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Deep brain stimulation in treatment resistant schizophrenia: A pilot randomized cross-over clinical trial.

ABSTRACT: BACKGROUND:Up to 30% of patients with schizophrenia are resistant to antipsychotic drug treatment, with 60% of such cases also failing to respond to clozapine. Deep brain stimulation (DBS) has been used in treatment resistant patients with other psychiatric disorders, but there is a lack of trials in schizophrenia, partly due to uncertainties over where to site the electrodes. This trial aimed to examine the effectiveness of nucleus accumbens (NAcc) and subgenual anterior cingulate cortex (subgenual ACC) targeted DBS; the primary outcome measure was PANSS total score, as assessed fortnightly. METHODS:Eight patients with schizophrenia, who met criteria for treatment resistance and were also resistant to/intolerant of clozapine, were randomly assigned using central allocation to receive DBS in the NAcc or subgenual ACC. An open stabilization phase lasting at least six months was followed by a randomized double-blind crossover phase lasting 24 weeks in those who met symptomatic improvement criteria. The primary end-point was a 25% improvement in PANSS total score. (ClinicalTrials.gov Identifier: NCT02377505; trial completed). FINDINGS:One implanted patient did not receive DBS due to complications of surgery. Of the remaining 7 patients, 2/3 with NAcc and 2/4 with subgenual ACC electrode placements met the symptomatic improvement criteria (58% and 86%, and 37% and 68% improvement in PANSS total score, respectively). Three of these patients entered the crossover phase and all showed worsening when the stimulation was discontinued. The fourth patient worsened after the current was switched off accidentally without her or the investigators' knowledge. Physical adverse events were uncommon, but two patients developed persistent psychiatric adverse effects (negative symptoms/apathy and mood instability, respectively). INTERPRETATION:These preliminary findings point to the possibility of DBS having therapeutic effects in patients with schizophrenia who do not respond to any other treatment. Larger trials with careful attention to blinding will be necessary to establish the extent of the benefits and whether these can be achieved without psychiatric side-effects.

SUBMITTER: Corripio I

PROVIDER: S-EPMC6953640 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Deep brain stimulation in treatment resistant schizophrenia: A pilot randomized cross-over clinical trial.

Corripio Iluminada I Roldán Alexandra A Sarró Salvador S McKenna Peter J PJ Alonso-Solís Anna A Rabella Mireia M Díaz Anna A Puigdemont Dolors D Pérez-Solà Víctor V Álvarez Enric E Arévalo Antonio A Padilla Pedro P PP Ruiz-Idiago Jesus M JM Rodríguez Rodrigo R Molet Joan J Pomarol-Clotet Edith E Portella Maria J MJ

EBioMedicine 20200108

<h4>Background</h4>Up to 30% of patients with schizophrenia are resistant to antipsychotic drug treatment, with 60% of such cases also failing to respond to clozapine. Deep brain stimulation (DBS) has been used in treatment resistant patients with other psychiatric disorders, but there is a lack of trials in schizophrenia, partly due to uncertainties over where to site the electrodes. This trial aimed to examine the effectiveness of nucleus accumbens (NAcc) and subgenual anterior cingulate corte ...[more]

PMID: 31927311

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Project description:BackgroundSubthalamic nucleus deep brain stimulation (STN-DBS) reduces tremor, muscle stiffness, and bradykinesia in people with Parkinson's Disease (PD). Walking speed, known to be reduced in PD, typically improves after surgery; however, other important aspects of gait may not improve. Furthermore, balance may worsen and falls may increase after STN-DBS. Thus, interventions to improve balance and gait could reduce morbidity and improve quality of life following STN-DBS. Physical therapy (PT) effectively improves balance and gait in people with PD, but studies on the effects of PT have not been extended to those treated with STN-DBS. As such, the efficacy, safety, and feasibility of PT in this population remain to be determined. The purpose of this pilot study is to address these unmet needs. We hypothesize that PT designed to target balance and gait impairment will be effective, safe, and feasible in this population.Methods/designParticipants with PD treated with STN-DBS will be randomly assigned to either a PT or control group. Participants assigned to PT will complete an 8-week, twice-weekly PT program consisting of exercises designed to improve balance and gait. Control group participants will receive the current standard of care following STN-DBS, which does not include prescription of PT. The primary aim is to assess preliminary efficacy of PT on balance (Balance Evaluation Systems Test). A secondary aim is to assess efficacy of PT on gait (GAITRite instrumented walkway). Participants will be assessed OFF medication/OFF stimulation and ON medication/ON stimulation at baseline and at 8 and 12 weeks after baseline. Adverse events will be measured over the duration of the study, and adherence to PT will be measured to determine feasibility.DiscussionTo our knowledge, this will be the first study to explore the preliminary efficacy, safety, and feasibility of PT for individuals with PD with STN-DBS. If the study suggests potential efficacy, then this would justify larger trials to test effectiveness and safety of PT for those with PD with STN-DBS.Trial registrationNCT03181282 (clinicaltrials.gov). Registered on 7 June 2017.

Project description:IntroductionAfter several years of brain-sensing technology development and proof-of-concept studies, adaptive deep brain stimulation (aDBS) is ready to better treat Parkinson's disease (PD) using aDBS-capable implantable pulse generators (IPGs). New aDBS devices are capable of continuous sensing of neuronal activity from the subthalamic nucleus (STN) and contemporaneous stimulation automatically adapted to match the patient's clinical state estimated from the analysis of STN activity using proprietary algorithms. Specific studies are necessary to assess superiority of aDBS vs conventional DBS (cDBS) therapy. This protocol describes an original innovative multicentre international study aimed to assess safety and efficacy of aDBS vs cDBS using a new generation of DBS IPG in PD (AlphaDBS system by Newronika SpA, Milan, Italy).MethodsThe study involves six investigational sites (in Italy, Poland and The Netherlands). The primary objective will be to evaluate the safety and tolerability of the AlphaDBS System, when used in cDBS and aDBS mode. Secondary objective will be to evaluate the potential efficacy of aDBS. After eligibility screening, 15 patients with PD already implanted with DBS systems and in need of battery replacement will be randomised to enter a two-phase protocol, including a 'short-term follow-up' (2 days experimental sessions during hospitalisation, 1 day per each mode) and a 'long-term follow-up' (1 month at home, 15 days per each mode).Ethics and disseminationThe trial was approved as premarket study by the Italian, Polish, and Dutch Competent Authorities: Bioethics Committee at National Oncology Institute of Maria Skłodowska-Curie-National Research Institute in Warsaw; Comitato Etico Milano Area 2; Comitato Etico IRCCS Istituto Neurologico C. Besta; Comitato Etico interaziendale AOUC Città della Salute e della Scienza-AO Ordine Mauriziano di Torino-ASL Città di Torino; De Medisch Ethisch Toetsingscommissie van Maastricht UMC. The study started enrolling patients in January 2021.Trial registration numberNCT04681534.

Project description:ObjectiveThe objective of this open-label, nonrandomized trial was to evaluate the efficacy and safety of bilateral caudate nucleus deep brain stimulation (DBS) for treatment-resistant tinnitus.MethodsSix participants underwent DBS electrode implantation. One participant was removed from the study for suicidality unrelated to brain stimulation. Participants underwent a stimulation optimization period that ranged from 5 to 13 months, during which the most promising stimulation parameters for tinnitus reduction for each individual were determined. These individual optimal stimulation parameters were then used during 24 weeks of continuous caudate stimulation to reach the endpoint. The primary outcome for efficacy was the Tinnitus Functional Index (TFI), and executive function (EF) safety was a composite z-score from multiple neuropsychological tests (EF score). The secondary outcome for efficacy was the Tinnitus Handicap Inventory (THI); for neuropsychiatric safety it was the Frontal Systems Behavior Scale (FrSBe), and for hearing safety it was pure tone audiometry at 0.5, 1, 2, 3, 4, and 6 kHz and word recognition score (WRS). Other monitored outcomes included surgery- and device-related adverse events (AEs). Five participants provided full analyzable data sets. Primary and secondary outcomes were based on differences in measurements between baseline and endpoint.ResultsThe treatment effect size of caudate DBS for tinnitus was assessed by TFI [mean (SE), 23.3 (12.4)] and THI [30.8 (10.4)] scores, both of which were statistically significant (Wilcoxon signed-rank test, 1-tailed; alpha = 0.05). Based on clinically significant treatment response categorical analysis, there were 3 responders determined by TFI (≥ 13-point decrease) and 4 by THI (≥ 20-point decrease) scores. Safety outcomes according to EF score, FrSBe, audiometric thresholds, and WRS showed no significant change with continuous caudate stimulation. Surgery-related and device-related AEs were expected, transient, and reversible. There was only one serious AE, a suicide attempt unrelated to caudate neuromodulation in a participant in whom stimulation was in the off mode for 2 months prior to the event.ConclusionsBilateral caudate nucleus neuromodulation by DBS for severe, refractory tinnitus in this phase I trial showed very encouraging results. Primary and secondary outcomes revealed a highly variable treatment effect size and 60%-80% treatment response rate for clinically significant benefit, and no safety concerns. The design of a phase II trial may benefit from targeting refinement for final DBS lead placement to decrease the duration of the stimulation optimization period and to increase treatment effect size uniformity.Clinical trial registration no.: NCT01988688 (clinicaltrials.gov).

Project description:BackgroundTo date, antidepressant drugs show limited efficacy, leaving a large number of patients experiencing severe and persistent symptoms of major depression. Previous open-label clinical trials have reported significant sustained improvements with deep brain stimulation (DBS) of the subcallosal cingulate gyrus (SCG) in patients with severe, chronic treatment-resistant depression (TRD). This study aimed to confirm the efficacy and measure the impact of discontinuation of the electrical stimulation.MethodsWe conducted a 6-month double-blind, randomized, sham-controlled crossover study in implanted patients with previous severe TRD who experienced full remission after chronic stimulation. After more than 3 months of stable remission, patients were randomly assigned to 2 treatment arms: the ON-OFF arm, which involved active electrode stimulation for 3 months followed by sham stimulation for 3 months, and the OFF-ON arm, which involved sham stimulation for 3 months followed by active stimulation for 3 months. The primary outcome measure was the difference in the 17-item Hamilton Rating Scale for Depression (HAMD-17) total score between sham and active stimulation.ResultsWe enrolled 5 patients in our trial. A Friedman repeated-measures analysis of variance revealed a significant effect of treatment (χ(2)1 = 5.0, p = 0.025) in patients with higher depression scores during sham stimulation. At the end of active stimulation, depression was remitted in 4 of 5 patients and none of them had experienced a relapse, whereas at the end of sham stimulation, 2 patients remained in remission, 2 relapsed and 1 showed a progressive worsening without reaching relapse criteria.LimitationsThe small sample size limited the statistical power and external validity.ConclusionThese preliminary findings indicate that DBS of the SCG is an effective and safe treatment for severe forms of TRD and that continuous electrical stimulation is required to maintain therapeutic effects.Trial registrationNCT01268137 (ClinicalTrials.gov).

Project description:ImportanceThe travel required to receive deep brain stimulation (DBS) programming causes substantial burden on patients and limits who can access DBS therapy.ObjectiveTo evaluate the efficacy of home health DBS postoperative management in an effort to reduce travel burden and improve access.Design, settings, and participantsThis open-label randomized clinical trial was conducted at University of Florida Health from November 2017 to April 2020. Eligible participants had a diagnosis of Parkinson disease (PD) and were scheduled to receive DBS independently of the study. Consenting participants were randomized 1:1 to receive either standard of care or home health postoperative DBS management for 6 months after surgery. Primary caregivers, usually spouses, were also enrolled to assess caregiver strain.InterventionsThe home health postoperative management was conducted by a home health nurse who chose DBS settings with the aid of the iPad-based Mobile Application for PD DBS system. Prior to the study, the home health nurse had no experience providing DBS care.Main outcomes and measuresThe primary outcome was the number of times each patient traveled to the movement disorders clinic during the study period. Secondary outcomes included changes from baseline on the Unified Parkinson's Disease Rating Scale part III.ResultsApproximately 75 patients per year were scheduled for DBS. Of the patients who met inclusion criteria over the entire study duration, 45 either declined or were excluded for various reasons. Of the 44 patients enrolled, 19 of 21 randomized patients receiving the standard of care (mean [SD] age, 64.1 [10.0] years; 11 men) and 23 of 23 randomized patients receiving home health who underwent a minimum of 1 postoperative management visit (mean [SD] age, 65.0 [10.9] years; 13 men) were included in analysis. The primary outcome revealed that patients randomized to home health had significantly fewer clinic visits than the patients in the standard of care arm (mean [SD], 0.4 [0.8] visits vs 4.8 [0.4] visits; P < .001). We found no significant differences between the groups in the secondary outcomes measuring the efficacy of DBS. No adverse events occurred in association with the study procedure or devices.Conclusions and relevanceThis study provides evidence supporting the safety and feasibility of postoperative home health DBS management.Trial registrationClinicalTrials.gov Identifier: NCT02474459.

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Deep brain stimulation in treatment resistant schizophrenia: A pilot randomized cross-over clinical trial.

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Deep brain stimulation in treatment resistant schizophrenia: A pilot randomized cross-over clinical trial.

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