Table 7. rTMS studies (comparator is placebo, different intensities, or different cranial locations) published from 2002 to April 2004.

Study (year, author, country)	Objective	Method	Results	Limitations
2003 Fitzgerald et al.(62) Australia	To prospectively evaluate the efficacy of high-frequency LDLPFC and low-frequency RPFC in treatment resistant depression and compared with a placebo-treated control group.	Double-blind randomized placebo-controlled trial. Primary outcome measured after 2 weeks treatment. Participants: 60 patients with treatment resistant depression who had failed to respond to therapy with multiple antidepressant medications were divided into 3 groups of 20 that did not differ in age, sex or any clinical variables. All patients completed the double-blind phase of the study. Intervention: 20, 5-second high-frequency LDLPFC trains at 10 Hz and 5 60 second low-frequency RPRC trains at 1 Hz applied daily for 2 weeks. Placebo stimulation applied with coil angled at 45 degrees from scalp resting on the side of one wing of the coil. Main outcome measure: score on Montgomery-Asberg Depression Rating Scale. Patients and raters were blind to treatment, but the clinician administering rTMS was aware of the treatment group. After the 10th session, a blinded assessment was made and the patients but not the raters were informed of their treatment group. Patients who had a reduction in MADRS score of >20% in the active treatment arms could continue with the same TMS condition for another 10 sessions. Patients not achieving this improvement offered option of crossing over to the other active treatment. Patients initially randomized to placebo were subsequently randomized to 1 of the 2 active treatments after initial review. During 2nd phase of study, raters remained blind to treatment type. Patients were not deliberately withdrawn from medication before the trial, but their doses were not allowed to have changed in the 4 weeks before commencement of or during the trial. Figure-8 coil.	Significant difference in response among the 3 groups with a significant difference between the high-frequency LDLPFC [reduction in mean score 13.5%±SD16.7%] and placebo [0.76%±16.2%] groups and between the low-frequency RPFC [15.0%±14.1%] and placebo groups (P<.005 for all) but not between the 2 treatment groups (P=.91). Concurrent use of medication did not have a statistically significant effect on primary outcome (P=.23). After phase 1, 7 (11%) of the 60 patients reported site discomfort or pain during rTMS and 6 (10%) reported a headache after rTMS. No difference n the incidence of these adverse effects (P=.08). 29 (48%) of patients correctly guessed their type of treatment before disclosure, 17 (42%) of 40 in the active treatment group (P=.34) and 12 (60%) of 20 in the placebo group (P=.37). The degree of response was the predominant reason given for the guess.	No a priori sample size calculation or justification reported. The a priori primary outcome of interest was measured after 2 weeks of treatment. After 2 weeks, the study is no longer considered double blind. Any analyses after the double-blind phase of the study is limited since patients were aware of their treatment.
2004 Hausmann et al.(66) Austria	To assess whether bilateral rTMS is superior to unilateral rTMS and that there is a speeding up effect in the add on group in comparison to the usual care group medicated with antidepressants alone.	Single centre, prospective double-blind placebo-controlled “add on” trial. 41 medication free patients with MDD without psychotic features admitted to a psychiatric unit were consecutively randomized into 3 groups. Group A1 (n=12) received unilateral active stimulation (20 Hz, 100% MT, 10 trains of 10 sec duration with a 90 sec intertrain interval) consisting of high-frequency rTMS over the LDLPFC and subsequent placebo low-frequency rTMS over the RDLPFC. Group A2 (n=13) received simultaneous bilateral active stimulation consisting of high-frequency rTMS over the LDLPFC and low-frequency RDLPFC rTMS (1 Hz for 10 min, 120% MT). Group C (n=13) received bilateral placebo stimulation. Stimulation was performed on 10 consecutive workdays. Antidepressants were started on the first day of stimulation and maintained throughout the stimulation period. Dosage remained constant throughout the trial. At entry patients underwent a 5 x half life washout period. The optimal LDLPFC and RDLPFC positions were determined by 3D MRI. Figure-8 coil.	Of 41 patients recruited, 38 completed the 2 week protocol. No significant differences between the 3 groups as well as between the pooled treatment groups (A1 and A2) and the placebo group regarding HDRS and BDI scores at baseline. No significant differences between the 2 active treatment groups in terms of HDRS and BDI scores over the course of treatment (day 7, 14, and 28). Groups A1 and A2 were pooled for comparison to Group C. At day 14 and 28 there was no statistically significant difference between rTMS (A1 and A2) and controls (Group C) in mean percentage decrease of the HDRS total score and the BDI. When testing the time course of the outcome variables, HDRS and BDI (days 0, 7, 14, 28) by repeated measures ANOVA, there was a significant effect of time on outcome variables in both groups, whereas there were no significant group differences in terms of a group by time interaction. The size of the interaction term for the HDRS amounted to 2.8 (95% CI -2.8 to 8.5) for day 14 versus baseline, and 3.0 (95% CI - 3.8 to 9.8) for day 28 versus baseline, where a positive value indicates a favour for group A1+A2. The corresponding values for BDI were 5.0 (95% CI - 3.2 to 13.2) and 5.7 (95% CI - 3.8 to 15.0) respectively.	No a priori sample size calculation or justification reported. Antidepressant regimens were variable. Duration of treatment was 10 days, outcome measured up to 28 days from baseline.
2003 Hoppner et al.(67) Germany	To compare clinical effects of 2 different stimulation procedures with placebo stimulation as add on treatments in patients with depressive disorders.	30 depressed patients. Every patient received an antidepressant in a constant dose over 2 weeks before and during the stimulation period. Patients were randomly allocated to receive high-frequency LDLPFC (twenty 20 Hz trains of 2 sec duration with intertrain interval of 60 sec), low-frequency FDLPFC (two 1 Hz trains of 60 sec duration with an intertrain interval of 3 minutes) or placebo stimulation on 10 out of 12 days (2 weeks with 5 sessions each week). Ten patients were included in each group. Placebo stimulation consisted of same conditions as the 20 Hz rTMS except that the coil was placed at a 90 degree angle to the head. Severity of depression was assessed by HDRS (21 items) and BDI. The rater was a psychiatrist who was blind to the stimulation procedure. Clinical response was defined as >50% improvement of baseline scores (HDRS, BDI) between pre and post treatment assessments. Figure-8 coil.	29/30 patients initially included in the study completed the treatment phase. One patient from the high-frequency treatment group refused to continue after 6 days because of insufficient effectiveness and headache. The other 29 patients did not report adverse effects. 5 patients in the 20Hz group were responders compared to 3 patients in the 1 Hz group and 5 patients who were placebo stimulated. Average reduction of baseline score was 61.8%. Only one of the patients was classified as responder according to both BDI and HDRS score criteria. HDRS scores significantly reduced among the 20 Hz group (day 5 P=.03; end of treatment P=.015) and placebo stimulation group (day 5 P=.017; end of treatment P≤.001) but was not statistically significant in the 1 Hz group. 2/9 patients treated by 20 Hz were “responders” based on BDI. One patient from 1 Hz “responded”. Two placebo stimulated patients “responded”. Within the 2 stimulation groups, reduction was observed after 5 days (20 Hz day 5, P=.008, end of treatment, P=.011; 1 Hz day 5, P=.039, end of treatment P=.029). For the placebo treatment group, improvement was statistically significant only at the end of treatment (P=.005).	No a priori sample size calculation or justification reported. Authors stated: 1) “Preliminary and explorative comparison study”. 2) “Small sample size” 3) Enhanced placebo effect of rTMS due to its “impressive name, its ability to cause involuntary movements as if by magic, its discomfort, and its bulky and sophisticated looking equipment.” 4) “Results of preliminary data points to the necessity of further research to be able to answer the still open questions regarding stimulation procedures of rTMS, location of stimulation and of the number of treatment sessions.”
2003 Nahas et al.(12) United States	To determine the safety feasibility and potential efficacy of using TMS to treat the depressive symptoms of bipolar affective disorder (BPAD).	23 depressed BPAD patients (12 BPI depressed state and 9 BPII depressed stated, 2 BPI mixed state) were enrolled. Patients assigned using “an urn randomization based on age and gender) to receive daily LDLPFC rTMS (5 Hz, 110% MT, 8 sec on, 22 sec off over 20 min) or placebo (coil angled 45 degrees off head) each weekday morning for 2 weeks. Blinded HDRS and Young Mania Rating Scales (YMRS) obtained weekly. Patients could take carbamazepine or valproate but eth dose had to be stable for 2 weeks prior to beginning treatment with persisting depression. All other psychotropic medications (especially antidepressants) were tapered over a 2 week washout period, longer for fluoxetine). Patients on lithium and lamotrigine were also excluded. Primary outcome variable: percentage change in HDRS at 2 weeks compared with day 1 of treatment (clinical response defined as >50% decline in HDRS or <10). Following last day of the 2 week period, the blind was broken for each patient. Patients initially randomized to placebo were offered the option of 2 weeks of active treatment at the same parameters. Treatment responders to either the active or later open TMS phase were offered the option of weekly maintenance TMS treatments over the next year. Figure-8 coil.	11 patients received rTMS. All patients guessed their status based on their clinical response (all responders guessed they were receiving active TMS and all clear nonresponders guessed placebo). No adverse cognitive effects of the TMS as measured by subjective complaints. No drop outs from the study. No patients stopped the study as a result of hypomania or mania and active rTMS did not cause a statistically significant within group increase in the YMRS (P=.49). 4/11 active TMS patients were responders. 4/12 placebo TMS patients were responders. Each group had one “remitter”. There was no significant difference between the 2 groups in HDRS change from baseline over the 2 weeks (P=.83). Mean % change in HDRS was 25% (SD, 32%) for the active TMS and 25% (SD, 31%) for the placebo TMS.	No a priori sample size calculation or justification reported. Small sample size. Two weeks duration. Only 2 week drug washout period. High placebo response.
2002 Boutros et al.(63) United States	“To provide efficacy and safety data for use of subthreshold rTMS as an augmentation strategy in treatment refractory depressed patients without any modifications on their current pharmacological therapy in a double-blind randomized fashion.”	22 patients diagnosed with MDD. Patients had to have failed 2 prior medication attempts. A score of at least 20 on the HDRS was required. Patients randomized into either placebo or active rTMS. Patients assessed at days 3, 5, 6, 8, and 10. A research assistant blinded to the treatment administered the depression score testing. Unblinded psychiatrist administered the rTMS. Blind broken following treatment #10. Following completion of the placebo course, patients were offered open label active rTMS. Treatment consisted of 10 left sided stimulation sessions administered over 10 consecutive weekdays. Each session consisted of 20, 2sec stimulation trains, with a 20 Hz frequency applied over 20 min with 58 second intervals between trains. Stimulations were delivered at 80% MT. Figure-8 coil. During placebo, the coil was angled 90 degrees to the head.	One patient dropped out of placebo rTMS after the first session – data from that patient was excluded from the analysis. 12 patients were randomized to receive active rTMS and 9 to placebo. There was no statistically significant difference between HDRS scores at baseline between the 2 groups. Analyses performed included a comparison between the HDRS scores following the last treatment with baseline as a covariate (ANCOVA). No difference between the 2 groups was found. A repeated measures ANOVA found that the slope associated with depression over time did not differ significantly between the 2 groups but a significant time effect (P=.001) occurred. Patients in both groups reported adverse effects (8 in active and 5 in placebo). Most frequent complaint was headache during o rafter the session. 3 patients in the active and 1 in the placebo reported transient scalp tenderness.	No a priori sample size calculation or justification reported. “Sample size used in the study was small”. Two week randomized duration.
2002 Padberg et al.(13) Germany	To test the hypothesis that antidepressant efficacy of rTMS is related to the stimulation intensity applied.	Parallel design controlled study of 31 patients with MDD who were pharmacotherapy resistant prior to rTMS. Patients randomized into a 2 week trial of LDLPFC rTMS either at 100% MT intensity (n=10) at 90% MT (n=10) or at a low intensity placebo condition (n=10). One patient dropped out due to withdrawal of consent after the second rTMS session. The dosage of the current unsuccessful antidepressant treatment was kept constant for at least 3 weeks prior to rTMS. Patients were examined by a psychiatrist uninvolved in rTMS treatment and blinded to the rTMS condition. Placebo was angled 90 degrees to the head. A 7 point clinical global impression (CGI) of severity scale was used as overall outcome measure. Figure-8 coil.	No significant differences were found between the groups for baseline HDRS, MADRS or CGI scores. Across treatment groups, depression scores significantly declined during rTMS (P<.001). The main effect of treatment group was not significant. Interaction of treatment group with time was significant for MADRS scores (P<.05) but not for HDRS scores. The linear effect on MADRS difference scores was significant (P<.05). Expressed in percent decrease of MADRS scores, placebo yielded a 4.1% (SE 5.2) reduction, 90% MT resulted in 15.1% (SE 6.6) decrease and 100% MT reduced MADRS scores by 33.2% (SE 8.9) The linear effect on HDRS scores showed was not statistically significant. Percent reductions of HDRS scores were 7.1% (SE 5.8) after placebo rTMS, 14.9% (SE 8.9) after 90% MT and 29.6% (SE 8.7) after 100% MT. One way ANOVA showed significant differences between groups for both duration of the hospital stay (P<.05) and the number or required antidepressant trials after rTMS (P<.001). No severe adverse effects of rTMS were observed.	No a priori sample size calculation or justification reported. “Small sample size”. “Regard findings as preliminary”.
2002 Conca et al.(65) Austria	To investigate the augmentation properties of rTMS combining low and high frequencies.	Recruited 36 severely depressed medicated in patients. Medication conditions defined using the classification of Thase and Rush (1995) – all patients had to be classified at stage 4 of treatment resistance indicating the failure to respond to 2 different adequate monotherapy trials of medications with different pharmacological profiles and the failure to respond to a 2nd augmentation strategy. Psychiatrists blinded to treatment methods completed the 21 item HDRS 1 day before the first treatment and 1 day after completion and 1 day after completion of the rTMS course. For inclusion, a minimum score of ≥24 had to be achieved. Clinical Global Improvement (CGI) completed 1 day after rTMS. Patients remained on the last prescribed pharmacotherapy. Patients randomly assigned to 3 different rTMS treatment modalities while on stable drugs for 5 consecutive days. rTMS administered on 5 consecutive days at 1 session/day. Group 1 (n=12) = 110% MT, 10Hz, 10 trains, train duration 10 seconds, each with a train interval of 60 seconds over the LDLPFC. Over the RDLPFC: 110% MT at 1 Hz, 1 train at 300 seconds. Group 2 (n=12) = only the LDLPFC was stimulated at 110% MT, 10Hz, 10 second train duration alternating with 110% MT, 1 Hz, 30 second train, with an interval of 6 seconds for 10 times/session. Group 3 (n=12) = standard stimulation over LDLPFC using 110% MT, 10 Hz, 13 train and 10 second train duration. Therapeutic outcome measurement was based on CGI scores. Patient response was defined as achieving at least moderate improvement (CGI improvement score >4) and being no more than mildly ill (CGI severity score <4). Figure-8 coil.	No statistical differences in clinical outcome between the groups. None of the demographic, illness, diagnosis, or co-diagnosis related data revealed any influence on the response rate except for handedness; right handed patients showed a weak statistical tendency to greater therapeutic response (non responders vs responders, P<.08). No seizures were observed. 7/36 patients (19.1%) experienced a mild headache during the first session which remitted spontaneously.	No a priori sample size calculation or justification reported. Small sample size “Preliminary findings”. No control group
2003 Schule et al.(68) Germany	To examine whether antidepressant pharmacotherapy can stabilize clinical improvement after rTMS monotherapy	26 drug-free patients. Open trial over 2 weeks 10-13 sessions, 10 Hz, 15 trains (each 10 seconds) with 30 second intertrain intervals) LDLPFC at 100% MT. Patients followed-up during standardized antidepressant pharmacotherapy with mirtazapine for a further 4 weeks. Severity of depression assessed using 21 item HDRS. Ratings performed before rTMS treatment (day 0) and after one week (day 7) and after 2 weeks of rTMS (day 14). Raters were not involved in rTMS treatment. Response to rTMS was defined by a reduction of at least 50% of the HDRS score after 2 weeks of rTMS compared to baseline. An overall response (rTMS followed by mirtazapine treatment) week 0-6) was defined by a decrease of at least 50% in the HDRS score after 6 weeks compared with baseline (week 6 response). Remission was defined as a HDRS score of 9 or less after 2 weeks or 6 weeks respectively.	10/26 (39%) of patients responded to rTMS by at least 50% reduction in the HDRS. 23% (6/26) were remitters (HDRS score ≤9). During subsequent antidepressant treatment, response and remission rates were further increased: after week 6, 77% of the patients (20/26) achieved clinical remission. The differences in the HDRS scores between rTMS responders and nonresponders became significant (P<.05) after 1 week of rTMS monotherapy and were observed up to the 2nd week of mirtazapine treatment. After 3 weeks of drug therapy, there were no more significant differenced between rTMS responders and nonresponders. 69% of the rTMS nonresponders (11/16) converted into 6-week responders. rTMS responders and nonresponders did not differ in severity of depressive symptoms at baseline, number of depressive episodes, and number of failed antidepressant trials during the current episode and duration of the current episode. Week-6 responders and nonresponders were comparable n baseline HDRS scores and number of depressive episodes. However, week-6 nonresponders were characterized by a significantly higher number of failed antidepressant trials before entering the study (P=.025) and a significantly longer duration of the current episode (P=.037) compared with week-6 responders. A significant deterioration of depressive symptoms occurred between the last rTMS treatment and the first administration of mirtazapine in rTMS responders (P=.002), but not in rTMS nonresponders (P=.375). An overall low but significant correlation (P=.025) between worsening on the HDRS score and duration of treatment interruption. The deterioration in rTMS responders was reversible in most cases: 9/10 rTMS responders showed an at least stabilized course during subsequent mirtazapine treatment (week 3-6). One rTMS responder became worse during pharmacotherapy.	No a priori sample size calculation or justification reported. No control group. Open study design. Half of the patients also received lithium, carbamazepine, or neuroleptics.
2003 Herwig et al.(69) Germany	To investigate the efficacy of neuronavigated rTMS guided according to the prefrontal metabolic state determine by PET.	Double-blind randomized placebo controlled pilot study 25 patients with MDD. 13 patients rTMS 12 patients placebo. Prior to rTMS, PET scans obtained. For stimulation, the DLPFC with lower metabolic activity compared to the contralateral hemisphere was selected. Stimulation parameters 15 Hz, 110% MT. A neuronavigational system (navigate the coil according to individual anatomy visualized by MRI) was used to place the magnetic coil above each individuals selected cortical region (active treatment: DLPFC; placebo treatment: midline parieto-occipital, intensity 90% of MT). rTMS was administered as an add-on to drugs. Depression related symptoms rated with BDI, HDRS, and MADRS scales. Responders were defined by a 50% reduction of the mean of the HDRS and MADRS ratings. Double blind=neither the raters nor the patients were informed about the stimulation condition. Ratings performed 5 times: Before stimulation After 4 stimulations After 7 stimulations At the end of the stimulation sessions and In responders 2 weeks after the stimulations sessions. Figure-8 coil.	Severe adverse effects not observed. Initial rating scores of the placebo and real stimulated patients did not differ between the groups. There were significant differences between the placebo and active stimulation groups in terms of the relative changes in scores (at the end of stimulations compared with the initial scores normalized to 100%) in percent in HDRS (P=.002) and MADRS (P<.001) but not for the self rating BDI (P=0.1). Responder rate=4/13 in active treatment group and 0/12 in the placebo group. The ratings performed 2 weeks after the stimulation sessions in the 4 responding real stimulated patients showed a persisting effect with a mean HDRS of 48% and mean MADRS of 44% of the initial rating scores. Authors concluded “preliminary results indicate that rTMS of prefrontal hypometabolism may not be advantageous to stimulation irrespective of the metabolic state.”	No a priori sample size calculation or justification reported. Not directly tested if the navigational approach led to better outcome than at the “5 cm rule”. “small sample size”