosis of current substance abuse (past month) or substance dependence within the
past year.