Transcranial Magnetic Stimulation for the Treatment of Schizophrenia
EXECUTIVE SUMMARY
Background: Schizophrenia is a serious psychiatric condition that sometimes condition which is sometimes resistant to medications or nonpharmacologic treatment. Transcranial magnetic stimulation (TMS) has been investigated as a treatment for certain symptoms of schizophrenia.
Objective: This Assessment will review the available evidence to determine if TMS therapy is effective as an adjunct treatment for schizophrenia.
Search methods: A search of the MEDLINE® database (via PubMed) was completed for the period up through May 2011. The search strategy used the terms “transcranial magnetic” and “schizophrenia” as textwords or subject terms. Articles were limited to those published in English language and enrolling human subjects. The MEDLINE® search was supplemented by an examination of article bibliographies and relevant review articles, which were searched for citations.
Study selection: The search was intended to identify randomized sham-controlled studies of TMS. To that end, meta-analyses of such trials were searched for and selected. Five meta-analyses were identified. Randomized sham-controlled clinical trials in which assessments were carried out beyond the period of treatment with TMS were also selected for review.
Main results: One meta-analysis of 10 studies examining the effect of TMS on positive symptoms of schizophrenia did not find a significant summary effect size of TMS. Of 3 meta-analyses including 5-9 studies examining the effect of TMS on negative symptoms of schizophrenia, one of the studies showed a significant effect size of 0.43(CI .05-.80). Of 4 meta-analyses including 7 to 10 studies examining the effect of TMS on auditory hallucinations, all showed a significant effect size of TMS ranging from 0.51 to 1.0. In these meta-analyses, outcomes of TMS were all evaluated at the end point of treatment. Thus the meta-analytic findings do not address the durability of the effect of TMS. The outcome of a mean effect or average difference cannot easily be translated into assessments of clinical response or clinical significance.
Of the 3 trials of high-frequency TMS for patients with predominantly negative symptoms, one of the trials showed a statistically significant improvement in negative symptoms at the end of treatment and at an assessment 4 weeks afterward. One of these trials included a treatment arm of low-frequency TMS, which did not show any effect on negative symptoms.
Of the 5 trials of low-frequency TMS in patients with resistant auditory hallucinations, none of the studies found a statistically significant effect of TMS on auditory hallucinations at the end point of treatment, and one found a statistically significant difference at final follow-up 7 weeks after treatment. One study found a statistically significant effect on an overall symptom scale at the end of treatment and at last follow-up. The one study showing an effect on auditory hallucinations used an unknown assessment instrument for hallucinations, showed atypical effects of TMS on positive and negative symptoms, and atypical improvements in symptoms beyond the treatment period. Of the studies that did not find an effect of TMS, one was the largest sham-controlled clinical trial of TMS and included a treatment arm which used functional MRI to more precisely locate the area of treatment.
Authors’ comments and conclusions: Although meta-analyses would suggest that there is at least a short-term effect of TMS on auditory hallucinations, such effects were not observed in a review of the subset of studies which attempted to examine more long-term outcomes of TMS. None of these studies showed statistically significant effects of TMS on auditory hallucinations at the end of treatment, and only one found a difference at final follow-up. Several of these clinical trials were published after the meta-analyses were published. Most of the studies of TMS are very small trials. The outcomes are assessed using a variety of assessment instruments.
Based on the available evidence, the Blue Cross and Blue Shield Association Medical Advisory Panel made the following judgments about whether TMS for the treatment of schizophrenia meets the Blue Cross and Blue Shield Association Technology Evaluation Center (TEC) criteria.
1. The technology must have final approval from the appropriate governmental regulatory bodies.
TMS does not have approval for schizophrenia indications. Devices for transcranial stimulation have received clearance by the U.S. Food and Drug Administration (FDA) for diagnostic uses. One device, NeoPulse (Neuronetics, Atlanta, GA) received approval in Canada and Israel as a therapy for depression. Although initially examined by the U.S. Food and Drug Administration (FDA) under a 510(k) application, the NeoPulse, now known as NeuroStar® TMS, received clearance for marketing as a “de novo” device in 2008. NeuroStar® TMS is indicated for the treatment of patients with depression who have failed one 6-week course of antidepressant medication.
2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes.
An important limitation of the evidence is lack of information beyond the acute period of treatment. Most of the clinical trials evaluate the outcomes at the point of the last TMS treatment, between 1 and 4 weeks. Relatively few studies evaluated patients beyond this time period. Although meta-analyses are consistent with short-term effects on auditory hallucinations, the clinical significance of the effect is uncertain.
3. The technology must improve the net health outcome; and
4. The technology must be as beneficial as any established alternatives.
The available evidence is insufficient to demonstrate that TMS is effective in the treatment of schizophrenia. Although 4 meta-analyses showed a significant effect on auditory hallucinations, the clinical significance of this outcome is uncertain, both in magnitude and duration of effect, since the outcomes were only assessed at the end of treatment.
Of the randomized clinical trials in which assessment was carried out beyond the time point of treatment, 1 of 4 trials of high-frequency TMS showed a significant mean difference on a negative symptom scale, an effect observed 4 weeks beyond treatment. Of 5 trials of low-frequency TMS for auditory hallucinations, one study showed a significant effect at the final follow-up time. This particular study had other anomalous findings, such as an effect on positive and negative symptoms, and further improvements beyond the time point of treatment.
5. The improvement must be attainable outside the investigational settings.
It has not yet been demonstrated whether TMS improves health outcomes in the investigational setting. Therefore, it cannot be demonstrated whether improvement is attainable outside the investigational settings.
For the above reasons, transcranial magnetic stimulation for the treatment of schizophrenia does not meet the TEC criteria.
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NOTICE OF PURPOSE: TEC Assessments are scientific opinions, provided solely for informational purposes. TEC Assessments should not be construed to suggest that the Blue Cross Blue Shield Association, Kaiser Permanente Medical Care Program or the TEC Program recommends, advocates, requires, encourages, or discourages any particular treatment, procedure, or service; any particular course of treatment, procedure, or service; or the payment or non-payment of the technology or technologies evaluated.
