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The effect of transcranial direct current stimulation on auditory hallucination in patients with schizophrenia
SCHRES-07344; No of Pages 2 Schizophrenia Research xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Schizophrenia Research journal homepage: www.elsevier.com/locate/schres
Letter to the Editor The effect of transcranial direct current stimulation on auditory hallucination in patients with schizophrenia Keywords: tDCS Brain stimuation Schizophrenia Hallucination Age
Approximately 75% of patients with schizophrenia experience auditory hallucinations, and many of these patients do not respond to longterm antipsychotic therapy. Recently, tDCS has attracted attention as a novel brain stimulation technique for treating patients with schizophrenia (Hasan et al., 2015). Brunelin et al. (2012) conducted the first randomized controlled trial of tDCS for reducing auditory verbal hallucinations. In this study, hallucination symptoms were significantly improved by active tDCS treatment compared with sham tDCS. However, conflicting findings indicating that bimodal tDCS treatment did not significantly improve hallucinatory symptoms have also been obtained (Fitzgerald et al., 2014). Although there remains controversy regarding the effectiveness of tDCS for auditory hallucinations in patients with schizophrenia, the pooled effects size of tDCS and the effects of within-participant variability have not yet been sufficiently investigated. A systematic search strategy was used to identify relevant studies on the PubMed, Embase, and Web of Science databases for articles published from database inception to April 2016. The following keywords, including synonyms and combinations, were used as search terms: “tDCS”, “transcranial direct current stimulation”, “schizophrenia”, “psychosis”, “psychotic disorder” and “hallucination”. Studies were included if they satisfied the following criteria: (1) articles written in English; (2) sham-controlled trials or open-label trials; (3) original articles, short communications or letters in peer-reviewed journals; (4) studies that included schizophrenia subjects; (5) auditory hallucination outcome measures that used the Positive and Negative Syndrome Scale (PANSS), the Auditory Hallucination Rating Scale (AHRS) or the Auditory Hallucination Subscale (AHS) of the Psychotic Symptom Rating Scales (PSYRATS). In cases involving overlapping samples, the study with the largest sample size was included. Pooled effect size was computed based on changes in hallucinatory symptom severities during the tDCS treatment. The meta-regression analysis assessed the modulating effects of age, gender, education year, and intelligence quotient (IQ); 1000 permutations were performed. In total, 3 sham-controlled trials and 3 open trials (n = 106) were included in this meta-analysis (Table 1; Supplementary Fig. 1). We found that the combined effect size was high (Hedges' g = 0.919; 95% CI = 0.636–1.202); in addition, the Higgins I2 test indicated moderately significant heterogeneity in the effect of tDCS (I2 = 67.9%, p = 0.008). When we conducted meta-regression analyses with 1000 permutations
to examine the potential roles of demographic and clinical variables in explaining heterogeneity across studies, we did not found the significant variables, but age was only variable which showed the trend level (p = 0.09, SE = 0.03). To our knowledge, this is the first study to investigate the meta-analytic result of the effect of tDCS on auditory hallucination in patients with schizophrenia. Consistent with earlier reviews, we found positive treatment effect of tDCS on auditory hallucination. Prior studies have indicated that gray matter volume reduction, cortical thinning, or hypoactivation in the frontal cortex are observed in patients with schizophrenia (Allen et al., 2012). In contrast, hyperactivation in temporal regions has been observed in patients with schizophrenia who were experiencing hallucinations (Jardri et al., 2011). These findings suggest that tDCS with an anode and a cathode would be useful in the treatment of schizophrenia patients suffering from auditory hallucinations. In meta-regression analysis, we found that the age of participants accounts for the variability of outcomes in trend level. Although we did not perform a meta-regression analysis of age at enrollment and duration of illness due to a lack of details in the included studies, this prior result suggests that the clinical characteristics of patients with schizophrenia, such as duration of illness, affect outcomes, may influence the effects of tDCS. Previously, the number of tDCS studies has focused on patients with chronic auditory hallucinations who did not respond to longterm antipsychotic medication. Moreover, there exists little evidence regarding treatment response in cases involving early-onset schizophrenia or first-episode psychosis (Palm et al., 2016). Therefore, to investigate the therapeutic effect of tDCS, additional well-designed randomized control trials that include young patients with early-stage schizophrenia should be performed. Several limitations of the present study should be addressed. First, this analysis includes open-label trials. Thus, we have not excluded confounders. Second, it is difficult to conclude that factors other than age do not affect treatment response given our analysis of an insufficient number of studies and the lack of details reported in the included articles. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.schres.2017.06.012.
Contributors Authors Jun Soo Kwon and Tae Young Lee were responsible for the design of the whole study and wrote the protocol. Author Tae Young Lee wrote the manuscript. Authors Tae Young Lee, Junhee Lee, and Minah Kim supported the analysis, interpretation and manuscript revision. All authors contributed and approved the final manuscript.
Role of funding source This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (NRF-2015R1C1A1A01053988) and (NRF-2017M3C7A1029610).
Conflict of interest None.
http://dx.doi.org/10.1016/j.schres.2017.06.012 0920-9964/© 2017 Elsevier B.V. All rights reserved.
Please cite this article as: Lee, T.Y., et al., The effect of transcranial direct current stimulation on auditory hallucination in patients with schizophrenia, Schizophr. Res. (2017), http://dx.doi.org/10.1016/j.schres.2017.06.012
2
Letter to the Editor
Table 1 Characteristics of participants in eligible studies. Studies
Agarwal et al. (2016) Brunelin et al. (2012) Brunelin et al. (2015) Fitzgerald et al. (2014) Frohlich et al. (2016) Smith et al. (2015)
N
36 15 16 11 13 15
Age mean (S.D.)
Female (%)
Duration of illness mean (S.D.)
Medication mean (S.D.)
Hallucination scale score Baseline
Follow-up
33.2 (12.6) 40.4 (9.9) 41 (10.3) 39.3 (11.7) 43.4 (12.6) 46.8 (11.1)
58.3
10.5 (10.5)
62.5 37.5 39.3 17.6
18.6 (12.6) 16.1 (3.3)
712.6 (599.3) 804.3 (368) 994 (714)
31.3 (4.8)a 28.3 (3.5)b 25.8 (5.4)a 3.6 (2.3)c 27 (6.9)b 2.6 (1.8)c
21.1 (8.9)a 19.9 (5.8)b 20.3 (6.7)a 3.0 (2.1)c 20.6 (8.1)b 2.5 (1.8)c
Effect size (Hedges' g) 1.411 1.706 0.881 0.262 0.823 0.054
Medication, chlorpromazine equivalent dose (mg). a Auditory Hallucination Rating Scale. b Auditory Hallucinations Subscale of the Psychotic Symptom Rating Scales. c Hallucinatory behavior determined using the Positive and Negative Syndrome Scale.
Acknowledgement
We thank In-Young Ahn, Shin-ae Yeom for literature searching. We also thank the authors of the study that sent the necessary details for the analysis. References Agarwal, S.M., Bose, A., Shivakumar, V., Narayanaswamy, J.C., Chhabra, H., Kalmady, S.V., Varambally, S., Nitsche, M.A., Venkatasubramanian, G., Gangadhar, B.N., 2016. Impact of antipsychotic medication on transcranial direct current stimulation (tDCS) effects in schizophrenia patients. Psychiatry Res. 235, 97–103. Allen, P., Modinos, G., Hubl, D., Shields, G., Cachia, A., Jardri, R., Thomas, P., Woodward, T., Shotbolt, P., Plaze, M., Hoffman, R., 2012. Neuroimaging auditory hallucinations in schizophrenia: from neuroanatomy to neurochemistry and beyond. Schizophr. Bull. 38, 695–703. Brunelin, J., Mondino, M., Gassab, L., Haesebaert, F., Gaha, L., Suaud-Chagny, M.F., Saoud, M., Mechri, A., Poulet, E., 2012. Examining transcranial direct-current stimulation (tDCS) as a treatment for hallucinations in schizophrenia. Am. J. Psychiatry 169, 719–724. Brunelin, J., Hasan, A., Haesebaert, F., Nitsche, M.A., Poulet, E., 2015. Nicotine smoking prevents the effects of frontotemporal transcranial direct current stimulation (tDCS) in hallucinating patients with schizophrenia. Brain Stimul. 8, 1225–1227. Fitzgerald, P.B., McQueen, S., Daskalakis, Z.J., Hoy, K.E., 2014. A negative pilot study of daily bimodal transcranial direct current stimulation in schizophrenia. Brain Stimul. 7, 813–816. Fröhlich, F., Burrello, T.N., Mellin, J.M., Cordle, A.L., Lustenberger, C.M., Gilmore, J.H., Jarskog, L.F., 2016. Exploratory study of once-daily transcranial direct current stimulation (tDCS) as a treatment for auditory hallucinations in schizophrenia. Eur. Psychiatry. 33, 54–60. Hasan, A., Wobrock, T., Palm, U., Strube, W., Padberg, F., Falkai, P., Fallgatter, A., Plewnia, C., 2015. Non-invasive brain stimulation for treatment of schizophrenic psychoses. Nervenarzt 86, 1481–1491. Jardri, R., Pouchet, A., Pins, D., Thomas, P., 2011. Cortical activations during auditory verbal hallucinations in schizophrenia: a coordinate-based meta-analysis. Am. J. Psychiatry 168, 73–81.
Palm, U., Segmiller, F.M., Epple, A.N., Freisleder, F.J., Koutsouleris, N., Schulte-Korne, G., Padberg, F., 2016. Transcranial direct current stimulation in children and adolescents: a comprehensive review. J. Neural Transm. (Vienna) 123, 1219–1234. Smith, R.C., Boules, S., Mattiuz, S., Youssef, M., Tobe, R.H., Sershen, H., Lajtha, A., Nolan, K., Amiaz, R., Davis, J.M., 2015. Effects of transcranial direct current stimulation (tDCS) on cognition, symptoms, and smoking in schizophrenia: a randomized controlled study. Schizophr. Res. 168, 260–266.
Tae Young Lee Junhee Lee Minah Kim Department of Psychiatry, Seoul National University, College of Medicine, Seoul, Republic of Korea Jun Soo Kwon Department of Psychiatry, Seoul National University, College of Medicine, Seoul, Republic of Korea Department of Brain and Cognitive Science, Seoul National University, College of Natural Science, Seoul, Republic of Korea Corresponding author at: Department of Psychiatry, Seoul National University, College of Medicine, 101 Daehak-no, Chongno-gu, Seoul 110-744, Republic of Korea. E-mail address: [email protected]. 5 February 2017 Available online xxxx
Please cite this article as: Lee, T.Y., et al., The effect of transcranial direct current stimulation on auditory hallucination in patients with schizophrenia, Schizophr. Res. (2017), http://dx.doi.org/10.1016/j.schres.2017.06.012
Contents lists available at ScienceDirect
Schizophrenia Research journal homepage: www.elsevier.com/locate/schres
Letter to the Editor The effect of transcranial direct current stimulation on auditory hallucination in patients with schizophrenia Keywords: tDCS Brain stimuation Schizophrenia Hallucination Age
Approximately 75% of patients with schizophrenia experience auditory hallucinations, and many of these patients do not respond to longterm antipsychotic therapy. Recently, tDCS has attracted attention as a novel brain stimulation technique for treating patients with schizophrenia (Hasan et al., 2015). Brunelin et al. (2012) conducted the first randomized controlled trial of tDCS for reducing auditory verbal hallucinations. In this study, hallucination symptoms were significantly improved by active tDCS treatment compared with sham tDCS. However, conflicting findings indicating that bimodal tDCS treatment did not significantly improve hallucinatory symptoms have also been obtained (Fitzgerald et al., 2014). Although there remains controversy regarding the effectiveness of tDCS for auditory hallucinations in patients with schizophrenia, the pooled effects size of tDCS and the effects of within-participant variability have not yet been sufficiently investigated. A systematic search strategy was used to identify relevant studies on the PubMed, Embase, and Web of Science databases for articles published from database inception to April 2016. The following keywords, including synonyms and combinations, were used as search terms: “tDCS”, “transcranial direct current stimulation”, “schizophrenia”, “psychosis”, “psychotic disorder” and “hallucination”. Studies were included if they satisfied the following criteria: (1) articles written in English; (2) sham-controlled trials or open-label trials; (3) original articles, short communications or letters in peer-reviewed journals; (4) studies that included schizophrenia subjects; (5) auditory hallucination outcome measures that used the Positive and Negative Syndrome Scale (PANSS), the Auditory Hallucination Rating Scale (AHRS) or the Auditory Hallucination Subscale (AHS) of the Psychotic Symptom Rating Scales (PSYRATS). In cases involving overlapping samples, the study with the largest sample size was included. Pooled effect size was computed based on changes in hallucinatory symptom severities during the tDCS treatment. The meta-regression analysis assessed the modulating effects of age, gender, education year, and intelligence quotient (IQ); 1000 permutations were performed. In total, 3 sham-controlled trials and 3 open trials (n = 106) were included in this meta-analysis (Table 1; Supplementary Fig. 1). We found that the combined effect size was high (Hedges' g = 0.919; 95% CI = 0.636–1.202); in addition, the Higgins I2 test indicated moderately significant heterogeneity in the effect of tDCS (I2 = 67.9%, p = 0.008). When we conducted meta-regression analyses with 1000 permutations
to examine the potential roles of demographic and clinical variables in explaining heterogeneity across studies, we did not found the significant variables, but age was only variable which showed the trend level (p = 0.09, SE = 0.03). To our knowledge, this is the first study to investigate the meta-analytic result of the effect of tDCS on auditory hallucination in patients with schizophrenia. Consistent with earlier reviews, we found positive treatment effect of tDCS on auditory hallucination. Prior studies have indicated that gray matter volume reduction, cortical thinning, or hypoactivation in the frontal cortex are observed in patients with schizophrenia (Allen et al., 2012). In contrast, hyperactivation in temporal regions has been observed in patients with schizophrenia who were experiencing hallucinations (Jardri et al., 2011). These findings suggest that tDCS with an anode and a cathode would be useful in the treatment of schizophrenia patients suffering from auditory hallucinations. In meta-regression analysis, we found that the age of participants accounts for the variability of outcomes in trend level. Although we did not perform a meta-regression analysis of age at enrollment and duration of illness due to a lack of details in the included studies, this prior result suggests that the clinical characteristics of patients with schizophrenia, such as duration of illness, affect outcomes, may influence the effects of tDCS. Previously, the number of tDCS studies has focused on patients with chronic auditory hallucinations who did not respond to longterm antipsychotic medication. Moreover, there exists little evidence regarding treatment response in cases involving early-onset schizophrenia or first-episode psychosis (Palm et al., 2016). Therefore, to investigate the therapeutic effect of tDCS, additional well-designed randomized control trials that include young patients with early-stage schizophrenia should be performed. Several limitations of the present study should be addressed. First, this analysis includes open-label trials. Thus, we have not excluded confounders. Second, it is difficult to conclude that factors other than age do not affect treatment response given our analysis of an insufficient number of studies and the lack of details reported in the included articles. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.schres.2017.06.012.
Contributors Authors Jun Soo Kwon and Tae Young Lee were responsible for the design of the whole study and wrote the protocol. Author Tae Young Lee wrote the manuscript. Authors Tae Young Lee, Junhee Lee, and Minah Kim supported the analysis, interpretation and manuscript revision. All authors contributed and approved the final manuscript.
Role of funding source This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (NRF-2015R1C1A1A01053988) and (NRF-2017M3C7A1029610).
Conflict of interest None.
http://dx.doi.org/10.1016/j.schres.2017.06.012 0920-9964/© 2017 Elsevier B.V. All rights reserved.
Please cite this article as: Lee, T.Y., et al., The effect of transcranial direct current stimulation on auditory hallucination in patients with schizophrenia, Schizophr. Res. (2017), http://dx.doi.org/10.1016/j.schres.2017.06.012
2
Letter to the Editor
Table 1 Characteristics of participants in eligible studies. Studies
Agarwal et al. (2016) Brunelin et al. (2012) Brunelin et al. (2015) Fitzgerald et al. (2014) Frohlich et al. (2016) Smith et al. (2015)
N
36 15 16 11 13 15
Age mean (S.D.)
Female (%)
Duration of illness mean (S.D.)
Medication mean (S.D.)
Hallucination scale score Baseline
Follow-up
33.2 (12.6) 40.4 (9.9) 41 (10.3) 39.3 (11.7) 43.4 (12.6) 46.8 (11.1)
58.3
10.5 (10.5)
62.5 37.5 39.3 17.6
18.6 (12.6) 16.1 (3.3)
712.6 (599.3) 804.3 (368) 994 (714)
31.3 (4.8)a 28.3 (3.5)b 25.8 (5.4)a 3.6 (2.3)c 27 (6.9)b 2.6 (1.8)c
21.1 (8.9)a 19.9 (5.8)b 20.3 (6.7)a 3.0 (2.1)c 20.6 (8.1)b 2.5 (1.8)c
Effect size (Hedges' g) 1.411 1.706 0.881 0.262 0.823 0.054
Medication, chlorpromazine equivalent dose (mg). a Auditory Hallucination Rating Scale. b Auditory Hallucinations Subscale of the Psychotic Symptom Rating Scales. c Hallucinatory behavior determined using the Positive and Negative Syndrome Scale.
Acknowledgement
We thank In-Young Ahn, Shin-ae Yeom for literature searching. We also thank the authors of the study that sent the necessary details for the analysis. References Agarwal, S.M., Bose, A., Shivakumar, V., Narayanaswamy, J.C., Chhabra, H., Kalmady, S.V., Varambally, S., Nitsche, M.A., Venkatasubramanian, G., Gangadhar, B.N., 2016. Impact of antipsychotic medication on transcranial direct current stimulation (tDCS) effects in schizophrenia patients. Psychiatry Res. 235, 97–103. Allen, P., Modinos, G., Hubl, D., Shields, G., Cachia, A., Jardri, R., Thomas, P., Woodward, T., Shotbolt, P., Plaze, M., Hoffman, R., 2012. Neuroimaging auditory hallucinations in schizophrenia: from neuroanatomy to neurochemistry and beyond. Schizophr. Bull. 38, 695–703. Brunelin, J., Mondino, M., Gassab, L., Haesebaert, F., Gaha, L., Suaud-Chagny, M.F., Saoud, M., Mechri, A., Poulet, E., 2012. Examining transcranial direct-current stimulation (tDCS) as a treatment for hallucinations in schizophrenia. Am. J. Psychiatry 169, 719–724. Brunelin, J., Hasan, A., Haesebaert, F., Nitsche, M.A., Poulet, E., 2015. Nicotine smoking prevents the effects of frontotemporal transcranial direct current stimulation (tDCS) in hallucinating patients with schizophrenia. Brain Stimul. 8, 1225–1227. Fitzgerald, P.B., McQueen, S., Daskalakis, Z.J., Hoy, K.E., 2014. A negative pilot study of daily bimodal transcranial direct current stimulation in schizophrenia. Brain Stimul. 7, 813–816. Fröhlich, F., Burrello, T.N., Mellin, J.M., Cordle, A.L., Lustenberger, C.M., Gilmore, J.H., Jarskog, L.F., 2016. Exploratory study of once-daily transcranial direct current stimulation (tDCS) as a treatment for auditory hallucinations in schizophrenia. Eur. Psychiatry. 33, 54–60. Hasan, A., Wobrock, T., Palm, U., Strube, W., Padberg, F., Falkai, P., Fallgatter, A., Plewnia, C., 2015. Non-invasive brain stimulation for treatment of schizophrenic psychoses. Nervenarzt 86, 1481–1491. Jardri, R., Pouchet, A., Pins, D., Thomas, P., 2011. Cortical activations during auditory verbal hallucinations in schizophrenia: a coordinate-based meta-analysis. Am. J. Psychiatry 168, 73–81.
Palm, U., Segmiller, F.M., Epple, A.N., Freisleder, F.J., Koutsouleris, N., Schulte-Korne, G., Padberg, F., 2016. Transcranial direct current stimulation in children and adolescents: a comprehensive review. J. Neural Transm. (Vienna) 123, 1219–1234. Smith, R.C., Boules, S., Mattiuz, S., Youssef, M., Tobe, R.H., Sershen, H., Lajtha, A., Nolan, K., Amiaz, R., Davis, J.M., 2015. Effects of transcranial direct current stimulation (tDCS) on cognition, symptoms, and smoking in schizophrenia: a randomized controlled study. Schizophr. Res. 168, 260–266.
Tae Young Lee Junhee Lee Minah Kim Department of Psychiatry, Seoul National University, College of Medicine, Seoul, Republic of Korea Jun Soo Kwon Department of Psychiatry, Seoul National University, College of Medicine, Seoul, Republic of Korea Department of Brain and Cognitive Science, Seoul National University, College of Natural Science, Seoul, Republic of Korea Corresponding author at: Department of Psychiatry, Seoul National University, College of Medicine, 101 Daehak-no, Chongno-gu, Seoul 110-744, Republic of Korea. E-mail address: [email protected]. 5 February 2017 Available online xxxx
Please cite this article as: Lee, T.Y., et al., The effect of transcranial direct current stimulation on auditory hallucination in patients with schizophrenia, Schizophr. Res. (2017), http://dx.doi.org/10.1016/j.schres.2017.06.012