Efficacy of high-frequency transcranial magnetic stimulation to improve negative symptoms in patients with Schizophrenia: A meta-analysis of randomized controlled trials.

BACKGROUNDCognitive impairments are core characteristics of schizophrenia, but are largely resistant to current treatments. Several recent studies have shown that high-frequency repetitive transcranial magnetic stimulation (rTMS) of the left dor-solateral prefrontal cortex (DLPFC) can reduce negative symptoms and improve certain cognitive deficits in schizophrenia patients. However, results are inconsistent across studies.AIMTo examine if high-frequency rTMS of the DLPFC can improve visual memory deficits in patients with schizophrenia.METHODSForty-seven chronic schizophrenia patients with severe negative symptoms on stable treatment regimens were randomly assigned to receive active rTMS to the DLPFC (n = 25) or sham stimulation (n = 22) on weekdays for four consecutive weeks. Patients performed the pattern recognition memory (PRM) task from the Cambridge Neuropsychological Test Automated Battery at baseline, at the end of rTMS treatment (week 4), and 4 wk after rTMS treatment (week 8). Clinical symptoms were also measured at these same time points using the Scale for the Assessment of Negative Symptoms (SANS) and the Positive and Negative Syndrome Scale (PANSS).RESULTSThere were no significant differences in PRM performance metrics, SANS total score, SANS subscores, PANSS total score, and PANSS subscores between active and sham rTMS groups at the end of the 4-wk treatment period, but PRM performance metrics (percent correct and number correct) and changes in these metrics from baseline were significantly greater in the active rTMS group at week 8 compared to the sham group (all P < 0.05). Active rTMS treatment also significantly reduced SANS score at week 8 compared to sham treatment. Moreover, the improvement in visual memory was correlated with the reduction in negative symptoms at week 8. In contrast, there were no between-group differences in PANSS total score and subscale scores at either week 4 or week 8 (all P > 0.05).CONCLUSIONHigh-frequency transcranial magnetic stimulation improves visual memory and reduces negative symptoms in schizophrenia, but these effects are delayed, potentially due to the requirement for extensive neuroplastic changes within DLPFC networks.

AimsTraditional antipsychotic treatment improves positive symptoms in schizophrenia but has little impact on negative and cognitive symptoms. TMS is a non-invasive neuromodulation technique which has been suggested to impact negative and cognitive symptoms of schizophrenia. This systematic review critically appraised the research evaluating the effect of TMS on negative and cognitive symptoms of schizophrenia. Furthermore, we carried out a meta-analysis of randomised controlled trials of the effect of TMS on negative symptoms in schizophrenia.MethodsSystematic review was carried out according to PRISMA guidelines. Cochrane Library, Ovid Medline, Science Direct and PubMed databases were searched for relevant studies using the search terms: “transcranial magnetic stimulation” OR “TMS” OR “repetitive transcranial magnetic stimulation” OR “r-TMS” OR “theta burst stimulation” OR “TBS” AND “negative symptoms” OR “cognitive dysfunction” OR “cognitive impairment” AND “schizophrenia” OR “psychosis”. Only randomised controlled trials evaluating the effect of TMS (rTMS or iTBS, intermittent theta burst) on negative and/or cognitive symptoms in schizophrenia were selected. Thirty-three studies were included in the systematic review. The Standardised mean difference (SMD) with 95% confidence interval (CI) was calculated for each study and pooled across studies using an inverse variance random effect model.ResultsSixteen studies demonstrated significant improvement in negative symptoms with a superior effect of TMS compared with sham intervention. Eight studies showed improvement in certain domains of cognition and one study showed a delayed effect on negative symptoms. Studies which showed positive effects on negative symptoms have used similar TMS parameters such as 10 Hz over L-DLPFC (Left dorsolateral prefrontal cortex) except for a few studies. Ten studies reported negative results for negative and/or cognitive symptoms, TMS parameters and duration of treatment used varied among these studies. Overall, SMD for SANS (Scale for Assessment of Negative Symptoms) was 0.89 (95%CI: 0.46–1.32, P < 0.00001) and for PANSS-N (Positive and Negative Syndrome scale-negative) was 0.67 (95%CI: 0.22–1.12, P < 0.00001), both in favour of TMS. The heterogeneity of the included studies was high, I2- 85% for SANS and 92% for the PANSS-N subscale with a small to moderate risk of publication bias.ConclusionHigh-frequency rTMS is more effective than sham in improving negative and cognitive symptoms in schizophrenia. Our results suggest the need for well-designed randomised controlled trials with larger sample sizes and standard harmonised cognitive assessments to assess the effect of TMS on negative and cognitive symptoms to provide sufficient evidence for inclusion in routine clinical practice.

BackgroundNegative symptoms in schizophrenia are associated with lower quality of life, worse functional prognosis and poorer response to the psychopharmacological treatment [1]. Many efforts have been made to find new approaches for negative symptoms, and neuromodulation techniques may represent a solution for these patients when antipsychotics have reached their limits of efficacy [2]. Transcranial magnetic stimulation (TMS) is based on the use of alternating magnetic fields to induce electrical current in the cortical areas, being mainly used for patients with treatment-resistant depression and it is considered safe and well tolerated [3].MethodsA narrative review of data regarding the efficacy of transcranial magnetic stimulation for patients with schizophrenia with prominent negative symptoms was performed. Papers published between January 2000 and July 2019 in the main electronic databases (PubMed, Cochrane, EMBASE, CINAHL) were included in this review. The keywords used for database search were “schizophrenia” and “negative symptoms” and “transcranial magnetic stimulation” or “repetitive transcranial magnetic stimulation”.ResultsThe treatment of negative symptoms in schizophrenia with high frequency TMS has been associated with favorable results in clinical trials. The targeted zones were dorsolateral prefrontal cortex, either bilaterally or only on the left side. The results varied upon the stimulation regimen, including duration, frequency, uni- versus bilaterally application etc. Two meta-analyses were identified and their results supported an effect size from 0.58 to 0.63 [2,3]. However, negative results derived from well designed clinical trials exist, which show no difference in the Positive and Negative Syndromes Scale (PANSS) - negative symptom score between rTMS and sham rTMS [4,5]. An exploratory analysis of a large-scale trial showed the impact of rTMS on different negative symptom domains confirmed no additional beneficial effect of the actove comparative to sham rTMS [5]. Also, data exist about the potential of rTMS for increasing task-related in frontal areas in patients with schizophrenia with negative predominant symptoms, which may grant further exploration of the mechanisms underlying the effects of rTMS.DiscussionData about the efficacy of TMS in schizophrenia with negative symptoms are controversial, because both evidence to support its efficacy and its lack of efficacy exist in clinical trials. However, meta-analyses support an important size effect which may be comparable to that of the pharmacological treatment.ReferencesVasiliu O, Vasile D, Făinărea AF, et al. Analysis of risk factors for antipsychotic-resistant schizophrenia in young patients- a retrospective analysis. Romanian Journal of Military Medicine 2018;CXXI(1):25–29.Dlabac-de Lange J, Knegtering R, Aleman A. Repetitive transcranial magnetic stimulation for negative symptoms of schizophrenia: review and meta-analysis. J ClinPsychiatry 2010;71:411–418.Freitas C, Fregni F, Pascual_leone A. Meta-analysis of the effects of repetitive transcranial magnetic stimulation (rTMS) on negative and positive symptoms in schizophrenia. Schizophr Res 2009;108:11–24.Mogg A, Purvis R, Eranti S, et al. Repetitive transcranial magnetic stimulation for negative symptoms of schizophrenia: a randomized controlled pilot study. Schizophr Res 2007;93:221–228.Hansbauer M, Wobrock T, Kunze B, et al. Efficacy of high-frequency repetitive transcranial magnetic stimulation on PANSS factors in schizophrenia with predominant negative symptoms- results from an exploratory re-analysis. Psychiatry Res 2018;263:22–29.

A randomized controlled trial of sequentially bilateral prefrontal cortex repetitive transcranial magnetic stimulation in the treatment of negative symptoms in schizophrenia

Background:Repetitive transcranial magnetic stimulation (rTMS) is a promising treatment strategy for negative symptoms. However, the evidence for its efficacy is mixed, with contradictory results between studies due to lack of consensus about the optimal stimulation parameters.Aim:The present study was planned to assess the safety and efficacy of 20-Hz rTMS over left dorsolateral prefrontal cortex (Lt-DLPFC) with more robust stimulation parameters for adjunctive treatment of negative symptoms in patients with schizophrenia.Materials and Methods:Thirty patients with negative symptoms of schizophrenia (Positive and Negative Syndrome Scale [PANSS] negative subscore ≥15) were randomized to receive a 4-week treatment with either real-rTMS (n = 15) or sham-rTMS (n = 15). The study outcomes were assessed at baseline, after 5th and 20th rTMS sessions with PANSS, Scale for the Assessment of Negative Symptoms (SANS), Calgary Depression Scale for Schizophrenia, Clinical Global Impressions-Severity of illness scale, and rTMS side-effect checklist.Results:There was significantly greater reduction in negative symptoms assessed by SANS score in the real rTMS group, compared with the sham rTMS group. There was no significant difference in the rate of side-effects reported between the two groups. The rTMS treatment was well-tolerated by all the patients, except one seizure episode reported in the active group.Conclusion:The high-frequency rTMS protocol was safe and well-tolerated, provided patients prone to developing seizure were excluded by baseline electroencephalography prior to starting of the treatment. The 20-Hz rTMS over Lt-DLPFC with more robust stimulation parameters (100% motor threshold and 40,000 pulses) might be an effective augmentation strategy for the treatment of negative symptoms in schizophrenia.

BackgroundThe negative symptoms of schizophrenia are not effectively treated with antipsychotic medications. Repetitive transcranial magnetic stimulation (rTMS) is an alternative approach that may be more effective in treating negative symptoms, but there has been little research comparing the effectiveness of different rTMS stimulation protocols.ObjectiveCompare the effect of four different rTMS protocols in the treatment of the negative symptoms of schizophrenia.MethodsNinety-six patients with schizophrenia who had prominent negative symptoms were randomly assigned to four treatment groups: 10 Hz, 20 Hz, theta burst stimulation (TBS), and mock rTMS (i.e., the control group). In the first three groups, the left dorsolateral prefrontal cortex was stimulated at 80% of the motor threshold five times per week for four weeks. Before and after the treatment, evaluators who were blind to the group assignment of patients administered the Positive and Negative Syndrome Scale (PANSS), the Scale for the Assessment of Negative Symptoms (SANS) and the Treatment Emergent Symptom Scale (TESS).ResultsThree of the 96 patients dropped out during the trial (two from the control group and one from the 20 Hz group). Compared to the control group, after 4 weeks of rTMS treatment all three treatment groups had lower scores on the PANSS negative symptom subscale, the PANSS general psychopathology subscale, and the SANS. The TBS group had significantly larger reductions in these scores than the 10 Hz group and the 20 Hz group, but there were no significant differences between the 10 Hz and 20 Hz groups. There were no pre- versus post-treatment differences in the PANSS positive symptom subscale scores between the four groups. No serious adverse events occurred and there were no statistically significant differences in the TESS scores across the four groups.ConclusionsWe find that rTMS, particularly the TBS stimulation protocol for rTMS, is a safe and effective treatment method for patients with schizophrenia who have prominent negative symptoms. Longitudinal studies with large samples are needed to optimize the rTMS treatment, to identify the stimulation protocol, duration, intensity and treatment interval that provides the best therapeutic result at the lowest risk to the patient.

Neural Correlates of RTMS Treatment of Negative Symptoms

Despite advances made in treating the positive symptoms of schizophrenia, treatment of negative symptoms remains an unmet therapeutic need. Adjunctive mirtazapine has shown promise for treatment of negative symptoms in several small clinical trials. To assess the efficacy of mirtazapine as an adjunctive treatment of negative symptoms in patients with chronic schizophrenia via meta-analysis. A systematic literature review of articles in English and Spanish was conducted in November 2011 by searching PubMed, the Cochrane Library, the Clinical Trial Registry of the NIH, and SIGLE (System for Grey Literature in Europe). Free text search terms for PubMed were "schizophrenia," "negative symptoms" and "mirtazapine." Publication date was not a limitation. Studies of people with schizophrenia/schizoaffective disorder were included in the meta-analysis if they were randomized, double-blind, and used the Positive and Negative Syndrome Scale (PANSS) as an outcome measure. Nine studies were initially identified. Five studies were included in the meta-analysis; 1 study was excluded for not using the PANSS, 3 were excluded as representing duplicate publications and open-label phases of one of the selected randomized control trials. Studies varied in the quality of their selection for participants with primary negative symptoms. Three of the 5 studies showed significant improvement in negative symptoms individually. The overall analysis showed improvement in negative symptoms with an effect size of 1.00 (0.084-1.918), which was statistically significant (p=0.032). Data from the negative symptoms subscale of the PANSS from 169 subjects was used in a forest plot to illustrate the relative strength of treatment effects. The variation in standard median deviation (SMD) attributable to heterogeneity was 27.35 %, indicating a high degree of heterogeneity. This meta-analysis supports the hypothesis that adding mirtazapine to treatment with antipsychotics can improve negative symptoms in schizophrenia. However, additional studies with more stringent negative symptom selection criteria and homogeneous use of antipsychotics are needed.

BackgroundNegative symptoms in schizophrenia are associated with impairments in social and cognitive functioning leading to substantial long-term disability. Available antipsychotic treatments have demonstrated only modest benefit in the improvement of negative symptoms.ObjectiveTo compare improvements in negative symptoms among patients treated with paliperidone palmitate 3-month (PP3M) or paliperidone palmitate 1-month (PP1M) long-acting injectable (LAI) formulations.MethodsData from a randomized double-blind (DB), phase-3, non-inferiority study in patients with schizophrenia were analyzed. Following screening, patients entered a 17-week open-label (OL) phase to receive flexibly dosed PP1M followed by a 48-week DB phase where patients were randomized (1:1) to receive either PP1M or PP3M. Positive and Negative Syndrome Scale (PANSS) total scores with emphasis on 7-item negative subscale scores for PP1M vs PP3M were assessed.ResultsOf 1429 patients enrolled, 1016 were randomized to receive PP3M (n=504) or PP1M (n=512). At baseline, mean (SD) PANSS negative subscale was 23.2 (4.60) and negative symptom factor score was 22.3 (4.87), indicating moderate-to-severe negative symptoms. Negative subscale and symptoms factor scores showed continuous improvements throughout OL (15.9 [4.99]) and DB (14.9 [4.81]) phases. Mean (SD) changes from DB baseline in the PANSS negative subscale score were comparable between PP1M (–1.4 [3.67]) and PP3M (–1.4 [3.63]) treatment groups.ConclusionTreatment with PP3M or PP1M demonstrated comparable improvement in negative symptoms in patients with moderate-to-severe negative symptoms and in patients with prominent negative symptoms. Long-term treatment with PP3M demonstrated benefit, suggesting that continuous antipsychotic medication treatment for >1 year is needed to achieve greater benefit for negative symptoms.Trial RegistrationClinicalTrials.gov Identifier: NCT01515423.

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.

Negative symptoms of schizophrenia are a prominent feature of the illness, and frequently remain refractory to treatment. Dehydroepiandrosterone (DHEA), along with its sulfated form, DHEA-S, is an important circulating neurosteroid with several vital neurophysiological functions, including the regulation of neuronal excitability and function. Since the administration of DHEA has demonstrated improvement in mood, sense of well-being, interest, activity, and energy in several subpopulations, we investigate the efficacy of DHEA in the management of the negative symptoms of schizophrenia. Thirty DSM-IV-diagnosed schizophrenic patients with prominent negative symptoms (inpatients in a large referral state hospital) were randomized to receive either DHEA or placebo in double-blind fashion, in addition to regular antipsychotic medication, dose-stabilized prior to study entry. The DHEA was titrated up to a dose of 100 mg in divided doses during 6 weeks. Results indicated significant improvement in negative symptoms (P<.001), as well as in depressive (P<.05) and anxiety (P<.001) symptoms in individuals receiving DHEA. This effect was especially noted in women. The improvement in negative symptoms was independent of improvement in depression. No differences were noted on the positive symptom subscale of the Positive and Negative Syndrome Scale (PANSS) or on the total PANSS score as compared with placebo. Subjects receiving DHEA demonstrated a significant increase in DHEA (P<.05) and DHEA-S (P<.01) plasma levels, without changes in cortisol levels. Increases in DHEA and plasma DHEA-S levels were correlated with improvement in negative symptoms (P<.05), but not with improvement in depressive and anxiety symptoms. No obvious adverse effects were experienced by participating subjects. Our preliminary observations report for the first time in double-blind fashion the efficacy of DHEA augmentation in the management of negative, depressive, and anxiety symptoms of schizophrenia. The findings from this study raise important issues regarding the role of neurosteroids in general, and DHEA in particular, in the ongoing symptomatology and pharmacotherapy of schizophrenia.

Efficacy of high-frequency repetitive transcranial magnetic stimulation on PANSS factors in schizophrenia with predominant negative symptoms – Results from an exploratory re-analysis

Treatment effects of conventional approaches with antipsychotics or psychosocial interventions are limited when it comes to reducing negative and cognitive symptoms in schizophrenia. While there is emerging clinical evidence that new, augmented protocols based on theta-burst stimulation can increase rTMS efficacy dramatically in depression, data on similar augmented therapies are limited in schizophrenia. The different patterns of network impairments in subjects may underlie that some but not all patients responded to given stimulation locations. Therefore, we propose an augmented theta-burst stimulation protocol in schizophrenia by stimulating both locations connected to negative symptoms: (1) the left dorsolateral prefrontal cortex (DLPFC), and (2) the vermis of the cerebellum. Ninety subjects with schizophrenia presenting negative symptoms and aging between 18 and 55years will be randomized to active and sham stimulation in a 1:1 ratio. The TBS parameters we adopted follow the standard TBS protocols, with 3-pulse 50-Hz bursts given every 200ms (at 5Hz) and an intensity of 100% active motor threshold. We plan to deliver 1800 stimuli to the left DLPFC and 1800 stimuli to the vermis daily in two 9.5-min blocks for 4weeks. The primary endpoint is the change in negative symptom severity measured by the Positive and Negative Syndrome Scale (PANSS). Secondary efficacy endpoints are changes in cognitive flexibility, executive functioning, short-term memory, social cognition, and facial emotion recognition. The difference between study groups will be analyzed by a linear mixed model analysis with the difference relative to baseline in efficacy variables as the dependent variable and treatment group, visit, and treatment-by-visit interaction as independent variables. The safety outcome is the number of serious adverse events. This is a double-blind, sham-controlled, randomized medical device study to assess the efficacy and safety of an augmented theta-burst rTMS treatment in schizophrenia. We hypothesize that social cognition and negative symptoms of patients on active therapy will improve significantly compared to patients on sham treatment. The study protocol is registered at "ClinicalTrials.gov" with the following ID: NCT05100888. All items from the World Health Organization Trial Registration Data Set are registered. Initial release: 10/19/2021.

Effects of rTMS on cognitive and negitive symptoms of schizophrenia: A randomized double-blind sham-controlled study

The effect of bilateral high-definition γ-tACS on negative symptoms and mismatch negativity in schizophrenia.