Repetitive transcranial magnetic stimulation: a putative add-on treatment for major depression in elderly patients

Psychiatry Research 126 (2004) 123 133 Repetitive transcranial magnetic stimulation: a putative add-on treatment for major depression in elderly patients a b c d Urs P. Mosimann, Wolfgang Schmitt, Benjamin D. Greenberg, Markus Kosel, e b e b Rene M. Muri, Magdalena Berkhoff, Christian W. Hess, Hans U. Fisch, d, Thomas E. Schlaepfer * a Institute for Ageing and Health, Newcastle General Hospital, Newcastle upon Tyne NE4 6BE, UK b Department of Psychiatry, Inselspital, Murtenstrasse 21, 3010 Bern, Switzerland c Department of Psychiatry and Human Behavior, Brown University School of Medicine, Providence, RI, USA d Department of Psychiatry, University Hospital, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany e Department of Neurology, Inselspital, Murtenstrasse 21, 3010 Bern, Switzerland Received 29 January 2003; received in revised form 1 October 2003; accepted 12 October 2003 Abstract Repetitive transcranial magnetic stimulation (rtms) is a recent putative treatment for affective disorders. Several studies have demonstrated antidepressant effects of rtms in younger patients; we aimed to assess its effect in older outpatients with treatment-resistant major depression. Twenty-four outpatients (mean ages62 years, S.D.s12) with major depression were randomized for sham or real stimulation and received 10 daily rtms sessions (20 Hz, 2-s trains, 28-s intertrain intervals, 100% of motor threshold) in addition to the antidepressant medication. For sham stimulation, the coil was tilted 908. Depression severity was assessed using the Hamilton Depression Rating Scale, the Beck Depression Inventory, items from the NIMH self-rated symptom scale, and a visual analog depression scale. Mini-Mental Status Examination performance, memory, and executive and attentional functions were measured to control for cognitive side effects. Depression ratings revealed significant antidepressant effects within 2 weeks in both sham and real stimulation groups; however, there were no between-group differences. Treatment with rtms was safe; adverse events were rare and not more prevalent in either group, and cognitive assessment did not show any deterioration. We were unable to demonstrate any additional antidepressant effects of real stimulation in elderly patients with treatment-resistant major depression. Therapeutic effects of rtms in this clinically challenging patient group remain to be demonstrated. 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Major depression; Antidepressant treatment; Cognition; Age; Geriatric depression *Corresponding author. Tel.: q49-228-287-5715; fax: 49-228-287-5025. E-mail address: schlaepf@jhmi.edu (T.E. Schlaepfer). 0165-1781/04/$ - see front matter 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.psychres.2003.10.006

124 U.P. Mosimann et al. / Psychiatry Research 126 (2004) 123 133 1. Introduction Studies of repetitive transcranial magnetic stimulation (rtms) are of considerable interest for the understanding of the basic neurophysiology of mood generation and modulation. The first observation that transcranial magnetic stimulation might lead to mood alterations in healthy volunteers is more than a decade old (Bickford et al., 1987) and has been followed by numerous studies (for reviews, see Wassermann and Lisanby, 2001; Martin et al., 2003). Antidepressant properties of rtms applied to the dorsolateral prefrontal cortex of depressed patients have been reported in controlled studies (Pascual-Leone et al., 1996; George et al., 1997; Klein et al., 1999; Loo et al., 1999; Padberg et al., 1999; Berman et al., 2000; George et al., 2000). All but one study found acute phase antidepressant effects (Loo et al., 1999). The comparison of these studies is difficult due to heterogeneous patient populations with respect to age and diagnosis and variable stimulation intensities and frequencies. Most authors used focal coils and applied rtms at high frequency ()1 Hz) to left dorsolateral prefrontal cortex (DLPFC). Some studies used stimulation intensities above motor threshold ()100% of motor threshold)(e.g. Loo et al., 1999), whereas others used stimulation intensities below motor threshold (e.g. Berman et al., 2000). The very few studies assessing rtms effects in relatively older patients were inconclusive with respect to antidepressant properties but point to a lesser effect than in younger patients (Figiel et al., 1998; Padberg et al., 1999). The explanation for this difference is not clear. Figiel et al. (1998) assumed that lesser antidepressant effects might be related to structural brain changes, often found in older depressed patients (Dahabra et al., 1998). An effective treatment for elderly depressed patients is urgently required, as conventional pharmacological strategies are often hampered by drug resistance, intolerance, and interactions that may lead to protracted, chronic courses with incomplete remission (Thomas et al., 2003). Electroconvulsive therapy (ECT) is commonly used as a non-pharmacological antidepressant treatment (Manly et al., 2000) but requires anesthesia. Recent studies (Janicak et al., 2002; Grunhaus et al., 2003) suggested similar antidepressant effects of ECT and rtms, and there is some evidence that rtms may be associated with less amnestic impairment (Little et al., 2000; Kosel et al., 2003; O Connor et al., 2003) than that associated with ECT. If this is confirmed for elderly patients, it will have important clinical implications, because age is a risk factor for cognitive impairment and the development of degenerative brain disorders. The aim of this sham-controlled, parallel-group study was to investigate antidepressant properties of rtms in relatively elderly depressed outpatients with treatment-resistant major depression and to monitor carefully for cognitive effects, both positive and negative, during treatment. To investigate a spectrum of different ages, patients aged 40 90 years were included. High frequency real or sham rtms was applied daily over 2 weeks to the left DLPFC. 2. Methods 2.1. Subjects Twenty-four patients were randomly included in either a sham or a real stimulation group and received 10 rtms sessions on 2= five consecutive workdays within 2 weeks. To be eligible for the study, patients had to be in the age range of 40 90 years and fulfill criteria for treatment-resistant major depression (DSM-IV, ICD-10) (American Psychiatric Association, 1994). Diagnoses were obtained from an in-depth clinical interview using sections 6, 7 and 8 of the Schedules for Clinical Assessment in Neuropsychiatry (SCAN) (World Health Organization, 1995). Treatment resistance was defined as follows: Patients needed to have been treated with at least two different antidepressant drugs in adequate dosage and duration, during the present episode of depression, without any response. Patients received rtms in addition to antidepressant medication, dosage had to remain stable for at least 2 weeks, and no new antidepressant drugs were allowed within the preceding 6 weeks. Exclusion criteria were current or past history of head injury, epilepsy, comorbid unstable medical or neurological illness or, for women,

U.P. Mosimann et al. / Psychiatry Research 126 (2004) 123 133 125 absence of reliable methods of birth control. Fortytwo outpatients, referred from general practitioners or psychiatrists, were evaluated. Eighteen patients were excluded before randomization mainly because of depressive symptoms due to other psychiatric disorders (i.e. dysthymia, ns10; obsessive-compulsive disorders, ns2; borderline personality disorder, ns2) and one patient because of unstable cardiac disease. Two patients incorrectly believed that they would receive TMS in a complementary medicine setting, and one was unable to travel 210 km from his home every day. The institutional ethical review board of the medical faculty of the University of Bern approved the study and all randomized patients provided written informed consent. Safety guidelines of the International Society of Transcranial Magnetic Stimulation (ISTS) were followed (Wassermann, 1998). Outcome ratings were assessed on a different floor of the building by a blinded rater (WS), who had no contact with the person applying the stimulations. Adverse events were assessed by open questions after the stimulation. 2.2. Assessment of severity of depression Severity of depression was assessed using four different depression scales. The 21-item Hamilton Depression Rating Scale (HAMD-21; Hamilton, 1960) was the primary outcome measure; the Beck Depression Inventory (BDI-21; Beck, 1987), depression items (1, 6, 15, and 18) from the NIMH self-rated symptom scale (NIMH scale), and a visual analogue scale (VAS) were secondary depression self-ratings. The HAMD-21 was applied before the first and after the last stimulation. For safety reasons, self-ratings were repeated after the fifth stimulation before the first weekend to detect disease progression or newly developed suicidal ideations. Subjects who showed G50% or G30% improvement in their HAMD ratings 2 weeks after baseline were classified as responders and partial responders, respectively. 2.3. Neuropsychological assessment Neuropsychological tests were used to assess cognitive function before the first and after the last stimulation. Test selection was theoretically motivated and included the assessment of global cognitive function (Mini-Mental-State Examination (MMSE; Folstein et al., 1975), and the measurement of verbal memory (i.e. learning, recall and recognition) with a verbal learning task (VLT; Oswald and Fleischmann, 1995). As the DLPFC was the target area of stimulation, three different tasks assessing frontal executive functions were used: the Stroop test (Stroop, 1935), Trail-Making Tests A and B (Trail AyB; Reitan, 1958), and a word fluency test (Fluency; Thurstone and Thurstone, 1962). 2.4. Stimulation parameters A Magstim rapid stimulator (Magstim Company Limited, Sheffield, UK) with a figure 8-shaped air-cooled coil was used for stimulation. All stimulations (sham and real) were applied to the left DLPFC, which was defined, as in previous studies, as the location 5 cm anterior to the location where motor evoked potentials were optimally elicited in the right abductor pollicis brevis muscle and where the motor threshold (MT) was measured (Pascual- Leone et al., 1996). Muscle contractions were observed visually, and no stereotaxic apparatus was used to determine stimulation localization. The coil used to assess MT and stimulate the DLPFC was the same. Motor threshold was determined daily before the stimulation in both groups, and most stimulations were done by the same person (UPM). During stimulations, patients were sitting upright in a comfortable armchair and the physician applying rtms was sitting behind the patient. For sham stimulation, the figure 8-shaped coil was turned 908, with the coil edge on the left DLPFC. Stimulation intensity was 100% of MT at 20 Hz, train duration was 2 s and inter-train interval was 28 s. Forty trains (1600 pulses) were applied in a 20-min session. 2.5. Statistics Data were analyzed for normal distribution (Kolmogorov Smirnov test). Since no significant deviation from normal distribution was found, means and standard deviations (S.D.) were report-

126 U.P. Mosimann et al. / Psychiatry Research 126 (2004) 123 133 Table 1 Demographics Real rtms Sham rtms Statistics (ns15) (ns9) Female:male 5:10 5:4 *N.S. Age (years) 60.0 (13.4) 64.4 (13.0) **N.S. Education (years) 13.2 (1.4) 13.0 (1.3) **N.S. Duration of current episode (years) 1.3 (2.0) 2.2 (2.8) **N.S. Age at onset (years) 35.9 (16.7) 52.8 (14.0) **Ps0.02 Number of previous episodes 6.9 (5.4) 4.2 (7.9) **NS Standard deviation (S.D.); *Fisher s exact t-test; **independent sample t-tests, N.S., non-significant. ed and parametric tests were used. Demographic data were compared with independent sample t- tests or Fisher s exact t-tests, respectively. Baseline ratings were compared with independent sample t- tests. Pearson correlations were used for correlation analysis, and repeated measures analyses of variance (ANOVAs) were used to assess changes of depression or cognition during treatment and between the groups. 3. Results 3.1. Demographics Table 1 summarizes the demographic data. There were no exclusions from the study after randomization. Groups did not differ with respect to age, gender, education, duration of the current episode or the number of previous episodes. Patients in the sham stimulation group were older at onset of the first episode (independent sample t-test, two-tailed: ts2.5, d.f.s22, Ps0.02). Table 2 presents an overview of individual patient characteristics. All but one patient in the sham stimulation group was treated with antidepressants. Seven patients were treated with a combination of antidepressants, and 10 patients additionally received mood stabilizers, mainly lithium-acetate. 3.2. Efficacy At baseline, independent sample t-tests did not reveal any significant differences in all depression ratings (independent sample t-tests: N.S.) (Table 3). The mean HAMD-21 reduction was 20% (S.D.s17) in the real stimulation group and 17% (S.D.s15) in the sham stimulation group. All depression ratings showed an improvement of depressive symptoms after 10 stimulations, but there were no significant within-group effects. Correlations between the self-ratings and the observer ratings were high (HAMD-BDI: rs0.67, P-0.01; HAMD-NIMH scale: rs0.52, P-0.05; HAMD-VAS: rs0.44, P-0.05). Change of HAMD-21 rating did not correlate with patients age or duration of the current episode (all Pearson correlations). Fig. 1 shows individual HAMD-21 changes (%) for each subject in the sham and real stimulation groups. Four patients (26.6%) receiving real stimulations were either responders (i.e.)50% decrease) or partial responders (i.e.)30% decrease). There were no responders in the sham stimulation group, but two patients responded partially (22.2%). Two of the responding patients in the real group had bipolar disease courses, and the two partial responders in the sham stimulation group were the oldest study participants (78 and 80 years old, respectively). Table 2 contains demographic details for these patients. The two groups did not differ with respect to response rate (Fisher s exact t-test: N.S.). 3.3. Adverse events Seven patients (47%) in the real stimulation group and five (56%) in the sham group reported adverse events. Table 2 presents an overview of adverse events.

U.P. Mosimann et al. / Psychiatry Research 126 (2004) 123 133 127 Table 2 Patients additional treatment, efficacy and adverse events GenderyAge Diagnosis Medication Mood stabiliser Stimulation Efficacy Adverse event Female, 75 MD-uni-recur Mianserin None Real NR Crying Female, 50 MD-uni-recur Citalopramynefazodone Lithium-acetate Real NR Crying Male, 41 MD-uni-recur Mianserinyvenlafaxine Lithium-acetate Real NR None Male, 69 MD-bip2 Citalopram Lithium-acetate Real R Suicidal ideations Male, 58 MD-uni-recur Maprotiline None Real PR Metallic taste Female, 79 MD-single Citalopramyclomipramine None Real PR None Female, 71 MD-uni-recur Trimipramine None Real NR None Female, 75 MD-uni-recur Citalopram None Real NR Conjunctivitis Female, 68 MD-bip1 Nefazodone Lithium-acetate Real NR None Female, 57 MD-uni-recur Fluoxetineytrimipramine None Real NR Nausea Female, 50 MD-uni-recur Paroxetine Lithium-acetate Real NR None Male, 42 MD-bip1 Sertaline None Real PR Toothache Female, 51 MD-uni-recur Paroxetineymianserin Sodium-valproate Real NR None Female, 41 MD-uni-recur Maprotiline Lithium-sulfate Real NR None Male, 69 MD-bip1 Trimipramine Sodium-valproate Real NR None Male, 55 MD-uni-recur Imipramine Lithium-acetate Sham NR Headache Female, 76 MD-single Moclobemide None Sham NR Dizziness Male, 80 MD-uni-recur Citalopramymianserin None Sham PR None Female, 51 MD-uni-recur Venlaflaxinyamitriptyline None Sham NR Nausea Male, 51 MD-uni-recur Citalopram None Sham NR Headache Female, 49 MD-single Mianserin None Sham NR Nausea Female, 78 MD-uni-recur Moclobemide None Sham PR None Female, 75 MD-single None None Sham NR None Male, 65 MD-uni-recur Mianserin None Sham NR None MD, major depression; course, uni (unipolar); bip1 (bipolar 1); bip2 (bipolar 2); recur (recurrent); single (single episode); NR, non-responder, PR, partial responder (30% HAMD reduction), R, responder (50% HAMD reduction). 3.4. Neuropsychological assessment Baseline neuropsychological ratings did not differ between the sham and real stimulation groups (MMSE, memory score, word fluency, trail-making and Stroop interference) (independent sample t-tests: N.S.). Table 4 summarizes the neuropsychological test scores. A detailed analysis of memory sub-scores showed that recognition abilities of sham-treated patients were poorer at baseline (ttest: tsy2.6, d.f.s10.1, Ps0.027). In both groups, free recall was significantly poorer compared with recognition in the verbal memory task (dependent sample t-tests: P-0.001 for baseline and after the 10th stimulation). Global cognitive performance (MMSE) did not change between baseline and the end of the study. Patients word fluency improved, but again there were no signif- Table 3 Depression ratings Real rtms Sham rtms Repeated measures ANOVA BL Mid End BL Mid End Within Between HAMD-21 28.5 (4.6) 23.3 (7.2) 24.5 (7.3) 20.4 (6.6) Fs33, d.f.s1, P-0.0001 N.S. BDI-21 29.9 (9.1) 26.7 (10.8) 24.3 (13.1) 28.1 (10.7) 24.6 (12.7) 23.4 (11.0) Fs10, d.f.s2, P-0.0001 N.S. NIMH scale 18.1 (3.9) 16.0 (4.9) 12.9 (7.5) 17.3 (4.4) 15.1 (7.0) 14.1 (7.2) Fs9, d.f.s2, Ps0.001 N.S. VAS 74.5 (15.8) 64.5 (20.7) 59.6 (25.4) 67.8 (18.5) 60.3 (13.3) 59.4 (21.2) Fs 4, d.f.s2, Ps0.042 N.S. Mean and standard deviation (S.D.); BL, Baseline; Mid, after 5th stimulation before the first weekend; End, after 10th stimulation.

128 U.P. Mosimann et al. / Psychiatry Research 126 (2004) 123 133 Fig. 1. Change from baseline (%) on the Hamilton Depression Rating Scale (HAMD). Each bar represents one patient s HAMD- 21 change in percentage. Negative values indicate a decrease of the initial rating, positive values an increase. The dotted vertical line indicates 30% decrease (partial responder), and the bold line 50% decrease (responder). icant between-group effects. Performance on the Stroop and Trail-Making tests did not change during the study and did not differ between the groups (repeated measures ANOVA: N.S.). 4. Discussion This parallel group study assessed effects of rtms applied to the left DLPFC as an add-on treatment to medication in elderly drug-resistant depressed patients. In both the real and sham rtms groups, depression improved in the range of 17 20% from baseline in observer ratings and selfratings after 10 stimulation sessions. However, real rtms did not have any additional antidepressant effects compared with sham rtms. This finding is in agreement with one previous controlled study (Loo et al., 1999) but in disagreement with most previous reports (Pascual-Leone et al., 1996; George et al., 1997; Klein et al., 1999; Padberg et al., 1999; Berman et al., 2000; George et al., 2000). Unfortunately, different stimulation parameters, different patient populations, and different study designs make comparisons with some of these studies difficult. Four reports are comparable to the present study with respect to study duration, stimulation site, localization and coil design (George et al., 1997, 2000; Loo et al., 1999; Berman et al., 2000) (Table 5). These studies found HAMD decreases after 2 weeks of stimulation of the left DLPFC in the range of 23 30% (Fig. 2). The 20% change in HAMD scores from baseline in the real stimulation group of our study approaches this range. A limitation of all previous studies and the present study is that sample sizes are relatively small and observation periods short. We observed older, treatment-resistant patients (meansage 62) and assessed rtms as an add-on to long-term antidepressant therapy. Patients in most previous

U.P. Mosimann et al. / Psychiatry Research 126 (2004) 123 133 129 Table 4 Neuropsychological ratings MMSE Real rtms Sham rtms Repeated measures ANOVA BL End BL End Within Between Verbal learning task 28.4 (1.6) 28.5 (1.7) 27.7 (2.3) 28.2 (1.9) N.S. N.S. (number of words) Learning 7.1 (0.9) 7.0 (0.9) 6.3 (1.8) 6.6 (0.9) Recall 4.4 (2.5) 3.8 (2.5) 3.3 (2.1) 2.6 (1.6) Recognition 7.4 (1.0) 7.6 (0.6) 5.4 (2.1) 6.3 (1.5) Total memory score 18.9 (3.8) 18.4 (3.2) 15.1 (5.3) 15.4 (3.1) N.S. N.S. FAS word fluency 19.7 (8.7) 22.7 (7.5) 23.0 (9.3) 27.6 (10.5) Fs7, d.f.s1, Ps0.01 N.S. (number of words) Trail-Making Test (time required s) Part A 45.5 (23.4) 39.6 (15.7) 67.4 (50.6) 58.3 (35.3) Part B 134.6 (59.7) 105.4 (55.1) 154 (73.2) 143 (68.8) Interference (B-A) 93.4 (50.4) 65.8 (44.2) 86.6 (58.1) 84.6 (50.0) N.S. N.S. Stroop Test (time required s) Part 1 17.0 (4.1) 14.9 (3.8) 18.9 (12.1) 21.2 (15.2) Part 2 25.0 (4.7) 23.1 (5.8) 28.6 (12.2) 27.9 (10.9) Part 3 52.4 (23.0) 48.1 (21.1) 58.8 (24.7) 50.8 (21.2) Interference (Part 3-2) 27.4 (19.8) 25.0 (17.1) 30.1 (16.2) 22.9 (15.1) N.S. N.S. Mean and standard deviation (S.D.); BL: Baseline; End: after the 10th stimulation. studies were 15 20 years younger, and one study (Berman et al., 2000) included patients free of antidepressant medication. Published reports were inconclusive regarding the antidepressant effect of rtms in elderly patients but pointed to a lesser effect (Figiel et al., 1998; Padberg et al., 1999). Although we did not find a correlation between age and depression ratings in the real stimulation group, this study adds further support to the finding. However, we cannot exclude that a delayed antidepressant response to real rtms in older patients might be a reason for lack of efficacy. In addition, the present patient population may differ from previous studies with respect to treatment resistance, since we required at least two failed medication trials for the current episode for inclusion into the trial. As in previous studies, we used the DLPFC for stimulation. This localization is based on the historical observation of depression-related hypometabolism of the prefrontal cortex. A recent study (Herwig et al., 2003) determined the most hypometabolic cortical areas with positron emission tomography and repetitively localized this area using a stereotaxic coil-navigation system. We determined stimulation localization with the method initially described by Pascual-Leone et al. (1996) and, to keep variability of stimulation localizations low, most stimulations were applied by the same person. Controlled studies comparing antidepressant effects of patients in which stimulation localization was determined by a stereotaxic device vs. visually determined are lacking. We assessed the use of rtms antidepressant treatment as closely as possible to a real clinical setting. Any additional technical equipment required for the use of rtms in this stetting will potentially diminish its advantages (e.g. low costs) over other non-pharmacological treatments such as ECT. A study investigating younger patients failed to demonstrate a correlation between coil cortex distance and antidepressant response (Kozel et al., 2000). In contrast, we found a negative correlation of this distance with antidepressant outcome and believe that this could be one of the variables explaining the poorer antidepressant rtms response in elderly patients (Mosimann et al., 2002). A greater prefrontal cortex-scalp distance, in comparison with motor cortex-scalp distance, would result in less intensive prefrontal stimula-

Table 5 Summary of controlled high frequency rtms depression studies George et al. (1997) Loo et al. (1999) Berman et al. (2000) George et al. (2000) This study Design Crossover Parallel group Parallel group Parallel group Parallel group Duration 4 weeks* 2 weeks 2 weeks 2 weeks 2 weeks Site of L-DLPFC L-DLPFC L-DLPFC L-DLPFC L-DLPFC stimulation Sham stimulation Coil 458 Coil 458 Coil 30 458 Coil 458 Coil 908 Intensity (%MT) 80 110 80 100 100 Frequency (Hz) 20 10 20 20** 20 No. of trains 20 20 20 20 20 Train duration 2 5 2 2 2 Inter-train interval 28 30 58 28 28 Medication in Partial Yes No Yes Yes the study Medication resistance Yes Yes Yes Mostly Yes Real Sham Real Sham Real Sham Real Sham Real Sham N 7 5 9 9 10 10 10 10 15 9 Age 42 41 46 51 45 37 43 49 60 64 Observer rating HAMD-21 HAMD-17 HAMD-25 HAMD-21 HAMD-21 Baseline 30 26 22 25 37 37 30 24 29 25 End 23 30 17 21 25 36 22 19 23 20 Responders w%x 14 0 1 0 6 0 6 0 Adverse events w%x 6 3 1 10 46 56 *George et al. (1997), only the first 2 weeks before the crossover are included for comparison; **George et al. (2000), high frequency rtms only; MT, individual motor threshold; L-DLPFC, left dorsolateral prefrontal cortex. 130 U.P. Mosimann et al. / Psychiatry Research 126 (2004) 123 133

U.P. Mosimann et al. / Psychiatry Research 126 (2004) 123 133 131 Fig. 2. Antidepressant effects, i.e. mean HAMD change in % after 2 weeks of either sham or real stimulation to compare HAMD changes of the present with previous studies (George et al., 1997; Loo et al., 1999; Berman et al., 2000; George et al., 2000). tion, as MT-determined stimulation intensity and the magnetic field produced by the coil decrease exponentially with the distance from the coil (Bohning et al., 2000). This effect could lead to poorer antidepressant effects. In support of this view, it appears that higher stimulation intensity may have stronger antidepressant effects (Padberg et al., 2002) but is also associated with a higher risk of convulsions (Wassermann 1998), especially in elderly patients receiving antidepressant medication. The HAMD reduction of 17% from baseline in our sham stimulation is in the range of those reported in previous studies. The sham responses ranged from a HAMD increase of 15% (George et al., 1997) to a decrease of 21% (George et al., 2000). The variability in sham response may be related to different sham techniques (i.e. different skull coil angles) (Table 5). An ideal sham would produce negligible cortical stimulation in conjunction with an acoustic artifact and scalp sensation comparable to active stimulation. Loo et al. (1999) concluded that none of the sham coil positions investigated in their study met the criteria for an ideal sham. On one hand, sham stimulation with the coil angled 458 has the advantage of minimal muscular contractions and the drawback of some active stimulation of the underlying cortex. However, an angle of 908 does not induce muscular contractions and has the advantage of the lowest possible stimulation of underlying brain structures (Lisanby et al., 2001). The rtms setting itself may be associated with different non-specific treatment effects such as daily contact with a physician, daily traveling often accompanied by relatives, and patients expectations of treatment effects. Furthermore, in all rtms settings, the physician applying rtms knows whether he uses placebo or active stimulation and double-blindness can never be fully reached. As in previous studies (Nedjat et al., 1998), the use of rtms was safe. None of the patients had to be excluded after randomization and no serious adverse events were reported. The number of adverse events was similar in both real and sham treatment groups. Depressed patients suffer from state-dependent cognitive decline, and our patients showed depression-typical subcortical memory impairment, i.e. impaired free recall with good preservation of recognition (Austin et al., 2001). However, cognitive performance did not deteriorate during the study, and even improved in verbal fluency in both the sham and real stimulation groups. This finding supports previous studies that assessed long-term rtms cognitive effects in depressed patients (Speer et al., 2001; Martis et al., 2003) and did not find any deterioration. In conclusion, both real rtms and sham rtms stimulation of the left prefrontal cortex had antidepressant properties in outpatients with a mean age of 62 years; however, no significant betweengroup differences were found. Treatment with rtms was safe, in terms of adverse events and effects on cognitive function. Therapeutic effects of rtms in an older, treatment-resistant patient group still remain to be demonstrated. Large multicenter rtms depression trials with longer study durations are required because elderly patients could potentially benefit from this non-pharmacological treatment. Such studies are needed before it can be decided whether or not rtms can be added to the armamentarium of antidepressant treatments.

132 U.P. Mosimann et al. / Psychiatry Research 126 (2004) 123 133 Acknowledgments This project was funded by grants 4038-044046 and 3231-044523 from the Swiss National Science Foundation to Dr Schlaepfer. References American Psychiatric Association, 1994. Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Author, Washington, DC. Austin, M.P., Mitchell, P., Goodwin, G.M., 2001. Cognitive deficits in depression: possible implications for functional neuropathology. British Journal of Psychiatry 178, 200 206. Beck, A., 1987. Beck Depression Inventory: Manual. Psychological Corporation, San Antonio, TX. Berman, R.M., Narasimhan, M., Sanacora, G., Miano, A.P., Hoffman, R.E., Hu, X.S., Charney, D.S., Boutros, N.N., 2000. A randomized clinical trial of repetitive transcranial magnetic stimulation in the treatment of major depression. Biological Psychiatry 47, 332 337. Bickford, R.G., Guidi, M., Fortesque, P., Swenson, M., 1987. Magnetic stimulation of human peripheral nerve and brain: response enhancement by combined magnetoelectrical technique. Neurosurgery 20, 110 116. Bohning, D.E., Shastri, A., Wasserman, E.M., Ziemann, U., Lorberbaum, J.P., Nahas, Z., Lomarev, M.P., George, M.S., 2000. BOLD-fMRIresponse to single-pulse transcranial magnetic stimulation (TMS). Journal of Magnetic Resonance Imaging 11, 569 574. Dahabra, S., Ashton, C.H., Bahrainian, M., Britton, P.G., Ferrier, I.N., McAllister, V.A., Marsh, V.R., Moore, P.B., 1998. Structural and functional abnormalities in elderly patients clinically recovered from early- and late-onset depression. Biological Psychiatry 44, 34 46. Figiel, G.S., Epstein, C., McDonald, W.M., Amazon-Leece, J., Figiel, L., Saldivia, A., Glover, S., 1998. The use of rapidrate transcranial magnetic stimulation (rtms) in refractory depressed patients. Journal of Neuropsychiatry and Clinical Neurosciences 10, 20 25. Folstein, M., Folstein, S., McHugh, P., 1975. Mini-mental state. A practical method for grading the cognitive state of patients for the clinician. Journal of Psychiatric Research 12, 189 198. George, M.S., Wassermann, E.M., Kimbrell, T.A., Little, J.T., Williams, W.E., Danielson, A.L., Greenberg, B.D., Hallett, M., Post, R.M., 1997. Mood improvement following daily left prefrontal repetitive transcranial magnetic stimulation in patients with depression: a placebo-controlled crossover trial. American Journal of Psychiatry 154, 1752 1756. George, M., Nahas, Z., Molloy, M., Speer, A., Oliver, N., Li, X., Arana, G., Risch, S., James, C., Ballenger, J., 2000. A controlled trial of daily left prefrontal cortex TMS for treating depression. Biological Psychiatry 48, 962 970. Grunhaus, L., Schreiber, S., Dolberg, O.T., Polak, D., Dannon, P.N., 2003. A randomized controlled comparison of electroconvulsive therapy and repetitive transcranial magnetic stimulation in severe and resistant non-psychotic major depression. Biological Psychiatry 53, 324 331. Hamilton, M., 1960. A rating scale for depression. Journal of Neurology, Neurosurgery and Psychiatry 23, 56 61. Herwig, U., Lampe, Y., Juengling, F.D., Wunderlich, A., Walter, H., Spitzer, M., Schonfeldt-Lecuona, C., 2003. Addon rtms for treatment of depression: a pilot study using stereotaxic coil-navigation according to PET data. Journal of Psychiatric Research 37, 267 275. Janicak, P.G., Dowd, S.M., Martis, B., Alam, D., Beedle, D., Krasuski, J., Strong, M.J., Sharma, R., Rosen, C., Viana, M., 2002. Repetitive transcranial magnetic stimulation vs. electroconvulsive therapy for major depression: preliminary results of a randomized trail. Biological Psychiatry 51, 659 667. 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: a double-blind controlled study. Archives of General Psychiatry 56, 315 320. Kosel, M., Frick, C., Lisanby, S.H., Fisch, H.U., Schlapfer, T.E., 2003. Magnetic seizure therapy improves mood in refractory major depression. Neuropsychopharmacology 28, 2045 2048. Kozel, F.A., Nahas, Z., de Brux, C., Molloy, M., Lorberbaum, J.P., Bohning, D., Risch, S.C., George, M.S., 2000. How coil-cortex distance relates to age, motor threshold, and antidepressant response to repetitive transcranial magnetic stimulation. Journal of Neuropsychiatry and Clinical Neurosciences 12, 376 384. Lisanby, S.H., Gutman, D., Luber, B., Schroeder, C., Sackheim, H.A., 2001. Sham TMS: intracerebral measurement of the induced electrical field and the induction of motor-evoked potentials. Biological Psychiatry 49, 460 463. Little, J., Kimbrell, T., Wassermann, E., Grafman, J., Figueras, S., Dunn, R., Danielson, A., Repella, J., Huggins, T., George, M., Post, R., 2000. Cognitive effects of 1- and 20-hertz repetitive transcranial magnetic stimulation in depression: preliminary report. Neuropsychiatry, Neuropsychology and Behavioral Neurology 13, 119 124. Loo, C., Mitchell, P., Sachdev, P., McDarmont, B., Parker, G., Gandevia, S., 1999. Double-blind controlled investigation of transcranial magnetic stimulation for the treatment of resistant major depression. American Journal of Psychiatry 156, 946 948. Manly, D., Oakley, S.J., Bloch, R., 2000. Electroconvulsive therapy in old-old patients. American Journal of Geriatric Psychiatry 8, 232 236. Martin, J.L., Barbanoj, M.J., Schlaepfer, T.E., Thompson, E., Perez, V., Kulisevsky, J., 2003. Repetitive transcranial magnetic stimulation for the treatment of depression. Systematic review and meta-analysis. British Journal of Psychiatry 182, 480 491. Martis, B., Alam, D., Dowd, S.M., Hill, S.K., Sharma, R.P., Rosen, C., Pliskin, N., Martin, E., Carson, V., Janicak, P.G., 2003. Neurocognitive effects of repetitive transcranial mag-

U.P. Mosimann et al. / Psychiatry Research 126 (2004) 123 133 133 netic stimulation in severe major depression. Clinical Neurophysiology 114, 1125 1132. Mosimann, U., Marre, S.C., Werlen, S., Schmitt, W., Hess, C.W., Fisch, H.U., Schlaepfer, T.E., 2002. Antidepressant effects of repetitive transcranial magnetic stimulation in the elderly: correlation between effect size and coil-cortex distance. Archives of General Psychiatry 59, 560 561. Nedjat, S., Folkerts, H.W., Michael, N.D., Arolt, V., 1998. Evaluation of the side effects after rapid-rate transcranial magnetic stimulation over the left prefrontal cortex in normal volunteers. Electroencephalograpy and Clinical Neurophysiology 107, 96. O Connor, M., Brenninkmeyer, C., Morgan, A., Bloomingdale, K., Thall, M., Vasile, R., Leone, A.P., 2003. Relative effects of repetitive transcranial magnetic stimulation and electroconvulsive therapy on mood and memory: a neurocognitive risk benefit analysis. Cognitive Behavior and Neurology 16, 118 127. Oswald, W.D., Fleischmann, T. (Eds.), 1995. Nurnberger- Alters-Inventar (NAI). Hogrefe Verlag, Gottingen, pp. 148 176. Padberg, F., Zwanzger, P., Thoma, H., Kathmann, N., Haag, C., Greenberg, B.D., Hampel, H., Moller, H.J., 1999. Repetitive transcranial magnetic stimulation (rtms) in pharmacotherapy-refractory major depression: comparative study of fast slow and sham rtms. Psychiatry Research 88, 163 171. Padberg, F., Zwanzger, P., Keck, M.E., Kathmann, N., Mikhaiel, P., Ella, R., Rupprecht, P., Thoma, H., Hampel, H., Toschi, N., Moller, H.J., 2002. Repetitive transcranial magnetic stimulation (rtms) in major depression: relation between efficacy and stimulation intensity. Neuropsychopharmacology 27, 638 645. Pascual-Leone, A., Rubio, B., Pallardo, F., Catala, M.D., 1996. Rapid-rate transcranial magnetic stimulation of left dorsolateral prefrontal cortex in drug-resistant depression. Lancet 348, 233 237. Reitan, R., 1958. Validity of the Trail Making Test as an indicator of organic brain damage. Perceptual and Motor Skills 8, 271 276. Speer, A.M., Repella, J.D., Figueras, S., Demian, N.K., Kimbrell, T.A., Wassermann, E.M., Post, R.M., 2001. Lack of adverse cognitive effects of 1 Hz and 20 Hz repetitive transcranial magnetic stimulation at 100% of motor threshold over the left prefrontal cortex in depression. Electroconvulsive Therapy 17, 259 263. Stroop, J., 1935. Studies of interference in serial verbal reactions. Journal of Experimental Psychology 18, 643 662. Thurstone, L.L., Thurstone, T.G., 1962. Chicago Test of Primary Mental abilities. Science Research Associates, Chicago. Thomas, A.J., Perry, R., Kalaria, R.N., Oakley, A., McMeekin, W., O Brien, J.T., 2003. Neuropathological evidence for ischemia in the white matter of the dorsolateral prefrontal cortex in late-life depression. International Journal of Geriatric Psychiatry 18, 7 13. Wassermann, E.M., 1998. Risk and safety of repetitive transcranial magnetic stimulation: report and suggested guidelines from the International Workshop on the Safety of Repetitive Transcranial Magnetic Stimulation, June 5 7, 1996. Electroencephalograpy and Clinical Neurophysiology 108, 1 16. Wassermann, E.M., Lisanby, S.H., 2001. Therapeutic application of repetitive transcranial magnetic stimulation: a review. Clinical Neurophysiology 112, 1367 1377. World Health Organization, 1995. Schedules for Clinical Assessment in Neuropsychiatry, Version 2. Author, Geneva, Switzerland.