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Therapeutic efficacy of right prefrontal slow repetitive transcranial magnetic stimulation in treatment-resistant depression: an open study.

Dr Ray Goggins
raygoggins@amindodyssey.com
The Burden Centre, Frenchay Hospital, Bristol, BSI6 IJB

Abstract

Recent studies have suggested that both high- and low-frequency repetitive transcranial magnetic stimulation (rTMS) have antidepressant effects in patients with major depression. An open study was conducted to assess the effects of slow rTMS on mood changes in patients with treatment-resistant depression. Twelve patients with treatment-resistant depression received daily sessions of rTMS (frequency, 1 Hz; pulse duration, 0.1 msec; field intensity, 10% above the motor threshold) over the right prefrontal regions (a total of 120 stimuli daily) over 10 consecutive days. 6 out of the 12 patients responded to treatment. Treatment resulted in a moderate but significant decrease in scores on the Hamilton Depression Rating Scale and the Montgomery-Asberg Rating Scale mean which persisted for 4 weeks after completion of treatment. No significant adverse effects were reported. These preliminary results suggest a therapeutic potential of daily right prefrontal low-frequency rTMS (1 Hz) in treatment-resistant depression however additional studies will be require to assess its true efficacy.

Background

Repetitive transcranial magnetic stimulation (rTMS) has been suggested to be effective for the treatment of major depression. (Ebmeier and Lappin 2001, George et al. 2000, Klein et al. 1999). It is a non-invasive means of electrically stimulating or inhibiting neurons in the cortex and it can modify neuronal activity locally and at distant sites when delivered in series of pulses. The type of excitability on the cortex depends on the frequency of stimulation with high frequency pulses (5-25Hz) generally exciting neurons and low frequency (0.3-1Hz) pulses generally inhibiting neurons (Ebmeier and Lappin 2001, Klein et al. 1999, Wassermann and Lisanby 2001). Imaging studies have linked depression with lateralised prefrontal metabolic dysfunction (Pascual-Leone et al. 1996). Therefore if these regions are indeed important in depression it has been proposed that repetitive stimulation to the right dorsolateral prefrontal cortex (RDLPF) at low frequency may help treat depressed patients. In the largest double blind placebo controlled trial to date using slow rTMS to the RDLPF in patients with major depression resulted in a greater than 50% improvement in their depression rating scales in 17 of 35 patients. In contrast only 8 of 32 patients responded in the placebo group (Klein et al. 1999). It is noteworthy that in contrast stimulating the left dorsolateral prefrontal cortex at high frequency also has antidepressant effects (George et al. 2000).

Method

Twelve patients meeting ICD-10 criteria for major depression volunteered for rTMS in preference to electroconvulsive therapy. The diagnosis of major depression was made by one psychiatrist using standardised interviewing (ICD-10, SCAN 2.1), (Wing et al. 1990). Additional inclusion criteria included Hamilton Depression Rating Scale (17 item clinician administered HDRS), (Hamilton 1967) greater than 19, in addition to a Montgomery-Asberg Depression Rating Scale (MADRS), (Montgomery and Asberg 1979) score greater than 23. Two patients had severe depression with psychotic symptoms. Clinical ratings were assessed at baseline (before treatment) at the end of treatment (two weeks) and one month following completion of treatment. For the purpose of the study treatment-resistant depression was defined as a failure to see a clinical response to 2 antidepressants taken on 2 separate occasions for at least a 6 week period respectively. Antidepressants doses varied from the minimum to the maximum BNF (British National Formulary) recommended therapeutic doses. A clinical response was determined by a clinician’s impression of change although objective rating scales were not used. The small sample of 4 men and 8 women aged between 24 and 70 was derived from both inpatient and outpatients. They provided written informed consent.
The treatment protocol used was based on the protocol applied in the largest double blind placebo controlled study to date of rTMS in depression (Klein et at 1999). Exclusion criteria included a diagnosis of a seizure disorder, current alcohol or substance abuse, moderate to severe learning disability, major physical illness, severe neurological disorder, personality disorder, a metal prosthesis in situ and pregnancy. Patient’s medications remained constant and none were receiving ongoing psychotherapy at the time of treatment. Treatment was administered in 10 daily sessions during a 2 week period. A stimulation frequency of 1 Hz was used over 2 minutes as it is thought that low frequency rTMS may be less likely to induce seizures (Pascaul-Leone et al. 1992).

Results

Response to treatment was defined by a HDRS score less than 7 and a MADRS less than 6. Six of the twelve patients responded and the significant response persisted for 4 weeks after completion of treatment in 5 of the patients (TABLE 1). The other 6 patients failed to show a significant improvement. One of the two patients with psychotic depression responded to treatment although the response was not sustained after 4 weeks. Patient satisfaction rate with the procedure was high. One patient withdrew midway through treatment due to feeling overstimulated and restless. With the exception of a headache in another patient, no other adverse side effects were described. Patient adverse effects were determined by spontaneous report and by a clinician’s symptoms review rather than by standardised interview schedules. Using Fishers exact probability test yielded a p value of 0.10 failing to reach statistical significance.

TABLE 1: Treatment response to rTMS in 12 patients

	Day 1 (Onset of Treatment)	Day 14 (End of treatment)	Day 42 (28 days post treatment)
	HDRS>19 and MADRS>23	HDRS<7 and MADRS<6	HDRS<7 and MADRS<6
DIAGNOSIS
Severe depression with psychotic symptoms	2	1	0
Recurrent Depressive Disorder, current episode depression	6	2	2
Single Depressive Episode	3	2	2
Bipolar Affective Disorder Current Episode Depression
Totals	12	6	5

Discussion

Electricity gets diffused by bone, however in contrast high intensity magnetic pulses pass readily through the skull (Ebmeier and Lappin 2001). This in theory makes it possible to attempt to focus magnetic pulses on particular brain structures (Klein et al. 1999). Many studies to date have examined the use of rTMS to the left dorsolateral prefrontal cortex in depression (Ebmeier and Lappin 2001) however few have studied rTMS to the RDLPF in treatment-resistant patients as in this study. While there are usually few side effects (headache is the most common) rTMS is not without risk, the most important being induction of seizures in seizure-prone individuals (Pascaul- Leone et al. 1992). This study used the same protocol as Klein 1999 which found substantial improvements with right prefrontal stimulation while George et al. 2000 and others have reported effects following left prefrontal stimulation.

In this study right prefrontal stimulation was chosen in preference due to the fact that it appears to be associated with a less propensity to induce seizures in seizure prone individuals (Pascaul- Leone et al. 1992).50% of the sample showed a clinically significant improvement.

However it is noteworthy that the improvement might not be due to rTMS, as it does not consider confounding factors such as placebo effect. In addition patients received concomitant antidepressants that could account for some of the improvement in half of the patients. There are a number of other limitations to this study. This was a small open study unrandomised and unblinded lacking statistical significance. Moreover patient satisfaction in treatment response was not clearly defined. However these preliminary results might suggest a therapeutic potential of daily right prefrontal low frequency rTMS (1 Hz) in treatment-resistant depression. Additional studies are needed to assess the efficacy of rTMS in treatment-resistant depression.

References

Ebmeier, KP. Lappin, JM. (2001) Electromagnetic Stimulation in Psychiatry. Advances in Psychiatric Treatment. Vol 7: 181-187. Hamilton, M. Development of a rating scale for primary depressive illness. Br J Soc Clin Psychol. 1967;6:278-296.
George MS, Nahas Z, Molloy M, Speer AM, Oliver NC, Li XB, Arana GW, Risch SC, Ballenger JC. A controlled trial of daily left prefrontal cortex TMS for treating depression. Biol Psychiatry. 2000 Nov 15;48(10):962-70.
Klein, E. Kreinin, I. Chistyakov, A. Koren, D. Mecz, L. Marmur, S. Ben-Shachar, D. Feinsod, M. (1999) Therapeutic Efficacy of Right Prefrontal Slow Repetitive Transcranial Magnetic Stimulation in Major Depression. Arch Gen Psychiatry 1999 Vol 56:315-320
Montgomery, SA, & Asberg, M. A new depression scale designed to be sensitive to change. Br J Psychiatry 1979; 134:382-389.
Pascaul-Leone, A, Catala, MD, Pascual, AP. (1996) Lateralised effects of rapid-rate transcranial magnetic stimulation of the prefrontal cortex on mood. Neurology. 1996;46:499-502.Pascaul-Leone A, Valls-Sole, .1, Brasil-Neto, JP, Cohen, LG, Hallett, M. (1992) Seizure induction and transcranial magnetic stimulation. Lancet. I 992;339:997-999Wassermann, EM, Lisanby, SH. (2001) Therapeutic application of repetitive transcranial magnetic stimulation: a review. Clinical Neurophysiology 112 (2001) 1367- 13 77
Wing, JK., Babor, T., Brugha, T., Burke, J., Cooper, J.E., Giel, R., Jablensky, A., Regier, D, Sartorius, N. (1990) SCAN: Schedules for clinical assessment in neuropsychiatry. Arch Gen Psych. 47, 5 89-593.

First published September 2003

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