Scientific Rationale for Drugs Enhancing Psychosocial Treatments. Donald C. Goff, MD Nathan Kline Institute NYU Medical School

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1 Scientific Rationale for Drugs Enhancing Psychosocial Treatments Donald C. Goff, MD Nathan Kline Institute NYU Medical School

2 Conflicts over the past 3 years Consultation: Eli Lilly, Bristol-Meyer-Squibb, Roche, Endo Pharmaceuticals, Genentech, Cypress Bioscience, Dianippon Sumitomo, and Takeda Pharmaceuticals. DMC: Otsuka. Research funding: Janssen, Pfizer, GSK, PamLab and Novartis. Patent applications: Genetic predictors of response to glutamatergic agents and folate.

3 Potential roles of pharmacologic agent Enhance a specific cognitive function(s) to facilitate performance (attention, memory, executive function, speed of processing) Enhance plasticity not specific to a single cognitive domain

4 Specific cognitive enhancers Match agent to patient based on cognitive deficit Match agent to task based on cognitive demands of psychosocial task Currently few agents with established efficacy: Example: psychostimulants

5 Agents that enhance plasticity Improve learning of skill Plasticity may only enhance performance of specific learned skill; not generalizable Example: D-cycloserine

6 In the absence of effective cognitive enhancers, we know very little about: Impact of cognitive improvement upon function Interactive effects with psychosocial interventions

7 Combied Cognitive Remediation (CR) and Functional Skills Training (FST) for Schizophrenia (n=114) 12 week randomized treatments CR with coaching; strategy & bridging FST CR + FST (sequential) Assessments (blind to treatment group): Brief Assessment of Cognition Scale (BACS) UCSD Performance-based Skills Assessment (UPSA) Social Skills Performance Assessment (SSPA) Specific Levels of Functioning Scale (SLOFS) Bowie et al, Am J Psychiatry 2012

8 Combined Cognitive Remediation (CR) and Functional Skills Training (FST) for Schizophrenia (n=114) BACS Composite Effect Size Significance CR 0.77 p<0.001 FST 0.05 NS Combined 0.73 p<0.001 UPSA Effect Size Significance CR 0.25 NS FST 0.51 p<0.001 Combined 0.63 p<0.001 Only CR improved cognitive performance; only FST improved functional capacity Bowie et al, Am J Psychiatry 2012

9 Combined Cognitive Remediation (CR) and Functional Skills Training (FST) for Schizophrenia (n=114) SSPA Effect Size Significance CR 0.16 NS FST 0.52 p<0.001 Combined 0.57 P<0.001 Only FST improved Social Skills Capacity Bowie et al, Am J Psychiatry 2012

10 Combined Cognitive Remediation (CR) and Functional Skills Training (FST) for Schizophrenia (n=114) SLOFS Effect Size Significance Interpersonal CR 0.12 Group effect NS FST 0.22 Combined 0.21 Community Activities Effect Size Significance CR 0.13 vs Combined p<0.001 FST 0.21 vs Combined p=0.051 Combined 0.36 Work skills Effect Size Significance CR 0.19 vs Combined p<0.001 FST 0.25 vs Combined p=0.04 Combined 0.44 Additive effects for Community Activities & Work

11 D-cycloserine I remember the time I was kidnapped and they sent back a piece of my finger to my father. He said he wanted more proof. Rodney Dangerfield

12 D-cycloserine Partial agonist at most NMDA receptors Twice the activity at NMDA receptors containing the NR2C subunit NR2C subunits involved in memory & thalamocortical connections NR2C expression selectively reduced in PFC in schizophrenia

13 D-cycloserine Memory consolidation effects observed after 24 hours Effective for new learning only Consolidation primarily involves the gist of memory Memory consolidation deficits in schizophrenia associated with psychosis D-cycloserine use for cognitive facilitation is not FDA approved.

14 Long term potentiation in the hippocampus Kandel, Science 2001

15 Effect of D-cycloserine vs. placebo on delayed thematic recall in schizophrenia (n=37) Delayed Thematic Recall DCS does not affect immediate memory ; improves delayed (one week) recall of story themes. Thematic Recall on Logical Memory Test placebo drug Week of Story Administration Goff, et al, Schiz Res 2008

16 DCS facilitation of CBT for delusions DOSE 1 (+ 1 hour) DOSE 2 (+ 1 hour) Week 1 CBT Exercise Week 2 CBT Exercise Week 3 BASELINE/VISIT 1 PSYRATS Alternative Beliefs VISIT 2 PSYRATS VISIT 3 PSYRATS

17 A placebo-controlled crossover trial of D-cycloserine facilitation of a CBT exercise for delusions (n=21) Order effect, baseline to week 2, p=.03 effect size 0.8 Gottleib et al, Schiz Res 2011

18 8 week, placebo-controlled trial of once-weekly DCS added to cognitive remediation D-cycloserine 50 mg or placebo once-weekly Brain Fitness cognitive remediation 3-5 times weekly Outcome measures: performance on auditory discrimination task, MATRICS

19 8 week, placebo-controlled trial of onceweekly DCS added to cognitive remediation Does DCS enhance learning of the auditory discrimination task? Does DCS effects generalize to the MATRICS battery?

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21 Change in performance on auditory discrimination task (n=36)

22 Change after 8 weeks from baseline in MATRICS composite score Change SE P-value D-cycloserine Placebo * Between Group Difference

23 Summary of preliminary results: DCS improved performance on practiced task (Auditory Discrimination) DCS did not improve performance on unpracticed cognitive tasks (MATRICS)

24 Conclusions Cognitive enhancers should be combined with psychosocial interventions to produce functional change Agents may compensate for specific cognitive deficits Agents that promote learning may not generalize beyond the trained task

25 Collaborators Massachusetts General Hospital Cori Cather, PhD Daphne Holt, MD Eric Macklin PhD Dara Manoach, PhD Josh Roffman, MD McLean Hospital Joseph Coyle, MD Boston University Jennifer Gottleib, PhD Michael Otto, PhD Funding: NARSAD (DG), K24 (DG), Conte Center (J Coyle)