Repetitive Transcranial Magnetic Stimulation (rTMS) in Combination with Escitalopram in Patients with Treatment-Resistant Major Depression. A Double-Blind, Randomised, Sham-Controlled Trial

Abstract

Background: The role of high-frequency rTMS over the left cortex as an add-on strategy in the treatment of major depression is still uncertain even in patients resistant to pharmacotherapy. We had planned a large sham TMS controlled study in the acute phase with a placebo-controlled relapse-prevention phase with escitalopram. However, because a recent meta-analysis showed only a small effect size of rTMS over sham TMS in the acute treatment phase of depressed patients, we decided to make an interim analysis.

Method: In patients with medication-resistant major depression we administered in a randomised trial 15 sessions of sham-controlled rTMS over three weeks in combination with 20 mg escitalopram daily. After the last rTMS, the patients were followed for another 9 weeks on 20 mg escitalopram daily. The antidepressant effect was measured by the HAM-D₆ as primary outcome scale.

Results: A total of 45 patients with complete data were randomised so that 23 patients received sham TMS and 22 patients received active, high-frequency rTMS over the left cortex. Over the 3 weeks, the active rTMS treatment was superior to sham TMS with effect sizes on the HAM-D₆ above 0.70, which indicates not only a statistically but also a clinically significant effect. The patients had typically been through two failed antidepressant treatment attempts with non-tricyclics before inclusion in the study. Both the rTMS and escitalopram were well-tolerated.

Conclusion: High-frequency rTMS over the left cortex is an add-on strategy of clinical significance in combination with escitalopram in patients with major depression resistant to non-tricyclic antidepressants.

References

• 1 Armitage P. Interim analyses in clinical trials.  Statist Med. 1991;  10 925-937
• 2 Avery DH, Holtzheimer PE, Fawaz W, Russo J, Neumaier J, Dunner DL, Haynor DR, Claypoole KH, Wajdik C, Roy-Byrne P. Controlled study of repetitive transcranial magnetic stimulation in medication-resistant major depression.  Biol Psychiatry. 2005;  59 187-194
• 3 Bagby, RM, Ryder AG, Schuller DR, Marshall MB. The Hamilton Depression Rating Scale: Has the gold standard become a lead weight?.  Am J Psychiatry. 2004;  161 2163-2177
• 4 Bech P. Dose-response relationship of pregabalin.  Pharmacopsychiatry. 2007;  40 1-6
• 5 Bech P. Pharmacological treatment of depressive disorders: a review. In: Maj M, Sartorius N (eds) Depressive disorders. WPA series on evidence an experience in psychiatry. Chichester: Wiley 2002 2nd edn, pp 89-126
• 6 Bech P. Rating scales for psychopathology, health status and quality of life. A compendium on documentation in accordance with the DSM-III-R and WHO systems. Springer: Berlin 1993
• 7 Bech P, Andersen HF, Wade A. Effective dose of escitalopram in moderate versus severe DSM-IV major depression.  Pharmacopsychiatry. 2006;  39 128-134
• 8 Bech P, Kastrup M, Rafaelsen OJ. Mini-compendium of rating scales for states of anxiety, depression, mania, schizophrenia with corresponding DSM-III syndromes.  Acta Psychiatr Scand. 1986;  73 ((suppl 326)) 7-37
• 9 Bech P, Rasmussen N-A, Olsen LR, Noerholm V, Abildgaard W. The sensitivity and specificity of the Major Depression Inventory, using the Present State Examination as the index of diagnostic validity.  J Affect Disord. 2001;  66 159-164
• 10 Burt T, Lisanby SH, Sackeim HA. Neuropsychiatric application of transcranial magnetic stimulation: a meta-analysis.  Int J Neuropsychophamacol. 2002;  5 73-103
• 11 EMEA . (2002) ICH Harmonised Tripartite Guideline E6 (R1): Guideline for Good Clinical Practice. Available from: http://www.emea.europa.eu/pdfs/human/ich/013595en.pdf. Last accessed 30. November 2007
• 12 Fava M, MacCall WV, Krystal A, Wessel T, Rubens R, Caron J, Amato D, Roth T. Eszopiclone co-administered with fluoxetine in patients with insomnia coexisting with major depressive disorder.  Biol Psychiatry. 2006;  59 1052-1060
• 13 George MS, Wassermann EM, Williams WA. Daily repetitive transcranial magnetic stimulation (rTMS) improves mood in depression.  Neuroreport. 1995;  6 1853-1856
• 14 Grunhaus L, Schreiber S, Dolberg OT, Polak D, Dannon PH. A randomised controlled comparison of electroconvulsive therapy and repetitive transcranial magnetic stimulation in severe and resistant major depression.  Biol Psychiatry. 2003;  53 324-331
• 15 Hedges LV, Olkin I. Statistical methods for meta-analysis. New York: Academic Press 1985: 78-85
• 16 Hoflich G, Kasper S, Hufnagel A, Ruhr S, Moller HJ. Application of transcranial magnetic stimulation in treatment of drug-resistant major depression - a report of two cases.  Hum Psychopharmacol. 1993;  8 361-365
• 17 Holtzheimer PE, Avery D, Schlaepfer TE. Antidepressant effects of repetitive transcranial magnetic stimulation.  Br J Psychiatry. 2004;  184 541-542
• 18 Lauritzen L, Odgaard K, Clemmesen L, Lunde M, Ohrstrom J, Black C, Bech P. Relapse prevention of paroxetine in ECT treated patients with major depression. A comparison with imipramine and placebo in medium-term continuation therapy.  Acta Psychiatr Scand. 1996;  94 241-251
• 19 Licht RW, Qvitzau S, Allerup P, Bech P. Validation of the Bech-Rafaelsen Melancholia Scale and the Hamilton Depression Scale in patients with major depression: is the total score a valid measure of illness severity?.  Acta Psychiatr Scand. 2005;  111 144-149
• 20 Lingjærde O, Ahlfors UG, Bech P, Dencker SJ, Elgen, K. The UKU side effect rating scale. A new comprehensive rating scale for psychotropic drugs and a cross-sectional study of side effects in neuroleptic-treated patients.  Acta Psychiatr Scand. 1987;  76 ((suppl 334)) 1-100
• 21 Lisanby SH, Pascual-Leone A, Sampson SM, Boylan LS, Burt T, Sackheim HA. Augmentation of sertraline antidepressant treatment with transcranial magnetic stimulation.  Biol Psychiatry. 2001;  49 81-82
• 22 Martin JL, Barbanoj MJ, Schlaepfer TE, Thompson E, Perez V, Kulisevsky J. Repetitive transcranial magnetic stimulation for the treatment of depression. Systematic review and meta-analysis.  Br J Psychiatry. 2003;  182 480-441
• 23 Olsen LR, Jensen DV, Noerholm V, Martiny K, Bech P. The internal and external validity of the Major Depression Inventory in measuring severity of depressive states.  Psychol Med. 2003;  33 351-356
• 24 Pascual-Leone A, Rubio B, Pallardo F. Rapid-rate transcranial magnetic stimulation of left dorsolated prefrontal cortex in drug-resistant depression.  Lancet. 1996;  348 233-237
• 25 Pridmose S, Fernandes JA, Nahas Z, Liberato C, George MS. Motor threshold in transcranial magnetic stimulation: a comparison of a neurophysiological method and a visualisation of movement method.  J ECT. 1998;  14 25-27
• 26 Prudic J, Haskett RF, Mulsant B, Malone KM, Pettinati HM, Stephens S, Greenberg R, Rifas SL, Sackeim HA. Resistance to antidepressant medications and short-term clinical response to ECT.  Am J Psychiatry. 1996;  153 985-992
• 27 Rickels K, Gordon PE, Mecklenburg R, Sablosky L, Whalen EM, Dion H. Iprindole in neurotic depressed general practice patients: a controlled study.  Psychosomatics. 1968;  9 202-214
• 28 Sackheim HA. A definition and measuring of treatment-resistant depression.  J Clin Psychiatry. 2001;  62 ((suppl 16)) 10-17
• 29 Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, Hergueta T, Baker R, Dunbar GC. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10.  J Clin Psychiatry. 1998;  59 ((Suppl 20)) 22-33 , , 34-57
• 30 Siegel S. Non-parametric statistics. New York: McGraw-Hill 1956
• 31 Stassen HH, Angst J, Delini-Stula A. Delayed onset of action of antidepressant drugs? Survey of results of Zurich meta-analysis.  Pharmacopsychiatry. 1996;  29 87-96
• 32 Stimpson N, Agravad N, Lewis G. Randomised controlled trials investigating pharmacological and psychological interventions for treatment-refractory depression. Systematic review.  Br J Psychiatr. 2002;  181 284-294
• 33 World Psychiatric Association. Symposium on therapy-resistant depression.  Pharmacopsychiatry. 1974;  7 69-224

Correspondence