Glutamate Probes in Adolescent Depression

This is a cross-sectional and longitudinal neurophysiology research study of 200 adolescent
subjects in varying stages of major depressive disorder (MDD). The aims of this study are
designed to gain an understanding of (1) the role of glutamate in the neurophysiology and
pharmacologic treatment of child and adolescent MDD; (2) the role of gamma-aminobutyric acid
(GABA) in the neurophysiology and pharmacologic treatment of child and adolescent MDD; (3)
the trajectory of glutamatergic and GABAergic functioning in human development with MDD.

Glutamate concentrations in the anterior cingulate cortex (ACC) and left dorsolateral
prefrontal (L-DLPFC) cortex will be evaluated using proton magnetic resonance spectroscopy
(MRS) at 3 Tesla (3T). Glutamatergic cortical excitability measures (with motor threshold and
intracortical facilitation paradigms), and GABAergic cortical inhibitory measures (with
cortical silent period and intracortical inhibition paradigms) will be studied using single
and paired-pulse transcranial magnetic stimulation (TMS) paradigms.

Inclusion Criteria:

1. Adolescents from the ages of 13 to 21, male or female.

2. Subjects with MDD (Groups 2, 3 & 4):

- Must have a diagnosis of Major Depressive Disorder (MDD)

- Single episode or recurrent; moderate to severe.

- The MDD diagnosis is based on the Kiddie Schedule for Affective Disorders and
Schizophrenia for School Aged Children - Past and Lifetime (K-SADS-PL).

- This semi-structured psychiatric interview will be administered by a
psychiatrist, Ph.D. level psychologist, or equivalent professional with extensive
clinical experience.

- Must have a Childhood Depression Rating Scale-Revised (CDRS-R) score of ≥ 40

- Must have a Clinical Global Impression Severity (CGI-S) Scale of ≥ 4

3. Group 1: (Healthy Controls; 50 Subjects): Healthy volunteers who are 13-21 years of
age with no current or lifetime mental health diagnoses and no current or lifetime
psychotropic medication treatment.

4. Group 2: (50 subjects): Subjects with moderate to severe MDD for which an SSRI has
been clinically indicated.

- If initiating SSRI treatment, medication must be started ± 7 days of the baseline
visit

- Subjects and parents in group 2 will be eligible to return in 6-8 weeks for a
follow up visit that includes mood assessments and evaluations.

- Subjects who have been adherent to their clinically prescribed medication will be
eligible for a second MRI/MRS scan and TMS measures within 7 days of the second
visit.

- Subjects who choose not to initiate treatment with an SSRI will have a baseline
visit only

- Subjects who discontinue or change their medication after the baseline will not
be eligible for a follow-up visit

Group 3: (50 subjects): Subjects with moderate to severe MDD that has responded to
treatment with an SSRI.

• Response will be defined as a 1 (very much) or 2 (much) improved on a
CGI-Improvement Scale. This is the current acceptable standard in child and adolescent
psychopharmacological research.

Group 4: (50 subjects): Subjects with moderate to severe MDD that has not responded to
treatment with an SSRI as defined above with CGI scale score.

5. Subject and parent or guardian (if under age 18) must be capable of providing informed
consent

6. Subjects and at least 1 parent must be fluent in English. • Subjects 18 years of age
or older do not require an English-speaking parent

Exclusion Criteria:

4.2 Exclusion Criteria For all Subjects:

1. Contraindications to MRI/MRS, as determined by the MRI safety screen and MRI safety
codes.

2. Subjects who are judged by the Principal Investigator to be at imminent risk for
self-harm or suicide as indicated by interview or C-SSRS.

3. Pregnancy or suspected pregnancy in females.

4. Metal in the head (except the mouth*), implanted medication pumps, cardiac pacemaker
(*subjects with braces will be excluded from MRI/MRS portion of the study only)

5. Prior brain surgery.

6. Risk for increased intracranial pressure such as a brain tumor.

7. Any unstable medical condition.

4.2.1 Exclusion Criteria for Healthy Control Group only:

1. Current or past mental health diagnoses in subjects or first degree relatives of
subjects.

2. Current or past mental health medications.

4.2.2 Exclusion Criteria for MDD Groups only:

1. Primary Axis I or II disorder other than MDD.

2. Unprovoked seizure history, seizure disorder, history of febrile seizures, first
degree relative with epilepsy

3. Taking medication(s) that lower seizure threshold

4. Any significant findings on the TMS adult safety screen (TASS).

4.2.3 Exclusion Criteria for Group 2 only:

1. Subject has started SSRI medication more than 7 days prior to the baseline visit.