rTMS in Treatment Resistant Depression

rTMS as an alternative to ECT

Background Electroconvulsive therapy (ECT) is highly effective in the treatment of severe
depression (UK ECT Review Group, 2003). During the past decade, transcranial magnetic
stimulation has emerged as a new anti-depressant treatment (e.g. Berman et al, 2000). Some
randomized trials suggest that repetitive transcranial magnetic stimulation (rTMS) might be
as effective as ECT in the treatment of non-psychotic depression (Grunhaus et al, 2000,
2003; Janicak et al, 2002; Rosa et all, 2003; Pridmore et al, 2000; Pridmore, 2000 ). Even
at 3 and 6 month follow up, patients treated with rTMS continue to do as well as those
treated with ECT (Dannon et al, 2002). A recent review also supported the efficacy of rTMS
in treatment resistant depression (Lee et al, 2012). However, other reviews and
meta-analyses show only moderate enthusiasm for transcranial magnetic stimulation as an
alternative to ECT (e.g. Martin et al, 2003; Schlaepfer et al, 2003) and emphasize the need
for further studies.

Given the small number of side effects and comparable efficacy to ECT, we would like to
continue investigating rTMS as an alternative to ECT. The study will aim to compare the
efficacy of sham vs. active rTMS in patients meeting standard criteria for ECT. In addition,
the study will also determine the safety and efficacy of this trial and provide data for a
power analysis to support a larger clinical trial if there is evidence of a clinically
relevant treatment effect.

Our sample population will include 40 adult patients from the Emory University Outpatient
Psychiatry Department and Atlanta community. Potential subjects may be identified by their
treating physicians as potential subjects for the study and after obtaining permission from
the patient, the physician will refer the patient to the research coordinator.

Subjects will enter a 4-week fixed-treatment phase and a variable 2-week extension for
clinical improvers (defined below). Subject will receive rTMS treatment according the FDA
approved protocol with treatments given five times a week daily Monday through Friday at 10
pulses/sec, 120% of motor threshold, and 3000 pulses/session for 4 weeks.

Patients who meet remission criteria (MADRS < 7 for one week, Riedel et al 2010) will be
tapered from rTMS. Patients who do not show sufficient improvement at the end of the fixed
4-week period (defined as a < 30% drop from baseline in MADRS scores) will be discontinued.
If patients improve sufficiently (i.e., > 30% reduction in MADRS score) but do not meet
remission criteria, treatment will continue for up to 2 additional weeks (variable 2-week
extension). In the variable phase, the MADRS assessments will be performed twice weekly and
improvers, but nonremitters, will continue receiving treatment during the variable 2-week
period if they show progressive improvement, defined as at least a 2-point MADRS score
reduction at every other rating. The acute trial will be terminated when patients meet the
stable remission criteria. The rTMS will then be tapered during a 3-week period.

Data Analysis Dichotomous outcomes (remission, response (defined as a 50% decrease in the
baseline MADRS)) will be assessed using a logistic regression model (SAS Institute Inc.,
Cary, North Carolina) with independent variables of treatment (active vs. sham), medication
resistance using the Antidepressant Treatment History Form (ATHF) (low vs. high), current
depressive episode duration (log transformed) and age (continuous). The primary analysis
will be conducted using the intention-to-treat (ITT) population, defined as all randomized
patients who started at least 1 treatment session. All the statistical tests will be
performed at the .05 significance level. Interactions were considered significant at the .15
significance level.

A primary purpose of the present study is to determine the safety and efficacy of this trial
and provide data for a power analysis to support a larger clinical trial if there is
evidence of a clinically relevant treatment effect.

Inclusion Criteria:

- Diagnosis of unipolar major depressive disorder or bipolar disorder, depressed phase
and on medication to prevent a manic episode

- Pretreatment Montgomery Åsberg Depression Rating Scale (MADRS) score ≥ 20

- Over age 18 years

- Meeting criteria for ECT according to standards outlined in American Psychiatric
Association Task Force on Electroconvulsive Therapy (2001) (American Psychiatric
Association Task Force on Electroconvulsive Therapy: The Practice of
Electroconvulsive Therapy: Recommendations for Treatment, Training and Privileging,
Task Force Report on ECT, 2nd Edition. Washington, DC, American Psychiatric
Association, 2001) and qualifying for ECT in the opinion of the study physician and
the subject's psychiatric provider.

- Subjects may be on psychotropic medications including antidepressants,
antipsychotics, benzodiazepines and anticonvulsants but the dosage of the medication
must be stable for at least 6 weeks

- Able and willing to provide informed consent

Exclusion Criteria:

- Be pregnant or lactating, planning to become pregnant within the next three months or
sexually active and not using birth control.

- 2. Diagnosis with the following conditions (current unless otherwise stated):

1. Have a neurological disorder, including a history of seizures, cerebrovascular
disease, primary or secondary tumors in central nervous system, stroke, cerebral
aneurysm or movement disorder or any lifetime history of loss of consciousness
due to head injury.

2. Any current Axis 1 psychotic disorder (including substance-induced psychosis,
psychotic disorder due to a medical condition, or major depression with
psychotic features), as defined by the MINI ( Mini International
Neuropsychiatric Interview; English Version 7.0.0 for Diagnostic and Statistical
Manual of Mental Disorders, Fifth Edition (DSM-5); Copyright 1992--‐2014 Sheehan
DV) at the screening visit;

3. Any lifetime Axis 1 psychotic disorder (excluding substance-induced psychosis,
or psychotic disorder due to a medical condition), or as defined by the MINI at
the screening visit;

4. Any current Axis II personality disorder that would interfere in the
participation of the study as determined through medical history or in the
opinion of the investigator;

5. Have a current amnestic disorder, dementia, or delirium as defined by Montreal
Cognitive Assessment of less than or equal to 16;

6. Any illicit substance use as determined by positive toxicology screen for drugs
of abuse; or alcohol and/or substance abuse or dependence within the past 3
months (90 days) as determined by the MINI at the screening visit

- Treatment histories including:

1. Failure to clinically remit to an adequate trial of electroconvulsive therapy
(ECT), defined as 8 bilateral or 10 unilateral treatments, in the current
episode;

2. Have failed prior treatment with vagal nerve stimulation (VNS);

3. Prior treatment with TMS.

- Have active suicidal intent or plan as defined by a positive answer to questions 4
and/or 5 on the Columbia-Suicide Severity Rating Scale (CSSRS): Screening version; or
more than one suicide attempt in lifetime; or a suicide attempt in the past twelve
months; or in the Investigator's opinion, is likely to attempt suicide within the
next six months.

- Participation in any drug or device clinical trial in the six weeks (42 days) prior
to the screening visit and/or participation in another clinical trial for the
duration of the study.

- Presence of any other condition or circumstance that, in the opinion of the
investigator, has the potential to prevent study completion and/or to have a
confounding effect on outcome assessments