Dr Shock MD PhD » Transcranial Magnetic Stimulation

TMS for medication resistant depression

Dr Shock — Tue, 04 May 2010 06:27:57 +0000

It’s been a while since my last post on this blog about transcranial magnetic stimulation (TMS).

Myself ‘m not impressed by it’s efficacy for treatment resistant depression. Especially in treatment resistant depression, whatever that may be, rTMS is probably best avoided for more evidence based form of treatments with proven efficacy.

The reason for this post about TMS is a recent publication in the Journal of Clinical Psychiatry. FDA approval for rTMS was based on a large, industry-sponsored, multicenter, double-blind, monotherapy study with 325 patients with “moderately treatment resistant depression” also discussed on this blog here. My opinion on this trial was

This is a trial very well done. Due to its design only the scores on time point of week 4 are truly double-blind. They introduced a new method for sham treatment: the sham coil had a embedded magnetic shield. This study also shows that longer treatment with rTMS is well tolerated. The use of pharmacotherapy treatment failure as an inclusion criterion every time amazes Dr Shock. There are far better treatment options e.g. plasma level controlled TCAs, lithium addition and ECT to name a few.

Considering the outcome on the time point at week 4, Dr Shock is not very impressed by the results. For significant difference with the primary outcome 6 patients had to be excluded from the analysis. The mean difference between active and sham on the severity scales is in the range of 2-3 points, significant but hardly clinical relevant. Absolute figures on response and remission at week 4 are not given in this article. Remission rate at 6 weeks on the HAMD-17 was 15.5% increasing to 22.6% at week 9 with open labeled therapy. Not very impressive.

Fortunately in this article the authors also state that rTMS was more effective in those with failure of just one antidepressant trial and minimal effective for those patients who failed 2-4 trials. Moreover, the efficacy of rTMS with a structural MRI-based neuro-avigational procedure can have the capacity to improve response to the rTMS treatment in TRD. Other such as altering stimulation frequency increasing dose, and the use of a neuro-navigationally guided rTMS based on pretreatment positron emission tomography (PET) scans did not improve efficacy.

The conclusion of this article sums it up nicely:

….questions remain about patient selection, how best to deliver the treatment, and it’s place in the treatment algorithm relative to existing treatments for depression

What is TMS?
rTMS is a non-invasive method to stimulate the brain. Weak electric currents are induced in the cortex of the brain by rapidly changing magnetic fields (electromagnetic induction). This way, brain activity can be triggered with minimal discomfort, no need for anesthesia, and no cognitive side-effects. Side effects of rTMS are: discomfort or pain from the stimulation of the scalp and associated nerves and muscles on the overlying skin and hearing from the loud click made by the TMS pulses. You can see a treatment with TMS in the video above.

Yip AG, & Carpenter LL (2010). Transcranial magnetic stimulation for medication-resistant depression. The Journal of clinical psychiatry, 71 (4), 502-3 PMID: 20409447

The placebo response of transcranial magnetic stimulation

Dr Shock — Thu, 04 Jun 2009 07:09:26 +0000

The field of placebo response with the use of devices as treatment for major depression is hardly researched. Herb one of my very much appreciated readers and commenter asked me about the evidence on the placebo response to devices for major depression, didn’t have an answer. Tried searching but to no effect until recent. A lot of devices such as treatment with Transcranial Magnetic Stimulation (rTMS), Vagus Nerve Stimulation (VNS) and transcranial direct current stimulation (tDCS) are under study for the treatment of depression, mostly treatment resistant depression.

Two recent meta-analyzes showed that placebo effect plays a significant role in clinical trials of major depressive disorder (MDD). The mean responder raters in the placebo group in antidepressant trials are 29.7% and the drug-placebo differences might be relatively small in patients with MDD due to the large placebo response.

rTMS studies are not optimal to say the least. The allocation to treatment arm is sometimes not mentioned,most of the randomized controlled trials are only single blind and a minority address the integrity of blinding, some of the trials only use completer analyses instead of intention to treat analyzes. For a recent update on the opinion of Dr Shock on rTMS for depression read a recent post on this blog: Transcranial Magnetic Stimulation Gains approval of the FDA for Depression.

In a recent meta analysis in PLoS Medicine they assessed the placebo response of escitalopram and perform an exploratory comparison with rTMS a non-pharmacological intervention trough a systematic review and meta-analysis of recent clinical trials of major depression.

The authors concluded:

We confirmed that placebo response in MDD is large regardless of the intervention and is associated with depression refractoriness and treatment combination (add-on rTMS studies). The magnitude of the placebo response seems to be related with study population and study design rather than the intervention itself.

Patients with severe depression and with treatment-resistant depression present a lower placebo response; while in trials that rTMS is as augmentation of an antidepressant drug, the placebo response is larger. More important the placebo-drug response appears to be larger than sham-rTMS response. This finding is contrary to conventional wisdom that sham devices would have a higher placebo response than placebo pills.

Drawback of this analysis is the difference in study population. In rTMS trials mostly treatment resistant depressed patients were included in contrast to the medication trial, the duration of the trials is shorter for rTMS trials, blinding in rTMS trials is mostly single blind, the rater doesn’t know the treatment condition. The authors used several statistic techniques to eliminate the influence of heterogeneity.

Why is this important?
I have always found it strange that such a new treatment should be tryed first on difficult to treat medication resistant depressed patients. The authors agree with me, in their meta-analyzes refractoriness is associated with a lower placebo response – and, in fact, a lower depression response. They suggest that since medication resistant depressed patients are very unresponsive to any intervention at all, rTMS studies should focus on non-refractory patients. At least future rTMS trials should quantify the degree of refractoriness of each patient. The placebo response is high in add-on rTMS trials – this could indicate there is a synergistic effect with the drug and, therefore, future trials could use a two-way factorial design (i.e., sham vs. real-rTMS and placebo vs. active drug) to address the relationship among rTMS and drug interventions.

Brunoni, A., Lopes, M., Kaptchuk, T., & Fregni, F. (2009). Placebo Response of Non-Pharmacological and Pharmacological Trials in Major Depression: A Systematic Review and Meta-Analysis PLoS ONE, 4 (3) DOI: 10.1371/journal.pone.0004824

rTMS Targeted with MRI Based Neuro-Navigation in Treatment-Resistant Depression

Dr Shock — Wed, 28 Jan 2009 04:02:25 +0000

Efficacy of rTMS for treatment resistant depression isn’t impressive to say the least. The results of studies show little clinical relevance of the efficacy compared to sham rTMS, many studies have reported limited effect sizes or response rates.

A recent study tried to address one of the main concerns that could be responsible for the lack of efficacy namely the way in which the rTMS treatment
is targeted over the Dorsolateral Prefrontal Cortex (DLPFC). The localization is done with “the 5 cm measure”, this involves the localization of the motor cortical site for optimal stimulation of a hand muscle, usually the abductor pollicis brevis, and then measurement 5 cm anteriorly along the scalp surface. This traditional method for targeting the DLPFC with rTMS may be suboptimal, potentially explaining the modest therapeutic effects of rTMS.

In this study the neuro-navigational method was used. This method generally involves localization of the scalp position that corresponds to a brain site identified on an MRI scan from an individual subject.

How was this study done?

we conducted a randomized double blind trial comparing left prefrontal rTMS localized either using the 5 cm method or a navigational technique. We hypothesized that the targeted rTMS would result in a greater therapeutic efficacy in major depressive disorder (MDD) compared with the ‘5 cm’ method. We utilized an ‘offline’ navigational technique to localize the site of DLPFC in the experimental group and compared this with the 5 cm localization method.

Fifty-one patients with treatment-resistant depression were randomized to receive a 3-week course (with a potential 1-week extension) of high-frequency (10 Hz) left-sided rTMS. Thirty trains (5 s duration) were applied daily 5 days per week at 100% of the resting motor threshold. Treatment was targeted with either the standard 5 cm technique (n=27) or using a neuro-navigational approach (n=24). This involved localizing the scalp location that corresponds to a specific site at the junction of Brodmann areas 46 and 9 in the DLPFC based on each individual subject’s MRI scan

The efficacy of rTMS with a structural MRI-based neuro-navigational procedure can have the capacity to improve response to the rTMS treatment in TRD. Other such as altering stimulation frequency
increasing dose, and the use of a neuro-navigationally guided rTMS based on pretreatment positron emission tomography (PET) scans did not improve efficacy.

At least a MRI is needed for this neuro-navigational method and:

The miniBIRD is quite inexpensive and the MRIreg and MRIcro software available as freeware. These are also relatively easy to use with training.

From this research it is hard to tell whether rTMS is efficacious for TRD since the results may have been confounded by non-specific effects given that we have not included a sham control group.
I hope this method might improve efficacy, what do you think?

Paul B Fitzgerald, Kate Hoy, Susan McQueen, Jerome J Maller, Sally Herring, Rebecca Segrave, Michael Bailey, Greg Been, Jayashri Kulkarni, Zafiris J Daskalakis (2009). A Randomized Trial of rTMS Targeted with MRI Based Neuro-Navigation in Treatment-Resistant Depression Neuropsychopharmacology DOI: 10.1038/npp.2008.233

Videos on Transcranial Magnetic Stimulation

Dr Shock — Mon, 22 Dec 2008 04:21:46 +0000

This is a dutch video on TMS used in a prior post on this blog: Look what TMS can do in the hand of a smart dutch psychologist.
Jan Martens is the author of Medblog.nl. He is conducting a historical research about the use of electricity and magnetism in psychiatry. He is now focussing on Transcranial Magnetic Stimulation (TMS).

He is looking for some old videos about TMS. In this recent post he collected several more recent videos on TMS. He is looking for old videos on this subject, can anyone help him out?

This morning I was looking at some videos on TED. This made me wonder if and what kind of videos are online available about TMS. I was hoping to find an old video no one ever heard that I could use for my reseach but unfortunatelly that did not happen. I tried Youtube with the search “transcranial magnetic stimulation” and only a handful of interesting modern videos were the result. No old videos about guinea pigs in a magnetic stimulator came up. Nevertheless I will present the videos below. So if you might come across interesting videos or other information about TMS please let me know in the comments

Nice collection of TMS videos.

Transcranial Magnetic Stimulation Gains approval of the FDA for Depression

Dr Shock — Fri, 17 Oct 2008 04:20:11 +0000

Two blogs announced the news that the FDA had approved rTMS for depression. Therapeutic Neuromodulation

Finally, 3 years after the first presentation of the trial data at the 2005 ACT meeting and one year after the publication of the results in Biological Psychiatry by Jonny O’Reardon the manufacturer Neuronetics got the treatment approved by the FDA for the treatment of depression…

Brain Stimulant has an excellent introduction about the history of rTMS with links to the press release.

My opinion on rTMS in depression has been discussed in several posts on this blog. Had to update some of the information regularly.

You can read a meta-analysis comparing rTMS trials in depression before and after 2002. Trials have improved.

In another trial was very well done but results with rTMS for depression were not very impressive.

Augmentation of antidepressants with rTMS was not successful compared to antidepressants and sham rTMS.

The fast track is reading an update number 1 about rTMS. A Cochrane review is discussed as well as 8 trials since than. In update number 2 other more recent trials are discussed about response prediction and localization of rTMS.

Open trials with rTMS for depression appear abundantly, read all about it here.

There is some good news with rTMS, it can improve working memory and has 8 other effects on brain function.

Overall Dr Shock isn’t impressed of the efficacy of rTMS in depression, what do you think?

Cost effectiveness of ECT versus rTMS

Dr Shock — Fri, 18 Jul 2008 04:50:02 +0000

On this blog a lot of posts are about rapid Transcranial Magnetic Stimulation (rTMS), in short Dr Shock is not convinced that rTMS is effective in depression. On Therapeutic Modulation there is an abstract of a recent published study in the Journal of Affective Disorders about the cost effectiveness of rTMS versus electroconvulsive therapy (ECT).

Their conclusion:

Informal care costs were higher for the rTMS group. Total treatment, service and informal care costs were also higher for the rTMS group. The cost-effectiveness acceptability curves indicated a very small probability that decision-makers would view rTMS as more cost-effective than ECT.

Visible Magnetic Fields

Dr Shock — Mon, 14 Jul 2008 02:21:00 +0000

rTMS is using electromagnetic fields to influence the brain,on this video you can see magnetic fields although not related to rTMS. The comment is very technical but the video is amazing, even scary.
From: Environmental graffiti

Combining their scientific experience with artistic instinct in sound, animation and programming they have created a ‘magnetic magnum opus’ – a ‘tour de force’ of immense invisible force brought down to human scale. And it is precisely the meeting of scale that makes the work so fascinating – to think that these tiny pulsating currents surround our planet on a scale inconceivable to man is not only a humbling thought, but an uplifting one. The inherent beauty of nature is again, in Wordswoth’s words, too much with us.

rTMS can Improve Working Memory

Dr Shock — Thu, 08 May 2008 19:49:00 +0000

Columbia University Medical Center has used conventional transcranial magnetic stimulation (TMS) to reduce the deficits in working memory associated with sleep deprivation.

On Brain Stimulant

rTMS can do other things as well, read about 8 Effects of TMS on Brain Function but how does TMS work?

rTMS not Effective for Depression

Dr Shock — Thu, 08 May 2008 05:42:00 +0000

Rapid Transcranial Magnetic Stimulation (rTMS) to the left prefrontal cortex is not more effective than sham rTMS for depression. This was the result of a recent published randomized controlled trial with 4 month follow-up.

rTMS is a non-invasive method to stimulate the brain. Weak electric currents are induced in the cortex of the brain by rapidly changing magnetic fields (electromagnetic induction). This way, brain activity can be triggered with minimal discomfort, no need for anesthesia, and no cognitive side-effects. Side effects of rTMS are: discomfort or pain from the stimulation of the scalp and associated nerves and muscles on the overlying skin and hearing from the loud click made by the TMS pulses.

The most recent Cochrane review concluded that there is no strong evidence for benefit from using transcranial magnetic stimulation to treat depression, although the small sample sizes do not exclude the possibility of benefit. Since then (2002) 8 randomized controlled trials were published about rTMS and depression, you can read about these trials here.

After the review only one other randomized sham controlled trial was published about rTMS for depression.

Considering the outcome on the time point at week 4, Dr Shock is not very impressed by the results. For significant difference with the primary outcome 6 patients had to be excluded from the analysis. The mean difference between active and sham on the severity scales is in the range of 2-3 points, significant but hardly clinical relevant. Absolute figures on response and remission at week 4 are not given in this article. Remission rate at 6 weeks on the HAMD-17 was 15.5% increasing to 22.6% at week 9 with open labeled therapy. Not very impressive.

Since some previous studies used relatively non-intense stimulation parameters in
the absence of a true placebo condition this trial used an intensive form of rTMS treatment:

Research physicians administered TMS at 110% resting MT (motor threshold) at frequency 10 Hz, in 5-second trains. Twenty trains were given each session with inter-train intervals of 55 seconds. Thus a total of 1000 TMS pulses were given per session and 10 000 per course.

In addition, very few reported meaningful follow-up data, in this study subjects were followed up for 4 months. To prevent unblinding placebo rTMS was delivered in the same way as real rTMS but using a purpose-built sham coil (Magstim Co.,Whitland, UK) that was visually identical to the real coil and made the same clicking sound but did not
deliver a magnetic field to scalp or cortex.

And these are the results:

Overall, Hamilton Depression Rating Scale (HAMD) scores were modestly reduced in both groups but with no significant grouprtime interaction (p=0.09) or group main effect (p=0.85) ; the mean difference in HAMD change scores wasx0.3 (95% CIx3.4 to 2.8). At end-of-treatment time-point, 32% of the real group were responders compared with 10% of the sham group (p=0.06) ; 25% of the real group met the remission criterion compared with 10% of the sham group (p=0.2) ; the mean difference in HAMD change scores was 2.9 (95% CI x0.7 to 6.5). There were no significant differences between the two groups on any secondary outcome measures. Blinding was difficult to maintain for both patients and raters.

In a comment they still want us to believe that rTMS can be promising. In the comment comparison is mad with antidepressants and ECT but these treatments have been studied far more often resulting in not very great advantages but much more evidence and meta analysis with greater power. Moreover, as with other failing treatments in the past rTMS is studied in all kinds of diagnoses. rTMS for Stroke?

A study by a group out of the University of Cologne in Germany has demonstrated that rTMS over the unaffected motor cortex of patients that have had a stroke will make their use of the affected hand more efficient and quicker.

rTMS for Parkinson’s disease and Dystonia?

Most studies to date have shown beneficial effects of rTMS or tDCS on clinical symptoms in Parkinson’s disease (PD) and support the notion of spatial specificity to the effects on motor and nonmotor symptoms. Stimulation parameters have varied widely, however, and some studies are poorly controlled. Studies of rTMS or tDCS in dystonia have provided abundant data on physiology, but few on clinical effects.

Nah, get out of here……….

There is now even deep TMS

This specific technology can excite or inhibit more areas of the brain than conventional TMS. Regular TMS is basically limited the brain’s outer layer, the neocortex, and can only reach about 1 to 2 centimeters into the brain. So it is limited in its ability to affect many brain areas. The new deep tms can stimulate inner brain areas without inducing unbearable electromagnetic fields cortically. This device currently has almost magical properties and it is somewhat difficult to distinguish company hype from real clinical benefit. I’m not sure at this point how selective this targeting technique is. I think it will be fairly difficult to selectively turn on or off specific brain areas without having unintentional effects.

Or cTMS.

Researchers have developed a better way to manipulate a person’s brain functioning. They have created a new type of transcranial magnetic stimulation (TMS) device (called controllable pulse width TMS or cTMS for short) that will allow rectangular pulse shapes of the magnetic fields. This device will enable researchers to control the width of the magnetic pulse that passes through the subjects skull.

Will keep you posted on all this, will it help TMS?. Let me know in the comments what you think?

Mogg, A., Pluck, G., Eranti, S., Landau, S., Purvis, R., Brown, R., Curtis, V., Howard, R., Philpot, M., McLoughlin, D. (2008). A randomized controlled trial with 4-month follow-up of adjunctive repetitive transcranial magnetic stimulation of the left prefrontal cortex for depression. Psychological Medicine, 38(03) DOI: 10.1017/S0033291707001663
Ebmeier, K., Herrmann, L. (2008). TMS â€“ the beginning of the end or the end of the beginning?. Psychological Medicine, 38(03) DOI: 10.1017/S0033291707001651

Again Open Label Research with rTMS

Dr Shock — Fri, 18 Apr 2008 06:34:00 +0000

Another open labeled trial with rTMS. It is a continuation trial after a recent double-blind placebo controlled trial with rTMS.This study is discussed in a recent post on this blog: Finally some good news about rTMS?

Considering the outcome on the time point at week 4, Dr Shock is not very impressed by the results. For significant difference with the primary outcome 6 patients had to be excluded from the analysis. The mean difference between active and sham on the severity scales is in the range of 2-3 points, significant but hardly clinical relevant.

The NICE guidelines use a difference of 3 point or more as clinical significant.

Another open trial is unethical to my opinion in this stage of development of rTMS.
Patients that were non responders on the double-blind sham controlled rTMS trial received an additional 6 weeks of active rTMS. The nonreponders on the active rTMS group also were continued on rTMS for 6 weeks. Both patients and investigators remained blind to prior treatment condition. The open label study had 2 phases: a 6 week antidepressant medication free acute phase treatment and a 3 week taper phase during which antidepressant medication was initiated. Patients received 5 rTMS sessions per week during 6 weeks followed by 3 times a week in week 7, 2 times a week in week 8 and once a week in the last week.

Results
Patients who received sham in the preceding randomized controlled trial (N = 85), the mean reduction in MADRS scores after 6 weeks of open-label active TMS was -17.0. Further, at 6 weeks, 36 (42.4%) of these patients achieved response on the MADRS, and 17 patients (20.0%) remitted. Remission was defined as a score under 10 on the MADRS. For those patients who received and did not respond to active TMS in the preceding randomized controlled trial (N = 73), the mean reduction in MADRS scores was -12.5, and response and remission rates were 26.0% and 11.0%, respectively.

A well just to let you know, we will wait for another open label trial.

What is interesting to know is that in in the sham to rTMS treatment group, failure to only one antidepressant trial before rTMS resulted in a greater likelihood of response. If resistant to more antidepressants before rTMS predicted less favorable outcome.

When is there going to be a sham controlled trial without medication resistant depressive patients?

You can read the abstract of this article on Therapeutic Neuromodulation Weblog

Avery, D.H. (2008). Transcranial magnetic stimulation in the acute treatment of major depressive disorder: clinical response in an open-label extension trial.. Journal of Clinical Psychiatry, 69(3), 441-451.