Updates Show Progress in TMS for Depression and Schizophrenia
By Arline Kaplan
Psychiatric Times September 2005 Vol. XXII Issue 10

Repetitive transcranial magnetic stimulation (rTMS), which allows for direct activation of neurons, will play an ever-expanding role in depression and schizophrenia treatment, according to recent reports from Mark S. George, M.D., and Alan L. Schneider, M.D. George, who is distinguished professor of psychiatry, radiology and neurology, and director of the Brain Stimulation Laboratory at the Medical University of South Carolina College of Medicine, provided updates on rTMS research at the 2005 American Psychiatric Association annual meeting.

"We call this electrodeless electrical stimulation," George said at a symposium. "Electrical energy in a coil induces a magnetic field, and the field passes unimpeded through the skin and skull and induces an electrical current in the brain."

The physiological effects of TMS depend upon the site and frequency of stimulation (Ontario Ministry of Health and Long-Term Care, 2004). The frequency of cortical stimulation varies. Rapid-rate or repetitive TMS usually refers to the application of TMS for a train of minutes at frequencies >1 Hz and is commonly used in treatment studies. Transcranial magnetic stimulation at ≤1 Hz is referred to as slow or low-frequency TMS. The ability to stimulate the brain at either high or low frequency is important, because high-frequency rTMS (e.g., 20 Hz) may increase cerebral blood flow and neuronal excitability in the region of the cortex under the coil, but low-frequency rTMS (≤1 Hz) may have the opposite effect.

The magnetic pulse is further described by its intensity in proportion to the motor threshold (MT) of the individual. The motor threshold is the lowest intensity of stimulation that, when applied to the motor cortex, causes a standard contraction of a muscle in at least five of 10 consecutive trials.

While TMS devices can excite the surface cortex of the brain, George explained that blood-oxygen-level-dependent functional magnetic resonance imaging (BOLD fMRI) has shown that cortical stimulation causes trans-synaptic deeper effects. For example, 1-Hz TMS over the left prefrontal cortex was associated with increased activity at the site of stimulation (Li et al., 2004). Activity was also increased in connected limbic regions, including the bilateral middle prefrontal cortex, right orbital frontal cortex, left hippocampus, mediodorsal nucleus of the thalamus, bilateral putamen, pulvinar and insula (t=3.85, p<0.001). Activity decreased in the right ventromedial frontal cortex.

As a research tool, George described TMS as "a wonderful way to look into the brain, study neuropsychological effects and measure cortical excitability." Additionally, for brief periods during stimulation, rTMS can block or inhibit a brain function. He explained the concept further in an article for Scientific American (George, 2003). Applying rTMS over an individual's speech-control motor area, for instance, can make them temporarily unable to speak. This functional knockout capability (which immediately reverses) allows neuroscientists to reexplore which part of the brain controls a particular part of the body. When rTMS is coupled with imaging techniques, it allows researchers to noninvasively monitor circuit activity and behavior.

As a potential treatment, rTMS is being evaluated for various neurological and psychiatric disorders, particularly depression, according to George. The dorsolateral prefrontal cortex has been the primary area of interest for stimulation in depression trials. This area is the most accessible for treatment with rTMS of the areas thought to be important in mood disturbances. George pointed out that there are some 62 published studies (n=1,415) exploring the use of prefrontal rTMS for depression. Of these, 26 were open and 31 sham-controlled, one compared rTMS to a medication, and five compared it to electroconvulsive therapy. He added that an active database listing descriptions and citations of completed and/or published studies on rTMS is available at .

According to George, there have been six meta-analyses looking at the efficacy of rTMS in depression. One meta-analysis involving 12 studies (n=230) concluded that left prefrontal rTMS is "an acute antidepressant treatment with statistically significant effect sizes and measurable clinical improvement" (Kozel and George, 2002).

Another meta-analysis by Gershon et al. (2003) concluded, "TMS shows promise as a novel antidepressant treatment" and that most data support an antidepressant effect of high-frequency rTMS administered to the left prefrontal cortex. Possible predictors of treatment success may include younger age, certain brain physiologic markers and absence of psychosis.

Current Trials
Currently, George said, large multisite trials are underway or nearing completion. These studies will be a substantial improvement of the literature, George said, because most of the published studies were conducted at single centers with small sample sizes.

One industry-sponsored study is expected to be completed this fall, George said. It involves some 280 outpatients recruited from academic and private research centers. The patients have a primary diagnosis of unipolar major depressive episode and are regarded as medication resistant. Patients are randomly assigned to active or sham treatment. Their trial consists of 30 treatments during a six-week period. Treatments are scheduled one per weekday and take about 45 to 60 minutes to complete. Patients remain awake during the procedure and require no anesthesia. Once participants complete the blinded phase, all nonresponsive patients can receive active TMS. A second follow-up study is for patients who improved with rTMS. It will evaluate how long any positive effects last, including possible retreatment if depressive symptoms return during the six-month period of the trial.

George said he and colleagues are involved in a multisite, randomized, controlled trial sponsored by the National Institute of Mental Health in which they are using rTMS to treat 240 unipolar depressed adults with moderate levels of treatment resistance (George, 2005). They are using rTMS parameters that maximize the stimulation duration and intensity within the published safety guidelines. They will investigate the safety and efficacy of repeated daily left prefrontal 5 Hz rTMS at 120% of motor threshold in a three-week, fixed-dose trial. In patients showing an antidepressant response after three weeks, rTMS will be administered for up to six weeks to achieve remission of clinical symptoms of depression. Patients who do not remit with the initial fixed-dose trial will be administered 1 Hz rTMS in an open trial over the right prefrontal cortex. Baseline magnetic resonance images will be used to determine the optimal stimulus intensity by adjusting for individual differences in cortical to skull distances. Researchers are also determining the long-term antidepressant effect of TMS in remitters, using a standardized continuation medication protocol over six months.

"We are focusing on remission. We don't want just improvement," George said at the symposium.

Additionally, they will be evaluating how stimulus location, demographic and/or clinical variables affect clinical response to TMS. After the four-year trial is over, George said he and his team hope to be able to plot who has responded and who hasn't and also gain new guidance about "where we should focus our efforts."

While the vast majority of rTMS prefrontal studies have found that rTMS has efficacy greater than sham, George said, the question remains whether daily prefrontal rTMS will be effective in a general psychiatric nonresearch setting.

Canadian Practice Setting
In Canada, several rTMS devices have been licensed by Health Canada. George described one study in a Canadian practice setting (Ledsome et al., 2005).

"There is a TMS referral system there. They had 77 people referred, and 65 completed the protocol. These are patients who were largely treatment resistant," he said.

The patients were referred by their physicians to a private medical clinic for rTMS treatment. Repetitive TMS was administered over the left prefrontal cortex at an intensity of 120% of motor threshold, frequency of 5 Hz (train length 8 sec, intertrain interval 22 sec, 40 trains) or frequency of 10 Hz (train length 5 sec, intertrain interval 25 sec, 50 trains) once or twice daily for 15 to 20 sessions. Outcome was assessed using the Beck Depression Inventory (BDI) before and after treatment.

In 65 patients, BDI decreased from a pretreatment score of 29.3 (1.3, SE of mean) to a posttreatment score of 17.8 (1.7). The response rate (decrease in BDI of 50%) was 46% and the remission rate (a decrease in the BDI to ≤8) was 25%. There was no correlation between age of the patients and percentage change in BDI over the range of 18 to 65 years.

According to news reports, the cost for a course of treatment is estimated at between $3,000 and $6,000, depending upon whether the patient needs maintenance sessions.

Schizophrenia Research
Although a growing number of studies are exploring the efficacy of rTMS for depression, few studies have evaluated its use for the treatment of schizophrenia. Schneider, who is affiliated with the David Geffen School of Medicine at the University of California, Los Angeles, through its San Fernando Valley Veterans Affairs Medical Center affiliate and is the research director at Gateways Hospital in Los Angeles, said he and colleagues are nearing completion on two double-blind studies investigating adjunctive use of rTMS for the treatment of such negative symptoms as restricted affect, diminished social drive and lack of volition in patients with schizophrenia. All patients continue to receive their atypical antipsychotics during treatment.

In one study, funded by the National Alliance for Research on Schizophrenia and Affective Disorders (NARSAD), 34 patients are randomized to either active rTMS or sham treatment for two weeks, five days per week. In the second study, funded by Stanley Medical Research Institute, 51 patients are randomized to 1 Hz, 10 Hz or sham treatment for four weeks, five days per week. In each study, patients are also seen one month posttreatment to assess any carryover effects. In addition, Schneider and colleagues are studying effects on hearing threshold after longer-term TMS exposure.

"We also have an open-label component where they can come in for 'maintenance' treatment," Schneider said, adding that nobody really has a firm grasp on the concept of maintenance treatment in TMS. The maintenance treatment is once every two weeks.

The patients in active treatment receive rTMS of the dorsolateral prefrontal cortex. We get there by activating the motor strip in their head, which produces a twitching in the hand, Schneider said. The dorsolateral prefrontal cortex, he added, is thought to control negative symptoms as well depressive symptoms. It is the same area that has been used in prior TMS trials to treat major depression.

Repetitive transcranial magnetic stimulation can be beneficial in schizophrenia, Schneider believes, possibly through a reversal of pre-existent or iatrogenically produced hypofrontality. This is the rationale for the use of only newer-generation atypical antipsychotics in his studies.

Outcome measures include the Scale for the Assessment of Negative Symptoms (SANS), the Wisconsin Card Sort Test (WCST) and the SF-36 Quality of Life questionnaire, which the patient fills out.

"From our initial analysis on NARSAD data, treatment clearly separates from placebo in terms of the [WCST] and SANS," Schneider said. He added that the study criteria allowed patients to enter with some positive symptoms as measured by the Brief Psychiatric Rating Scale (BPRS) and the Positive and Negative Symptom Scale (PANSS).

"We have had a large number who have spontaneously reported that their residual hallucinations (usually auditory) have remitted with treatment, which is not at all what we were looking at," he said. "This is clearly a different effect than has been seen in the direct stimulation of the temporoparietal cortex."

(In recent months, three studies [Chibbaro et al., 2005; Hoffman et al., 2005; Lee et al., 2005] have been published on the use of low-frequency rTMS applied to the temporoparietal cortex for patients reporting auditory hallucinations--Ed.)

Asked about patients' responses to treatment, Schneider told Psychiatric Times, "Their persistence is very interesting. These are schizophrenic patients who [by definition] are often poorly motivated. Yet our dropout rate is one on NARSAD and one on Stanley to date. It is very unusual in and of itself to get people to come in five days per week. Granted, most of these people are being transported. Nevertheless to get them up and moving at 8 a.m. is a feat."

The patients, Schneider said, report that with the treatment they subjectively feel clearer and that they can think better. He relayed an anecdote in which one patient who was quite negative at the start of the study came in later and told the staff about going to a family wedding and dancing. Another patient who according to Schneider was "one of the most slovenly people" he had ever seen, came in one day clean shaven and relatively well dressed for him. Two patients who were previously unemployed are now employed, and another is applying for work.

Safety
Transcranial magnetic stimulation is generally safe with minimal adverse effects, George said at the APA symposium. Both single-pulse TMS and rTMS, he said, can cause discomfort at the site of stimulation and muscle tension headache (<10%). Some data show a temporary increase in auditory threshold when the patient does not wear earplugs during the procedure.

"Obviously any metal in the brain could be affected. And right now, we are screening out people with pacemakers," George said.

With regard to neuropsychological deficits, George said there are no known adverse effects on cognition.

Repetitive TMS can cause an unintended seizure if researchers are not careful, according to George. It has happened about 15 times over the last 20 years of research. The risk of seizures relates to higher intensity (strength of voltage), higher frequency, duration of the stimulation and spacing between the stimulations.

Because of that risk, George said the International Society for Transcranial Stimulation in 2002 issued a consensus statement on managing the risks of rTMS when it is used in research studies (Belmaker et al., 2003).

According to the consensus document, individuals who administer rTMS should be trained as "first responders" in order to render appropriate care in the event of seizure, and rTMS should be performed in a medical setting under medical supervision with appropriate emergency facilities to manage seizures and their consequences. Additionally, patients and research participants should be continuously monitored during the administration of rTMS for signs of epileptic activity or other adverse effects by a trained individual, according to criteria established in the clinical or experimental protocol.

Belmaker et al. (2003) also stated that patients and study participants should be informed of the risk of seizure and its possible medical and social consequences and the dosage of rTMS should generally be limited by published safety guidelines.

References
Belmaker B, Fitzgerald P, George MS et al. (2003), Managing the risks of repetitive transcranial stimulation. CNS Spectr 8(7):489.

Chibbaro G, Daniele M, Alagona G et al. (2005), Repetitive transcranial magnetic stimulation in schizophrenic patients reporting auditory hallucinations. Neurosci Lett 383(1-2):54-57.

George MS (2003), Stimulating the brain. Sci Am 289(3):66-73.

George MS (2005), New findings on daily prefrontal repetitive transcranial magnetic stimulation for depression. Scientific and clinical report session 14. No. 43. Presented at the 158th Annual Meeting of the American Psychiatric Association. Atlanta; May 21-26.

Gershon AA, Dannon PN, Grunhaus L (2003), Transcranial magnetic stimulation in the treatment of depression. Am J Psychiatry 160(5):835-845.

Hoffman RE, Gueorguieva R, Hawkins KA et al. (2005), Temporoparietal transcranial magnetic stimulation for auditory hallucinations: safety, efficacy and moderators in a fifty patient sample. Biol Psychiatry 58(2):97-104.

Kozel FA, George MS (2002), Meta-analysis of left prefrontal repetitive transcranial magnetic stimulation (rTMS) to treat depression. J Psychiatr Pract 8(5):270-275.

Ledsome JR, Glass IES, George MS (2005), Effectiveness of repetitive transcranial magnetic stimulation (rTMS) in the treatment of depression. J ECT 21(1):59-60.

Lee SH, Kim W, Chung YC et al. (2005), A double blind study showing that two weeks of daily repetitive TMS over the left or right temporoparietal cortex reduces symptoms in patients with schizophrenia who are having treatment-refractory auditory hallucinations. Neurosci Lett 376(3):177-181.

Li X, Nahas Z, Kozel FA et al. (2004), Acute left prefrontal transcranial magnetic stimulation in depressed patients is associated with immediately increased activity in prefrontal cortical as well as subcortical regions. Biol Psychiatry 55(9):882-890.

Ontario Ministry of Health and Long-Term Care (2004), Repetitive Transcranial Magnetic Stimulation for the Treatment of Major Depressive Disorder: Health Technology Scientific Literature and Policy Review. Available at: http://www.health.gov.on.ca/english/providers/

http://program/mas/reviews/docs/rtms_0604.pdf