Transcranial magnetic stimulation (TMS) appears nearer to approval by the U.S. Food and Drug Administration as an "electrodeless" alternative or complement to electroconvulsive therapy (ECT) for refractory depression. An application for this indication has been filed by medical device manufacturer Neotonus Inc. of Atlanta.
"We anticipate FDA clearance before the middle of this year," Stanford Miller, director of Neotonus' neuroscience division, told Psychiatric Times.
In June 1998, the FDA approved use of the Neotonus magnetic stimulator to enhance peripheral nerve innervation in treating urinary incontinence in women. In November 1999, the U.S. Patent and Trademark Office ruled that Neotonus' application for transcranial treatment with the magnetic stimulator contained "patentable and allowable subject matter."
In announcing that patent ruling, Neotonus stated, "The decision clears the way for issuance of a patent on Neotonus' landmark technology, which can be used for the noninvasive treatment of depression, epilepsy, Alzheimer's disease and a host of other neurological disorders."
In a review that did not find enough studies to affirm clinical application across this range of conditions, Mark George, M.D., and colleagues (1999) characterized TMS as a "promising new research and, perhaps, therapeutic tool." They added, however, "More work remains before it can be fully integrated in psychiatry's diagnostic and therapeutic armamentarium" (George et al., 1999).
Overall, George et al. offered an enthusiastic assessment of the potential of TMS:
The capacity to noninvasively excite or inhibit focal cortical areas represents a remarkable advance for neuroscience research. As an interventional probe in neuropsychiatric disorders, rTMS [repetitive TMS] has the potential of taking functional imaging one step further by elucidating causal relationships .
TMS Depolarizes Neurons
Magnetic stimulation treatment, like ECT, depolarizes neurons. TMS is more focal than ECT, however, and is administered without the anesthesia and neuromuscular blockade ECT requires. In addition, in contrast to the surgical setting required for ECT to support general anesthesia and recovery, the TMS procedure can be conducted in an outpatient setting. George et al. (1999) noted, "Subjects [receiving TMS] usually notice no adverse effects except for occasional mild headache and discomfort at the site of the stimulation."
In ECT, a sufficiently high level of electrical current passes through the resistance of skull and tissue, stimulating pain receptors in the scalp and depolarizing neurons over a broad area. In TMS, a magnetic field emanating from a magnetic stimulator unit placed against the skull passes without resistance into the brain to a depth of approximately 2 cm. The magnetic field produces ionic flow in neuronal tissue by inducing an electrical current that flows parallel and opposite to the direction of current in the wire coil of the appliance.
The current in the magnetic stimulator coil is pulsed by capacitor discharge at low (1 Hz) to high frequency (up to 60 Hz), inducing magnetic fields lasting approximately 100 to 200 microseconds with an intensity of up to 2 tesla. This is comparable to the static field used in magnetic resonance imaging (George et al., 1999). The low-frequency stimulators present less risk of seizure; this risk is further mitigated by employing 10% to 20% less magnetic field intensity than is correlated, in each procedure, with the motor threshold necessary for a magnetic pulse over the primary motor cortex to induce muscle movement.
According to product bulletins on the magnetic stimulators manufactured by Cadwell Laboratories in Kennewick, Wash., the FDA no longer requires an investigational device exemption (IDE) for research on cortical stimulation with the low-frequency stimulator; however, the requirements of local review boards remain. The IDE does remain a requirement for research involving high-frequency stimulators (exceeding 1 Hz). The Cadwell water-cooled magnetic stimulators are currently approved for peripheral nerve and spinal cord stimulation; an application for transcranial administration was previously denied by the FDA. James Cadwell, M.D., indicated to PT that the growing body of research and interest in the area may prompt them to file a new application for TMS. For example, the Cadwell low-intensity stimulator was utilized in a recent TMS study in which the severity of auditory hallucinations was reduced (Hoffman et al., 2000).
The magnetic stimulator manufactured by Neotonus incorporates a figure-eight wire coil around a ferromagnetic core, rather than the commonly employed air core. According to Yvonne M. Greene, M.D., director of clinical affairs at Neotonus, this design presents less impedance of current flow, and it obviates the need for the appliance to have a water-based (or other) external cooling system. The design also enables a higher electrical current and a stronger magnetic field. In an anesthetized patient, this could be directed to depths of approximately 6 cm, depths that are now only reached with implanted stimulators.
Efficacy for Depression
An open comparative study of the effectiveness of ECT and of rTMS was published in Biological Psychiatry (Grunhaus et al., 2000a). Forty patients with major depression (19 also having psychotic symptoms) were randomly assigned to either treatment. These inpatients and outpatients had been referred for ECT due to lack of response to antidepressants and/or for psychotic depression.
The ECT series consisted of between seven to 14 treatments (mean=9.6) administered twice weekly. Electrode placement was initially right unilateral but could be switched to bilateral if improvement was not apparent by the sixth treatment. The rTMS series of 20 treatments was conducted with a Magstim magnetic stimulator over the left dorsolateral prefrontal cortex (LDLPFC) at 10 Hz for two seconds (first eight patients) or six seconds (last 12 patients) at 90% of motor threshold, administered five times a week for four weeks.
Depressive symptom severity in patients without psychotic symptoms, assessed with a battery of instruments, appeared to improve to a similar extent with both treatment procedures. The ECT was significantly more effective, however, for patients with both depression and psychosis. Grunhaus et al. (2000a) observed that these results "support an important role for rTMS in the treatment of severe MDD [major depressive disorder]." They added, however, "Additional blinded studies are needed to precisely define this role."
A blinded, sham-treatment-controlled study of rTMS conducted in 20 patients with treatment-refractory major depression was reported in the same issue of Biological Psychiatry (Berman et al., 2000). Patients received either active rTMS or sham treatment with the magnetic stimulator on the skull, but angled 30 to 45 degrees off the scalp. The active rTMS series of 20 procedures over 10 consecutive weekdays was applied with 20 Hz for two seconds at the LDLPFC at 80% of motor threshold.
In comparison to the patients receiving the sham treatment, those receiving rTMS evidenced statistically superior improvement on the Hamilton Depression Rating Scale (HAM-D) scores from baseline to completion of treatment. The clinical reduction in symptoms was characterized as "modest" by the researchers; only one of 10 patients who received the active treatment evidenced a robust response and decrease in clinical severity. Three other patients demonstrated a 40% to 45% reduction in HAM-D scores; no patients receiving sham treatment demonstrated even partial response.
The researchers were encouraged by the modest clinical improvement in these patients who had not previously responded to antidepressant treatment. They point out that optimal rTMS treatment parameters remain to be defined from such variables as stimulus frequency and intensity; stimulus localization; magnetic stimulator coil shape; capacitor discharge characteristics; number of stimulations and duration of treatment; and the cognitive/affective state during stimulation.
Progress Reported at Meeting
At the third annual meeting of the International Society of Transcranial Stimulation (ISTS), progress was made in defining these parameters and evaluating rTMS treatment efficacy. This meeting was held May 10, 2000 in Chicago, in conjunction with the Society of Biological Psychiatry's annual meeting.
Researchers from the Ludwig-Maximilian University in Munich, Germany, used a parallel, sham-treatment-controlled design to ascertain whether the practice of administering less magnetic field intensity than the motor threshold actually reduces antidepressant efficacy (Padberg et al., 2000). Thirty patients with major depression refractory to antidepressant medication were randomly assigned to receive sham or active rTMS at either 100% or 90% of motor threshold daily for 10 days. Patients' depression symptoms were rated with both the HAM-D and the Montgomery-Asberg Depression Rating Scale (MADRS).
The researchers reported significantly more improvement in patients receiving the higher magnetic stimulation intensity. In this group, HAM-D and MADRS scores were decreased by 30% and 34%, respectively, from baseline to the end of treatment. In contrast, the patients receiving rTMS at 90% of motor threshold had a mean 13% reduction in MADRS scores but no significant change in the HAM-D. No change in either scale occurred with patients receiving the sham treatment.
Padberg et al. (2000) concluded, "The present study provides preliminary evidence that a higher stimulation intensity related to MT [motor threshold] has stronger antidepressant effects than subthreshold rTMS."
Thirty-one patients being treated for major depression at the Medical University of South Carolina were given rTMS at either 20 Hz or 5 Hz, or sham treatment, in a parallel-design, double-blind study (Nahas et al., 2000). While there was clear separation between the sham treatment and both active treatments, the percent change in HAM-D scores after two weeks of daily rTMS was not significantly different between those receiving treatment with 20 Hz or 5 Hz.
"There is a non-significant trend for higher antidepressant effect with lower frequency rTMS," the researchers observed, adding, "this is difficult to generalize with this small sample size." Given this trend and the lower seizure risk associated with higher frequency, Nahas and colleagues (2000) recommended that others treating depression with rTMS should consider using lower frequencies.
Two reports compared the effectiveness of rTMS to that of ECT for patients with severe depression. Patients at the University of Illinois were randomly assigned to receive either a standard course of bitemporal ECT or 10 to 20 sessions of rTMS (Janicak et al., 2000). Each of the rTMS sessions consisted of 20 five-second stimulations at 10 Hz and 110% of motor threshold.
Fourteen patients had completed the study at the time of Janicak et al.'s report, seven each receiving rTMS or ECT. One additional patient who did not respond to the ECT also received rTMS treatment. The researchers found comparable improvement in HAM-D scores with both procedures: 59% mean reduction with rTMS and 50% with ECT. Four of eight patients treated with rTMS and three of seven receiving ECT met the criteria of response to treatment with a HAM-D score of less than eight. The one patient who received rTMS after being unresponsive to ECT showed significant improvement with rTMS, according to researchers, although not sufficient to meet their criteria for clinical response.
Grunhaus et al. reported preliminary data analysis from 18 additional patients with non-delusional depression from the previously cited study (Grunhaus et al., 2000a). The rTMS was found, again, equally effective as ECT "in this population of very sick and medication resistant depressives" (Grunhaus et al., 2000b). Based upon the results of their published study and the current report, they recommended that the rTMS be attempted in patients with non-delusional depression before a course of ECT is pursued.
Berman RM, Narasimhan M, Sanacora G et al. (2000), A randomized clinical trial of repetitive transcranial magnetic stimulation in the treatment of major depression. Biol Psychiatry 47(4):332-337.
George MS, Lisanby SH, Sackeim HA (1999), Transcranial magnetic stimulation: applications in neuropsychiatry. Arch Gen Psychiatry 56(4):300-311 [comment].
Grunhaus L, Dannon PN, Schreiber S et al. (2000a), Repetitive transcranial magnetic stimulation is as effective as electroconvulsive therapy in the treatment of nondelusional major depressive disorder: an open study. Biol Psychiatry 47(4):314-324.
Grunhaus L, Dannon PN, Schreiber S (2000b), A comparison of transcranial magnetic stimulation and electroconvulsive therapy in non-delusional major depression. A replication study. Presented at the 3rd Annual Meeting of the International Society of Transcranial Stimulation (ISTS). Chicago; May 10.
Hoffman RE, Boutros N, Hu S et al. (2000), Transcranial magnetic stimulation and auditory hallucinations in schizophrenia. Lancet 355(9209):1073-1075 [letter].
Janicak PG, Martis B, Krasuski J et al. (2000), Repetitive transcranial magnetic stimulation (rTMS) vs electroconvulsive therapy (ECT) for depression. Presented at the 3rd Annual Meeting of the International Society of Transcranial Stimulation (ISTS). Chicago; May 10.
Nahas Z, Molloy M, Speer A et al. (2000), How fast to stimulate? The role of frequency in the antidepressant effect of left prefrontal rTMS. Presented at the 3rd Annual Meeting of the International Society of Transcranial Stimulation (ISTS). Chicago; May 10.
Padberg F, Zwanzger P, Mikhaiel P et al. (2000), Stimulation intensity and antidepressant action of repetitive transcranial magnetic stimulation: a placebo-controlled study. Presented at the 3rd Annual Meeting of the International Society of Transcranial Stimulation (ISTS). Chicago; May 10.