Skip to main content Accessibility help

Efficacy of bilateral repetitive transcranial magnetic stimulation for negative symptoms of schizophrenia: results of a multicenter double-blind randomized controlled trial

  • J. J. Dlabac-de Lange (a1) (a2) (a3), L. Bais (a3) (a4), F. D. van Es (a1), B. G. J. Visser (a1), E. Reinink (a4), B. Bakker (a4), E. R. van den Heuvel (a5), A. Aleman (a3) and H. Knegtering (a1) (a2) (a3) (a4)...



Few studies have investigated the efficacy of repetitive transcranial magnetic stimulation (rTMS) treatment for negative symptoms of schizophrenia, reporting inconsistent results. We aimed to investigate whether 10 Hz stimulation of the bilateral dorsolateral prefrontal cortex during 3 weeks enhances treatment effects.


A multicenter double-blind randomized controlled trial was performed in 32 patients with schizophrenia or schizo-affective disorder, and moderate to severe negative symptoms [Positive and Negative Syndrome Scale (PANSS) negative subscale ⩾15]. Patients were randomized to a 3-week course of active or sham rTMS. Primary outcome was severity of negative symptoms as measured with the Scale for the Assessment of Negative Symptoms (SANS) and the PANSS negative symptom score. Secondary outcome measures included cognition, insight, quality of life and mood. Subjects were followed up at 4 weeks and at 3 months. For analysis of the data a mixed-effects linear model was used.


A significant improvement of the SANS in the active group compared with sham up to 3 months follow-up (p = 0.03) was found. The PANSS negative symptom scores did not show a significant change (p = 0.19). Of the cognitive tests, only one showed a significant improvement after rTMS as compared with sham. Finally, a significant change of insight was found with better scores in the treatment group.


Bilateral 10 Hz prefrontal rTMS reduced negative symptoms, as measured with the SANS. More studies are needed to investigate optimal parameters for rTMS, the cognitive effects and the neural basis.


Corresponding author

* Address for correspondence: J. J. Dlabac-de Lange, Department of Psychiatry, University of Groningen, University Medical Center Groningen, Postbox 30.001, 9700 RB Groningen, The Netherlands. (Email:


Hide All
Aghababian, V, Auquier, P, Baumstarck-Barrau, K, Lancon, C (2011). Relationship between insight and self-reported quality of life among schizophrenic patients. L'Encephale 37, 162171.
Andreasen, NC (1982). Negative symptoms in schizophrenia. Definition and reliability. Archives of General Psychiatry 39, 784788.
Anonymous (1944). Army Individual Test Battery: Manual of Directions and Scoring. War Department, Adjutant General's Office: Washington, DC.
Anonymous (1998). Development of the World Health Organization WHOQOL-BREF quality of life assessment. The WHOQOL Group. Psychological Medicine 28, 551558.
Barr, MS, Farzan, F, Tran, LC, Fitzgerald, PB, Daskalakis, ZJ (2012). A randomized controlled trial of sequentially bilateral prefrontal cortex repetitive transcranial magnetic stimulation in the treatment of negative symptoms in schizophrenia. Brain Stimulation 5, 337346.
Beam, W, Borckardt, JJ, Reeves, ST, George, MS (2009). An efficient and accurate new method for locating the F3 position for prefrontal TMS applications. Brain Stimulation 2, 5054.
Ben-Shachar, D, Gazawi, H, Riboyad-Levin, J, Klein, E (1999). Chronic repetitive transcranial magnetic stimulation alters β-adrenergic and 5-HT2 receptor characteristics in rat brain. Brain Research 816, 7883.
Berlim, MT, van den Eynde, F, Tovar-Perdomo, S, Daskalakis, ZJ (2013). Response, remission and drop-out rates following high-frequency repetitive transcranial magnetic stimulation (rTMS) for treating major depression: a systematic review and meta-analysis of randomized, double-blind and sham-controlled trials. Psychological Medicine 44, 225239.
Berman, RM, Prudic, J, Brakemeier, EL, Olfson, M, Sackeim, HA (2008). Subjective evaluation of the therapeutic and cognitive effects of electroconvulsive therapy. Brain Stimulation 1, 1626.
Birchwood, M, Smith, J, Drury, V, Healy, J, Macmillan, F, Slade, M (1994). A self-report Insight Scale for psychosis: reliability, validity and sensitivity to change. Acta Psychiatrica Scandinavica 89, 6267.
Cohen, E, Bernardo, M, Masana, J, Arrufat, FJ, Navarro, V, Valls-Solé, J, Boget, T, Barrantes, N, Catarineu, S, Font, M, Lomeña, FJ (1999). Repetitive transcranial magnetic stimulation in the treatment of chronic negative schizophrenia: a pilot study. Journal of Neurology, Neurosurgery, and Psychiatry 67, 129130.
Cordes, J, Thunker, J, Agelink, MW, Arends, M, Mobascher, A, Wobrock, T, Schneider-Axmann, T, Brinkmeyer, J, Mittrach, M, Regenbrecht, G, Wolwer, W, Winterer, G, Gaebel, W (2010). Effects of 10 Hz repetitive transcranial magnetic stimulation (rTMS) on clinical global impression in chronic schizophrenia. Psychiatry Research 177, 3236.
Dlabac-de Lange, JJ, Knegtering, R, Aleman, A (2010). Repetitive transcranial magnetic stimulation for negative symptoms of schizophrenia: review and meta-analysis. Journal of Clinical Psychiatry 71, 411418.
Ehlis, AC, Herrmann, MJ, Plichta, MM, Fallgatter, AJ (2007). Cortical activation during two verbal fluency tasks in schizophrenic patients and healthy controls as assessed by multi-channel near-infrared spectroscopy. Psychiatry Research 156, 113.
Eisenegger, C, Treyer, V, Fehr, E, Knoch, D (2008). Time-course of “off-line” prefrontal rTMS effects – a PET study. NeuroImage 42, 379384.
Fenton, WS, McGlashan, TH (1991). Natural history of schizophrenia subtypes. II. Positive and negative symptoms and long-term course. Archives of General Psychiatry 48, 978986.
Fenton, WS, McGlashan, TH (1994). Antecedents, symptom progression, and long-term outcome of the deficit syndrome in schizophrenia. American Journal of Psychiatry 151, 351356.
Fitzgerald, PB, Herring, S, Hoy, K, McQueen, S, Segrave, R, Kulkarni, J, Daskalakis, ZJ (2008). A study of the effectiveness of bilateral transcranial magnetic stimulation in the treatment of the negative symptoms of schizophrenia. Brain Stimulation 1, 2732.
Gasquet, I, Haro, JM, Novick, D, Edgell, ET, Kennedy, L, Lepine, JP, SOHO Study Group (2005). Pharmacological treatment and other predictors of treatment outcomes in previously untreated patients with schizophrenia: results from the European Schizophrenia Outpatient Health Outcomes (SOHO) study. International Clinical Psychopharmacology 20, 199205.
George, MS, Post, RM (2011). Daily left prefrontal repetitive transcranial magnetic stimulation for acute treatment of medication-resistant depression. American Journal of Psychiatry 168, 356364.
Gershon, AA, Dannon, PN, Grunhaus, L (2003). Transcranial magnetic stimulation in the treatment of depression. American Journal of Psychiatry 160, 835845.
Giel, R, Nienhuis, FJ (1996). SCAN-2.1: Schedules for Clinical Assessment in Neuropsychiatry (in Dutch). WHO: Geneva/Groningen.
Glahn, DC, Ragland, JD, Abramoff, A, Barrett, J, Laird, AR, Bearden, CE, Velligan, DI (2005). Beyond hypofrontality: a quantitative meta-analysis of functional neuroimaging studies of working memory in schizophrenia. Human Brain Mapping 25, 6069.
Gonul, AS, Kula, M, Esel, E, Tutus, A, Sofuoglu, S (2003). A Tc-99 m HMPAO SPECT study of regional cerebral blood flow in drug-free schizophrenic patients with deficit and non-deficit syndrome. Psychiatry Research 123, 199205.
Goyal, N, Nizamie, SH, Desarkar, P (2007). Efficacy of adjuvant high frequency repetitive transcranial magnetic stimulation on negative and positive symptoms of schizophrenia: preliminary results of a double-blind sham-controlled study. Journal of Neuropsychiatry and Clinical Neurosciences 19, 464467.
Grant, DA, Berg, EA (1948). A behavioral analysis of degree of reinforcement and ease of shifting to new responses in a Weigl-type card-sorting problem. Journal of Experimental Psychology 38, 404411.
Hajak, G, Marienhagen, J, Langguth, B, Werner, S, Binder, H, Eichhammer, P (2004). High-frequency repetitive transcranial magnetic stimulation in schizophrenia: a combined treatment and neuroimaging study. Psychological Medicine 34, 11571163.
Holi, MM, Eronen, M, Toivonen, K, Toivonen, P, Marttunen, M, Naukkarinen, H (2004). Left prefrontal repetitive transcranial magnetic stimulation in schizophrenia. Schizophrenia Bulletin 30, 429434.
Ikezawa, K, Iwase, M, Ishii, R, Azechi, M, Canuet, L, Ohi, K, Yasuda, Y, Iike, N, Kurimoto, R, Takahashi, H, Nakahachi, T, Sekiyama, R, Yoshida, T, Kazui, H, Hashimoto, R, Takeda, M (2009). Impaired regional hemodynamic response in schizophrenia during multiple prefrontal activation tasks: a two-channel near-infrared spectroscopy study. Schizophrenia Research 108, 93103.
Jandl, M, Bittner, R, Sack, A, Weber, B, Gunther, T, Pieschl, D, Kaschka, WP, Maurer, K (2005). Changes in negative symptoms and EEG in schizophrenic patients after repetitive transcranial magnetic stimulation (rTMS): an open-label pilot study. Journal of Neural Transmission 112, 955967.
Jin, Y, Kemp, AS, Huang, Y, Thai, TM, Liu, Z, Xu, W, He, H, Potkin, SG (2012). Alpha EEG guided TMS in schizophrenia. Brain Stimulation 5, 560568.
Jin, Y, Potkin, SG, Kemp, AS, Huerta, ST, Alva, G, Thai, TM, Carreon, D, Bunney, WE Jr (2006). Therapeutic effects of individualized alpha frequency transcranial magnetic stimulation (alphaTMS) on the negative symptoms of schizophrenia. Schizophrenia Bulletin 32, 556561.
Kapur, S, Remington, G, Zipursky, RB, Wilson, AA, Houle, S (1995). The D2 dopamine receptor occupancy of risperidone and its relationship to extrapyramidal symptoms: a PET study. Life Sciences 57, 103107.
Karow, A, Pajonk, FG (2006). Insight and quality of life in schizophrenia: recent findings and treatment implications. Current Opinion in Psychiatry 19, 637641.
Kay, SR, Fiszbein, A, Opler, LA (1987). The Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Schizophrenia Bulletin 13, 261276.
Kirkpatrick, B, Fenton, WS, Carpenter, WT Jr, Marder, SR (2006). The NIMH-MATRICS consensus statement on negative symptoms. Schizophrenia Bulletin 32, 214219.
Kirkpatrick, B, Strauss, GP, Nguyen, L, Fischer, BA, Daniel, DG, Cienfuegos, A, Marder, SR (2011). The brief negative symptom scale: psychometric properties. Schizophrenia Bulletin 37, 300305.
Klein, E, Kolsky, Y, Puyerovsky, M, Koren, D, Chistyakov, A, Feinsod, M (1999). Right prefrontal slow repetitive transcranial magnetic stimulation in schizophrenia: a double-blind sham-controlled pilot study. Biological Psychiatry 46, 14511454.
Klemm, E, Danos, P, Grünwald, F, Kasper, S, Moller, HJ, Biersack, HJ (1996). Temporal lobe dysfunction and correlation of regional cerebral blood flow abnormalities with psychopathology in schizophrenia and major depression – a study with single photon emission computed tomography. Psychiatry Research 68, 110.
Ko, JH, Monchi, O, Ptito, A, Bloomfield, P, Houle, S, Strafella, AP (2008). Theta burst stimulation-induced inhibition of dorsolateral prefrontal cortex reveals hemispheric asymmetry in striatal dopamine release during a set-shifting task: a TMS-[11C]raclopride PET study. European Journal of Neuroscience 28, 21472155.
Kole, MH, Fuchs, E, Ziemann, U, Paulus, W, Ebert, U (1999). Changes in 5-HT1A and NMDA binding sites by a single rapid transcranial magnetic stimulation procedure in rats. Brain Research 826, 309312.
Lahti, AC, Holcomb, HH, Medoff, DR, Weiler, MA, Tamminga, CA, Carpenter, WT Jr (2001). Abnormal patterns of regional cerebral blood flow in schizophrenia with primary negative symptoms during an effortful auditory recognition task. American Journal of Psychiatry 158, 17971808.
Lako, IM, Bruggeman, R, Knegtering, H, Wiersma, D, Schoevers, RA, Slooff, CJ, Taxis, K (2012). A systematic review of instruments to measure depressive symptoms in patients with schizophrenia. Journal of Affective Disorders 140, 3847.
Lako, IM, van den Heuvel, ER, Knegtering, H, Bruggeman, R, Taxis, K (2013). Estimating dopamine D2 receptor occupancy for doses of 8 antipsychotics: a meta-analysis. Journal of Clinical Psychopharmacology 33, 675681.
Lane, HY, Chang, YC, Liu, YC, Chiu, CC, Tsai, GE (2005). Sarcosine or d-serine add-on treatment for acute exacerbation of schizophrenia: a randomized, double-blind, placebo-controlled study. Archives of General Psychiatry 62, 11961204.
Leucht, S, Pitschel-Walz, G, Abraham, D, Kissling, W (1999). Efficacy and extrapyramidal side-effects of the new antipsychotics olanzapine, quetiapine, risperidone, and sertindole compared to conventional antipsychotics and placebo. A meta-analysis of randomized controlled trials. Schizophrenia Research 35, 5168.
Liemburg, E, Castelein, S, Stewart, R, van der Gaag, M, Aleman, A, Knegtering, H, Genetic Risk and Outcome of Psychosis (GROUP) Investigators (2013). Two subdomains of negative symptoms in psychotic disorders: established and confirmed in two large cohorts. Journal of Psychiatric Research 47, 718725.
Lisanby, SH, Gutman, D, Luber, B, Schroeder, C, Sackeim, HA (2001). Sham TMS: intracerebral measurement of the induced electrical field and the induction of motor-evoked potentials. Biological Psychiatry 49, 460463.
Lisanby, SH, Maddox, JH, Prudic, J, Devanand, DP, Sackeim, HA (2000). The effects of electroconvulsive therapy on memory of autobiographical and public events. Archives of General Psychiatry 57, 581590.
Loo, CK, McFarquhar, TF, Mitchell, PB (2008). A review of the safety of repetitive transcranial magnetic stimulation as a clinical treatment for depression. International Journal of Neuropsychopharmacology 11, 131147.
Loo, CK, Mitchell, PB (2005). A review of the efficacy of transcranial magnetic stimulation (TMS) treatment for depression, and current and future strategies to optimize efficacy. Journal of Affective Disorders 88, 255267.
Mennemeier, M, Triggs, W, Chelette, K, Woods, A, Kimbrell, T, Dornhoffer, J (2009). Sham transcranial magnetic stimulation using electrical stimulation of the scalp. Brain Stimulation 2, 168173.
Milev, P, Ho, BC, Arndt, S, Andreasen, NC (2005). Predictive values of neurocognition and negative symptoms on functional outcome in schizophrenia: a longitudinal first-episode study with 7-year follow-up. American Journal of Psychiatry 162, 495506.
Mogg, A, Purvis, R, Eranti, S, Contell, F, Taylor, JP, Nicholson, T, Brown, RG, McLoughlin, DM (2007). Repetitive transcranial magnetic stimulation for negative symptoms of schizophrenia: a randomized controlled pilot study. Schizophrenia Research 93, 221228.
Montgomery, SA, Asberg, M (1979). A new depression scale designed to be sensitive to change. British Journal of Psychiatry 134, 382389.
Murphy, BP, Chung, YC, Park, TW, McGorry, PD (2006). Pharmacological treatment of primary negative symptoms in schizophrenia: a systematic review. Schizophrenia Research 88, 525.
Novak, T, Horacek, J, Mohr, P, Kopecek, M, Skrdlantova, L, Klirova, M, Rodriguez, M, Spaniel, F, Dockery, C, Hoschl, C (2006). The double-blind sham-controlled study of high-frequency rTMS (20 Hz) for negative symptoms in schizophrenia: negative results. Neuro Endocrinology Letters 27, 209213.
Potkin, SG, Alva, G, Fleming, K, Anand, R, Keator, D, Carreon, D, Doo, M, Jin, Y, Wu, JC, Fallon, JH (2002). A PET study of the pathophysiology of negative symptoms in schizophrenia. Positron emission tomography. American Journal of Psychiatry 159, 227237.
Prikryl, R, Kasparek, T, Skotakova, S, Ustohal, L, Kucerova, H, Ceskova, E (2007). Treatment of negative symptoms of schizophrenia using repetitive transcranial magnetic stimulation in a double-blind, randomized controlled study. Schizophrenia Research 95, 151157.
Prikryl, R, Ustohal, L, Prikrylova Kucerova, H, Kasparek, T, Venclikova, S, Vrzalova, M, Ceskova, E (2013). A detailed analysis of the effect of repetitive transcranial magnetic stimulation on negative symptoms of schizophrenia: a double-blind trial. Schizophrenia Research 149, 167173.
Rabany, L, Weiser, M, Werbeloff, N, Levkovitz, Y (2011). Assessment of negative symptoms and depression in schizophrenia: revision of the SANS and how it relates to the PANSS and CDSS. Schizophrenia Research 126, 226230.
Rey, A (1958). L'examin clinique en psychologie (The examined clinical psychology). Presses universitaires de France: Paris.
Sabri, O, Erkwoh, R, Schreckenberger, M, Cremerius, U, Schulz, G, Dickmann, C, Kaiser, HJ, Steinmeyer, EM, Sass, H, Buell, U (1997). Regional cerebral blood flow and negative/positive symptoms in 24 drug-naive schizophrenics. Journal of Nuclear Medicine 38, 181188.
Sachdev, P, Loo, C, Mitchell, P, Malhi, G (2005). Transcranial magnetic stimulation for the deficit syndrome of schizophrenia: a pilot investigation. Psychiatry and Clinical Neurosciences 59, 354357.
Sanfilipo, M, Lafargue, T, Rusinek, H, Arena, L, Loneragan, C, Lautin, A, Rotrosen, J, Wolkin, A (2002). Cognitive performance in schizophrenia: relationship to regional brain volumes and psychiatric symptoms. Psychiatry Research 116, 123.
Schmand, B, Bakker, D, Saan, R, Louman, J (1991). The Dutch Reading Test for Adults: a measure of premorbid intelligence level. Tijdschrift voor gerontologie en geriatrie 22, 1519.
Schneider, AL, Schneider, TL, Stark, H (2008). Repetitive transcranial magnetic stimulation (rTMS) as an augmentation treatment for the negative symptoms of schizophrenia: a 4-week randomized placebo controlled study. Brain Stimulation 1, 106111.
Schutter, DJ, van Honk, J (2006). A standardized motor threshold estimation procedure for transcranial magnetic stimulation research. Journal of ECT 22, 176178.
Selemon, LD, Mrzljak, J, Kleinman, JE, Herman, MM, Goldman-Rakic, PS (2003). Regional specificity in the neuropathologic substrates of schizophrenia: a morphometric analysis of Broca's area 44 and area 9. Archives of General Psychiatry 60, 6977.
Shad, MU, Tamminga, CA, Cullum, M, Haas, GL, Keshavan, MS (2006). Insight and frontal cortical function in schizophrenia: a review. Schizophrenia Research 86, 5470.
Shi, C, Yu, X, Cheung, EF, Shum, DH, Chan, RC (2014). Revisiting the therapeutic effect of rTMS on negative symptoms in schizophrenia: a meta-analysis. Psychiatry Research 215, 505513.
Shioiri, T, Kato, T, Inubushi, T, Murashita, J, Takahashi, S (1994). Correlations of phosphomonoesters measured by phosphorus-31 magnetic resonance spectroscopy in the frontal lobes and negative symptoms in schizophrenia. Psychiatry Research 55, 223235.
Sibon, I, Strafella, AP, Gravel, P, Ko, JH, Booij, L, Soucy, JP, Leyton, M, Diksic, M, Benkelfat, C (2007). Acute prefrontal cortex TMS in healthy volunteers: effects on brain 11C-alphaMtrp trapping. NeuroImage 34, 16581664.
Slotema, CW, Blom, JD, Hoek, HW, Sommer, IE (2010). Should we expand the toolbox of psychiatric treatment methods to include repetitive transcranial magnetic stimulation (rTMS)? A meta-analysis of the efficacy of rTMS in psychiatric disorders. Journal of Clinical Psychiatry 71, 873884.
Strafella, AP, Paus, T, Barrett, J, Dagher, A (2001). Repetitive transcranial magnetic stimulation of the human prefrontal cortex induces dopamine release in the caudate nucleus. Journal of Neuroscience 21, RC157.
Strous, RD, Maayan, R, Lapidus, R, Stryjer, R, Lustig, M, Kotler, M, Weizman, A (2003). Dehydroepiandrosterone augmentation in the management of negative, depressive, and anxiety symptoms in schizophrenia. Archives of General Psychiatry 60, 133141.
van den Burg, W, Saan, RJ, Deelman, BG (1985). 15-Woordentest. Provisional Manual (15 - Word Test Provisional Manual). University Hospital: Groningen.
Verhage, F (1983). Revised Scoring Method. University Hospital: Groningen.
Wechsler, D (1997). Wechsler Adult Intelligence Scale, 3rd edn. Psychological Corp.: San Antonio, TX.
Wolkin, A, Sanfilipo, M, Wolf, AP, Angrist, B, Brodie, JD, Rotrosen, J (1992). Negative symptoms and hypofrontality in chronic schizophrenia. Archives of General Psychiatry 49, 959965.


Efficacy of bilateral repetitive transcranial magnetic stimulation for negative symptoms of schizophrenia: results of a multicenter double-blind randomized controlled trial

  • J. J. Dlabac-de Lange (a1) (a2) (a3), L. Bais (a3) (a4), F. D. van Es (a1), B. G. J. Visser (a1), E. Reinink (a4), B. Bakker (a4), E. R. van den Heuvel (a5), A. Aleman (a3) and H. Knegtering (a1) (a2) (a3) (a4)...


Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed