Despite advances in both pharmacotherapy and psychotherapy for major depression, non-response and partial-response remain relatively common outcomes, motivating the search for new treatments. This application is concerned with the development of one such novel treatment, based on one of the particular successes of translational research: the augmentation of exposure-based cognitive-behavior therapy (CBT) with d-cycloserine (DCS). In this application, we propose a study of the efficacy of DCS for augmenting therapeutic learning relevant for the treatment of depression (i.e., outside the extinction learning where DCS has been shown to have success). Specifically, appropriate to an R-21 mechanism (PA-11-261), we investigate the role of DCS in enhancing declarative memory in depressed individuals, as evaluated by standardized tests and the retention of cognitive therapy session material. In seeking to extend the therapeutic targets for DCS augmentation, we are also proposing to study an active comparison agent. This agent, modafinil, appears to offer cognitive enhancing effects among both sleep deprived and non-sleep deprived individuals, but also appears to have drug-state (e.g., mood and side) effects that are not characteristic of DCS augmentation. For this reason, drug-context effects may affect memory retention over time. Hence, we will evaluate memory enhancement effects both during the period of drug action as well as one week later when no drug is taken. Overall, we propose to examine cognitive function and memory performance over 4 study sessions in 96 men and women with major depression, who, in a double-blind fashion, will be randomly assigned to either: (1) 50mg DCS, (2) 250mg DCS, (3) 100mg modafinil, or (4) placebo administered on Study Weeks 2 and 3. The memory tests include both items unique to a given study week (i.e., item categorization, the HVLT, and digits backward), and memory tasks that are repeated over time (logical memory tasks and the cognitive therapy content), that allow assessment of memory and retention effects across one-week periods (i.e., from Week 2 to Week 3 and from Week 3 to Week 4). We believe this study is the next logical step toward the goal of extending CBT augmentation effects for depression. If study aims are achieved in this R21 study, we will proceed with a R01 application at the conclusion of the funding period, working to show whether augmentation of therapeutic learning leads to an earlier and/or more robust treatment response for depressed patients undergoing CBT.

Public Health Relevance

This application is concerned with the development of a new combination treatment for depression, where single doses of medication are used to aid the retention of therapeutic learning from cognitive-behavior therapy (CBT). Our first step for this longer-term goal is to examine whether specific declarative memory processes can be augmented, and whether these effects extend to the learning of cognitive therapy content. Specifically, we will examine whether d-cycloserine and modafinil, relative to placebo administration, can improve memory for therapy relevant material in depressed individuals.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Exploratory/Developmental Grants (R21)
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Interventions Committee for Adult Disorders (ITVA)
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Muehrer, Peter R
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Boston University
Schools of Arts and Sciences
United States
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Hofmann, Stefan G; Curtiss, Joshua; McNally, Richard J (2016) A Complex Network Perspective on Clinical Science. Perspect Psychol Sci 11:597-605
Hofmann, Stefan G; Carpenter, Joseph K; Curtiss, Joshua (2016) Interpersonal Emotion Regulation Questionnaire (IERQ): Scale Development and Psychometric Characteristics. Cognit Ther Res 40:341-356
Reynolds, Gretchen O; Otto, Michael W; Ellis, Terry D et al. (2016) The Therapeutic Potential of Exercise to Improve Mood, Cognition, and Sleep in Parkinson's Disease. Mov Disord 31:23-38
Otto, Michael W; Kredlow, M Alexandra; Smits, Jasper A J et al. (2016) Enhancement of Psychosocial Treatment With D-Cycloserine: Models, Moderators, and Future Directions. Biol Psychiatry 80:274-83
Hofmann, Stefan G (2016) Psychodynamic therapy: a poorly defined concept with questionable evidence. Evid Based Ment Health 19:63
Wu, Jade Q; Szpunar, Karl K; Godovich, Sheina A et al. (2015) Episodic future thinking in generalized anxiety disorder. J Anxiety Disord 36:1-8
Hofmann, Stefan G; Fang, Angela; Brager, Daniel N (2015) Effect of intranasal oxytocin administration on psychiatric symptoms: A meta-analysis of placebo-controlled studies. Psychiatry Res 228:708-14
Caballo, Vicente E; Arias, Benito; Salazar, Isabel C et al. (2015) Psychometric properties of an innovative self-report measure: The Social Anxiety Questionnaire for adults. Psychol Assess 27:997-1012
Hofmann, Stefan G; Barlow, David H; Clark, David M et al. (2015) Treatments for social anxiety disorder: considerations regarding psychodynamic therapy findings. Am J Psychiatry 172:393