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H-coil repetitive transcranial magnetic stimulation for the treatment of bipolar depression: an add-on, safety and feasibility study

The World Journal of Biological Psychiatry, 2010; Early Online, 1–8 ORIGINAL INVESTIGATION
H-coil repetitive transcranial magnetic stimulation for the treatment
of bipolar depression: an add-on, safety and feasibility study

EIRAN VADIM HAREL 1 , ABRAHAM ZANGEN 3 , YIFTACH ROTH 3 , IRVING RETI 4 , YORAM BRAW 1,5 & YECHIEL LEVKOVITZ 1,2 1 The Emotion-Cognition Research Center, Shalvata Mental Health Care Center, Hod-Hasharon, Israel (affi liated to the Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel), 2 Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel, 3 Department of Neurobiology, The Weitzman Institute of Science, Rehovot, Israel, 4 Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD, USA and 5 Department of Behavioral Sciences, Ariel University Center of Samaria, Ariel, Israel Abstract
Objectives. The H1-Coil is a novel transcranial magnetic stimulation (TMS) device capable of inducing a magnetic fi eld with
a deeper and wider distribution than standard coils. This pilot study evaluated the safety and feasibility of the H1-Coil as
adjuvant treatment for bipolar depression (BPD). Methods. Nineteen patients diagnosed as having BPD and under treatment
with psychotropic medication were enrolled in the study. They received daily prefrontal repetitive TMS (rTMS: 20 Hz, 2 s
on, 20 s off, totaling 1680 stimuli) every weekday for four consecutive weeks. The primary outcome measure was the change
from baseline in the Hamilton Depression Rating Scale (HDRS-24) score a week after the last treatment session. Results. A
signifi cant mean decrease of 12.9 points in the HDRS-24 scale ( P Ͻ 0.001) was found. Response rate was 63.2% and remis-
sion rate was 52.6%. Treatment was well tolerated in terms of headache and overall discomfort, and there were no signifi cant
change in cognitive functioning or mood switches. One patient had a short induced generalized seizure without complica-tions. Conclusions. An add-on H-coil rTMS treatment protocol in BPD subjects indicated improvement in bipolar depression symptoms. Sham-control studies to further determine the effi cacy and safety of the H-Coil for BPD are warranted. Key words: Bipolar depression , transcranial magnetic stimulation , cognitive function , affective disorder
treatment for unipolar depression (Holtzheimer et al. 2001, McNamara et al. 2001, Burt et al. 2002, Kozel Depressive symptoms are dominant in approximately and George 2002, Aarre et al. 2003, Martin et al. one-third of the time during the course of bipolar 2003, Couturier 2005, O’Reardon et al. 2007). disorder (BPD) and are the major cause of disability Surprisingly, very few rTMS studies and case reports and impairment (Judd et al. 2002). The treatment World J Biol Psychiatry Downloaded from by Tel Aviv University on 12/19/10 for BPD consists mainly of mood stabilizers. The role have been conducted with patients who suffer from of antidepressants during the depressive phase of the bipolar depression. Two small randomized controlled illness has not been fully established. A recent large trials (RCTs; Dolberg et al. 2002, Nahas et al. 2003,) effectiveness study (STEP-BD) found no superiority of adjunct antidepressants to a mood stabilizer in the tested the effi cacy of rTMS in BPD, as have a few treatment of BPD, leaving clinicians with limited case studies (Erfurth et al. 2000, Tharayil et al. 2005, tools for dealing with this long-lasting, disabling Tamas et al. 2007). The fi rst RCT (Nahas et al. phase of the illness (Sachs et al. 2007). 2003) was a 2-week study on 23 subjects assigned to Advances in brain stimulation techniques have either sham treatment or rTMS (left prefrontal stim- raised new hopes for BPD treatment. Repetitive ulation at 5Hz, 110% motor threshold for 8 s, with transcranial magnetic stimulation (rTMS) has proven an off period of 22 s, and a 20-min session duration). effective, and was recently given FDA approval as a The rTMS treatment was an adjunct to the mood Correspondence: Yechiel Levkovitz, MD, The Emotion-Cognition Research Center, The Shalvata Mental Health Center, Hod-Hasharon, Israel. Tel: ϩ972 9 9798644. Fax: ϩ972 9 9798643. E-mail: (Received 7 April 2010; accepted 8 July 2010) ISSN 1562-2975 print/ISSN 1814-1412 online 2010 Informa HealthcareDOI: 10.3109/15622975.2010.510893 stabilizers valproic acid or carbamazepine. There was no signifi cant decrease in the primary outcome mea- sure which was the change from baseline in the Hamilton Depression Rating Scale (HDRS) scores Patients diagnosed as having BPD (type I or II) and (Nahas et al. 2003). In comparison to the sham con- currently experiencing an episode of depression dition, however, the results of the treatment arm according to DSM IV criteria were recruited for this indicated a trend towards an improvement in mood- study. Other inclusion criteria were age between 18 related symptoms. The other double-blind, random- and 65 years, an HDRS (17 items) score of Ͼ 18, a ized, sham-controlled study (Dolberg et al. 2002) stable mood stabilizer regimen for at least 2 weeks enrolled 20 bipolar depressed patients randomized before study entry and a stable regimen of antide- to receive 20 treatment days of rTMS (10 patients) pressants, if taken, for at least 4 weeks prior to study or 10 treatment days of sham followed by 20 treat- entry (for a full list of medications see Table I). The ment days of active rTMS (10 patients). The results following were considered to be mood stabilizers: of that study demonstrated signifi cant improvement valproate, lithium, carbamazepine, lamotrigine, olan- in depression rating scales after the 10 treatment zapine, quetiapine and risperidone. A therapeutic days (2 weeks) of active rTMS compared to sham. level was necessary for valproate, lithium and car- This difference disappeared when the two groups went on to receive 2 more weeks of active treatment 4 – 12 μ g/ml, respectively) taken during the 2 weeks (4 weeks of active treatment vs. 2 weeks of sham ϩ before enrollment. Exclusion criteria were any other 2 weeks of active treatment). A recent open-label Axis I disorder, any known risk factor for seizures, a study (Dell ’ Osso et al. 2009) tested the effi cacy of mood cycle of less than 4 weeks, psychotic features low frequency, navigation-guided rTMS treatment in the current episode of depression, substance abuse (3 weeks of 1 Hz, 110% MT, 300 stimuli/day to the during the past year, and a high suicide risk based right dorsolateral prefrontal cortex) as a supplement on clinical assessment or a suicide attempt during to mood stabilizers in 11 subjects with type I or type II bipolar depression who did not respond to previ- The study was approved by the local and national ous pharmacological treatment. Six of the subjects review board (IRB) committees, and was conducted (54.5%) had decreased HDRS-21 scores of Ͼ 50% at the Shalvata Mental Health Center, associated (defi ned as response) and four subjects (36.3%) had with the Sackler Faculty of Medicine at Tel-Aviv an HDRS score Ͻ 8 (defi ned as remission) on the University, Israel. The mental health center accepts referrals from a pre-determined catchment area. One hypothesis explaining the moderate clinical Twenty apparently healthy volunteers were enrolled effects of rTMS in depression could be the limited to serve as a control group for the cognitive assess- depth of direct stimulation by standard rTMS coils. ment and did not receive any rTMS treatment. They In comparison, the H1-Coil induces a magnetic fi eld were recruited by advertisements posted around the with larger distribution and depth than the standard mental health center. They had no Axis I psychiatric TMS coils, without a signifi cant increase in the inten- disorder, as assessed by an interview for mental health sity of the electric fi eld induced in superfi cial cortical history. They were not reimbursed and were free to regions (Roth et al. 2002, Zangen et al. 2005). Phan- withdraw at any time without prejudice. The Beck tom brain (a spherical homogeneous volume conduc- Depression Inventory II (BDI-II) scores (highest tor) measurements have shown that when using BDI-II score of 8) ruled out the presence of depres- World J Biol Psychiatry Downloaded from by Tel Aviv University on 12/19/10 120% of the average motor thresholds of the study sion among the controls. They were matched in age subjects, the H-coil can reach an effective fi eld at a and education level to the depressed patients. depth of 3 cm beneath the surface, while the standard All study participants signed an informed consent fi gure-8 coil can reach a depth of less than 1 cm form prior to their inclusion in the study. (Roth et al. 2007). In two studies using the H-coil: a safety study in healthy volunteers (Levkovitz et al. 2007) and a safety and feasibility study in major depression (Levkovitz et al. 2009), the stimulation The screening procedure included a structured clin- was well tolerated and an improvement in depressive ical interview by a trained senior psychiatrist clini- symptoms was found. No cognitive deterioration or cian (YL or EVH) in order to determine suitability other serious adverse effects were evident. according to the inclusion and exclusion criteria. The purpose of the current study was to explore During the active treatment phase, daily rTMS ses- the safety and feasibility of H1-Coil rTMS as an sions were scheduled in a 5-day sequence for four adjuvant treatment to mood stabilizers and antide- consecutive weeks. A total of 20 sessions were con- ing the study of the bipolar depressed subjects (n World J Biol Psychiatry Downloaded from by Tel Aviv University on 12/19/10 World J Biol Psychiatry Downloaded from by Tel Aviv University on 12/19/10 conducted 1 week after the last active treatment recording electrical activity in the abductor pollicis (Visit 21) and was defi ned as the primary effi cacy brevis using surface electrodes. MT was defi ned as the lowest intensity of stimulation able to produce Clinical assessments for effi cacy were performed at motor-evoked potentials of at least 50 μ V in fi ve out baseline and Visits 4, 10, 15, 20, and 21. The primary of 10 trials. The coil was then placed 5.5 cm anterior effi cacy outcome measure was defi ned as any change to the motor spot (i.e. the prefrontal cortex), and spa- in the Hamilton Depression Rating Scale (HDRS-24) tial coordinates were recorded with markings on a cap from baseline (Visit 1) to the primary effi cacy time placed on the subject’s head to ensure placement point at the follow-up visit 1 week after end of treat- reproducibility. The MT was determined each time, ment (Visit 21). Secondary outcome measures were: and all pulses were delivered by an expert physician the response rate defi ned as a 50% decrease in the in trains of 20 Hz at 120% of the measured MT. Each HDRS-24 from baseline to the fi nal follow-up visit, rTMS session consisted of 42 trains with a 2-s dura- remission rates defi ned as HDRS-24 scores of Ͻ 10 tion for each, and a 20-s inter-train interval (a total on the fi nal follow-up visit, changes in the Hamilton of 1680 magnetic pulses delivered per session). Anxiety Rating Scale (HAM-A), changes in the CGI-Severity (CGI-S) and CGI-Improvement (CGI-I) questionnaires and changes in the self-report BDI-II, and the Pittsburgh Sleep Quality Index (PSQI). The demographic data are presented in a tabular Safety was assessed during the study by means of format. The means and standard deviations (SD) of a variety of measures. Following the completion of continuous variables and a count and percentage of each treatment session, the scalp was inspected for categorical variables were compiled. Baseline values possible skin lesions. The subjects were also asked to of the BPD subjects and the controls were compared rate their current headache intensity on a self-graded t -tests, chi-square tests, or Fisher questionnaire by marking an “ X ” on a 10-cm visual depending on the type of data. Paired t -test was used analogue scale (VAS, 1-10) within 5 min after the to compare the clinical rating scale data at the screen- rTMS session. A medical assessment was conducted ing and baseline visits. The slope of change in clini- by a psychiatrist at visits 1, 4, 10, 15, and 20, in which cal rating scales over 5 weeks (from baseline until the subjects were asked to report any physical changes Visit 21) was estimated from repeated measures related to rTMS treatment. Blood pressure and pulse analysis of variance models (SAS Proc MIXED). rates were measured, and the Young Mania Rating The change from baseline value was modeled as a Scale (YMRS) was used as a safety measure for eval- function of the time in weeks for each rating scale. uating the risk of mood switch at the same visits. Eight factors (age, gender, number of past depres- Another safety measure was a battery of cognitive sive episodes, number of past psychiatric hospitaliza- tests (the Cambridge Neuropsychological Test Auto- tions, motor threshold at baseline, number of manic mated Battery, CANTAB), administered at baseline, episodes, duration of the current episode, and num- Visit 11 and at the fi nal follow-up visit. The CANTAB ber of antidepressants used in the current episode) tasks were divided into four domains: psychomotor were tested for prognostic characteristics. Each of speed (reaction time), visuospatial memory (paired them was included separately in the repeated mea- associative learning), sustained attention (rapid visual sures analysis models. A repeated measure analysis of information processing), and frontal lobe-related/ variance model (SAS Proc MIXED) was developed executive functions (Stockings of Cambridge [SOC] for each of the CANTAB tests. The change from base- World J Biol Psychiatry Downloaded from by Tel Aviv University on 12/19/10 line to each visit was modeled as a function of the subject category (i.e. control or BPD patient), base-line value, number of visit, and subject’s clinical status by visit interaction. The adjusted means of the various The H1-Coil rTMS sessions were conducted using a tests between the subjects category were compared Magstim Super Rapid stimulator (Magstim, UK) (LSMEANS command with PDIFF option) at each with the novel H1-Coil, which is an extracorporeal visit. A P value of Յ 0.05 was considered signifi cant. No adjustment for multiple testing was carried out. stimulation. The optimal spot on the scalp for All analyses were performed using SAS version 9.1 or stimulation of the right abductor pollicis brevis mus- higher. The database was locked on 22 March 2009. cle was located, and the motor threshold (MT) was established by delivering single stimulations to the motor cortex. The MT was measured by gradually increasing the stimulation intensity (using single pulse Thirty-one subjects were screened for this study. mode, applying one pulse every 5 s, i.e. 0.2 Hz) and Nineteen BPD patients met the inclusion/exclusion criteria. Demographic data, medical history and a list of medications taken during the study are H-Coil rTMS treatment was well tolerated by the presented in Table I. Two subjects were excluded subjects. The average degree of headache as evaluated from the study after 4 and 17 treatment days due to by a VAS scale of 1 – 10 at 5 min after each treat - noncompliance with the study protocol. The two patients did not complain of any physical side effects. 3.91), 0.91(SD ϭ 1.78), 1.59 (SD ϭ 2.89) and 1.07 A signifi cant decrease of 12.9 points in HDRS-24 (SD ϭ 2.15) on Visits 1, 4, 10, 15 and 20, respec- score (the primary effi cacy outcome measure) was tively. Hemodynamic measurements revealed neither evident at the follow-up visit (the primary effi cacy increases nor decreases in mean blood pressure or time point) (Figure 1; P Ͻ 0.001). The response rate pulse rate (127/78 and 75 at baseline and 124/83 and at the follow-up visit was 63.2% (12/19) and the 72 at Visit 20). Inspection of the scalp (conducted remission rate was 52.6% (10/19). The data of the before and immediately after each session) revealed two subjects who had been excluded prior to visit 21 no skin lesions. There were no mood switches to were included. There was a signifi cant change from hypomanic or manic states as assessed by the YMRS. baseline throughout the study protocol for the CGI-S One patient had an induced generalized seizure that ( P Ͻ 0.0001) and HAM-A ( P ϭ 0.0052) scores, lasted for less than 10 s, was self-limited, and did not cause any physical injury. The patient had post-ictal ( P ϭ 0.3613; Table II) values. amnesia and confusion that resolved after 30 min. She We looked for correlations between eight factors had been taking lithium 900 mg/day (blood level of (age, gender, number of past depressive episodes, 0.79 before entering the study), and the seizure number of past psychiatric hospitalizations, num- occurred on the 12th treatment day, at the 19th rTMS ber of past manic episodes, duration of the current train. Her MT was 51% of stimulator maximum episode, and number of antidepressants used dur- intensity, meaning that stimulation intensity was ing the current episode) and the clinical outcome measures in order to detect possible prognostic 61% of maximum power output. No other medical characteristics. The number of past depressive condition existed and no other medication taken. episodes and the number of antidepressants used Assessment of cognitive functions did not reveal during the current episode were negatively corre- any negative impact on cognition. Signifi cant differ- lated with improvement as assessed by the CGI ences in all of the measured cognitive fi elds were found at baseline between the BPD patients and the ϭ 4.85; P ϭ 0.0449, F (1,16) ϭ 13.83, controls. The BPD patients ’ baseline performance ϭ 0.0023]. There were no signifi cant correlations for the other tested parameters. In an attempt to was signifi cantly poorer (Table III). The slower identify a correlation between severity of depression processing time of the BPD subjects at baseline and response to H-Coil rTMS in our sample, we compared to the controls was no longer evident on divided the subjects into three groups according cognitive assessments administered after 10 days of to depression severity based on the HDRS-24 score treatment nor at the fi nal follow-up visit (Table III).
The signifi cant difference between the two groups ϭ Ͼ 30). Our results failed to reveal any that had been seen on the SWM task at baseline association between response rates and severity of was no longer present at the time of the second assessment (Table III). No correlations were found World J Biol Psychiatry Downloaded from by Tel Aviv University on 12/19/10 Figure 1. Hamilton Depression Rating Scale (HDRS) scores from baseline to the follow-up visit 1 week after the last treatment day.
Table II. Slopes of changes from baseline in the clinical scales over 5 weeks.
HDRS, Hamilton depression rating scale; CGI-S, clinical global impression severity; CGI-I, clinical global impression improvement; BDI, Beck depression inventory; PSQI, Pittsburgh sleep quality index; HAM-A, Hamilton anxiety rating scale.
The treatment was generally well tolerated in their HDRS-24 scores either at baseline or at any terms of discomfort. One patient experienced a generalized tonic-clonic seizure. Due to the small sample size, it is not possible to estimate whether the H-coil rTMS treatment has a greater risk of Discussion
inducing a seizure compared to other forms of This preliminary study is the fi rst to examine the rTMS. No seizures were induced in any of the effect of add-on deep-TMS stimulation of prefrontal patients in a previous study by our team, in which regions in the treatment of BPD. The results suggest we applied the H-coil rTMS on 65 unipolar a possible positive therapeutic effect of the H-coil depressed subjects without concomitant medica- deep-TMS on depressive symptoms in BPD when tion and followed the same treatment protocol as used as adjuvant therapy together with mood stabi- described for the current study (20 Hz, 2 s, 120% lizers and antidepressants. The improvement in MT) (Levkovitz et al. 2009). Another earlier safety depressive symptoms was indicated by an improve- study (Levkovitz et al. 2007) on eight healthy sub- ment in the HDRS and CGI values over time. jects using 20 Hz, 1 s, 120% MT did not show any Improvement was also observed in the HAM-A seizure activity. A possible contributor to seizure scores. Response rates according to the HDRS at the induction in the patient described in the current primary effi cacy time-point (the last follow-up visit) study was the concomitant use of lithium which reached as high as 63.2%, and remission rates were could increase the risk of seizure by lowering the 52.6%. Our results substantiated those of a recent motor threshold. Lithium is known to prolong open-label trial (Dell ’ Osso et al. 2009), which evalu- seizure activity during electroconvulsive therapy ated right dorsolateral low frequency rTMS in BPD (Girish et al. 2003), and a previous case report of subjects, and showed a 54.5% response rate and a rTMS-induced seizure lends credence to the possi- 36.3% remission rate. The poorer results reported in bility that concomitant use of lithium by our patient the two RCTs described earlier (Dolberg et al. 2002, might have contributed to seizure induction (Tharayil Nahas et al. 2003) could be related to the shorter et al. 2005). The actual role of lithium in increasing duration of treatment, seeing as longer rTMS proto- the risk of seizure induction by rTMS is not yet cols have proven to be more effective in the treat- known. Data on a much larger patient population treated with H-coil rTMS for BPD with and without World J Biol Psychiatry Downloaded from by Tel Aviv University on 12/19/10 Table III. Comparison of the cognitive test results between the BPD subjects and the healthy controls at baseline, after 10 treatment days (2nd test), and 1 week after the last treatment day (3rd test).
SOC, Stocking of Cambridge; PAL, paired associative learning; RVP, rapid visual processing; SWM, spatial working memory; RTI, reaction time.
Italic entries indicate values for which difference was eliminated throughout the treatment between the patients and the control group.
Dell ’ Osso B, Mundo E, D ’ Urso N, Pozzoli S, Buoli M, Ciabatti concurrent lithium would be required in order to MT, et al. 2009. Augmentative repetitive navigated transcranial estimate the risk of seizure induction by the H-Coil magnetic stimulation (rTMS) in drug-resistant bipolar depres- in general and with concurrent lithium treatment. No deterioration in the cognitive functioning (as Dolberg OT, Dannon PN, Schreiber S, Grunhaus L. 2002. measured by the CANTAB) of the BPD patients was Transcranial magnetic stimulation in patients with bipolar depression: a double blind, controlled study. Bipolar Disord observed. Furthermore, there was an improvement in reaction time and spatial working memory, although Erfurth A, Michael N, Mostert C, Arolt V. 2000. Mania and rapid this improvement did not correlate with a decrease in transcranial magnetic stimulation. Am J Psychiatry 157:835 – 836. the severity of depression. Again, a larger sample might Girish K, Gangadhar BN, Janakiramaiah N, Sarvanan ESM. have reached a clearer conclusion about the possible 2003. EEG seizure duration during ECT: effect of concurrent psychotropic drugs. Ann Indian Acad Neurol 6:17 – 20. positive effects of either the use of rTMS or the Holtzheimer PE III, Russo J, Avery DH. 2001. A meta-analysis improvement in depression on cognitive functions. of repetitive transcranial magnetic stimulation in the treatment Since this is an add-on study, the subjects were of depression. Psychopharmacol Bull 35:149 – 169. being treated concurrently with mood stabilizers and Judd LL, Akiskal HS, Schettler PJ, Endicott J, Maser J, Solomon antidepressants at a steady dosage throughout the DA, et al. 2002. The long-term natural history of the weekly symptomatic status of bipolar I disorder. Arch Gen Psychiatry rTMS treatment. The type of antidepressants taken by the subjects varied widely. As such, we cannot draw Kozel FA, George MS. 2002. Meta-analysis of left prefrontal conclusions about the relative effi cacy of any given repetitive transcranial magnetic stimulation (rTMS) to treat antidepressant in combination with rTMS. Further- depression. J Psychiatr Pract 8:270 – 275. more, among the different mood stabilizers used by Levkovitz Y, Harel EV, Roth Y, Braw Y, Most D, Katz L, et al. 2009. Deep transcranial magnetic stimulation over the prefron- the patients, some, such as lithium and lamotrigine are tal cortex: evaluation of antidepressant and cognitive effects in believed to have antidepressant properties. Therefore, depressive patients. Brain Stimulation 2:188 – 200. it is rather diffi cult to defi ne the role of concurrent Levkovitz Y, Roth Y, Harel EV, Braw Y, Sheer A, Zangen A. 2007. A medications in the outcome of rTMS treatment. randomized controlled feasibility and safety study of deep transcra- The design of the current study has several limita- nial magnetic stimulation. Clin Neurophysiol 118:2730 – 2744. Martin JL, Barbanoj MJ, Schlaepfer TE, Thompson E, P é rez V, tions; it was an open study, a small sample size and Kulisevsky J. 2003. Repetitive transcranial magnetic stimula- an add-on design. This makes it impossible to rule out tion for the treatment of depression. Systematic review and a possible placebo effect and expectancy bias, and the meta-analysis. Br J Psychiatry 182:480 – 491. possibility of improvement having been the result of McNamara B, Ray JL, Arthurs OJ, Boniface S. 2001. Transcranial other factors, such as the natural course of the illness magnetic stimulation for depression and other psychiatric disorders. Psychol Med 31:1141 – 1146. cannot be discounted. Nevertheless, given the chronic Nahas Z, Kozel FA, Li X, Anderson B, George MS. 2003. Left and severe nature of BPD and the lack of available prefrontal transcranial magnetic stimulation (TMS) treatment satisfactory therapeutic options, the results of this cur- of depression in bipolar affective disorder: a pilot study of acute rent pilot study suggest a possible new treatment that safety and effi cacy. Bipolar Disord 5:40 – 47. requires further examination. In light of this pilot O’Reardon JP, Solvason HB, Janicak PG, Sampson S, Isenberg KE, Nahas Z, et al. 2007. Effi cacy and safety of transcranial study, a randomized controlled study is warranted. magnetic stimulation in the acute treatment of major depres-sion: a multisite randomized controlled trial. Biol Psychiatry 62:1208 – 1216 (Epub 14 June 2007). Acknowledgements
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