Dr Shock MD PhD

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 – the beginning of the end or the end of the beginning?. Psychological Medicine, 38(03) DOI: 10.1017/S0033291707001651

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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.

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Even a Dutch research group published a placebo controlled trial with rTMS. Not that they found rTMS to be significantly better than sham TMS after two weeks of treatment. Both groups had a reduction of 2.5 points on the Hamilton Depression Rating Scale (17-item version) and 1 point in the second week, the decrease never passed 20% in either group.

Their point being a continuing improvement in the rTMS and the sham rTMS group during the follow-up of 3 months. This resulted in a significant mean difference of more than 4 points in favor of the rTMS group over the sham group. Now that is weird, stopping a treatment and patients continue to improve in both groups, favoring the real treatment group.

This could be explained by some shortcomings of this trial:

• The placebo condition was treatment with the coil in an angle of 45 degrees, it is argued that this is not really a sham condition but could still have an effect.


• The dosage was set at 80% of the motor treshhold which is low, mostly a dosage of 120% is used.


• Groups differed in their male/female ratio


• Early drop outs during treatment were not included in the analysis.


• Patients were kept on medication such as benzodiazepines and antidepressants.


• Fancy statistics were used, this always gets me superstitious

Koerselman, F. (2004). a 3-month, follow-up, randomized, placebo-controlled study of repetitive transcranial magnetic stimulation in depression. Journal of Clinical Psychiatry, 65(10), 1323-1328.

Localisation of rTMS

With rTMS the location were the treatment is applied is usually on the Left Dorsolateral Prefrontal Cortex (LDPC). This localization is based on localizing the part of the left motor cortex representing the muscles of the right thumb (abductor of the pollicis brevis). Stimulation leads to a twitching of the right thumb. The coil is placed about 5 cm in front of this mark. Mostly a frequency of 1 or more HZ is used, stimulation of 1 or more per second. This results in activation of neuronal tissue.

In a recent publication the they tried low frequency over the right cortex. They placed the coil 5 cm in front of the right motor cortex. Low frequency reduces neuronal firing of the cortex. The treatment group showed significant improvement, the sham group didn't. Improvement meaning a reduction on the Hamilton Rating Scale for Depression. Group comparison was not performed, probably because this wouldn't result in a significant difference because the groups were very small (6 patients each). All patients having benefit from treatment relapsed within 2-3 months.
Limitations besides small sample size: placebo condition was again applying the coil in 45 degrees which might not be placebo after all, patients received antidepressants and benzodiazepines during the trial.

Kauffmann, C.D., Cheema, M.A., Miller, B.E. (2004). Slow right perfrontal transcranial magnetic stimulation as a reatment for medication-resistant depression: A double-blind, placebo-controlled study. Depression and Anxiety, 19(1), 59-62. DOI: 10.1002/da.10144

The application of left or right TMS was also studied in a larger sample of treatment resistant depressed patients who continued their antidepressants and anticonvulsants during the trial. High frequency left-sided repetitive TMS was compared to low frequency stimulation to the right prefrontal cortex. Both conditions were better than sham condition although their efficacy was not impressive after 2 weeks. Even a further single blind continuation didn't result in clinical impressive efficacy. What this research learns us is that maybe we should increase the number of treatments and the number of stimuli. Until now mostly 10 days during 2 weeks with 10000 stimuli might be to less. Maybe non response to left high frequency might be followed by right low frequency as treatment option. Limitations were blindness of patients,and continuation of medication during treatment.

Fitzgerald, P.B. (2003). Transcranial Magnetic Stimulation in the Treatment of Depression. Archives of General Psychiatry, 60(Octobre), 1002-1008.

Response prediction

A brave attempt was made to look at response prediction for rTMS. Number of antidepressant trials before treatment and current illness duration were a priori hypothesized as of importance for response to rTMS. In this placebo controlled trial with 15 subjects (7 rTMS, 8 sham rTMS) no significant advantage for active rTMS over sham rTMS could be shown as a treatment for depression. Nevertheless the authors suggests that short ilness duration (less than 4 years) predicts better improvement compared to the group with an illness duration of 10 or more years. Subjects with 7 or more antidepressant trials (lifetime) did better than those with fewer trials.
Limitations of this trial:
small sample size, inadequate placebo condition, recruitment of patients with advertising, selected patient sample relatively young,and long illness duration.

Holtzheimer, P.E., Russo, J., Claypoole, K.H., Roy-Byrne, P., Avery, D.H. (2004). Shorter duration of depressive episode may predict response to repetitive transcranial magnetic stimulation. Depression and Anxiety, 19(1), 24-30. DOI: 10.1002/da.10147

Conclusions
Together with a prior post as update number 1 on rTMS it can be concluded that efficacy of rTMS in depression is not impressive if any. Many questions still remain to be solved before it can be added to the arsenal as treatment for depression. The most important questions are:

• Which technical decisions should be made about frequency of treatment, duration of treatment, localization of treatment (left or right)


• Which patient group might benefit: treatment resistant patients or not treatment resistant patients.


• Should medication be continued or not


• Should rTMS be tapered after response and if so in what frequency?


• What is the best placebo condition?

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The information in this review suggests 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.

This was the conclusion of the authors of the Cochrane library about Transcranial magnetic stimulation for treating depression.

Since then (2002) 8 randomized controlled trials were published about rTMS and depression

Search strategy in PubMed:"Transcranial Magnetic Stimulation/therapeutic use"[Mesh] AND "Depressive Disorder/therapy"[Mesh] AND ("2003/02/12"[PDat] : "2008/02/10"[PDat] AND English[lang] AND Randomized Controlled Trial[ptyp])

The most recent randomized controlled trial is already discussed on this blog: At last 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. 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.

This same group studied rTMS as form of long-term maintenance therapy for depression. 10 Patients who had responded to an acute course of rTMS for their depression participated in this open label case series. The maintenance rTMS ranged from 6 months to 6 years for these patients.The maintenance rTMS was started directly after response to the acute treatment. Response was defined as a reduction of 50% or more on the 17-item Hamilton Rating Scale for Depression.

rTMS was applied to the left prefrontal cortex at 100% of motor threshold. This location is mostly used in depression. The dosage seems low, usually 120% or 130% above motor threshold is used. The number of pulses per session ranged from 2000-3000. The frequency of sessions was determined by the clinical course of the patient.


5 Patients experienced marked benefit of maintenance rTMS (a mean of 257 sessions) with a mean of 2.1 sessions per week. Three of them didn't need additional treatment such as antidepressants.

2 Patients experienced moderate benefit of maintenance rTMS. Both experienced a recurrence of a depressive episode in a period of 12-18 months. They received a mean of 125 sessions with a frequency of 1.8 per week.

3 Patients received no benefit of maintenance rTMS.

Two patients were still treated with rTMS as maintenance treatment at the time of publication (2005). No serious side effects were reported.

Limitations
Open label, no fixed treatment parameters, small number of patients.

In another study augmentation of amitriptyline with rTMS was studied. 46 Outpatients with non-psychotic depression were randomized to rTMS or sham rTMS (using a placebo coil). During 4 weeks with 5 sessions of stimulation over the dorsolateral prefrontal cortex, 5Hz rTMS, 120% above motor threshold. The subjects received 1250 pulses per day. Seven days prior to the start of rTMS all patients received 50 mg of amitriptyline at evening and the dose was increased by 50 mg every second day. The mean daily dose was 110.2 mg/day which is considered to be very low.

The response rate and remission rates were significantly higher for rTMS compared to sham rTMS, response was 95% versus 46%, which is unusually high. Remission was 54% versus 12%. Real rTMS showed a significant difference with sham rTMS at the end of the first week of this four week trial. These results are in contrast with 3 earlier add-on studies. Two trials with a sham controlled design couldn't find a significant difference between real rTMS and sham rTMS as add-on strategy. The other trial was an open label trial.

This result is also in strong contrast with a recent add-on study of rTMS to mirtazepine and venlafaxine. This augmentation study is discussed in a recent post on this blog: rTMS augmentation not useful.

Repetitive Transcranial Magnetic Stimulation (rTMS) together with mirtazapine or venlafaxine was not better than these antidepressants with sham rTMS. Response in both treatment groups was 31%, response defined as a reduction of 50% or more on two of three depression severity scales. Even the decrease of scores on the depression rating scales did not differ significantly between real and sham rTMS.There was also no accelerated antidepressant effect, no acceleration of a clinical improvement.

To be continued, stay tuned.......


RUMI, D., GATTAZ, W., RIGONATTI, S., ROSA, M., FREGNI, F., ROSA, M., MANSUR, C., MYCZKOWSKI, M., MORENO, R., MARCOLIN, M. (2005). Transcranial magnetic stimulation accelerates the antidepressant effect of amitriptyline in severe depression: A double-blind placebo-controlled study. Biological Psychiatry, 57(2), 162-166. DOI: 10.1016/j.biopsych.2004.10.029

O'Reardon, J. (2005). Long-Term Maintenance Therapy for Major Depressive Disorder With rTMS. Journal of Clinical Psychiatry, 66(12), 1524-1528.

OREARDON, J., SOLVASON, H., JANICAK, P., SAMPSON, S., ISENBERG, K., NAHAS, Z., MCDONALD, W., AVERY, D., FITZGERALD, P., LOO, C. (2007). Efficacy and Safety of Transcranial Magnetic Stimulation in the Acute Treatment of Major Depression: A Multisite Randomized Controlled Trial. Biological Psychiatry, 62(11), 1208-1216. DOI: 10.1016/j.biopsych.2007.01.018

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A large study to the efficacy and safety of rTMS is recently published. The primary outcome criterion for rTMS for treatment of depression was the difference between the mean MADRS score before minus the score at week 4 of treatment. The difference between rTMS and sham TMS was not significant (p=0.057)at week 4. There was a baseline imbalance between groups. Six patients had a MADRS baseline score between 14 and 19 which is in the mild range. They were unevenly randomized across the two groups (i.e., 4 to the active and 2 to the sham). Excluding these six from the analysis finally resulted in a significant difference between groups (p=0.038), favoring active treatment. At week 6 the baseline to endpoint change on the MADRS was not significant with or without the six afore mentioned patients.

With the Hamilton Ratings Scale for Depression 17 and 24 item version (HAMD-17, HAMD-24), the difference of the mean change at week 4 was significant for both rating scales in favor of the active treatment. This advantage was sustained at week 6.

Mean differences of scores of depression severity scales are very sensitive measures. They easily lead to significant differences but are these differences not only significant but also clinically relevant.

For comparison clinician rated global illness severity showed significant greater improvement with the active treatment already at week 2 continuing to week 6.
Response rates, that is a reduction of 50% or more on the severity scale from baseline until week 4 and 6 was significantly higher for the active treatment compared to the sham treatment for all three rating scales.

Remission rates were not significantly higher for the active treatment except for the MADRS at week 6 and HAMD-24 at week 6. Remission is what you should seek in the treatment of depression. Remission rate at week 6 defined as a score on the HAMD-17 lower than 7 was 15.5%.

Patient reported mood change and global improvement were not significantly higher for the active treatment compared to sham rTMS.

Side effects of rTMS
There was more scalp discomfort and pain with the active treatment. There were no seizures. 16 serious were reported, 9 in the active treatment and 7 in the sham treatment, mostly due to disease related exacerbation.

This is the first large (n=301), multi site (23 US, 2 Australia, 1 Canada), placebo controlled trial on medication free depressed patients. Patients were required to have failed at least one but no more than four adequate antidepressant treatments. Patients with lack of response to ECT were excluded.


Dr Shock's opinion
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.


Article discussed:
Biol Psychiatry. 2007 Dec 1;62(11):1208-16. Epub 2007 Jun 14.
Efficacy and safety of transcranial magnetic stimulation in the acute treatment
of major depression: a multisite randomized controlled trial.
O'Reardon JP, Solvason HB, Janicak PG, Sampson S, Isenberg KE, Nahas Z, McDonald
WM, Avery D, Fitzgerald PB, Loo C, Demitrack MA, George MS, Sackeim HA.
PMID: 17573044 [PubMed - in process]

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