MRI Studies of Emotion in Depression

Specific Aim 1: To characterize the function of basic neural systems involved in emotion
perception and regulation in TRD.

- Experiment 1.1: Neural responses to emotional faces in TRD (neutral, low and high
intensity sad facial expressions).

o Hypothesis 1.1: Patients with TRD, relative to HC participants, will evidence
increased activation in the amygdala/parahippocampal gyrus to sad compared to neutral
faces.

- Experiment 1.2: Neural responses during negative emotion regulation in TRD (cognitive
reappraisal).

- Hypothesis 1.2: Patients with TRD, relative to HC participants, will show enhanced
activation of the amygdala during the generation of negative affect and will be
impaired in their ability to recruit PFC/ACC regions during attempts to
down-regulate negative affect.

Specific Aim 2: To characterize changes in emotion-processing neural networks associated
with ketamine and rapid antidepressant response.

- Experiment 2.1: Neural changes in response to emotional faces associated with ketamine
and rapid antidepressant response.

o Hypothesis 2.1a: Ketamine, compared to midazolam, will be associated with reduced
activation in the amygdala to sad compared to neutral faces. 2.1b: Antidepressant
response, compared to non-response, will be specifically associated with changes in
PFC/ACC function.

- Experiment 2.2: Neural changes during negative emotion regulation (cognitive
reappraisal) associated with ketamine and rapid antidepressant response.

- Hypothesis 2.2a: Ketamine, compared to midazolam, will be associated with reduced
activation in the amygdala during negative emotion generation and enhanced PFC/ACC
function during down-regulation of negative affect. 2.2b: Antidepressant response,
compared to non-response, will be specifically associated with enhancement of
PFC/ACC function.

Specific Aim 3 (Exploratory): To investigate functional and effective connectivity between
emotion perception/generation neural systems and cognitive emotional regulation systems.
Hypothesis 3: TRD compared to HC will be characterized by abnormal connectivity between
PFC/ACC and amygdala, which will normalize with rapid antidepressant response.

The setting of research will be MSSM. All research participants will be recruited and
screened through the Mood and Anxiety Disorders Program (MAP) (Director: Dan V. Iosifescu,
M.D.) at MSSM. MAP is one of the major clinical research programs of the Department of
Psychiatry, with research funding from NIH, the Department of Defense, NARSAD, and industry.

Inclusion Criteria:

- Male or female participants, 18-70 years of age;

- Participants must be free of any psychiatric condition (for the healthy volunteer
group) or meet DSM-IV criteria for major depressive disorder, without psychotic
features, based on the Structured Clinical Interview for DSM-IV TR Axis I Disorders
(SCID);

- Participants have demonstrated inadequate response to a minimum of 1 adequate
antidepressant treatment trial in current episode (e.g. TRD);

- Participants must be willing to undergo washout of psychotropic medications that he
or she is taking;

- Participants must have a level of understanding of the English language sufficient to
agree to all tests and examinations required by the study and must be able to
participate fully in the informed consent process.

Exclusion Criteria:

- Lifetime diagnosis of schizophrenia or any psychotic disorder, bipolar disorder,
pervasive developmental disorders or mental retardation;

- Current diagnosis of obsessive-compulsive disorder (OCD), but not other anxiety
disorders;

- Diagnosis of a substance use disorder within the past six months; all participants
must have a negative urine toxicology test on the day of the fMRI, prior to the scan;

- Female participants who are pregnant, nursing, for may become pregnant;

- Any unstable medical illnesses including hepatic, renal, gastroenterologic,
respiratory, cardiovascular (including ischemic heart disease); endocrinologic,
neurologic (including history of severe head injury), immunologic, or hematologic
disease;

- Clinically significant abnormalities of laboratories, physical examination, or ECG;

- Participants judged to be at serious suicidal risk by the PI or another
study-affiliated psychiatrist;

- Any contraindications to MRI, including pacemakers or metallic objects in the body.