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

Archival Report

Biological Psychiatry

Left Prefrontal High-Frequency Repetitive Transcranial Magnetic Stimulation for the Treatment of Schizophrenia with Predominant Negative Symptoms: A Sham-Controlled, Randomized Multicenter Trial Thomas Wobrock, Birgit Guse, Joachim Cordes, Wolfgang Wölwer, Georg Winterer, Wolfgang Gaebel, Berthold Langguth, Michael Landgrebe, Peter Eichhammer, Elmar Frank, Göran Hajak, Christian Ohmann, Pablo E. Verde, Marcella Rietschel, Raees Ahmed, William G. Honer, Berend Malchow, Thomas Schneider-Axmann, Peter Falkai, and Alkomiet Hasan

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 5 .53, effect size 5 .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 5 .047, effect size 5 .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: Brain stimulation, Evidence-based psychiatry, Negative symptoms, Randomized controlled trial, Repetitive transcranial magnetic stimulation, Schizophrenia http://dx.doi.org/10.1016/j.biopsych.2014.10.009

Schizophrenia is the most debilitating psychiatric disorder and is associated with a significant disease-related burden leading to tremendous direct and indirect treatment costs (1,2). 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 (3–5). These symptoms are highly prevalent, are very stable over time, are associated with cognitive impairment, and predict poor functional outcome and quality of life (3–5). 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 (6). 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 (7). 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 (7). Certain rTMS devices with specific protocols have been approved by the U.S. Food and Drug

SEE COMMENTARY ON PAGE

ISSN: 0006-3223

& 2014 Society of Biological Psychiatry 1 Biological Psychiatry ]]], 2014; ]:]]]–]]] www.sobp.org/journal

Biological Psychiatry

rTMS for Schizophrenia Negative Symptoms

Administration for patients with depression with poor or incomplete response to pharmacotherapy (8). 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 (9–12). High-frequency rTMS applied to the dorsolateral prefrontal cortex (DLPFC) can modulate extrastriatal and mesostriatal dopaminergic pathways that may contribute to negative symptoms (13,14), suggesting rTMS may be a promising therapeutic option for negative symptoms of schizophrenia. This possibility is particularly important because reduced left DLPFC activation (15) and reduced prefrontal white matter volumes (16) have been linked to negative symptoms of schizophrenia and facilitatory and inhibitory DLPFC projections are critically involved in the modulation of dopaminergic networks (17,18). However, physiologic studies indicate disrupted plasticity in schizophrenia, which may reduce the efficacy of noninvasive brain stimulation (19–21). 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 (18,22–24). 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, raterblinded and patient-blinded clinical trial. The inclusion criteria were International Classification of Diseases, Tenth Revision, diagnosis of schizophrenia (25) (F20.xx, confirmed by the MiniInternational Neuropsychiatric Interview Plus interview (26)), 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) (27) 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 (28).

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 (29) and 1000 stimuli (20 trains with 50 stimuli per train, 30-sec intertrain interval) per session (30). 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 (31) (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 (32–34). 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). 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 (30). The randomization procedure is described in Supplement 1.

Figure 1. Trial 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 (extensionphase visits at days 28, 45, and 105; no treatment in either group). rTMS, repetitive transcranial magnetic stimulation.

2

Biological Psychiatry ]]], 2014; ]:]]]–]]] www.sobp.org/journal

Biological Psychiatry

rTMS for Schizophrenia Negative Symptoms

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) (35) and the Montgomery–Åsberg Depression Rating Scale (MADRS) (36), overall illness severity measured by Clinical Global Impressions (CGI) score (37), and general functioning measured by the Global Assessment of Functioning (GAF) scale (38). A response in negative symptoms was defined as improvement of $20% (39) 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 (40).

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 (43). 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.

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 (41). 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 5 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 5 2σ2/θ2(z.8 2 z.025)2 E 63, with SD σ 5 6, assumed difference θ 5 3, 80% and 2.5% quantiles of the standard normal distribution z.8 5 .84, z.025 5 21.96 and effect size θ/σ 5 .5. For these calculations, a two-group normal test with twosided type I significance level of α 5 .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 5 62 per group. Additionally, post hoc power analyses using actual sample sizes and observed variances σ2 were calculated. A sufficient power of 1 2 β . .8 was achieved simulating the following assumed differences: PANSSnegative, θ 5 3; PANSSpositive, θ 5 2; PANSStotal, θ 5 7; CDSS, θ 5 2; MADRS, θ 5 3.5; CGI, θ 5 .4; GAF, θ 5 6 (42). 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-totreat population, defined as all patients randomly assigned into a treatment group who started at least one treatment session (8). 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

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 5 76) or sham (n 5 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.

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 5 51.2, p , .001]. There was no significant difference in the amount of improvement between active and sham rTMS groups [F1,122.7 5 .4, p 5 .53,

Biological Psychiatry ]]], 2014; ]:]]]–]]] www.sobp.org/journal

3

Biological Psychiatry

rTMS for Schizophrenia Negative Symptoms

Table 1. Baseline Characteristics and Association of Clinical Features with Negative Symptoms Active rTMS (n 5 76)

Sham rTMS (n 5 81)

df

p

Gender (Male:Female)

62:14

56:25

3.3

1

.07a

Employment (Employed:Not Employed)

14:62

10:71

1.1

1

.29a

LR χ²

Variable

Association with Negative Symptoms in Total Sample

Active vs. Sham

20:28:28

21:29:31

.0

2

.98a

Hand Preference (Right:Not Right)

62:11

66:10

.1

1

.74a

Antidepressant Use (Yes:No)

28:47

30:50

.0

1

.98a

Center (Duesseldorf:Goettingen:Regensburg)

Mean

SD

Mean

SD

F

p

.02b Spearman correlation

c

df

p

Age (Years)

36.2

10.5

34.9

9.1

.7

1,155

.41d

p

Education (Years)e

11.5

1.9

11.3

2.0

.6

1,148

.43d

Left Resting Motor Thresholdf

47.0

8.8

46.4

11.6

.1

1,139

.74d

PANSS negative symptomsg

25.6h

4.6

25.1i

3.7

.5

1,153

.48d

PANSS positive symptoms

14.3

4.6

13.0

3.6

3.3

1,145

.07d

.27

.001

PANSS total

79.7

15.8

76.0

13.5

2.3

1,144

.13d

.64

,.001

Clinical Global Impressions score for severityj

4.6

.9

4.7

.9

Z 5 2.6

1

.54k

.51

,.001

Global Assessment of Functioningl

52.1

11.6

53.5

12.1

.5

1,140

.49d

2.49

,.001

572

435

597

486

.0

1,142

.95m

.03

.69

5.2

3.5

5.1

3.8

.1

1,146

.81d

.26

.001

14.8

6.0

13.6

6.1

1.6

1,152

.21d

.44

,.001

Trail Making Test A time (sec)

36.6

19.8

38.5

16.1

.7

1,137

.41m

.28

.001

Trail Making Test B time (sec)

90.8

55.3

87.9

40.1

.0

1,133

.97m

.24

.006

Severity of Illness and Treatment

Antipsychotic Dose (Chlorpromazine Equivalents) (mg/day) Depression Related Calgary Depression Scale for Schizophrenian Montgomery–Åsberg Depression Rating Scale

o

Cognitive

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.

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, 21.2 to 2.3).

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

4

Biological Psychiatry ]]], 2014; ]:]]]–]]] www.sobp.org/journal

(improvement of $20% compared with baseline PANSS negative score) compared with 27 patients (43%) in the sham rTMS group [likelihood ratio χ2 1 5 .1, p 5 .73]. Additional analyses of response using the 25%/50% PANSS change thresholds (44,45) 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 5.0, p 5 .03] and MADRS scores [F1,120.1 5 13.6, p , .001] but no difference between groups in the amount of change. The CGI measure of illness severity improved over

Biological Psychiatry

rTMS for Schizophrenia Negative Symptoms

Table 2. Primary and Secondary Outcome Measures at the Beginning and the End of 21 Days of rTMS Treatment Active rTMS

Outcome Measure

Sham rTMS

Day 0

Day 21

Day 0

Day 21

(n 5 76)a

(n 5 62)b

(n 5 81)c

(n 5 64)d

Mean

SD

Mean

SD

Mean

SD

Mean

SD

Interaction Between Group and Time of Measurement F

df

pe

Effect Sizef

PANSS Score Negative

25.6

4.6

22.7

6.1

25.1

3.7

22.7

5.8

.4

1,122.7

.53

.09

Positive

14.3

4.6

12.4

4.1

13.0

3.6

12.4

4.6

4.0

1,119.2

.047

.30

Total

79.7

15.8

73.2

18.0

76.0

13.5

71.6

17.8

2.4

1,116.7

.12

.13

5.2

3.5

4.4

3.5

5.1

3.8

4.6

4.4

.1

1,118.5

.72

.10

Montgomery–Åsberg Depression Rating Scale

14.8

6.0

12.0

7.3

13.6

6.1

12.6

8.5

1.6

1,120.5

.21

.27

Clinical Global Impressions score for severity

4.6

.9

4.4

.9

4.7

.9

4.5

1.0

χ² 5 2.7

5

.74g

.11

52.1

11.6

56.0

12.2

53.5

12.1

55.5

11.5

.4

1,120.7

.52

.16

2.1

1,114.4

.15h

.07

Calgary Depression Scale for Schizophrenia

Global Assessment of Functioning Antipsychotic Dose (Chlorpromazine Equivalents) (mg/day)

572

435

569

383

597

486

564

438

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.

time [Z1 5 23.1, p 5 .002] as did the assessment of functioning with the GAF [F1,120.4 5 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 5 4.0, p 5 .049] but not for the Trails B measure [F1,97.7 5 2.3, p 5 .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 5 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 5 13.2, p , .001], and there was greater improvement in the active rTMS group [F1,119.2 5 4.0, p 5 .047, effect size .30]. Patients in the active rTMS group had slightly higher PANSS positive subscores at day 0 [F1,145 5 3.3, p 5 .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, .0222.47) (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 6 3.8 vs. 13.2 6 3.6)

[F1,142 5 .0, p 5 .88]. Antipsychotic dose equivalents were unchanged over time in both groups [F1,114.6 5 .7, p 5 .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 5 12/4) and facial muscle twitching (n 5 3/3). Additional side effects were fatigue (n 5 1/1), psychotic ideation (n 5 1/1), discomfort at the stimulation site (n 5 1/0), and general discomfort (n 5 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 χ2 1 5 3.3, p 5 .07] but continued the intervention. Considering total study visits, 13 active rTMS patients and 16 sham rTMS patients reported adverse events [likelihood ratio χ2 1 5 .4, p 5 .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 χ2 1 5 .1, p 5 .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

Biological Psychiatry ]]], 2014; ]:]]]–]]] www.sobp.org/journal

5

Biological Psychiatry

rTMS for Schizophrenia Negative Symptoms

Figure 2. Scores for severity of symptoms during the trial. Data appear as mean 6 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.

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

6

Biological Psychiatry ]]], 2014; ]:]]]–]]] www.sobp.org/journal

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 (46). 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 (22–24), 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 (28,47). 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

Biological Psychiatry

rTMS for Schizophrenia Negative Symptoms

rTMS studies calculated a mean effect size of .79 for rTMS treatment of negative symptoms (24). 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 (24). 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 (48). 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 (22–24), 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 (18,49). 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 (50). However, other studies investigating effects of 20,000 stimuli at higher frequencies (20 Hz) and lower or the same stimulation intensities (90%2110%) as our study yielded inconsistent results (47,51–53). 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 (24). 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 (8,54). 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 (31). 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 (55). 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 (56,57). 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 (58). The question whether neuronavigation provides an advantage in clinical trials with repetitive stimulation sessions remains elusive. Specific advantages of our study are the wellcharacterized 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 (59) or from electroconvulsive treatment (60). Most rTMS research on treatment of hallucinations in schizophrenia focuses on low-frequency stimulation of the temporal lobe (22), and the Patient Outcomes Research Team guidelines (61) recommended on the basis of two positive meta-analyses the application of 1Hz 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,

Biological Psychiatry ]]], 2014; ]:]]]–]]] www.sobp.org/journal

7

Biological Psychiatry

rTMS for Schizophrenia Negative Symptoms

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 (62). Recent evidence suggests that the response to rTMS can be predicted using anatomic biomarkers and the concept of bimodal response heterogeneity (63). 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 (64) 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 (30) 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, BristolMyers 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

8

Biological Psychiatry ]]], 2014; ]:]]]–]]] www.sobp.org/journal

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, JanssenCilag, Eli Lilly and Company, Lundbeck, Meda, Merck, Merz, Novartis, Pfizer, Proctor & Gamble, Sanofi-Aventis, ScheringPlough, 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.

ARTICLE INFORMATION From the Department of Psychiatry and Psychotherapy (TW, BG), Georg-August-University Goettingen, Goettingen; Centre of Mental Health (TW), County Hospitals Darmstadt-Dieburg, Groß-Umstadt; Department of Psychiatry and Psychotherapy (JC, WW, GW, WG), Heinrich-Heine University, Düsseldorf; Charité–Universitätsmedizin Berlin (GW), Berlin; Department of Psychiatry and Psychotherapy (JC, WW, WG), Medical Faculty, Heinrich, Heine University, Düsseldorf; Department of Psychiatry and Psychotherapy (BL, ML, PE, EF), University of Regensburg, Regensburg; Department of Psychiatry, Psychosomatics and Psychotherapy (ML), kbo-Lech-Mangfall-Clinics, Agatharied; Department of Psychiatry, Psychosomatics and Psychotherapy (GH), Sozialstiftung Bamberg, Bamberg; Coordination Centre for Clinical Trials (CO, PEV), Heinrich-Heine University, Düsseldorf; Department of Genetic Epidemiology in Psychiatry (MR), Institute of Central Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim; Institut für anwendungsorientierte Forschung und klinische Studien GmbH (RA), Goettingen, Germany; Department of Psychiatry and Institute of Mental Health (WGH), University of British Columbia, Vancouver, British Columbia, Canada; and Department of Psychiatry and Psychotherapy (BM, TS-A, PF, AH), Ludwig-Maximilians-University, Munich, Germany. Address correspondence to Thomas Wobrock, M.D., Centre of Mental Health, County Hospitals DarmstadtDieburg, Krankenhausstr 7, 64823 Groß-Umstadt, Germany; E-mail: [email protected].

Biological Psychiatry

rTMS for Schizophrenia Negative Symptoms

Received Jul 2, 2014; revised Sep 16, 2014; accepted Oct 4, 2014. Supplementary material cited in this article is available online at http://dx.doi.org/10.1016/j.biopsych.2014.10.009.

20.

21.

REFERENCES 1.

2.

3. 4.

5. 6.

7.

8.

9.

10.

11. 12.

13.

14.

15.

16.

17.

18.

19.

Sun SX, Liu GG, Christensen DB, Fu AZ (2007): Review and analysis of hospitalization costs associated with antipsychotic nonadherence in the treatment of schizophrenia in the United States. Curr Med Res Opin 23:2305–2312. Gustavsson A, Svensson M, Jacobi F, Allgulander C, Alonso J, Beghi E, et al. (2011): Cost of disorders of the brain in Europe 2010. Eur Neuropsychopharmacol 21:718–779. An der Heiden W, Hafner H (2010): Course and Outcome. Chichester: Wiley-Blackwell. Kirkpatrick B, Fenton WS, Carpenter WT Jr, Marder SR (2006): The NIMH-MATRICS consensus statement on negative symptoms. Schizophr Bull 32:214–219. Buchanan RW (2007): Persistent negative symptoms in schizophrenia: an overview. Schizophr Bull 33:1013–1022. Hasan A, Falkai P, Wobrock T, Lieberman J, Glenthoj B, Gattaz WF, et al. (2012): 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. World J Biol Psychiatry 13:318–378. Ziemann U, Paulus W, Nitsche MA, Pascual-Leone A, Byblow WD, Berardelli A, et al. (2008): Consensus: Motor cortex plasticity protocols. Brain Stimul 1:164–182. George MS, Lisanby SH, Avery D, McDonald WM, Durkalski V, Pavlicova M, et al. (2010): Daily left prefrontal transcranial magnetic stimulation therapy for major depressive disorder: A sham-controlled randomized trial. Arch Gen Psychiatry 67:507–516. Paus T, Jech R, Thompson CJ, Comeau R, Peters T, Evans AC (1997): Transcranial magnetic stimulation during positron emission tomography: A new method for studying connectivity of the human cerebral cortex. J Neurosci 17:3178–3184. Rounis E, Lee L, Siebner HR, Rowe JB, Friston KJ, Rothwell JC, et al. (2005): Frequency specific changes in regional cerebral blood flow and motor system connectivity following rTMS to the primary motor cortex. Neuroimage 26:164–176. Eisenegger C, Treyer V, Fehr E, Knoch D (2008): Time-course of “offline” prefrontal rTMS effects—a PET study. Neuroimage 42:379–384. Lee L, Siebner HR, Rowe JB, Rizzo V, Rothwell JC, Frackowiak RS, et al. (2003): Acute remapping within the motor system induced by low-frequency repetitive transcranial magnetic stimulation. J Neurosci 23:5308–5318. Cho SS, Strafella AP (2009): rTMS of the left dorsolateral prefrontal cortex modulates dopamine release in the ipsilateral anterior cingulate cortex and orbitofrontal cortex. PLoS One 4:e6725. 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. J Neurosci 21:RC157. Hill K, Mann L, Laws KR, Stephenson CM, Nimmo-Smith I, McKenna PJ (2004): Hypofrontality in schizophrenia: A meta-analysis of functional imaging studies. Acta Psychiatr Scand 110:243–256. Sanfilipo M, Lafargue T, Rusinek H, Arena L, Loneragan C, Lautin A, et al. (2000): Volumetric measure of the frontal and temporal lobe regions in schizophrenia: Relationship to negative symptoms. Arch Gen Psychiatry 57:471–480. Laruelle M, Kegeles LS, Abi-Dargham A (2003): Glutamate, dopamine, and schizophrenia: From pathophysiology to treatment. Ann N Y Acad Sci 1003:138–158. Prikryl R, Kucerova HP (2013): Can repetitive transcranial magnetic stimulation be considered effective treatment option for negative symptoms of schizophrenia? J ECT 29:67–74. Daskalakis ZJ, Christensen BK, Fitzgerald PB, Chen R (2008): Dysfunctional neural plasticity in patients with schizophrenia. Arch Gen Psychiatry 65:378–385.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36. 37.

38.

39.

Frantseva MV, Fitzgerald PB, Chen R, Moller B, Daigle M, Daskalakis ZJ (2008): Evidence for impaired long-term potentiation in schizophrenia and its relationship to motor skill learning. Cereb Cortex 18: 990–996. Hasan A, Wobrock T, Rajji T, Malchow B, Daskalakis ZJ (2013): Modulating neural plasticity with non-invasive brain stimulation in schizophrenia. Eur Arch Psychiatry Clin Neurosci 263:621–631. Freitas C, Fregni F, Pascual-Leone A (2009): Meta-analysis of the effects of repetitive transcranial magnetic stimulation (rTMS) on negative and positive symptoms in schizophrenia. Schizophr Res 108: 11–24. Dlabac-de Lange JJ, Knegtering R, Aleman A (2010): Repetitive transcranial magnetic stimulation for negative symptoms of schizophrenia: Review and meta-analysis. J Clin Psychiatry 71: 411–418. 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 Res 215:505–513. World Health Organization (2010) International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10). Geneva: WHO. Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, et al. (1998): The Mini-International Neuropsychiatric Interview (M.I.N.I.): The development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 59(Suppl 20):22–33; quiz 34–57. Kay SR, Fiszbein A, Opler LA (1987): The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 13: 261–276. Cordes J, Thunker J, Agelink MW, Arends M, Mobascher A, Wobrock T, et al. (2010): Effects of 10 Hz repetitive transcranial magnetic stimulation (rTMS) on clinical global impression in chronic schizophrenia. Psychiatry Res 177:32–36. Rothwell JC (1997): Techniques and mechanisms of action of transcranial stimulation of the human motor cortex. J Neurosci Methods 74:113–122. Cordes J, Falkai P, Guse B, Hasan A, Schneider-Axmann T, Arends M, et al. (2009): Repetitive transcranial magnetic stimulation for the treatment of negative symptoms in residual schizophrenia: Rationale and design of a sham-controlled, randomized multicenter study. Eur Arch Psychiatry Clin Neurosci 259(Suppl 2):S189–S197. 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. Biol Psychiatry 49: 460–463. Homan RW, Herman J, Purdy P (1987): Cerebral location of international 10-20 system electrode placement. Electroencephalogr Clin Neurophysiol 66:376–382. Herwig U, Padberg F, Unger J, Spitzer M, Schonfeldt-Lecuona C (2001): Transcranial magnetic stimulation in therapy studies: Examination of the reliability of “standard” coil positioning by neuronavigation. Biol Psychiatry 50:58–61. Herwig U, Satrapi P, Schonfeldt-Lecuona C (2003): Using the international 10-20 EEG system for positioning of transcranial magnetic stimulation. Brain Topogr 16:95–99. Addington D, Addington J, Maticka-Tyndale E (1993): Assessing depression in schizophrenia: The Calgary Depression Scale. Br J Psychiatry Suppl 22:39–44. Montgomery SA, Asberg M (1979): A new depression scale designed to be sensitive to change. Br J Psychiatry 134:382–389. 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. Endicott J, Spitzer RL, Fleiss JL, Cohen J (1976): The global assessment scale. A procedure for measuring overall severity of psychiatric disturbance. Arch Gen Psychiatry 33:766–771. Beitinger R, Lin J, Kissling W, Leucht S (2008): Comparative remission rates of schizophrenic patients using various remission criteria. Prog Neuropsychopharmacol Biol Psychiatry 32:1643–1651.

Biological Psychiatry ]]], 2014; ]:]]]–]]] www.sobp.org/journal

9

Biological Psychiatry

rTMS for Schizophrenia Negative Symptoms

40. 41.

42.

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

53.

10

Tombaugh TN (2004): Trail Making Test A and B: Normative data stratified by age and education. Arch Clin Neuropsychol 19:203–214. Gerlach J, Korsgaard S, Clemmesen P, Lauersen AM, Magelund G, Noring U, et al. (1993): The St. Hans Rating Scale for extrapyramidal syndromes: Reliability and validity. Acta Psychiatr Scand 87:244–252. Faul F, Erdfelder E, Lang AG, Buchner A (2007): G*Power 3: A flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods 39:175–191. Krueger C, Tian L (2004): A comparison of the general linear mixed model and repeated measures ANOVA using a dataset with multiple missing data points. Biol Res Nurs 6:151–157. Leucht S (2014): Measurements of response, remission, and recovery in schizophrenia and examples for their clinical application. J Clin Psychiatry 75(suppl 1):8–14. Leucht S, Davis JM, Engel RR, Kissling W, Kane JM (2009): Definitions of response and remission in schizophrenia: Recommendations for their use and their presentation. Acta Psychiatr Scand Suppl (438):7–14. Honer WG, Thornton AE, Chen EY, Chan RC, Wong JO, Bergmann A, et al. (2006): Clozapine alone versus clozapine and risperidone with refractory schizophrenia. N Engl J Med 354:472–482. Mogg A, Purvis R, Eranti S, Contell F, Taylor JP, Nicholson T, et al. (2007): Repetitive transcranial magnetic stimulation for negative symptoms of schizophrenia: A randomized controlled pilot study. Schizophr Res 93:221–228. LeLorier J, Gregoire G, Benhaddad A, Lapierre J, Derderian F (1997): Discrepancies between meta-analyses and subsequent large randomized, controlled trials. N Engl J Med 337:536–542. Stanford AD, Corcoran C, Bulow P, Bellovin-Weiss S, Malaspina D, Lisanby SH (2011): High-frequency prefrontal repetitive transcranial magnetic stimulation for the negative symptoms of schizophrenia: A case series. J ECT 27:11–17. Prikryl R, Ustohal L, Prikrylova Kucerova H, Kasparek T, Venclikova S, Vrzalova M, et al. (2013): A detailed analysis of the effect of repetitive transcranial magnetic stimulation on negative symptoms of schizophrenia: A double-blind trial. Schizophr Res 149:167–173. Novak T, Horacek J, Mohr P, Kopecek M, Skrdlantova L, Klirova M, et al. (2006): The double-blind sham-controlled study of high-frequency rTMS (20 Hz) for negative symptoms in schizophrenia: Negative results. Neuro Endocrinol Lett 27:209–213. Barr MS, Farzan F, Rajji TK, Voineskos AN, Blumberger DM, Arenovich T, et al. (2013): Can repetitive magnetic stimulation improve cognition in schizophrenia? Pilot data from a randomized controlled trial. Biol Psychiatry 73:510–517. Fitzgerald PB, Herring S, Hoy K, McQueen S, Segrave R, Kulkarni J, et al. (2008): A study of the effectiveness of bilateral transcranial

Biological Psychiatry ]]], 2014; ]:]]]–]]] www.sobp.org/journal

54.

55.

56.

57.

58.

59.

60.

61.

62.

63.

64.

magnetic stimulation in the treatment of the negative symptoms of schizophrenia. Brain Stimul 1:27–32. Herwig U, Fallgatter AJ, Hoppner J, Eschweiler GW, Kron M, Hajak G, et al. (2007): Antidepressant effects of augmentative transcranial magnetic stimulation: Randomised multicentre trial. Br J Psychiatry 191:441–448. Berlim MT, Broadbent HJ, Van den Eynde F (2013): Blinding integrity in randomized sham-controlled trials of repetitive transcranial magnetic stimulation for major depression: A systematic review and metaanalysis. Int J Neuropsychopharmacol 16:1173–1181. Rusjan PM, Barr MS, Farzan F, Arenovich T, Maller JJ, Fitzgerald PB, et al. (2010): Optimal transcranial magnetic stimulation coil placement for targeting the dorsolateral prefrontal cortex using novel magnetic resonance image-guided neuronavigation. Hum Brain Mapp 31: 1643–1652. Fitzgerald PB, Maller JJ, Hoy KE, Thomson R, Daskalakis ZJ (2009): Exploring the optimal site for the localization of dorsolateral prefrontal cortex in brain stimulation experiments. Brain Stimul 2: 234–237. Slotema CW, Blom JD, de Weijer AD, Diederen KM, Goekoop R, Looijestijn J, et al. (2011): Can low-frequency repetitive transcranial magnetic stimulation really relieve medication-resistant auditory verbal hallucinations? Negative results from a large randomized controlled trial. Biol Psychiatry 69:450–456. Gottlieb JD, Cather C, Shanahan M, Creedon T, Macklin EA, Goff DC (2011): D-cycloserine facilitation of cognitive behavioral therapy for delusions in schizophrenia. Schizophr Res 131:69–74. Pompili M, Lester D, Dominici G, Longo L, Marconi G, Forte A, et al. (2013): Indications for electroconvulsive treatment in schizophrenia: A systematic review. Schizophr Res 146:1–9. Buchanan RW, Kreyenbuhl J, Kelly DL, Noel JM, Boggs DL, Fischer BA, et al. (2010): The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements. Schizophr Bull 36:71–93. Ridding MC, Ziemann U (2010): Determinants of the induction of cortical plasticity by non-invasive brain stimulation in healthy subjects. J Physiol 588:2291–2304. Downar J, Geraci J, Salomons TV, Dunlop K, Wheeler S, McAndrews MP, et al. (2014): Anhedonia and reward-circuit connectivity distinguish nonresponders from responders to dorsomedial prefrontal repetitive transcranial magnetic stimulation in major depression. Biol Psychiatry 76:176–185. Hamada M, Murase N, Hasan A, Balaratnam M, Rothwell JC (2013): The role of interneuron networks in driving human motor cortical plasticity. Cerebr Cortex 23:1593–1605.