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Long-lasting effects of high frequency repetitive transcranial magnetic stimulation in major depressed patients
Psychiatry Research 150 (2007) 181 – 186 www.elsevier.com/locate/psychres
Brief report
Long-lasting effects of high frequency repetitive transcranial magnetic stimulation in major depressed patients Marco Bortolomasi a , Alessandra Minelli c,d,⁎, Giorgio Fuggetta b , Michele Perini a , Sandra Comencini a , Antonio Fiaschi b , Paolo Manganotti b Casa di Cura “Villa S. Chiara”, Verona, Italy Sezione di Neurologia Riabilitativa, Dipartimento di Scienze Neurologiche e della Visione, Policlinico “Giambattista Rossi”, Universita' di Verona, Verona, Italy c Sezione di Fisiologia, Dipartimento di Scienze Neurologiche e della Visione, Universita' di Verona, Verona, Italy d F.C. Donders Centre for Cognitive Neuroimaging, PO Box 9101, NL-6500 HB Nijmegen, The Netherlands a
b
Received 10 November 2005; received in revised form 15 April 2006; accepted 20 April 2006
Abstract The majority of previous clinical studies have indicated that repetitive transcranial magnetic stimulation (rTMS) may have antidepressant effects. Herein, we investigated the longitudinal, long-term antidepressant efficacy of daily left prefrontal cortex (PFC) rTMS for a 1-week period. Nineteen patients were randomly assigned to two treatment groups at 90% of individual motor threshold (MT): Twelve received active repetitive transcranial magnetic stimulation and seven received sham treatment. Each patient underwent five sessions of twenty 2-s trains of 20 Hz rTMS with 800 stimuli/day. The Beck Depression Inventory and the Hamilton Depression Rating Scale were used to assess severity of depression at 1, 4 and 12 weeks post-therapy. A significant reduction of baseline depression scores was observed after 1 week of active treatment that lasted for 1 month, indicating improvement of depressive symptoms. No significant effects were observed in patients receiving sham treatment. The results of this controlled study are in agreement with the findings of previous studies suggesting that daily left PFC rTMS has an antidepressant effect. © 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Depressive mood; TMS; Hamilton Depression Rating Scale; Beck Depression Inventory
1. Introduction Interest in the possible therapeutic application of repetitive transcranial magnetic stimulation (rTMS) in various psychiatric disorders has rapidly increased.
⁎ Corresponding author. F.C. Donders Centre for Cognitive Neuroimaging, PO Box 9101, NL-6500 HB Nijmegen, The Netherlands. Tel.: +31 24 36 68236; fax: +31 24 36 10989. E-mail address: [email protected] (A. Minelli).
Repetitive TMS of the prefrontal cortex (PFC) holds the potential of being able to selectively modulate activity in brain areas in pathological processes such as major depression, mania, obsessive–compulsive disorder, post-traumatic stress disorder and schizophrenia (for review, see George et al., 1999). Several studies have suggested that PFC rTMS may have therapeutic benefits on major depression (Pascual-Leone et al., 1996; Nahas et al., 1998; Klein et al., 1999; Berman et al., 2000; George et al., 2000; Loo and Mitchell, 2005; Miniussi et al., 2005).
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At present, the optimal parameters for repetitive transcranial magnetic stimulation (e.g. frequency, intensity, localization) in the treatment of depression have not been standardized. If we consider several studies (Klein et al., 1999; Padberg et al., 1999; Loo et al., 1999; George et al., 2000; Eschweiler et al., 2000; Berman et al., 2000; Garcia-Toro et al., 2001a,b; Lisanby et al., 2001; Christyakov et al., 2005; Miniussi et al., 2005; Rumi et al., 2005), we can see that these have varied greatly in the rTMS parameters used (stimulus frequency, intensity, and number of stimuli). Despite some attempts to standardize TMS parameters, there is still little empirical evidence to guide the choice of these and it is not known what technical parameters produce the greatest clinical benefit. Recently, however, the review of Gershon et al. (2003) presented evidence that some types of parameters produce better results than others. TMS can either excite or inhibit cortical areas of the brain depending on whether the repetitive stimulation is applied at high or low frequencies. When delivered over the PFC in depressed adults, it causes increased activity in the cortex with more relative regional brain blood flow measured by SPECT (Single Photon Emission Computed Tomography). This suggests that the frequency of rTMS plays a role in the modulation of cortical activity (Nahas et al., 2001). In the studies reviewed by Gershon et al. (2003) that measured clinical remission of depressive symptoms, 41% of all patients treated with high-frequency rTMS to the left prefrontal cortex achieved a 50% reduction in their Hamilton depression scale scores. An analysis of different studies suggests that those using higher magnetic pulses (George et al., 2000; Pridmore et al., 2000; Janicak et al., 2002), that is with a motor threshold (MT) above or equal to 100%, had better results than those in which less intense pulses were given (George et al., 1997; Garcia-Toro et al., 2001a,b; Berman et al., 2000). The rationale for the use of lateralized TMS is based on the hypothesis that mood disorders may result from a relative imbalance of the frontal lobes. It has been suggested that depression occurs with a hypofunctioning left frontal lobe as indicated by neuroanatomical and neuroradiological studies (Cummings, 1993; Hirano et al., 1998). Several studies found significant differences between active and sham stimulation associated with a long-term effect in depressed patients (Klein et al., 1999; Padberg et al., 1999; Loo et al., 1999; George et al., 2000; Eschweiler et al., 2000; Berman et al., 2000; GarciaToro et al., 2001a,b; Lisanby et al., 2001; Christyakov et al., 2005; Miniussi et al., 2005; Rumi et al., 2005). Some studies have described the longitudinal, long-term outcome of this type of active treatment in severely
depressed individuals (Dannon et al., 2002; Janicak et al., 2002). The aim of this controlled study was to investigate the outcome of depressed patients treated for 1 month with high frequency rTMS on the left frontal lobe at long time periods. 2. Methods 2.1. Patients Patients who met the DSM-IV clinical criteria for major depression and drug resistance were invited to participate in the study, which was approved by the local ethical committee. Nineteen patients (11 women, 8 men; mean age 55.6 years, S.D. 15.4 years; range 44– 56 years) provided written informed consent. Participants were randomly assigned to two treatment groups to receive either active rTMS (n = 12) or sham rTMS (n = 7). The two groups were matched for age and sex and were homogenous in terms of clinical parameters. Relevant demographic and clinical characteristics of the two treatment groups are shown in Table 1. All patients were right-handed, with no history of brain trauma or seizure disorders, and they had normal neurological examinations. According to the safety criteria for rTMS (Wassermann, 1998), patients with pacemakers, mobile metal implants or implanted medication pumps were excluded. The pharmacological regimen was not changed throughout the course of the study. The pharmacotherapy was similar in both groups, consisting of either tricyclic or SSRI (serotonin reuptake inhibitors) drugs.
Table 1 Relevant patients' characteristics at baseline Active rTMS Sham rTMS Significant test Demographics Age (years) Gender (f/m) Clinical characteristics Unipolar/bipolar depression Clinical history Past depressive episodes No hospitalization Suicide attempts Previous ECT Treatment SSRI TCA No medication
45–56 7/5
44–53 4/3
NS NS
10/2
6/1
NS
12
7
NS
12 6 6
7 3 2
NS NS NS
8 3 1
6 2 0
NS NS NS
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2.2. Stimulation protocol A magnetic stimulation (Magstim Rapid, UK) was used with a 90-mm external circular coil. We used a circular coil instead of a focal coil for two reasons: first because we preferred to have a stabler rTMS measure over the motor areas, and second because we wanted to obtain a more diffuse effect over the frontal areas. Initially the motor threshold (MT) was determined in all patients over the left motor cortex, by finding the minimal intensity that produced a motor response in the right thenar eminence (TE) muscles of the hand. The examimation was performed by a neurologist (P.M.) who is an expert in clinical neurophysiology. As in the majority of previous studies (George et al., 1995, 1997; Pascual-Leone et al., 1996; Berman et al., 2000; Grunhaus et al., 2000; Padberg et al., 2002), during treatment the coil was positioned over the left prefrontal area (without crossing the midline) at a point 5 cm anterior to the scalp position at which the MT was determined. For the coil position over the frontal areas, we followed the standard criteria. For the sham treatment group, the stimulation coil was placed perpendicular to the scalp surface without direct contact. The coil position was fixed for all TMS sessions, and stimulation at this site evoked minimal motor activity. Moreover, stimulation parameters were identical for patients assigned randomly to active or sham rTMS stimulation conditions. Each patient underwent 5 sessions per week, and each session included a total of 800 stimuli/day delivered in 20 trains of 20-Hz rTMS at 90% of the motor evoked potential threshold. Each train had lasted 2 s with a 60-s intertrain pause. The patients were naive to rTMS prior to the study and were not familiar with the differences between sham and active rTMS regarding acoustic and tactile artefacts. 2.3. Clinical assessment Patients were examined by one psychiatrist (M.B.) and one clinical psychologist (S.C.). Severity of depression was assessed using the 24-item Hamilton Depression Rating Scale (HAMD) (Hamilton, 1960) and the 21-item Beck Depression Inventory (BDI) (Beck et al., 1961) at baseline, as well as after 1, 4 and 12 weeks of rTMS. Both the HAMD and the BDI were used as primary outcome measures. The rater was unaware of the rTMS treatment. 2.4. Statistical procedures The different measures used to assess depressive symptoms were analyzed separately. Two analyses of
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variance (ANOVA), with repeated measures, for the BDI and HAMD scales, respectively, were applied for the analysis of rTMS efficacy and to reject the null hypothesis that the possible improvement of depressive symptoms in the depressed patients could be attributed to non-specific effects. The ANOVAs had one between-subjects factor, namely the treatment group (active TMS, and sham TMS), and one within-subjects factor, the time point (baseline, weeks 1, 4 and 12). Post-hoc comparisons were performed with the paired t-test adjusted for multiple comparisons by the Bonferroni method. All statistical tests were 2-tailed and a value of P < 0.05 was considered significant. Statistical analyses were performed using SPSS Version 11.0. 3. Results All 19 patients completed the study per protocol. The treatment was generally well tolerated and no noteworthy side effects were reported. Five patients complained of discomfort, experiencing facial muscle twitches during stimulation. Three patients reported mild headache that lasted for a few hours after treatment. All patients treated by with rTMS referred to marked drowsiness for several hours immediately following the stimulation. Six patients referred to subjective improvement of sleep after the first stimulation session. Patients treated with the sham condition did not report any symptoms related to drowsiness or sleep. The main effect of time point (BDI, F(3, 51) = 9.856, P < 0.001; HAMD, F(3, 51) = 9.585, P < 0.001) showed that depression scores significantly declined across treatment groups during rTMS. Post-hoc comparisons showed a similar outcome of scores on both scales with a significant difference between the baseline value and those at 1 and 4 weeks after treatment (BDI: 25.42, 12.25 and 11.67; HAMD: 25.17, 11.33 and 11.42, respectively). Indeed t-test comparisons were highly statistically significant [comparison between baseline versus 1 week condition: t(11) = 4.919, P < 0.001 for the BDI and t(11) = 4.304, P < 0.001 for the HAMD; comparison between baseline versus 4 weeks condition: t(11) = 4.793, P < 0.001 for the BDI and t(11)= 4.374, P < 0.001 for the HAMD]. No significant outcome differences were observed for either the BDI or the HAMD scores in the control group of patients between the baseline values and those at 1, 4 and 12 weeks after sham rTMS treatment. The treatment group by time point interaction also showed significant differences (BDI, F(3, 51) = 4.931, P < 0.01; HAMD, F(3, 51) = 2.844, P < 0.05). BDI posthoc comparisons showed a significant difference in
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Fig. 1. Beck Depression Inventory score of active TMS stimulation versus sham stimulation.
scores between the two treatment groups, with a lower score in the active rTMS group with respect to the sham TMS group after 1 (12.25 vs. 22.43) and 4 weeks of treatment (11.67 vs. 24.57). Congruent to the BDI, the HAMD post-hoc comparisons showed a significant difference between the two groups, with a lower score in the active rTMS group compared with the sham rTMS group after 1 (11.33 vs. 18.29) and 4 weeks of treatment (11.42 vs. 19.14). Thus, no significant differences were found between groups for either baseline BDI or HAMD scores. To sum up, patients treated by active rTMS compared with those treated by sham rTMS showed a statistically significant improvement of depressive symptoms in both the BDI (Fig. 1) and HAMD scales (Fig. 2). A significant difference between groups, with a reduction in baseline depression scores for the active rTMS group, was noted at 1 and 4 weeks following rTMS. After 3 months, patients treated with active rTMS reverted to the previous depressive mood state. 4. Discussion In this controlled trial, two different fast rTMS conditions were compared in patients with major depression. We observed significant antidepressant effects following left frontal high frequency TMS; while antidepressant effects of fast rTMS of the left dorsolateral PFC have been demonstrated in previous studies (Pascual-Leone et al., 1996; George et al., 1997, 2000; Klein et al., 1999; Padberg et al., 1999, 2002; Berman et al., 2000; Garcia-Toro et al., 2001a,b; review: Martin et al., 2003). One key aspect of the present study is that we monitored the effect of high frequency rTMS for a 3-month follow-up period using two evaluative scales. Significant improvement as assessed by both the BDI and HAMD scores was seen at 1 week and 4 weeks post-
therapy in the active rTMS group, while no improvements in outcome were observed in the control group. When the entire patient cohort was considered, there were no significant improvements in outcome in rTMStreated patients at 3 months. However, it is worth noting that the changes in rating scores did last for at least 3 months in two patients, suggesting a genuine effect rather than non-specific placebo events. In a recent review, Martin et al. (2003) noted differences between rTMS and sham TMS using either the BDI or the HAMD after 2 weeks of treatment for left dorsolateral PFC at high frequency. Right dorsolateral prefrontal cortex at low frequency also caused significant differences on the HAMD. In this study no adverse effects were reported in either group, except for mild cephalgia reported by three patients treated with anti-inflammatory drugs. No safety concerns were raised with rTMS using the parameters in this study. Thus, in addition to the previous hypothesis, we suggest a possible effect of rTMS in strengthening the action of antidepressant drugs. Given the substantial delay in symptomatic improvement seen with traditional antidepressant medication (Stassen et al., 1993, 1994), another potential use of TMS might be in augmenting or hastening the clinical response in pharmacologically treated patients. Nevertheless, further studies with large patient cohorts for longer periods of time are necessary. Another finding of our study was that we observed the presence of subjective drowsiness in all patients treated with rTMS. The patients reported subjective improvement of sleepiness after the first stimulation sessions; however, patients treated with sham stimulation reported no such benefit. Prior to treatment most of these patients suffered from insomnia. Also, although this effect was only supported by patients' subjective reports, this symptom was consistent across all the patients treated with rTMS. Because the patients were
Fig. 2. Hamilton Depression Rating Scale score of active TMS stimulation versus sham stimulation.
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taking drugs before rTMS and these drugs were not changed during the sham and active stimulation, we think that probably the effect of subjective drowsiness is due to active rTMS stimulation. Our study did not compare the long-term effects of rTMS with electroconvulsive therapy (ECT). Few studies have compared long courses of high-frequency rTMS to ECT (Grunhaus et al., 2000, 2003; Pridmore et al., 2000; Dannon et al., 2002; Janicak et al., 2002). Dannon et al. (2002) monitored the duration of mood effects in depressed patients comparing fast rTMS over the left frontal lobe to ECT over long time periods (3 and 6 months) and found no relevant differences (about 20% for both groups). Moreover patients reported equally low scores that were not significantly different in HAMD at the 6-month follow-up. Thus, the authors suggested that the clinical gains obtained with rTMS last at least as long as those obtained with ECT. Grunhaus et al. (2003) carried out a follow-up study in which only patients with nonpsychotic major depression for whom 4 weeks of antidepressant pharmacotherapy had failed were included. In the ECT group, 60% of patients responded compared with 55% treated with rTMS. All together, these studies have shown comparable results between rTMS and ECT in depressed patients. These results are important because rTMS treatment could be a valid, safer and more tolerable alternative to ECT for severe or resistant depressed patients. In conclusion, rTMS may have a prolonged effect on mood in depressed patients. The results of this study justify further clinical research in rTMS with particular emphasis on its long-term effects. Future studies will also need to standardize the multitude of stimulation parameters including the intensity, frequency and the train duration as well as the number and frequency of sessions. As a final note, regardless of its potential clinical role in the treatment of depression, further studies with rTMS will likely provide important information about the neuroanatomical structures and pathophysiological mechanisms that are important in mood regulation. References Beck, A.T., Ward, C.H., Mendelson, M., Mock, J., Erbauch, J., 1961. An inventory for measuring depression. Archives of General Psychiatry 4, 561–571. Berman, R.M., Narasimhan, M., Saracora, G., Miano, A.P., Hoffman, R.E., Hu, X.S., Charney, D.S., Boutros, N.S., 2000. A randomized clinical trial of repetitive transcranial magnetic stimulation in the treatment of major depression. Biological Psychiatry 47, 332–337. Christyakov, A., Kaplan, B., Rubichek, O., Kreinin, I., Koren, D., Feinsod, M., Klein, E., 2005. Antidepressant effects of different schedules of repetitive transcranial magnetic stimulation vs.
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Brief report
Long-lasting effects of high frequency repetitive transcranial magnetic stimulation in major depressed patients Marco Bortolomasi a , Alessandra Minelli c,d,⁎, Giorgio Fuggetta b , Michele Perini a , Sandra Comencini a , Antonio Fiaschi b , Paolo Manganotti b Casa di Cura “Villa S. Chiara”, Verona, Italy Sezione di Neurologia Riabilitativa, Dipartimento di Scienze Neurologiche e della Visione, Policlinico “Giambattista Rossi”, Universita' di Verona, Verona, Italy c Sezione di Fisiologia, Dipartimento di Scienze Neurologiche e della Visione, Universita' di Verona, Verona, Italy d F.C. Donders Centre for Cognitive Neuroimaging, PO Box 9101, NL-6500 HB Nijmegen, The Netherlands a
b
Received 10 November 2005; received in revised form 15 April 2006; accepted 20 April 2006
Abstract The majority of previous clinical studies have indicated that repetitive transcranial magnetic stimulation (rTMS) may have antidepressant effects. Herein, we investigated the longitudinal, long-term antidepressant efficacy of daily left prefrontal cortex (PFC) rTMS for a 1-week period. Nineteen patients were randomly assigned to two treatment groups at 90% of individual motor threshold (MT): Twelve received active repetitive transcranial magnetic stimulation and seven received sham treatment. Each patient underwent five sessions of twenty 2-s trains of 20 Hz rTMS with 800 stimuli/day. The Beck Depression Inventory and the Hamilton Depression Rating Scale were used to assess severity of depression at 1, 4 and 12 weeks post-therapy. A significant reduction of baseline depression scores was observed after 1 week of active treatment that lasted for 1 month, indicating improvement of depressive symptoms. No significant effects were observed in patients receiving sham treatment. The results of this controlled study are in agreement with the findings of previous studies suggesting that daily left PFC rTMS has an antidepressant effect. © 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Depressive mood; TMS; Hamilton Depression Rating Scale; Beck Depression Inventory
1. Introduction Interest in the possible therapeutic application of repetitive transcranial magnetic stimulation (rTMS) in various psychiatric disorders has rapidly increased.
⁎ Corresponding author. F.C. Donders Centre for Cognitive Neuroimaging, PO Box 9101, NL-6500 HB Nijmegen, The Netherlands. Tel.: +31 24 36 68236; fax: +31 24 36 10989. E-mail address: [email protected] (A. Minelli).
Repetitive TMS of the prefrontal cortex (PFC) holds the potential of being able to selectively modulate activity in brain areas in pathological processes such as major depression, mania, obsessive–compulsive disorder, post-traumatic stress disorder and schizophrenia (for review, see George et al., 1999). Several studies have suggested that PFC rTMS may have therapeutic benefits on major depression (Pascual-Leone et al., 1996; Nahas et al., 1998; Klein et al., 1999; Berman et al., 2000; George et al., 2000; Loo and Mitchell, 2005; Miniussi et al., 2005).
0165-1781/$ - see front matter © 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.psychres.2006.04.010
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At present, the optimal parameters for repetitive transcranial magnetic stimulation (e.g. frequency, intensity, localization) in the treatment of depression have not been standardized. If we consider several studies (Klein et al., 1999; Padberg et al., 1999; Loo et al., 1999; George et al., 2000; Eschweiler et al., 2000; Berman et al., 2000; Garcia-Toro et al., 2001a,b; Lisanby et al., 2001; Christyakov et al., 2005; Miniussi et al., 2005; Rumi et al., 2005), we can see that these have varied greatly in the rTMS parameters used (stimulus frequency, intensity, and number of stimuli). Despite some attempts to standardize TMS parameters, there is still little empirical evidence to guide the choice of these and it is not known what technical parameters produce the greatest clinical benefit. Recently, however, the review of Gershon et al. (2003) presented evidence that some types of parameters produce better results than others. TMS can either excite or inhibit cortical areas of the brain depending on whether the repetitive stimulation is applied at high or low frequencies. When delivered over the PFC in depressed adults, it causes increased activity in the cortex with more relative regional brain blood flow measured by SPECT (Single Photon Emission Computed Tomography). This suggests that the frequency of rTMS plays a role in the modulation of cortical activity (Nahas et al., 2001). In the studies reviewed by Gershon et al. (2003) that measured clinical remission of depressive symptoms, 41% of all patients treated with high-frequency rTMS to the left prefrontal cortex achieved a 50% reduction in their Hamilton depression scale scores. An analysis of different studies suggests that those using higher magnetic pulses (George et al., 2000; Pridmore et al., 2000; Janicak et al., 2002), that is with a motor threshold (MT) above or equal to 100%, had better results than those in which less intense pulses were given (George et al., 1997; Garcia-Toro et al., 2001a,b; Berman et al., 2000). The rationale for the use of lateralized TMS is based on the hypothesis that mood disorders may result from a relative imbalance of the frontal lobes. It has been suggested that depression occurs with a hypofunctioning left frontal lobe as indicated by neuroanatomical and neuroradiological studies (Cummings, 1993; Hirano et al., 1998). Several studies found significant differences between active and sham stimulation associated with a long-term effect in depressed patients (Klein et al., 1999; Padberg et al., 1999; Loo et al., 1999; George et al., 2000; Eschweiler et al., 2000; Berman et al., 2000; GarciaToro et al., 2001a,b; Lisanby et al., 2001; Christyakov et al., 2005; Miniussi et al., 2005; Rumi et al., 2005). Some studies have described the longitudinal, long-term outcome of this type of active treatment in severely
depressed individuals (Dannon et al., 2002; Janicak et al., 2002). The aim of this controlled study was to investigate the outcome of depressed patients treated for 1 month with high frequency rTMS on the left frontal lobe at long time periods. 2. Methods 2.1. Patients Patients who met the DSM-IV clinical criteria for major depression and drug resistance were invited to participate in the study, which was approved by the local ethical committee. Nineteen patients (11 women, 8 men; mean age 55.6 years, S.D. 15.4 years; range 44– 56 years) provided written informed consent. Participants were randomly assigned to two treatment groups to receive either active rTMS (n = 12) or sham rTMS (n = 7). The two groups were matched for age and sex and were homogenous in terms of clinical parameters. Relevant demographic and clinical characteristics of the two treatment groups are shown in Table 1. All patients were right-handed, with no history of brain trauma or seizure disorders, and they had normal neurological examinations. According to the safety criteria for rTMS (Wassermann, 1998), patients with pacemakers, mobile metal implants or implanted medication pumps were excluded. The pharmacological regimen was not changed throughout the course of the study. The pharmacotherapy was similar in both groups, consisting of either tricyclic or SSRI (serotonin reuptake inhibitors) drugs.
Table 1 Relevant patients' characteristics at baseline Active rTMS Sham rTMS Significant test Demographics Age (years) Gender (f/m) Clinical characteristics Unipolar/bipolar depression Clinical history Past depressive episodes No hospitalization Suicide attempts Previous ECT Treatment SSRI TCA No medication
45–56 7/5
44–53 4/3
NS NS
10/2
6/1
NS
12
7
NS
12 6 6
7 3 2
NS NS NS
8 3 1
6 2 0
NS NS NS
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2.2. Stimulation protocol A magnetic stimulation (Magstim Rapid, UK) was used with a 90-mm external circular coil. We used a circular coil instead of a focal coil for two reasons: first because we preferred to have a stabler rTMS measure over the motor areas, and second because we wanted to obtain a more diffuse effect over the frontal areas. Initially the motor threshold (MT) was determined in all patients over the left motor cortex, by finding the minimal intensity that produced a motor response in the right thenar eminence (TE) muscles of the hand. The examimation was performed by a neurologist (P.M.) who is an expert in clinical neurophysiology. As in the majority of previous studies (George et al., 1995, 1997; Pascual-Leone et al., 1996; Berman et al., 2000; Grunhaus et al., 2000; Padberg et al., 2002), during treatment the coil was positioned over the left prefrontal area (without crossing the midline) at a point 5 cm anterior to the scalp position at which the MT was determined. For the coil position over the frontal areas, we followed the standard criteria. For the sham treatment group, the stimulation coil was placed perpendicular to the scalp surface without direct contact. The coil position was fixed for all TMS sessions, and stimulation at this site evoked minimal motor activity. Moreover, stimulation parameters were identical for patients assigned randomly to active or sham rTMS stimulation conditions. Each patient underwent 5 sessions per week, and each session included a total of 800 stimuli/day delivered in 20 trains of 20-Hz rTMS at 90% of the motor evoked potential threshold. Each train had lasted 2 s with a 60-s intertrain pause. The patients were naive to rTMS prior to the study and were not familiar with the differences between sham and active rTMS regarding acoustic and tactile artefacts. 2.3. Clinical assessment Patients were examined by one psychiatrist (M.B.) and one clinical psychologist (S.C.). Severity of depression was assessed using the 24-item Hamilton Depression Rating Scale (HAMD) (Hamilton, 1960) and the 21-item Beck Depression Inventory (BDI) (Beck et al., 1961) at baseline, as well as after 1, 4 and 12 weeks of rTMS. Both the HAMD and the BDI were used as primary outcome measures. The rater was unaware of the rTMS treatment. 2.4. Statistical procedures The different measures used to assess depressive symptoms were analyzed separately. Two analyses of
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variance (ANOVA), with repeated measures, for the BDI and HAMD scales, respectively, were applied for the analysis of rTMS efficacy and to reject the null hypothesis that the possible improvement of depressive symptoms in the depressed patients could be attributed to non-specific effects. The ANOVAs had one between-subjects factor, namely the treatment group (active TMS, and sham TMS), and one within-subjects factor, the time point (baseline, weeks 1, 4 and 12). Post-hoc comparisons were performed with the paired t-test adjusted for multiple comparisons by the Bonferroni method. All statistical tests were 2-tailed and a value of P < 0.05 was considered significant. Statistical analyses were performed using SPSS Version 11.0. 3. Results All 19 patients completed the study per protocol. The treatment was generally well tolerated and no noteworthy side effects were reported. Five patients complained of discomfort, experiencing facial muscle twitches during stimulation. Three patients reported mild headache that lasted for a few hours after treatment. All patients treated by with rTMS referred to marked drowsiness for several hours immediately following the stimulation. Six patients referred to subjective improvement of sleep after the first stimulation session. Patients treated with the sham condition did not report any symptoms related to drowsiness or sleep. The main effect of time point (BDI, F(3, 51) = 9.856, P < 0.001; HAMD, F(3, 51) = 9.585, P < 0.001) showed that depression scores significantly declined across treatment groups during rTMS. Post-hoc comparisons showed a similar outcome of scores on both scales with a significant difference between the baseline value and those at 1 and 4 weeks after treatment (BDI: 25.42, 12.25 and 11.67; HAMD: 25.17, 11.33 and 11.42, respectively). Indeed t-test comparisons were highly statistically significant [comparison between baseline versus 1 week condition: t(11) = 4.919, P < 0.001 for the BDI and t(11) = 4.304, P < 0.001 for the HAMD; comparison between baseline versus 4 weeks condition: t(11) = 4.793, P < 0.001 for the BDI and t(11)= 4.374, P < 0.001 for the HAMD]. No significant outcome differences were observed for either the BDI or the HAMD scores in the control group of patients between the baseline values and those at 1, 4 and 12 weeks after sham rTMS treatment. The treatment group by time point interaction also showed significant differences (BDI, F(3, 51) = 4.931, P < 0.01; HAMD, F(3, 51) = 2.844, P < 0.05). BDI posthoc comparisons showed a significant difference in
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Fig. 1. Beck Depression Inventory score of active TMS stimulation versus sham stimulation.
scores between the two treatment groups, with a lower score in the active rTMS group with respect to the sham TMS group after 1 (12.25 vs. 22.43) and 4 weeks of treatment (11.67 vs. 24.57). Congruent to the BDI, the HAMD post-hoc comparisons showed a significant difference between the two groups, with a lower score in the active rTMS group compared with the sham rTMS group after 1 (11.33 vs. 18.29) and 4 weeks of treatment (11.42 vs. 19.14). Thus, no significant differences were found between groups for either baseline BDI or HAMD scores. To sum up, patients treated by active rTMS compared with those treated by sham rTMS showed a statistically significant improvement of depressive symptoms in both the BDI (Fig. 1) and HAMD scales (Fig. 2). A significant difference between groups, with a reduction in baseline depression scores for the active rTMS group, was noted at 1 and 4 weeks following rTMS. After 3 months, patients treated with active rTMS reverted to the previous depressive mood state. 4. Discussion In this controlled trial, two different fast rTMS conditions were compared in patients with major depression. We observed significant antidepressant effects following left frontal high frequency TMS; while antidepressant effects of fast rTMS of the left dorsolateral PFC have been demonstrated in previous studies (Pascual-Leone et al., 1996; George et al., 1997, 2000; Klein et al., 1999; Padberg et al., 1999, 2002; Berman et al., 2000; Garcia-Toro et al., 2001a,b; review: Martin et al., 2003). One key aspect of the present study is that we monitored the effect of high frequency rTMS for a 3-month follow-up period using two evaluative scales. Significant improvement as assessed by both the BDI and HAMD scores was seen at 1 week and 4 weeks post-
therapy in the active rTMS group, while no improvements in outcome were observed in the control group. When the entire patient cohort was considered, there were no significant improvements in outcome in rTMStreated patients at 3 months. However, it is worth noting that the changes in rating scores did last for at least 3 months in two patients, suggesting a genuine effect rather than non-specific placebo events. In a recent review, Martin et al. (2003) noted differences between rTMS and sham TMS using either the BDI or the HAMD after 2 weeks of treatment for left dorsolateral PFC at high frequency. Right dorsolateral prefrontal cortex at low frequency also caused significant differences on the HAMD. In this study no adverse effects were reported in either group, except for mild cephalgia reported by three patients treated with anti-inflammatory drugs. No safety concerns were raised with rTMS using the parameters in this study. Thus, in addition to the previous hypothesis, we suggest a possible effect of rTMS in strengthening the action of antidepressant drugs. Given the substantial delay in symptomatic improvement seen with traditional antidepressant medication (Stassen et al., 1993, 1994), another potential use of TMS might be in augmenting or hastening the clinical response in pharmacologically treated patients. Nevertheless, further studies with large patient cohorts for longer periods of time are necessary. Another finding of our study was that we observed the presence of subjective drowsiness in all patients treated with rTMS. The patients reported subjective improvement of sleepiness after the first stimulation sessions; however, patients treated with sham stimulation reported no such benefit. Prior to treatment most of these patients suffered from insomnia. Also, although this effect was only supported by patients' subjective reports, this symptom was consistent across all the patients treated with rTMS. Because the patients were
Fig. 2. Hamilton Depression Rating Scale score of active TMS stimulation versus sham stimulation.
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taking drugs before rTMS and these drugs were not changed during the sham and active stimulation, we think that probably the effect of subjective drowsiness is due to active rTMS stimulation. Our study did not compare the long-term effects of rTMS with electroconvulsive therapy (ECT). Few studies have compared long courses of high-frequency rTMS to ECT (Grunhaus et al., 2000, 2003; Pridmore et al., 2000; Dannon et al., 2002; Janicak et al., 2002). Dannon et al. (2002) monitored the duration of mood effects in depressed patients comparing fast rTMS over the left frontal lobe to ECT over long time periods (3 and 6 months) and found no relevant differences (about 20% for both groups). Moreover patients reported equally low scores that were not significantly different in HAMD at the 6-month follow-up. Thus, the authors suggested that the clinical gains obtained with rTMS last at least as long as those obtained with ECT. Grunhaus et al. (2003) carried out a follow-up study in which only patients with nonpsychotic major depression for whom 4 weeks of antidepressant pharmacotherapy had failed were included. In the ECT group, 60% of patients responded compared with 55% treated with rTMS. All together, these studies have shown comparable results between rTMS and ECT in depressed patients. These results are important because rTMS treatment could be a valid, safer and more tolerable alternative to ECT for severe or resistant depressed patients. In conclusion, rTMS may have a prolonged effect on mood in depressed patients. The results of this study justify further clinical research in rTMS with particular emphasis on its long-term effects. Future studies will also need to standardize the multitude of stimulation parameters including the intensity, frequency and the train duration as well as the number and frequency of sessions. As a final note, regardless of its potential clinical role in the treatment of depression, further studies with rTMS will likely provide important information about the neuroanatomical structures and pathophysiological mechanisms that are important in mood regulation. References Beck, A.T., Ward, C.H., Mendelson, M., Mock, J., Erbauch, J., 1961. An inventory for measuring depression. Archives of General Psychiatry 4, 561–571. Berman, R.M., Narasimhan, M., Saracora, G., Miano, A.P., Hoffman, R.E., Hu, X.S., Charney, D.S., Boutros, N.S., 2000. A randomized clinical trial of repetitive transcranial magnetic stimulation in the treatment of major depression. Biological Psychiatry 47, 332–337. Christyakov, A., Kaplan, B., Rubichek, O., Kreinin, I., Koren, D., Feinsod, M., Klein, E., 2005. Antidepressant effects of different schedules of repetitive transcranial magnetic stimulation vs.
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