Entertainment & Media

A pilot double-blind sham-controlled trial of repetitive transcranial magnetic stimulation for patients with refractory schizophrenia treated with clozapine

A pilot double-blind sham-controlled trial of repetitive transcranial magnetic stimulation for patients with refractory schizophrenia treated with clozapine
of 5
All materials on our website are shared by users. If you have any questions about copyright issues, please report us to resolve them. We are always happy to assist you.
Related Documents
  A pilot double-blind sham-controlled trial of repetitive transcranial magneticstimulation for patients with refractory schizophrenia treated with clozapine Danilo Rocha de Jesus a, ⁎ , Alexei Gil a , Leonardo Barbosa a , Maria Inês Lobato a ,Pedro Vieira da Silva Magalhães a , Gabriela Pereira de Souza Favalli a , Marco Antonio Marcolin b ,Za fi ris Jeffrey Daskalakis c , Paulo da Silva Belmonte-de-Abreu a a Department of Psychiatry, Federal University of Rio Grande do Sul-RS, Brazil b Institute of Psychiatry, University of Sao Paulo, Faculty of Medicine, Sao Paulo-SP, Brazil c Schizophrenia Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada a b s t r a c ta r t i c l e i n f o  Article history: Received 20 May 2010Received in revised form 17 November 2010Accepted 17 November 2010 Keywords: Auditory hallucinationsrTMSClinical TrialGeneral psychopathologyQuality of life Schizophrenia is a complex and heterogeneous psychiatric disorder. Auditory verbal hallucinations occur in50 – 70% of patients with schizophrenia and are associated with signi fi cant distress, decreased quality of lifeand impaired social functioning. This study aimed to investigate the effects of active compared with sham 1-Hzrepetitive transcranial magneticstimulation (rTMS)appliedtothelefttemporal-parietal cortex inpatientswith schizophrenia treated with clozapine. Symptom dimensions that were evaluated included generalpsychopathology,severityofauditory hallucinations, quality oflifeandfunctionality. Seventeen right-handedpatientswithrefractoryschizophreniaexperiencingauditoryverbalhallucinationsandtreatedwithclozapinewere randomly allocated to receive either active rTMS or sham stimulation. A total of 384 min of rTMS wasadministered over 20 days using a double-masked, sham-controlled, parallel design. There was a signi fi cantreduction in Brief Psychiatric Rating Scale (BPRS) scores in the active group compared with the shamgroup. There was no signi fi cant difference between active and sham rTMS on Quality of Life Scale (QLS),Auditory Hallucinations Rating Scale (AHRS), Clinical Global Impressions (CGI) and functional assessmentstaging (FAST) scores. Compared with sham stimulation, active rTMS of the left temporoparietal cortex inclozapine-treatedpatientsshowedapositiveeffectongeneralpsychopathology.However,therewasnoeffecton refractory auditory hallucinations. Further studies with larger sample sizes are needed to con fi rm these fi ndings.© 2010 Elsevier Ireland Ltd. All rights reserved. 1. Introduction Schizophrenia is a complex and heterogeneous psychiatricdisorder. It is known that about 30% of the patients with schizophre-nia do not respond adequately to pharmacological treatment. In thiscontext, refractory criteria were developed. The SchizophreniaAlgorithm of the International Psychopharmacology Algorithm Proj-ect (IPAP) de fi nes that a patient is considered to be refractory if he orshe failed to respond to two trials of 4 to 6 weeks' duration of monotherapy with two different second generation antipsychotics(SGAs) (or two trials with a  fi rst generation antipsychotic (FGA), if SGAs are not available). For these patients, treatment with clozapinemay be considered.Auditoryhallucinations(AHs)ofspokenspeechoccurin50 – 70%of patients with schizophrenia and often produce high levels of distressand functional disability. It is known that 25% of these patients sufferfrom refractory AHs (Shergill et al., 1998). Neuroimaging studies suggest that activation of brain regions underlying speech perceptionplay a role in producing AHs (Dierks et al., 1999; Shergill et al., 2000;Suzuki et al., 1993; Silbersweig et al., 1995; Lennox et al., 2000;Woodruff et al., 1994, 1997). Low frequency repetitive transcranialmagnetic stimulation (e.g., 1 Hz rTMS) has been shown to reduceexcitability of the cortex (Chen et al., 1997). Therefore, when applied to the left temporoparietal cortex (LTPC), it may reduce theexcitability of this area, which is critical to speech perception (Fiezet al., 1996) and has been implicated in the genesis of AHs(Silbersweig et al., 1995; Lennox et al., 2000). In animal studies, 1 Hz rTMS can produce similar effects to long-term depression, andthey can last many weeks (Post et al., 1999; for review see Hoffman and Cavus, 2002). Previous studies have shown that 1 Hz rTMSappliedto the LTPCcanreduce the severityof the AHs(Hoffmanet al.,2000, 2005; Rosa et al., 2007; Poulet et al., 2005; Fitzgerald et al.,2005; Vercammen et al., 2009). A recent review conducted byFitzgerald and Daskalakis (2008) found that rTMS may be able tosubstantially reduce the experience of auditory hallucinations inpatients for whom symptoms persist despite optimal medication Psychiatry Research 188 (2011) 203 – 207 ⁎  Corresponding author. Postal address: 19 Princess Street, Toronto, Ontario, Canada,Zip code: M5A 4C8. Tel.: +1 647 860 7227. E-mail address:  danilorocha@hotmail.com (D.R. de Jesus).0165-1781/$  –  see front matter © 2010 Elsevier Ireland Ltd. All rights reserved.doi:10.1016/j.psychres.2010.11.022 Contents lists available at ScienceDirect Psychiatry Research  journal homepage: www.elsevier.com/locate/psychres  treatment. Vercammen et al. (2009) conducted a study in which 38patients with schizophrenia suffering from frequent medication-resistant AHs were randomly allocated to receive left-sided rTMS,bilateralrTMSorsham.Theyfoundthatcomparedtobilateralorshamstimulation, rTMS of the left temporoparietal region appears mosteffective in reducing auditory hallucinations, and additionally mayhave an effect on general psychopathology. Rosa et al. (2007)conducted a double-masked, sham-controlled, parallel design studycomparing 1 Hz rTMS applied to the LTPC to sham stimulation inassociation with clozapine treatment. Eleven patients were enrolled.Rosa et al. concluded that active rTMS in association with clozapinecan be administered safely to treat auditory hallucinations, althoughits clinical utility was considered questionable. That is, no signi fi cantclinical effects were observed in the sample studied, possibly becauseof the small sample and/or due to the high degree of refractoriness inthe patients.The purpose of this study was to examine the effects of 1 Hz rTMSapplied to the LTPC in a larger sample size ( n =17) of clozapine-treatedpatientswithrefractoryschizophrenia(RS)usinganextendedrTMSprotocol.Moreover, wealso examinedgeneralpsychopathologyseverity, quality of life and functionality in these patients, as rTMSmay have both regional and distant cortical effects as a result of interhemispheric transsynaptic signal propagation (Ilmoniemi et al.,1997) that may translate into a broad improvement in psychoticsymptoms. 2. Methods  2.1. Subjects Patients met diagnostic criteria for schizophrenia (using OPCRIT 4.0) and wereconsidered as having RS, with daily AHs occurring at least  fi ve times per day despitetreatmentwithastabledoseofatleast400 mg/dayofclozapineforaperiodlongerthan4 months and at least two adequate trials of antipsychotic medications in the past,including at least one atypical antipsychotic drug other than clozapine. Subjects wereall right-handed (self-reported), men and women from 18 to 65 years old, with a Brief Psychiatric Rating Scale (BPRS) score of at least 27. Women in fertile age must havebeen using an appropriate contraceptive method. Exclusion criteria included suiciderisk, pregnancy, prior history of seizures, neurosurgery or head trauma, use of pacemaker or intracranial metallic clip, neurological disease, signi fi cant unstablemedical condition, estimated IQ  ≤ 80, current alcohol or drug abuse, or inability toprovide informed consent. A total of 17 patients were enrolled. All patients were naiveto rTMS treatments. The study protocol was approved by the Ethics Committee of Hospital de Clínicas de Porto Alegre. A signed, informed consent was obtained fromevery patient. At baseline, the two groups were similar in terms of gender, income,number of psychiatric hospitalizations, age of onset of auditory hallucinations, dosageof clozapine, BPRS, FAST, Quality of Life Scale, Auditory Hallucinations Rating Scale, andClinical Global Impressions scores.  2.2. rTMS protocol Patients were randomly allocated to rTMS and sham groups. Randomization wasmade by Sequentially-Numbered, Opaque, Sealed Envelopes (SNOSE). The two groupswere similar in terms of age, gender and BPRS scores. The study used a doubled-masked,parallel design. Study participants, clinical raters, and all personnel responsible for theclinical care of the patient remained masked to allocated condition and allocationparameters.ANeurosoftNeuro-MS(NeurosoftLtd,Russia)and fi gure-8coilwereutilizedin the rTMS sessions. Stimulation was administered at an intensity of 90% of the motorthreshold, which was ascertained prior to the fi rst session of each week.Motorthreshold(MT)wasbasedonvisualizationoftracemotormovementsin5/10trieswhenstimulatingprimary motor cortex. This method has been reported to be as sensitive as EMG-basedmethods of detecting MT (Pridmore et al., 1998). Active stimulation was administered to the LTPC, exactly halfway between the left temporal (T3) and left parietal (P3) sitesaccording to the International 10 – 20 EEG electrode position system. Stimulationfrequency was 1 Hz while subjects were lying down on a bed. There was no break inthe stimulation trains. Sham stimulation was administered using the same coil, applied5 cmlateraltoF3,perpendiculartotheparasagittalplane,abovethelefttemporalmuscle.Inthispositionthecoil – cortexdistanceisessentiallylarger(morethan3 cmv.1 – 1.5 cm)compared to F3, and the electromagnetic  fi eld reaching the cortex was thereforesubstantially weaker. Toavoid the possible effectiveness ofthe sham stimulation, thecoilwas angled at 45°, touching the skull not with the centre but with the rim opposite thehandle,andthestimulationintensitywasreducedto80%ofMT(Herwigetal.,2007).This form of sham stimulation had the effect of inducing local sensations above the temporalmuscle similar to the disturbances caused by the real stimulation (Praeg et al., 2005). Clozapine use was continued during the trial, without dose changes. Patients received8 min of active/sham stimulation on day I, 16 min on day II, and 20 min for the next 18days,makingatotalof20sessions,5sessions/week(MondaythroughFriday)for4 weeks.Afterthecompletionofthestudy,patientsrandomizedtotheshamconditionwereofferedactive rTMS utilizing the same parameters as the masked phase of the trial.  2.3. Clinical Measures The 18-item Brief Psychiatric Rating Scale (BPRS) was used as the primary outcomevariable and to assess positive and negative symptoms, as well as conceptualdisorganization and general psychopathology. It is a psychopathological assessmentscale composed of 18 items which have been extensively used in the assessment of patients with schizophrenia. It has also been used in the assessment of the therapeuticresponsetoantipsychoticsbyKaneetal.,andinthedevelopmentofcriteriafor refractoryschizophrenia (Alves et al., 2005). Using the 18-item BPRS factor analysis proposed by Alvesetal(2005)forpatientswithrefractoryschizophrenia,weanalyzedscoresofthetwogroups on each of the four factors, namely: Negative/Disorganization, composed of emotionalwithdrawal,disorientation,bluntedaffect,mannerisms/posturingand concep-tual disorganization; Excitement, composed of excitement, hostility, tension, grandiosity,and uncooperativeness, grouped variables that evoke brain excitement or a manic-likesyndrome; Positive, composed of unusual thought content, suspiciousness, andhallucinatory behavior; and Depressive, composed of depressive mood, guilt feelings,andmotorretardation,clearlyrelatedtoadepressivesyndrome . AHsareknowntohaveanegative impact on the quality of life of the patients with schizophrenia (Van de Willigeetal.,2005).TomeasuretheeffectofchangeinAHsscoresonthequalityoflife,theQualityofLifeScale(QLS,Heinrichsetal.,1984)wasused.Thetoolisa21-itemscalecompletedby clinically trained staff after a semi-structured interview and chart review that assessesquality oflife. Items are scored ona 7-point scale withhigherratingsrepresenting higherlevelsofsatisfaction.TheClinicalGlobalImpressions(CGI)scalewasusedtoassessoverallclinical improvement. A 7-item Auditory Hallucinations Rating Scale (AHRS) was used toassess hallucination frequency, number of distinct speaking voices, perceived loudness,vividness,attentionalsalience, lengthof hallucinations (single words, phrases, sentences,or extended discourse), and degree of distress. The FAST scale was used to assessfunctionality. It consists of 24 items, grouped in six speci fi c areas of functionality:autonomy, work, cognitive functioning,  fi nances, interpersonal relationships and leisure.Thehigherthescore,theworseisthepatient´sfunctionality.Allscaleswereascertainedatbaseline,day7,day14,day21,day28andday60.Thelaterassessmenthappened30 daysafter the last active/placebo rTMS session, 60 days from baseline. All clinical assessmentswereundertakenbyapsychiatristfromtheSchizophreniaprogramofHospitaldeClinicasdePortoAlegreandathird-yearresidentofPsychiatry,bothwelltrainedinthescalesthatwereusedinthisstudy.Also,theseniorauthordiscussedandreviewedallscoreswiththeraters.  2.4. Statistical analysis Scores from ratingscales wereanalyzed from week 0 to 8 ascontinuousdata. Mann-Whitney's U test was used to test for group differences in score changes from baseline toendpoint. To evaluate within-group changes, Wilcoxon's signed-rank test was used. Wealso used multivariate repeated measures analysis of variance (ANOVA) to test groupdifferences in trajectory changes. This approach is useful as it is not constrained bysphericity, unlike the traditional repeated measures ANOVA. All tests are two-tailed. 3. Results Demographic data and BPRS, QLS, FAST, AHRS and CGI scores atbaseline are shown in Table 1.Changes in BPRS scores from baseline to endpoint were signi fi -cantly greater in the active group (  Z  =3.04,  p =0.002). In therepeated measures ANOVA, total BPRS scores were signi fi cantlylower in the active compared to the sham group ( F  =6.63, df=5,  p =0.016). The only signi fi cant difference between groups was seenin the Excitement factor ( F  =7.23, df=5,  p =0.003). No signi fi cantdifference was seen in negative/disorganization symptoms ( F  =1.23,df=5,  p =0.36), positive symptoms ( F  =0.97, df=5,  p =0.48) ordepressive symptoms ( F  =1.21, df=5,  p =0.37), and the Negative/Disorganization, Positive and Depressive factors of the BPRS, respec-tively. BPRS, AHRS and CGI scores are presented in Table 2. BPRSscores over time are illustrated in Fig. 1.In analyses of within-group changes in the BPRS scores, everypatient in the active group had a reduction in BPRS scores relative tobaseline assessments (  Z  =2.52,  p =0.012). This effect was not seen inthe sham group (  Z  =0.42,  p =0.67). The active group did not have asigni fi cant deterioration and showed some improvement, althoughnot statistically signi fi cant, from weeks 4 to 8 (  Z  =0.41,  p =0.68),while the sham group displayed a signi fi cant worsening (  Z  =2.03,  p -=0.042) (Fig. 2). There were no signi fi cant differences between 204  D.R. de Jesus et al. / Psychiatry Research 188 (2011) 203 –  207   active and sham groups in terms of QLS, AHRS, CGI and FAST scores(  p N 0.05).Therewasa signi fi cantdifference in the meanagesbetween groups(active group=46±9.84, sham group=36.5±6.36,  p =0.03).After the completion of the study, despite being offered activetreatment, no subjects from the sham group agreed to receive activerTMS immediatelyafter the treatment courseand only one receivedit3 months later, limiting any meaningful interpretation of the data.  3.1. Safety/tolerability The procedure was well tolerated. Only two patients of the activetreatment group (11.7 %) referred to light headache after the  fi rstthree sessions that was transient and responsive to acetaminophen.No seizures occurred. 4. Discussion The results of this study showed that subthreshold active 1 HzrTMS of the left temporoparietal cortex had a positive effect ongeneral psychopathology in patients with refractory schizophreniatreatedwithclozapine.Bycontrast,therewasnosigni fi cantdifferencebetween active and sham rTMS on the severity of auditory hallucina-tions. However, the effect of rTMS on general psychopathology in theactive group as re fl ected by BPRS scores shows that active rTMSapplied to the temporoparietal cortex of patients with schizophreniatreated with clozapine can have therapeutic effects that do not justoverlap with the effects of clozapine. Finally there were also nosigni fi cant effects on other measures of psychopathology, functional-ity or quality of life, i.e., CGI, FAST and QLS scores.Active rTMS was associated with signi fi cant improvement of BPRSscores compared to sham stimulation, mainly in the Excitement factor(items tension, grandiosity, hostility, uncooperativeness and excite-ment), that may be related to a state of brain hyperexcitability(Daskalakis et al., 2002). A possible explanation for this could be an  Table 1 Characteristics of 17 patients sample.Active group( n =8)Sham group( n =9)  p Age ª 46±9.84 36.5±6.36 0.03Gender (F/M) 3/5 2/7Years of education (as grades completed) ª 11.25±2.1 10.44±2.8 0.51Monthly income ª  γ 893.3±602 973±541 0.77Marital status (Single/Married) 8/0 9/0No. of psychiatric hospitalizations  b 3.5 (12) 4 (4) 0.9Age of onset of Auditory Hallucinations ª 21±3.1 20.5±3 0.74Number of months since last hallucinationfree period of a month or greater ª233.25±67.5 186.4±58.7 0.147Dosage of clozapine, mg  b 700 (200) 650 (100) 0.822BPRS ª 36.25±8.27 33.11±7.55 0.43AHRS ª 31±3.62 26.78±7.15 0.145FAST ª 49±10.32 49.44±13.150.941QLS ª 51.38±20 44.56±20.230.496CGI ª 5.5±1.19 5.11±1 0.491ª Data reported as mean±standard deviation. b Data reported as median and interquartile range. γ USD.  Table 2 Effects of rTMS on BPRS, CGI and AHRS scores over time.Measure Baseline Week 1 Week 2 Week 3 Week 4 Week 8BPRS scoresTotalActive 36.25±8.27 26.25±8.56 24.75±9.19 26.88±9.17 25.13±8.18 23.88±7.99Sham 33.11±7.55 31.67±11.57 28.33±10.87 29.44±10.78 28±7.34 29.56±7.29Positive factorActive 10.13±3 9.75±4.06 10.37±3.85 9.5±2.87 10.25±4.2 9.75±4.16Sham 10.56±3.24 11.44±4.39 10.66±3.46 9.66±3.42 9.22±2.48 9.22±2.48Negative/Disorganization factorActive 8.88±2.35 6.62±2.82 5.75±2.65 7±2.92 6.8±1.95 9.5±3.81Sham 8.56±2.96 8.55±4.06 7.33±3.16 7.77±3.11 7.33±2.34 12.56 ±4.79Excitement factorActive 5.5±2.82 1.25±1.38 1.5±0.92 3.62±3.73 1.5±1.41 1.25±1.28Sham 3.56±4.15 3.88±4.22 3.77±5.38 4.66±4.55 3.88±4.37 3.89±4.37Depressive factorActive 5.88±2.9 3.25±2.12 2.25±1.16 4.12±2.85 2.37±2.26 2.25±2.18Sham 4±3.12 3.33±2.59 3.33±2.69 3.33±2.82 3.55±3.24 3.56±3.24CGI scoresActive 5.5±1.19 5±1.06 5.13±1.12 5±1.06 5.13±1.12 5±1.06Sham 5.1±1.05 5.11±1.05 5.33±1 5.11±1.05 5.11±1.05 5.11±1.05AHRS scoresActive 31±3.62 29.63±4.2 29.25±3.53 30.25±4.9 25.88±4.99 27.13±3.35Sham 26.78±7.15 26.44±9 24.44±9 24.67±8.9 25.22±8.81 25.44±8.61 a mean±standard deviation. Fig. 1.  Total BPRS scores for active rTMS versus sham stimulation. Changes in BPRSscores from baseline to endpoint were signi fi cantly greater in the active group(  Z  =3.04,  p =0.002). Error bar is standard error. Abbreviations: BPRS=Brief Psychiatric Rating Scale, rTMS=repetitive transcranial magnetic stimulation.205 D.R. de Jesus et al. / Psychiatry Research 188 (2011) 203 –  207   improvementonthecorticalinhibition(CI)ontheactivegroup.CIrefersto the mechanisms through which cortical output is regulated byinhibitory gamma-aminobutyric acid (GABA) interneurons. CI de fi citsassessed by TMS paradigms, such as paired-pulse inhibition andfacilitation (ppTMS), cortical silent period (CSP) and transcallosalinhibition(TCI),havebeendemonstratedinpatientswithschizophrenia(Daskalakis et al., 2002). CI is regulated by GABA A  and GABA B neurotransmission.TreatmentwithclozapineisassociatedwithgreaterCI in persons with schizophrenia, and this increase may be related topotentiation of GABA B  receptor mediated inhibition (Daskalakis et al.,2008; Liu et al., 2009). Moreover, the same authors con fi rmed that CIde fi cits are related to severity of psychotic symptoms. Repetitive TMShas also been shown to potentiate cortical GABA B  receptor mediatedinhibition (Daskalakis et al., 2006), which can lead to symptomatic improvement. Hence, the combination of rTMS and clozapine may actsynergistically towards further enhancing GABA B  inhibitory mecha-nisms in patients with refractory schizophrenia, who demonstrate thegreatest GABAergic de fi cits. Similarly to our fi ndings, Vercammen et al.(2009) found that 12 sessions of 1 Hz rTMS applied to the lefttemporoparietal cortex of patients with medication-resistant schizo-phrenia may have aneffect on generalpsychopathology, asassessed byscores on the Positive and Negative Syndrome Scale, whereas bilateralor sham stimulation were not effective.The mean age was signi fi cantly different between groups (active =46±9.84, sham=36.5±6.36,  p =0.03). However, there was no corre-lation between age and BPRS scores at baseline or at the end of thetreatment.The treatment parameters were comparable to those used inprevious rTMS studies in schizophrenia, except for the number andduration of rTMS sessions. In this study, 20 sessions with duration of 20 min each (except for the  fi rst two sessions) and without breaks inthe stimulation trains were performed, whereas in the vast majorityof previous studies the number of sessions varied from 6 to 15, withmean duration of 16 min and with breaks in the stimulation trains. Itis known that, similarly to pharmacological treatment, there is a cleartrend for therapeutic ef  fi cacy to relate to the  “ dose ”  of treatment, interms of the intensity of stimulation, the number of pulses providedper day and the number of days of treatment (Fitzgerald et al., 2005). The fact that we tended to use longer treatment durations withoutstimulation breaks suggests that the potential to fi nd temporal effectsof rTMS was greater.This study has several limitations. The most important was thelimited small sample size that could explain the lack of effect on theseverity of AHs. Interestingly, we found a positive effect in generalpsychopathologybutnotinAHs,asaforementioned.Thiscouldbedueto the poor reliability of some patients to report their AHs ( D'Alfonsoet al., 2002; Rosa et al., 2007), mainly when reporting number of distinct speaking voices, perceived loudness, vividness and attention-al salience, whereas general psychopathology includes both objectiveand subjective measures, determining changes in general psychopa-thology to be easier to index. Moreover, rTMS may have both regionaland distant cortical effects as a result of interhemispheric transsy-naptic signal propagation (Ilmoniemi et al., 1997). Thus, rTMS of the LTPC can affect other cortical areas and determine positive effects indifferent psychopathological dimensions. The lack of effect on qualityof life and functionality could also be explained by the small powerand sample size, but also because changes in aspects such as work,leisure, interpersonal relationships and social network may needmore time to be observed and depend on psychosocial and individualfactors. The high refractoriness of the patients enrolled in this study isassociated with low levels of quality of life and functionality, andprobably determined the relatively low response to the treatmentsavailable.Finally, our results suggest that subthreshold 1 Hz rTMS applied tothe LTPC can be safely used in patients with refractory schizophreniaand can lead to symptomatic improvement in psychopathologicaldimensions that are not directly related to the stimulation site. This isrelevant because, despite the advances in psychopharmacologicaltreatments, at the present time very limited help is available to thesepatients. Con fl icts of Interest All authors declare that they have no con fl icts of interest. Role of the funding source Funding for this study was provided by Fundo de Incentivo a Pesquisa (FIPE) fromHospital de Clínicas de Porto Alegre, UFRGS (Project No. 06382). FIPE had no furtherrolein studydesign; in thecollection, analysisandinterpretation ofdata; inthe writingof the report; and in the decision to submit the paper for publication. Contributors Authors de Jesus, Belmonte de Abreu, Marcolin and Favalli designed the study andwrote the protocol. Authors de Jesus and Daskalakis managed the literature searchesand analyses. Author Magalhães undertook the statistical analysis, and authors Gil andBarbosadidclinicalexaminations.AuthorsdeJesusandLobatodidrTMStreatments.Allauthors participated on the preparation of the manuscript. All authors contributed toand have approved the  fi nal manuscript.  Acknowledgements ThisworkwassupportedbytheFundodeIncentivoaPesquisa(FIPE)fromHospitaldeClínicasdePortoAlegre(ProjectNo.06382).TheNeuro-MSmagneticstimulatorwaskindly donated by Gerdau S.A. References Alves, T.M., Pereira, J.C., Elkis, H., 2005. The psychopathological factors of refractoryschizophrenia. Revista Brasileira de Psiquiatria 27 (2), 108 – 112.Chen, R., Classen, J., Gerloff, C., Celnik, P., Wassermann, E.M., Hallett, M., Cohen, L.G.,1997. Depression of motor cortex excitability by low-frequency transcranialmagnetic stimulation. Neurology 48, 1398 – 1403.D'Alfonso, A.A., Aleman, A., Kessels, R.P., Schouten, E.A., Postma, A., van Der Linden, J.A.,Cahn, W., Greene, Y., de Haan, E.H., Kahn, R.S., 2002. Transcranial magneticstimulation of left auditory cortex in patients with schizophrenia: effects onhallucinations and neurocognition. The Journal of Neuropsychiatry and ClinicalNeurosciences 14 (1), 77 – 79.Daskalakis,Z.J.,Christensen,B.K.,Chen,R.,Fitzgerald,P.B.,Zipursky,R.B.,Kapur,S.,2002.Evidence for impaired cortical inhibition in schizophrenia using transcranialmagnetic stimulation. Archives of General Psychiatry 59, 347 – 354. Fig. 2.  BPRS scores for each subject from active rTMS and sham groups. Subjectsfrom the active group had a signi fi cant reduction in BPRS scores from baseline toendpoint (  Z  =3.04,  p =0.002). Abbreviations: BPRS=Brief Psychiatric Rating Scale,rTMS=repetitive transcranial magnetic stimulation.206  D.R. de Jesus et al. / Psychiatry Research 188 (2011) 203 –  207   Daskalakis, Z.J., Möller, B., Christensen, B.K., Fitzgerald, P.B., Gunraj, C., Chen, R., 2006.The effects of repetitive transcranial magnetic stimulation on cortical inhibition inhealthy human subjects. Experimental Brain Research 174 (3), 403 – 412.Daskalakis,Z.J.,Christensen,B.K.,Fitzgerald,P.B.,Moller,B.,Fountain,S.I.,Chen,R.,2008.Increased cortical inhibition in persons with schizophrenia treated with clozapine. Journal of Psychopharmacology 22, 203 – 209.Dierks,T.,Linden,D.E.J.,Jandl,M.,Formisano,E.,Goebel,R.,Lanfermann,H.,Singer,W.,1999.Activation of Heschl's gyrus during auditory hallucinations. Neuron 22, 615 – 621.Fiez, J.A., Raichle, M.E., Balota, D.A., Tallal, P., Petersen, S.E., 1996. PET activation of posteriortemporalregionsduringauditorywordpresentationandverbgeneration.Cerebral Cortex 6, 1 – 10.Fitzgerald, P.B., Daskalakis, J.Z., 2008. A review of repetitive transcranial magneticstimulation use in the treatment of schizophrenia. Canadian Journal of Psychiatry53 (9), 567 – 576.Fitzgerald, P.B., Benitez, J., Daskalakis, J.Z., Brown, T.L., Marston, N.A., de Castella, A.,Kulkarni, J., 2005. A double-blind sham-controlled trial of repetitive transcranialmagneticstimulationinthetreatmentofrefractoryauditoryhallucinations.Journalof Clinical Psychopharmacology 25 (4), 358 – 362.Heinrichs,D.W.,Hanlon,T.E.,CarpenterJr.,W.T.,1984.TheQualityofLifeScale:aninstrumentfor rating the schizophrenic de fi cit syndrome. Schizophrenia Bulletin 10 (3), 388 – 398.Herwig, U., Fallgatter, A.J., Höppner, J., Eschweiler, G.W., Kron, M., Hajak, G., Padberg, F.,Naderi-Heiden, A., Abler, B., Eichhammer, P., Grossheinrich, N., Hay, B., Kammer, T.,Langguth, B., Laske, C., Plewnia, C., Richter, M.M., Schulz, M., Unterecker, S., Zinke, A.,Spitzer, M., Schönfeldt-Lecuona, C., 2007. Antidepressant effects of augmentativetranscranialmagneticstimulation:randomisedmulticentretrial.TheBritishJournalof Psychiatry 191, 441 – 448.Hoffman, R.E., Cavus, I., 2002. Slow transcranial magnetic stimulation, long-termdepotentiation, and brain hyperexcitability disorders. The American Journal of Psychiatry 159, 1093 – 1102.Hoffman, R.E., Boutros, N.N., Hu, S., Berman, R.M., Krystal, J.H., Charney, D.S., 2000.Transcranial magnetic stimulation of left temporoparietal cortex in schizophrenicpatients reporting auditory hallucinations. Lancet 355, 1073 – 1075.Hoffman, R.E., Gueorguieva, R., Hawkins, K.A., Varanko, M., Boutros, N.N., Wu, Y.T.,Carroll, K., Krystal, J.H., 2005. Temporoparietal transcranial magnetic stimulationfor auditory hallucinations: safety, ef  fi cacy and moderators in a  fi fty patientsample. Biological Psychiatry 15;58 (2), 97 – 104.Ilmoniemi, R.J., Virtanen, J., Ruohonen, J., Karhu, J., Aronen, H.J., Näätänen, R., Katila, T.,1997. Neuronal responses to magnetic stimulation reveal cortical reactivity andconnectivity. NeuroReport 8 (16), 3537 – 3540.Lennox, B.R., Park, S.B.G., Medley, I., Morris, P.G., Jones, P.B., 2000. The functionalanatomy of auditory hallucinations in schizophrenia. Psychiatry Research:Neuroimaging Section 100, 13 – 20.Liu, S.K., Fitzgerald, P.B., Daigle, M., Chen, R., Daskalakis, Z.J., 2009. The relationshipbetween cortical inhibition, antipsychotic treatment, and the symptoms of schizophrenia. Biological Psychiatry 15;65 (6), 503 – 509.Post, R.M., Kimbrell, T.A., McCann, U.D., Runn, R.T., Osuch, E.A., Speer, A.M., Weiss, S.,1999. Repetitive transcranial magnetic stimulation as a neuropsychiatric tool:present status and future potential. The Journal of ECT 15, 39 – 56.Poulet, E., Brunelin, J., Bediou, B., Bation, R., Forgeard, L., Dalery, J., 2005. Slowtranscranialmagnetic stimulation can rapidly reduce resistant auditory hallucinations inschizophrenia. Biological Psychiatry 57, 188 – 191.Praeg,E.,Herwig,U.,Lutz,K.,2005.Theroleoftherightdorsalpremotorcortexinvisuomotorlearning: a transcranial magnetic stimulation study. NeuroReport 16, 1715 – 1718.Pridmore, S., Fernandes Filho, J.A., Nahas, Z., Liberatos, C., George, M.S., 1998. Motorthresholdintranscranialmagneticstimulation: acomparisonofaneurophysiologicalmethod and a visualization of movement method. The Journal of ECT 14, 25 – 27.Rosa, M.O., Gattaz, W.F., Rosa, M.A., Rumi, D.O., Tavares, H., Myczkowski, M., Sartorelli,M.C., Rigonatti, S.P., Elkis, H., Cabral, S.B., Teixeira, M.J., Marcolin, M.A., 2007. Effectsof Repetitive Transcranial Magnetic Stimulation on Auditory HallucinationsRefractory to Clozapine. The Journal of Clinical Psychiatry 68 (10), 1528 – 1532.Shergill, S.S., Murray, R.M., McGuire, P.K., 1998. Auditory hallucinations: a review of psychological treatments. Schizophrenia Research 32, 137 – 150.Shergill, S.S., Brammer, M.J., Williams, S.C.R., Murray, R.M., McGuire, P.K., 2000.Mapping auditory hallucinations in schizophrenia using functional magneticresonance imaging. Archives of General Psychiatry 57, 1033 – 1038.Silbersweig, D.A., Stern, E., Frith, C., Cahill, C., Holmes, A., Grootoonk, S., 1995. Afunctional neuroanatomy of hallucinations in schizophrenia. Nature 378, 176 – 179.Suzuki, M., Yuasa, S., Minabe, Y., Murata, M., Kuracki, M., 1993. Left superior temporalblood fl owincreases in schizophrenic andschizophreniform patients withauditoryhallucinations: a longitudinal case study using 123I-IMP SPECT. European Archivesof Psychiatry and Clinical Neuroscience 242, 257 – 261.Van de Willige, G., Wiersma, D., Nienhuis, F.J., Jenner, J.A., 2005. Changes in quality of life in chronic psychiatric patients: a comparison between EuroQol (EQ-5D) andWHOQoL. Quality of Life Research 14 (2), 441 – 451.Vercammen, A., Knegtering,H., Bruggeman,R.,Westenbroek,H.M.,Jenner,J.A., Slooff, C.J.,Wunderink, L., Aleman, A., 2009. Effects of bilateral repetitive transcranial magneticstimulation ontreatmentresistant auditory-verbalhallucinationsinschizophrenia:arandomized controlled trial. Schizophrenia Research 114 (1 – 3), 172 – 179.Woodruff, P.W.R., Brammer, M., Mellers, J., Wright, E.B., Williams, S., 1994. Auditoryhallucinations and perception of external speech. Lancet 346, 1035.Woodruff, P.W.R., Wright, I.C., Bullimore, E.T., Brammer, M., Howard, R.J., Williams, S.,1997. Auditory hallucinations and the temporal cortical response to speech inschizophrenia: A functional magnetic resonance imaging study. The American Journal of Psychiatry 154, 1676 – 1682.207 D.R. de Jesus et al. / Psychiatry Research 188 (2011) 203 –  207 
Similar documents
View more...
Related Search
We Need Your Support
Thank you for visiting our website and your interest in our free products and services. We are nonprofit website to share and download documents. To the running of this website, we need your help to support us.

Thanks to everyone for your continued support.

No, Thanks