Elsevier

Psychiatry Research

Volume 88, Issue 3, 29 November 1999, Pages 163-171
Psychiatry Research

Repetitive transcranial magnetic stimulation (rTMS) in pharmacotherapy-refractory major depression: comparative study of fast, slow and sham rTMS

https://doi.org/10.1016/S0165-1781(99)00092-XGet rights and content

Abstract

In previous studies, fast repetitive transcranial magnetic stimulation (rTMS) with a frequency >1 Hz demonstrated substantial antidepressant effects compared to sham rTMS. However, it is not clear whether fast rTMS is superior to slow rTMS (frequency ≤1 Hz) which is safe at therapeutically promising higher intensities. The aim of this double-blind study was to compare the action of fast, slow and sham rTMS. Eighteen patients with pharmacotherapy-resistant major depression were randomized to receive fast (10 Hz), slow (0.3 Hz) or sham rTMS with 250 stimuli/day for 5 successive days. rTMS was applied at 90% motor threshold intensity to the left dorsolateral prefrontal cortex. Scores on the Hamilton Depression Rating Scale (HDRS), but not on the Montgomery–Åsberg Depression Rating Scale (MADRS), showed a statistically significant time×group interaction with a reduction of 19% after slow rTMS. However, the effect was clinically marginal and not reflected by self-rating scores. Verbal memory and reaction performance were not impaired after rTMS, and there was even a statistically significant time×group interaction with improvement of verbal memory performance after fast rTMS. In conclusion, this study further supported the safety of rTMS but does not show any clinically meaningful antidepressant efficacy of rTMS at 250 daily stimuli over 5 days in pharmacotherapy-refractory major depression.

Introduction

Recently, transcranial magnetic stimulation (TMS), widely used in human cortical neurophysiology (Barker et al., 1985, Hallett, 1996), has been reported to have therapeutic effects in several neuropsychiatric disorders, including major depression (George et al., 1999). In case reports and open pilot studies, antidepressant effects were observed after repetitive TMS (rTMS) (Höflich et al., 1993, Grisaru et al., 1994, George et al., 1995, George et al., 1998, Kolbinger et al., 1995, Geller et al., 1997, Feinsod et al., 1998, Avery et al., 1999, Nahas et al., 1999). Three placebo-controlled trials and two larger open-label studies showed an antidepressant action of rTMS in depressed outpatients and patients with pharmacotherapy-resistant depression (Pascual-Leone et al., 1996, George et al., 1997, Figiel et al., 1998, Klein et al., 1999, Pridmore et al., 1999). However, largely varying stimulation parameters have been used in studies of therapeutic rTMS, and optimal parameters have not been established.

The majority of studies investigating rTMS as an antidepressant treatment suggested that a high-frequency or fast rTMS (defined as a frequency >1 Hz) is particularly effective (George et al., 1995, George et al., 1997, Pascual-Leone et al., 1996, Figiel et al., 1998, Avery et al., 1999, Pridmore et al., 1999). In contrast, several open trials and case reports indicated antidepressant effects of low-frequency or slow rTMS (defined as a frequency ≤1 Hz) (Höflich et al., 1993, Grisaru et al., 1994, Kolbinger et al., 1995, Conca et al., 1996, Geller et al., 1997, Feinsod et al., 1998). Recently, these results were confirmed by a randomized placebo-controlled study where a 1-Hz slow rTMS of the right prefrontal cortex was successfully applied (Klein et al., 1999).

The aim of the present study was to compare the antidepressant efficacy and tolerability of fast, slow and sham stimulation in patients with medication–refractory major depression. In order to monitor cognitive side effects, we tested verbal learning and reaction time before and after rTMS. Length of rTMS treatment and number of daily stimuli were similar to a prior pilot study which indicated antidepressant effects of slow rTMS (Kolbinger et al., 1995).

Section snippets

Patients

Eighteen right-handed patients from the Department of Psychiatry, Ludwig–Maximilian University Munich were included [age=51.2±16.1 years, 11 women (age: 51.1±15.1 years), seven men (age: 51.3±18.3 years)]. All patients met DSM-IV criteria for Major Depressive Disorder (single episode in three, recurrent depression in 15). All patients gave their written informed consent for this study, after the procedure had been fully explained. The study was approved by the local ethics committee. Patients

Clinicians’ ratings

HDRS scores tended to decrease from pre-treatment to post-treatment across groups (F1,15=3.58; P<0.10). No overall difference was found between treatment groups (F2,15=0.93; n.s.). The interaction of treatment groups and time was significant (F2,15=3.76; P<0.05). In the sham rTMS group, the mean HDRS score was unchanged between baseline (22.2±8.8) and day 5 (23.5±10.4) [t(5)=−0.62; n.s.]. In the slow rTMS group, the HDRS score significantly decreased by 19% from 26.7±9.4 to 21.5±21.5 [t

Discussion

In this double-blind parallel study, two active rTMS conditions with different stimulation frequencies were compared to sham rTMS. HDRS scores showed a statistically significant time×group interaction and were decreased by 19% from baseline after slow rTMS. MADRS scores showed a statistical trend towards a time×group interaction. Tolerability of rTMS treatment was excellent and no serious side effects occurred.

The finding of a mild antidepressant effect of slow rTMS is consistent with previous

Acknowledgements

The authors thank Dr. Patrick Mikhaiel for helpful discussions, as well as Simon Neulinger and Felician Iancu for their assistance. They also thank Magstim Company Ltd. and Micromed Medizin-Elektronik GmbH for kind support.

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    This work was presented in part at the XXIst Congress of the Collegium Internationale Neuro-Psychopharmacologicum, Glasgow, UK, July 12–16, 1998, and at the International Symposium on Transcranial Magnetic Stimulation, Göttingen, Germany, September 30–October 4, 1998.

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