Acta Neuropsychiatr. 2015 Apr;27(2):119-25. doi: 10.1017/neu.2014.44. Epub 2015 Jan 13. A 2-year follow-up study of patients participating in our transcranial pulsating electromagnetic fields augmentation in treatment-resistant depression. Bech P1, Lindberg L1, Straasø B1, Larsen ER2. Author information
11Psychiatric Research Unit,Psychiatric Centre North Zealand,Copenhagen University Hospital,Hillerød,Denmark.
22Department of Affective Disorders,Mood Disorders Research Unit,Aarhus University Hospital,Denmark. Abstract
OBJECTIVE:
We have made a 2-year follow-up study to evaluate the effect of repeated transcranial pulsating electromagnetic fields (T-PEMF) augmentation in patients who had achieved remission but later on relapsed, as well as to identify factors contributing to treatment-resistant depression in patients who did not respond to T-PEMF.
METHODS:
Using the Longitudinal Expert Assessment of All Data approach the patients were classified in four groups: A: patients who achieved remission; B: patients with doubtful effect; C: patients with no effect; and D: patients who were hard-to-assess.
RESULTS:
In group A, comprising 27 patients, 13 had relapsed; they obtained a clear remission after a repeated course of T-PEMF augmentation. In group D, comprising 16 patients, we identified misdiagnostic factors both concerning the event of remission after the previous T-PEMF augmentation and concerning the aetiology (psychosocial stressors and co-morbid conditions). Compared with the other groups, the group D patients had a smaller number of previous episodes (p=0.09) and a longer duration of the current episode (p=0.01).
CONCLUSION:
T-PEMF has an effect among patients who relapsed after remission with the first series of T-PEMF. Treatment-resistant depression is a condition that has a high degree of multivariate problems. Misuse of alcohol or drugs, severe somatic disorders and other psychosocial problems may need other kinds of treatment before T-PEMF augmentation. Acta Neuropsychiatr. 2014 Oct 2:1-7. [Epub ahead of print]

The Diagnostic Apathia Scale predicts a dose-remission relationship of T-PEMF in treatment-resistant depression.

Bech P¹, Lunde M¹, Lauritzen L¹, Straasø B¹, Lindberg L¹, Vinberg M², Undén M¹, Hellström LC³, Dissing S⁴, Larsen ER⁵.

Author information

• ¹1Psychiatric Research Unit,Psychiatric Centre North Zealand,Copenhagen University Hospital,Hillerød,Denmark.
• ²2Department of Psychiatry,Psychiatric Centre Copenhagen,Copenhagen University Hospital,Copenhagen,Denmark.
• ³3Psychiatric Research Unit,Psychiatric Centre Copenhagen,Copenhagen University Hospital,Copenhagen NV,Denmark.
• ⁴4Department of Cellular and Molecular Medicine,Panum institute,University of Copenhagen,Copenhagen,Denmark.
• ⁵5Department of Affective Disorders,Mood Disorders Research Unit,Aarhus University Hospital,Aarhus,Denmark.

Abstract

OBJECTIVE:

The aim of this study was to evaluate the predictive validity of the apathy subsyndrome in patients with therapy-resistant depression in the dose-remission study with transcranial pulsating electromagnetic fields (T-PEMF).

METHODS:

The apathy subsyndrome consists of the symptoms of fatigue, concentration and memory problems, lack of interests, difficulties in making decisions, and sleep problems. We evaluated 65 patients with therapy-resistant depression. In total, 34 of these patients received placebo T-PEMF in the afternoon and active T-PEMF in the morning, that is, one daily dose. The remaining 31 patients received active T-PEMF twice daily. Duration of treatment was 8 weeks in both groups. The Hamilton Depression Scale (HAM-D17) and the Bech-Rafaelsen Melancholia Scale (MES) were used to measure remission. We also focused on the Diagnostic Apathia Scale, which is based on a mixture of items from the MINI and the HAM-D17/MES.

RESULTS:

In patients without apathy, the remission rate after T-PEMF was 83.9% versus 58.8% in patients with apathy (p?0.05). In patients without apathy receiving one active dose daily 94.4% remitted versus 50% for patients with apathy (p?0.05). In patients without apathy who received two active doses 69.9% remitted versus 66.7% for patients with apathy (p?0.05).

CONCLUSION:

Taking the baseline diagnosis of the apathy syndrome into consideration, we found that in patients without apathy one daily dose of T-PEMF is sufficient, but in patients with apathy two daily doses are necessary. Including the apathy syndrome as predictor in future studies would seem to be clinically relevant. Acta Neuropsychiatr. 2014 Oct;26(5):272-9. doi: 10.1017/neu.2014.5.

Dose-remission of pulsating electromagnetic fields as augmentation in therapy-resistant depression: a randomized, double-blind controlled study.

Straasø B¹, Lauritzen L¹, Lunde M¹, Vinberg M², Lindberg L¹, Larsen ER³, Dissing S⁴, Bech P¹.

Author information

• ¹1Psychiatric Research Unit,Psychiatric Centre North Zealand,Copenhagen University Hospital,Hillerød,Denmark.
• ²2Department of Psychiatry,Psychiatric Centre Copenhagen,Copenhagen University Hospital,Denmark.
• ³3Department of Affective Disorders,Mood Disorders Research Unit,Aarhus University Hospital,Denmark.
• ⁴4Department of Cellular and Molecular Medicine,Panum Institute,University of Copenhagen,Copenhagen,Denmark.

Abstract

OBJECTIVE:

To evaluate to what extent a twice daily dose of Transcranial Pulsating ElectroMagnetic Fields (T-PEMF) was superior to once daily in patients with treatment-resistant depression as to obtaining symptom remission after 8 weeks of augmentation therapy.

METHODS:

A self-treatment set-up of the T-PEMF device was used allowing self-administration by patients in own homes. All patients were treated for 30 min per T-PEMF session. The antidepressant medication the patients were receiving at baseline remained unchanged during the trial. The patients were randomised to either one T-PEMF dose (active dose in the morning and sham in the afternoon) or two T-PEMF doses (active dose both morning and afternoon) in a double-blind procedure. A score of 7 or less on the Hamilton Depression Scale (HAM-D17) was the criterion of remission.

RESULTS:

In total 34 patients received active T-PEMF once a day and 31 patients twice daily. After 5 weeks of therapy remission was obtained in 26.5% and 32.3% on one dose and two doses of T-PEMF, respectively. After 8 weeks the rate of remission was 73.5% and 67.7%, respectively. The side effects as measured by the Udvalget for Kliniske Undersøgelser scale showed a better toleration of the antidepresssive medication in both treatment groups, which was reflected by the WHO-5 well-being scale with increased scores in both groups of patients.

CONCLUSION:

The high remission rate obtained by the T-PEMF augmentation was not a dose effect (one versus two daily T-PEMF sessions) but was explained by the extension of the treatment period from 5 to 8 weeks.

Int Rev Psychiatry.  2011 Oct;23(5):400-12. doi: 10.3109/09540261.2011.614223.

The use of ECT and MST in treating depression.

Allan CL, Ebmeier KP.

Source

Department of Psychiatry, University of Oxford, Oxford, UK.

Abstract

Electroconvulsive therapy (ECT) has been used clinically since 1938. Its most common use is in the treatment of depression: first line treatment where rapid recovery is a priority, but more frequently as an effective treatment for patients who do not respond to pharmacological and psychological approaches. Whilst it is widely hailed as an effective treatment, concerns about its effect on cognition remain. The development of magnetic seizure therapy (MST) over the past decade has attempted to devise a therapy with comparable efficacy to ECT, but without the associated cognitive side effects. The rationale for this is that MST uses magnetic fields to induce seizures in the cortex, without electrical stimulation of brain structures involved with memory. MST has been used successfully in the treatment of depression, yet there is a dearth of literature in comparison with ECT. We present a systematic review of the literature on ECT (from 2009-2011) and MST (from 2001-2011).

Biol Psychiatry. 2010 Jul 15;68(2):163-9. Epub 2010 Apr 10.

Transcranial low voltage pulsed electromagnetic fields in patients with treatment-resistant depression.

Martiny K, Lunde M, Bech P.

Psychiatric Research Unit, Mental Health Center North Zealand, Hillerød, Denmark. Klaus.Martiny@regionh.dk

Abstract

BACKGROUND: Approximately 30% of patients with depression are resistant to antidepressant drugs. Repetitive transcranial magnetic stimulation (rTMS) has been found effective in combination with antidepressants in this patient group. The aim of this study was to evaluate the antidepressant effect of a new principle using low-intensity transcranially applied pulsed electromagnetic fields (T-PEMF) in combination with antidepressants in patients with treatment-resistant depression.

METHODS: This was a sham-controlled double-blind study comparing 5 weeks of active or sham T-PEMF in patients with treatment-resistant major depression. The antidepressant treatment, to which patients had been resistant, was unchanged 4 weeks before and during the study period. Weekly assessments were performed using both clinician-rated and patient-rated scales. The T-PEMF equipment was designed as a helmet containing seven separate coils located over the skull that generated an electrical field in tissue with orders of magnitude weaker than those generated by rTMS equipment.

RESULTS: Patients on active T-PEMF showed a clinically and statistically significant better outcome than patients treated with sham T-PEMF, with an onset of action within the first weeks of therapy. Effect size on the Hamilton 17-item Depression Rating Scale was .62 (95% confidence interval .21-1.02). Treatment-emergent side effects were few and mild.

CONCLUSION: The T-PEMF treatment was superior to sham treatment in patients with treatment-resistant depression. Few side effects were observed. Mechanism of the antidepressant action, in light of the known effects of PEMF stimulation to the brain, is discussed.

Encephale. 2009 Dec;35 Suppl 7:S325-9.

[Electrostimulation techniques in treatment for severe depression]

[Article in French]

Millet B.

Université Rennes 1, Chu de Rennes, Hôpital Guillaume Régnier, 108 Avenue du Général Leclerc, 35000 Rennes. bruno.millet@univ-rennes1.fr

Abstract

Electroconvulsivotherapy represents a key indication for severe Major Depressive Episode (MDE). However, an hospitalization with a general anaesthesia allowing a seizure induction followed by an almost systematic post-epileptic delirium justifies the development of other brain electrostimulation techniques. Trans-cranial Magnetic Stimulation (TMS) is a technique which offers to transform an electromagnetic field within the brain in an electric one. This therapeutic has been approved in 2008 in the MDE indication by the Food and Drug Administration. However a better knowledge of brain stimulation parameters such as the number of sequences, intensity, frequency, and the brain target, is necessary. Indeed it could enable to get some more homogeneous clinical results which will drive to the use of this technique in daily practice. Neurosurgical procedures represent also a stake for a better treatment of severe chronic and resistant depression. Whereas Vagus Nerve Stimulation (DBS) failed to be developed in France, Deep Brain Stimulation (DBS) is currently under development in this indication with some promising preliminary results.

J Affect Disord. 2009 Nov;118(1-3):94-100. Epub 2009 Feb 26.

Low frequency (1-Hz), right prefrontal repetitive transcranial magnetic stimulation (rTMS) compared with venlafaxine ER in the treatment of resistant depression: a double-blind, single-centre, randomized study.

Bares M, Kopecek M, Novak T, Stopkova P, Sos P, Kozeny J, Brunovsky M, Höschl C.

Prague Psychiatric Centre, Ustavni 91, Prague 8 – Bohnice, 181 03, Czech Republic.

Abstract

BACKGROUND: Previous studies have shown effectiveness of repetitive transcranial magnetic stimulation (rTMS) in the treatment of depression. This double-blind study compared efficacy of l Hz rTMS over the right prefrontal dorsolateral cortex with venlafaxine ER in the treatment of resistant depression. METHODS: A total of 60 inpatients with depressive disorder (DSM-IV criteria), who previously did not respond to at least one antidepressant treatment, were randomly assigned to 1 Hz rTMS with placebo and venlafaxine ER with sham rTMS for 4 weeks. The primary outcome measure was score change in the Montgomery-Asberg Depression Rating Scale (MADRS). We also used Clinical Global Impression (CGI) and Beck Depressive. Inventory-Short Form (BDI-SF). The response was defined as a >or=50% reduction of MADRS score. RESULTS: There were no significant differences between treatment groups in MADRS (p=0.38), BDI-SF (p=0.56) and CGI (p=0.17) scores from baseline to endpoint. Response rates for rTMS (33%) and venlafaxine (39%) as well as remission (MADRS score<or=10 points) rates (19% vs. 23%) and drop-out rate did not differ between treatment groups. There were significant reductions of MADRS, CGI and BDI-SF scores in both groups. LIMITATIONS: Small sample size. No placebo arm was included for ethical reasons, because both treatments have previously been reported to be more effective than placebo. Relatively short duration of antidepressant treatment. CONCLUSION: The findings of this study suggest that, at least in the acute treatment, the right sided rTMS produces clinically relevant reduction of depressive symptomatology in patients with resistant depression comparable to venlafaxine ER. Larger sample sizes are required to confirm these results.

J Clin Psychiatry. 2008 Jun;69(6):930-4.

An open-label, prospective study of repetitive transcranial magnetic stimulation (rTMS) in the long-term treatment of refractory depression: reproducibility and duration of the antidepressant effect in medication-free patients.

Demirtas-Tatlidede A, Mechanic-Hamilton D, Press DZ, Pearlman C, Stern WM, Thall M, Pascual-Leone A.

Berenson-Allen Center for Noninvasive Brain Stimulation, Harvard Medical School, and the Department of Neurology, Behavioral Neurology Unit, Beth Israel Deaconess Medical Center, Boston, Mass 02215, USA.

Abstract

OBJECTIVE: Several studies have assessed the acute antidepressant effects of repetitive transcranial magnetic stimulation (rTMS), and many have revealed positive results. However, the impact of rTMS throughout the long course of major depressive disorder (MDD) and the efficacy of rTMS in the treatment of depressive relapses still remain to be elucidated.

METHOD: Sixteen medication-free patients with refractory MDD (diagnosed according to DSM-IV) who initially had clinically significant antidepressant responses to a 10-day course of 10-Hz rTMS were consecutively admitted to the protocol from 1997 to 2001 and were followed for 4 years. The cohort was studied during a total of 64 episodes of depressive relapse. Severity of depression was evaluated with the Hamilton Rating Scale for Depression (HAM-D) and the Beck Depression Inventory (BDI) prior to and after completion of each rTMS treatment course. Clinically significant response was defined as a reduction in HAM-D score of at least 50%. Safety was assessed by serial neurologic examinations and neuropsychological evaluations.

RESULTS: Approximately one half of the patients individually sustained a clinically significant response to the repeated courses of rTMS; the mean +/- SD decrease in HAM-D scores was 64.8% +/- 12.6% (p < .0001), and, in BDI scores, 60.4% +/- 20.6% (p < .0001). Despite the lack of adjuvant antidepressant medication, the mean interval between treatment courses was approximately 5 months, and the medication-free period ranged from 26 to 43 months. Transcranial magnetic stimulation was well tolerated, and evaluations regarding the safety of the repeated applications of rTMS revealed no findings of concern.

CONCLUSIONS: Repeated rTMS applications have demonstrated a reproducible antidepressant effect in patients with refractory depression who initially showed a clinically significant benefit. The duration of effect varied across patients, but benefits were sustained for a mean of nearly 5 months. Further studies with larger cohorts will be useful in determining the long-term effectiveness of rTMS maintenance therapy.

Pharmacopsychiatry. 2008 Mar;41(2):41-7.

Repetitive transcranial magnetic stimulation (rTMS) in combination with escitalopram in patients with treatment-resistant major depression: a double-blind, randomised, sham-controlled trial.

Bretlau LG, Lunde M, Lindberg L, Undén M, Dissing S, Bech P.

Psychiatric Research Unit, Frederiksborg General Hospital, Hillerød, Denmark.

Abstract

BACKGROUND: The role of high-frequency rTMS over the left cortex as an add-on strategy in the treatment of major depression is still uncertain even in patients resistant to pharmacotherapy. We had planned a large sham TMS controlled study in the acute phase with a placebo-controlled relapse-prevention phase with escitalopram. However, because a recent meta-analysis showed only a small effect size of rTMS over sham TMS in the acute treatment phase of depressed patients, we decided to make an interim analysis. METHOD: In patients with medication-resistant major depression we administered in a randomised trial 15 sessions of sham-controlled rTMS over three weeks in combination with 20 mg escitalopram daily. After the last rTMS, the patients were followed for another 9 weeks on 20 mg escitalopram daily. The antidepressant effect was measured by the HAM-D(6) as primary outcome scale. RESULTS: A total of 45 patients with complete data were randomised so that 23 patients received sham TMS and 22 patients received active, high-frequency rTMS over the left cortex. Over the 3 weeks, the active rTMS treatment was superior to sham TMS with effect sizes on the HAM-D(6) above 0.70, which indicates not only a statistically but also a clinically significant effect. The patients had typically been through two failed antidepressant treatment attempts with non-tricyclics before inclusion in the study. Both the rTMS and escitalopram were well-tolerated. CONCLUSION: High-frequency rTMS over the left cortex is an add-on strategy of clinical significance in combination with escitalopram in patients with major depression resistant to non-tricyclic antidepressants. Pharmacopsychiatry. 2008 Mar;41(2):41-7.

Repetitive transcranial magnetic stimulation (rTMS) in combination with escitalopram in patients with treatment-resistant major depression: a double-blind, randomised, sham-controlled trial.

Bretlau LG, Lunde M, Lindberg L, Undén M, Dissing S, Bech P.

Psychiatric Research Unit, Frederiksborg General Hospital, Hillerød, Denmark.

Abstract

BACKGROUND: The role of high-frequency rTMS over the left cortex as an add-on strategy in the treatment of major depression is still uncertain even in patients resistant to pharmacotherapy. We had planned a large sham TMS controlled study in the acute phase with a placebo-controlled relapse-prevention phase with escitalopram. However, because a recent meta-analysis showed only a small effect size of rTMS over sham TMS in the acute treatment phase of depressed patients, we decided to make an interim analysis.

METHOD: In patients with medication-resistant major depression we administered in a randomised trial 15 sessions of sham-controlled rTMS over three weeks in combination with 20 mg escitalopram daily. After the last rTMS, the patients were followed for another 9 weeks on 20 mg escitalopram daily. The antidepressant effect was measured by the HAM-D(6) as primary outcome scale.

RESULTS: A total of 45 patients with complete data were randomised so that 23 patients received sham TMS and 22 patients received active, high-frequency rTMS over the left cortex. Over the 3 weeks, the active rTMS treatment was superior to sham TMS with effect sizes on the HAM-D(6) above 0.70, which indicates not only a statistically but also a clinically significant effect. The patients had typically been through two failed antidepressant treatment attempts with non-tricyclics before inclusion in the study. Both the rTMS and escitalopram were well-tolerated.

CONCLUSION: High-frequency rTMS over the left cortex is an add-on strategy of clinical significance in combination with escitalopram in patients with major depression resistant to non-tricyclic antidepressants.

Encephale. 2007 Mar-Apr;33(2):126-34.

[Efficacy of repetitive transcranial magnetic stimulation (rTMS) in major depression: a review]

[Article in French]

Brunelin J, Poulet E, Boeuve C, Zeroug-vial H, d’Amato T, Saoud M.

EA 3092, UCBL, Professeur J. Daléry, CH Le Vinatier, 95 boulevard Pinel, 69677 Bron cedex.

Abstract

INTRODUCTION: In 1985, Barker et al. showed that it was possible to stimulate both nerves and brain using external magnetic stimulation without significant pain. During the past 10 years, therapeutic effects of repeated Transcranial Magnetic Stimulation (rTMS) have been widely studied in psychiatry and its efficacy has been demonstrated in the treatment of major depressive disorders, particularly as an alternative to electroconvulsivotherapy (ECT). Facing the large range of studies, we found necessary to propose an up-to-date review in French of the methodological and therapeutic variations among them.

METHOD: Based on an exhaustive consultation of Medline data and the Avery-George-Holtzheimer Database of rTMS Depression-Studies, supplemented by a manual research, only works evaluating the therapeutic efficacy of rTMS on depressive symptoms were retained, excluding all studies exclusively investigating the stimulation parameters or the tolerance as well as case reports.

RESULTS: Out the 66 available reports we retained 30 studies. After a description of the main results of these 30 studies, several elements of the 66 will be discussed. Open studies demonstrated that short courses rTMS (5 to 10 sessions) produced a decrease in the mean Hamilton Depression Ratting Scale (HDRS) scores, although significant remission of depression in individuals was rare. Most authors had used high frequency rTMS applied to the left Dorso Lateral Prefrontal Cortex (left DLPFC). However, low frequency rTMS applied to the right DLPFC was also followed by significant reduction of HDRS scores. Parallel arm, double blind versus placebo studies are designed to clarify the therapeutic efficacy of rTMS therapy but conclude in contradicting results. Literature data globally confirms a greater efficacy of rTMS compared to placebo (37% responders in the active group vs 20% in the sham). This efficacy could in fact be even greater because the sham procedure is disputable in most studies. Indeed, positioning rTMS coil at 45 or 90 from the scalp may not represent an accurate sham procedure and the use of real sham coil is to be recommended. Only one study has suggested that associating rTMS and ECT could decrease the number of general anesthesia required. Therapeutic efficacy has been shown by either inhibiting the right DLPFC or by stimulating the left DLPFC, although some patients exhibit paradoxical responses. High frequency rTMS (>5 Hz) increases cortical excitability and metabolism, while low-frequency rTMS stimulation ( 1 Hz) has the opposite effect. Other parameters are: relevant: intensity (from 80 to 110% of motor threshold), total number of stimulations (from 120 to 2 000) and total number of rTMS sessions (from 5 to 20). As suggested in most recent studies, higher-intensity pulses, higher number of stimulation or longer treatment courses may be more effective. Greater responsiveness to rTMS may be predicted by several patients’ factors, including the absence of psychosis, younger age and previous response to rTMS therapy.

DISCUSSION: Conclusions on these factors and others, such as the importance of anatomically accurate coil placement and the distance from the coil to the brain, await further investigation. Despite heterogeneity of these reports according to methodology and treatment parameters, the antidepressive properties of rTMS now appear obvious, opening interesting prospects, in particular in the treatment of pharmacoresistant major depressive patients and, we hope, administered as adjuvant therapy in non-resistant depression.

CONCLUSION: Thus, many questions remain unanswered concerning the optimal stimulation parameters, privileged indications and maintenance sessions. This justifies the development of structured evaluation trials on larger samples.

Am J Psychiatry. 2006 Jan;163(1):88-94.

A randomized, controlled trial of sequential bilateral repetitive transcranial magnetic stimulation for treatment-resistant depression.

Fitzgerald PB, Benitez J, de Castella A, Daskalakis ZJ, Brown TL, Kulkarni J.

Alfred Psychiatry Research Centre, the Alfred and Monash University Department of Psychological Medicine, Melbourne, Victoria, Australia. paul.fitzgerald@med.monash.edu.au

Abstract

OBJECTIVE: High-frequency left-side repetitive transcranial magnetic stimulation (rTMS) and low-frequency stimulation to the right prefrontal cortex have both been shown to have antidepressant effects, but doubts remain about the magnitude of previously demonstrated treatment effects. The authors evaluated sequentially combined high-frequency left-side rTMS and low-frequency rTMS to the right prefrontal cortex for treatment-resistant depression. METHOD: The authors conducted a 6-week double-blind, randomized, sham-controlled trial in 50 patients with treatment-resistant depression. Three trains of low-frequency rTMS to the right prefrontal cortex of 140 seconds’ duration at 1 Hz were applied daily, followed immediately by 15 trains of 5 seconds’ duration of high-frequency left-side rTMS at 10 Hz. Sham stimulation was applied with the coil angled at 45 degrees from the scalp, resting on the side of one wing of the coil. The primary outcome variable was the score on the Montgomery-Asberg Depression Rating Scale. RESULTS: There was a significantly greater response to active than sham stimulation at 2 weeks and across the full duration of the study. A significant proportion of the study group receiving active treatment met response (11 of 25 [44%]) or remission (nine of 25 [36%]) criteria by study end compared to the sham stimulation group (two of 25 [8%] and none of 25 respectively). CONCLUSIONS: Sequentially applying both high-frequency left-side rTMS and low-frequency rTMS to the right prefrontal cortex, has substantial treatment efficacy in patients with treatment-resistant major depression. The treatment response accumulates to a clinically meaningful level over 4 to 6 weeks of active treatment.

J Clin Psychiatry. 2005 Dec;66(12):1569-75.

Does rTMS hasten the response to escitalopram, sertraline, or venlafaxine in patients with major depressive disorder? A double-blind, randomized, sham-controlled trial.

Rossini D, Magri L, Lucca A, Giordani S, Smeraldi E, Zanardi R.

Department of Psychiatry, School of Medicine, Vita-Salute University, San Raffaele Hospital, Via Stamina d’Ancona 20, 20127 Milan, Italy.

Abstract

BACKGROUND/OBJECTIVE: Repetitive transcranial magnetic stimulation (rTMS) has been mainly studied as adjunctive treatment for drug-resistant patients. We assessed the effectiveness of rTMS started concomitantly with antidepressant medications in non-drug-resistant major depressive disorder patients. We also evaluated if, among the 3 antidepressants administered, one had a better synergy with rTMS. METHOD: In this 5-week, double-blind, randomized, sham-controlled study, we recruited 99 inpatients suffering from a major depressive episode (DSM-IV criteria). They were randomly assigned to receive venlafaxine, sertraline, or escitalopram in combination with a 2-week period of sham or active 15-Hz rTMS on the left dorso-lateral prefrontal cortex. Data were gathered from February 2004 to June 2005. RESULTS: The active rTMS group showed a significantly faster reduction in Hamilton Rating Scale for Depression (HAM-D) scores compared with the sham group (p = .0029). The response and remission rates were significantly greater in the active rTMS group after the stimulation period (p = .002 and p = .003, respectively), but not at the endpoint. We found no significant difference in HAM-D score reduction among the 3 drugs administered, either in the active or in the sham group. CONCLUSION: These findings support the efficacy of rTMS in hastening the response to antidepressant drugs in patients with major depressive disorder. The effect of rTMS seems to be unaffected by the specific concomitantly administered drug.

Biol Psychiatry. 2005 Mar 15;57(6):571-6.

Antidepressant-like effects of cranial stimulation within a low-energy magnetic field in rats.

Carlezon WA Jr, Rohan ML, Mague SD, Meloni EG, Parsegian A, Cayetano K, Tomasiewicz HC, Rouse ED, Cohen BM, Renshaw PF.

Department of Psychiatry, Harvard Medical School and McLean Hospital, Belmont, MA 02478, USA. carlezon@mclean.harvard.edu

BACKGROUND: Evidence suggests that a novel type of magnetic resonance imaging (MRI) scan called echo planar magnetic resonance spectroscopic imaging (EP-MRSI) has mood-elevating actions in humans during the depressive phases of bipolar disorder. We examined whether a low-energy component of EP-MRSI (low-field magnetic stimulation [LFMS]) has antidepressant-like, locomotor-stimulating, or amnestic effects in rats. METHODS: We examined the effects of LFMS on immobility in the forced swim test (FST) and activity within an open field in separate groups of rats. After exposure to forced swimming, rats received LFMS (three 20-min sessions at 1.5 G/cm and .75 V/m) before behavioral testing. We also examined the effects of LFMS on fear conditioning (FC), a learning paradigm that also involves exposure to stressful conditions. RESULTS: Low-field magnetic stimulation reduced immobility in the FST, an antidepressant-like effect qualitatively similar to that of standard antidepressants. Low-field magnetic stimulation did not alter locomotor activity or FC. CONCLUSIONS: Low-field magnetic stimulation has antidepressant-like effects in rats that seem unrelated to locomotor-activating or amnestic effects. These findings raise the possibility that electromagnetic fields can affect the brain biology and might have physiologic consequences that offer novel approaches to therapy for psychiatric disorders. These same consequences might render MRI-based scans more invasive than previously appreciated.

Neuroreport. 2005 Nov 7;16(16):1839-42.

Effects of repetitive transcranial magnetic stimulation in depression: a magnetoencephalographic study.

Maihofner C, Ropohl A, Reulbach U, Hiller M, Elstner S, Kornhuber J, Sperling W.

Departments of aNeurology bPsychiatry and Psychotherapy cInstitute for Experimental Physiology and Pathophysiology, University of Erlangen – Nuremberg, Erlangen, Germany.

Recently, repetitive transcranial magnetic stimulation has evolved as a potential therapeutic tool to interfere with brain changes associated with neurological and psychiatric diseases. Little is known about its mode of action, however. Here, we investigated effects of repetitive transcranial magnetic stimulation on spontaneous magnetoencephalographic activity in patients with major depression. Before treatment, depressed patients showed a significant increase in slow magnetoencephalographic activity (2-6 Hz) over the left prefrontal cortex, compared with healthy controls. This activity significantly decreased during 10 days of repetitive transcranial magnetic stimulation, paralleled by clinical improvement. We conclude that therapeutic repetitive transcranial magnetic stimulation effects can be mirrored by changes of spontaneous magnetoencephalographic activity.

Psychiatry Res. 2005 Nov 15;137(1-2):1-10. Epub 2005 Oct 12.

Transcranial magnetic stimulation in treatment-resistant depressed patients: A double-blind, placebo-controlled trial.

Rossini D, Lucca A, Zanardi R, Magri L, Smeraldi E.

Department of Psychiatry, School of Medicine, Vita-Salute University, San Raffaele Hospital, via Stamira d’Ancona 20, Milan 20127, Italy.

This 5-week, randomized, double-blind, placebo-controlled trial investigated the efficacy and tolerability of high frequency repetitive transcranial magnetic stimulation (rTMS) directed to the left prefrontal cortex in drug-resistant depressed patients. Fifty-four patients were randomly assigned to receive 10 daily applications of either real or sham rTMS. Subjects assigned to receive active stimulation were divided into two further subgroups according to the intensity of stimulation: 80% vs. 100% of motor threshold (MT). At study completion, the response rates were 61.1% (n=11), 27.8% (n=5) and 6.2% (n=1) for the 100% MT group, 80% MT group and sham group, respectively. A significant difference (Pearson chi(2) test) was found between the 100% MT and sham groups, while the 80% MT group did not differ significantly from the sham group. Between the two active groups, a marginally significant difference was observed. Analysis of variance with repeated measures on Hamilton Depression Rating Scale scores revealed a significantly different decrease over time of depressive symptomatology among the three treatment groups. Treatment response appeared to be unrelated to the demographic and clinical characteristics recorded, and on the whole the technique was well tolerated. The results of this double-blind trial showed that rTMS may be a useful and safe adjunctive treatment for drug-resistant depressed patients.

Prog Neuropsychopharmacol Biol Psychiatry. 2005 Oct 19; [Epub ahead of print]

A double-blind sham controlled study of right prefrontal repetitive transcranial magnetic stimulation (rTMS): Therapeutic and cognitive effect in medication free unipolar depression during 4 weeks.

Januel D, Dumortier G, Verdon CM, Stamatiadis L, Saba G, Cabaret W, Benadhira R, Rocamora JF, Braha S, Kalalou K, Vicaut PE, Fermanian J.

Unite de recherche clinique, EPS de Ville Evrard a Saint Denis, G03, 5 Rue du Dr Delafontaine 93200 Saint-Denis, France.

BACKGROUND: Transcranial magnetic stimulation (TMS) has become a therapeutic tool in psychiatric diseases. METHODOLOGY: The objective was to evaluate the efficacy of TMS in unipolar depression: the percentage of responders (>50% HDRS reduction) and remission (HDRS score </=8, after four weeks of active TMS treatment in depressed patients free of any antidepressive agent versus placebo-TMS. RESULTS: 27 patients were randomized in two groups: rTMS (N=11) versus sham TMS (N=16). Statistical differences were detected between sham and TMS treated groups on remission (0/16 versus 4/11 p=0.032, 1/16 versus 6/11 0.028 and 1/16 versus 7/11 p=0.011 at day 14, day 21 and day 28, respectively) and on response (2/16 versus 5/11 at day 14 (NS), 2/16 versus 7/11 p=0.0115 at day 21 and 1/16 versus 7/11 (p=0.025) day 28, respectively, using the exact Fisher test). Significant differences were observed between day 1 versus day 8 (p<0.01), day 15, day 21 and day 28 (p<0.001) in TMS group and only versus day 21 (p<0.01) and day 28 (p<0.05) for the sham group. ANOVA comparison between TMS and sham groups was significant at day 14 and day 28 (p<0.05). LIMITATIONS: The few number of patients. CONCLUSION: Our study has shown an efficacy of right rTMS in free medication unipolar depression over a month. Nevertheless, number of patients included is limited and multicentric studies will be necessary to specify the antidepressive action of TMS.

Psychiatry Res. 2005 Nov 15;137(1-2):113-21. Epub 2005 Oct 11.

Chronic repetitive transcranial magnetic stimulation is antidepressant but not anxiolytic in rat models of anxiety and depression.

Hargreaves GA, McGregor IS, Sachdev PS.

School of Psychiatry, University of New South Wales, Sydney, 2052, Australia; Neuropsychiatric Institute, Prince of Wales Hospital, Barker Street, Randwick, NSW 2031, Australia.

Transcranial magnetic stimulation (TMS) has been proposed as a treatment for depression and anxiety disorders. While the antidepressant effect has been modelled in animals, there have been few attempts to examine a possible anxiolytic effect of repetitive TMS (rTMS) in animal models. We administered 18 days of rTMS to male Sprague-Dawley rats. On days 10 through 18, rats were tested in several anxiety models (social interaction, emergence, elevated plus-maze, and predator odor avoidance) and in the forced swim test. No group differences were apparent on any of the anxiety models, while TMS produced an antidepressant effect in the forced swim test. Interestingly, on day 1 of the forced swim test, the home cage control group displayed increased swimming behaviour compared with sham-treated animals, suggesting an observable level of stress may have accompanied sham treatment. The results from the forced swim test suggested that TMS had modest antidepressant properties, but it did not show anxiolytic properties in the models examined. The study also suggested that stress associated with handling should be taken into account in the interpretation of TMS studies in animals.

Curr Psychiatry Rep. 2005 Oct;7(5):381-90.

Transcranial magnetic stimulation for the treatment of depression in neurologic disorders.

Fregni F, Pascual-Leone A.

Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, KS 452, Boston, MA 02215, USA. ffregni@bidmc.harvard.edu.

Depression is commonly associated with neurologic disorders. Although depression in neurologic conditions often is associated with a negative impact on quality of life, it frequently is poorly managed. Some factors, such as a multidrug regimen, lack of efficacy, and side effects of antidepressants may explain why depression is not adequately treated in patients with neurologic disorders. Therefore, this population needs new approaches for depression treatment, and repetitive transcranial magnetic stimulation (rTMS) may be one of them because it has been shown to be effective for the treatment of depression alone and depression in certain neurologic diseases such as Parkinson’s disease and stroke. rTMS is a noninvasive, focal, and painless treatment associated with few, mild side effects. It may be effective in the treatment of neurologic diseases such as Parkinson’s disease, stroke, and epilepsy. In this paper, we discuss the potential risks and benefits of rTMS treatment for depression in Parkinson’s disease, epilepsy, stroke, multiple sclerosis, and Alzheimer’s disease. Lastly, a framework that includes the parameters of stimulation (intensity, frequency, number of pulses, and site of stimulation) for the treatment of depression in neurologic diseases is proposed.

J Psychiatr Res. 2005 Oct 28; [Epub ahead of print]

Striatal dopamine release after prefrontal repetitive transcranial magnetic stimulation in major depression: Preliminary results of a dynamic [(123)I] IBZM SPECT study.

Pogarell O, Koch W, Popperl G, Tatsch K, Jakob F, Zwanzger P, Mulert C, Rupprecht R, Moller HJ, Hegerl U, Padberg F.

Department of Psychiatry, Ludwig-Maximilians-University, Nussbaumstr. 7, D-80336 Munich, Germany.

Though there is considerable evidence that prefrontal repetitive transcranial magnetic stimulation (rTMS) exerts antidepressant effects, the neurobiological action of rTMS in patients with depression is poorly understood. Preclinical studies in animals and humans have demonstrated that prefrontal rTMS can induce dopamine release in mesostriatal and mesolimbic regions. We therefore investigated whether rTMS also modulates striatal dopaminergic neurotransmission in depressed patients using a dynamic [(123)I] iodobenzamide (IBZM) single photon emission computed tomography (SPECT) approach. Five patients with a major depressive episode (DSM-IV) underwent an acute 10Hz rTMS challenge with 3000 stimuli over the left dorsolateral prefrontal cortex during an [(123)I] IBZM-SPECT bolus and constant infusion protocol. In four subjects the protocol was repeated after a three week rTMS standard treatment. Striatal IBZM binding to dopamine D(2) receptors was assessed with a region-of-interest (ROI) technique. The change in striatal IBZM binding after the rTMS challenge was regarded as measure of change in endogenous striatal dopamine. Data of nine SPECT investigations showed a significant reduction by 9.6+/-6.2% in IBZM binding to striatal dopamine D(2) receptors after rTMS challenge compared to baseline (p=0.01, Wilcoxon test). In this preliminary study, the reduction of IBZM binding observed after rTMS challenge is suggestive of a release in endogenous dopamine induced by prefrontal rTMS. In future, this approach can be used to differentiate specific and non-specific reward-related effects of rTMS on dopaminergic neurotransmission.

Rev Med Suisse. 2005 Sep 21;1(33):2162-4, 2166.

[Novel brain stimulation techniques: therapeutic perspectives in psychiatry]

[Article in French]

Berney A, Vingerhoets F.

Service de psychiatrie de liaison, CHUV, 1011 Lausanne. Alexandre.Berney@chuv.ch

Recent advances have allowed the development of new physical techniques in neurology and psychiatry, such as Transcranial Magnetic Stimulation (TMS), Vagus Nerve Stimulation (VNS), and Deep Brain Stimulation (DBS). These techniques are already recognized as therapeutic approaches in several late stage refractory neurological disorders (Parkinson’s disease, tremor, epilepsy), and currently investigated in psychiatric conditions, refractory to medical treatment (obsessive-compulsive disorder, resistant major depression). In Paralell, these new techniques offer a new window to understand the neurobiology of human behavior.

Curr Psychiatry Rep. 2005 Oct;7(5):381-90.

Transcranial magnetic stimulation for the treatment of depression in neurologic disorders.

Fregni F, Pascual-Leone A.

Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, KS 452, Boston, MA 02215, USA. ffregni@bidmc.harvard.edu.

Depression is commonly associated with neurologic disorders. Although depression in neurologic conditions often is associated with a negative impact on quality of life, it frequently is poorly managed. Some factors, such as a multidrug regimen, lack of efficacy, and side effects of antidepressants may explain why depression is not adequately treated in patients with neurologic disorders. Therefore, this population needs new approaches for depression treatment, and repetitive transcranial magnetic stimulation (rTMS) may be one of them because it has been shown to be effective for the treatment of depression alone and depression in certain neurologic diseases such as Parkinson’s disease and stroke. rTMS is a noninvasive, focal, and painless treatment associated with few, mild side effects. It may be effective in the treatment of neurologic diseases such as Parkinson’s disease, stroke, and epilepsy. In this paper, we discuss the potential risks and benefits of rTMS treatment for depression in Parkinson’s disease, epilepsy, stroke, multiple sclerosis, and Alzheimer’s disease. Lastly, a framework that includes the parameters of stimulation (intensity, frequency, number of pulses, and site of stimulation) for the treatment of depression in neurologic diseases is proposed.

Exp Neurol. 2005 Sep 26; [Epub ahead of print]

Repetitive transcranial magnetic stimulation of the dorsolateral prefrontal cortex and cortical excitability in patients with major depressive disorder.

Bajbouj M, Brakemeier EL, Schubert F, Lang UE, Neu P, Schindowski C, Danker-Hopfe H.

Department of Psychiatry, Charite-University Medicine Berlin, Campus Benjamin Franklin, Eschenallee 3, 14050 Berlin, Germany.

Repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex is a relatively non-invasive technique with putative therapeutic effects in major depression. However, the exact neurophysiological basis of these effects needs further clarification. Therefore, we studied the impact of ten daily sessions of left, dorsolateral prefrontal rTMS on motor cortical excitability, as revealed by transcranial magnetic stimulation-elicited motor-evoked potentials in 30 patients. As compared to the non-responders, responders (33%) showed changes in parameters pointing towards a reduced cortical excitability. These results suggest that repetitive transcranial magnetic stimulation of the dorsolateral, prefrontal cortex may have inhibitory effects on motor cortical neuronal excitability in patients with major depressive disorder. Furthermore, measurement of motor cortical excitability may be a useful tool for investigating and monitoring inhibitory brain effects of antidepressant stimulation techniques like rTMS.

Epilepsy Behav. 2005 Sep;7(2):182-9.

Transcranial magnetic stimulation treatment for epilepsy: can it also improve depression and vice versa?

Fregni F, Schachter SC, Pascual-Leone A.

Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA. ffregni@bidmc.harvard.edu

Comorbidity with depression is an important determinant of the quality of life for patients with epilepsy. Antidepressant medications can effectively treat depression in epileptic patients, but drug-drug interactions and epileptogenic effects of these drugs pose therapeutic challenges. The mood-stabilizing effects of antiepileptic medications may not be sufficient to treat depression. Therefore, treatments that alleviate the burden of depression without increasing seizure risk or, better yet, with the possibility of improving seizure control are worth exploring. Neuroimaging techniques, such as functional magnetic resonance imaging, are providing novel insights into the pathophysiology of depression in epilepsy. For example, there appears to be prominent brain prefrontal hypoactivity, which may be sustained by the hyperactivity of the seizure focus. If so, neuromodulatory approaches that suppress epileptic focus hyperactivity and concurrently enhance prefrontal activity may be ideally suited. Indeed, vagus nerve stimulation has been shown to yield simultaneous antiseizure and mood effects. Another neuromodulatory technique, transcranial magnetic stimulation (TMS), can also modulate brain activity, but in a noninvasive, painless, and focal manner. Depending on the stimulation parameters, it is possible to enhance or reduce activity in the targeted brain region. Furthermore, TMS has been shown to be effective in treating depression, and preliminary data suggest that this treatment may also be effective for epilepsy treatment. This article reviews these data and explores further the question of whether depression and epilepsy can be simultaneously treated with TMS for optimal therapeutic impact.

J Affect Disord. 2005 Nov;88(3):255-67. Epub 2005 Sep 2.

A review of the efficacy of transcranial magnetic stimulation (TMS) treatment for depression, and current and future strategies to optimize efficacy.

Loo CK, Mitchell PB.

School of Psychiatry, University of NSW, Psychiatrist, Black Dog Institute and South Eastern Sydney Illawarra Area Health Service, Australia.

BACKGROUND: There is a growing interest in extending the use of repetitive transcranial magnetic stimulation (rTMS) beyond research centres to the widespread clinical treatment of depression. Thus it is timely to critically review the evidence for the efficacy of rTMS as an antidepressant treatment. Factors relevant to the efficacy of rTMS are discussed along with the implications of these for the further optimization of rTMS. METHOD: Clinical trials of the efficacy of rTMS in depressed subjects are summarized and reviewed, focusing mainly on sham-controlled studies and meta-analyses published to date. RESULTS: There is a fairly consistent statistical evidence for the superiority of rTMS over a sham control, though the degree of clinical improvement is not large. However, this data is derived mainly from two-week comparisons of rTMS versus sham, and evidence suggests greater efficacy with longer treatment courses. Studies so far have also varied greatly in approaches to rTMS stimulation (with respect to stimulation site, stimulus parameters etc) with little empirical evidence to inform on the relative merits of these approaches. LIMITATIONS: Only studies published in English were reviewed. Many of the studies in the literature had small sample sizes and different methodologies, making comparisons between studies difficult. CONCLUSIONS: Current published studies and meta-analyses have evaluated the efficacy of rTMS as given in treatment paradigms that are almost certainly suboptimal (e.g of two weeks’ duration). While the data nevertheless supports positive outcomes for rTMS, there is much scope for the further refinement and development of rTMS as an antidepressant treatment. Ongoing research is critical for optimizing the efficacy of rTMS.

Neuro Endocrinol Lett. 2005 Aug 30;26(4) [Epub ahead of print]

Repetitive transcranial magnetic stimulation in a patient suffering from depression and rheumatoid arthritis: Evidence for immunmodulatory effects.

Langguth B, Braun S, Aigner JM, Landgrebe M, Weinerth J, Hajak G, Eichhammer P.

Department of Psychiatry, Psychosomatics and Psychotherapy, University of Regensburg, Germany. Berthold.Langguth@medbo.de.

Repetitive transcranial magnetic stimulation (rTMS) has been suggested as antidepressive treatment strategy [1]. The mechanism of action by which the antidepressive effect is brought about remains unclear at present. Here, we report findings in a patient suffering from recurrent major depression and rheumatoid arthritis. Improvement of depressive symptoms during 20 Hz rTMS of the left dorsolateral prefrontal cortex was repeatedly associated with a systemic inflammatory reaction, suggesting that rTMS induced an immunmodulatory effect.

Psychiatry Clin Neurosci. 2005 Aug;59(4):425-32.

Clinical application of single-pulse transcranial magnetic stimulation for the treatment of depression.

Fujita K, Koga Y.

Kyorin University School of Medicine Department of Neuropsychiatry, Mitaka, Tokyo, Japan. kenichi3@sd5.so-net.ne.jp

Transcranial magnetic stimulation (TMS) has been recently suggested for the treatment of patients with major depression. Based on the results of the authors’ pilot study showing a possible antidepressive effect of single-pulse TMS, a clinical trial was conducted involving patients with major depression. For the present study single-photon emission computed tomography (SPECT) was recorded for six of the target patients to study the effects of TMS on the local blood flow volume. Twenty-three inpatients meeting the Diagnostic and Statistical Manual of Mental Disorders (4th edn; DSM-IV) criteria for major depression were invited to participate in the study. Depressive symptoms were rated using the Hamilton Rating Scale for Depression (HAM-D). Patients were given 10 stimuli over the frontal area of both sides for a total of 20 stimuli in a session. The subjects had daily TMS session for 5 days as an add-on therapy. In addition, six patients had their quantitative (99m)Tc-ethyl cysteinate dimer SPECT images measured before and after TMS treatment. Compared with the value 2 days prior to the start of TMS therapy (24.2 +/- 4.9), the average HAM-D scale dropped significantly to 15.3 +/- 6.6 on the day after completion of such therapy. The results of SPECT showed that the regional cerebral blood flow (rCBF) of the bilateral frontal region had increased in four out of six patients when comparing before and after treatment. The present study shows that single-pulse TMS, which is widely used as a neurological test method, possesses a wide range of antidepressive effects without inducing adverse reactions. The results suggest that although repetitive TMS is steadily becoming the mainstay technique today, single-pulse TMS also possesses sufficient antidepressive effects.

Seizure. 2005 Sep;14(6):387-92.

Low-frequency repetitive transcranial magnetic stimulation for seizure suppression in patients with extratemporal lobe epilepsy-a pilot study.

Kinoshita M, Ikeda A, Begum T, Yamamoto J, Hitomi T, Shibasaki H.

Department of Neurology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawaharacho, Sakyoku, Kyoto 606-8507, Japan.

We evaluated the effect of low-frequency repetitive transcranial magnetic stimulation (rTMS) on seizure frequency in adult patients with medically intractable extratemporal lobe epilepsy (ETLE). Seven patients with medically intractable ETLE received low-frequency rTMS at 0.9 Hz, basically two sets of 15 min stimulation per day for five days in a week, with the stimulus intensity of 90% of resting motor threshold (RMT). The number of seizures during two weeks before and after the stimulation of one week was compared. Furthermore, RMT and active motor threshold (AMT) were measured before and after rTMS for each daily session. After low-frequency rTMS of one week, the frequency of all seizure types, complex partial seizures (CPSs) and simple partial seizures was reduced by 19.1, 35.9 and 7.4%, respectively. The patients with smaller difference between RMT and AMT before rTMS had higher reduction rate of CPSs. A favorable tendency of seizure reduction, though not statistically significant, during two weeks after low-frequency rTMS was demonstrated in medically intractable ETLE patients. As far as CPSs are concerned, smaller decrease of motor threshold by voluntary muscle contraction was associated with better response to rTMS.

Biol Psychiatry. 2005 Jan 15;57(2):162-6.

Transcranial magnetic stimulation accelerates the antidepressant effect of amitriptyline in severe depression: a double-blind placebo-controlled study.

Rumi DO, Gattaz WF, Rigonatti SP, Rosa MA, Fregni F, Rosa MO, Mansur C, Myczkowski ML, Moreno RA, Marcolin MA.

Institute of Psychiatry, University of São Paulo, Faculty of Medicine, São Paulo-SP, Brazil. drumi@usp.br

Abstract

BACKGROUND: Transcranial magnetic stimulation (TMS) is a noninvasive method to stimulate the cortex, and the treatment of depression is one of its potential therapeutic applications. Three recent meta analyses strongly suggest its benefits in the treatment of depression. The present study investigates whether repetitive TMS (rTMS) accelerates the onset of action and increases the therapeutic effects of amitriptyline. METHODS: Forty-six outpatients meeting DSM-IV criteria for nonpsychotic depressive episode were randomly assigned to receive rTMS (n = 22) or sham repetitive TMS (sham) (n = 24) during 4 weeks over dorsolateral prefrontal cortex (DLPFC) in this double-blind controlled trial. All patients were concomitantly taking amitriptyline (mean dose 110 mg/d). The rTMS group received 20 sessions (5 sections per week) of 5 Hz rTMS (120% of motor threshold and 1250 pulses per session). Sham stimulation followed the same schedule, however, using a sham coil. The efficacy variables were the Hamilton Depression Rating Scale-17 items (HAM-D/17), the Montgomery-Asberg Depression Rating Scale (MADRS), a Visual Analogue Scale (VAS), and the Clinical Global Impression (CGI). Tolerability was assessed by clinical examination and a safety screening of TMS side effects. RESULTS: Repetitive TMS had a significantly faster response to amitriptyline. There was a significant decrease in HAM-D/17 scores, already after the first week of treatment (p < .001 compared with baseline and p < .001 compared with sham). The decrease in HAM-D/17 scores in the rTMS group was significantly superior compared with the sham group throughout the study (p < .001 at fourth week). CONCLUSIONS: Repetitive TMS at 5 Hz accelerated the onset of action and augmented the response to amitriptyline.

Transcranial magnetic stimulation in persons younger than the age of 18.

Quintana H.

Department of Psychiatry, Division of Child and Adolescent Psychiatry, Louisiana State University Health Science Center, School of Medicine, New Orleans, Louisiana 70112-2822, USA. Hquint@lsuhsc.edu

OBJECTIVES: To review the use of transcranial magnetic stimulation (single-pulse TMS, paired TMS, and repetitive TMS [rTMS]) in persons younger than the age of 18 years. I discuss the technical differences, as well as the diagnostic, therapeutic, and psychiatric uses of TMS/rTMS in this age group. METHODS: I evaluated English-language studies from 1993 to August 2004 on nonconvulsive single-pulse, paired, and rTMS that supported a possible role for the use of TMS in persons younger than 18. Articles reviewed were retrieved from the MEDLINE database and Clinical Scientific index. RESULTS: The 48 studies reviewed involved a total of 1034 children ages 2 weeks to 18 years; 35 of the studies used single-pulse TMS (980 children), 3 studies used paired TMS (20 children), and 7 studies used rTMS (34 children). Three studies used both single and rTMS. However, the number of subjects involved was not reported. CONCLUSIONS: Single-pulse TMS, paired TMS, and rTMS in persons younger than 18 has been used to examine the maturation/activity of the neurons of various central nervous system tracts, plasticity of neurons in epilepsy, other aspects of epilepsy, multiple sclerosis, myoclonus, transcallosal inhibition, and motor cortex functioning with no reported seizure risk. rTMS has been applied to psychiatric disorders such as ADHD, ADHD with Tourette’s, and depression. Adult studies support an antidepressant effect from repetitive TMS, but there is only one study that has been reported on 7 patients that used rTMS to the left dorsal prefrontal cortex on children/adolescents with depression (5 of the 7 subjects treated responded). Although there are limited studies using rTMS (in 34 children), these studies did not report significant adverse effects or seizures. Repetitive TMS safety, ethical, and neurotoxicity concerns also are discussed.

Neuron. 2005 Jan 20;45(2):181-3.

Toward establishing a therapeutic window for rTMS by theta burst stimulation.

Paulus W.

Department of Clinical Neurophysiology, University of Goettingen, D-37075 Goettingen, Germany.

In this issue of Neuron, Huang et al. show that a version of the classic theta burst stimulation protocol used to induce LTP/LTD in brain slices can be adapted to a transcranial magnetic stimulation (TMS) protocol to rapidly produce long lasting (up to an hour), reversible effects on motor cortex physiology and behavior. These results may have important implications for the development of clinical applications of rTMS in the treatment of depression, epilepsy, Parkinson’s, and other diseases.

Psychiatry Res. 2005 Oct 10; [Epub ahead of print]

Chronic repetitive transcranial magnetic stimulation is antidepressant but not anxiolytic in rat models of anxiety and depression.

Hargreaves GA, McGregor IS, Sachdev PS.

School of Psychiatry, University of New South Wales, Sydney, 2052, Australia; Neuropsychiatric Institute, Prince of Wales Hospital, Barker Street, Randwick, NSW 2031, Australia.

Transcranial magnetic stimulation (TMS) has been proposed as a treatment for depression and anxiety disorders. While the antidepressant effect has been modelled in animals, there have been few attempts to examine a possible anxiolytic effect of repetitive TMS (rTMS) in animal models. We administered 18 days of rTMS to male Sprague-Dawley rats. On days 10 through 18, rats were tested in several anxiety models (social interaction, emergence, elevated plus-maze, and predator odor avoidance) and in the forced swim test. No group differences were apparent on any of the anxiety models, while TMS produced an antidepressant effect in the forced swim test. Interestingly, on day 1 of the forced swim test, the home cage control group displayed increased swimming behaviour compared with sham-treated animals, suggesting an observable level of stress may have accompanied sham treatment. The results from the forced swim test suggested that TMS had modest antidepressant properties, but it did not show anxiolytic properties in the models examined. The study also suggested that stress associated with handling should be taken into account in the interpretation of TMS studies in animals.

Psychiatr Pol. 2004 Mar-Apr;38(2):217-25.

[Estimation of therapeutical efficacy of weak variable magnetic fields with low value of induction in patients with depression]

[Article in Polish]

Sieron A, Hese RT, Sobis J, Cieslar G.

Z Katedry i Kliniki Chorob Wewnetrznych i Medycyny Fizykalnej Wydzialu Lekarskiego w Zabrzu Slaskiej AM w Katowicach.

AIM: Preliminary results of research on the therapeutical efficacy of weak variable magnetic fields with low value of induction used as magnetostimulation in patients with depression not reacting to two consecutive, correctly applied anti-depressant pharmacological treatment are presented in the paper. METHOD: The examined patients (24 persons aged 18-65 years) treated with anti-depressants accessible in Poland were randomly divided into 2 groups. In 1 group (11 persons–9 women and 2 men) magnetostimulation with the use of a weak variable magnetic field with a low value of induction of 15 microT generated by the VIOFOR JPS device (Poland) lasting 12 minutes daily for 15 days was added to pharmacological therapy. Patients from 2 groups (13 persons–11 women and 2 men) were exposed to exposure with the same device. The intensity of depression was estimated with Beck’s, Montgomery-Asberg’s and Hamilton’s scales. RESULTS: As a result of a cycle of active magnetostimulation a distinct, statistically significant decrease of intensification of depression, both in the 7th and 15th day exposure was obtained, while in the sham-exposed group only slight, transient decrease of intensification of depression in the 7th day of sham-exposure was observed. CONCLUSIONS: It was concluded that adding magnetostimulation to pharmacological therapy results in a progressive, significant reduction of intensification of depression symptoms.

Psychiatry Res. 2005 Oct 11; [Epub ahead of print]

Transcranial magnetic stimulation in treatment-resistant depressed patients: A double-blind, placebo-controlled trial.

Rossini D, Lucca A, Zanardi R, Magri L, Smeraldi E.

Department of Psychiatry, School of Medicine, Vita-Salute University, San Raffaele Hospital, via Stamira d’Ancona 20, Milan 20127, Italy.

This 5-week, randomized, double-blind, placebo-controlled trial investigated the efficacy and tolerability of high frequency repetitive transcranial magnetic stimulation (rTMS) directed to the left prefrontal cortex in drug-resistant depressed patients. Fifty-four patients were randomly assigned to receive 10 daily applications of either real or sham rTMS. Subjects assigned to receive active stimulation were divided into two further subgroups according to the intensity of stimulation: 80% vs. 100% of motor threshold (MT). At study completion, the response rates were 61.1% (n=11), 27.8% (n=5) and 6.2% (n=1) for the 100% MT group, 80% MT group and sham group, respectively. A significant difference (Pearson chi(2) test) was found between the 100% MT and sham groups, while the 80% MT group did not differ significantly from the sham group. Between the two active groups, a marginally significant difference was observed. Analysis of variance with repeated measures on Hamilton Depression Rating Scale scores revealed a significantly different decrease over time of depressive symptomatology among the three treatment groups. Treatment response appeared to be unrelated to the demographic and clinical characteristics recorded, and on the whole the technique was well tolerated. The results of this double-blind trial showed that rTMS may be a useful and safe adjunctive treatment for drug-resistant depressed patients.

Bipolar Disord. 2005;7 Suppl 5:13-23.

Newer treatment studies for bipolar depression.

Gao K, Calabrese JR.

NIMH Bipolar Research Center, Mood Disorders Program, University Hospitals of Cleveland/Case Western Reserve University School of Medicine, Cleveland, OH, USA.

Objective: Depressive symptoms of bipolar disorder have more negative impact on a patient’s life than manic symptoms. This review focused on the emerging efficacy data for treatments in bipolar depression. Methods: English-language literature cited in Medline was searched with terms bipolar depression, clinical trial, and trial. Randomized, placebo-controlled trials of newer studies with older agents and all studies with newer or novel agents were prioritized. Open-label studies of novel agents presented at major scientific meetings were also included. Results: Olanzapine, olanzapine-fluoxetine combination (OFC), and quetiapine were superior to placebo in the acute treatment of bipolar depression. Lamotrigine only significantly reduced core symptoms of depression compared with placebo. Pramipexole, a dopamine D2/D3 receptor agonist and omega-3 fatty acids, a polyunsaturated fatty acid, augmentation to mood stabilizer (MS) had superiority to placebo in reducing depressive symptoms. Topiramate augmentation of an MS was equally as effective as Bupropion-SR. Patients treated with an MS responded well to the addition of agomelatine, a melatonin receptor agonist with 5-HT2C antagonist properties. However, inositol and repetitive transcranial magnetic stimulation did not separate from placebo. Lamotrigine and olanzapine, and to a lesser extent, divalproex, are superior to placebo in preventing depressive relapses. All agents were relatively well tolerated. Conclusions: Olanzapine, OFC, and quetiapine are effective in the acute treatment of bipolar depression. Compared with lithium and divalproex, lamotrigine is more effective in preventing bipolar depression. Larger controlled studies of the other agents in the acute and maintenance treatment of bipolar depression are warranted.

Zh Nevrol Psikhiatr Im S S Korsakova. 1999;99(10):26-9.

[Transcranial magnetic stimulation in neurotic depression]

[Article in Russian]

Stikhina NIa, Lyskov EB, Lomarev MP, Aleksanian ZA, Mikhailov VO, Medvedev SV.

Transcranial magnetic stimulation (TMS) was applied in combination with psychotherapy in patients with neurotic depression, including 15 patients of the experimental group and 14 patients of the control one. 10 sessions of daily TMS for the patients from the experimental group (0.015 T, 40 pulses per sec) were performed at the same time for 20 min (twice for 10 min with 5-min interval) in a room which excluded any external stimulation. TMS was performed by contact method: 5 cm coil was applied to the left prefrontal area. The control group received the imitation of TMS-procedure stimulation. The improvement of mental state was in 13 patients of experimental group and in 3 of control one. The course of TMS resulted in a significant attenuation of depression by the Hamilton Depression Rating scale (from 22.9 to 8.6) and the Anxiety Inventory (from 39.4 to 26.6), that was significantly higher in comparison with the control. There weren’t found any TMS-related changes in blood pressure and pulse rate as well as any pathological EEG symptoms.

Biomed Sci Instrum. 2003;39:466-70.

Autoradiographic evaluation of electromagnetic field effects on serotonin (5HT1A) receptors in rat brain.

Johnson MT, McCullough J, Nindl G, Chamberlain JK.

Terre Haute Center for Medical Education, Indiana University School of Medicine, Terre Haute, IN 47809, USA.

Serotonin (5HT1A) is a chemical mediator of inflammation and the largest single neurotransmitter system of the brain. Its secretion and physiological actions mediate stress and pain, affecting both immune and nervous system functions through the hypothalamic-pituitary-adrenal axis. Serotonin receptor dysfunction is well-characterized in mental disturbances like depression and anxiety. Transcranial magnetic stimulation has been used therapeutically to treat refractory disorders like non-responsive depression and may act in part through its effect on 5HT1A receptors. Previously we have shown that in vitro, 5HT1A receptor binding to a radioactive agonist can be modulated by specific intensity and frequency electromagnetic fields (EMFs). In the present report we have used quantitative receptor autoradiography to evaluate 5HT1A receptor density in rat brain and the impact of pulsed EMF exposure on receptor binding in key brain regions. Rats used in this study had whole body exposures to either a geofield control or to pulsed EMFs to evaluate the treatment for chemically-induced tendinitis. Since the brains were exposed coincidentally as a consequence of the main experiment, we investigated the potential for EMF-induced changes in areas such as the hippocampus. This pilot study should provide a detailed understanding of magnetic field effects on stress-responsive brain regions and will lead to a more coordinated approach to the use of such modalities for therapeutic intervention in humans.

Fortschr Neurol Psychiatr. 2001 Sep;69(9):402-9.

[Which patients with major depression benefit from prefrontal repetitive magnetic stimulation]

[Article in German]

Eschweiler GW, Plewnia C, Bartels M.

Universitatsklinik fur Psychiatrie und Psychotherapie Tubingen. eschweiler@med.uni-tuebingen.de

Antidepressive benefit of prefrontal repetitive magnetic stimulation (RTMS) for one or two weeks varies between 6 % and 60 % (mean 37 %) improvement of the Hamilton depression scale vs. 12 % improvement following sham RTMS. This variance is probably caused by study specific stimulus parameters but also by genetic, psychopathological and neuropsychological characteristics of the patients as well as by the functional state of the cortex area below the stimulation coil.Data from 10 open and 7 sham controlled studies including two own studies comprising more than 300 patients with major depression have been published to date. In synopsis several positive predictors for antidepressive response of prefrontal RTMS become apparent: 1) younger age, 2) somatic signs of anxiety, 3) lack of cortical hyperactivity below the magnetic coil pulsed by 10 Hz stimuli, 4) cortical hypermetabolism below the 1 Hz pulsed coil.Negative predictors of response to prefrontal RTMS were: 1) Advanced age, 2) prefrontal atrophy, 3) cognitive impairment in neuropsychological tasks assigned to the prefrontal cortex, 4) psychotic symptoms, 5) cortical hyperactivity below 10 Hz pulsed coil 6) non-response to electroconvulsive therapy (ECT).While prefrontal RTMS will probably not replace ECT in severe major depression with psychotic symptoms it could be beneficial especially in younger anxious patients without cognitive impairment.

Nord J Psychiatry. 2003;57(3):227-32.

Efficacy of repetitive transcranial magnetic stimulation in depression: a review of the evidence.

Aarre TF, Dahl AA, Johansen JB, Kjonniksen I, Neckelmann D.

Nordfjord Psychiatric Centre, N-6770 Nordfjordeid, Norway. trond.aarre@helse-forde.no

Repetitive transcranial magnetic stimulation (rTMS) is a novel treatment in psychiatry. We reviewed all published evidence on the efficacy of this treatment option in depressive disorders. An extensive electronic and manual search for eligible research reports identified only 12 studies that met the predetermined criteria for inclusion. rTMS was administered differently in most studies, and patient characteristics varied widely. A formal meta-analysis of the studies was thus not possible. Instead, we conducted a qualitative evaluation of the included studies. The antidepressive efficacy was not consistent, and where efficacy was demonstrated, it was modest in most studies. Some patients had good but transient responses to rTMS. Treatment gains were not maintained beyond the treatment period. Comparisons with electroconvulsive therapy (ECT) indicated the superiority of ECT. More, larger and more carefully designed studies are needed to demonstrate convincingly a clinically relevant effect of rTMS. We conclude that there is insufficient evidence for rTMS as a valid treatment for depression at present.

Int J Neurosci. 1996 Oct;87(1-2):5-15.

Suicidal behavior is attenuated in patients with multiple sclerosis by treatment with electromagnetic fields.

Sandyk R.

NeuroCommunication Research Laboratories, Danbury, CT 06811, USA.

A marked decrease in the levels of serotonin (5-HT) and its metabolite (5-HIAA) has been demonstrated in postmortem studies of suicide victims with various psychiatric disorders. Depression is the most common mental manifestation of multiple sclerosis (MS) which accounts for the high incidence of suicide in this disease. CSF 5-HIAA concentrations are reduced in MS patients and nocturnal plasma melatonin levels were found to be lower in suicidal than in nonsuicidal patients. These findings suggest that the increased risk of suicide in MS patients may be related to decreased 5-HT functions and blunted circadian melatonin secretion. Previous studies have demonstrated that extracerebral applications of pulsed electromagnetic fields (EMFs) in the picotesla range rapidly improved motor, sensory, affective and cognitive deficits in MS. Augmentation of cerebral 5-HT synthesis and resynchronization of circadian melatonin secretion has been suggested as a key mechanism by which these EMFs improved symptoms of the disease. Therefore, the prediction was made that this treatment modality would result in attenuation of suicidal behavior in MS patients. The present report concerns three women with remitting-progressive MS who exhibited suicidal behavior during the course of their illness. All patients had frequent suicidal thoughts over several years and experienced resolution of suicidal behavior within several weeks after introduction of EMFs treatment with no recurrence of symptoms during a follow-up of months to 3.5 years. These findings demonstrate that in MS pulsed applications of picotesla level EMFs improve mental depression and may reduce the risk of suicide by a mechanism involving the augmentation of 5-HT neurotransmission and resynchronization of circadian melatonin secretion.

Percept Mot Skills. 1996 Oct;83(2):491-8.

Weak, but complex pulsed magnetic fields may reduce depression following traumatic brain injury.

Baker-Price LA, Persinger MA.

Department of Psychology, Laurentian University, Sudbury, Ontario, Canada.

Many patients who display psychological depression following a traumatic brain injury do not respond completely to antidepressant drugs. We hypothesized that this type of depression is strongly correlated with subclinical, complex partial seizure-activity within the hippocampal-amygdaloid region that continues for months to years after apparent neurological and behavioral “recovery.” Four depressed patients who had sustained traumatic brain injuries and who exhibited mild to moderate brain impairment according to standardized tests received 30 min. of weak (1 microT) burst-firing magnetic fields across the temporal lobes once per week for 5 weeks. There was a significant improvement of depression and reduction of phobias while physical symptoms and other complaints were not changed

Pol J Pharmacol. 2002 Nov-Dec;54(6):633-9.

Effect of combined treatment with paroxetine and transcranial magnetic stimulation (TMS) on the mitogen-induced proliferative response of rat lymphocytes.

Roman A, Vetulani J, Nalepa I.

Laboratory of Intracellular Signalling, Department of Biochemistry, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, PL 31-343 Krakow, Poland. roman@if-pan.krakow.pl

Depression is associated with abnormal functions of the immune system. In this study, we investigated how two modem antidepressant therapies, chronic treatment with transcranial magnetic stimulation (TMS) and administration of an antidepressant belonging to selective serotonin reuptake inhibitors (SSRI), paroxetine, affect the proliferative response of thymocytes and splenocytes stimulated in vitro with various mitogens. Paroxetine (10 mg/kg) and TMS (B = 1.2 T, f = 30 Hz, t = 330 s) were applied once daily for 12 consecutive days, while, if given jointly paroxetine was injected 30 min before TMS. The mitogens used were: concanavalin A (Con A), pokeweed mitogen (PWM) or lipopolysaccharide (LPS). While either treatment applied alone had no effect on proliferative response, the joint application of paroxetine and TMS significantly depressed it. The literature data suggest that pulsed magnetic field may directly inhibit mitogen-activated lymphocyte proliferation, which is also inhibited by the presence of high level of serotonin. The present results suggest that both effects are additive, and because of that application of both treatments, whose effects alone are insufficient to prompt the reaction, possibly because adaptive changes during chronic treatment, results in a significant inhibition of lymphocyte proliferation.

Epilepsy Behav. 2003 Oct;4 Suppl 3:S46-54.

Treatment of depression in patients with epilepsy: problems, pitfalls, and some solutions.

Krishnamoorthy ES.

T.S. Srinivasan Institute of Neurological Sciences and Research, Public Health Centre, Chennai, India. E.S.Krishnamoorthy@ion.ucl.ac.uk

Many people with epilepsy suffer from comorbid depression. Despite this, there have been few studies addressing the treatment of depression in this population, and the literature on psychiatric management techniques in patients with epilepsy is composed largely of opinions rather than evidence from randomized, controlled trials or other systematic investigations. Antidepressant drugs, including tricyclics and selective serotonin reuptake inhibitors, can be used to treat patients with epilepsy and comorbid depression. Nonpharmacological treatment options include vagus nerve stimulation, transcranial magnetic stimulation, and psychological therapies including cognitive-behavioral therapy, individual or group psychotherapy, patient support groups, family therapy, and counseling. Another important area that remains largely uninvestigated is psychiatric research in patients with epilepsy in non-Western cultures (with the exception of Japan). Factors such as problems with access to and acceptability of therapies in many developing nations have further implications for the treatment of psychiatric disorders in epilepsy.