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).

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.

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

Adverse events for the visits on which study drugs were administered were assessed at the end of that session and (retrospectively) one week later for events occurring within several hours after that session (at Weeks 2 and 3, and retrospectively at 4). Serious adverse events were reported for the 4-week trial period as a whole.

Adverse events were assessed by open query