STIM'ZO : Examining tDCS as an add-on Treatment for Persistent Symptoms in Schizophrenia

Study Overview
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Brief Summary
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This project aims to provide the proof of concept for transcranial direct-current stimulation (tDCS) in the treatment of resistant/persistent Schizophrenia symptoms. The purpose is to investigate the effect of tDCS on symptoms in schizophrenic patients demonstrating a partial response to a first frequently prescribed antipsychotic medication. An early optimization of the therapeutic strategy must constitute an important factor for prognosis. Hypothesize is that tDCS should alleviate symptoms in patients depending on the clinical characteristics. In this study, stimulation is an add-on treatment to antipsychotic medication, and will be used in a broad variety of patients, i.e. in patients with varied durations of illness, various symptoms profiles, and various levels of treatment response. This in turn will allow the determination of the extent to which results can be generalized to varied patient populations, as well as the extent to which various therapeutic targets (e.g. different symptom dimensions, cognitive performance and brain connectivity) may be improved with tDCS. Despite interesting preliminary results, our team is unable to describe optimal non-invasive brain stimulation (NIBS) response markers. This study is a randomized, double blind, controlled, French multicenter study (11 centers). The investigators plan to include 144 patients with persistent symptoms in schizophrenia. Seventy two subjects will receive active tDCS and 72 subjects will receive sham tDCS (placebo). Hypothesize is a lasting effect of active tDCS on the schizophrenic symptoms as measured by the number of responders, defined as a decrease of at least 25% of symptoms as measured by a standardized clinical scale score (PANSS) between baseline and after the 10-session tDCS regimen. Furthermore, the participants believe that an in depth understanding of the cortical effects of tDCS could constitute an important step towards improving the technique and developing treatment response markers. An analysis of the effects on cortical activity and plasticity markers could be an interesting approach.

Official Title
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STIM'ZO : Examining tDCS as an add-on Treatment for Persistent Symptoms in Schizophrenia (SCH)

Conditions
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Mental Disorders, Schizophrenia

Intervention / Treatment
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* Device: Neuroconn or Neuroelectric tDCS stimulator
* Device: Sham tDCS


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of schizophrenia according to DSM 5.0 (Diagnostic and Statistical Manuel 5.0) criteria Presence of symptoms despite the optimization of the antipsychotic dosage (based on prescriber's judgment) for at least 6 weeks, i.e. a dosage increase cannot be considered due to tolerability issues and/or is judged unlikely to bring sufficient clinical improvement. This will be operationalized by a minimum Negative PANSS score of 20 and at least one item scoring > 4; OR a minimum Positive PANSS score of 20 with at least one item scoring > 4 (e.g. delusion or hallucination), indicating persistent negative symptoms and/or persistent positive symptoms, Patient under curatorship/guardianship or not Age between 18 and 65 years old. Covered by, or having the right to Social Security Patient who understands the French language Informed consent signed Exclusion Criteria: Other neuropsychiatric disorders (psychiatric history will be assessed using the MINI 6.0 (Mini International Neuropsychiatric Interview 6.0)) including bipolar disorders and mood depression disorders - (NB: Patients with substance related and addictive disorders will not be excluded from the study, but these data will be carefully recorded). Contraindications for tDCS (neurologic stimulator, pacemaker, cardiac defibrillator, cardiac prosthesis, vascular prosthesis, intracranial clips or clamps, cerebrospinal fluid derivation, metallic splinters in the eyes), Increase in total composite PANSS score of at least 20% between screening and enrollment visits Women who are pregnant Patients whose clinical condition requires in patient procedure under constraint

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active tDCS<br>Stimulation will be performed using an tDCS stimulator (Neuroconn or Neuroelectric tDCS stimulator) with two 7×5 cm (35 cm2) sponge electrodes soaked in a saline solution (0.9% NaCl). The anode will be placed with the middle of the electrode over a point midway between F3 and FP1 (left prefrontal cortex: dorsolateral prefrontal cortex, assumed to correspond to a region including Brodmann's Areas (BA) 8, 9, 10, and 46, depending on the patient). The cathode will be located over a point midway between T3 and P3 (left temporo-parietal junction, assumed to correspond to a region including BA 22, 39, 40, 41, and 42, depending on the patient). The stimulation level will be set at 2 mA for 20 minutes during stimulation sessions twice a day for 5 consecutive weekdays. The twice daily sessions will be separated by at least 2 hours. | Device: Neuroconn or Neuroelectric tDCS stimulator<br>* Stimulation parameters were chosen in conformity with those for the treatment of schizophrenic symptoms (Brunelin et al, 2012), adapted according to the latest data from the literature and the tDCS operating stimulator. The experimental tDCS group will receive the ACTIVE stimulation with the following parameters: oscillatory Direct Current with high frequency random noise stimulation (hf-tRNS - 100 to 500 Hz), Intensity = 2 mA, offset = + 1 mA, seance duration = 20 minutes ramp up/ramp down 30 seconds. Total number of sessions = 10 (sessions twice daily for 5 days separated by at least 2 hours for 5 consecutive weekdays).<br>|
| Sham Comparator: Sham tDCS<br> | Device: Sham tDCS<br>* The control group will receive the SHAM stimulation (placebo) following the same regimen (i.e., twice daily sessions separated by at least 2 hours for 5 consecutive weekdays). Sham stimulation consists of a 20 minutes session including 40 seconds of active stimulation (same parameters as in the ACTIVE arm) at the beginning of the sessions, whatever the stimulator<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of responders | The number of responders is based on the Positive and Negative Syndrome Scale (PANSS) score in the active and the sham group after 5 days of tDCS. According to Leucht et al (2009), response is defined as a decrease of at least 25% in the Positive and Negative Syndrome Scale (PANSS, Kay et al., 1987) score after the intervention. | Between baseline (day 0) and after 10-sessions of tDCS regimen (day 5) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Positive and Negative Syndrome Scale (PANSS) score | Long-term clinical efficacy of active tDCS on schizophrenic symptoms is assessed by PANSS score measured between baseline (day 0), after 10-sessions of tDCS regimen (day 5), 1 month after tDCS (day 30), 3 months after tDCS (day 90) and 6 months after tDCS (day 180). The PANSS is a 30-item rater-administered assessment scale of the psychopathological symptoms observed in patients experiencing psychotic states, in particular schizophrenia. The items are noted from 1 to 7. It allows the calculation of the scores for three syndromic dimensions (positive, negative, and general psychopathology), both from a categorical and dimensional perspective. It is particularly recommended for determining a psychopathological profile, to look for predictive elements of an evolution, and to evaluate the respective efficacies of diverse therapeutic strategies. | Baseline, day 5 (after 10-sessions of tDCS regimen), 1 month, 3 months and 6 months after the last tDCS session | 
| Auditory Hallucination Rating Scale (AHRS) score | Long-term clinical efficacy of active tDCS on schizophrenic symptoms is assessed by AHRS score measured between baseline (day 0), after 10-sessions of tDCS regimen (day 5), 1 month after tDCS (day 30), 3 months after tDCS (day 90) and 6 months after tDCS (day 180). The AHRS score measures the severity of auditory hallucinations. | Baseline, day 5 (after 10-sessions of tDCS regimen), 1 month, 3 months and 6 months after the last tDCS session | 
| Psycho-Sensory hAllucinations Scale (PSAS) score | Long-term clinical efficacy of active tDCS on schizophrenic symptoms is assessed by PSAS score measured between baseline (day 0), after 10-sessions of tDCS regimen (day 5), 1 month after tDCS (day 30), 3 months after tDCS (day 90) and 6 months after tDCS (day 180). The PSAS score measures the delusions and severity of hallucinations | Baseline, day 5 (after 10-sessions of tDCS regimen), 1 month, 3 months and 6 months after the last tDCS session | 
| Calgary Depression Scale for Schizophrenia (CDSS) score | Long-term clinical efficacy of active tDCS on schizophrenic symptoms is assessed by CDSS score measured between baseline (day 0), after 10-sessions of tDCS regimen (day 5), 1 month after tDCS (day 30), 3 months after tDCS (day 90) and 6 months after tDCS (day 180). The CDSS score measures depression. | Baseline, day 5 (after 10-sessions of tDCS regimen), 1 month, 3 months and 6 months after the last tDCS session | 
| Clinical Global Impression (CGI) score | Long-term clinical efficacy of active tDCS on schizophrenic symptoms is assessed by CGI score measured between baseline (day 0), after 10-sessions of tDCS regimen (day 5), 1 month after tDCS (day 30), 3 months after tDCS (day 90) and 6 months after tDCS (day 180). The CGI score measures the severity of symptoms and response to treatment. | Baseline, day 5 (after 10-sessions of tDCS regimen), 1 month, 3 months and 6 months after the last tDCS session | 
| Shortened Quality of Life questionnaire score | Quality of life is assessed by S-QoL18 (Shortened Quality of Life questionnaire) scale. S-QoL18 scale assesses eight dimensions : psychological well-being, self-esteem, family relationships, relationships with friends, resilience, physical well-being, autonomy and sentimental life. | Baseline and 6 months after the last tDCS session | 
| Scale to assess Unawareness of Mental Disorder (SUMD) score | SMUD score (Scale to assess Unawareness of Mental Disorder score) assesses the effect of tDCS on patients' attitudes toward treatment of schizophrenia | Baseline and 3 months after the last tDCS session | 
| Medication Adherence rating Scale (MARS) score | MARS score assesses the effect of tDCS on patients' attitudes toward treatment of schizophrenia | Baseline and 3 months after the last tDCS session | 
| Brief Medication Questionnaire (BMQ) scores | BMQ scores (BMQ and BMQ tDCS) assesses the effect of tDCS on patients' attitudes toward treatment of schizophrenia | Baseline and 3 months after the last tDCS session | 
| Source monitoring test score | Source memory test is performed at baseline and after 10-sessions of tDCS regimen to investigate the effect of tDCS on source monitoring capacities, a cognitive function that may underlie psychotic symptoms (Brunelin et al. 2006). | Baseline and day 5 (after 10-sessions of tDCS regimen) | 
| Functional magnetic resonance imaging (MRI) | In order to evaluate treatment-related changes in functional brain connectivity, a functional MRI scans is performed at baseline (day 0), after 10-sessions of tDCS regimen (day 5) and 1 month after the last tDCS session (day 30). | Baseline, day 5 (after 10-sessions of tDCS regimen) and 1 month after the last tDCS session | 
| Anatomical magnetic resonance imaging (MRI) | In order to evaluate treatment-related changes in functional brain connectivity, an anatomical MRI scans is performed at baseline (day 0), after 10-sessions of tDCS regimen (day 5) and 1 month after the last tDCS session (day 30). | Baseline, day 5 (after 10-sessions of tDCS regimen) and 1 month after the last tDCS session | 
| Total serum Brain-Derived-Neurotrophic Factor (BDNF) | Total serum BDNF level is measured to investigate the association between neural markers and clinical response to tDCS. It is hypothised that total serum BDNF is a predictive neural marker of therapeutic response. | Baseline | 
| Serum Brain-Derived-Neurotrophic Factor (BDNF) isoforms | Serum BDNF isoforms level is measured to investigate the association between neural markers and clinical response to tDCS. It is hypothised that serum BDNFisoforms is a predictive neural marker of therapeutic response. | Baseline | 
| Self-evaluation of Negative Symptoms (SNS) score | The Self-evaluation of Negative Symptoms scale is a French self-administered questionnaire composed of 20 items organized into 5 domains of negative symptoms of schizophrenia (social withdrawal, diminished emotional range, alogia, avolition, anhedonia). | Baseline, 1 month and 3 months after the last tDCS session | 
| Fargerström test score | The Fargerström test for nicotine dependence (FTND) is a short form includes six questions designed to estimate the degree of nicotine dependence in tobacco smoking. | Baseline, 1 month and 6 months after the last tDCS session | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sham, Schizophrenia, Transcranial direct-current stimulation (tDCS), Positive and Negative Syndrome Scale (PANSS), Functional Magnetic Resonance Imaging (fRMI), Brain-Derived-Neurotrophic Factor (BDNF)