Download PDF
Pharmacopsychiatry 2006; 39(2): 52-59
DOI: 10.1055/s-2006-931542
Original Paper
© Georg Thieme Verlag KG Stuttgart · New York

High-Frequency Repetitive Transcranial Magnetic Stimulation Improves Refractory Depression by Influencing Catecholamine and Brain-Derived Neurotrophic Factors

T. Yukimasa1 , R. Yoshimura1 , A. Tamagawa2 , T. Uozumi2 , K. Shinkai1 , N. Ueda1 , S. Tsuji2 , J. Nakamura1
  • 1Department of Psychiatry, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, Fukuoka 807-8555, Japan
  • 2Department of Neurology, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, Fukuoka, 807-8555, Japan
Further Information

Publication History

Received: 11.7.2005 Revised: 30.9.2005

Accepted: 26.10.2005

Publication Date:
23 March 2006 (online)

Also available at
    Permissions and Reprints

Introduction: Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive and easily tolerated method of altering cortical physiology. To date, numerous open and sham controlled clinical trials have explored the antidepressant potential of rTMS. In the present study, we investigated clinical trials of high-frequency rTMS (20 Hz) for treatment of refractory depression, and also examined the effect of rTMS on plasma levels of catecholamine metabolites and brain-derived neurotropic factor (BDNF). Methods: Twenty-six depressed inpatients who met the DSM-IV criteria for major depressive disorder and had failed to respond to treatment with at least two antidepressant drugs given at adequate doses (above 150 mg/day in an equivalent dose of imipramine) and durations (at least 4 weeks for each drug) were enrolled in this study. Eleven were males, 15 females. The ages of the subjects ranged from 19 to 78 years old (mean ± SD = 52.9 ± 17.8). All patients were administered left prefrontal 20 Hz rTMS at 80 % MT (total 800 pulses a day) over ten daily sessions. The plasma levels of 3-methoxy-4-hydroxyphenylglycol (MHPG) and homovanillic acid (HVA) were analyzed by high-performance liquid chromatography. The plasma levels of BDNF were also measured with the sandwich ELISA method. Results: The mean 17-item Hamilton Rating Scale for Depression (Ham-D) score of 20.5 ± 5.2 before rTMS was significantly decreased to 15.6 ± 7.3 after rTMS. Nine of 26 patients (35 %) demonstrated some improvement (Ham-D ≥ 25 %) by rTMS. The levels of plasma MHPG, but not those of HVA, were significantly reduced after rTMS treatment, and a negative correlation was observed between the change in plasma MHPG levels and the change in scores of agitation. In addition, the plasma levels of BDNF were significantly increased by 23 % in responders and partial responders, but not in nonresponders, after rTMS treatment, and a trend for association was found between the changes in Ham-D scores and changes in plasma BDNF levels in all patients after rTMS treatment. Conclusion: These results suggest that rTMS treatment brings about some improvement in refractory depression, especially for symptoms such as agitation, by influencing MHPG and BDNF, which is in accordance with previous reports showing that BDNF was increased by various antidepressants treatments.

References

  • 1 Altar C A, Whitehead R E, Chen R, Wortwein G, Madsen T M. Effects of electroconvulsive seizures and antidepressant drugs on brain-derived neurotrophic factor protein in rat brain.  Biol Psychiatry. 2003;  54 703-709
    CrossrefPubMedGoogle Scholar
  • 2 Angelucci F, Oliviero A, Pilato F, Saturno E, Dileone M, Versace V, Musumeci G, Batocchi A P, Tonali P A, Di Lazzaro V. Transcranial magnetic stimulation and BDNF plasma levels in amyotrophic lateral sclerosis.  Neuroreport. 2004;  22 717-720
    PubMedGoogle Scholar
  • 3 Ballenger J C. Psychopharmacology of the anxiety disorders.  Psychiatr Clin North Am. 1984;  7 757-771
    PubMedGoogle Scholar
  • 4 Barker A T. An introduction to basic principles of magnetic nerve stimulation.  J Clin Neurophysiol. 1991;  8 26-37
    PubMedGoogle Scholar
  • 5 Ben-Shachar D, Belmaker R H, Grisaru N, Klein E. Transcranial magnetic stimulation induces alterations in brain monoamines.  J Neural Transm. 1997;  104 191-197
    CrossrefPubMedGoogle Scholar
  • 6 Ben-Shachar D, Gazawi H, Riboyad-Levin J, Klein E. Chronic transcranial magnetic stimulation alters beta-adrenergic and 5-HT2 receptor characteristics in rat brain.  Brain Res. 1999;  816 78-83
    CrossrefPubMedGoogle Scholar
  • 7 Berman R M, Narasimhan M, Sanacora G, Miano A P, Hoffman R E, Hu X S. et al . A randomized clinical trial of repetitive transcranial magnetic stimulation in the treatment of major depression.  Biol Psychiatry. 2000;  48 332-337
    PubMedGoogle Scholar
  • 8 Burt T, Lisanby S H, Sackeim H A. Neuropsychiatric applications of transcranial magnetic stimulation: a metaanalysis.  Int J Neuropsychopharmacol. 2002;  5 73-103
    PubMedGoogle Scholar
  • 9 Couturier J L. Efficacy of rapid-rate repetitive transcranial magnetic stimulation in the treatment of depression: a systematic review and meta-analysis.  J Psychiatry Neurosci. 2005;  30 83-90
    PubMedGoogle Scholar
  • 10 Eschweiler G W, Plewnia C, Bartels M. Which patients with major depression benefit from prefrontal repetitive magnetic stimulation?.  Fortschr Neurol Psychiatr. 2001;  69 402-409
    Article in Thieme ConnectPubMedGoogle Scholar
  • 11 Eschweiler G W, Wegerer C, Schlotter W, Spandl C, Stevens A, Bartels M. et al . Left prefrontal activation predicts therapeutic effects of repetitive transcranial magnetic stimulation (rTMS) in major depression.  Psychiatry Res. 2000;  99 161-172
    PubMedGoogle Scholar
  • 12 Figiel G S, Epstein C, McDonald W M, Amazon-Leece J, Figiel L, Saldivia A. et al . The use of rapid-rate transcranial magnetic stimulation (rTMS) in refractory depressed patients.  J Neuropsychiat Clin Neurosci. 1998;  10 20-25
    PubMedGoogle Scholar
  • 13 Fitzgerald P B, Brown T L, Daskalakis Z J. The application of transcranial magnetic stimulation in psychiatry and neurosciences research.  Acta Psychiatr Scand. 2002;  105 324-340
    CrossrefPubMedGoogle Scholar
  • 14 Fitzgerald P B, Brown T L, Marston N A, Daskalakis Z J, De Castella A, Kulkarni J. Transcranial magnetic stimulation in the treatment of depression. A double-blind, placebo-controlled trial.  Arch Gen Psychiatry. 2003;  60 1002-1008
    CrossrefPubMedGoogle Scholar
  • 15 Fleischmann A, Sternheim A, Etgen A M, Li C, Grisaru N, Belmaker R H. Transcranial magnetic stimulation downregulates β-adrenoreceptors in rat cortex.  J Neural Transm. 1996;  103 1361-1366
    CrossrefPubMedGoogle Scholar
  • 16 Garcia-Toro M, Mayol A, Arnillas H, Capllonch I, Ibarra O, Crespi M. et al . Modest adjunctive benefit with transcranial magnetic stimulation in medication-resistant depression.  J Affect Disord. 2001;  64 271-275
    CrossrefPubMedGoogle Scholar
  • 17 Garcia-Toro M, Pascual-Leone A, Romera M, Gonzalez A, Mico J, Ibarra O. et al . Prefrontal repetitive transcranial magnetic stimulation as add on treatment in depression.  J Neurol Neurosurg Psychiat. 2001;  71 546-548
    CrossrefPubMedGoogle Scholar
  • 18 George M S, Lisanby S, Sackeim H A. Transcranial magnetic stimulation: applications in neuropsychiatry.  Arch Gen Psychiatry. 1999;  56 300-311
    CrossrefPubMedGoogle Scholar
  • 19 George M S, Wassermann E M, Kimbrell T A, Little J T, Williams W E, Danielson A L. et al . Mood improvement following daily left prefrontal repetitive transcranial magnetic stimulation in patients with depression. A placebo-controlled crossover trial.  Am J Psychiatry. 1997;  154 1752-1756
    PubMedGoogle Scholar
  • 20 George M S, Wassermann E M, Williams W A, Callanhan A, Ketter T A, Basser P. et al . Daily repetitive transcranial magnetic stimulation (rTMS) improves mood in depression.  Neuroreport. 1995;  6 1853-1856
    CrossrefPubMedGoogle Scholar
  • 21 Gershon A A, Dannon P N, Grunhaus L. Transcranial magnetic stimulation in the treatment of depression.  Am J Psychiatry. 2003;  160 835-845
    CrossrefPubMedGoogle Scholar
  • 22 Hashimoto K, Shimizu E, Iyo M. Critical role of brain-derived neurotrophic factor in mood disorders.  Brain Res Rev. 2004;  45 104-114
    CrossrefPubMedGoogle Scholar
  • 23 Jaconsen J P, MØrk A. The effect of escitalopram, desipramine, electroconvulsive seizures and lithium on brain-derived neurotrophic factor mRNA and protein expression in the rat brain and the correlation to 5-HT and 5-HIAA levels.  Brain Res. 2004;  1024 183-192
    CrossrefPubMedGoogle Scholar
  • 24 Karege F, Perret G, Bondolfi G, Schwald M, Bertschy G, Aubry J M. Decreased serum brain-derived neurotrophic factor levels in major depressed patients.  Psychiatry Res. 2002;  109 143-148
    CrossrefPubMedGoogle Scholar
  • 25 Karege F, Schwald M, Cisse M. Postnatal developmental profile of brain-derived neurotrophic factor in rat brain and platelets.  Neurosci Lett. 2002;  328 261-264
    CrossrefPubMedGoogle Scholar
  • 26 Karege F, Bondolfi G, Gervasoni N, Schwald M, Aubry J -M, Bertschy G. Low brain-derived neurotrophic factor (BDNF) levels in serum of depressed patients probably results from lowered platelet BDNF release unrelated to platelet reactivity.  Biol Psychiatry. 2005;  57 1068-1072
    CrossrefPubMedGoogle Scholar
  • 27 Keck M E, Welt T, Müller M B, Uhr M, Ohl F, Wigger A. et al . Repetitive transcranial magnetic stimulation increases the release of dopamine in the mesolimbic and mesostriatal system.  Neuropharmacology. 2002;  43 101-109
    CrossrefPubMedGoogle Scholar
  • 28 Kole M H, Fuchs E, Ziemann U, Paulus W, Ebert U. Changes in 5-HT1A and NMDA binding sites by a single rapid transcranial magnetic stimulation procedure in rats.  Brain Res. 1999;  826 309-312
    CrossrefPubMedGoogle Scholar
  • 29 Lang U E, Hellweg R, Gallinat J. BDNF serum concentrations in healthy volunteers are associated with depression-related personality traits.  Neuropsychopharmacology. 2004;  29 795-798
    CrossrefPubMedGoogle Scholar
  • 30 Lommatzsch M, Zingeler D, Schuhbaeck K, Schloetcke K, Zingler C, Schuff-Werner P, Virchow J C. The impact of age and gender on BDNF levels in human platelets and plasma.  Neurobiology Aging. 2005;  26 115-123
    CrossrefPubMedGoogle Scholar
  • 31 Loo C, Mitchell P, Sachdev P, Mcdarmant B, Parker G, Gandevia S. Double-blind controlled investigation of transcranial magnetic stimulation for the treatment of resistant major depression.  Am J Psychiatry. 1999;  156 946-948
    PubMedGoogle Scholar
  • 32 Marangell L B, Silver F M, Yudofsky S C. Psychopharmacology and electroconvulsive therapy. In Hales RE, Yudofsky SC, Talbott JA, eds Textbook of Psychiatry. 3rd edition Washington DC; American Psychiatric Press 1999: 1025-1132
    Google Scholar
  • 33 Mayberg H S, Silva J A, Brannan S K, Tekell J L, Mahurin R K, McGinnis S, Jerabek P A. The functional neuroanatomy of the placebo effect.  Am J Psychiatry. 2002;  159 728-737
    Google Scholar
  • 34 Minegishi A, Ishizaki T. Determination of free 3-methoxy-4-hydroxyphenylglycol with several other monoamine metabolites in plasma by high-performance liquid chromatography with amperometric detection.  J Chromatogr. 1984;  311 51-57
    PubMedGoogle Scholar
  • 35 Muller M B, Toschi N, Kresse A E, Post A, Keck M E. Long-term repetitive transcranial magnetic stimulation increases the expression of brain-derived neurotrophic factor and cholecystokinin mRNA, but not neuropeptide tyrosine mRNA in specific areas of rat brain.  Neuropsychopharmacol. 2000;  23 205-215
    PubMedGoogle Scholar
  • 36 Nakamura J, Yoshimura R, Okuno T, Ueda N, Hachida M, Yasumoto K. et al . Association of plasma free-3-methoxy-4-hydroxyphenyl(ethylene)glycol, natural killer cell activity and delirium in postoperative patients.  Int Clin Psychopharmacol. 2001;  16 339-343
    PubMedGoogle Scholar
  • 37 Pan W, Banks W A, Fasold M B, Blush J, Kastin A J. Transport of brain-derived neurotrophic factor across the blood-brain barrier.  Neuropharmacology. 1998;  37 1553-1561
    CrossrefPubMedGoogle Scholar
  • 38 Pascual-Leone A, Rubio B, Pallardo F, Catala M D. Rapid-rate transcranial magnetic stimulation of left dorsolateral prefrontal cortex in drug-resistant depression.  Lancet. 1996;  348 233-237
    CrossrefPubMedGoogle Scholar
  • 39 Radka S F, Holst P A, Fritsche M, Altar C A. Presence of brain-derived neurotrophic factor in brain and human and rat but not mouse serum detected and by a sensitive and specific immunoassay.  Brain Res. 1996;  709 122-130
    CrossrefPubMedGoogle Scholar
  • 40 Rumi D O, Gattaz W F, Rigonatti S P, Rosa M A, Fregni R F, Rosa M A, Fregni F, Rosa M O, Mansur C, Myczkowski M L, Moreno R A, Marcolin M A. Transcranial magnetic stimulation accelerates the antidepressant effect of amitriptyline in severe depression: a double-blind placebo-controlled study.  Biol Psychiatry. 2005;  57 162-166
    CrossrefPubMedGoogle Scholar
  • 41 Russo-Neustadt A, Ha T, Ramirez R, Kesslak J P. Physical activity-antidepressant treatment combinations: impact on brain-derived neurotrophic factor and behavior in an animal model.  Behav Brain Res. 2001;  120 87-95
    CrossrefPubMedGoogle Scholar
  • 42 Shimizu E, Hashimoto K, Okuma N, Koike K, Komatsu N, Kumakiri C. et al . Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants.  Biol Psychiatry. 2003;  54 70-75
    CrossrefPubMedGoogle Scholar
  • 43 Shinkai K, Yoshimura R, Ueda N, Okamoto K, Nakamura J. Associations between baseline plasma MHPG (3-methoxy-4-hydroxyphenylglycol) levels and clinical responses with respect to milnacipran versus paroxetine treatment.  J Clin Psychopharmacol. 2004;  24 11-17
    PubMedGoogle Scholar
  • 44 Siever L J, Davis K L. Overview: toward a dysregulation hypothesis of depression.  Am J Psychiatry. 1985;  142 1017-1031
    PubMedGoogle Scholar
  • 45 Smith M A, Makino S, Kvetnansky R, Post R M. Stress and glucocorticoids affect the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus.  J Neurosci. 1995;  15 1768-1777
    PubMedGoogle Scholar
  • 46 Stahl S M. Essential Psychopharmacology Cambridge University Press. Cambridge; 2000
    Google Scholar
  • 47 Ueda N, Yoshimura R, Shinkai K, Nakamura J. Plasma levels of catecholamine metabolites predict the response to sulpiride or fluvoxamine in major depression.  Pharmacopsychiatry. 2002;  35 175-181
    Article in Thieme ConnectPubMedGoogle Scholar
  • 48 Weissman M M, Bland R C, Canino G J, Faravelli C, Greenwald S, Hwu H G. et al . Cross-national epidemiology of major depression and bipolar disorder.  JAMA. 1996;  276 293-299
    CrossrefPubMedGoogle Scholar
  • 49 Yamada S, Yajima J, Harano K, Miki K, Nakamura J, Tsuda A. et al . Saliva level of free 3-methoxy-4-hydroxyphenylglycol in psychiatric outpatients with anxiety.  Int Clin Psychopharmacol. 2000;  13 213-217
    PubMedGoogle Scholar
  • 50 Yeung P K, Buckley S J, Pedder S C, Dingemanse J. Determination of 3,4-dihydroxyphenylacetic acid and 5-hydroxyindoleacetic acid in human plasma by a simple and rapid high-performance liquid chromatography assay.  J Pharm Sci. 1996;  85 451-453
    CrossrefPubMedGoogle Scholar
  • 51 Yoshimura R, Ueda N, Shinkai K, Nakamura J. Plasma levels of homovanillic acid and the response to risperidone in first episode untreated acute schizophrenia.  Int Clin Psychopharmacol. 2003;  18 107-111
    PubMedGoogle Scholar
  • 52 Yoshimura R, Nakamura J, Shinkai K, Ueda N. Clinical response to antidepressant treatment and 3-methoxy-4-hydroxyphenylglycol levels: mini review.  Prog Neuro-Psychopharmacol Biol Psychiatry. 2004;  28 611-616
    CrossrefPubMedGoogle Scholar
  • 53 Yoshimura R, Nakamura J, Shinkai K, Goto M, Yamada Y, Kaji K. et al . An open study of risperidone liquid in the acute phase of schizophrenia.  Hum Psychopharm. 2005;  20 243-248
    PubMedGoogle Scholar

Reiji Yoshimura

Department of Psychiatry

University of Occupational and Environmental Health

1-1 Iseigaoka, Yahatanishi-ku Kitakyushu, Fukuoka 807-8555

Phone: +81 93 691 7253

Fax: +81 93 692 4894

Email: yoshi621@med.uoeh-u.ac.jp

      >