As many as 30% of people suffering from depression do not respond to antidepressant treatment1. When treatment options are exhausted psychiatrists often turn to electroconvulsive therapy (ECT).  An electric current is used to cause a brief seizure in the brain. Although this is a relatively safe method of treatment, impairments of both cognition and memory are potential side effects2.

Transcranial magnetic stimulation or TMS is similar to ECT but uses electromagnetic pulses to generate electrical current in specific regions of the brain that are known to modulate mood.  TMS is less likely to cause side effects and has thus been proposed as a possible alternative therapy for those suffering from treatment-resistant depression.

With TMS, an electromagnetic coil, called an “8-coil”, is placed on the scalp and generates a  brief but powerful magnetic pulse. This induces a small electrical current which depolarizes neurons in the cortex 3. The 8-coil works to a maximum depth of 1.5-2.5 cm. In contrast, deep TMS is applied using an H-coil, which modulates excitability up to a maximum depth of 6cm4. Consequently, deep TMS influences not only cortical activity, but also the activity of deeper neuronal circuits.

TMS for Depression

Early TMS studies used single pulse stimulations. A variant of TMS, repetitive transcranial magnetic stimulation (rTMS), utilizes repetitive stimulations at different frequencies to modulate cortical activity 2. rTMS has been tested as a treatment for various neurological and psychiatric disorders.

Brain circuits thought to be involved in Major Depressive Disorder (MDD) include the prefrontal cortex, cingulate gyrus, amygdala, ventral striatum and medial thalamus5. These networks govern executive functioning and mood regulation. According to the imbalance hypothesis of Major Depressive Disorder (MDD), major depression is associated with prefrontal cortex asymmetry with relative hypoactivity in the left dorsolateral prefrontal cortex (DLPFC), along with relative hyperactivity in the right DLPFC6. High frequency rTMS stimulation increases cortical excitability, while low frequency stimulation is inhibitory. Thus, rTMS efficacy is linked to either high frequency stimulation of the left DLPC or low frequency inhibition of the right DLPFC2.

Safety of TMS

Unlike ECT, which may impact cognition and memory, there have been reports of improved cerebral functioning after high-frequency stimulation with rTMS in normal participants2. Furthermore, rTMS, unlike ECT, does not require general anesthesia 7. The greatest risk associated with rTMS is the risk of seizure.  However, this appears to occur infrequently.  More common side effects include headache, lightheadedness, tingling or twitching or facial muscles, and scalp irritation at the site of the coil.

Efficacy of TMS as a Treatment for Depression

There has been some debate over the efficacy of rTMS for the treatment of depression. Although there have been numerous studies of rTMS, the lack of procedural standardization makes interpretation of these studies difficult. Furthermore, most of these individual studies are underpowered, thus meta-analytic studies seem to be most informative with regard to assessing the efficacy of  rTMS.

A meta-analysis from Coutierier and colleagues concluded that rTMS was not an effective treatment8. The analysis included only randomized controlled trials, with rTMS application over the left DLPFC.  Unfortunately, six studies included in this analysis did not have enough power to detect a difference between sham control and treatment9.

Aurre and colleagues10 reviewed 12 studies for an evaluation of rTMS efficacy in depression. The studies varied in the way rTMS was administered, treatment duration, control condition and patient characteristics and were too diverse for formal meta-analysis. Consequently, results were inconsistent, with an overall clinically insufficient antidepressant effect.

Burt and colleagues analyzed nine open trials and 16 controlled studies11.  Their mean effect sizes were 1.37 and .67 respectively. Meta-analysis showed that rTMS has superior outcomes when compared to sham treatment, but the two week course has only a modest clinical effect, indicating that a longer course of rTMS may be necessary for optimal treatment response 9.

Recent large randomized placebo controlled studies12-14 have found that rTMS is more effective than sham stimulation at decreasing MADRS scores.

Limitations of Interpreting rTMS Studies

Most studies seem to suggest that rTMS is a legitimate treatment for depression. However, many have reported initial success at reducing depressive symptoms, but have failed to show the same success two weeks post-treatment2. Besides the differences in methodologies and small sample sizes of most rTMS studies, interpretation of the larger placebo controlled trials is complicated by the questionable suitability of the sham coil as the placebo control, since the sensation of the two treatments is significantly different 2. Furthermore, variability of effect sizes in the studies can reflect the variability of study parameters.  So far no study presents clear variables that predict efficacy 7.

Potential Areas of Future Study

Most studies have focused on left DLPFC stimulation. According to the imbalance hypothesis of MDD, inhibiting the right side by low frequency stimulation can be just as effective 9. Some open trial studies have shown positive results using this approach (low frequency inhibition of the right DLPC)15,in contrast to the mixed results in controlled trials. Bilateral DLPFC stimulation studies have had negative outcomes 9. Stimulating other brain regions can also be effective. Low frequency stimulation of the right parietal cortex or high frequency stimulation of the cerebellar cortex could be beneficial 9.

The best way to deliver rTMS is still controversial. Some studies show that treatments of higher intensities are more likely to have positive results 16, but many do not demonstrate this effect9.  A recent study suggests that stimulation of deep brain structures may be necessary for the maximal efficacy of the rTMS. Levkovitz and colleagues developed an H coil that is able to deliver higher intensity stimulation to deeper brain regions.  High intensity H coil stimulation of left DLPFC was more effective than bilateral rTMS stimulation of the DLPFC with lower intensity stimulation 6. It is possible, however, that the positive effect seen may have been due to the greater brain volume being stimulated rather than deeper brain stimulation.

TMS and Pregnancy

TMS, if effective, would be an ideal treatment for women who develop depressive symptoms during pregnancy in that there would be no exposure to mediations.  To our knowledge, there has been only one study assessing the safety and effectiveness of rTMS in pregnant patients with depression.

In this study, 30 depressed pregnant patients received rTMS over the left prefrontal cortex for 6 days per week for 3 weeks.17   All of these women were considered to be “treatment-refractory”, meaning that they had failed to respond to treatment with at least two pharmacologically distinct antidepressant.  After 18 sessions of rTMS, the mean HAMD score for the study group decreased from 26.77?±?5.58 at baseline to 13.03?±?6.93 (p?<?0.001).  After the treatment period, 41.4 % of the study group demonstrated significant mood improvements as indexed by a reduction of more than 50 % on the HAMD score. In addition, 20.7 % attained remission (HAMD score?<?8).  The treatment was well tolerated, and no significant adverse effects were reported.

This study indicates that rTMS may be a useful treatment option for women with depression during pregnancy.  However, more study is required in order to determine which women are likely to benefit from this treatment.  Most of the women included in this study had moderate depressive symptoms.  Given the preliminary nature of this data, ECT may be a better option for women with more severe or treatment-refractory depressive symptoms and women with suicidality and/or psychotic symptoms.

Summary

Although there is some convincing evidence to indicate that excitation of the left DLFPC with TMS is effective for treating depression, there is not enough clinical and scientific evidence to validate an rTMS specific paradigm at this point2. rTMS is potentially a safer alternative to ECT; however, ECT is more widely used because there is not yet consensus regarding the optimal delivery of rTMS.  Nor do we know for which populations rTMS is most useful. Further study of rTMS is needed before we can recommend TMS for the treatment of patients with treatment-resistant depression.

Maria Barsky, BS

Snezana Milanovic, MD

 

References

1. Fava M, Davidson KG. Definition and epidemiology of treatment-resistant depression. Psychiatr Clin North Am. Jun 1996;19(2):179-200.

2. Wassermann EM, Zimmermann T. Transcranial magnetic brain stimulation: therapeutic promises and scientific gaps. Pharmacol Ther. Jan 2012;133(1):98-107.

3. Januel D, Dumortier G, Verdon CM, et al. A double-blind sham controlled study of right prefrontal repetitive transcranial magnetic stimulation (rTMS): therapeutic and cognitive effect in medication free unipolar depression during 4 weeks. Prog Neuropsychopharmacol Biol Psychiatry. Jan 2006;30(1):126-130.

4. Bersani FS, Minichino A, Enticott PG, et al. Deep transcranial magnetic stimulation as a treatment for psychiatric disorders: A comprehensive review. Eur Psychiatry. May 3 2012.

5. Price JL, Drevets WC. Neural circuits underlying the pathophysiology of mood disorders. Trends Cogn Sci. Jan;16(1):61-71.

6. Levkovitz Y, Harel EV, Roth Y, et al. Deep transcranial magnetic stimulation over the prefrontal cortex: evaluation of antidepressant and cognitive effects in depressive patients. Brain Stimul. Oct 2009;2(4):188-200.

7. Herrmann LL, Ebmeier KP. Factors modifying the efficacy of transcranial magnetic stimulation in the treatment of depression: a review. J Clin Psychiatry. Dec 2006;67(12):1870-1876.

8.  Couturier JL. Efficacy of rapid-rate repetitive transcranial magnetic stimulation in the treatment of depression: a systematic review and meta-analysis. J Psychiatry Neurosci. Mar 2005;30(2):83-90.

9.  Loo CK, Mitchell PB. A review of the efficacy of transcranial magnetic stimulation (TMS) treatment for depression, and current and future strategies to optimize efficacy. J Affect Disord. Nov 2005;88(3):255-267.

10. Aarre TF, Dahl AA, Johansen JB, Kjonniksen I, Neckelmann D. Efficacy of repetitive transcranial magnetic stimulation in depression: a review of the evidence. Nord J Psychiatry. 2003;57(3):227-232.

11. Burt T, Lisanby SH, Sackeim HA. Neuropsychiatric applications of transcranial magnetic stimulation: a meta analysis. Int J Neuropsychopharmacol. Mar 2002;5(1):73-103.

12. Schutter DJ. Antidepressant efficacy of high-frequency transcranial magnetic stimulation over the left dorsolateral prefrontal cortex in double-blind sham-controlled designs: a meta-analysis. Psychol Med. Jan 2009;39(1):65-75.

13. O’Reardon JP, Solvason HB, Janicak PG, et al. Efficacy and safety of transcranial magnetic stimulation in the acute treatment of major depression: a multisite randomized controlled trial. Biol Psychiatry. Dec 1 2007;62(11):1208-1216.

14. George MS, Padberg F, Schlaepfer TE, et al. Controversy: Repetitive transcranial magnetic stimulation or transcranial direct current stimulation shows efficacy in treating psychiatric diseases (depression, mania, schizophrenia, obsessive-complusive disorder, panic, posttraumatic stress disorder). Brain Stimul. Jan 2009;2(1):14-21.

15. Schutter DJ. Quantitative review of the efficacy of slow-frequency magnetic brain stimulation in major depressive disorder. Psychol Med. Nov 2010;40(11):1789-1795.

16. Gershon AA, Dannon PN, Grunhaus L. Transcranial magnetic stimulation in the treatment of depression. Am J Psychiatry. May 2003;160(5):835-845.

17.  Hizli Sayar G, Ozten E, Tufan E, Cerit C, Kagan G, Dilbaz N, Tarhan N. Transcranial magnetic stimulation during pregnancy. Arch Womens Ment Health. 2013 Nov 20.