Ignite Creation Date:
2024-05-05 @ 5:20 PM
Last Modification Date:
2024-10-26 @ 9:30 AM
Study NCT ID:
NCT00436020
Status:
COMPLETED
Last Update Posted:
2020-10-19
First Post:
2007-02-14
Brief Title:
rTMS in the Treatment of Bipolar Depression
Sponsor:
Bayside Health
Organization:
Bayside Health
Study Overview
Official Title:
A Double-blind Sham Controlled Trial of rTMS in the Treatment of Bipolar Depression
Status:
COMPLETED
Status Verified Date:
2020-10
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Bipolar affective disorder BPAD is
A serious mental illness
Estimated to be present in as high as 64 of the population in Western populations
Associated with considerable disability and high morbidity
Characterized by periods of both lowered and elevated mood ie depression and maniahypomania respectively
The depressive aspect of bipolar disorder is often overlooked possibly due to its less dramatic nature despite its significant impact on the lives of those affected Bipolar depression BPAD-DP is associated with a twenty fold increased risk of suicide and typically lasts three to five times as long as a manic or hypomanic episode Despite this there has been relatively sparse investigation of treatments for BPAD-DP with guidelines based primarily on expert judgment rather than clinical trials In addition a significant proportion of patients with bipolar depression do not respond to the range of commonly used medications One of the only substantially new treatments developed for unipolar depression in recent years has been the advent of repetitive transcranial magnetic stimulation rTMS Repetitive TMS has been evaluated in over 20 trials conducted over the last ten years but no substantive trials have explored its use in bipolar depression We propose to do this conducting a large scale clinical trial The trial will include the assessment of both high frequency left sided rTMS as there is clearly the greatest evidence for the effectiveness of this in unipolar depression and low frequency right sided rTMS as this there is growing evidence of the effectiveness of this in unipolar depression and we have an excellent pilot study to suggest its potential in BPAD-DP and it has never previously been assessed in a clinical trial exclusively targeting this patient group Our previous research strongly supports the effectiveness of rTMS paradigms including low frequency right-sided stimulation in unipolar depression and suggests these may have value in BPAD-DP As BPAD-DP is clearly a clinical problem of significant impact and with limited treatment options there is a pressing need for the development and definitive testing of novel treatments such as rTMS
A serious mental illness
Estimated to be present in as high as 64 of the population in Western populations
Associated with considerable disability and high morbidity
Characterized by periods of both lowered and elevated mood ie depression and maniahypomania respectively
The depressive aspect of bipolar disorder is often overlooked possibly due to its less dramatic nature despite its significant impact on the lives of those affected Bipolar depression BPAD-DP is associated with a twenty fold increased risk of suicide and typically lasts three to five times as long as a manic or hypomanic episode Despite this there has been relatively sparse investigation of treatments for BPAD-DP with guidelines based primarily on expert judgment rather than clinical trials In addition a significant proportion of patients with bipolar depression do not respond to the range of commonly used medications One of the only substantially new treatments developed for unipolar depression in recent years has been the advent of repetitive transcranial magnetic stimulation rTMS Repetitive TMS has been evaluated in over 20 trials conducted over the last ten years but no substantive trials have explored its use in bipolar depression We propose to do this conducting a large scale clinical trial The trial will include the assessment of both high frequency left sided rTMS as there is clearly the greatest evidence for the effectiveness of this in unipolar depression and low frequency right sided rTMS as this there is growing evidence of the effectiveness of this in unipolar depression and we have an excellent pilot study to suggest its potential in BPAD-DP and it has never previously been assessed in a clinical trial exclusively targeting this patient group Our previous research strongly supports the effectiveness of rTMS paradigms including low frequency right-sided stimulation in unipolar depression and suggests these may have value in BPAD-DP As BPAD-DP is clearly a clinical problem of significant impact and with limited treatment options there is a pressing need for the development and definitive testing of novel treatments such as rTMS
Detailed Description:
Bipolar affective disorder is a serious mental illness with significant mortality and morbidity 1 Some estimates of prevalence in Western populations are as high as 64 2 The depressive aspect of bipolar disorder is often overlooked possibly due to its less dramatic nature despite its significant impact on the lives of those who suffer from it 3 Bipolar depression is associated with a twenty fold increased risk of suicide 4 and typically lasts three to five times as long as a manic or hypomanic episode 5 6
Despite this there has been relatively sparse investigation of treatments for bipolar depression with guidelines based primarily on expert judgment rather than randomized controlled trials 7 First line treatment typically involves treatment with a mood stabilizer - lithium sodium valproate or carbamazepine 7 Addition of an antidepressant such as an SSRI buproprion or venlafaxine may be indicated if depression persists although there is a possibility of inducing rapid cycling and manic or manic episodes Alternative agents such as lamotrigine and atypical antipsychotics may also be considered 7 However there is little firm evidence in this area and the lack of controlled studies in the treatment of bipolar depression was described by Thase in 2005 7 as an embarrassment to the field In addition to this lack of evidence of efficacy it is clear that a significant proportion of patients with bipolar depression do not respond to the range of commonly used treatments including medication combinations 8 It is clear that the depressive phase of bipolar disorder is an important clinical problem and one in which there is a considerable need for the development of new treatments
rTMS is a technique that was first developed in the mid 1980s which involves the use of a time variable magnetic field to stimulate brain activity rTMS methods have generally been found to be well tolerated safe and without complications such as the use of an anesthetic that are required with more invasive forms of brain stimulation such as electroconvulsive therapy
The ability of rTMS to affect mood was first noted in normal controls in the late 1980s Studies using focal stimulation of the dorsolateral prefrontal cortex DLPFC in depression first appeared in the mid 1990s 9-11 These studies produced promising results with reduced depression severity following left prefrontal cortex PFC stimulation Since that time a considerable number of trials of left DLPFC rTMS have been conducted The majority of these studies have used 5-20 Hz stimulation frequency Most of these have predominately been small in sample size and of short duration ie 10 treatments CIA pub 11 They have also been confounded by concerns about the choice of sham stimulation type 12 and variation in stimulation dose provided The studies with the most robust clinical effects have used a higher number of pulses per subject and higher stimulation intensity levels suggesting a dose - response relationship CIA pub 211 They have almost exclusively focused on the treatment of patients with unipolar major depression although some of these studies have included a subset of patients with BPAD-DP
There have been at least 6 meta-analyses of the antidepressant effects of left PFC rTMS All but one have shown greater antidepressant effects of 2 weeks of HFL-TMS compared to sham these included an analysis of 6 reports 13 of 12 studies 14 of 16 studies 15 of 10 studies 16 and a Cochrane review of 14 17 The single negative study included only 6 reports with 91 subjects and as such had less power than most of the other meta-analyses Of the larger studies Holtzheimer et al reported a weighted mean effect size of 081 14 Burt et al reported an effect size of 067 15 and Kozel at al an effect size of 053 16 These are moderate to large effects However the studies repeatedly report that the overall clinical results observed were not that impressive For example a mean overall improvement of only 238 on the HAMD in the blinded studies reviewed in 14 compared to 73 in the sham group
Attempting to address the issue of definitely establishing the efficacy of rTMS in depression a large international trial has been recently completed Conducted by a private TMS manufacturer Neuronetics Pty Ltd this involved a randomized trial of HFL-TMS 10Hz compared to placebo over up to 9 weeks of treatment The results of this study show the statistically superiority of active over sham rTMS treatment 18 Currently the results of this trial are being utilized in support of an FDA application for the Neuronetics device for treatment of depression M Demitrack personal communication
In addition to sham controlled trials there have also been a series of trials comparing HFL-TMS to ECT 19-22 Encouragingly these have reported no differences in responses rates between ECT and HFL-TMS except for one study including psychotic patients showing greater benefit with ECT in the psychotic group 22 and a second trial which recently reported better responses with bilateral or unilateral ECT of unlimited treatment duration compared to a fixed course of 3 weeks of unilateral left PFC rTMS 23 However some of these studies have not necessarily had sufficient power to detect subtle differences between the groups
More recently several alternative rTMS paradigms have shown promise Low frequency rTMS applied to right PFC LFR-TMS contrary to high frequency rTMS is known to reduce local cortical excitability 24 The initial trial of LFR-TMS established its efficacy in a non treatment resistant sample of patients 25 Funded by a previous NHMRC grant we have conducted research establishing the efficacy of LFR-TMS as compared to HFL-TMS and placebo CIA 15
Previous Study 1
In this study 60 patients were randomized to either HFL-TMS or LFR-TMS or a sham stimulation condition n20 in each group All had treatment resistant depression TRD and had failed multiple antidepressant medication trials mean number 57 34 There were no baseline clinical or demographic differences between the three groups Over the double blind phase of the study there was clearly an antidepressant effect of both active groups that was superior to the response to sham stimulation There was a continued improvement in both active groups across the 4 weeks of the study for the group as whole after the 4 weeks of treatment the mean percentage change in MADRS score from baseline was 480 179 range 151 - 875 These results demonstrated that both HFL-TMS and LFR-TMS have substantial therapeutic efficacy and that robust clinical response appeared to require at least 20 sessions of treatment with the parameters used However only a sub-population of patients responded to treatment
The equivalence of HFL-TMS and LFR-TMS has also been demonstrated in a more recent study 26
Previous Study 2
We have also conducted a large scale clinical effectiveness trial of LFR-TMS comparing 1 Hz and 2 Hz stimulation to right PFC CIA 47 This study involved the randomization of 130 patients with treatment resistant major depression to receive right PFC stimulation in a single daily 15 minute train at either 1 or 2 Hz 2 Hz stimulation was investigated as a potential way of doubling the number of applied stimuli within identical treatment time to increase the treatment dose and potentially enhance treatment response Treatment response was equivalent between the 2 groups 623 240 change in the 1 Hz group 647 210 change in the 2 Hz group over 4 weeks with no difference in response This does not support the substitution of 2 Hz as an optimal condition for LFR-TMS
Another alternative paradigm is sequential bilateral rTMS SBrTMS the application of HFL-TMS and LFR-TMS one after the other in the same treatment sessions We have recently completed the first large study of this technique and the first to extend treatment beyond 10 days CIA 33
Previous Study 3 In the study conducted we combined HFL-TMS and LFR-TMS sequentially in each treatment session in a trial comparing active to sham stimulation n50 25 per group Importantly treatment was provided for up to 6 weeks longer than any previously published rTMS trial In this study there was clearly a marked benefit of active over sham stimulation There was a significant difference between the groups at 2 weeks F125255 p0001 which remained significant at all other trial time points F54439 p0005 Patients continued to respond across the 6 weeks of active treatment
Most critically by study end 13 of 25 patients in the active group 50 and only 2 in the sham group met response criteria on the HAMD 9 patients in the active group 36 and no patients in the sham group met criteria for clinical remission A further 45 of patients in the sham group who crossed over to active treatment at trial end went on to respond in a manner meeting response criteria 33 remission criteria
rTMS in Bipolar Disorder - Depressive Phase Markedly fewer trials have been conducted investigating the effects of rTMS in BPAD Of these a small number have focused on the treatment of mania using high-frequency stimulation applied to the right DLPFC Initial open studies of this technique appeared promising although negative results have also been published 27 and there is need for a substantive definitive trial
Even fewer studies have focused specifically on the treatment of BPAD-DP In the first of these Dolberg et al randomized 20 patients to HFL-TMS or placebo 28 Unfortunately the brief report published provides few experimental details but the active group appeared to do better than the sham group after 2 weeks of treatment In contrast in the only other randomized trial Nahas et al found no difference in response between active HFL-TMS and sham in a study of 23 patients 29 In this study there was a response rate of 36 in the active and 33 in the sham group The authors questioned whether the type of sham coil they used was really in part active due the degree of brain stimulation produced with the coil orientation they applied The same group followed 7 patients who responded to active rTMS over 12 months providing weekly maintenance rTMS 30 There appeared to be some degree of benefit of maintenance treatment although this was difficult to quantify due to the open nature of the follow up
The only other source of information about the usefulness of rTMS in BPAD-DP comes from the description of the response of these patients in general trials with mixed samples Unfortunately some of the larger studies including the Neuronetics trial described above 18 have excluded BPAD patients and most of the studies other than our own have had too small samples to allow meaningful data to be extracted on subgroups In studies we have conducted none of which was designed to directly investigate rTMS responses in BPAD a total of 50 BPAD-DP have been treated to date These have been treated across 5 separate trials In most of these trials the number of subjects is too limited to draw any useful inferences However a total of 21 patients with BPAD-DP received LFR-TMS in the clinical effectiveness trial described above over a 4 week period study 2 In this group there was a significant reduction in Hamilton Depression Rating Scale HAMD scores between baseline and week 2 baseline 216 57 week 2 12063 p0001 and between baseline and week 4 baseline 216 57 week 4 9763 p0001 Interestingly given that this is the first published sample with a treatment duration of greater than 2 weeks the group showed a significant reduction in HAMD scores between week 2 and 4 p005 indicating the benefit of the longer period of treatment 15 71 of these patients met response criteria 50 reduction in HAMD scores by trial end
Although this study did not include a sham control group it strongly suggests that low frequency right sided rTMS has therapeutic potential in BPAD-DP which warrants the conduct of a definitive randomized controlled trial Despite widespread communication within the international rTMS research community the CIA of this grant is a committee member of the International Society for Transcranial Magnetic Stimulation we are aware of no large study exploring the use of rTMS in BPAD-DP that is completed and unpublished or currently underway In addition we are not aware of any current or past studies exploring the role of LFR-TMS in this condition
OTHER GAPS IN THE LITERATURE Clearly BPAD is a relapsing illness and there is no substantive data on the impact of rTMS on longer term outcomes Long term follow-up data with rTMS treatment is very limited in general One study has reported similar 6 month relapse rates following rTMS and ECT treatment 31 but only considered the outcome in a limited group of patients n21 in the rTMS group Unpublished data from the Neuronetics trial CIA 52 suggests that relapse rates post rTMS are similar or lower than those seen in previously published large ECT studies M Demitrack personal communication We have reported relapse and re-treatment at an average time of 9 months post acute treatment but this sample was not comprehensively followed between the end of acute treatment and relapse CIA 36 We will aim to significantly contribute to understanding the outcome of treatment by including structured assessments over a 12 month follow up period in this study
Hypotheses Research Questions
Primary Hypotheses
1 Treatment with high frequency left sided rTMS will result in a greater reduction in HAMD scores than sham rTMS
2 Treatment with low frequency right sided rTMS will result in a greater reduction in HAMD scores than sham rTMS
Secondary Hypotheses 3 Greater than 50 of treatment responders to rTMS will continue to experience clinical benefits from rTMS as indexed by HAMD scores remaining within 25 of the HAMD score achieved at the end of the acute treatment phase during the 6 months of post acute treatment follow up
4 Treatment with high frequency left sided rTMS and low frequency right sided rTMS will both be well tolerated as assessed by a retention rate in treatment of greater than 90
Methodology including project design and sequence of procedures
Experimental Design The study has been designed to allow the reporting of results in a manner consistent with the international CONSORT guidelines
The study will involve a 4-week 20 session randomized double-blind clinical trial with 3 treatment arms conducted at a two sites Alfred Psychiatry Research Centre in Melbourne and the Centre for Addiction and Mental Health Department of Psychiatry University of Toronto Toronto Ontario Canada
Randomization will occur via the generation of a computer number sequence with stratification by site and diagnosis of bipolar I or bipolar II disorder Subjects will be randomized immediately prior to the commencement of the first treatment session after the measurement of bilateral resting motor thresholds with standard means CIA 2
The main study phase phase 1 will involve the 4 week randomized controlled trial conducted under strict double-blind conditions Fidelity of the blinding process will be assessed at the end of this period with patients and raters
Phase 2 will involve the provision of open label treatment with LFR-TMS to patients who received sham treatment and wish to receive active rTMS
Responders to active treatment from phase 1 or 2 will enter phase 3 a 6 month follow up period where participants will be reassessed at 2 weeks 1 3 and 6 months
Subjects
Sample Size We aim to recruit 40 patients into each group total n120 The sample size calculation for the study was conducted based on the within group standard deviation of 7 this was the upper limit of the standard deviation for the bipolar patients HAMD scores in the low frequency right sided rTMS trial data provided above and between group difference of 50 points change in 2 active groups of 12 based on 4 week change data above and change of 7 in the sham group allowing for a substantial placebo response With an alpha of 005 the study will have a power of 091 to detect a difference in end scores between the 3 groups calculation in PASS 80
Clinical Measures Demographic variables and potential co-variates will be recorded at baseline following a clinical interview These will include the duration of the current episode years from first diagnosis number of previous episodes type and dose of current and previous treatment and family history of mood disorder
Clinical measures will be performed at randomization at 2 and 4 weeks as well as at the follow up assessments A trained rater who is blind to treatment type will administer all measures Raters will be required to maintain 90 reliability on the primary outcome assessments on ratings with 6 monthly assessments based on videotaped interviews
The primary outcome variable will be scores on the 17-item Hamilton Rating Scale for Depression HAMD 33 In addition we will use the Inventory of Depressive Symptomatology IDS - Clinician Version and Patient version 34 In addition we will rate patients on the Young Mania Rating Scale YMRS to assess for the possibility of emergent manic symptoms 35
Assessments made at baseline to explore potential predictors of clinical response will include the CORE rating of melancholia 36 the Measure of Parental Styles 37 the Depressive Personality Inventory 38 and the Costello and Comrey trait anxiety measure 39
To assess for the possibility that rTMS treatment may result in cognitive side effects we will assess cognition at baseline and the end of 4 weeks of treatment with the following tests They may also provide evidence of improved executive frontal functioning produced with the treatment Personal Memory Questionnaire Block Design Test Verbal Paired Associates Recall and Recognition Visual Paired Associates Digit Span WAIS Simple and Complex Reaction Time Finger Tapping Test Verbal Fluency Trail making AB
TMS Treatment TMS will be administered with Medtronic Magpro30 magnetic stimulators using 70mm figure of 8 coils Prior to the commencement of treatment TMS single pulse TMS will be used to measure the resting motor thresholds RMT for the abductor pollicis brevis APB bilaterally in all subjects using standard published methods CIA 2
Stimulation parameters rTMS will be administered on a daily basis 5 days per week for all subjects Left 10Hz 110 RMT 40 Trains 5 second duration 25 second inter-train interval ie 2000 pulses Right 1 Hz 110 RMT 1 Train of 1200 pulses Sham Sham patients will be successively randomized to sham stimulation on either the left or right at the same stimulation parameters but using a sham coil
The sessions have been matched for treatment duration Missed sessions will be made up by an extension of the treatment duration but only one missed session will be allowed per week
The two active conditions have been matched for approximate treatment duration rather than pulse number in keeping with previous research CIA 15 Matching for pulse number would result in either a left treatment schedule with significantly fewer pulses than appears effective in other studies or an excessively long right treatment schedule
Stimulation localization This will follow a slight modification of standard procedures Firstly the site for the optimal activation of the abductor pollicis brevis muscle in the contralateral hand will be located whilst stimulating the relevant motor cortical region at supra-threshold intensity This site will be marked on the scalp We will then measure 6 cm anteriorly on the scalp surface and mark it with ink This point will be then used as the site of stimulation The majority of rTMS studies have measured 5 cm anteriorly However this has been shown to result consistently in localization that is posterior to the dorsolateral PFC 40 The measurement described here should result in more consistent treatment of dorsolateral PFC but still provide considerable stimulation overlap with the established 5 cm site
MRI scan Each subject will undergo a 3D sagittally orientated T1 weighted structural MR scan on the 15 Tesla MRI scanner at the Alfred or Toronto Western Hospital 128 slices Analysis of scalp to cortex distance in prefrontal cortex and at the site of stimulation will be conducted using previously published methods 41 by a post doctoral research fellow with considerable experience in structural neuroimaging analysis using the ANALYSE software package During scanning the site of motor cortex and the stimulation site will be marked on the scalp with 2 vitamin E capsules This will also allow the post hoc analysis of our actual site of stimulation in comparison to cortical landmarks of the DLPFC
Electroencephalography EEG EEG before treatment will be used to examine mean absolute spectral power within 5 frequency bands The mean absolute power in squared microvolts per hertz will then be computed within the following 5 frequency bands delta 05-35 Hz theta 35-75 Hz alpha 75-125 Hz beta 1 125-205 Hz and beta 2 205-325 Hz EEG activation spectral power will be assessed at rest eyes open and closed and during cognitive engagement in several tasks
Concurrent Treatment
Medications will be continued during rTMS if considered safe to do so Patients will only enter the study if there has been no dose increase in the 4 weeks prior to randomization and there has been no significant improvement 15 change in depression in one week between screening and the first study assessment visit based on HAMD ratings at these two visits The commencement of any new psychotropic medication will not be allowed in the 4 weeks prior to study entry and during the study period The continuation of antidepressant medication mood stabilizers places the trial in a realistic clinical framework We will minimize the confounding effect of medication by
1 Ensuring the patients are stable stable dose and not improving prior to entry
2 Controlling for medication status in secondary statistical analyzes This way of dealing with medication effects has appeared to quite satisfactory in our previous trials CIA 15 33 and not confounded treatment effects
Statistical Analysis The primary analysis will be conducted on HAMD and secondary analysis on the IDS scores from baseline to week 4 using the last observation carried forward method in the case of subjects who exit the study prematurely ANOVA tests and 2 tests will be used to examine differences between demographic and clinical characteristics between the groups for continuous and categorical variables following testing for normality of the data Repeated measures general linear models will be computed to look for differences in group scores across the study time points baseline week 2 week 4 with group as the between subjects variable Concurrent antidepressant use will be included in a secondary analysis as a covariate
Analysis of the follow up phase will descriptively compare the number of patients who continue to report depressive symptoms below the HAMD threshold for clinical response
1 Fitzgerald PB Is it time to introduce repetitive transcranial magnetic stimulation into standard clinical practice for the treatment of depressive disorders Aust N Z J Psychiatry 2003 37 5-11
2 Fitzgerald PB et al Transcranial magnetic stimulation in the treatment of depression a double-blind placebo-controlled trial Archives of General Psychiatry 2003 60 1002-8
3 Fitzgerald PB et al A Randomized Controlled Trial of Sequential Bilateral Repetitive Transcranial Magnetic Stimulation for Treatment-Resistant Depression American Journal of Psychiatry 2006 163 88-94
4 Loo CK et al A review of the efficacy of transcranial magnetic stimulation TMS treatment for depression and current and future strategies to optimize efficacy J Affect Disord 2005 88 255-67
5 George MS et al Daily repetitive transcranial magnetic stimulation rTMS improves mood in depression Neuroreport 1995 6 1853-6
6 George MS et al Mood improvement following daily left prefrontal repetitive transcranial magnetic stimulation in patients with depression A placebo-controlled crossover trial Am J Psychiatry 1997 154 1752-6
7 Pascual-Leone A et al Rapid-rate transcranial magnetic stimulation of the left dorsolateral prefrontal cortex in drug-resistant depression Lancet 1996 348 233-7
8 Lisanby SH et al Sham TMS intracerebral measurement of the induced electrical field and the induction of motor-evoked potentials Biol Psychiatry 2001 49 460-3
9 McNamara B et al Transcranial magnetic stimulation for depression and other psychiatric disorders Psychol Med 2001 31 1141-6
10 Holtzheimer PE 3rd et al A meta-analysis of repetitive transcranial magnetic stimulation in the treatment of depression Psychopharmacological Bulletin 2001 35 149-69
11 Burt T et al Neuropsychiatric applications of transcranial magnetic stimulation a meta analysis International Journal of Neuropsychopharmacology 2002 5 73-103
12 Kozel A et al Meta-analysis of left prefrontal repetitive transcranial magnetic stimulation rTMS to treat depression Journal of Clinical Practice 2002 8 270-5
13 Martin JL et al Repetitive transcranial magnetic stimulation for the treatment of depression Systematic review and meta-analysis Br J Psychiatry 2003 182 480-91
14 Pridmore S et al Comparison of unlimited numbers of rapid transcranial magnetic stimulation rTMS and ECT treatment sessions in major depressive episode Int J Neuropsychopharmacol 2000 3 129-34
15 Janicak PG et al Repetitive transcranial magnetic stimulation versus electroconvulsive therapy for major depression preliminary results of a randomised trial Biological Psychiatry 2002 51 659-67
16 Grunhaus L et al Repetitive transcranial magnetic stimulation is as effective as electroconvulsive therapy in the treatment of nondelusional major depressive disorder an open study Biological Psychiatry 2000 47 314-24
17 Grunhaus L et al Effects of transcranial magnetic stimulation on severe depression Similarities with ECT Biological Psychiatry 1998 43 76S
18 Chen R et al Depression of motor cortex excitability by low-frequency transcranial magnetic stimulation Neurology 1997 48 1398-403
19 Klein E et al Therapeutic efficiency of right prefrontal slow repetitive transcranial magnetic stimulation in major depression a double blind controlled trial Archives of General Psychiatry 1999 56 315-20
20 Isenberg K et al Low frequency rTMS stimulation of the right frontal cortex is as effective as high frequency rTMS stimulation of the left frontal cortex for antidepressant-free treatment-resistant depressed patients Ann Clin Psychiatry 2005 17 153-9
21 Loo CK et al Double-blind controlled investigation of bilateral prefrontal transcranial magnetic stimulation for the treatment of resistant major depression Psychol Med 2003 33 33-40
22 Cohen CI et al The efficacy and safety of bilateral rTMS in medication-resistant depression J Clin Psychiatry 2003 64 613-4
23 Conca A et al Combining high and low frequencies in rTMS antidepressive treatment preliminary results Hum Psychopharmacol 2002 17 353-6
24 Hausmann A et al No benefit derived from repetitive transcranial magnetic stimulation in depression a prospective single centre randomised double blind sham controlled add on trial J Neurol Neurosurg Psychiatry 2004 75 320-2
25 Rybak M et al An attempt to increase the rate and magnitude of the antidepressant effect of transcranial magentic stimulation German Journal of Psychiatry 2005 8 59-65
26 Fitzgerald PB et al A Naturalistic Study of the Use of Transcranial Magnetic Stimulation in the Treatment of Depressive Relapse Aust N Z J Psychiatry 2006 in press
27 Dannon PN et al Three and six-month outcome following courses of either ECT or rTMS in a population of severely depressed individuals--preliminary report Biol Psychiatry 2002 51 687-90
28 Holtzheimer PE 3rd et al Shorter duration of depressive episode may predict response to repetitive transcranial magnetic stimulation Depress Anxiety 2004 19 24-30
29 Nahas Z et al Safety and benefits of distance-adjusted prefrontal transcranial magnetic stimulation in depressed patients 55-75 years of age a pilot study Depress Anxiety 2004 19 249-56
30 Fitzgerald PB et al The application of transcranial magnetic stimulation in psychiatry and neurosciences research Acta Psychiatr Scand 2002 105 324-40
31 Fava M Diagnosis and definition of treatment-resistant depression Biol Psychiatry 2003 53 649-59
32 Khan A et al Severity of depression and response to antidepressants and placebo an analysis of the Food and Drug Administration database J Clin Psychopharmacol 2002 22 40-5
33 Hadzi-Pavlovic D et al Inter-rater reliability of a refined index of melancholia the CORE system J Affect Disord 1993 27 155-62
34 Parker G et al The development of a refined measure of dysfunctional parenting and assessment of its relevance in patients with affective disorders Psychol Med 1997 27 1193-203
35 Huprich SK et al The Depressive Personality Disorder Inventory an initial examination of its psychometric properties J Clin Psychol 1996 52 153-9
36 Costello CG et al Scales for measuring depression and anxiety J Psychol 1967 66 303-13
37 Herwig U et al Transcranial magnetic stimulation in therapy studies examination of the reliability of standard coil positioning by neuronavigation Biological Psychiatry 2001 50 58-61
38 Nahas Z et al Brain effects of TMS delivered over prefrontal cortex in depressed adults role of stimulation frequency and coil-cortex distance J Neuropsychiatry Clin Neurosci 2001 13 459-70
Despite this there has been relatively sparse investigation of treatments for bipolar depression with guidelines based primarily on expert judgment rather than randomized controlled trials 7 First line treatment typically involves treatment with a mood stabilizer - lithium sodium valproate or carbamazepine 7 Addition of an antidepressant such as an SSRI buproprion or venlafaxine may be indicated if depression persists although there is a possibility of inducing rapid cycling and manic or manic episodes Alternative agents such as lamotrigine and atypical antipsychotics may also be considered 7 However there is little firm evidence in this area and the lack of controlled studies in the treatment of bipolar depression was described by Thase in 2005 7 as an embarrassment to the field In addition to this lack of evidence of efficacy it is clear that a significant proportion of patients with bipolar depression do not respond to the range of commonly used treatments including medication combinations 8 It is clear that the depressive phase of bipolar disorder is an important clinical problem and one in which there is a considerable need for the development of new treatments
rTMS is a technique that was first developed in the mid 1980s which involves the use of a time variable magnetic field to stimulate brain activity rTMS methods have generally been found to be well tolerated safe and without complications such as the use of an anesthetic that are required with more invasive forms of brain stimulation such as electroconvulsive therapy
The ability of rTMS to affect mood was first noted in normal controls in the late 1980s Studies using focal stimulation of the dorsolateral prefrontal cortex DLPFC in depression first appeared in the mid 1990s 9-11 These studies produced promising results with reduced depression severity following left prefrontal cortex PFC stimulation Since that time a considerable number of trials of left DLPFC rTMS have been conducted The majority of these studies have used 5-20 Hz stimulation frequency Most of these have predominately been small in sample size and of short duration ie 10 treatments CIA pub 11 They have also been confounded by concerns about the choice of sham stimulation type 12 and variation in stimulation dose provided The studies with the most robust clinical effects have used a higher number of pulses per subject and higher stimulation intensity levels suggesting a dose - response relationship CIA pub 211 They have almost exclusively focused on the treatment of patients with unipolar major depression although some of these studies have included a subset of patients with BPAD-DP
There have been at least 6 meta-analyses of the antidepressant effects of left PFC rTMS All but one have shown greater antidepressant effects of 2 weeks of HFL-TMS compared to sham these included an analysis of 6 reports 13 of 12 studies 14 of 16 studies 15 of 10 studies 16 and a Cochrane review of 14 17 The single negative study included only 6 reports with 91 subjects and as such had less power than most of the other meta-analyses Of the larger studies Holtzheimer et al reported a weighted mean effect size of 081 14 Burt et al reported an effect size of 067 15 and Kozel at al an effect size of 053 16 These are moderate to large effects However the studies repeatedly report that the overall clinical results observed were not that impressive For example a mean overall improvement of only 238 on the HAMD in the blinded studies reviewed in 14 compared to 73 in the sham group
Attempting to address the issue of definitely establishing the efficacy of rTMS in depression a large international trial has been recently completed Conducted by a private TMS manufacturer Neuronetics Pty Ltd this involved a randomized trial of HFL-TMS 10Hz compared to placebo over up to 9 weeks of treatment The results of this study show the statistically superiority of active over sham rTMS treatment 18 Currently the results of this trial are being utilized in support of an FDA application for the Neuronetics device for treatment of depression M Demitrack personal communication
In addition to sham controlled trials there have also been a series of trials comparing HFL-TMS to ECT 19-22 Encouragingly these have reported no differences in responses rates between ECT and HFL-TMS except for one study including psychotic patients showing greater benefit with ECT in the psychotic group 22 and a second trial which recently reported better responses with bilateral or unilateral ECT of unlimited treatment duration compared to a fixed course of 3 weeks of unilateral left PFC rTMS 23 However some of these studies have not necessarily had sufficient power to detect subtle differences between the groups
More recently several alternative rTMS paradigms have shown promise Low frequency rTMS applied to right PFC LFR-TMS contrary to high frequency rTMS is known to reduce local cortical excitability 24 The initial trial of LFR-TMS established its efficacy in a non treatment resistant sample of patients 25 Funded by a previous NHMRC grant we have conducted research establishing the efficacy of LFR-TMS as compared to HFL-TMS and placebo CIA 15
Previous Study 1
In this study 60 patients were randomized to either HFL-TMS or LFR-TMS or a sham stimulation condition n20 in each group All had treatment resistant depression TRD and had failed multiple antidepressant medication trials mean number 57 34 There were no baseline clinical or demographic differences between the three groups Over the double blind phase of the study there was clearly an antidepressant effect of both active groups that was superior to the response to sham stimulation There was a continued improvement in both active groups across the 4 weeks of the study for the group as whole after the 4 weeks of treatment the mean percentage change in MADRS score from baseline was 480 179 range 151 - 875 These results demonstrated that both HFL-TMS and LFR-TMS have substantial therapeutic efficacy and that robust clinical response appeared to require at least 20 sessions of treatment with the parameters used However only a sub-population of patients responded to treatment
The equivalence of HFL-TMS and LFR-TMS has also been demonstrated in a more recent study 26
Previous Study 2
We have also conducted a large scale clinical effectiveness trial of LFR-TMS comparing 1 Hz and 2 Hz stimulation to right PFC CIA 47 This study involved the randomization of 130 patients with treatment resistant major depression to receive right PFC stimulation in a single daily 15 minute train at either 1 or 2 Hz 2 Hz stimulation was investigated as a potential way of doubling the number of applied stimuli within identical treatment time to increase the treatment dose and potentially enhance treatment response Treatment response was equivalent between the 2 groups 623 240 change in the 1 Hz group 647 210 change in the 2 Hz group over 4 weeks with no difference in response This does not support the substitution of 2 Hz as an optimal condition for LFR-TMS
Another alternative paradigm is sequential bilateral rTMS SBrTMS the application of HFL-TMS and LFR-TMS one after the other in the same treatment sessions We have recently completed the first large study of this technique and the first to extend treatment beyond 10 days CIA 33
Previous Study 3 In the study conducted we combined HFL-TMS and LFR-TMS sequentially in each treatment session in a trial comparing active to sham stimulation n50 25 per group Importantly treatment was provided for up to 6 weeks longer than any previously published rTMS trial In this study there was clearly a marked benefit of active over sham stimulation There was a significant difference between the groups at 2 weeks F125255 p0001 which remained significant at all other trial time points F54439 p0005 Patients continued to respond across the 6 weeks of active treatment
Most critically by study end 13 of 25 patients in the active group 50 and only 2 in the sham group met response criteria on the HAMD 9 patients in the active group 36 and no patients in the sham group met criteria for clinical remission A further 45 of patients in the sham group who crossed over to active treatment at trial end went on to respond in a manner meeting response criteria 33 remission criteria
rTMS in Bipolar Disorder - Depressive Phase Markedly fewer trials have been conducted investigating the effects of rTMS in BPAD Of these a small number have focused on the treatment of mania using high-frequency stimulation applied to the right DLPFC Initial open studies of this technique appeared promising although negative results have also been published 27 and there is need for a substantive definitive trial
Even fewer studies have focused specifically on the treatment of BPAD-DP In the first of these Dolberg et al randomized 20 patients to HFL-TMS or placebo 28 Unfortunately the brief report published provides few experimental details but the active group appeared to do better than the sham group after 2 weeks of treatment In contrast in the only other randomized trial Nahas et al found no difference in response between active HFL-TMS and sham in a study of 23 patients 29 In this study there was a response rate of 36 in the active and 33 in the sham group The authors questioned whether the type of sham coil they used was really in part active due the degree of brain stimulation produced with the coil orientation they applied The same group followed 7 patients who responded to active rTMS over 12 months providing weekly maintenance rTMS 30 There appeared to be some degree of benefit of maintenance treatment although this was difficult to quantify due to the open nature of the follow up
The only other source of information about the usefulness of rTMS in BPAD-DP comes from the description of the response of these patients in general trials with mixed samples Unfortunately some of the larger studies including the Neuronetics trial described above 18 have excluded BPAD patients and most of the studies other than our own have had too small samples to allow meaningful data to be extracted on subgroups In studies we have conducted none of which was designed to directly investigate rTMS responses in BPAD a total of 50 BPAD-DP have been treated to date These have been treated across 5 separate trials In most of these trials the number of subjects is too limited to draw any useful inferences However a total of 21 patients with BPAD-DP received LFR-TMS in the clinical effectiveness trial described above over a 4 week period study 2 In this group there was a significant reduction in Hamilton Depression Rating Scale HAMD scores between baseline and week 2 baseline 216 57 week 2 12063 p0001 and between baseline and week 4 baseline 216 57 week 4 9763 p0001 Interestingly given that this is the first published sample with a treatment duration of greater than 2 weeks the group showed a significant reduction in HAMD scores between week 2 and 4 p005 indicating the benefit of the longer period of treatment 15 71 of these patients met response criteria 50 reduction in HAMD scores by trial end
Although this study did not include a sham control group it strongly suggests that low frequency right sided rTMS has therapeutic potential in BPAD-DP which warrants the conduct of a definitive randomized controlled trial Despite widespread communication within the international rTMS research community the CIA of this grant is a committee member of the International Society for Transcranial Magnetic Stimulation we are aware of no large study exploring the use of rTMS in BPAD-DP that is completed and unpublished or currently underway In addition we are not aware of any current or past studies exploring the role of LFR-TMS in this condition
OTHER GAPS IN THE LITERATURE Clearly BPAD is a relapsing illness and there is no substantive data on the impact of rTMS on longer term outcomes Long term follow-up data with rTMS treatment is very limited in general One study has reported similar 6 month relapse rates following rTMS and ECT treatment 31 but only considered the outcome in a limited group of patients n21 in the rTMS group Unpublished data from the Neuronetics trial CIA 52 suggests that relapse rates post rTMS are similar or lower than those seen in previously published large ECT studies M Demitrack personal communication We have reported relapse and re-treatment at an average time of 9 months post acute treatment but this sample was not comprehensively followed between the end of acute treatment and relapse CIA 36 We will aim to significantly contribute to understanding the outcome of treatment by including structured assessments over a 12 month follow up period in this study
Hypotheses Research Questions
Primary Hypotheses
1 Treatment with high frequency left sided rTMS will result in a greater reduction in HAMD scores than sham rTMS
2 Treatment with low frequency right sided rTMS will result in a greater reduction in HAMD scores than sham rTMS
Secondary Hypotheses 3 Greater than 50 of treatment responders to rTMS will continue to experience clinical benefits from rTMS as indexed by HAMD scores remaining within 25 of the HAMD score achieved at the end of the acute treatment phase during the 6 months of post acute treatment follow up
4 Treatment with high frequency left sided rTMS and low frequency right sided rTMS will both be well tolerated as assessed by a retention rate in treatment of greater than 90
Methodology including project design and sequence of procedures
Experimental Design The study has been designed to allow the reporting of results in a manner consistent with the international CONSORT guidelines
The study will involve a 4-week 20 session randomized double-blind clinical trial with 3 treatment arms conducted at a two sites Alfred Psychiatry Research Centre in Melbourne and the Centre for Addiction and Mental Health Department of Psychiatry University of Toronto Toronto Ontario Canada
Randomization will occur via the generation of a computer number sequence with stratification by site and diagnosis of bipolar I or bipolar II disorder Subjects will be randomized immediately prior to the commencement of the first treatment session after the measurement of bilateral resting motor thresholds with standard means CIA 2
The main study phase phase 1 will involve the 4 week randomized controlled trial conducted under strict double-blind conditions Fidelity of the blinding process will be assessed at the end of this period with patients and raters
Phase 2 will involve the provision of open label treatment with LFR-TMS to patients who received sham treatment and wish to receive active rTMS
Responders to active treatment from phase 1 or 2 will enter phase 3 a 6 month follow up period where participants will be reassessed at 2 weeks 1 3 and 6 months
Subjects
Sample Size We aim to recruit 40 patients into each group total n120 The sample size calculation for the study was conducted based on the within group standard deviation of 7 this was the upper limit of the standard deviation for the bipolar patients HAMD scores in the low frequency right sided rTMS trial data provided above and between group difference of 50 points change in 2 active groups of 12 based on 4 week change data above and change of 7 in the sham group allowing for a substantial placebo response With an alpha of 005 the study will have a power of 091 to detect a difference in end scores between the 3 groups calculation in PASS 80
Clinical Measures Demographic variables and potential co-variates will be recorded at baseline following a clinical interview These will include the duration of the current episode years from first diagnosis number of previous episodes type and dose of current and previous treatment and family history of mood disorder
Clinical measures will be performed at randomization at 2 and 4 weeks as well as at the follow up assessments A trained rater who is blind to treatment type will administer all measures Raters will be required to maintain 90 reliability on the primary outcome assessments on ratings with 6 monthly assessments based on videotaped interviews
The primary outcome variable will be scores on the 17-item Hamilton Rating Scale for Depression HAMD 33 In addition we will use the Inventory of Depressive Symptomatology IDS - Clinician Version and Patient version 34 In addition we will rate patients on the Young Mania Rating Scale YMRS to assess for the possibility of emergent manic symptoms 35
Assessments made at baseline to explore potential predictors of clinical response will include the CORE rating of melancholia 36 the Measure of Parental Styles 37 the Depressive Personality Inventory 38 and the Costello and Comrey trait anxiety measure 39
To assess for the possibility that rTMS treatment may result in cognitive side effects we will assess cognition at baseline and the end of 4 weeks of treatment with the following tests They may also provide evidence of improved executive frontal functioning produced with the treatment Personal Memory Questionnaire Block Design Test Verbal Paired Associates Recall and Recognition Visual Paired Associates Digit Span WAIS Simple and Complex Reaction Time Finger Tapping Test Verbal Fluency Trail making AB
TMS Treatment TMS will be administered with Medtronic Magpro30 magnetic stimulators using 70mm figure of 8 coils Prior to the commencement of treatment TMS single pulse TMS will be used to measure the resting motor thresholds RMT for the abductor pollicis brevis APB bilaterally in all subjects using standard published methods CIA 2
Stimulation parameters rTMS will be administered on a daily basis 5 days per week for all subjects Left 10Hz 110 RMT 40 Trains 5 second duration 25 second inter-train interval ie 2000 pulses Right 1 Hz 110 RMT 1 Train of 1200 pulses Sham Sham patients will be successively randomized to sham stimulation on either the left or right at the same stimulation parameters but using a sham coil
The sessions have been matched for treatment duration Missed sessions will be made up by an extension of the treatment duration but only one missed session will be allowed per week
The two active conditions have been matched for approximate treatment duration rather than pulse number in keeping with previous research CIA 15 Matching for pulse number would result in either a left treatment schedule with significantly fewer pulses than appears effective in other studies or an excessively long right treatment schedule
Stimulation localization This will follow a slight modification of standard procedures Firstly the site for the optimal activation of the abductor pollicis brevis muscle in the contralateral hand will be located whilst stimulating the relevant motor cortical region at supra-threshold intensity This site will be marked on the scalp We will then measure 6 cm anteriorly on the scalp surface and mark it with ink This point will be then used as the site of stimulation The majority of rTMS studies have measured 5 cm anteriorly However this has been shown to result consistently in localization that is posterior to the dorsolateral PFC 40 The measurement described here should result in more consistent treatment of dorsolateral PFC but still provide considerable stimulation overlap with the established 5 cm site
MRI scan Each subject will undergo a 3D sagittally orientated T1 weighted structural MR scan on the 15 Tesla MRI scanner at the Alfred or Toronto Western Hospital 128 slices Analysis of scalp to cortex distance in prefrontal cortex and at the site of stimulation will be conducted using previously published methods 41 by a post doctoral research fellow with considerable experience in structural neuroimaging analysis using the ANALYSE software package During scanning the site of motor cortex and the stimulation site will be marked on the scalp with 2 vitamin E capsules This will also allow the post hoc analysis of our actual site of stimulation in comparison to cortical landmarks of the DLPFC
Electroencephalography EEG EEG before treatment will be used to examine mean absolute spectral power within 5 frequency bands The mean absolute power in squared microvolts per hertz will then be computed within the following 5 frequency bands delta 05-35 Hz theta 35-75 Hz alpha 75-125 Hz beta 1 125-205 Hz and beta 2 205-325 Hz EEG activation spectral power will be assessed at rest eyes open and closed and during cognitive engagement in several tasks
Concurrent Treatment
Medications will be continued during rTMS if considered safe to do so Patients will only enter the study if there has been no dose increase in the 4 weeks prior to randomization and there has been no significant improvement 15 change in depression in one week between screening and the first study assessment visit based on HAMD ratings at these two visits The commencement of any new psychotropic medication will not be allowed in the 4 weeks prior to study entry and during the study period The continuation of antidepressant medication mood stabilizers places the trial in a realistic clinical framework We will minimize the confounding effect of medication by
1 Ensuring the patients are stable stable dose and not improving prior to entry
2 Controlling for medication status in secondary statistical analyzes This way of dealing with medication effects has appeared to quite satisfactory in our previous trials CIA 15 33 and not confounded treatment effects
Statistical Analysis The primary analysis will be conducted on HAMD and secondary analysis on the IDS scores from baseline to week 4 using the last observation carried forward method in the case of subjects who exit the study prematurely ANOVA tests and 2 tests will be used to examine differences between demographic and clinical characteristics between the groups for continuous and categorical variables following testing for normality of the data Repeated measures general linear models will be computed to look for differences in group scores across the study time points baseline week 2 week 4 with group as the between subjects variable Concurrent antidepressant use will be included in a secondary analysis as a covariate
Analysis of the follow up phase will descriptively compare the number of patients who continue to report depressive symptoms below the HAMD threshold for clinical response
1 Fitzgerald PB Is it time to introduce repetitive transcranial magnetic stimulation into standard clinical practice for the treatment of depressive disorders Aust N Z J Psychiatry 2003 37 5-11
2 Fitzgerald PB et al Transcranial magnetic stimulation in the treatment of depression a double-blind placebo-controlled trial Archives of General Psychiatry 2003 60 1002-8
3 Fitzgerald PB et al A Randomized Controlled Trial of Sequential Bilateral Repetitive Transcranial Magnetic Stimulation for Treatment-Resistant Depression American Journal of Psychiatry 2006 163 88-94
4 Loo CK et al A review of the efficacy of transcranial magnetic stimulation TMS treatment for depression and current and future strategies to optimize efficacy J Affect Disord 2005 88 255-67
5 George MS et al Daily repetitive transcranial magnetic stimulation rTMS improves mood in depression Neuroreport 1995 6 1853-6
6 George MS et al Mood improvement following daily left prefrontal repetitive transcranial magnetic stimulation in patients with depression A placebo-controlled crossover trial Am J Psychiatry 1997 154 1752-6
7 Pascual-Leone A et al Rapid-rate transcranial magnetic stimulation of the left dorsolateral prefrontal cortex in drug-resistant depression Lancet 1996 348 233-7
8 Lisanby SH et al Sham TMS intracerebral measurement of the induced electrical field and the induction of motor-evoked potentials Biol Psychiatry 2001 49 460-3
9 McNamara B et al Transcranial magnetic stimulation for depression and other psychiatric disorders Psychol Med 2001 31 1141-6
10 Holtzheimer PE 3rd et al A meta-analysis of repetitive transcranial magnetic stimulation in the treatment of depression Psychopharmacological Bulletin 2001 35 149-69
11 Burt T et al Neuropsychiatric applications of transcranial magnetic stimulation a meta analysis International Journal of Neuropsychopharmacology 2002 5 73-103
12 Kozel A et al Meta-analysis of left prefrontal repetitive transcranial magnetic stimulation rTMS to treat depression Journal of Clinical Practice 2002 8 270-5
13 Martin JL et al Repetitive transcranial magnetic stimulation for the treatment of depression Systematic review and meta-analysis Br J Psychiatry 2003 182 480-91
14 Pridmore S et al Comparison of unlimited numbers of rapid transcranial magnetic stimulation rTMS and ECT treatment sessions in major depressive episode Int J Neuropsychopharmacol 2000 3 129-34
15 Janicak PG et al Repetitive transcranial magnetic stimulation versus electroconvulsive therapy for major depression preliminary results of a randomised trial Biological Psychiatry 2002 51 659-67
16 Grunhaus L et al Repetitive transcranial magnetic stimulation is as effective as electroconvulsive therapy in the treatment of nondelusional major depressive disorder an open study Biological Psychiatry 2000 47 314-24
17 Grunhaus L et al Effects of transcranial magnetic stimulation on severe depression Similarities with ECT Biological Psychiatry 1998 43 76S
18 Chen R et al Depression of motor cortex excitability by low-frequency transcranial magnetic stimulation Neurology 1997 48 1398-403
19 Klein E et al Therapeutic efficiency of right prefrontal slow repetitive transcranial magnetic stimulation in major depression a double blind controlled trial Archives of General Psychiatry 1999 56 315-20
20 Isenberg K et al Low frequency rTMS stimulation of the right frontal cortex is as effective as high frequency rTMS stimulation of the left frontal cortex for antidepressant-free treatment-resistant depressed patients Ann Clin Psychiatry 2005 17 153-9
21 Loo CK et al Double-blind controlled investigation of bilateral prefrontal transcranial magnetic stimulation for the treatment of resistant major depression Psychol Med 2003 33 33-40
22 Cohen CI et al The efficacy and safety of bilateral rTMS in medication-resistant depression J Clin Psychiatry 2003 64 613-4
23 Conca A et al Combining high and low frequencies in rTMS antidepressive treatment preliminary results Hum Psychopharmacol 2002 17 353-6
24 Hausmann A et al No benefit derived from repetitive transcranial magnetic stimulation in depression a prospective single centre randomised double blind sham controlled add on trial J Neurol Neurosurg Psychiatry 2004 75 320-2
25 Rybak M et al An attempt to increase the rate and magnitude of the antidepressant effect of transcranial magentic stimulation German Journal of Psychiatry 2005 8 59-65
26 Fitzgerald PB et al A Naturalistic Study of the Use of Transcranial Magnetic Stimulation in the Treatment of Depressive Relapse Aust N Z J Psychiatry 2006 in press
27 Dannon PN et al Three and six-month outcome following courses of either ECT or rTMS in a population of severely depressed individuals--preliminary report Biol Psychiatry 2002 51 687-90
28 Holtzheimer PE 3rd et al Shorter duration of depressive episode may predict response to repetitive transcranial magnetic stimulation Depress Anxiety 2004 19 24-30
29 Nahas Z et al Safety and benefits of distance-adjusted prefrontal transcranial magnetic stimulation in depressed patients 55-75 years of age a pilot study Depress Anxiety 2004 19 249-56
30 Fitzgerald PB et al The application of transcranial magnetic stimulation in psychiatry and neurosciences research Acta Psychiatr Scand 2002 105 324-40
31 Fava M Diagnosis and definition of treatment-resistant depression Biol Psychiatry 2003 53 649-59
32 Khan A et al Severity of depression and response to antidepressants and placebo an analysis of the Food and Drug Administration database J Clin Psychopharmacol 2002 22 40-5
33 Hadzi-Pavlovic D et al Inter-rater reliability of a refined index of melancholia the CORE system J Affect Disord 1993 27 155-62
34 Parker G et al The development of a refined measure of dysfunctional parenting and assessment of its relevance in patients with affective disorders Psychol Med 1997 27 1193-203
35 Huprich SK et al The Depressive Personality Disorder Inventory an initial examination of its psychometric properties J Clin Psychol 1996 52 153-9
36 Costello CG et al Scales for measuring depression and anxiety J Psychol 1967 66 303-13
37 Herwig U et al Transcranial magnetic stimulation in therapy studies examination of the reliability of standard coil positioning by neuronavigation Biological Psychiatry 2001 50 58-61
38 Nahas Z et al Brain effects of TMS delivered over prefrontal cortex in depressed adults role of stimulation frequency and coil-cortex distance J Neuropsychiatry Clin Neurosci 2001 13 459-70
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None