Improving Therapeutic Learning in Depression: Proof of Concept

Phase 2

Completed

Conditions: Major Depressive Disorder

Interventions: Drug: 250 mg DCS
Drug: 100 mg Modafinil
Drug: Placebo

Registration Number: NCT02376257

Lead Sponsor: Boston University Charles River Campus

Brief Summary: 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).

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 36

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 & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
250 mg DCS	250 mg DCS	Baseline assessment (week 1), two weekly sessions when 250mg DCS is administered, and final week (week 4) when retention is assessed.
100 mg modafinil	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.
Placebo	Placebo	Baseline assessment (week 1), two weekly sessions when placebo is administered, and final week (week 4) when retention is assessed.

Primary Outcome Measures

Name	Time	Method
Recall of Cognitive Therapy Content	Week 2 and Week 3	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.
1 Week Delayed Recall of Emotional Story Items	Week 2 and Week 3	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.
1 Week Delayed Recall Logical Memory	Week 2 and Week 3	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.

Secondary Outcome Measures

Name	Time	Method
Immediate Memory Measured by the Hopkins Verbal Learning Task	Baseline, Week 1, Week 2, Week 3	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.
Skills of Cognitive Therapy	Week 2 and Week 3	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.
Digits Backward	Baseline, Week 1, Week 2, Week 3	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.
Logical Memory Immediate Recall	Week 1, Week 2, Week 3	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.
Immediate Recall of Emotional Story Items	Week 1, Week 2, Week 3	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.