Elsevier

Biological Psychiatry

Volume 48, Issue 10, 15 November 2000, Pages 962-970
Biological Psychiatry

Priority communication
A controlled trial of daily left prefrontal cortex TMS for treating depression

https://doi.org/10.1016/S0006-3223(00)01048-9Get rights and content

Abstract

Background: Transcranial magnetic stimulation (TMS) is a new technology for noninvasively stimulating the brain. Several studies have suggested that daily stimulation of the left prefrontal cortex with TMS for 2 weeks has probable antidepressant effects. We conducted a parallel-design, double-masked, sham-controlled study to address whether 2 weeks of daily TMS over the left prefrontal cortex has antidepressant activity greater than sham.

Methods: Thirty medication-free adult outpatients with nonpsychotic, major depressive (n = 21) or bipolar (n = 9) (depressed phase) disorder who were in a current major depression (Hamilton Rating Scale for Depression [HRSD] 21-item score of >18) were treated each weekday for 2 weeks. Subjects were randomly assigned to receive either daily active (20 subjects) or sham (10 subjects) stimulation. Additionally, the 20 active subjects were equally divided between slower (5 Hz) and faster (20 Hz) frequency treatment. Antidepressant response was defined as greater than a 50% improvement in the baseline HRSD.

Results: Active TMS resulted in significantly more responders (9/20) than did sham (0/10) (χ2 = 6.42, p < .01). The number of responders did not differ significantly between the two active cells (3/10 faster and 6/10 slower). Expressed as a percent change from baseline, active TMS subjects had significantly greater improvement on the Beck Depression Inventory as well as the Hamilton Anxiety Rating Scale than did those who received sham.

Conclusions: Daily left prefrontal TMS for 2 weeks significantly reduced depression symptoms greater than did sham. The two forms of active TMS treatment did not differ significantly.

Introduction

Transcranial magnetic stimulation (TMS) is a new method for noninvasively stimulating the brain George and Belmaker 2000, George et al 1999a. A brief but powerful electric current is passed through a small coil of wires on the scalp. This generates a powerful but local magnetic field, which passes unimpeded through the skull and induces a weaker focal electric current in the brain Barker et al 1985, Roth et al 1991, Saypol et al 1991. The highly localized TMS magnetic field typically has a strength of about 1–1.5 T (or 30,000 times the earth’s magnetic field, or about the same intensity as the static magnetic field used in clinical magnetic reonance imaging [MRI]) (Bohning 2000). Although different coil designs allow for a focal or more diffuse stimulation, current technology is not able to stimulate deep brain structures directly. Transcranial magnetic stimulation can be performed in outpatient laboratory settings and, unlike electroconvulsive therapy (ECT), does not cause a seizure or require anesthesia. Subjects usually notice no adverse effects except for occasional mild headache and discomfort at the site of the stimulation. Recent technologic advances led to the development of magnetic stimulators that could repeatedly stimulate faster than once per second (1 Hz). This, by convention, is called repetitive transcranial magnetic stimulation (rTMS). There is some evidence from work in animals (Post et al 1997) and humans Pascual-Leone et al 1991, Pascual-Leone et al 1994 that stimulation at different frequencies may have divergent and even antagonistic effects on neuronal activity Kimbrell et al 1999, Wassermann et al 1998, with higher frequencies exciting the brain and slower frequencies inhibiting activity.

Clinical depressions are very common, with one out of five Americans having an episode during their life (Kessler et al 1994). Many depressions can be treated effectively, but as many as 50–60% have incomplete recovery or a significant side effect burden with current treatments. The pathophysiology of depression is incompletely understood, yet certain neurotransmitters such as serotonin, norepinephrine, and dopamine are likely to be involved. Additionally, specific brain regions such as the dorsolateral prefrontal cortex (DLPFC) (George et al 1994) and deeper limbic areas have been shown to be functioning abnormally on brain imaging studies of depressed subjects (for reviews, see George et al 1998a, Ketter et al 1996).

The search for better treatments combined with emerging knowledge of mood-regulating circuits prompted exploratory work with TMS in depression. Initially, researchers used a round coil with nonfocal stimulation over the vertex, with inconclusive results Grisaru et al 1994, Hoflich et al 1993, Kolbinger et al 1995. In 1994, George and Wassermann (1994)reasoned that focal stimulation with rTMS over the left DLPFC might have antidepressant effects. This thinking was based on abnormalities found in functional neuroimaging studies of depression, as well as from studies showing that changes in prefrontal cortex activity predict response to ECT (Nobler et al 1994). Initial open trials Figiel et al 1998, George et al 1995 and then crossover designs George et al 1997, George et al 1996 have shown a significant antidepressant effect of left prefrontal TMS.

Building on these earlier studies, we initiated a sham-controlled parallel-design trial of left prefrontal cortex rTMS in antidepressant medication–free depressed adults. Additionally, to better understand whether the frequency of stimulation was important in this putative antidepressant effect we used two different stimulation frequencies with theoretically divergent brain effects.

Section snippets

Subjects

Thirty-two depressed adults enrolled in a 2-week double-masked sham-controlled trial. (Here we use the term mask in the same way that the older term blind was used in studies.) After full explanation of the procedures, all subjects signed a written informed consent approved by the Medical University of South Carolina Institutional Review Board and the U.S. Food and Drug Administration (FDA) Devices Section. They were randomly assigned to either sham treatment (n = 10) or active treatment (n =

Subjects

Two subjects who had been randomized to receive active slower TMS did not tolerate the procedure and dropped out after less than three treatments. They were excluded from final analysis. Thus, included in the final analysis were 30 subjects who completed all treatments and who met DSM-IV criteria for either major unipolar depression (21 subjects) or bipolar depression, depressive phase (nine). The baseline HRSD means and SDs by group were 23.8 (4.1), sham, and 28.1 (6.1), active (30 [5.8],

Discussion

In this double-masked parallel-design study, 2 weeks of TMS applied over the left prefrontal cortex was associated with a significantly greater antidepressant response (as measured by the number of subjects who responded) than sham. There were no significant differences between the two active TMS treatment arms (faster or slower TMS). Assessing antidepressant response as percent improvement from baseline failed to show significant group differences using the HSRD-21. However, analysis of other

Acknowledgements

This study was funded by a Young Investigator Grant to Dr. George from the National Alliance for Research on Schizophrenia and Depression.

This work was performed at the Medical University of South Carolina and presented in abstract form at the 1998 annual meeting of the American Psychiatric Association (interim analysis) (Nahas et al 1998a) and the 1999 annual meeting of the Society of Biological Psychiatry (complete analysis) (Nahas et al, in press-b).

References (53)

  • E.M Wassermann et al.

    Crossed reduction of motor cortex excitability by 1 Hz transcranial magnetic stimulation

    Neurosci Lett

    (1998)
  • D.E Bohning

    Introduction and overview of TMS physics

  • D.E Bohning et al.

    Mapping transcranial magnetic stimulation (TMS) fields in vivo with MRI

    Neuroreport

    (1997)
  • C.E Coffey et al.

    Subcortical white matter hyperintensities on magnetic resonance imagingClinical and neuroanatomical correlates of depressed elderly

    J Clin Neuropsychiatry Clin Neurosci

    (1989)
  • J Endicott et al.

    A diagnostic interviewThe schedule for affective disorders and schizophrenia

    Arch Gen Psychiatry

    (1978)
  • G.S Figiel et al.

    The use of rapid rate transcranial magnetic stimulation (rTMS) in refractory depressed patients

    J Neuropsychiatry Clin Neurosci

    (1998)
  • M.S George et al.

    Transcranial Magnetic Stimulation in Neuropsychiatry

    (2000)
  • M.S George et al.

    Prefrontal cortex dysfunction in clinical depression

    Depression

    (1994)
  • M.S George et al.

    Transcranial magnetic stimulationApplications in neuropsychiatry

    Arch Gen Psychiatry

    (1999)
  • M.S George et al.

    Transcranial magnetic stimulation—a new method for investigating the neuroanatomy of depression

  • M.S George et al.

    Low frequency daily left prefrontal rTMS improves mood in bipolar depressionA placebo-controlled case report

    Hum Psychopharmacol

    (1998)
  • M.S George et al.

    Prefrontal repetitive transcranial magnetic stimulation (rTMS) changes relative perfusion locally and remotely

    Hum Psychopharmacol

    (1999)
  • M.S George et al.

    Rapid-rate transcranial magnetic stimulation (rTMS) and ECT

    Convuls Ther

    (1994)
  • M.S George et al.

    Changes in mood and hormone levels after rapid-rate transcranial magnetic stimulation of the prefrontal cortex

    J Neuropsychiatry Clin Neurosci

    (1996)
  • M.S George et al.

    Daily repetitive transcranial magnetic stimulation (rTMS) improves mood in depression

    Neuroreport

    (1995)
  • M.S George et al.

    Mood improvements following daily left prefrontal repetitive transcranial magnetic stimulation in patients with depressionA placebo-controlled crossover trial

    Am J Psychiatry

    (1997)
  • Cited by (0)

    See accompanying Editorial, in this issue.

    View full text