Major Depressive Disorder
Conditions
Keywords
Cognitive behavior therapy (CBT), d-cycloserine (DCS), Modafinil
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.
Interventions
DRUG250 mg DCS
Drug
DRUG100 mg Modafinil
Drug
DRUGPlacebo
Drug
Sponsors
Boston University Charles River Campus
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 250 mg DCS Baseline assessment (week 1), two weekly sessions when 250mg DCS is administered, and final week (week 4) when retention is assessed.
250 mg DCS: Drug | 13 |
| 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.
100 mg Modafinil: Drug | 12 |
| Placebo Baseline assessment (week 1), two weekly sessions when placebo is administered, and final week (week 4) when retention is assessed.
Placebo: Drug | 11 |
| Total | 36 |
Baseline characteristics
| Characteristic | 250 mg DCS | 100 mg Modafinil | Placebo | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 13 Participants | 12 Participants | 11 Participants | 36 Participants |
| Age, Continuous | 34.9 years STANDARD_DEVIATION 14 | 26.4 years STANDARD_DEVIATION 8.1 | 27.7 years STANDARD_DEVIATION 10.8 | 29.9 years STANDARD_DEVIATION 11.7 |
| Digits backwards | 8.3 Number of correct trials STANDARD_DEVIATION 2.7 | 9.5 Number of correct trials STANDARD_DEVIATION 2.5 | 11.3 Number of correct trials STANDARD_DEVIATION 2.5 | 9.6 Number of correct trials STANDARD_DEVIATION 2.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 0 Participants | 2 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 12 Participants | 9 Participants | 31 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Immediate Memory measured by the Hopkins Verbal Learning Task | 8.5 number of correctly recalled words STANDARD_DEVIATION 1.3 | 9.6 number of correctly recalled words STANDARD_DEVIATION 1.1 | 9.6 number of correctly recalled words STANDARD_DEVIATION 1.7 | 9.2 number of correctly recalled words STANDARD_DEVIATION 1.4 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 2 Participants | 3 Participants | 7 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 1 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) White | 8 Participants | 9 Participants | 5 Participants | 22 Participants |
| Sex/Gender, Customized Female | 7 Participants | 6 Participants | 7 Participants | 20 Participants |
| Sex/Gender, Customized Male | 5 Participants | 5 Participants | 4 Participants | 14 Participants |
| Sex/Gender, Customized Transgender | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 13 | 0 / 12 | 0 / 11 |
| other Total, other adverse events | 4 / 13 | 7 / 12 | 7 / 11 |
| serious Total, serious adverse events | 0 / 13 | 0 / 12 | 0 / 11 |
Outcome results
Primary
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.
Time frame: Week 2 and Week 3
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 250 mg DCS | 1 Week Delayed Recall Logical Memory | Week 2 | 1.8 units on a scale | Standard Deviation 2.3 |
| 250 mg DCS | 1 Week Delayed Recall Logical Memory | Week 3 | 9.5 units on a scale | Standard Deviation 5 |
| 100 mg Modafinil | 1 Week Delayed Recall Logical Memory | Week 2 | 4.4 units on a scale | Standard Deviation 4.3 |
| 100 mg Modafinil | 1 Week Delayed Recall Logical Memory | Week 3 | 12.8 units on a scale | Standard Deviation 5.5 |
| Placebo | 1 Week Delayed Recall Logical Memory | Week 2 | 5.0 units on a scale | Standard Deviation 3.8 |
| Placebo | 1 Week Delayed Recall Logical Memory | Week 3 | 13.6 units on a scale | Standard Deviation 5.1 |
Primary
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.
Time frame: Week 2 and Week 3
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 250 mg DCS | 1 Week Delayed Recall of Emotional Story Items | Week 2 | 13.5 units on a scale | Standard Deviation 10.4 |
| 250 mg DCS | 1 Week Delayed Recall of Emotional Story Items | Week 3 | 25.0 units on a scale | Standard Deviation 13.9 |
| 100 mg Modafinil | 1 Week Delayed Recall of Emotional Story Items | Week 2 | 21.3 units on a scale | Standard Deviation 8 |
| 100 mg Modafinil | 1 Week Delayed Recall of Emotional Story Items | Week 3 | 37.3 units on a scale | Standard Deviation 12.3 |
| Placebo | 1 Week Delayed Recall of Emotional Story Items | Week 2 | 16.1 units on a scale | Standard Deviation 9.5 |
| Placebo | 1 Week Delayed Recall of Emotional Story Items | Week 3 | 26.4 units on a scale | Standard Deviation 11.9 |
Primary
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.
Time frame: Week 2 and Week 3
Population: Data was missing for two participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 250 mg DCS | Recall of Cognitive Therapy Content | Week 2 | 25.4 Number of correct units of information | Standard Deviation 2.9 |
| 250 mg DCS | Recall of Cognitive Therapy Content | Week 3 | 28.2 Number of correct units of information | Standard Deviation 4.2 |
| 100 mg Modafinil | Recall of Cognitive Therapy Content | Week 2 | 26.8 Number of correct units of information | Standard Deviation 4 |
| 100 mg Modafinil | Recall of Cognitive Therapy Content | Week 3 | 29.7 Number of correct units of information | Standard Deviation 3.9 |
| Placebo | Recall of Cognitive Therapy Content | Week 2 | 24.7 Number of correct units of information | Standard Deviation 4 |
| Placebo | Recall of Cognitive Therapy Content | Week 3 | 28.7 Number of correct units of information | Standard Deviation 5.4 |
Secondary
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.
Time frame: Baseline, Week 1, Week 2, Week 3
Population: Data is missing for two participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 250 mg DCS | Digits Backward | Week 3 | 9.6 Number of correct trials | Standard Deviation 2.7 |
| 250 mg DCS | Digits Backward | Week 1 | 9.25 Number of correct trials | Standard Deviation 2.8 |
| 250 mg DCS | Digits Backward | Week 2 | 10.0 Number of correct trials | Standard Deviation 3.2 |
| 250 mg DCS | Digits Backward | Baseline | 8.3 Number of correct trials | Standard Deviation 2.7 |
| 100 mg Modafinil | Digits Backward | Week 1 | 10.4 Number of correct trials | Standard Deviation 2.2 |
| 100 mg Modafinil | Digits Backward | Week 2 | 11.3 Number of correct trials | Standard Deviation 2 |
| 100 mg Modafinil | Digits Backward | Baseline | 9.5 Number of correct trials | Standard Deviation 2.5 |
| 100 mg Modafinil | Digits Backward | Week 3 | 11.4 Number of correct trials | Standard Deviation 2.2 |
| Placebo | Digits Backward | Week 2 | 12.1 Number of correct trials | Standard Deviation 1.7 |
| Placebo | Digits Backward | Baseline | 11.3 Number of correct trials | Standard Deviation 2.5 |
| Placebo | Digits Backward | Week 3 | 11.7 Number of correct trials | Standard Deviation 2.4 |
| Placebo | Digits Backward | Week 1 | 12.2 Number of correct trials | Standard Deviation 2.2 |
Secondary
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.
Time frame: Baseline, Week 1, Week 2, Week 3
Population: Data is missing for two participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 250 mg DCS | Immediate Memory Measured by the Hopkins Verbal Learning Task | Baseline | 8.5 Number of words recalled | Standard Deviation 1.3 |
| 250 mg DCS | Immediate Memory Measured by the Hopkins Verbal Learning Task | Week 1 | 7.8 Number of words recalled | Standard Deviation 1.7 |
| 250 mg DCS | Immediate Memory Measured by the Hopkins Verbal Learning Task | Week 2 | 8.7 Number of words recalled | Standard Deviation 1.6 |
| 250 mg DCS | Immediate Memory Measured by the Hopkins Verbal Learning Task | Week 3 | 8.8 Number of words recalled | Standard Deviation 1.8 |
| 100 mg Modafinil | Immediate Memory Measured by the Hopkins Verbal Learning Task | Week 3 | 10.1 Number of words recalled | Standard Deviation 1.1 |
| 100 mg Modafinil | Immediate Memory Measured by the Hopkins Verbal Learning Task | Baseline | 9.6 Number of words recalled | Standard Deviation 1.1 |
| 100 mg Modafinil | Immediate Memory Measured by the Hopkins Verbal Learning Task | Week 2 | 9.7 Number of words recalled | Standard Deviation 1.3 |
| 100 mg Modafinil | Immediate Memory Measured by the Hopkins Verbal Learning Task | Week 1 | 9.9 Number of words recalled | Standard Deviation 1.2 |
| Placebo | Immediate Memory Measured by the Hopkins Verbal Learning Task | Week 3 | 9.4 Number of words recalled | Standard Deviation 2.2 |
| Placebo | Immediate Memory Measured by the Hopkins Verbal Learning Task | Week 1 | 9.4 Number of words recalled | Standard Deviation 1.5 |
| Placebo | Immediate Memory Measured by the Hopkins Verbal Learning Task | Week 2 | 9.6 Number of words recalled | Standard Deviation 1.3 |
| Placebo | Immediate Memory Measured by the Hopkins Verbal Learning Task | Baseline | 9.6 Number of words recalled | Standard Deviation 1.7 |
Secondary
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.
Time frame: Week 1, Week 2, Week 3
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 250 mg DCS | Immediate Recall of Emotional Story Items | Week 2 | 34.4 Number of story units recalled | Standard Deviation 12.6 |
| 250 mg DCS | Immediate Recall of Emotional Story Items | Week 1 | 22.4 Number of story units recalled | Standard Deviation 11.9 |
| 250 mg DCS | Immediate Recall of Emotional Story Items | Week 3 | 38.4 Number of story units recalled | Standard Deviation 12.9 |
| 100 mg Modafinil | Immediate Recall of Emotional Story Items | Week 2 | 46.8 Number of story units recalled | Standard Deviation 10.9 |
| 100 mg Modafinil | Immediate Recall of Emotional Story Items | Week 1 | 35.2 Number of story units recalled | Standard Deviation 9.4 |
| 100 mg Modafinil | Immediate Recall of Emotional Story Items | Week 3 | 49.9 Number of story units recalled | Standard Deviation 12.4 |
| Placebo | Immediate Recall of Emotional Story Items | Week 1 | 32.2 Number of story units recalled | Standard Deviation 13.3 |
| Placebo | Immediate Recall of Emotional Story Items | Week 3 | 43.4 Number of story units recalled | Standard Deviation 11.3 |
| Placebo | Immediate Recall of Emotional Story Items | Week 2 | 35.5 Number of story units recalled | Standard Deviation 11 |
Secondary
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.
Time frame: Week 1, Week 2, Week 3
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 250 mg DCS | Logical Memory Immediate Recall | Week 1 | 14.8 Number of story units recalled | Standard Deviation 4.3 |
| 250 mg DCS | Logical Memory Immediate Recall | Week 3 | 18.5 Number of story units recalled | Standard Deviation 3 |
| 250 mg DCS | Logical Memory Immediate Recall | Week 2 | 17.7 Number of story units recalled | Standard Deviation 3.4 |
| 100 mg Modafinil | Logical Memory Immediate Recall | Week 3 | 21.5 Number of story units recalled | Standard Deviation 2.2 |
| 100 mg Modafinil | Logical Memory Immediate Recall | Week 1 | 17.1 Number of story units recalled | Standard Deviation 2.8 |
| 100 mg Modafinil | Logical Memory Immediate Recall | Week 2 | 17.8 Number of story units recalled | Standard Deviation 4.1 |
| Placebo | Logical Memory Immediate Recall | Week 3 | 21.2 Number of story units recalled | Standard Deviation 2.9 |
| Placebo | Logical Memory Immediate Recall | Week 1 | 16.2 Number of story units recalled | Standard Deviation 4.7 |
| Placebo | Logical Memory Immediate Recall | Week 2 | 18.2 Number of story units recalled | Standard Deviation 2.9 |
Secondary
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.
Time frame: Week 2 and Week 3
Population: Data is missing for one participant.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 250 mg DCS | Skills of Cognitive Therapy | Week 2 | 23.3 units on a scale | Standard Deviation 6.4 |
| 250 mg DCS | Skills of Cognitive Therapy | Week 3 | 26.4 units on a scale | Standard Deviation 8.5 |
| 100 mg Modafinil | Skills of Cognitive Therapy | Week 2 | 20.5 units on a scale | Standard Deviation 5.5 |
| 100 mg Modafinil | Skills of Cognitive Therapy | Week 3 | 24.3 units on a scale | Standard Deviation 7.2 |
| Placebo | Skills of Cognitive Therapy | Week 2 | 24.8 units on a scale | Standard Deviation 5.6 |
| Placebo | Skills of Cognitive Therapy | Week 3 | 25.7 units on a scale | Standard Deviation 4.4 |