Psychiatric Annals

CME Article 

The Potential Role of Repetitive Transcranial Magnetic Stimulation in Treating Severe Depression

Philip G. Janicak, MD; Sheila M. Dowd, PhD; Mary Jane Strong, APRN, MS, CS; Danesh Alam, MD; Dennis Beedle, MD

Abstract

Current estimates indicate that 121 million people suffer from depression, with approximately 6% of men and 9% of women experiencing a depressive episode annually.1 Depression can significantly diminish the emotional and socio-economic abilities of patients and loved ones. First-line treatments for depression include antidepressants, psychotherapy, or their combination. Empirical data and clinical experience show that patients refractory to or intolerant of psychopharmacotherapy can benefit from electroconvulsive therapy (ECT). A substantial number of depressed patients, however, cannot tolerate, do not respond to, or are unwilling to accept, ECT.2 While it is the most established somatic therapy for severe depression, its use continues to decrease.

This decrease may be associated with several factors. In our work with both ECT and repetitive transcranial magnetic stimulation (rTMS), we have found that many patients have powerful negative images of ECT. Further, for those who undergo this procedure, there are well-documented adverse effects, primarily short-term anterograde, retrograde, and autobiographical memory deficits.3 In addition, ECT often requires inpatient hospitalization, is associated with substantial controversy, and is costly.4 For example, an average course of ECT (8 to 10 treatments) is approximately $20,000 at our institution.

Thus, there is a clear need to develop effective, better tolerated, better accepted, and less expensive therapies. Alternative nonpharmacologic, biological therapies that have shown potential benefit in controlled trials5 include bright light therapy, rTMS, and vagal nerve stimulation (VNS). Other potential therapies still in experimental stages of development include acupuncture, deep brain stimulation (DBS), exercise,6 psychosurgery and gamma knife capsulotomy.

This article focuses on the potential role of rTMS as part of an integrated treatment strategy for more severely depressed patients.

TMS is a noninvasive technique that allows focal stimulation of the brain in people who are awake and alert. It produces powerful brief pulsating magnetic fields that induce electrical activity in the brain. These fields are significantly different from the low-level static magnetic fields that are used in alternative medicine. Research in TMS is widespread, focusing on a variety of applications.

rTMS uses an electromagnetic coil applied to the scalp to produce intense, localized, fluctuating magnetic fields to painlessly stimulate a small area of the cortex. These fields are produced by a large electrical current passed through a line connected to the stimulation coil. This current is turned off and on in a rapid fashion (eg, on for 1 millisecond or less, off for a few milliseconds). Unlike electrical current, these electrically induced magnetic fields pass through various tissues (eg, scalp, skull) and enter the brain unimpeded. They then produce neuronal depolarization in a localized area (ie, 1 to 2 cm in depth, 1 to 2 cm in diameter) under the stimulating coil, usually increasing metabolism and blood flow in that area. rTMS also produces distal effects which may be more relevant to its potential antidepressant properties.

Early observations while using TMS as a physiological probe indicated that some patients experienced mood elevation.7 Subsequent human and animal studies noted a number of similar effects induced by rTMS, ECT (or ECS) and antidepressants on the endocrine system, sleep parameters, and in certain behavioral and biochemical measures that indicate potential antidepressant properties.8 For example, antidepressants, ECS, and rTMS all prolong effort in a forced swim test of rats. In animal models, TMS also has been reported to induce ECT-like changes in brain monoamines.9

While another article in this issue will discuss other neuropsychiatric conditions for which TMS has been considered (see page 146), most studies have focused on depression. Several recent meta-analyses of human trials have supported a potential therapeutic effect with rTMS for depression using varying study designs.10–14 In the context of these…

Current estimates indicate that 121 million people suffer from depression, with approximately 6% of men and 9% of women experiencing a depressive episode annually.1 Depression can significantly diminish the emotional and socio-economic abilities of patients and loved ones. First-line treatments for depression include antidepressants, psychotherapy, or their combination. Empirical data and clinical experience show that patients refractory to or intolerant of psychopharmacotherapy can benefit from electroconvulsive therapy (ECT). A substantial number of depressed patients, however, cannot tolerate, do not respond to, or are unwilling to accept, ECT.2 While it is the most established somatic therapy for severe depression, its use continues to decrease.

This decrease may be associated with several factors. In our work with both ECT and repetitive transcranial magnetic stimulation (rTMS), we have found that many patients have powerful negative images of ECT. Further, for those who undergo this procedure, there are well-documented adverse effects, primarily short-term anterograde, retrograde, and autobiographical memory deficits.3 In addition, ECT often requires inpatient hospitalization, is associated with substantial controversy, and is costly.4 For example, an average course of ECT (8 to 10 treatments) is approximately $20,000 at our institution.

Thus, there is a clear need to develop effective, better tolerated, better accepted, and less expensive therapies. Alternative nonpharmacologic, biological therapies that have shown potential benefit in controlled trials5 include bright light therapy, rTMS, and vagal nerve stimulation (VNS). Other potential therapies still in experimental stages of development include acupuncture, deep brain stimulation (DBS), exercise,6 psychosurgery and gamma knife capsulotomy.

This article focuses on the potential role of rTMS as part of an integrated treatment strategy for more severely depressed patients.

TMS: Definition and Application

TMS is a noninvasive technique that allows focal stimulation of the brain in people who are awake and alert. It produces powerful brief pulsating magnetic fields that induce electrical activity in the brain. These fields are significantly different from the low-level static magnetic fields that are used in alternative medicine. Research in TMS is widespread, focusing on a variety of applications.

rTMS uses an electromagnetic coil applied to the scalp to produce intense, localized, fluctuating magnetic fields to painlessly stimulate a small area of the cortex. These fields are produced by a large electrical current passed through a line connected to the stimulation coil. This current is turned off and on in a rapid fashion (eg, on for 1 millisecond or less, off for a few milliseconds). Unlike electrical current, these electrically induced magnetic fields pass through various tissues (eg, scalp, skull) and enter the brain unimpeded. They then produce neuronal depolarization in a localized area (ie, 1 to 2 cm in depth, 1 to 2 cm in diameter) under the stimulating coil, usually increasing metabolism and blood flow in that area. rTMS also produces distal effects which may be more relevant to its potential antidepressant properties.

Early observations while using TMS as a physiological probe indicated that some patients experienced mood elevation.7 Subsequent human and animal studies noted a number of similar effects induced by rTMS, ECT (or ECS) and antidepressants on the endocrine system, sleep parameters, and in certain behavioral and biochemical measures that indicate potential antidepressant properties.8 For example, antidepressants, ECS, and rTMS all prolong effort in a forced swim test of rats. In animal models, TMS also has been reported to induce ECT-like changes in brain monoamines.9

While another article in this issue will discuss other neuropsychiatric conditions for which TMS has been considered (see page 146), most studies have focused on depression. Several recent meta-analyses of human trials have supported a potential therapeutic effect with rTMS for depression using varying study designs.10–14 In the context of these trials, there are several important stimulation parameters to consider when applying rTMS for therapeutic purposes (Sidebar 1, see page 140).

Sidebar 1.

Stimulation Parameters in rTMS for Therapeutic Purposes

Coil

  • Configuration (eg, circular, figure eight)
  • Location of stimulation

Motor Threshold Stimulation Frequency

  • Single; paired pulse
  • Slow repetitive (<1 hertz)
  • Rapid repetitive (=1 to 20 hertz)

Stimulation Trains

  • Number
  • Duration

Duration of the Intertrain Interval Number of Treatment Sessions

When rTMS is used as a treatment for depression, one of the major questions has been what constitutes the optimal set of these parameters. While this question is not entirely resolved, existing data provide considerable direction as to the most effective approach. We will briefly review these issues to establish the context in which to discuss the potential efficacy of rTMS in comparison to ECT. The following parameters have been refined over a series of trials, primarily comparing real to sham rTMS or using rTMS to augment ongoing antidepressant therapy.

Coil, Coil Configuration, and Location of Stimulation

The coil itself is composed of a tightly wound ferromagnetic material (usually copper) encased in a heavy plastic protective covering. While various coil configurations have been used, the figure-eight coil has been the most commonly employed. This is a flat coil, and the point of intersection of the two loops is the point of closest contact with the scalp site to be stimulated. The magnetic field is the strongest at this point.15

Although initial studies of rTMS involved stimulation over the vertex, most subsequent trials in depression have stimulated the left dorsolateral pre-frontal cortex (DLPFC). This was in part because neuroimaging studies in depression demonstrated abnormalities in pre-frontal cortical functioning, and it was hypothesized that stimulation of this area might result in an antidepressant effect.16

Motor Threshold

Because the motor threshold (MT) can vary widely, it is determined for each patient to help localize the site of stimulation and to define a safe level of stimulus output to avoid a seizure. Identifying the stimulation site to determine MT can be done both visually or by an electrophysiologic criterion. In the visual method, the coil placement over the left primary motor cortex is adjusted in a pattern of progressive variations while also varying the intensity of stimulation, until reliable, visible contractions are seen in the right abductor pollicis brevis or first dorsal interosseous muscle.

The electrophysiologic method is similar but uses 5 to 10 motor-evoked potentials of 50 microvolts to objectify the site. A point 5 cm anterior and parasagittal to this location most commonly is used as the left DLPFC stimulation site.

Stimulation intensity is determined initially and periodically during a course of treatment relative to each patient's MT, which can be highly variable both among and within subjects. The Medical University of South Carolina group has suggested that a higher intensity of stimulation as a function of the MT (eg, 100% MT, 110% MT, 120% MT) may have more robust antidepressant effects, since the magnetic field declines logarithmically with distance from the coil.17 Intensities greater than 120% MT generally have been avoided because of the potential to increase seizure risk.18 While an inadvertent seizure is the most serious complication, this is a rare event with the present safety guidelines.

Stimulation Frequency

Most studies have used higher frequencies (ie, rapid repetitive at 1 to 20 hertz) over the left DLPFC, leading to neuronal excitation. A smaller database, however, supports the use of lower frequencies (ie, slow repetitive at less than 1 hertz) over other areas, such as the right DLPFC, leading to neuronal inhibition. The rationale to use a higher frequency over the left side is based in part on the observation of decreased regional cerebral blood flow and hypometabolism reported in imaging studies of the left DLPFC in major depression.

Number and Duration of Stimulations

The number of stimulations delivered is determined by the frequency (hertz) and the stimulation train duration (typically 2 to 6 seconds). A typical pattern would be a 5-second stimulation train at 10 hertz (ie, 50 stimulations), followed by a 30-second intertrain interval (ITI). This pattern is then repeated several times (eg, 20 times for a total of 1,000 stimulations per session).

The entire number of stimulations delivered in blind, parallel or crossover studies with medicated or unmedicated depressed patients has varied considerably (eg, between 8,000 and 90,000 stimulations per treatment course). Based on our pilot study comparing rTMS to ECT, it appears that a higher number of total stimulations per course and a higher number of sessions (eg, 20 to 30) may be necessary for more severe depression.19

ITI

A related parameter is ITI, which is the duration in seconds between two stimulation trains. Chen et al.20 have demonstrated that shorter ITIs (less than 1 second) are more likely to increase the risk of seizures, especially when higher frequencies (eg, 20 hertz) and intensities (greater than 100% MT) of stimulation are used.

Number of Treatment Sessions

A typical acute treatment course duration in recent studies has been 2 to 6 weeks, or 10 to 30 treatment sessions, usually given five times per week.

rTMS Versus ECT

With this background, we will review the trial data comparing rTMS with ECT, focusing on the results of our pilot study. To our knowledge, four published trials and one study presented in abstract form have compared rTMS to ECT directly for more severely depressed patients.19,21–24 These trials are summarized in Table 1 (see page 140). Participants were considered clinically appropriate for a course of ECT, usually due to treatment resistance and, to a lesser extent, medication intolerance. All involved random assignment to either modality. Stimulation intensities ranged from 90% to 110% MT, and the number of sessions ranged from 10 to 20. All concluded that, at least in nonpsychotic patients, rTMS and ECT produced a similar reduction in depressive symptoms. Pridmore et al.25 also reported that rTMS may be used in combination with ECT to achieve the same efficacy with fewer ECT sessions.

Summary of rTMS Versus ECT Studies

Table 1:

Summary of rTMS Versus ECT Studies

In a follow-up trial of the first Grunhaus report,21 Dannon et al.26 found the relapse rates to be similar in both the initial rTMS and ECT responders maintained on standard pharmacotherapy.

There were, however, many limitations to these trials. They were usually pilot studies at a single site and included small sample sizes and a heterogeneous group of depressed subjects (unipolar, bipolar; psychotic, nonpsychotic). Also, concomitant medications were present in some studies.

If found to have clinical utility, advantages of rTMS as applied in the comparative studies with ECT include the absence of seizure induction and therefore no need for anesthesia. Further, there is no evidence of cognitive disruption, and patients remain completely alert and independent during and immediately after the procedure. While an inadvertent seizure can occur rarely, the most common adverse effects (eg, local pain at site of stimulation; post-treatment headaches) are usually mild and generally well-tolerated. Presently, relative contraindications to the use of rTMS include metallic implants in the head, cardiac pacemakers, pregnancy, and a history of seizures. However, if determined to be effective, rTMS may be safer than medication in certain clinical scenarios (eg, pregnancy).

In our trial comparing rTMS to bilateral ECT, 31 patients with major depressive disorder (unipolar or bipolar; psychotic or nonpsychotic) who were clinically appropriate for ECT were assigned randomly to rTMS or ECT.19 Nonresponders to either initial treatment had the option to crossover to the alternate arm.

We selected the following rTMS parameters: frequency of 10 hertz; train duration of 5 seconds (ie, 50 pulses per train); 20 trains per session; and a 30-second ITI. These parameters resulted in 1,000 stimulations per treatment session during 10 to 20 treatment sessions. Thus, subjects received a minimum of 10,000 stimulations and a maximum of 20,000 stimulations during a 2- to 4-week period. Those randomized to rTMS received stimulations with a figure-eight insulated coil over the left DLPFC at 110% intensity relative to MT. Those randomized to ECT received four to 12 treatments with bitemporal electrode placement stimulation (Sidebar 2, see page 141).

Sidebar 2.

Treatment Parameters for Pilot Study

ECT Treatment Parameters

  • M-W-F treatment schedule

  • MECTA SR-I

  • Bitemporal electrode placement

  • 100% oxygenation

  • Methohexitol (1 mg/kg)

  • Succinylcholine (1 mg/kg)

  • Minimal rescue medications (eg, anxiolytic, sedative-hypnotic)

rTMS Treatment Parameters

  • Monday through Friday treatment schedule

  • Magstim Super Rapid with double 70 mm coil

  • Left DLPFC; 100% MT; 10 Hz

  • Twenty, 50 stimulation trains; 5-second duration

    • 1,000 stimulations per session
    • Up to 10,000–20,000 stimulations per course
  • 30-second intertrain intervals

  • Minimal rescue medications (eg, anxiolytic, sedative-hypnotic)

The primary outcome measure was the 24-item Hamilton Depression Rating Scale (HDRS).27 Patients received a minimum of 10 rTMS sessions or four ECT treatments and then ended the trial if they met criteria for response (ie, a 50% or greater decrease from baseline HDRS and a final score of 8 or lower). If they did not meet criteria, they continued in the trial for another week before reassessment with the HDRS. If they still did not meet criteria for response, they received 1 more week of treatment and then ended the trial.

Tables 2 and 3 provide the percent change in the HDRS for the rTMS group, the ECT group, and the total sample, as well as the number of patients in each group who met our criteria for response. While the trend favored ECT, there was no significant difference between these treatment groups (Figure 1, see page 142). Further, the improvement in the ECT group was comparable to that seen in other ECT trials using a similarly matched group of patients (Table 4, see page 143).28 Table 5 lists the adverse effects observed in both treatment arms. Of note, neurocognitive testing was administered to the rTMS group both pre- and post-treatment, and no evidence for cognitive disruption was observed.29

Mean HDRS Scores in the Pilot Study

Table 2:

Mean HDRS Scores in the Pilot Study

Treatment Responders in the rTMS versus ECT Groups

Table 3:

Treatment Responders in the rTMS versus ECT Groups

Rates of improvement in HDRS scores between the rTMS and ECT groups across the treament duration.

Figure 1.

Rates of improvement in HDRS scores between the rTMS and ECT groups across the treament duration.

Demographic and Clinical Profile of Randomized Study Participants19

Table 4:

Demographic and Clinical Profile of Randomized Study Participants19

Adverse Effects Associated with rTMS and ECT

Table 5:

Adverse Effects Associated with rTMS and ECT

The strengths of our trial included a more severely ill, depressed sample; random assignment; relatively aggressive rTMS and ECT treatment parameters; and the limited use of rescue medications (ie, lorazepam or zolpidem as needed). All other psychotropics were stopped for 3 days before beginning treatment and throughout the randomized phase. Trial limitations included the small sample size, the lack of a sham control, and nonblinded assessment. This was, however, a pilot study to assess the potential efficacy of rTMS in this patient group.

Given these caveats, our preliminary analysis indicates that rTMS may produce similar efficacy to bitemporal ECT in at least some patients who would otherwise require ECT. These findings also are consistent with the other rTMS/ECT comparative trials. Thus far, no serious adverse effects (eg, seizure, cognitive) have been reported with rTMS in any of these trials.

Summary

rTMS may be an alternative for at least some patients when used as an intermediate strategy between antidepressants and ECT. It also may be a viable augmentation strategy combined with medication or ECT for patients with more severe depression.22,30–32 Compared with ECT, rTMS appears to have a much better adverse effect profile, including few, if any, cognitive adverse effects. It is also more efficient to administer, and more cost effective (eg, no need for anesthesia induction, seizure induction or operating room recovery monitoring). As an important social benefit, rTMS may engender less stigma than ECT. In considering the potential role for rTMS in the treatment of major depression, we have developed a treatment strategy that incorporates this modality (Figure 2, see page 144).33

Potential role of rTMS in treating a major depressive episode.

Figure 2.

Potential role of rTMS in treating a major depressive episode.

References

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Summary of rTMS Versus ECT Studies

Author (Year) Patients/Design Parameters Comments
Grunhaus (2000)21 40 patients with MDD Random assignment to UND-ECT or rTMS (eight patients switched to bilateral ECT) Assessment: HDRS L-DLPFC, 10 hertz, 90% MT 2-second trains (n = 8) or 6-second trains (n = 12) ITI not reported 20 trains per session Up to 20 sessions rTMS = ECT in nonpsychotic group ECT > TMS in psychotic group Based on percent change in HDRS Psychotic patients in ECT group were taking medications
Pridmore (2000)22 32 patients with MDD Random assignment to UND-ECT or rTMS Assessments: HDRS, BDI, VAS L-DLPFC, 20 hertz, 100% MT 2-second trains 28-second ITI 30 to 35 trains per session Mean: 12 (±3.4) sessions rTMS = ECT Based on percent change in HDRS and remission rates
Janicak (2002)23 31 patients with MDD Random assignment, with crossover option for nonresponders rTMS or BT-ECT Assessment: HDRS L-DLPFC, 10 hertz, 110% MT 5-second trains 30-second ITI 20 trains per sessions Mean: 14 (±3.4) sessions rTMS = ECT Based on percent change in HDRS and a priori definition of response Minimal rescue medications
Grunhaus (2002)24 40 nonpsychotic patients with MDD Random assignment to rTMS or UND-ECT (seven patients switched to BL-ECT) Assessments: HDRS; GAF L-DLPFC, 10 hertz, 90% MT 6-second trains 30-second ITI 20 trains per session Up to 20 sessons rTMS = ECT Based on percent change in HDRS and GAF 60 or higher
McLoughlin (2004)25 30 patients with MDD Random assignment to rTMS or BT-ECT Assessment: HDRS (17-item), BDI-II (raters blinded) L-DLPFC, 10 hertz, 110% MT 5-second trains 55-second ITI 20 trains per sesion Up to 15 sessions rTMS = ECT in reducing depression Based on change in HDRS and BDI Patients continued medications

Mean HDRS Scores in the Pilot Study

Baseline Final % Change
rTMS (n = 17) 33 (±7.9) 15 (±11.0) 51% (±36)
ECT (n = 14) 34 (±8.7) 11 (±9.0) 67% (±27)
Total (n = 31) 33 (±8.0) 13 (±10.2) 58% (±33)

Treatment Responders in the rTMS versus ECT Groups

HAM-D: (50% or8%) Responders HAM-D: (<50% and >8%) Nonresponders Response Rate
rTMS (n = 17) 7 10 41%
ECT (n = 14) 6 8 50%

Demographic and Clinical Profile of Randomized Study Participants19

rTMS ECT
Number of participants 17 14
Gender (M/F) 12/5 7/7
Mean age 43 (±15) 44 (±15)
Diagnosis:
  Bipolar-psychotic 2 2
  Bipolar-nonpsychotic 5 2
  Unipolar-psychotic 2 4
  Unipolar-nonpsychotic 8 6
Mean number of treatments 15 (±5) 7 (±3)

Adverse Effects Associated with rTMS and ECT

rTMS ECT
Serious Adverse Events None None
Mild Adverse Effects Facial twitching Erythema at site of coil placement Anxiety before and during treatment Localized to stimulation site: <list-item>

Mild pain or discomfort

</list-item><list-item>

Feelings of warmth

</list-item><list-item>

Tapping sensation

</list-item><list-item>

Headache

</list-item>
Short-term memory impairment Drowsiness shortly after treatment Postictal and anesthesia-induced confusion

Sidebar 1.

Stimulation Parameters in rTMS for Therapeutic Purposes

Coil

  • Configuration (eg, circular, figure eight)
  • Location of stimulation

Motor Threshold Stimulation Frequency

  • Single; paired pulse
  • Slow repetitive (<1 hertz)
  • Rapid repetitive (=1 to 20 hertz)

Stimulation Trains

  • Number
  • Duration

Duration of the Intertrain Interval Number of Treatment Sessions

Sidebar 2.

Treatment Parameters for Pilot Study

ECT Treatment Parameters

  • M-W-F treatment schedule

  • MECTA SR-I

  • Bitemporal electrode placement

  • 100% oxygenation

  • Methohexitol (1 mg/kg)

  • Succinylcholine (1 mg/kg)

  • Minimal rescue medications (eg, anxiolytic, sedative-hypnotic)

rTMS Treatment Parameters

  • Monday through Friday treatment schedule

  • Magstim Super Rapid with double 70 mm coil

  • Left DLPFC; 100% MT; 10 Hz

  • Twenty, 50 stimulation trains; 5-second duration

    • 1,000 stimulations per session
    • Up to 10,000–20,000 stimulations per course
  • 30-second intertrain intervals

  • Minimal rescue medications (eg, anxiolytic, sedative-hypnotic)

Educational Objectives

  1. Describe the administration of transcranial magnetic stimulation (TMS).

  2. Discuss the data from preliminary trials of TMS versus ECT.

  3. Explain a method to integrate TMS into a treatment strategy for severely ill depressed patients.

Authors

Dr. Janicak is professor of psychiatry, Rush University Medical Center, and medical director, Rush Psychiatric Clinical Research Center, Chicago, IL. Dr. Dowd is assistant professor of psychiatry, Rush University Medical Center. Ms. Strong is assistant professor, Rush University Medical Center, and program director, Rush Psychiatric Clinical Research Center.Dr.Alam is assistant professor of psychiatry, University of Illinois at Chicago. Dr. Beedle is assistant professor of clinical psychiatry, University of Illinois College of Medicine at Chicago.

Address reprint requests to: Philip J. Janicak, MD, Rush University Medical Center, Marshall Field IV, 1720 W. Polk, Chicago, IL, 60612.

Dr. Janicak, Dr. Dowd, and Ms. Strong receive grant or research support from Neuronetics Inc. Drs. Alam and Beedle have no industry relationships to disclose.

10.3928/00485713-20050201-06

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