rTMS update part 2

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?