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Archival Report| Volume 77, ISSUE 11, P979-988, June 01, 2015

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Left Prefrontal High-Frequency Repetitive Transcranial Magnetic Stimulation for the Treatment of Schizophrenia with Predominant Negative Symptoms: A Sham-Controlled, Randomized Multicenter Trial

      Abstract

      Background

      Investigators are urgently searching for options to treat negative symptoms in schizophrenia because these symptoms are disabling and do not respond adequately to antipsychotic or psychosocial treatment. Meta-analyses based on small proof-of-principle trials suggest efficacy of repetitive transcranial magnetic stimulation (rTMS) for the treatment of negative symptoms and call for adequately powered multicenter trials. This study evaluated the efficacy of 10-Hz rTMS applied to the left dorsolateral prefrontal cortex for the treatment of predominant negative symptoms in schizophrenia.

      Methods

      A multicenter randomized, sham-controlled, rater-blinded and patient-blinded trial was conducted from 2007–2011. Investigators randomly assigned 175 patients with schizophrenia with predominant negative symptoms and a high-degree of illness severity into two treatment groups. After a 2-week pretreatment phase, 76 patients were treated with 10-Hz rTMS applied 5 days per week for 3 weeks to the left dorsolateral prefrontal cortex (added to the ongoing treatment), and 81 patients were subjected to sham rTMS applied similarly.

      Results

      There was no statistically significant difference in improvement in negative symptoms between the two groups at day 21 (p = .53, effect size = .09) or subsequently through day 105. Also, symptoms of depression and cognitive function showed no differences in change between groups. There was a small, but statistically significant, improvement in positive symptoms in the active rTMS group (p = .047, effect size = .30), limited to day 21.

      Conclusions

      Application of active 10-Hz rTMS to the left dorsolateral prefrontal cortex was well tolerated but was not superior compared with sham rTMS in improving negative symptoms; this is in contrast to findings from three meta-analyses.

      Keywords

      Schizophrenia is the most debilitating psychiatric disorder and is associated with a significant disease-related burden leading to tremendous direct and indirect treatment costs (
      • Sun S.X.
      • Liu G.G.
      • Christensen D.B.
      • Fu A.Z.
      Review and analysis of hospitalization costs associated with antipsychotic nonadherence in the treatment of schizophrenia in the United States.
      ,
      • Gustavsson A.
      • Svensson M.
      • Jacobi F.
      • Allgulander C.
      • Alonso J.
      • Beghi E.
      • et al.
      Cost of disorders of the brain in Europe 2010.
      ). Among the complex symptoms of schizophrenia, negative symptoms such as amotivation and affective flattening remain some of the most vexing challenges for effective treatment and improvement in outcome (
      • An der Heiden W.
      • Hafner H.
      Course and Outcome.
      ,
      • Kirkpatrick B.
      • Fenton W.S.
      • Carpenter Jr, W.T.
      • Marder S.R.
      The NIMH-MATRICS consensus statement on negative symptoms.
      ,
      • Buchanan R.W.
      Persistent negative symptoms in schizophrenia: an overview.
      ). These symptoms are highly prevalent, are very stable over time, are associated with cognitive impairment, and predict poor functional outcome and quality of life (
      • An der Heiden W.
      • Hafner H.
      Course and Outcome.
      ,
      • Kirkpatrick B.
      • Fenton W.S.
      • Carpenter Jr, W.T.
      • Marder S.R.
      The NIMH-MATRICS consensus statement on negative symptoms.
      ,
      • Buchanan R.W.
      Persistent negative symptoms in schizophrenia: an overview.
      ). For many patients, negative symptoms persist in the face of effective antipsychotic drug treatment of positive symptoms such as hallucinations and delusions, and adjunctive medications or psychosocial interventions have limited benefit (
      • Hasan A.
      • Falkai P.
      • Wobrock T.
      • Lieberman J.
      • Glenthoj B.
      • Gattaz W.F.
      • et al.
      World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Schizophrenia, part 1: Update 2012 on the acute treatment of schizophrenia and the management of treatment resistance.
      ).
      Repetitive transcranial magnetic stimulation (rTMS) is a neuromodulatory noninvasive brain stimulation technique using repetitive application of magnetic pulses through the scalp leading to an excitability shift up in the stimulated cortical areas that can last several hours (
      • Ziemann U.
      • Paulus W.
      • Nitsche M.A.
      • Pascual-Leone A.
      • Byblow W.D.
      • Berardelli A.
      • et al.
      Consensus: Motor cortex plasticity protocols.
      ). Pharmacologic challenges in healthy subjects and repetitive measures of motor cortical excitability indicate that the brain activity changes after rTMS are related to molecular processes of plasticity (
      • Ziemann U.
      • Paulus W.
      • Nitsche M.A.
      • Pascual-Leone A.
      • Byblow W.D.
      • Berardelli A.
      • et al.
      Consensus: Motor cortex plasticity protocols.
      ). Certain rTMS devices with specific protocols have been approved by the U.S. Food and Drug Administration for patients with depression with poor or incomplete response to pharmacotherapy (
      • George M.S.
      • Lisanby S.H.
      • Avery D.
      • McDonald W.M.
      • Durkalski V.
      • Pavlicova M.
      • et al.
      Daily left prefrontal transcranial magnetic stimulation therapy for major depressive disorder: A sham-controlled randomized trial.
      ). Positron emission tomography studies indicate that rTMS increases brain activity and cerebral blood flow both at the site of cortical stimulation and in interconnected sites and that these effects outlast the duration of stimulation (
      • Paus T.
      • Jech R.
      • Thompson C.J.
      • Comeau R.
      • Peters T.
      • Evans A.C.
      Transcranial magnetic stimulation during positron emission tomography: A new method for studying connectivity of the human cerebral cortex.
      ,
      • Rounis E.
      • Lee L.
      • Siebner H.R.
      • Rowe J.B.
      • Friston K.J.
      • Rothwell J.C.
      • et al.
      Frequency specific changes in regional cerebral blood flow and motor system connectivity following rTMS to the primary motor cortex.
      ,
      • Eisenegger C.
      • Treyer V.
      • Fehr E.
      • Knoch D.
      Time-course of “off-line” prefrontal rTMS effects—a PET study.
      ,
      • Lee L.
      • Siebner H.R.
      • Rowe J.B.
      • Rizzo V.
      • Rothwell J.C.
      • Frackowiak R.S.
      • et al.
      Acute remapping within the motor system induced by low-frequency repetitive transcranial magnetic stimulation.
      ). High-frequency rTMS applied to the dorsolateral prefrontal cortex (DLPFC) can modulate extrastriatal and mesostriatal dopaminergic pathways that may contribute to negative symptoms (
      • Cho S.S.
      • Strafella A.P.
      rTMS of the left dorsolateral prefrontal cortex modulates dopamine release in the ipsilateral anterior cingulate cortex and orbitofrontal cortex.
      ,
      • Strafella A.P.
      • Paus T.
      • Barrett J.
      • Dagher A.
      Repetitive transcranial magnetic stimulation of the human prefrontal cortex induces dopamine release in the caudate nucleus.
      ), suggesting rTMS may be a promising therapeutic option for negative symptoms of schizophrenia. This possibility is particularly important because reduced left DLPFC activation (
      • Hill K.
      • Mann L.
      • Laws K.R.
      • Stephenson C.M.
      • Nimmo-Smith I.
      • McKenna P.J.
      Hypofrontality in schizophrenia: A meta-analysis of functional imaging studies.
      ) and reduced prefrontal white matter volumes (
      • Sanfilipo M.
      • Lafargue T.
      • Rusinek H.
      • Arena L.
      • Loneragan C.
      • Lautin A.
      • et al.
      Volumetric measure of the frontal and temporal lobe regions in schizophrenia: Relationship to negative symptoms.
      ) have been linked to negative symptoms of schizophrenia and facilitatory and inhibitory DLPFC projections are critically involved in the modulation of dopaminergic networks (
      • Laruelle M.
      • Kegeles L.S.
      • Abi-Dargham A.
      Glutamate, dopamine, and schizophrenia: From pathophysiology to treatment.
      ,
      • Prikryl R.
      • Kucerova H.P.
      Can repetitive transcranial magnetic stimulation be considered effective treatment option for negative symptoms of schizophrenia?.
      ). However, physiologic studies indicate disrupted plasticity in schizophrenia, which may reduce the efficacy of noninvasive brain stimulation (
      • Daskalakis Z.J.
      • Christensen B.K.
      • Fitzgerald P.B.
      • Chen R.
      Dysfunctional neural plasticity in patients with schizophrenia.
      ,
      • Frantseva M.V.
      • Fitzgerald P.B.
      • Chen R.
      • Moller B.
      • Daigle M.
      • Daskalakis Z.J.
      Evidence for impaired long-term potentiation in schizophrenia and its relationship to motor skill learning.
      ,
      • Hasan A.
      • Wobrock T.
      • Rajji T.
      • Malchow B.
      • Daskalakis Z.J.
      Modulating neural plasticity with non-invasive brain stimulation in schizophrenia.
      ).
      Three meta-analyses of relatively small, heterogeneous single-center trials (with a maximum of 18 patients per treatment group; main target region was left DLPFC) of rTMS for negative symptoms suggest an effect size of .27–.53 compared with sham rTMS (
      • Prikryl R.
      • Kucerova H.P.
      Can repetitive transcranial magnetic stimulation be considered effective treatment option for negative symptoms of schizophrenia?.
      ,
      • Freitas C.
      • Fregni F.
      • Pascual-Leone A.
      Meta-analysis of the effects of repetitive transcranial magnetic stimulation (rTMS) on negative and positive symptoms in schizophrenia.
      ,
      • Dlabac-de Lange J.J.
      • Knegtering R.
      • Aleman A.
      Repetitive transcranial magnetic stimulation for negative symptoms of schizophrenia: Review and meta-analysis.
      ,
      • Shi C.
      • Yu X.
      • Cheung E.F.
      • Shum D.H.
      • Chan R.C.
      Revisiting the therapeutic effect of rTMS on negative symptoms in schizophrenia: A meta-analysis.
      ). Although there is still no evidence from multicenter randomized controlled trials, the application of rTMS for the treatment of negative symptoms of schizophrenia is a complementary treatment option discussed in the field. Our goal was to determine whether active 10-Hz rTMS would be superior to sham rTMS for the treatment of negative symptoms in patients with schizophrenia in the first large and adequately powered, multicenter, randomized controlled clinical trial.

      Methods And Materials

      Written informed consent was obtained from all subjects after complete description of the study. The local ethics committees approved the protocol, which was conducted in accordance with the Declaration of Helsinki.

      Subjects

      We enrolled 197 inpatients and outpatients from three German university hospital centers (Goettingen, Duesseldorf, Regensburg) for this multicenter randomized, sham-controlled, rater-blinded and patient-blinded clinical trial. The inclusion criteria were International Classification of Diseases, Tenth Revision, diagnosis of schizophrenia (
      World Health Organization
      International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10).
      ) (F20.xx, confirmed by the Mini-International Neuropsychiatric Interview Plus interview (
      • Sheehan D.V.
      • Lecrubier Y.
      • Sheehan K.H.
      • Amorim P.
      • Janavs J.
      • Weiller E.
      • et al.
      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.
      )), age 18–60 years, and an illness duration of at least 1 year. A predominantly negative symptom syndrome was confirmed by a Positive and Negative Syndrome Scale (PANSS) (
      • Kay S.R.
      • Fiszbein A.
      • Opler L.A.
      The positive and negative syndrome scale (PANSS) for schizophrenia.
      ) negative subscore >20 points, one of items N1–N7 scoring ≥4, and no reduction of ≥10% in PANSS negative subscore in the 2 weeks before intervention. Antipsychotic medication had to be stable for 2 weeks before study inclusion. The exclusion criteria were clinically relevant psychiatric comorbidity (including current misuse of or dependence on illegal drugs or alcohol), concomitant treatment with anticonvulsant drugs or benzodiazepines (lorazepam >2 mg/day, diazepam >10 mg/day), history of epileptic seizures or epileptic activity on baseline electroencephalography (EEG), previous treatment with rTMS, a contraindication for rTMS, verbal IQ <85, clinically relevant unstable medical conditions, involuntary hospitalization, or pregnancy (
      • Cordes J.
      • Thunker J.
      • Agelink M.W.
      • Arends M.
      • Mobascher A.
      • Wobrock T.
      • et al.
      Effects of 10 Hz repetitive transcranial magnetic stimulation (rTMS) on clinical global impression in chronic schizophrenia.
      ).

      Intervention

      From 2007–2011, patients with schizophrenia entered a pretreatment assessment 12–16 days before the baseline visit at day 0. Patients meeting the exclusion criteria in this pretreatment period were withdrawn from the study. Eligible patients entered a 3-week, rater-blinded and patient-blinded, parallel-group rTMS intervention (active rTMS vs. sham rTMS added to ongoing treatment) period completed by day 21, followed by a 12-week extension phase (assessments at days 28, 45, and 105; no further rTMS treatment) (Figure 1). Patients randomly assigned to the active condition received 10-Hz rTMS applied to the left DLPFC (EEG International 10-20 system, F3-electrode, five treatment sessions per week during the 3-week treatment period) with an intensity of 110% of the individual resting motor threshold (
      • Rothwell J.C.
      Techniques and mechanisms of action of transcranial stimulation of the human motor cortex.
      ) and 1000 stimuli (20 trains with 50 stimuli per train, 30-sec intertrain interval) per session (
      • Cordes J.
      • Falkai P.
      • Guse B.
      • Hasan A.
      • Schneider-Axmann T.
      • Arends M.
      • et al.
      Repetitive transcranial magnetic stimulation for the treatment of negative symptoms in residual schizophrenia: Rationale and design of a sham-controlled, randomized multicenter study.
      ). Patients randomly assigned to the sham intervention were treated identically, but the magnetic coil was tilted over one wing at an angle of 45 degrees leading to similar skin sensations with significantly reduced biological activity compared with active stimulation (
      • Lisanby S.H.
      • Gutman D.
      • Luber B.
      • Schroeder C.
      • Sackeim H.A.
      Sham TMS: Intracerebral measurement of the induced electrical field and the induction of motor-evoked potentials.
      ) (see Figure S1 in Supplement 1 for an example of coil orientation). The F3-position is assumed to correspond to Brodmann areas 8, 9, or 46 on the media frontal gyrus (
      • Homan R.W.
      • Herman J.
      • Purdy P.
      Cerebral location of international 10-20 system electrode placement.
      ,
      • Herwig U.
      • Padberg F.
      • Unger J.
      • Spitzer M.
      • Schonfeldt-Lecuona C.
      Transcranial magnetic stimulation in therapy studies: Examination of the reliability of “standard” coil positioning by neuronavigation.
      ,
      • Herwig U.
      • Satrapi P.
      • Schonfeldt-Lecuona C.
      Using the international 10-20 EEG system for positioning of transcranial magnetic stimulation.
      ). All participating sites used the same stimulators (MagPro X100; Medtronic A/S, Copenhagen, Denmark) and passively cooled MCF-B65 figure-of-eight coils (Medtronic A/S).
      Figure thumbnail gr1
      Figure 1Trial study plan. After a screening period, patients with schizophrenia entered a pretreatment assessment 12–16 days before the baseline visit at day 0. Patients meeting the exclusion criteria in this pretreatment period were withdrawn from the study. Eligible patients entered a 3-week, patient-blinded and rater-blinded, parallel-group repetitive transcranial magnetic stimulation intervention (active vs. sham repetitive transcranial magnetic stimulation) period followed by a 12-week extension phase (extension-phase visits at days 28, 45, and 105; no treatment in either group). rTMS, repetitive transcranial magnetic stimulation.
      Study monitoring for safety and Good Clinical Practice aspects was performed by the Coordination Centre for Clinical Trials Duesseldorf (http://www.uniklinik-duesseldorf.de/kks). The trial has been registered at http://www.clinicaltrials.gov (NCT00783120), and the trial protocol has been published (
      • Cordes J.
      • Falkai P.
      • Guse B.
      • Hasan A.
      • Schneider-Axmann T.
      • Arends M.
      • et al.
      Repetitive transcranial magnetic stimulation for the treatment of negative symptoms in residual schizophrenia: Rationale and design of a sham-controlled, randomized multicenter study.
      ). The randomization procedure is described in Supplement 1.

      Baseline Assessment and Efficacy Measures

      The primary outcome measure was change in PANSS negative subscore after 3 weeks of intervention. The PANSS is a reliable instrument to rate psychopathology in schizophrenia trials. Raters were trained by reviewing standardized videotaped interviews. The secondary outcomes reported here are changes in PANSS positive subscore, PANSS total score, depressive symptoms measured by the Calgary Depression Scale for Schizophrenia (CDSS) (
      • Addington D.
      • Addington J.
      • Maticka-Tyndale E.
      Assessing depression in schizophrenia: The Calgary Depression Scale.
      ) and the Montgomery–Åsberg Depression Rating Scale (MADRS) (
      • Montgomery S.A.
      • Asberg M.
      A new depression scale designed to be sensitive to change.
      ), overall illness severity measured by Clinical Global Impressions (CGI) score (

      Guy W (1976): Clinical Global Impressions. In: ECDEU Assessment Manual for Psychopharmacology. Revised DHEW Pub. (ADM). Rockville, MD: National Institute for Mental Health, 218–222.

      ), and general functioning measured by the Global Assessment of Functioning (GAF) scale (
      • Endicott J.
      • Spitzer R.L.
      • Fleiss J.L.
      • Cohen J.
      The global assessment scale. A procedure for measuring overall severity of psychiatric disturbance.
      ). A response in negative symptoms was defined as improvement of ≥20% (
      • Beitinger R.
      • Lin J.
      • Kissling W.
      • Leucht S.
      Comparative remission rates of schizophrenic patients using various remission criteria.
      ) compared with baseline PANSS negative score. Complex visual scanning, motor speed, and the ability to shift strategies were measured with time required for the Trail Making Test A and B (
      • Tombaugh T.N.
      Trail Making Test A and B: Normative data stratified by age and education.
      ).

      Safety Measures

      All patients underwent standard EEG to exclude epileptic activity. Standardized assessment of motor side effects was done with the St. Hans Rating Scale for extrapyramidal syndromes (
      • Gerlach J.
      • Korsgaard S.
      • Clemmesen P.
      • Lauersen A.M.
      • Magelund G.
      • Noring U.
      • et al.
      The St. Hans Rating Scale for extrapyramidal syndromes: Reliability and validity.
      ). Vital signs and standard laboratory measures were registered during the trial. Spontaneous side effects, adverse events and serious adverse events were documented.

      Sample Size and Statistical Analyses

      A power calculation was based on the primary study endpoint. A difference of θ = 3 points in improvement of PANSS negative subscore between intervention groups can be considered clinically meaningful. The required sample size in each group and at each time point (day 0/day 21) was computed as n = 2σ22(z.8z.025)2 ≈ 63, with SD σ = 6, assumed difference θ = 3, 80% and 2.5% quantiles of the standard normal distribution z.8 = .84, z.025 = −1.96 and effect size θ/σ = .5. For these calculations, a two-group normal test with two-sided type I significance level of α = .05 was assumed. A Monte Carlo simulation was performed as a probabilistic sensitivity analysis with 2000 scenarios, resulting in an estimated required sample size of n = 62 per group. Additionally, post hoc power analyses using actual sample sizes and observed variances σ2 were calculated. A sufficient power of 1 − β > .8 was achieved simulating the following assumed differences: PANSSnegative, θ = 3; PANSSpositive, θ = 2; PANSStotal, θ = 7; CDSS, θ = 2; MADRS, θ = 3.5; CGI, θ = .4; GAF, θ = 6 (
      • Faul F.
      • Erdfelder E.
      • Lang A.G.
      • Buchner A.
      G*Power 3: A flexible statistical power analysis program for the social, behavioral, and biomedical sciences.
      ).
      The association between severity of negative symptoms and positive symptoms and associations with level of function, antipsychotic dose, measures of depression, and cognitive function were assessed with Spearman rank correlation. The primary outcome analysis was performed in the intention-to-treat population, defined as all patients randomly assigned into a treatment group who started at least one treatment session (
      • George M.S.
      • Lisanby S.H.
      • Avery D.
      • McDonald W.M.
      • Durkalski V.
      • Pavlicova M.
      • et al.
      Daily left prefrontal transcranial magnetic stimulation therapy for major depressive disorder: A sham-controlled randomized trial.
      ). The primary outcome variable was PANSS negative subscore. Secondary outcome variables were PANSS positive and total scores; portion of responders; and scores of CDSS, MADRS, CGI, and GAF. The Kolmogorov-Smirnov test was used to test continuous variables for deviations from the normal distribution. Demographic and clinical characteristics were compared between groups, and where relevant, analyses were controlled for these factors or covariates. For the intention-to-treat population, primary and secondary outcomes were analyzed with general linear mixed model analysis of covariance, nonrestrictively assuming an unstructured covariance matrix (
      • Krueger C.
      • Tian L.
      A comparison of the general linear mixed model and repeated measures ANOVA using a dataset with multiple missing data points.
      ). The between-subject factor was group (active/sham); the within-subject factor was time of visit (day 0/day 21). The statistic analyzed for significance was the interaction between time of measurement and group, indicating whether or not the change in outcome variables over time differed between groups. In a secondary analysis, the mixed model analysis of covariance was extended, considering all data from the extension phase. If the normality assumption was violated, analyses were performed on logarithmic transformed variables, or the Breslow-Day test for homogeneity of the odds ratios was applied. Effect sizes for the interaction between group and measurement time and 95% confidence intervals were calculated.

      Results

      Study Subjects

      The investigators screened 197 patients, until the recruitment objective was reached. A total of 175 patients were enrolled and randomly assigned into a treatment group. After a 2-week period of assessment of eligibility, 157 patients received either active (n = 76) or sham (n = 81) rTMS treatment; 127 patients remained in the sample at day 21 (see Supplement 1 for dropout analysis and Consolidated Standards of Reporting Trials diagram). Study patients were selected based on having clinically significant, stable negative symptoms. In the overall sample, greater severity of negative symptoms was associated with lower level of function, greater severity of positive symptoms, depression, and impairment on a cognitive test linked to frontal lobe function (Table 1). Negative symptoms and depression can be challenging to distinguish. In the present sample, patients treated with antidepressant medications had higher negative symptom scores than patients not treated with antidepressants, suggesting untreated depression was not the source of negative symptoms. Negative symptoms can be mimicked by neurologic side effects of antipsychotics. However, there was no significant correlation between negative symptom severity and antipsychotic dose in these patients. At day 0, there were no statistically significant differences in any of the demographic or clinical measures between groups (Table 1). Study site differences are presented in Supplement 1.
      Table 1Baseline Characteristics and Association of Clinical Features with Negative Symptoms
      Active rTMS (n = 76)Sham rTMS (n = 81)Active vs. ShamAssociation with Negative Symptoms in Total Sample
      VariableLR χ²dfpp
      Gender (Male:Female)62:1456:253.31.07
      Comparison by LR test.
      Employment (Employed:Not Employed)14:6210:711.11.29
      Comparison by LR test.
      Center (Duesseldorf:Goettingen:Regensburg)20:28:2821:29:31.02.98
      Comparison by LR test.
      Hand Preference (Right:Not Right)62:1166:10.11.74
      Comparison by LR test.
      Antidepressant Use (Yes:No)28:4730:50.01.98
      Comparison by LR test.
      .02
      Result from analysis of variance comparing negative symptoms between patients prescribed and not prescribed antidepressants.
      MeanSDMeanSDFdfpSpearman correlation
      Analyses of correlations with negative symptoms are based on 133–154 patients.
      p
      Age (Years)36.210.534.99.1.71,155.41
      Comparison by analysis of variance.
      Education (Years)
      Duration of education was available for 70 patients in the active group and for 80 patients in the sham group.
      11.51.911.32.0.61,148.43
      Comparison by analysis of variance.
      Left Resting Motor Threshold
      For resting motor threshold, the sample size was 69 (active group) and 72 (sham group).
      47.08.846.411.6.11,139.74
      Comparison by analysis of variance.
      Severity of Illness and Treatment
       PANSS negative symptoms
      Scores on the positive and negative symptom subscales of the PANSS range from 7–49, with higher scores denoting more severe illness.
      25.6
      For one patient with pretreatment phase data included in the intention-to-treat analysis, day 0 data were missing. Data were available for 75 patients (negative symptoms and Montgomery–Åsberg Depression Rating Scale) and for 63–72 patients for other measures.
      4.625.1
      For one patient with pretreatment phase data included in the intention-to-treat analysis, day 0 data were missing. Data were available for 80 patients (negative symptoms) and for 72–79 patients for other measures.
      3.7.51,153.48
      Comparison by analysis of variance.
       PANSS positive symptoms14.34.613.03.63.31,145.07
      Comparison by analysis of variance.
      .27.001
       PANSS total79.715.876.013.52.31,144.13
      Comparison by analysis of variance.
      .64<.001
       Clinical Global Impressions score for severity
      The Clinical Global Impressions score for severity ranges from 1 (not mentally ill) to 7 (extremely ill).
      4.6.94.7.9Z = −.61.54
      Comparison by Mann-Whitney U test.
      .51<.001
       Global Assessment of Functioning
      The Global Assessment of Functioning score ranges from 1–100, with higher scores indicating better functioning.
      52.111.653.512.1.51,140.49
      Comparison by analysis of variance.
      −.49<.001
      Antipsychotic Dose (Chlorpromazine Equivalents) (mg/day)572435597486.01,142.95
      Comparison on logarithmic transformed variable by analysis of variance.
      .03.69
      Depression Related
       Calgary Depression Scale for Schizophrenia
      The Calgary Depression Scale for Schizophrenia ranges from 0–27, with higher scores indicating more severe depression.
      5.23.55.13.8.11,146.81
      Comparison by analysis of variance.
      .26.001
       Montgomery–Åsberg Depression Rating Scale
      The Montgomery–Åsberg Depression Rating Scale ranges from 0–60, with higher scores indicating more severe depression.
      14.86.013.66.11.61,152.21
      Comparison by analysis of variance.
      .44<.001
      Cognitive
       Trail Making Test A time (sec)36.619.838.516.1.71,137.41
      Comparison on logarithmic transformed variable by analysis of variance.
      .28.001
       Trail Making Test B time (sec)90.855.387.940.1.01,133.97
      Comparison on logarithmic transformed variable by analysis of variance.
      .24.006
      LR, likelihood ratio; PANSS, Positive and Negative Syndrome Scale; rTMS, repetitive transcranial magnetic stimulation.
      a Comparison by LR test.
      b Result from analysis of variance comparing negative symptoms between patients prescribed and not prescribed antidepressants.
      c Analyses of correlations with negative symptoms are based on 133–154 patients.
      d Comparison by analysis of variance.
      e Duration of education was available for 70 patients in the active group and for 80 patients in the sham group.
      f For resting motor threshold, the sample size was 69 (active group) and 72 (sham group).
      g Scores on the positive and negative symptom subscales of the PANSS range from 7–49, with higher scores denoting more severe illness.
      h For one patient with pretreatment phase data included in the intention-to-treat analysis, day 0 data were missing. Data were available for 75 patients (negative symptoms and Montgomery–Åsberg Depression Rating Scale) and for 63–72 patients for other measures.
      i For one patient with pretreatment phase data included in the intention-to-treat analysis, day 0 data were missing. Data were available for 80 patients (negative symptoms) and for 72–79 patients for other measures.
      j The Clinical Global Impressions score for severity ranges from 1 (not mentally ill) to 7 (extremely ill).
      k Comparison by Mann-Whitney U test.
      l The Global Assessment of Functioning score ranges from 1–100, with higher scores indicating better functioning.
      m Comparison on logarithmic transformed variable by analysis of variance.
      n The Calgary Depression Scale for Schizophrenia ranges from 0–27, with higher scores indicating more severe depression.
      o The Montgomery–Åsberg Depression Rating Scale ranges from 0–60, with higher scores indicating more severe depression.

      Primary Outcome Measure

      Analyses were carried out with the intention-to-treat population, using the original assignments and beginning at day 0 when the first clinical data were collected. The PANSS negative symptom subscore did not differ between the active and sham rTMS groups at baseline or after 21 days of treatment. A significant improvement between day 0 and day 21 occurred in both groups [F1,122.5 = 51.2, p < .001]. There was no significant difference in the amount of improvement between active and sham rTMS groups [F1,122.7 = .4, p = .53, effect size .09] (Table 2 and Figure 2). The mean difference between the two treatment groups in change in PANSS negative subscores between day 0 and day 21 was .5 (95% confidence interval, −1.2 to 2.3).
      Table 2Primary and Secondary Outcome Measures at the Beginning and the End of 21 Days of rTMS Treatment
      Active rTMSSham rTMS
      Day 0Day 21Day 0Day 21Interaction Between Group and Time of Measurement
      (n = 76)
      For one patient with pretreatment phase data included in the intention-to-treat analysis, day 0 data were missing. Data were available for 75 patients (negative symptoms and Montgomery–Åsberg Depression Rating Scale) and for 69–72 patients for other measures.
      (n = 62)
      Data were available for 62 patients (negative symptoms and Montgomery–Åsberg Depression Rating Scale) and for 58–60 patients for other measures. One patient who remained in the study had no available day 21 data.
      (n = 81)
      For one patient with pretreatment phase data included in the intention-to-treat analysis, day 0 data were missing. Data were available for 80 patients (negative symptoms) and for 72–79 patients for other measures.
      (n = 64)
      Data were available for 64 patients (negative symptoms, Calgary Depression Scale for Schizophrenia, and Montgomery–Åsberg Depression Rating Scale) and for 62–63 patients for other measures.
      Outcome MeasureMeanSDMeanSDMeanSDMeanSDFdfp
      Results from intention-to-treat analysis, statistics for interaction between group and time of measurement.
      Effect Size
      Corresponding to Cohen’s d, effect sizes for the interaction between group and time of measurement were calculated by subtracting the mean score at day 21 from the mean score at day 0 for each group, then determining the difference between the two groups (rTMS active, control subjects) and dividing the results by the pooled SDs.
      PANSS Score
       Negative25.64.622.76.125.13.722.75.8.41,122.7.53.09
       Positive14.34.612.44.113.03.612.44.64.01,119.2.047.30
       Total79.715.873.218.076.013.571.617.82.41,116.7.12.13
      Calgary Depression Scale for Schizophrenia5.23.54.43.55.13.84.64.4.11,118.5.72.10
      Montgomery–Åsberg Depression Rating Scale14.86.012.07.313.66.112.68.51.61,120.5.21.27
      Clinical Global Impressions score for severity4.6.94.4.94.7.94.51.0χ² = 2.75.74
      Clinical Global Impressions score was classified into the groups low (not more than moderately ill) and high (at least markedly ill). For the transformed variables, the Breslow-Day test was used to check for inhomogeneities between the groups across the times of visit.
      .11
      Global Assessment of Functioning52.111.656.012.253.512.155.511.5.41,120.7.52.16
      Antipsychotic Dose (Chlorpromazine Equivalents) (mg/day)5724355693835974865644382.11,114.4.15
      Analysis on logarithmic transformed variable.
      .07
      PANSS, Positive and Negative Syndrome Scale; rTMS, repetitive transcranial magnetic stimulation.
      a For one patient with pretreatment phase data included in the intention-to-treat analysis, day 0 data were missing. Data were available for 75 patients (negative symptoms and Montgomery–Åsberg Depression Rating Scale) and for 69–72 patients for other measures.
      b Data were available for 62 patients (negative symptoms and Montgomery–Åsberg Depression Rating Scale) and for 58–60 patients for other measures. One patient who remained in the study had no available day 21 data.
      c For one patient with pretreatment phase data included in the intention-to-treat analysis, day 0 data were missing. Data were available for 80 patients (negative symptoms) and for 72–79 patients for other measures.
      d Data were available for 64 patients (negative symptoms, Calgary Depression Scale for Schizophrenia, and Montgomery–Åsberg Depression Rating Scale) and for 62–63 patients for other measures.
      e Results from intention-to-treat analysis, statistics for interaction between group and time of measurement.
      f Corresponding to Cohen’s d, effect sizes for the interaction between group and time of measurement were calculated by subtracting the mean score at day 21 from the mean score at day 0 for each group, then determining the difference between the two groups (rTMS active, control subjects) and dividing the results by the pooled SDs.
      g Clinical Global Impressions score was classified into the groups low (not more than moderately ill) and high (at least markedly ill). For the transformed variables, the Breslow-Day test was used to check for inhomogeneities between the groups across the times of visit.
      h Analysis on logarithmic transformed variable.
      Figure thumbnail gr2
      Figure 2Scores for severity of symptoms during the trial. Data appear as mean ± SE in blue for active repetitive transcranial magnetic stimulation and in red for sham repetitive transcranial magnetic stimulation. There were no significant differences in negative or total Positive and Negative Syndrome Scale scores between the active and sham repetitive transcranial magnetic stimulation group (A, C). Patients in the active repetitive transcranial magnetic stimulation group had a greater improvement of Positive and Negative Syndrome Scale positive subscores at day 21 (difference between day 0 and day 21), but this small difference did not persist in the extension phase (B). Depressive symptoms (D, E) and global functioning (F) did not differ between groups after the intervention or during the extension phase. CDSS, Calgary Depression Scale for Schizophrenia; GAF, Global Assessment of Functioning; MADRS, Montgomery–Åsberg Depression Rating Scale; PANSS, Positive and Negative Syndrome Scale; rTMS, repetitive transcranial magnetic stimulation.

      Secondary Outcome Measures

      Prespecified secondary analyses were done. For negative symptoms at day 21, 28 patients (46%) in the active rTMS group were classified as having a clinical response (improvement of ≥20% compared with baseline PANSS negative score) compared with 27 patients (43%) in the sham rTMS group [likelihood ratio χ21 = .1, p = .73]. Additional analyses of response using the 25%/50% PANSS change thresholds (
      • Leucht S.
      Measurements of response, remission, and recovery in schizophrenia and examples for their clinical application.
      ,
      • Leucht S.
      • Davis J.M.
      • Engel R.R.
      • Kissling W.
      • Kane J.M.
      Definitions of response and remission in schizophrenia: Recommendations for their use and their presentation.
      ) showed no group differences (Supplement 1). Measures of severity of depressive symptoms showed the same pattern of change as negative symptoms, with improvement over time in CDSS [F1,119.6 = 5.0, p = .03] and MADRS scores [F1,120.1 = 13.6, p < .001] but no difference between groups in the amount of change. The CGI measure of illness severity improved over time [Z1 = −3.1, p = .002] as did the assessment of functioning with the GAF [F1,120.4 = 17.5, p < .001], but the amount of change did not differ between the two treatment groups. For the cognitive test, significant improvement over time was observed for the Trails A measure [F1,102.4 = 4.0, p = .049] but not for the Trails B measure [F1,97.7 = 2.3, p = .14]. The former result likely represents a practice effect, and there was no difference between the treatment groups in the amount of change over time.
      The PANSS total score improved over time in both groups [F1,116.3 = 32.3, p < .001]. For PANSS positive symptom severity, there was improvement over time between day 0 and day 21 in both groups [F1,118.9 = 13.2, p < .001], and there was greater improvement in the active rTMS group [F1,119.2 = 4.0, p = .047, effect size .30]. Patients in the active rTMS group had slightly higher PANSS positive subscores at day 0 [F1,145 = 3.3, p = .07] (Table 1). The mean difference between the two treatment groups in the change in PANSS positive subscores between day 0 and day 21 was 1.3 (95% confidence interval, .02−2.47) (Table 2 and Figure 2).

      Treatment Adherence, Antipsychotic Dose Equivalents, and Blinding

      Between day 0 and day 21, the mean number of completed treatment sessions (maximum 15) was comparable between active and sham stimulation (13.1 ± 3.8 vs. 13.2 ± 3.6) [F1,142 = .0, p = .88]. Antipsychotic dose equivalents were unchanged over time in both groups [F1,114.6 = .7, p = .39] (Table 2). Treatment condition was not classified correctly by either patients (correct classifications, 50%) or blinded raters (correct classifications, 52%).

      Side Effects

      Side effects reported during stimulation included headache (active/sham, n = 12/4) and facial muscle twitching (n = 3/3). Additional side effects were fatigue (n = 1/1), psychotic ideation (n = 1/1), discomfort at the stimulation site (n = 1/0), and general discomfort (n = 1/0). There was no overall difference in frequency of reported side effects between the two groups; 17 patients receiving active rTMS and 9 patients receiving sham rTMS reported 28 spontaneous side effects [likelihood ratio χ21 = 3.3, p = .07] but continued the intervention. Considering total study visits, 13 active rTMS patients and 16 sham rTMS patients reported adverse events [likelihood ratio χ21 = .4, p = .54]. Two active rTMS patients and five sham rTMS patients withdrew consent because of adverse events. The global rate of extrapyramidal motor symptoms did not differ between groups [likelihood ratio χ21 = .1, p = .82].
      The intervention was well tolerated, and no seizures or other life-threatening events occurred. Two serious adverse events were reported before the first treatment session (hospitalization). During the treatment period, there was one serious adverse event in the active group (acute deterioration in symptoms) and two in the sham group (one patient became suicidal, and one event was unspecified, but the patient was later restored to health) that led to withdrawal from the study. In each group, there was one additional serious adverse event not requiring withdrawal (active group, suicidality; sham group, event requiring hospitalization). In the extension phase, two serious adverse events in the active group (two hospitalizations owing to deterioration in symptoms) and four serious adverse events in the sham group (two requiring hospitalizations, suicidality, melperone intoxication) were reported.

      Extension Phase

      The day 105 assessments were completed by 37 patients from the active rTMS group and 31 patients from the sham rTMS group. None of the primary or secondary outcome measures showed significant group differences over the whole time period (Figure 2).

      Discussion

      Compared with sham rTMS, augmentation of antipsychotic medication with active 10-Hz rTMS applied to the left DLPFC in patients with predominant negative symptoms of schizophrenia did not offer a benefit for the target symptoms over the 3-week, rater-blind and patient-blind portion or during the extension phase of this study. The global severity of illness and the severity of negative symptoms in this patient group were high, comparable in these domains to patients with refractory forms of schizophrenia (
      • Honer W.G.
      • Thornton A.E.
      • Chen E.Y.
      • Chan R.C.
      • Wong J.O.
      • Bergmann A.
      • et al.
      Clozapine alone versus clozapine and risperidone with refractory schizophrenia.
      ). Higher negative symptom severity was correlated with higher positive symptoms, more severe depressive symptoms, and greater cognitive and functional impairment. Negative symptom severity improved over time in both active and sham treatment groups, possibly related to a rater bias or to the setting of a clinical trial providing social and emotional support for study patients by the research team. The unexpected small improvement in positive symptoms in the active treatment group compared with the sham treatment group supports the idea that this group of patients was not totally treatment refractory.
      Three meta-analyses of single-center rTMS studies with limited sample size comparing sham treatment for negative symptoms in schizophrenia reported effect sizes of .27, .43, and .53 (
      • Freitas C.
      • Fregni F.
      • Pascual-Leone A.
      Meta-analysis of the effects of repetitive transcranial magnetic stimulation (rTMS) on negative and positive symptoms in schizophrenia.
      ,
      • Dlabac-de Lange J.J.
      • Knegtering R.
      • Aleman A.
      Repetitive transcranial magnetic stimulation for negative symptoms of schizophrenia: Review and meta-analysis.
      ,
      • Shi C.
      • Yu X.
      • Cheung E.F.
      • Shum D.H.
      • Chan R.C.
      Revisiting the therapeutic effect of rTMS on negative symptoms in schizophrenia: A meta-analysis.
      ), with the latter two being statistically significant. However, direct comparison of the present findings with the two available smaller studies of patients with similar profiles of total and negative symptoms as well as similar treatment protocols reveals a similar lack of response (
      • Cordes J.
      • Thunker J.
      • Agelink M.W.
      • Arends M.
      • Mobascher A.
      • Wobrock T.
      • et al.
      Effects of 10 Hz repetitive transcranial magnetic stimulation (rTMS) on clinical global impression in chronic schizophrenia.
      ,
      • Mogg A.
      • Purvis R.
      • Eranti S.
      • Contell F.
      • Taylor J.P.
      • Nicholson T.
      • et al.
      Repetitive transcranial magnetic stimulation for negative symptoms of schizophrenia: A randomized controlled pilot study.
      ). The sample size of our study exceeds the total sample size of all nine foregoing 10-Hz rTMS studies combined and will significantly change effect sizes in future meta-analyses. A recent meta-analysis of this previous group of only 10-Hz rTMS studies calculated a mean effect size of .79 for rTMS treatment of negative symptoms (
      • Shi C.
      • Yu X.
      • Cheung E.F.
      • Shum D.H.
      • Chan R.C.
      Revisiting the therapeutic effect of rTMS on negative symptoms in schizophrenia: A meta-analysis.
      ). On the basis of this remarkable effect size, the authors proposed several features of study design could contribute to detect improvement, including a pretreatment PANSS negative score of ≥20, treatment for ≥3 weeks, targeting the left DLPFC, using a stimulus calibrated to 110% resting motor threshold, and a 10-Hz frequency (
      • Shi C.
      • Yu X.
      • Cheung E.F.
      • Shum D.H.
      • Chan R.C.
      Revisiting the therapeutic effect of rTMS on negative symptoms in schizophrenia: A meta-analysis.
      ). The present study fulfilled these criteria but still failed to show a benefit of the intervention. Apart from the possibility of different treatment-moderating factors such as baseline characteristics and concomitant medication, the major contributing factor to the discrepancy between the present finding of no benefit of rTMS and the positive meta-analyses may be the larger sample size in the present study (
      • LeLorier J.
      • Gregoire G.
      • Benhaddad A.
      • Lapierre J.
      • Derderian F.
      Discrepancies between meta-analyses and subsequent large randomized, controlled trials.
      ).
      The present study has some possible limitations. A focus on patients in earlier phase of illness and perhaps more comprehensive assessment of negative symptoms using alternative rating scales might have detected a small beneficial effect of rTMS with greater sensitivity. The relatively small total number of stimuli (15,000) used in the present study warrants discussion in the context of our negative result. Although proof-of-concept trials using the same stimulation patterns and the same or even smaller numbers of stimuli have been positive (
      • Freitas C.
      • Fregni F.
      • Pascual-Leone A.
      Meta-analysis of the effects of repetitive transcranial magnetic stimulation (rTMS) on negative and positive symptoms in schizophrenia.
      ,
      • Dlabac-de Lange J.J.
      • Knegtering R.
      • Aleman A.
      Repetitive transcranial magnetic stimulation for negative symptoms of schizophrenia: Review and meta-analysis.
      ,
      • Shi C.
      • Yu X.
      • Cheung E.F.
      • Shum D.H.
      • Chan R.C.
      Revisiting the therapeutic effect of rTMS on negative symptoms in schizophrenia: A meta-analysis.
      ), whether or not a higher number of applied stimuli or repetitive sessions on the same day might increase the efficacy of rTMS for negative symptoms in schizophrenia remains actively debated (
      • Prikryl R.
      • Kucerova H.P.
      Can repetitive transcranial magnetic stimulation be considered effective treatment option for negative symptoms of schizophrenia?.
      ,
      • Stanford A.D.
      • Corcoran C.
      • Bulow P.
      • Bellovin-Weiss S.
      • Malaspina D.
      • Lisanby S.H.
      High-frequency prefrontal repetitive transcranial magnetic stimulation for the negative symptoms of schizophrenia: A case series.
      ). One study using the same stimulation frequency (10 Hz) and intensity (120% resting motor threshold) but with 20,000 stimuli showed a superiority of the active condition in reducing negative symptoms (
      • Prikryl R.
      • Ustohal L.
      • Prikrylova Kucerova H.
      • Kasparek T.
      • Venclikova S.
      • Vrzalova M.
      • et al.
      A detailed analysis of the effect of repetitive transcranial magnetic stimulation on negative symptoms of schizophrenia: A double-blind trial.
      ). However, other studies investigating effects of 20,000 stimuli at higher frequencies (20 Hz) and lower or the same stimulation intensities (90%−110%) as our study yielded inconsistent results (
      • Mogg A.
      • Purvis R.
      • Eranti S.
      • Contell F.
      • Taylor J.P.
      • Nicholson T.
      • et al.
      Repetitive transcranial magnetic stimulation for negative symptoms of schizophrenia: A randomized controlled pilot study.
      ,
      • Novak T.
      • Horacek J.
      • Mohr P.
      • Kopecek M.
      • Skrdlantova L.
      • Klirova M.
      • et al.
      The double-blind sham-controlled study of high-frequency rTMS (20 Hz) for negative symptoms in schizophrenia: Negative results.
      ,
      • Barr M.S.
      • Farzan F.
      • Rajji T.K.
      • Voineskos A.N.
      • Blumberger D.M.
      • Arenovich T.
      • et al.
      Can repetitive magnetic stimulation improve cognition in schizophrenia? Pilot data from a randomized controlled trial.
      ,
      • Fitzgerald P.B.
      • Herring S.
      • Hoy K.
      • McQueen S.
      • Segrave R.
      • Kulkarni J.
      • et al.
      A study of the effectiveness of bilateral transcranial magnetic stimulation in the treatment of the negative symptoms of schizophrenia.
      ). The possibility remains that the stimulation protocol used here may not have been optimal. The decision for this stimulation protocol was made at a time when only four rTMS studies for the treatment of negative symptoms of schizophrenia were available, but as outlined earlier, our protocol was consistent with the recommendations derived from the latest meta-analysis in the field (
      • Shi C.
      • Yu X.
      • Cheung E.F.
      • Shum D.H.
      • Chan R.C.
      Revisiting the therapeutic effect of rTMS on negative symptoms in schizophrenia: A meta-analysis.
      ).
      Another limitation could be the relatively high rate of withdrawal from the study (27.4% from randomization); this was related to the schizophrenia population because other available multicenter rTMS studies with patients with depression reported lower dropout rates (
      • George M.S.
      • Lisanby S.H.
      • Avery D.
      • McDonald W.M.
      • Durkalski V.
      • Pavlicova M.
      • et al.
      Daily left prefrontal transcranial magnetic stimulation therapy for major depressive disorder: A sham-controlled randomized trial.
      ,
      • Herwig U.
      • Fallgatter A.J.
      • Hoppner J.
      • Eschweiler G.W.
      • Kron M.
      • Hajak G.
      • et al.
      Antidepressant effects of augmentative transcranial magnetic stimulation: Randomised multicentre trial.
      ). Patients with schizophrenia experiencing negative symptoms with reduced capacity for social interaction have understandable challenges in completing intensive trials. An additional limitation relates to our sham condition. For sham rTMS, we used angulation of the active magnetic coil 45 degrees away from the skull, which induces a reduced magnetic field and might have had at least a minimal biological effect (
      • Lisanby S.H.
      • Gutman D.
      • Luber B.
      • Schroeder C.
      • Sackeim H.A.
      Sham TMS: Intracerebral measurement of the induced electrical field and the induction of motor-evoked potentials.
      ). At the time of the study planning in 2007, we decided to use this control condition because it generates some skull sensations and makes it more difficult for patients to guess whether they have received active or sham rTMS. Today, manufactured sham coils provide certain methodologic advantages in terms of blinding and biological activity. However, a more recent meta-analysis did not find differences between active and sham rTMS in terms of the number of participants correctly guessing their treatment allocation and did not find differences in terms of blinding integrity between the use of an angulated coil or a sham coil (
      • Berlim M.T.
      • Broadbent H.J.
      • Van den Eynde F.
      Blinding integrity in randomized sham-controlled trials of repetitive transcranial magnetic stimulation for major depression: A systematic review and meta-analysis.
      ). Because our blinding was appropriate and because the sham treatment group also showed an improvement in the symptoms, this limitation does not affect our overall conclusions. Finally, the use of the EEG International 10-20 system for the localization of the DLFPC may not be ideal. More accurate localization of the DLPFC with magnetic resonance imaging may have improved the delivery of stimuli; however, research comparing different localization methods showed a sufficient accuracy of the EEG International 10-20 system (
      • Rusjan P.M.
      • Barr M.S.
      • Farzan F.
      • Arenovich T.
      • Maller J.J.
      • Fitzgerald P.B.
      • et al.
      Optimal transcranial magnetic stimulation coil placement for targeting the dorsolateral prefrontal cortex using novel magnetic resonance image-guided neuronavigation.
      ,
      • Fitzgerald P.B.
      • Maller J.J.
      • Hoy K.E.
      • Thomson R.
      • Daskalakis Z.J.
      Exploring the optimal site for the localization of dorsolateral prefrontal cortex in brain stimulation experiments.
      ).
      The application of a neuronavigation system using individual anatomic or functional magnetic resonance imaging could be speculated to reduce the variability in locating the coil within a given or between different patients. However, one study used functional magnetic resonance imaging to locate the stimulation coil to the area of maximal hallucinatory activation in the left temporoparietal area to treat auditory verbal hallucinations and similarly could not show a beneficial effect of active 1-Hz rTMS compared with sham rTMS (
      • Slotema C.W.
      • Blom J.D.
      • de Weijer A.D.
      • Diederen K.M.
      • Goekoop R.
      • Looijestijn J.
      • et al.
      Can low-frequency repetitive transcranial magnetic stimulation really relieve medication-resistant auditory verbal hallucinations? Negative results from a large randomized controlled trial.
      ). The question whether neuronavigation provides an advantage in clinical trials with repetitive stimulation sessions remains elusive. Specific advantages of our study are the well-characterized population of patients with schizophrenia with predominant negative symptoms, the large sample size allowing the presentation of a negative result, the multicentric design, and the study protocol hitting the highest criteria for subject allocation and blinding in rTMS trials.
      Secondary outcome measures showed no advantage for active rTMS in reducing severity of symptoms of depression. These symptoms were globally less severe than the symptoms observed in patients with a primary diagnosis of major depression and may overlap with negative symptoms in our patients. The greater improvement in positive symptom severity in the active rTMS group was very modest in size, and the slightly higher scores at baseline in this group may have increased the likelihood of change. However, the rTMS effect on positive symptoms in patients treated with antipsychotic medications may be analogous to the modest improvements reported from pharmacologic interventions such as cycloserine directed at the glutamatergic system (
      • Gottlieb J.D.
      • Cather C.
      • Shanahan M.
      • Creedon T.
      • Macklin E.A.
      • Goff D.C.
      D-cycloserine facilitation of cognitive behavioral therapy for delusions in schizophrenia.
      ) or from electroconvulsive treatment (
      • Pompili M.
      • Lester D.
      • Dominici G.
      • Longo L.
      • Marconi G.
      • Forte A.
      • et al.
      Indications for electroconvulsive treatment in schizophrenia: A systematic review.
      ). Most rTMS research on treatment of hallucinations in schizophrenia focuses on low-frequency stimulation of the temporal lobe (
      • Freitas C.
      • Fregni F.
      • Pascual-Leone A.
      Meta-analysis of the effects of repetitive transcranial magnetic stimulation (rTMS) on negative and positive symptoms in schizophrenia.
      ), and the Patient Outcomes Research Team guidelines (
      • Buchanan R.W.
      • Kreyenbuhl J.
      • Kelly D.L.
      • Noel J.M.
      • Boggs D.L.
      • Fischer B.A.
      • et al.
      The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements.
      ) recommended on the basis of two positive meta-analyses the application of 1-Hz rTMS for this indication. Our present findings suggest on the one hand complementary research strategies for positive symptoms but on the other hand strike a note of caution regarding the generalizability of single-center study–based meta-analytic findings for an intervention with high interindividual response variability, such as rTMS. Recommendations concerning the application of 10-Hz rTMS for the treatment of negative symptoms may need revision in the context of the present findings. Future multicenter studies are needed to investigate whether longer stimulation periods, specific pharmacologic treatment during rTMS, other stimulation targets, or different stimulation protocols are more effective in the improvement of negative symptoms in patients with schizophrenia.
      The clinical efficacy of patterned rTMS (e.g., theta burst stimulation), other noninvasive brain stimulation techniques, and combined stimulation and psychotherapy approaches will need to be in the focus of future research. Also, biological investigations should devote special attention to individual factors that may influence the response to rTMS, such as genetics, attention, age, and concomitant treatment (
      • Ridding M.C.
      • Ziemann U.
      Determinants of the induction of cortical plasticity by non-invasive brain stimulation in healthy subjects.
      ). Recent evidence suggests that the response to rTMS can be predicted using anatomic biomarkers and the concept of bimodal response heterogeneity (
      • Downar J.
      • Geraci J.
      • Salomons T.V.
      • Dunlop K.
      • Wheeler S.
      • McAndrews M.P.
      • et al.
      Anhedonia and reward-circuit connectivity distinguish nonresponders from responders to dorsomedial prefrontal repetitive transcranial magnetic stimulation in major depression.
      ). Future studies will need to identify predictive markers to target specifically patient subgroups with a high likelihood to respond to rTMS. Finally, the individual interneuron architecture has been shown more recently to be one critical factor to determine the plasticity responses to cortical transcranial magnetic stimulation pulses (
      • Hamada M.
      • Murase N.
      • Hasan A.
      • Balaratnam M.
      • Rothwell J.C.
      The role of interneuron networks in driving human motor cortical plasticity.
      ) and could possibly be a further explanation for the lack of response in a portion of schizophrenia patients. In terms of side effects, the active rTMS intervention was well tolerated, and the main challenge for patient acceptance appears to be the need for treatment 5 days per week.
      In conclusion, our results do not support the application of 10-Hz rTMS over 3 weeks with 1000 stimuli per day to the left DLPFC as an efficacious add-on treatment for predominant negative symptoms in patients with schizophrenia.

      Acknowledgments And Disclosures

      This work was supported by the Deutsche Forschungsgemeinschaft Grant No. FA–210/1. The trial protocol has been published (
      • Cordes J.
      • Falkai P.
      • Guse B.
      • Hasan A.
      • Schneider-Axmann T.
      • Arends M.
      • et al.
      Repetitive transcranial magnetic stimulation for the treatment of negative symptoms in residual schizophrenia: Rationale and design of a sham-controlled, randomized multicenter study.
      ) and is available at [email protected].
      TW has received paid speakerships from Alpine Biomed, AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Company, I3G, Janssen-Cilag, Novartis, Lundbeck, Roche, Sanofi-Aventis, Otsuka, and Pfizer; has accepted travel or hospitality not related to a speaking engagement from AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Company, Janssen-Cilag, and Sanofi-Synthelabo; and has received restricted research grants from AstraZeneca, Cerbomed, I3G, and AOK (health insurance company). JC was a member of an advisory board of Roche; accepted travel or hospitality not related to a speaking engagement from Servier; and received support for symposia from inomed, Localite, MagVenture, Roche, MAG & More, neuroConn, Syneika, FBI-Medizintechnik, Spitzer Arzneimittel, and DiaMedic. WW has received paid speakerships from Bristol-Myers Squibb, Essex Pharma, Janssen-Cilag, Lilly Deutschland, and Pfizer Neuroscience and is a member of the Neuroscience Academy of Roche Pharma. WG has received symposia support from Janssen-Cilag GmbH, Neuss, Lilly Deutschland GmbH, Bad Homburg, and Servier, Munich and is a member of the Faculty of the Lundbeck International Neuroscience Foundation, Denmark. BL received honoraria and speakers’ fees from ANM, AstraZeneca, Autifony Therapeutics, Lundbeck, Merz, MagVenture, Novartis, Pfizer, and Servier; research funding from the Tinnitus Research Initiative, the German Research Foundation, the German Bundesministerium für Bildung und Forschung, the American Tinnitus Association, AstraZeneca, and cerbomed; funding for equipment from MagVenture and Deymed Diagnostic; and travel and accommodation payments from Eli Lilly and Company, Lundbeck, Servier, and Pfizer. GH has received payments as speaker, consultant, or author or for research funding during the last 5 years from Actelion Pharmaceuticals, Affectis Pharmaceuticals, AstraZeneca, Bayerische Motorenwerke, Bundesministerium für Bildung und Forschung, Bundesministerium für Strahlenschutz, Bristol-Meyers Squibb, Cephalon, Daimler Benz, Deutsche Forschungsgesellschaft, Elsevier, EuMeCom, Essex, Georg Thieme, Gerson Lerman Group Council of Healthcare Advisors, GlaxoSmithKline, Janssen-Cilag, Eli Lilly and Company, Lundbeck, Meda, Merck, Merz, Novartis, Pfizer, Proctor & Gamble, Sanofi-Aventis, Schering-Plough, Sepracor, Servier, Springer, Urban & Fischer, and Volkswagen. WGH is an unpaid member of the Advisory Board of In Silico Biosciences and a paid consultant to Otsuka/Lundbeck, Roche, Novartis, Eli Lilly and Company, MDH Consulting, and the Canadian Agency on Drugs and Technology in Health. PF was honorary speaker for Janssen-Cilag, AstraZeneca, Eli Lilly and Company, Bristol-Myers Squibb, Lundbeck, Pfizer, Bayer Vital, SmithKline Beecham, Wyeth, and Essex. During the last 5 years, but not presently, PF was a member of the advisory boards of Janssen-Cilag, AstraZeneca, Eli Lilly and Company, and Lundbeck. AH has been invited to scientific meetings by Lundbeck, Janssen-Cilag, and Pfizer; received a paid speakership from Desitin; and is a member of the advisory board of Roche. All other authors report no biomedical financial interests or potential conflicts of interest.
      ClinicalTrials.gov: Repetitive Transcranial Magnetic Stimulation (rTMS) for the Treatment of Negative Symptoms in Schizophrenia (RESIS); http://www.clinicaltrials.gov/ct2/show/NCT00783120; NCT00783120.

      Appendix A. Supplementary materials

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