Repetitive transcranial magnetic stimulation for the treatment of negative symptoms in residual schizophrenia: rationale and design of a sham-controlled,randomized multicenter study

Current meta-analysis revealed small, but significant effects of repetitive transcranial magnetic stimulation (rTMS) on negative symptoms in patients with schizophrenia. There is a need for further controlled, multicenter trials to assess the clinical efficacy of rTMS on negative symptoms in schizophrenia in a larger sample of patients. The objective of this multicenter, randomized, sham-controlled, rater- and patient-blind clinical trial is to investigate the efficacy of 3-week 10-Hz high frequency rTMS add on to antipsychotic therapy, 15 sessions per 3 weeks, 1,000 stimuli per session, stimulation intensity 110% of the individual motor threshold) of the left dorsolateral prefrontal cortex for treating negative symptoms in schizophrenia, and to evaluate the effect during a 12 weeks of follow-up. The primary efficacy endpoint is a reduction of negative symptoms as assessed by the negative sum score of the positive and negative symptom score (PANSS). A sample size of 63 in each group will have 80% power to detect an effect size of 0.50. Data analysis will be based on the intention to treat population. The study will be conducted at three university hospitals in Germany. This study will provide information about the efficacy of rTMS in the treatment of negative symptoms. In addition to psychopathology, other outcome measures such as neurocognition, social functioning, quality of life and neurobiological parameters will be assessed to investigate basic mechanisms of rTMS in schizophrenia. Main limitations of the trial are the potential influence of antipsychotic dosage changes and the difficulty to ensure adequate blinding.

     

Memory impairment in schizophrenia: a meta-analysis.

OBJECTIVE: Memory impairment is well documented in schizophrenia. Less is known, however, about the exact magnitude, pattern, and extent of the impairment. The effect of potential moderator variables, such as medication status and duration of illness, is also unclear. In this article, the authors presented meta-analyses of the published literature on recall and recognition memory performance between patients with schizophrenia and normal comparison subjects. METHOD: Meta-analyses were conducted on 70 studies that reported measures of long-term memory (free recall, cued recall, and recognition of verbal and nonverbal material) and short-term memory (digit span). Tests of categorical models were used in analyses of potential moderators (clinical variables and study characteristics). RESULTS: The findings revealed a significant and stable association between schizophrenia and memory impairment. The composite effect size for recall performance was large. Recognition showed less, but still significant, impairment. The magnitude of memory impairment was not affected by age, medication, duration of illness, patient status, severity of psychopathology, or positive symptoms. Negative symptoms showed a small but significant relation with memory impairment. CONCLUSIONS: This meta-analysis documented significant memory impairment in schizophrenia. The impairment was stable, wide ranging, and not substantially affected by potential moderating factors such as severity of psychopathology and duration of illness.     

Treatment of negative symptoms of schizophrenia using repetitive transcranial magnetic stimulation in a double-blind, randomized controlled study

OBJECTIVE: To verify whether high-frequency rTMS applied above the area of the left prefrontal cortex in 15 stimulation sessions with maximum stimulation intensity is able to modify negative symptoms of schizophrenia in a double-blind, randomized controlled study. METHODS: Twenty-two patients with schizophrenia stabilized on antipsychotic medication with prominent negative symptoms were included in the trial. They were divided into two groups: eleven were treated with effective rTMS and eleven with ineffective "sham" rTMS. The ineffectiveness of the sham rTMS was achieved through the stimulation coil position. Stimulation was applied to the left dorsolateral prefrontal cortex. The stimulation frequency was 10 Hz. Stimulation intensity was 110% of the motor threshold intensity. Each patient received 15 rTMS sessions on 15 consecutive working days. Each daily session consisted of 15 applications of 10-second duration and 30-second intervals between sequences. There were 1500 stimuli per session. RESULTS: During real rTMS treatment a statistically significant decrease of negative symptoms was found (approximately 29% reduction in the PANSS negative symptom subscale and 50% reduction in the SANS). No adverse events occurred during therapy except for a mild headaches. In sham rTMS treatment a decrease of negative symptoms was also identified, but to a lesser extent than in real rTMS (about 7% in negative subscale PANSS and 13% in SANS). The change in SANS achieved statistical significance. Mutual comparison revealed a greater decrease of negative symptoms in favor of real rTMS in contrast to sham rTMS. CONCLUSION: The augmentation of rTMS enabled patients to experience a significant decrease in the severity of the negative symptoms. Our results support the therapeutic potential of rTMS at higher frequency for negative symptoms of schizophrenia.     

A systematic review and meta-analysis of the use of repetitive transcranial magnetic stimulation for auditory hallucinations treatment in refractory schizophrenic patients

Background. The use of repetitive transcranial magnetic stimulation (rTMS) remains a promising therapeutic tool in the treatment of schizophrenia. Symptoms such as auditory hallucinations (AH) find contradictory results in many studies. Here we present an up-to-date systematic review and meta-analysis of rTMS in the treatment of AH in schizophrenia. Methods. We searched Pubmed-MEDLINE from 1999 to 2013 for double-blinded randomized sham-controlled trials that applied slow rTMS on the left temporoparietal cortex and assessed the outcome results using Hallucination Change Scale or Auditory Hallucination Rating Scale or Scale for Auditory Hallucinations (SAH). We identified 10 studies suitable for the meta-analysis. Results. We found a positive sized effect in favor of rTMS [random-effects model Hedges’ g = 0.011, I-squared = 58.1%]. There was some variability between study effect sizes, but the sensitivity analysis concluded that none of them had sufficient weight to singularly alter the results of our meta-analysis. Discussion. rTMS appears to be an effective treatment for AH. The left temporoparietal cortex seems to be the area in which rTMS is effective. Although meta-analysis is a powerful analytical tool, more studies must be conducted in order to obtain a more expressive sample size to perform a more accurate analytical approach.     

重复经颅磁刺激治疗对精神分裂症患者阴性症状的疗效和安全性:系统综述

背景:阴性症状是精神分裂症治疗的难点之一,抗精神病药物对其疗效较差.重复经颅磁刺激(repetitive transcranial magnetic stimulation,rTMS)是一项新型脑皮质刺激技术,被认为是一项安全而有前景的精神障碍治疗方法,近年来临床研究及新的治疗模式增多,rTMS治疗阴性症状的疗效和安全性评价需要更新.目标:探索rTMS治疗对精神分裂症患者阴性症状的有效性及安全性.方法:我们从以下数据库搜索了相关的临床对照试验:PubMed、EMBASE、the Cochrane Library、EBSCO、Web of science、中国知网、维普、万方、中国生物医学文摘数据库、台湾学术文献数据库等数据库,检索时间截止于2017年1月2日.按照预先定好的纳入和排除标准筛选研究文献,提取数据后应用RevMan 5.3和Stata 14.0对数据进行统计分析.对纳入研究进行质量评价,采用Cochrane风险评估偏倚工具评估各种偏倚的风险性.结合GRADE(Grades of Recommendation,Assessment,Development,and Evaluation,GRADE)系统推荐分级方法为参照标准,进行主要结局指标证据水平的分级.结果:总共检索到3500篇文献,最终29篇文献纳入meta分析,合计样本量1440例.进行meta分析后发现,抗精神病药物治疗合并使用rTMS可改善患者的阴性症状(SMD=-0.40,95%CI=-0.62~-0.18).根据Cochrane风险评估偏倚工具对疗效的评估的偏倚进行评估,其中6篇研究评价为"高偏倚风险",其它为"无法判断".根据GRADE分级的评估、制定和评价标准,该疗效评估指标的证据质量是"中等".rTMS治疗的可接受性较好(RR=0.75,95%CI=0.49~1.15,基于28项研究的1492例样本),但接受rTMS治疗的患者出现轻微不良反应的比率更高(RR=2.20,95%CI=1.53~3.18,基于23项研究的1296例样本).结论:抗精神病药物治疗合并使用rTMS治疗可以一定程度改善精神分裂症患者的阴性症状,可接受性较好,不良反应较轻.但是本研究存在发表性偏倚,且研究的异质性较高,所以对结果进行解释时需要慎重.     

四种模式的重复经颅磁刺激治疗精神分裂症阴性症状的随机对照试验（英文）

背景:抗精神病药物对精神分裂症阴性症状的疗效欠佳。重复经颅磁刺激(rTMS)或许是治疗阴性症状的另一种更有效的方法,但很少有关于不同模式rTMS治疗有效性比较的研究。目标:比较四种不同模式rTMS对治疗精神分裂症阴性症状的效果。方法:96例有明显阴性症状的精神分裂症患者随机分为四个治疗组:10赫兹,20赫兹,θ波脉冲刺激(TBS),和模拟rTMS治疗(即对照组)。在前三组,采用运行阈值的80%对左背外侧前额叶皮层进行刺激,每周五次,持续四周。治疗前后,由对患者分组单盲的评估者采用阳性和阴性症状量表(PANSS)、阴性症状评估量表(SANS)和不良反应量表(TESS)进行评估。结果:96例患者中3名患者中途退出试验(两个来自对照组和一个来自20赫兹组)。与对照组相比,经rTMS治疗4周后,3个治疗组PANSS阴性症状分量表、PANSS一般精神病理分量表和SANS量表得分较低。TBS组这些量表的减分显著大于10赫兹组和20赫兹组,但10赫兹和20赫兹两组间无显著差异。四组之间PANSS阳性症状分量表评分治疗前后没有显著差异。未发生严重不良事件,并且4组TESS评分无统计学显著差异。结论:我们发现rTMS治疗,特别是TBS刺激模式对于伴有明显阴性症状的精神分裂症患者是一种安全有效的治疗方法。我们需要进行大样本的纵向研究,以优化rTMS治疗,并确定刺激模式,持续时间,刺激强度以及治疗时间间隔,从而以最低的风险为患者提供最佳的治疗结果。     

Efficacy of adjuvant high frequency repetitive transcranial magnetic stimulation on negative and positive symptoms of schizophrenia: preliminary results of a double-blind sham-controlled study

The potential effect of repetitive transcranial magnetic stimulation (rTMS) on core positive and negative symptoms in schizophrenia has not yet been clearly established. The aim of this study was to examine the efficacy of adjuvant 10 Hz, suprathreshold left prefrontal rTMS in negative symptoms of schizophrenia in a double-blind sham-controlled design. Additionally, our study also investigated the suitability of applying the same stimulus condition on positive symptoms. Ten right-handed schizophrenia patients received sham or active 10 Hz suprathreshold rTMS to the left dorsolateral prefrontal cortex with psychopathology, depression and global improvement ratings before and after rTMS sessions. Compared to sham, active rTMS significantly improved negative symptoms, irrespective of change in depressive symptoms.     

The efficacy of zotepine in treating acute negative symptoms of schizophrenia: The results of a meta-analysis

INTRODUCTION: Zotepine is a unique antipsychotic drug, having effects which are both antiserotonergic and antidopaminergic that may make it more effective in the treatment of negative symptoms of schizophrenia than more conventional agents. METHOD: A meta-analysis was performed on the effect of zotepine on the negative symptoms in seven double-blind studies, as measured by the SANS scale. RESULTS: Of the trials selected for this meta-analysis, one showed significant improvement in acute negative symptoms in favour of zotepine. Negative symptoms measured in the other trials showed trends in favour of zotepine, except for one study where the trend was in favour of perazine. The meta-analysis showed zotepine to be significantly better then either placebo or conventional antipsychotic comparators using the standardized treatment difference methodology, and it confirmed the results from a previous study using patients with predominantly negative symptoms. CONCLUSION: Zotepine may have a place in the treatment of this group of patients where conventional antipsychotic drugs have had little effect. ( Int J Psych Clin Pract 2000; 4: 209 - 214)     

Left prefrontal repetitive transcranial magnetic stimulation in schizophrenia

In a double-blind, controlled study, we examined the therapeutic effects of high-frequency left prefrontal repetitive transcranial magnetic stimulation (rTMS) on schizophrenia symptoms. A total of 22 chronic hospitalized schizophrenia patients were randomly assigned to 2 weeks (10 sessions) of real or sham rTMS. rTMS was given with the following parameters: 20 trains of 5-second 10-Hz stimulation at 100 percent motor threshold, 30 seconds apart. Effects on positive and negative symptoms, self-reported symptoms, rough neuropsychological functioning, and hormones were assessed. Although there was a significant improvement in both groups in most of the symptom measures, no real differences were found between the groups. A decrease of more than 20 percent in the total PANSS score was found in 7 control subjects but only 1 subject from the real rTMS group. There was no change in hormone levels or neuropsychological functioning, measured by the MMSE, in either group. Left prefrontal rTMS (with the used parameters) seems to produce a significant nonspecific effect of the treatment procedure but no therapeutic effect in the most chronic and severely ill schizophrenia patients.     

Right prefrontal slow repetitive transcranial magnetic stimulation in schizophrenia: a double-blind sham-controlled pilot study.

BACKGROUND: The aim of this study was to extend our previous work on the therapeutic efficacy of repetitive transcranial magnetic stimulation (rTMS) in major depression to patients with schizophrenia. METHODS: Thirty-five inpatients with schizophrenia were randomly assigned to either right prefrontal rTMS or sham treatment and were rated before and after treatment for positive, negative, and depressive symptoms. RESULTS: Thirty-one subjects (rTMS = 16, sham = 15) completed a 2-week treatment protocol. No serious adverse effects were reported; however, rTMS was not superior to sham treatment on any of the clinical ratings. CONCLUSIONS: In contrast to our previous positive findings in major depression, right prefrontal slow rTMS does not appear to have a beneficial effect for actively psychotic patients with schizophrenia.     

Placebo Response in Repetitive Transcranial Magnetic Stimulation Trials of Treatment of Auditory Hallucinations in Schizophrenia: A Meta-Analysis

Several meta-analyses have assessed the response of patients with schizophrenia with auditory verbal hallucinations (AVH) to treatment with repetitive transcranial magnetic stimulation (rTMS); however, the placebo response has never been explored. Typically observed in a therapeutic trial, the placebo effect may have a major influence on the effectiveness of rTMS. The purpose of this meta-analysis is to evaluate the magnitude of the placebo effect observed in controlled studies of rTMS treatment of AVH, and to determine factors that can impact the magnitude of this placebo effect, such as study design considerations and the type of sham used.The study included twenty-one articles concerning 303 patients treated by sham rTMS. A meta-analytic method was applied to obtain a combined, weighted effect size, Hedges’s g. The mean weighted effect size of the placebo effect across these 21 studies was 0.29 (P < .001). Comparison of the parallel and crossover studies revealed distinct results for each study design; placebo has a significant effect size in the 13 parallel studies (g = 0.44, P < 10⁻⁴), but not in the 8 crossover studies (g = 0.06, P = .52). In meta-analysis of the 13 parallel studies, the 45° position coil showed the highest effect size. Our results demonstrate that placebo effect should be considered a major source of bias in the assessment of rTMS efficacy. These results fundamentally inform the design of further controlled studies, particularly with respect to studies of rTMS treatment in psychiatry.Key words: rTMS, placebo, schizophrenia, auditory hallucination, meta-analysis, sham coil     

Potential clinical targets of repetitive transcranial magnetic stimulation treatment in schizophrenia

Despite the introduction of atypical antipsychotic drugs, treatment-resistant symptoms still represent a serious problem in schizophrenia. Currently, there is evidence from clinical studies suggesting that treatment with repetitive transcranial magnetic stimulation (rTMS) may improve schizophrenia symptoms. Our review provides an overview of clinical rTMS studies in schizophrenic patients. A systematic search of the literature (Cochrane and Medline databases up to December 2005) was conducted. Most studies showed methodological problems due to their explorative character and small sample sizes. In some studies, a treatment effect of high-frequency rTMS applied over the prefrontal cortex was seen with respect to negative symptoms. On the other hand, low-frequency rTMS in the temporal lobe area might lead to a suppression of auditory hallucinations. It is concluded that larger sham-controlled studies are required to allow an adequate assessment of the clinical and neurobiological effects of rTMS in schizophrenic patients. The currently available data provide insufficient evidence to support the use of rTMS as an adjuvant treatment for schizophrenic psychopathology, but encourage further investigation of rTMS as a novel treatment approach.     

Therapeutic and neurophysiologic aspects of transcranial magnetic stimulation in schizophrenia.

The use of repetitive transcranial magnetic stimulation (rTMS) in psychiatry provides the therapeutic field with a new tool. Since its introduction in the mid 1980s, the vast majority of studies have focussed on depression. A growing body of evidence suggests that rTMS is effective in the treatment of depression if dorsolateral prefrontal cortex is stimulated. Less is known about its efficacy in schizophrenia. Neuroimaging investigations in schizophrenia suggest abnormalities in the prefrontal and temporoparietal cortex (TPC), which are correlated with psychopathological dimensions. Based on its modulatory effect, rTMS seems to be a promising tool in exploring cortical excitability and reducing auditory hallucinations (AH) and negative symptoms. Neurophysiologic studies of patients suffering from schizophrenia using rTMS indicate high cortical excitability and a lack of transcallosal inhibition. In the therapeutic field, researches provide encouraging results, even though some studies indicate limited benefits. The most promising therapeutic effect seems to be the capability of rTMS to reduce AH if TPC is targeted using slow-frequency. The current paper aims to provide a review of the literature of the use of rTMS in schizophrenia.     

利培酮与舒必利治疗精神分裂症阴性症状Meta分析

目的：采用Meta分析方法比较利培酮与舒必利治疗精神分裂症阴性症状的临床疗效。方法：将利培酮与舒必利治疗精神分裂症阴性症状的16个中文的随机对照研究进行再分析。结果：16个研究的合并效应量（WMD）为-0．58（-1．37，0．21；P〉0．05）。阳性与阴性症状量表（PANSS）阴性因子（N）亚组的WMD为-0．84（-1．91，0．24；P〉0．05）；阴性症状评定量表（SANS）亚组的WMD为0．19，（-0．77，1．15；P〉0．05）。结论：利培酮与舒必利对精神分裂症阴性症状的疗效无显著差别。     

A randomized,double blind,sham-controlled trial of repetitive transcranial magnetic stimulation (rTMS) in the treatment of negative symptoms in schizophrenia

BackgroundResearch has implicated hypofrontality in the pathogenesis of Negative symptoms of schizophrenia.These symptoms are often resistant to treatment. Repetitive Transcranial Magnetic Stimulation (rTMS) has been shown to reverse this hypofrontality. Higher frequency rTMS has shown better promise, but so far there has been very little research in this area.ObjectiveWe aimed to evaluate the efficacy of high-frequency (20 Hz) unilateral rTMS over the left Dorso-Lateral Pre-frontal Cortex (DLPFC) in the improvement of Negative symptoms in Schizophrenia. Methods:100 patients of schizophrenia with predominantly negative symptoms, were enrolled for this randomized, sham-controlled, double-blind trial.Each participant received 20 sessions of rTMS at 20 Hz frequency and 100% motor threshold, via either the active or the sham coil, over 4 weeks. A total of 2000 pulses were imparted in 10 trains per session. Negative symptoms were assessed with the SANS and PANSS. CDSS was used to rule out depressive symptoms. Assessments were carried out at baseline, post-intervention, and 1-month, 2-months, 3-months and 4-months follow ups.ResultsThe improvement in the negative symptoms (Anhedonia, Alogia, Avolition, Attention impairment) in active group was statistically significant at 0.01 and 0.05 (p-value) as compared to sham group.ConclusionsThese results suggest that high-frequency rTMS may lead to improvement in negative symptoms of schizophrenia. It may be worth considering its use as an adjunct to pharmacological treatment of negative symptoms.     

重复经颅磁刺激对首发精神分裂症患者血清脑源性神经营养因子的影响

目的：初步探讨高频重复经颅磁刺激（rTMS）对以阴性症状为主的首发精神分裂症患者血清脑源性神经营养因子（BDN F ）水平的影响。方法采用随机、双盲、对照研究,选取符合国际疾病分类第十版（ICD－10）中精神分裂症诊断标准的门诊患者70例。在常规抗精神病药物治疗的基础上,按照随机数字表法分为真刺激组（n ＝35）和伪刺激组（n ＝35）,并在基线时和治疗4周末时进行BDNF浓度测定和PANSS评估。结果治疗4周后,真刺激组的PANSS总分、阴性症状分和一般精神病理分均低于伪刺激组,BDNF浓度高于伪刺激组,差异均有统计学意义（P ＜0．05）。真刺激组BDNF浓度变化值与PANSS总分及各因子分变化值均无相关性（P ＞0．05）。两组不良反应差异无统计学意义（P ＞0．05）。结论 rTMS治疗可显著增加首发精神分裂症患者的血清BDNF浓度,但其浓度变化与临床症状（尤其是阴性症状）的改善无相关性。     

Efficacy of repetitive transcranial magnetic stimulation for Tourette syndrome: A systematic review and meta-analysis

Background

While previous studies have investigated the effect of repetitive transcranial magnetic stimulation (rTMS) in treating Tourette syndrome (TS), the results remain inconclusive.

Peer-to-peer psychoeducation in schizophrenia: a new approach

OBJECTIVE: To evaluate the feasibility of the first peer-to-peer psychoeducation program in schizophrenia. METHOD: We developed a 5-step curriculum for structured training of peer moderators. In step 1, peer moderators participate in regular psychoeducation, and in step 2, they participate in workshops on knowledge about schizophrenia and moderation techniques. In step 3, peer moderators conduct peer-to-peer groups in the presence of a mental health professional, and in step 4, they conduct the groups independently with regular supervision. Further peer moderators are recruited in step 5. Psychoeducation by trained peer moderators comprises 8 60-minute group sessions (warm-up, symptoms, diagnosis, causes, medication, psychosocial therapy, warning signs, coping with schizophrenia) with 6 to 10 patients per group. The feasibility of the 5-step curriculum was evaluated by conducting a pilot study of 7 peer groups with 2 peer moderators. Evaluation of peer-moderated groups was done from January 2003 to July 2004 using inpatients of a university hospital who had schizophrenia or schizoaffective disorder according to ICD-10. The primary outcomes of interest were change in knowledge and concept of illness from baseline to endpoint. RESULTS: Two peer moderators conducted psychoeducational groups with a total of 49 patients in the presence of a physician (step 3). On the whole, conduction of peer-moderated groups worked well. Knowledge of illness increased significantly (N = 44, p < .001), and concept of illness changed significantly in 3 subscales: trust in physician (N = 40, p = .002) and trust in medication (N = 40, p = .001) increased, and negative treatment expectations decreased (N = 40, p = .001). Subjective assessments of peer moderators by participating patients were positive. CONCLUSION: First results suggest that peer-to-peer psychoeducation in schizophrenia according to the 5-step curriculum is feasible and may be comparable to professional psychoeducation in regard to short-term outcomes.     

重复经颅磁刺激对军人慢性精神分裂症患者阴性症状及认知功能的疗效分析

目的研究高频重复经颅磁刺激（rTMS）对军人慢性精神分裂症患者阴性症状及认知功能的疗效。方法将42例以阴性症状为主的住院军人慢性精神分裂症患者随机分为研究组（21例）和对照组（21例）。研究组在原有抗精神病药物种类及剂量不变的同时给予经左侧背外侧前额叶的4周共20次高频（15Hz）rTMS刺激,对照组采用假rTMS刺激。治疗前后对两组分别进行阳性和阴性症状量表（PANSS）、17项汉密尔顿抑郁量表（HAMD17）、治疗中出现的不良反应量表（TESS）评定及事件相关电位P300测定。结果研究组治疗后PANSS量表阴性症状因子分由（35.1±4.5）降至（25.5±4.1）,治疗后较治疗前显著下降（t=2.92,P〈0.05）,而对照组治疗前后则无变化（P〉0.05）,研究组疗效明显优于对照组（F=21.6,P〈0.05）;其它因子分及HAMD17治疗前、后均无变化。与治疗前比较,治疗后在CZ点,研究组P300的P2、P3波幅升高（P均〈0.05）;而对照组P300各项指标治疗前后变化均无统计学意义（P均〉0.05）。结论高频rTMS能有效治疗慢性精神分裂症患者的阴性症状,并改善认知功能。