Repetitive Transcranial Magnetic Stimulation (rTMS) for Treatment Resistant Depressive Disorder
Repetitive Transcranial Magnetic Stimulation (rTMS) for Treatment Resistant Depressive Disorder
Major Depressive Disorder (MDD) is one of the most prevalent mental illnesses in North
 America, in which 30% - 40% fail to respond to conventional treatment. Repetitive
 Transcranial Magnetic Stimulation (rTMS) has been shown to be an effective therapeutic tool
 for the treatment of MDD. This form of treatment involves a series of magnetic pulses
 directed to the brain for about 30 minutes. Importantly, such treatment is very safe and well
 tolerated. However, to date, most treatment studies show modest efficacy due to limitations,
 including: 1) treatments that are delivered to only one side of the brain; 2) treatment that
 does not directly target a specific brain region associated with depression; 3) treatments
 that are of short duration; 4) treatments that are of insufficient intensity; and 5)
 insufficient understanding of the brain mechanisms responsible for therapeutic effect. This
 study is designed to directly address all of these limitations, as well as explore brain
 mechanisms (e.g. cortical excitability) through which treatment is optimized.
Several studies have demonstrated that rTMS is an efficacious treatment for treatment
 resistant major depressive disorder (TRD). However, recent meta-analyses, and more recent,
 large, multi-centre studies, have provided evidence suggesting that rTMS, at best, provides
 modest therapeutic efficacy compared to sham stimulation.

 Several reasons may account for this modest therapeutic effect. First, the majority of these
 studies involved left-sided treatment alone to the dorsolateral prefrontal cortex (DLPFC),
 which is a significant limitation when considering that electroconvulsive therapy - another
 form of brain stimulation used in TRD - has been shown to be less efficacious when used
 unilaterally, compared to bilaterally.

 Second, sub-optimal methods were utilized to target the DLPFC (i.e., '5-cm anterior method'),
 limiting the treatment potential of what is inherently a targeted form of treatment. In this
 regard, recent data from the investigators suggests that treatment directly targeting the
 DLPFC provides enhanced therapeutic efficacy compared to the '5-cm anterior' method.

 Third, treatment durations were typically short (i.e., 2-4 weeks). Fourth, stimulation
 intensity may have been insufficient by not taking into consideration coil-to-cortex
 distance, which is of particular importance when considering that this parameter may
 contribute significantly to rTMS-induced antidepressant response. Fifth, there has not been a
 study that has examined TRD across the lifespan in a way that addresses the differences
 between older and younger adults. Therefore, the investigators propose to conduct a study
 evaluating the efficacy of rTMS for TRD that directly addresses all 5 of these major
 limitations.

 This study will compare bilateral rTMS to unilateral rTMS and will involve targeting the
 DLPFC using cortical co-registration techniques, as well as treatments of optimal duration
 (i.e., up to 6 weeks) and intensity parameters (i.e., adjusted for coil-to-cortex distance).
 The use of distance cortical co-registration and adjustment for coil-to-cortex distance
 addresses the major limitation (lack of stimulation intensity to compensate for age-related
 prefrontal atrophy) in studies that have examined rTMS in an elderly sample. Preliminary data
 from this research group provide compelling evidence that rTMS may, indeed, be effective when
 some of these limitations are optimized in both younger and older adults. Finally, it is also
 essential that research investigate the mechanisms of therapeutic efficacy, so that increases
 in understanding can be translated into enhanced treatment. For several reasons, cortical
 excitability may represent a neurophysiological process through which the therapeutic effects
 of rTMS are mediated. Recent advances in electroencephalography (EEG) technology now permit
 direct measurement of excitability from the DLPFC; thus, we are now able to ascertain whether
 these are mechanisms through which the therapeutic effects of rTMS in TRD are mediated.

 Hypotheses:

 Hypothesis 1: Treatment with bilateral and high frequency left rTMS (HFL-rTMS) will both
 result in a greater reduction in 17-item Hamilton Depression Rating Scale (HAM-D17) scores
 compared to sham rTMS.

 Hypothesis 2: Bilateral rTMS will result in a significantly greater number of patients
 reaching criteria for therapeutic response and remission on the HAM-D17 compared to
 unilateral or sham rTMS.

 Hypothesis 3: An increase of excitability following HFL-rTMS to the left DLPFC (in the case
 of bilateral rTMS or HFL-rTMS) and a decrease in excitability following low frequency
 right-rTMS (LFR-rTMS; in the case of bilateral rTMS) to the right DLPFC will mediate the
 relationship between rTMS and response in TRD. Finally, the induction of gamma activity
 following rTMS will be associated with improved treatment efficacy.

 Hypothesis 4: rTMS will result in improved executive function in patients over age 60 with
 TRD.
Inclusion Criteria:

 -  voluntary and competent to consent

 -  diagnosis of MDD, as confirmed by the Structured Clinical Interview for the DSM-IV
 (SCID-IV)

 -  18 - 85 years of age

 -  failed to achieve clinical response, or did not tolerate, at least 2 separate
 antidepressant trials of sufficient dosage for at least 6 wks

 -  have a score of 20 or greater on the HAM-D17

 -  have not had an increase or initiation of any psychoactive therapy in the 4 wks prior
 to testing

 -  if a woman of childbearing potential, must be on an effective means of birth control

 Exclusion Criteria:

 -  history of DSM-IV confirmed diagnosis of substance dependence in the last 6 months, or
 substance abuse in the last month

 -  concomitant, major, unstable medical or neurologic illness

 -  history of seizures

 -  acutely suicidal and/or homicidal

 -  pregnant

 -  have metal implants

 -  history of psychosurgery

 -  co-morbid diagnosis of borderline and/or antisocial personality disorder. as confirmed
 by the SCID for Axis II Disorders (SCID-II)

 -  are currently (or in the past 4 weeks) taking more than 2 mg of lorazepam, or
 equivalent, daily

 -  ECT treatment in the current episode