The purpose of this study is to determine whether repetitive high field transcranial
magnetic stimulation of the left or right frontal lobes is beneficial for the treatment of
depression that is refractory to antidepressant medication.
Despite the utility of modern psychotropic medications, depression remains a medical problem
with major societal impact. Electroconvulsive therapy (ECT) is an effective somatic
treatment for depression. However, ECT has disadvantages, including risks attendant with
general anesthesia and significant cognitive side effects (e.g. confusion and memory loss).
An effective but safer somatic therapy for depression could help many patients.
The brain can be stimulated non-invasively by using time-varying magnetic fields to induce
electrical currents within the cerebral cortex, a technique known as transcranial magnetic
stimulation. Preliminary investigations have provided promising evidence of improved mood
associated with high frequency repetitive transcranial magnetic stimulation (rTMS) of left
prefrontal cortex in patients with medication-resistant major depression. However, the role
of stimulus laterality in the effects of prefrontal rTMS have not been tested
systematically. Furthermore, previous studies have likely been confounded by inadequate
patient blinding and by a lack of standardization of psychotropic medication treatment.
Therefore, we propose to use a carefully controlled clinical trial to directly test the
hypothesis that the effects of prefrontal rTMS on mood are related to the laterality of
magnetic stimulation. We also intend to improve blinding in comparison to previous studies
by: 1) employing a parallel-group study design comparing real and simulated rTMS, as opposed
to a crossover study design; 2) using specially constructed sham magnetic coils which can be
placed directly on the scalp surface, to more effectively simulate rTMS; and 3) using trains
of weak electrical impulses to simulate the cutaneous scalp stimulation associated with
rTMS. We will minimize confounding effects of medications and antidepressant withdrawal by:
1) requiring that all patients have fail a monitored clinical trial of an SSRI or other
comparable antidepressant prior to rTMS; and 2) continuing pharmacological treatment of
depression during the rTMS phase of the trial. Demonstration of therapeutic efficacy of rTMS
in this rigorously controlled clinical trial would provide a foundation for further
investigation and development of this novel potential treatment modality.
- All patients will meet DSM-IV criteria for Major Depressive Episode (without
- All patients will have a total score of 18 or higher and a score of at least 3 on
item number 1 of the 24 item Hamilton Rating Scale for Depression (HAM-D).
- All patients will have failed to respond to at least two separate trials of treatment
for at least 4 weeks with therapeutic dosages of antidepressant medication (including
at least one SSRI) or will have been intolerant of at least three different
antidepressant medications (including at least one SSRI).
- Patient medications will be reviewed prior to enrollment in this study. Patients
taking medications that may lower seizure threshold (e.g. metronidazole) will be
excluded if the particular medication cannot be stopped or altered without affecting
the patient's routine medical care.
- History of neurological illness, epilepsy or seizure disorder, intracranial tumor, or
major head trauma leading to loss of consciousness of any length.
- Evidence of central nervous system disease based on baseline complete neurological
examination, EEG and contrast-enhanced computerized tomography or magnetic resonance
imaging of the brain.
- History of implanted pacemaker or medication pump, metal plate in skull, or metal
objects in the eye or skull.
- Axis II diagnosis of Cluster A (paranoid, schizoid, or schizotypal) or Cluster B
(antisocial, borderline, histrionic, or narcissistic) personality disorder.
- Axis II diagnosis of mental retardation.
- History of schizophrenia, schizoaffective disorder, other functional psychosis,
rapid-cycling bipolar illness, or alcohol or drug abuse within the past year.
- Need for rapid clinical response due to conditions such as inanition, psychosis, or
suicidality (defined as suicide attempt during the current major depressive episode
or having a specific plan for committing suicide).
- A medical condition that is not well controlled, such as diabetes or hypertension, or
concomitant medical or nutritional problems necessitating hospitalization.
- Patients taking anticonvulsant mood stabilizers (e.g. carbamazepine, valproic acid).
- Patients otherwise unable to grant informed consent.