Glutamate Probes in Adolescent Depression
Glutamate Probes in Adolescent Depression
The purpose of this study is to learn if measures of brain chemicals from a brain scan called
 Magnetic Resonance Imaging and Spectroscopy (MRI/MRS) and brain activity (known as cortical
 excitability and inhibition) collected by Transcranial Magnetic Stimulation (TMS) are
 different in adolescents with depression who are in different stages of treatment.

 Researchers are conducting this study to learn more about how the brain works in adolescents
 with depression and without depression (healthy controls). This is important because it may
 identify a biological marker (a measure of how bad an illness is) for depression that could
 one day be used to identify depressed adolescents who would benefit from certain treatments
 (medications for example) or to monitor how well treatments are working.
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.