Treatment of Depression With Connectivity Guided Robotically Delivered rTMS

The investigators propose a randomized, double-blind, 4-week trial of rTMS to the left
dorsolateral prefrontal cortex (DLPFC) for subjects with MDD all of whom are concurrently
receiving pharmaceutical and psychotherapeutic interventions. Arm 1 delivers active rTMS to
the left DLPFC using the standard aiming strategy. Arm 2 delivers active rTMS to the left
anterior DLPFC using connectivity-based, image-guided aiming. Arm 3 delivers active rTMS to
the left posterior DLPFC using connectivity-based, image-guided aiming. In all three arms,
rTMS is administered in an image-guided, robotic manner to ensure therapist blinding and
equivalent subject experiences across arms. In all three arms, the following stimulation
protocol will be used: 10 Hz rTMS delivered in 4 sec trains with 26 sec inter-train
intervals, 37.5 minutes/session (i.e. 3,000 pulses/session), 5 sessions/week, for 4 weeks.
Neuroimaging will be used both for treatment planning and to characterize any rTMS-induced
network plasticity using resting-state functional magnetic resonance imaging (rs-fMRI) at
week 4 of each treatment arm. Clinical assessments and neuropsychological tests will be
administered weekly throughout treatment (weeks 1-4).

Inclusion Criteria:

1. Males or females with MDD receiving treatment at the Laurel Ridge Treatment Center
(LRTC) between the ages of 18-65 years.

2. Meeting the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-V) criteria for MDD as determined using the Mini-International Psychiatric
Interview (MINI).

3. Meeting the Montgomery-Ashberg Depression Rating Scale (MADRS>18) criteria for
treatment resistance in MDD despite completing at least one adequate trial of an
Selective Serotonin Reuptake Inhibitor (SSRI) or Serotonin-Norepinephrine Reuptake
Inhibitor (SNRI) at an FDA-recommended dose for at least 6-8 weeks.

4. Subjects on SSRIs or other antidepressants, hypnotic medications including modulators
of Gamma-Aminobutyric Acid (GABA)-A receptor function, trazodone, atypical neuroleptic
or other psychotropic medications such as prazosin may enter the study if they are
deemed to be on a stable dose of their medication.

5. Able to provide written informed consent.

6. Able to read and write English.

Exclusion Criteria:

1. Subjects with a diagnostic history of bipolar disorder, schizophrenia or
schizoaffective disorder or currently exhibiting psychotic features as confirmed by
MINI.

2. Serious, active suicidal risk as assessed by evaluating psychiatrist. Serious active
suicidal risk is determine as imminent risk of suicide reflected in a subject having a
plan and intent to end his or her life. History of suicidality in itself is not
exclusion for participation in this protocol so long as the evaluating psychiatrist
determines that there is an absence of serious active suicidal risk and the means to
keep subjects safe.

3. Substance use disorder during the 3 months prior to screening; except for Mild or
Moderate Alcohol Use Disorder according to DSM-5 V criteria.

4. Any history or signs of serious medical or neurological illness including seizure
disorders. Except for seizures, a subject with a clinical abnormality may be included
only if the study clinician considers the illness will not introduce additional risk
and will not interfere with the study procedures.

5. History of traumatic brain injury (TBI) with loss of consciousness for 20 minutes or
more as determined by the Brief Traumatic Brain Injury Screen (TBI Screening Tool).

6. Positive urine pregnancy test at screening.

7. Any history or signs of metal objects (e.g. surgical clips, cardiac pacemakers, metal
implants, etc.) in the body at the time of screening. MRI can have risks for persons
with foreign bodies implanted in their body.