From Medscape Pharmacists
How Does TMS Work in Treating Refractory Depression?
Medscape Pharmacists. 2008; ©2008 Medscape
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Joel Lamoure, RPh, BSP, FASCP
Transcranial magnetic stimulation (TMS) seems to be a much needed treatment for patients with major depressive disorder who are treatment resistant. What is the pharmacologic mechanism of TMS?
Response from Joel Lamoure, RPh, BSP, FASCP
Assistant Professor, Department of Psychiatry, University of Western Ontario, London, Ontario, Canada; Mental Health Pharmacist, London Health Sciences Centre, London, Ontario, Canada
TMS is a noninvasive technique that uses magnetic fields to induce weak electric currents in brain tissue. As a result, brain neurons can be excited without the need for external electrodes. Instead, a coil is placed near the head of the human or animal over part of the brain, such as the dorsolateral prefrontal cortex. 
TMS can be classified into different types. The focus of this article will be rTMS, where the "r" represents a repetitive cycle. There are 2 different subtypes of rTMS: high-frequency and low-frequency. High-frequency rTMS may be defined as a 3- to 20-Hz application to the left prefrontal cortex, and low-frequency rTMS is defined as 1 Hz or less applied to the right prefrontal cortex. 
Pure unipolar depression is defined in the literature as having an incidence of 1.5% to 19%.  Despite effective treatment options that include medications to reregulate the balance of neurotransmitters in the brain (eg, serotonin, dopamine, monoamines, and norepinephrine) and behavioral interventions (eg, cognitive behavioral therapy), there are numerous treatment failures secondary to side effects: accessibility, adherence to the medication, or onset of action. 
The overall estimated incidence of treatment-refractory depression increases with the number of episodes a patient experiences. For example, the rate of recovery (sustained remission) in treated patients with only 1 major depressive episode is about 50%, whereas patients who have suffered 3 episodes experience a recurrence of their symptoms about 90% of the time.  When considered from the perspective of patient morbidity and quality of life, if remission is not achieved initially with treatment, 67.6% of patients will relapse within 2 years vs 15.2% of patients who initially achieved remission of symptoms. 
In patients with treatment-refractory depression, options such as electroconvulsive therapy (ECT) may need to be considered. Although biweekly ECT has a shorter onset latency than rTMS, it requires interventions using anesthesiologists and is associated with memory loss (secondary to the length of the seizure as 1 variable) and actual induction of a seizure.  As such, it is important to determine whether the patient is on any medications that may impact seizure threshold, as this can lead to complications and present a therapeutic challenge.
Analysis of the literature from May 2003 to the present yielded 14 studies of rTMS. However, several of those studies involved concurrent pharmacotherapy arms that may serve as a confounder, due to the efficacy of monotherapy using rTMS. Gershon and colleagues  conducted an analysis of the literature where pharmacotherapy interventions were removed (as defined by medication resistance); they found that 4 in 10 subjects were partial or full responders to rTMS vs no responders in the "sham" rTMS group. A sham group is similar to a placebo arm, where the magnetic coil has been shielded to minimize the amount of magnetic emissions from the coil. These numbers held true in other nonpharmacotherapy treated groups where George and colleagues  identified significantly more patients responding to rTMS ( 9 in 20) than in the placebo arm ( 0 in 20), with a P < .01 rendering it statistically significant. Treatment was provided each weekday for 2 weeks.
With this evidence, the question is revisited as to what impact the rTMS has on the brain. There are noted changes in the prefrontal cortex and paralimbic activity, even after a 2-week course of rTMS, analogous to the study conducted by George and colleagues.
In another study, Teneback and colleagues  identified increased activity at the cingulate and increased paralimbic blood flow after 2 weeks of treatment. This finding is important as the cingulate effect has been demonstrated to be blunted in depressed patients; intriguingly, antidepressants such as fluoxetine have also been shown to increase cingulate activity.  The researchers hypothesized that patients who responded to rTMS had increased inferior frontal activity at baseline, which may serve as a predictor of rTMS response. 
From a neurotransmitter perspective, rTMS had an impact on upregulation of the beta-adrenergic receptors in the frontal cortex, on downregulation of the serotonin (5-HT 2 ) receptors in the frontal cortex, and on monoamine levels. [7,8] Thus, there are alterations in brain physiology and neurochemistry that may be unique to rTMS. 
From a safety perspective, rTMS was originally thought to be generally well-tolerated. However, mild adverse effects were identified, including slight discomfort due to facial muscle twitching (14%) and mild-to-moderate headache (9%), compared with no identified adverse effects in placebo arms.  Management of these adverse effects may include reduction of the stimulus intensity by 10% for the facial twitches, and analgesics, if tolerated, for headaches.  Unlike with ECT, there were no reports of memory impairment, concentration problems, or cognitive changes. 
O'Reardon JP, Solvason HB, Janicak PG, et al. Efficacy and safety of transcranial magnetic stimulation in the acute treatment of major depression: a multisite randomized controlled trial. Biol Psychiatry. 2007;62:1208-1216. Abstract
Gershon AA, Dannon PN, Grunhaus L. Transcranial magnetic stimulation in the treatment of depression. Am J Psychiatry. 2003;160:835-845. Abstract
Menkes DL, Bodnar P, Ballesteros RA, Swenson MR. Right frontal lobe slow frequency repetitive transcranial magnetic stimulation (SF r-TMS) is an effective treatment for depression: a case-control pilot study of safety and efficacy. J Neurol Neurosurg Psychiatry. 1999;67:113-115. Abstract
MacQueen G. Neurobiology of depression: a complex disorder. Presented in London , Ontario , January 16, 2008.
George MS, Nahas Z, Molloy M, et al. A controlled trial of daily left prefrontal cortex TMS for treating depression. Biol Psychiatry. 2000;48:962-970. Abstract
Teneback CC, Nahas Z, Speer AM, et al. Changes in prefrontal cortex and paralimbic activity in depression following two weeks of daily left prefrontal TMS. Neuropsychiatry Clin Neurosci. 1999;11:426-435.
Ben-Shachar D, Gazawi H, Riboyad-Levin J, Klein E. Chronic repetitive transcranial magnetic stimulation alters beta-adrenergic and 5-HT2 receptor characteristics in rat brain. Brain Res. 1999;816:78-83. Abstract
Ben-Shachar D, Belmaker RH, Grisaru N, Klein E. Transcranial magnetic stimulation induces alterations in brain monoamines. J Neural Transm. 1997;104:191-197. Abstract
Klein E, Kreinin I, Chistyakov A, et al. Therapeutic efficacy of right prefrontal slow repetitive transcranial magnetic stimulation in major depression. Arch Gen Psychiatry. 1999;56:315-320. Abstract
Joel Lamoure, RPh, BSP, FASCP , Assistant Professor, Department of Psychiatry, University of Western Ontario, London, Ontario, Canada; Mental Health Pharmacist, London Health Sciences Centre, London, Ontario, Canada
Disclosure: Joel Lamoure, RPh, BSP, FASCP, has disclosed that he has received grants for clinical research from Eli Lilly Canada. Mr. Lamoure has also disclosed that he has received grants for educational activities from Eli Lilly Canada and Purdue Pharma Canada . Mr. Lamoure has also disclosed that he has served as an advisor or consultant to Pfizer Canada . Mr. Lamoure has also disclosed that he has received honoraria from Eli Lilly Canada, Pfizer Canada , and Purdue Pharma Canada .