Rudyard Frogoso
Brief description of patient problem/setting (summarize the case very briefly)
There was a case in grand rounds involving a 27y/o female PPH schizophrenia x 2 years. Self-care deteriorating due to increasing negative symptoms (i.e. increased thought disorganization, anhedonia). Treatment involved standard of care such as psychotherapy, psychotropic meds, mood stabilizers. The resident mentioned in passing that there was some research involving Transcranial Magnetic Stimulation having beneficial effects when combined with standard of care.
Search Question (including outcomes or criteria to be tracked)
Does Transcranial Magnetic Stimulation as an adjunct to standard of care (i.e. psychotherapy, psychotropic meds, mood stabilizers) help improve the negative symptoms of schizophrenia?
What kind of question is this? (boxes now checkable in Word)
☐Prevalence ☐Screening ☐Diagnosis
☐Prognosis ☐Treatment ☐Harms
Assuming that the highest level of evidence to answer your question will be meta-analysis or systematic review, what other types of study might you include if these are not available (or if there is a much more current study of another type)?
A meta-analysis of well-designed prospective trials
PICO search terms
| P | I | C | O |
| Patients with negative symptoms of schizophrenia (i.e. anhedonia, poverty of thought, disorganized thoughts) | Transcranial Magnetic Stimulation
Psychotropic Medications Psychotherapy |
Psychotropic medications
Psychotherapy |
Improved negative symptoms |
| Improved adverse effects |
Search tools and strategy used:
[Please indicate what data bases/tools you used, provide a list of the terms you searched together in each tool, and how many articles were returned using those terms]:
Database: Pubmed
MeSH Terms: magnetize; transcranially; magnetic; magnetizing; magnetism; transcranial; schizophrenia; magnet; schizophrenias; stimulation; transcranial magnetic stimulation; stimulations; magnetics; negative symptoms
Filters: 10 years, English
Results: 367 results
Database: Cochrane Library
Search Terms: Transcranial Magnetic Stimulation; Schizophrenia
Results: 3 results
Transcranial Magnetic Stimulation None of these reviews were included because they mainly synthesized low to very-low quality evidence
Results found:
Identify at least 3 articles (or other appropriate reputable sources) that answer your specific question with the highest available level of evidence (you will probably need to look at more than 3 articles to get the 3 most focused and highest level articles to address your question)
Please post the citation and abstract for each article (to include the journal and authors’ names and date) and say why you chose it. Please also note what kind of article it is (e.g. meta-analysis, cohort study, or independent blind comparison with gold standard of diagnosis, etc.).
At the bottom of each abstract, please comment on what your key points are from this article (including any points or concepts included in the article, but not present in the abstract – i.e. make the concepts understandable to the reader)
1.
Repetitive transcranial magnetic stimulation for negative symptoms of schizophrenia: review and meta-analysis. Dlabac-de Lange JJ, Knegtering R, Aleman A. J Clin Psychiatry. 2010 Apr;71(4):411-8. doi: 10.4088/JCP.08r04808yel. Epub 2010 Feb 23. Review. PubMed PMID: 20361909.
Article Type: Meta-analysis
Abstract
BACKGROUND:
Repetitive transcranial magnetic stimulation (rTMS) has been proposed as a treatment for the negative symptoms of schizophrenia. During the past decade, several trials have reported on the efficacy of rTMS treatment; however, the results were inconsistent.
OBJECTIVE:
To assess the efficacy of prefrontal rTMS for treating negative symptoms of schizophrenia.
DATA SOURCES:
A literature search was performed in PubMed, ISI Web of Science, and EMBASE for the years 1985 through July 2008. The search terms used (language not specified) were “transcranial magnetic stimulation,” “negative symptoms,” and “schizophrenia.” A cross-reference search of eligible articles was performed to identify studies not found in the computerized search.
STUDY SELECTION:
Studies selected were randomized controlled trials assessing the therapeutic efficacy of prefrontal rTMS for negative symptoms in schizophrenia.
DATA EXTRACTION:
Effect sizes (Cohen d) of each study were calculated. The overall standardized mean difference was calculated under a random effects model with 95% confidence intervals.
DATA SYNTHESIS:
Nine trials, involving 213 patients, were included in the meta-analysis. The overall mean weighted effect size for rTMS versus sham was in the small-to-medium range and statistically significant (d = 0.43; 95% CI, 0.05-0.80). When including only the studies using a frequency of stimulation of 10 Hz, the mean effect size increased to 0.63 (95% CI, 0.11-1.15). When including only the studies requiring participants to be on a stable drug regimen before and during the study, the mean weighted effect size decreased to 0.34 (95% CI, 0.01-0.67). Studies with a longer duration of treatment (> or =3 weeks) had a larger mean effect size when compared to studies with a shorter treatment duration: d = 0.58 (95% CI, 0.19-0.97) and d = 0.32 (95% CI, -0.3 to 0.95), respectively.
CONCLUSIONS:
The results of this meta-analysis warrant further study of rTMS as a potential treatment of negative symptoms of schizophrenia.
2.
Efficacy Towards Negative Symptoms and Safety of Repetitive Transcranial Magnetic Stimulation Treatment for Patients with Schizophrenia: A Systematic Review. Wang J, Zhou Y, Gan H, Pang J, Li H, Wang J, Li C. Shanghai Arch Psychiatry. 2017 Apr 25;29(2):61-76. doi: 10.11919/j.issn.1002-0829.217024. PubMed PMID: 28765677; PubMed Central PMCID: PMC5518263.
Article Type: Meta-Analysis
Abstract
BACKGROUND:
Negative symptoms are one of the most difficult areas in the treatment of schizophrenia because antipsychotics are often less effective towards them. Repetitive transcranial magnetic stimulation (rTMS) is a new technique for cerebral cortex stimulation and is believed to be a safe and promising method for the treatment of mental disorders. As the clinical research and new treatment models have increased in recent years, the efficacy towards negative symptoms and safety evaluation of rTMS treatment should also be updated.
AIMS:
To explore the efficacy and safety of rTMS in the treatment of negative symptoms for patients with schizophrenia.
METHODS:
We searched for relevant controlled clinical trials from the following databases: PubMed, EMBASE, the Cochrane Library, EBSCO, Web of Science, China National Knowledge Infrastructure (CNKI), VIP, Wanfang Data, SINOMED, and Airiti Library. The retrieval time went up to January 2, 2017. The research literature was screened according to the predefined inclusion and exclusion criteria. After data extraction, statistical analysis was conducted by using RevMan 5.3 and Stata 14. Quality evaluation was done on the included research articles. The Cochrane risk of bias assessment tool was adopted for assessing risk of bias. The GRADE (Grades of Recommendation, Assessment, Development, and Evaluation) system recommendation grading method was used as the reference standard.
RESULTS:
A total of 3500 articles were retrieved. In the end, there were 29 articles included in the meta-analysis with a total sample size of 1440. After the meta-analysis, it was found that the use of antipsychotic treatment combined with rTMS could improve the negative symptoms of patients (SMD=-0.40, 95% CI= -0.62~-0.18). Based on the bias of the efficacy evaluation assessed by the Cochrane risk of bias assessment tool, there were 6 studies rated as having “high risk of bias” and the rest were rated as “unable to determine”. According to the assessment, development and evaluation criteria of the GRADE classification, the evidence quality for the efficacy evaluation index was “moderate”. The acceptability of rTMS treatment was better (RR= 0.75, 95% CI= 0.49~1.15, based on the 1492 samples from the 28 studies), however, the patients who received the rTMS treatment had a higher rate of mild adverse effects (RR= 2.20, 95% CI= 1.53~ 3.18, based on the 1296 samples from the 23 studies).
CONCLUSIONS:
The use of the antipsychotic treatment incorporated with rTMS treatment can slightly improve the negative symptoms of patients with schizophrenia and has better acceptability and fewer adverse effects. Nevertheless, there is publication bias in this study and the heterogeneity of the study is relatively high. Therefore, we need to be cautious when interpreting the results.
KEYWORDS:
meta analysis; negative symptoms; repetitive transcranial magnetic stimulation treatment; schizophrenia; systematic review
3.
Revisiting the therapeutic effect of rTMS on negative symptoms in schizophrenia: a meta-analysis. Shi C, Yu X, Cheung EF, Shum DH, Chan RC. Psychiatry Res. 2014 Mar 30;215(3):505-13. doi: 0.1016/j.psychres.2013.12.019. Epub 2013 Dec 21. PubMed PMID: 24411074; PubMed Central PMCID: PMC4127383.
Article Type: Meta-Analysis
Abstract
This study sought to determine the moderators in the treatment effect of repetitive transcranial magnetic stimulation (rTMS) on negative symptoms in schizophrenia. We performed a meta-analysis of prospective studies on the therapeutic application of rTMS in schizophrenia assessing the effects of both low-frequency and high-frequency rTMS on negative symptoms. Results indicate that rTMS is effective in alleviating negative symptoms in schizophrenia. The effect size was moderate (0.63 and 0.53, respectively). The effect size of rTMS on negative symptoms in sham-controlled trials was 0.80 as measured by the SANS and 0.41 as measured by the PANSS. A longer duration of illness was associated with poorer efficacy of rTMS on negative symptoms. A 10 Hz setting, at least 3 consecutive weeks of treatment, treatment site at the left dorsolateral prefrontal cortex (DLPFC) and a 110% motor threshold (MT) were found to be the best rTMS parameters for the treatment of negative symptoms. The results of our meta-analysis suggest that rTMS is an effective treatment option for negative symptoms in schizophrenia. The moderators of rTMS on negative symptoms included duration of illness, stimulus frequency, duration of illness, position and intensity of treatment as well as the type of outcome measures used.
4)
Left prefrontal high-frequency repetitive transcranial magnetic stimulation for the treatment of schizophrenia with predominant negative symptoms: a sham-controlled, randomized multicenter trial. Wobrock T, Guse B, Cordes J, Wölwer W, Winterer G, Gaebel W, Langguth B, Landgrebe M, Eichhammer P, Frank E, Hajak G, Ohmann C, Verde PE, Rietschel M, Ahmed R, Honer WG, Malchow B, Schneider-Axmann T, Falkai P, Hasan A. Biol Psychiatry. 2015 Jun 1;77(11):979-88. Doi: 10.1016/j.biopsych.2014.10.009. Epub 2014 Oct 23. PubMed PMID: 25582269
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.
https://www.biologicalpsychiatryjournal.com/article/S0006-3223(14)00789-6/fulltext
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Summary of Evidence
rTMS = repetitive transcranial magnetic stimulation
| Author (Date) | Level of Evidence | Sample/Setting
(# of subjects/ studies, cohort definition etc. ) |
Outcome(s) studied | Key Findings | Limitations and Biases |
| Dlabac-de Lange JJ, Knegtering R, Aleman A. J Clin Psychiatry. 2010 | Meta-Analysis of Randomized Controlled Trials | 9 Trials
231 patients Schizophrenic patients with predominantly negative symptoms (i.e. anhedonia, poverty of thought) |
Improvement of negative symptoms of schizophrenia (i.e. anhedonia, poverty of thought) | Overall weighted mean effect of rTMS vs placebo is small but statistically significant (d = 0.43; 95% CI, 0.05-0.80) [better outcomes of negative symptoms following rTMS]
Patients on stable drug regimens + rTMS weren’t affected as much d= 0.34; (95% CI, 0.01-0.67) Longer duration of rTMS had more effect than shorter courses d = 0.58 (95% CI, 0.19-0.97) and d = 0.32 (95% CI, -0.3 to 0.95), respectively |
Small sample size (n=231)
Broader confidence intervals and effect size intervals compared to the 3 other studies in this mini-cat (i.e. CI, -0.3 to 0.95) Emphasis on rTMS studies that were >3 weeks meaning bias against short-term (<3 weeks) of rTMS) |
| Wang J, Zhou Y, Gan H, Pang J, Li H, Wang J, Li C. Shanghai Arch Psychiatry. 2017 | Meta-Analysis of mostly Randomized Control Trials; includes some observational studies | 29 studies
1440 patients Schizophrenic patients with predominantly negative symptoms (i.e. anhedonia, poverty of thought) |
Improvement of negative symptoms of schizophrenia after rTMS (i.e. anhedonia, poverty of thought)
Adverse effects of rTMS |
rTMS + antipsychotic treatment improved negative symptoms (SMD=-0.40, 95% CI= -0.62~-0.18)
rTMS is an acceptable method of treatment (RR= 0.75, 95% CI= 0.49~1.15) Patients who received rTMS had higher incidence of “acceptable” side effects (i.e. headaches, pain in site of applications) [RR= 2.20, 95% CI= 1.53~ 3.18] |
High heterogeneity among the studies (some results vary)
Some of the studies in the 29 studies that were included had sample sizes <100 (high risk of bias). A number of these were used to determine adverse effects. While the researchers conclude that that there are “better acceptability and fewer adverse effects” with TMS, their statistics say otherwise with the Risk Ratio of adverse effects involved with TMS to be significantly greater than 1 (RR= 2.20, 95% CI= 1.53~ 3.18) |
| Shi C, Yu X, Cheung EF, Shum DH, Chan RC. Psychiatry Res. 2014 | Meta-Analysis of prospective studies | 16 studies
348 patients Schizophrenic patients with predominantly negative symptoms (i.e. anhedonia, poverty of thought) |
Improvement of negative symptoms of schizophrenia after rTMS (i.e. anhedonia, poverty of thought)
Adverse effects of rTMS |
After treatment, the effect size was TMS was 0.63 meaning 72.57% of the patients were affected by the treatment. The wording is deceptive. What they mean by “affected” doesn’t necessarily mean statistically significant
They mention that the best parameter of TMS is on the left dorsolateral prefrontal cortex They also mention adverse effects such as pain present in a frequency that was defined as “acceptable” |
Mostly assessed prospective studies
Heavy emphasis on protective factors (later onset of schizophrenia, shorter duration of disease) which may mean that this cohort may have a higher probability of responding to [any] treatment Adverse effects mostly assessed using PANSS questionnaire, sometimes with the patient and researcher not even on the same site |
| Wobrock T, Guse B, Cordes J, Wölwer W, Winterer G, Gaebel W, Langguth B, Landgrebe M, Eichhammer P, Frank E, Hajak G, Ohmann C, Verde PE, Rietschel M, Ahmed R, Honer WG, Malchow B, Schneider-Axmann T, Falkai P, Hasan A. Biol Psychiatry. 2015 | Multi-center, double-blind, Randomized Controlled Trial | 175 patients studied over 4 years
Schizophrenic patients with predominantly negative symptoms (i.e. anhedonia, poverty of thought) 10-Hz rTMS treatment for 5 days per week for 3 weeks. The placebo had the same setting using a machine that looked like the rTMS but was fake |
Improvement of negative symptoms of schizophrenia after rTMS (i.e. anhedonia, poverty of thought)
Adverse effects of rTMS |
No significant difference in improvement of negative symptoms after 3 weeks (p=0.53)
Equivocal improvement of positive symptoms after 21 days (p=0.047) Application of rTMS was well tolerated |
Small sample size
Short-treatment window (3 weeks) but followed up patients up to 105 days |
Conclusion
Article 1
Transcranial magnetic stimulation is the process of applying changing magnetic fields to cause electric current to flow in a small region of the brain. This is mainly used in cases that involve altered states of cortical excitability. The magnetic field is focused on the scalp and the resulting electric current inhibits “unwanted” neural activity.
This article compared TMS vs sham (placebo), and TMS while under a stable drug regimen. The researchers also explored using different frequencies and different durations of the TMS. They used the concept of effect size (Cohen’s d) to compare the results. An effect size is a measure of a magnitude of a phenomenon. The larger the Cohen’s d, the more significant the effect of the treatment.
Pertinent to this case, when TMS was used to on patients with a stable drug regimen, the Cohen’s d decreased to 0.34 (95% CI, 0.01-0.67). This means that only 62% of the treatment group was affected. This may seem impressive, but compared to placebo, which had a Cohen’s d of 0.43 (65% affected), this actually did worse. Standard of care + TMS = worse. The researchers explained this by mentioning that patients who are already on specific drug regimens tend to have worse symptoms anyway hence a worse response. They could not make a recommendation regarding the effectiveness of TMS.
Article 2
This article mentions that antipsychotic treatment (i.e. psychotherapy, psychotropic medications) improved the negative symptoms of 1440 patients (SMD=-0.40, 95% CI= -0.62~-0.18). This is a huge study that involved a lot of patients but a number of the studies included (6) has a high risk of bias. This was determined using the GRADE classification and the SANS scale. The remaining articles were deemed acceptable but the overall heterogeneity in the study was high. This means that there is a huge variation of outcomes between the studies used. The researchers also mention adverse effects (i.e. epilepsy, headache, dizziness, insomnia, irritation, pain on stimulation site). While the researchers conclude that that there are “better acceptability and fewer adverse effects” with TMS, their statistics say otherwise with the Risk Ratio of adverse effects involved with TMS to be significantly greater than 1 (RR= 2.20, 95% CI= 1.53~ 3.18)
Article 3
This meta-analysis included 16 studies involving 348 participants. Patients were assessed for negative symptoms before and after treatment using one of 2 scales: Positive and Negative Syndrome Scale (PANSS), and SANS (Scale for the Assessment of Negative Symptoms). These scales usually involves an interview with 30 items in total. 7 items will assess for positive symptoms, 7 items will assess for negative symptoms, and 16 items will assess for a General psychopathology. After treatment, the effect size was TMS was 0.63 meaning 72.57% of the patients were affected by the treatment. They mention good predictive factors include earlier time of diagnosis, shorter symptom duration, and intensity of treatment. They mention that the best parameter of TMS is on the left dorsolateral prefrontal cortex. They also mention adverse effects such as pain present in a frequency that was defined as “acceptable”.
Article 4
This RCT is unlike the other articles because it claims that there are no significant differences between TMS and placebo in improvement of negative symptoms. The difference of this study is that TMS was only studied short-term (<3 weeks) compared to the other articles.
Clinical Bottom Line:
Transcranial magnetic stimulation in conjunction to standard of care (i.e. psychotropic meds, psychotherapy) is a safe method to decrease negative symptoms of schizophrenia. While there are more adverse effects associated with TMS (i.e. headache), these effects are minor and pose no long-lasting negative effects.
Two of the three articles support the fact that TMS as an adjunct to psychotherapy and psyche meds improve negative outcomes of schizophrenia. One randomized controlled trial, Wobrock et. Al., 2015, found significant difference in negative symptoms after rTMS. There is a slight increase of acceptable adverse effects (i.e. dizziness, pain on application site) and a non-statistically significant increase unacceptable side-effects (i.e. seizures).
Among the articles, Wang et. Al., (2017) has the most weight due to the more participants, and being more recent. It is very difficult to set up Randomized control trials in psychiatry due to both logistical and ethical concerns but Wang et. Al., included the most RCTs. While Shi et. Al., (2014) demonstrated an acceptable amount of heterogeneity in their studies, they mainly used prospective studies.
Shi et. Al., (2014), and Wang et. Al., (2017) both mention adverse effects in that common acceptable effects such as dizziness, and pain on the application site have a slight increase. This is compared to unacceptable side effects such as seizures and epilepsy. Both studies mention that there is no statistically significant increase in these so-called unacceptable effects.
Wobrock et. Al., found no significant improvement in negatives symptoms with rTMS. There was little mention of whether these patients were in stable drug regimens or not. The one thing that makes this study different is that 2 weeks before administering rTMS, they pre-treated their patients with the psychiatric standard of care (i.e. psychotherapy, psychotropic meds). The study provided good insight to short-term effects (3 weeks) of rTMS which is most likely what most people who will get rTMS due to insurance reasons.
