Investigating Predictors of Treatment Response in Treatment-Resistant Depression (TRD) With Interleaved TMS/fMRI
Investigating Predictors of Treatment Response in Treatment-Resistant Depression (TRD) With Interleaved TMS/fMRI
The purpose of this trial is identify biomarkers of response to repetitive transcranial
 magnetic stimulation (rTMS) in individuals with first episode or treatment resistant
 depression. These biomarkers include simultaneous TMS-fMRI (functional magnetic resonance
 imaging), a blood smear, cognitive and behavioural assessments, questionnaires, and
 neurophysiology.
This study is enrolling 60 individuals with treatment-resistant depression.

 All patients will receive four weeks of 1-Hz rTMS to the right dorsolateral prefrontal cortex
 (R_DLPFC). In addition, all patients will undergo baseline and post-treatment measures,
 including rTMS while they are in the MRI scanner, neurophysiology (Electroencephalography
 (EEG)/Near-Infrared Spectroscopy (NIRS)), cognitive testing, behavioural assessments and a
 blood smear. There will also be a 1-week, 4-week, and 12-week follow-up following completion
 of the treatment course.
TRD Patient Inclusion Criteria:

 Patients will be included if they:

 1. are outpatients

 2. are voluntary and competent to consent to treatment

 3. have a Mini-International Neuropsychiatric Interview (MINI) confirmed diagnosis of
 MDD, single or recurrent

 4. are between the ages of 18 and 80 years

 5. have failed to achieve a clinical response to at least one adequate dose of an
 antidepressant based on an Antidepressant Treatment History Form (ATHF) score of score
 ≥ 3 in the current episode OR have been unable to tolerate at least 2 separate trials
 of antidepressants of inadequate dose and duration (ATHF 1 or 2)

 6. have a score ≥ 22 on the IDS item

 7. have had no increase or initiation of any psychotropic medication in the 4 weeks prior
 to initiation of rTMS

 8. able to adhere to the treatment schedule

 9. pass the TMS adult safety screening (TASS) questionnaire

 First Episode Depression Inclusion Criteria:

 Patients will be included if they:

 1. are outpatients

 2. are voluntary and competent to consent to treatment

 3. have a Mini-International Neuropsychiatric Interview (MINI) confirmed diagnosis of
 MDD, single or recurrent

 4. are between the ages of 18 and 80 years

 5. have never received and adequate antidepressant trial and are not currently taking any
 antidepressant.

 6. have a score ≥ 12 on the IDS item

 7. are on no psychotropic medication for the 4 weeks prior to initiation of rTMS, with
 the exception of lorazepam up to 2mg or equivalent dose of benzodiazepine or
 prescribed sleeping aids including (zopiclone up to 15mg/d, zolpidem up to 10mg/d).

 8. able to adhere to the treatment schedule

 9. pass the TMS adult safety screening (TASS) questionnaire

 Patient Exclusion Criteria:

 Patients are excluded if they:

 1. have a history of substance dependence or abuse within the last 3 months

 2. have a concomitant major unstable medical illness, cardiac pacemaker or implanted
 medication pump

 3. have active suicidal intent

 4. are pregnant

 5. have a lifetime Mini-International Neuropsychiatric Interview (MINI) diagnosis of
 bipolar I or II disorder, schizophrenia, schizoaffective disorder, schizophreniform
 disorder, delusional disorder, or current psychotic symptoms

 6. have a MINI diagnosis of obsessive compulsive disorder, post-traumatic stress disorder
 (current or within the last year), anxiety disorder (generalized anxiety disorder,
 social anxiety disorder, panic disorder), or dysthymia, assessed by a study
 investigator to be primary and causing greater impairment than MDD

 7. have a diagnosis of any personality disorder, and assessed by a study investigator to
 be primary and causing greater impairment than MDD

 8. have failed a course of ECT in the current episode or previous episode

 9. have received rTMS for any previous indication due to the potential compromise of
 expectancy effects

 10. have any significant neurological disorder or insult including, but not limited to:
 any condition likely to be associated with increased intracranial pressure, space
 occupying brain lesion, any history of seizure except those therapeutically induced by
 ECT, cerebral aneurysm, Parkinson's disease, Huntington's chorea, multiple sclerosis,
 significant head trauma with loss of consciousness for greater than 5 minutes

 11. have an intracranial implant (e.g., aneurysm clips, shunts, stimulators, cochlear
 implants, or electrodes) or any other metal object within or near the head, excluding
 the mouth, that cannot be safely removed

 12. If participating in psychotherapy, must have been in stable treatment for at least 3
 months prior to entry into the study, with no anticipation of change in the frequency
 of therapeutic sessions, or the therapeutic focus over the duration of the study

 13. have a clinically significant laboratory abnormality, in the opinion of the one of the
 principal investigators

 14. are currently (or in the last 4 weeks) taking lorazepam greater than 2 mg daily (or
 equivalent) or any dose of an anticonvulsant, due to the potential to limit rTMS
 efficacy

 15. have a non-correctable clinically significant sensory impairment (i.e., cannot hear
 well enough to cooperate with interview).

 16. have failed more than 5 adequate trials of medication in the current episode.

 17. Exclusion criteria for MRI: Those with a history of cranial, thoracic or abdominal
 surgery, with pacemakers, artificial joins or other metallic implants will be excluded
 from the MRI scan. Subjects that have agreed to participate in the MRI portion of the
 study will be pre- screened for any potential metal fragments in the body
 (particularly in the orbits) if they have had any history of doing metal work or have
 been involved in use/deployment of ammunitions/explosives, welding, piping etc.). In
 these cases a CT scan will be performed prior to the MRI scan

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 Healthy Control Inclusion Criteria

 Participants will be included if they:

 1. are voluntary and competent to consent to the study

 2. are between the ages of 18 and 80

 3. are fluent in English, sufficient to complete interviews and cognitive testing

 4. have no history of Axis I or Axis II disorders, as determined by the MINI

 5. pass the TMS adult safety screening (TASS) questionnaire

 Healthy Control Exclusion Criteria:

 Participants will be excluded if they:

 1. have a lifetime Mini-International Neuropsychiatric Interview (MINI) diagnosis of
 bipolar I or II disorder, schizophrenia, schizoaffective disorder, schizophreniform
 disorder, delusional disorder, or current psychotic symptoms

 2. have a MINI diagnosis of obsessive compulsive disorder, post-traumatic stress disorder
 (current or within the last year), anxiety disorder (generalized anxiety disorder,
 social anxiety disorder, panic disorder), dysthymia or any personality disorder

 3. have history of bipolar disorder or psychosis in first degree relative (parents,
 siblings, offspring)

 4. are unable to provide family history of biological family (i.e., adopted persons are
 not eligible)

 5. have a history of substance dependence within the last 3 months

 6. have a concomitant major unstable medical illness

 7. have any significant neurological disorder or insult including, but not limited to:
 any condition likely to be associated with increased intracranial pressure, space
 occupying brain lesion, cerebral aneurysm, Parkinson's disease, Huntington's chorea,
 multiple sclerosis, significant head trauma with loss of consciousness for greater
 than or equal to 5 minutes

 8. have a non-correctable clinically significant sensory impairment (i.e., cannot hear
 well enough to cooperate with interview).

 9. have a personal or family history of seizures

 10. Exclusion criteria for MRI: Those with a history of cranial, thoracic or abdominal
 surgery, with pacemakers, artificial joins or other metallic implants will be excluded
 from the MRI scan. Those who are pregnant will also be excluded from the MRI scan.
 Subjects that have agreed to participate in the MRI portion of the study will be
 pre-screened for any potential metal fragments in the body (particularly in the
 orbits) if they have had any history of doing metal work or have been involved in
 use/deployment of ammunitions/explosives, welding, piping etc.)