Improving Therapeutic Learning in Depression: Proof of Concept

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 study is concerned with the development of one such novel treatment, the augmentation of exposure-based cognitive-behavior therapy (CBT) with d-cycloserine (DCS).

Study Overview

• Status: Completed
• Conditions: Major Depressive Disorder
• Intervention / Treatment: Drug: 250 mg DCS; Drug: 100 mg Modafinil; Drug: Placebo

Detailed Description

Investigators will study 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, the study investigates the role of DCS in enhancing declarative memory in depressed individuals, as evaluated by standardized tests and the retention of cognitive therapy session material. Investigators will also study an active comparison agent, modafinil, which 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. Therefore, drug-context effects may affect memory retention over time. Hence, the study will evaluate memory enhancement effects both during the period of drug action as well as one week later when no drug is taken. Overall, investigators will 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) 250mg DCS, (2) 100mg modafinil, or (3) placebo administered on Study Weeks 2 and 3. The memory tests include both items unique to a given study week and memory tasks that are repeated over time that allow assessment of memory and retention effects across one-week periods.

• Study Type: Interventional
• Enrollment (Actual): 36
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Boston University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Must have a DSM diagnosis of major depression as determined by structured diagnostic interview
• Must be free of psychotropic medications other than serotonin selective reuptake inhibitors (SSRIs) for at least 2 weeks
• No current suicidal ideation
• Able to speak and understand English
• Must be between the ages of 18 and 65, inclusive
• Must be a male, or a female who is not of childbearing potential (i.e., surgically sterile, postmenopausal for at least 1 year) or who is non-pregnant, non-lactating and using a medically accepted method of contraception. Acceptable methods of contraception include condoms (male or female) with or without a spermicidal agent, diaphragm or cervical cap with spermicide, medically prescribed IUD, hormonal contraceptives. A woman of childbearing potential who is not currently sexually active must agree to use a medically accepted method of contraception should she become sexually active while participating in the trial

Exclusion Criteria:

• A DSM diagnosis of dementia, neurodegenerative disease, or other organic mental disorder; substance use disorder other than nicotine or caffeine in the last 3 months; bulimia or anorexia within the last 3 months; lifetime history of psychotic disorder or, bipolar disorder, or developmental disorder;
• A diagnosis of organic brain syndrome, mental retardation, or other cognitive dysfunction that could interfere with a participants capacity to participate in CBT or to complete safety and efficacy assessments
• A history of seizures (apart from childhood febrile seizures) or head trauma causing ongoing cognitive impairment
• An uncontrolled, unstable clinically significant medical condition (e.g., renal, endocrine, hepatic, respiratory, cardiovascular, hematologic, immunologic or cerebrovascular disease, or malignancy, or poorly controlled hypertension (> 150/90mmHg) that may interfere with the interpretation of safety and efficacy evaluations in the opinion of the study physician or investigator
• Medical illness including hypertension, cardiac disease, liver disease, pulmonary diseases, central nervous system disease, and epilepsy;
• Recent (1 year) suicidal attempts or current suicidal ideation
• For women, currently pregnant, plans to be pregnant in the next 2 months, or currently breastfeeding
• Treatment with phenytoin, isoniazid, or propranolol or known sensitivity to modafinil or cycloserine
• A history of head trauma causing loss of consciousness, seizure or ongoing cognitive impairment
• Use of psychotropic medication (including stimulants) other than SSRIs
• Current daily use of alcohol or regular binge alcohol use as determined on the medical screen
• Insufficient command of the English language (i.e., cannot carry on a conversation with an interviewer in the English language or read associated text)
• Receipt of CBT in the previous five years

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 250 mg DCS; Baseline assessment (week 1), two weekly sessions when 250mg DCS is administered, and final week (week 4) when retention is assessed.	Drug: 250 mg DCS; Drug; Other Names: d-cycloserine
Active Comparator: 100 mg modafinil; Baseline assessment (week 1), two weekly sessions when 100 mg modafinil is administered, and final week (week 4) when retention is assessed.	Drug: 100 mg Modafinil; Drug
Placebo Comparator: Placebo; Baseline assessment (week 1), two weekly sessions when placebo is administered, and final week (week 4) when retention is assessed.	Drug: Placebo; Drug

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recall of Cognitive Therapy Content	A modified Cognitive Therapy Awareness Scale (CTAS) was used to assess delayed memory for cognitive therapy content from the computerized CBT. Higher scores indicate better memory for CBT skills. Scores range from 0 to 40.	Week 2 and Week 3
1 Week Delayed Recall of Emotional Story Items	1 Week Delayed Recall of a Threat-Related Story. Scores can range from 0 to 74, with higher scores reflect greater memory for story items.	Week 2 and Week 3
1 Week Delayed Recall Logical Memory	Higher scores reflect greater recall of Wechsler Memory Scale (WMS) Story B content assessed one week after last rehearsal. Possible scores range from 0 to 25.	Week 2 and Week 3

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Logical Memory Immediate Recall	Immediate Story Recall from the Wechsler Memory Scale Story B. Higher scores reflect greater recall of the story material from the previous week. Possible scores range from 0 to 25.	Week 1, Week 2, Week 3
Immediate Memory Measured by the Hopkins Verbal Learning Task	The Hopkins Verbal Learning Test (HVLT) consists of a 12-item word list, composed of four words from each of the three semantic categories. The patient's free recall of the list is recorded. The same procedure is repeated for two more trials. The total recall score for the third trial was used as the recorded score and ranged from a minimum of zero to a maximum of 12 correct answers.	Baseline, Week 1, Week 2, Week 3
Immediate Recall of Emotional Story Items	Immediate recall score of items from the Emotional Story presentation. Scores can range from 0 to 74, with higher scores reflect greater memory for story items.	Week 1, Week 2, Week 3
Skills of Cognitive Therapy	This measure assesses the self-reported use of skills from cognitive therapy. Scores can range from 8 to 40, and higher scores indicate greater use.	Week 2 and Week 3
Digits Backward	The examiner reads a list of digits and asks that each digit be read backwards. The score is the total number of trials completed correctly; scores range from 0 to 16. Higher scores indicate better performance.	Baseline, Week 1, Week 2, Week 3

Collaborators and Investigators

• Sponsor: Boston University Charles River Campus
• Investigators: Principal Investigator: Michael W Otto, Ph. D, Boston University

Publications and helpful links

General Publications

• Otto MW, Lee J, Hofmann SG, Hearon BA, Smits JA, Rosenfield D, Fava M, Wright JH. Examining the efficacy of d-cycloserine to augment therapeutic learning in depression. Contemp Clin Trials. 2016 May;48:146-52. doi: 10.1016/j.cct.2016.03.009. Epub 2016 Apr 16.

Study record dates

Study Major Dates

• Study Start (Actual): September 16, 2014
• Primary Completion (Actual): April 21, 2017
• Study Completion (Actual): May 1, 2017

Study Registration Dates

• First Submitted: July 11, 2014
• First Submitted That Met QC Criteria: February 25, 2015
• First Posted (Estimate): March 3, 2015

Study Record Updates

• Last Update Posted (Actual): September 19, 2018
• Last Update Submitted That Met QC Criteria: August 22, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Keywords: Modafinil; Cognitive behavior therapy (CBT); d-cycloserine (DCS)
• Additional Relevant MeSH Terms: Mental Disorders; Mood Disorders; Depressive Disorder; Depressive Disorder, Major; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antimetabolites; Anti-Bacterial Agents; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; Antitubercular Agents; Central Nervous System Stimulants; Antibiotics, Antitubercular; Anti-Infective Agents, Urinary; Renal Agents; Wakefulness-Promoting Agents; Cycloserine; Modafinil
• Other Study ID Numbers: R21MH102646 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No