An interventional study of Transcranial direct current stimulation and Executive function training in Schizophrenia, Schizophrenia Spectrum Disorder and Schizophrenia and Related Disorders, sponsored by University of Toronto. Withdrawn at 1 site in Canada. Open to participants aged 18 Years to 65 Years. Per ClinicalTrials.gov, last updated 2024-07-30.
Sponsored by University of Toronto · Not applicable, Interventional, and Treatment
Schizophrenia-spectrum disorders are the most persistent, debilitating, and economically burdensome mental illnesses worldwide. Cognitive remediation (CR) is a psychological intervention based on principles of learning and neuroplasticity to improve cognitive abilities. The investigators previously developed a novel CR intervention specifically targeting executive functions and aimed here to enhance its effect on functioning by combining it with Transcranial direct current stimulation (tDCs). The primary goal is to determine whether receiving tDCS prior to CR improves one's ability to engage in cognitive activities and enhance cognitive abilities. To do so, 40 participants will be recruited with schizophrenia-spectrum disorders from Ontario Shores inpatient units, half of whom will receive real tDCS and half will receive sham tDCS, whereas all will receive CR. This study will provide important information on whether the outcome of training executive function can be further enhanced with non-invasive brain stimulation.
Schizophrenia-spectrum disorders are the most persistent, debilitating, and economically burdensome mental illnesses worldwide, and are associated with the greatest per-patient expense of all mental health conditions. Schizophrenia is associated with a 15-20 year decrease in life expectancy, 5-fold increase in likelihood of death by suicide, and a significant decrease in quality of life. Antipsychotic medications are the first line treatment for individuals with schizophrenia-spectrum disorders and are prescribed to nearly every service-user. However, in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) trial (one of the largest antipsychotic trials in 1493 individuals with schizophrenia), medication effects on psychosocial functioning were small (d = 0.25). Thus, the primary treatment available to all individuals with schizophrenia does little to improve community functioning. This may partially be a result of the limited efficacy of antipsychotic medication to improve neurocognitive abilities, widely recognized as a core feature of schizophrenia, and one recommendation stemming from the CATIE trial was that "more intensive psychosocial rehabilitative services, including cognitive rehabilitation, may be needed to affect more substantial gains in functioning."
Cognitive remediation (CR) is a psychological intervention based on principles of learning and neuroplasticity to improve neurocognitive abilities with the ultimate goal of improving community functioning. The neuroplastic effects of CR are well established with evidence for increased gray matter volume in the hippocampus and amygdala, increased activation of the medial prefrontal cortex, and increased amplitude of the mismatch negativity event-related potential following CR. In two recent randomized controlled trials (RCTs), we also demonstrated that CR improves synchronization of neural networks in the alpha and theta frequency bands. Meta-analyses support moderate transfer of these neurophysiological improvements to neurocognitive abilities (d = 0.45) and community functioning (d = 0.37). In a recent systematic review, we reported that CR approaches vary widely, but approaches that incorporate training of executive functions are generally the most effective. Based on these findings we developed a novel CR intervention specifically targeting executive functions and conducted two double-blind RCTs, in which targeted executive function training (ET) produced greater improvements in neurophysiology, neurocognition, functional skills and real-world community functioning compared to other leading forms of CR. This intervention is approximately half the duration of other CR programs, yet produces larger effect size improvements in community functioning.
Further augmentation of CR is needed to increase effect size and impact on community functioning in schizophrenia. One such augmentation strategy is via interventions that are known to enhance neuroplasticity, which is the underlying mechanism of learning. A promising neuroplasticity enhancing methodology is via non-invasive brain stimulation.
Transcranial direct current stimulation (tDCs) is the most common form of non-invasive transcranial electric stimulation (tES). Unlike other forms of transcranial electric stimulation (for example electroconvulsive therapy of ECT), tDCS is designed to modify cortical excitability by making underlying neurons more or less likely to fire but is not designed to induce depolarization or action potential in the neurons. tDCS involves application of a weak, constant (i.e., "direct") electric current from one electrode (anode) placed on the scalp to another (cathode) in order to modify cortical excitability. The application strength can be measured by amplitude of the current applied (usually one or two Amperes) and duration of application (usually around 20-30 minutes). tDCS is thought to be relatively safe with main side effect of local skin irritation and local skin burn. The risk of inducing a seizure is extremely low (mainly pediatric case report evidence), and in fact tDCS has literature support suggesting potentially anti-seizure effects. tDCS has been investigated for several therapeutic applications including cognitive disorders with promising results. There are some preliminary studies that support the feasibility, safety and promising efficacy of tDCS in combination with CR in schizophrenia. These studies are generally small and focused on cognitive domains such as working memory. More studies are needed to evaluate the added value of tDCS on effect size and impact on executive and community functioning.
Although cognitive remediation approaches such as ET improve community functioning for people with schizophrenia-spectrum disorders, these approaches may be further refined to improve efficacy. One option is to combine ET with neurostimulation designed to prime the brain for enhanced learning. In order to further increase the efficiency and effectiveness of ET it is necessary to determine whether receiving tDCS prior to engaging in this cognitive training intervention may enhance one's ability to engage in cognitive activities, or may improve their cognitive abilities. This will provide important information regarding whether the outcomes of ET can be further enhanced, which will directly inform clinical methods and optimize the effectiveness of this treatment.
The primary goal of this study is to:
(1) Examine the efficacy of combined Executive Training and tDCS compared to Executive Training combined with sham tDCS on neurocognition and functioning.
The participants for this study will be recruited from Ontario Shores inpatient units, specifically Complex General Psychiatry (CGP) inpatient units, which historically averages a length of stay of 51 to 159 days depending on the specific unit and typically comprises 70 to 75 patients at any given time with diagnoses of schizophrenia/schizophrenia spectrum disorders. Inpatients who are not expected to be discharged for 4 weeks (period needed for study interventions) will be enrolled. However, if a participant is discharged before the end of the treatment, arrangements will be made for him/her to complete the intervention by coming on-site daily for tDCS and ET.
Participants will be randomized using an online random number table to receive actual tDCS prior to engaging in ET or sham tDCS prior to engaging in ET. All participants will receive ET. The randomization sequence will be pre-generated by the study coordinator who will then inform the treating clinician. Three assessments will be completed over the course of the study: one within 1 to 2 weeks of the start of the intervention, one within 1 to 2 weeks after the intervention is complete, and one 3-months after the intervention is complete. Each assessment will last about 2.5 hours and can be conducted over two days according to participant preference. These assessments will involve paper/pencil tests and questionnaires, computerized tests, and Electroencephalogram (EEG) recordings.
Primary and secondary outcomes will be examined using Linear Mixed Models on the Intent-to-Treat sample with missing data interpolated using maximum likelihood estimation. The primary endpoint is the 3-month follow-up assessment, and secondary endpoint of post-intervention will also be examined.
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Exclusion Criteria:
All interventions will involve 4 weeks of group intervention consisting of two 1-hour group sessions per week and additional practice between sessions. Half of study participants will be randomized to receive 30 minutes of transcranial direct current stimulation (tDCS) prior to beginning each ET session. ET session will begin immediately after tDCS.
Behavioral: Transcranial direct current stimulation · Behavioral: Executive function training
All interventions will involve 4 weeks of group intervention consisting of two 1-hour group sessions per week and additional practice between sessions. Half of study participants will be randomized to receive 30 minutes of sham transcranial direct current stimulation (tDCS) prior to beginning each ET session. ET session will begin immediately after tDCS. During the sham tDCS, the procedures will be exactly the same as the real tDCS (e.g., application of electrodes), however, no stimulation will be provided when the device turned on.
Behavioral: Executive function training
Participants will receive bilateral prefrontal anodal stimulation with cathode placed on the back of the upper neck. Transcranial direct current stimulation (tDCS) will be delivered by a research assistant under the supervision of a psychiatrist.
Also known as: tDCS
The Executive Training (ET) aspect of the study will be completed by all participants. ET sessions consist of 50% of the session practicing computerized cognitive training exercises, and 50% of the session developing cognitive strategies to use in the computerized exercises. Participants are encouraged to complete 40 minutes of computerized training per day, and complete strategy worksheets, on the unit or in the library at Ontario Shores between sessions. ET will be delivered virtually and group sessions will be conducted using the online platform Zoom. For any group sessions, a PHIPA and PIPEDA compliant license will be used. This means that participants will not be able to record their screen using Zoom or a third-party program. Dr. Best will also go through some rules during the first group Zoom session regarding the use of third-party equipment and the importance of confidentiality.
Also known as: ET, Cognitive remediation, CR
Specific Levels of Functioning (SLOF)
The SLOF scale is a measure of community functioning
Time frame: Change from baseline to 3-month follow-up
Cambridge Neuropsychological Test Automated Battery (CANTAB)
The CANTAB is a battery consisting of highly sensitive, precise and objective measures of cognitive function. It includes tests of working memory, learning and executive function; visual, verbal and episodic memory; attention, information processing and reaction time; social and emotion recognition, decision making and response control.
Time frame: baseline within 1-2 weeks of start of intervention, 1-2 week follow-up after intervention complete, 3-month follow up
Reading subtest of the Wide Range Achievement Test (WRAT)
The WRAT is an academic skills assessment which measures reading skills and provides an estimate of premorbid intellectual ability.
Time frame: baseline within 1-2 weeks of start of intervention, 1-2 week follow-up after intervention complete, 3-month follow up
Questionnaire About the Process of Recovery (QPR)
The QPR was developed from service users' accounts of recovery from psychosis in collaboration with local service users. It asks people living with psychosis about aspects of recovery that are meaningful to them, and is strongly associated with general psychological wellbeing, quality of life and empowerment. This version contains 22 items while the response to each statement is scored on a 5-point Likert scale ranging from "0 = strongly disagree" to "4 = strongly agree". The lowest possible score is 0 and the highest score could be 88. Higher scores would indicate better recovery.
Time frame: baseline within 1-2 weeks of start of intervention, 1-2 week follow-up after intervention complete, 3-month follow up
Brief Psychiatric Rating Scale (BPRS)
The BPRS measures psychopathology and symptom severity and is sensitive to changes in symptom levels
Time frame: baseline within 1-2 weeks of start of intervention, 1-2 week follow-up after intervention complete, 3-month follow up
Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q)
The Q-LES-Q is a sensitive measure of the degree of enjoyment and satisfaction experienced by subjects in various areas of daily functioning.
Time frame: baseline within 1-2 weeks of start of intervention, 1-2 week follow-up after intervention complete, 3-month follow up
Dysfunctional Attitudes Scale (DAS)
DAS is a 40-item self-report measure assessing self-defeating attitudes theorized to underlie clinical depression and anxiety. The degree of agreement to each statement is scored on a 7-point Likert scale (1 = agree totally, 2 = agree very much, 3 = agree slightly, 4 = neutral, 5 = disagree slightly, 6 = disagree very much, 7 = disagree totally). The lowest possible scale is 40 while the highest possible scale is 280. Higher scores would indicate more negative beliefs.
Time frame: baseline within 1-2 weeks of start of intervention, 1-2 week follow-up after intervention complete, 3-month follow up
Brief Core Schema Scale (BCSS)
The BCSS is a 24-item self-report measure assessing positive and negative judgments individuals hold about themselves and others. Responses are first given dichotomously as "no" or "yes". "No" is scored as 0 and if the answers are "yes", the intensity of beliefs are then rated on a 4-point scale (1 = believe it slightly, 2 = believe it moderately, 3 = believe it very much, 4 = believe it totally). The lowest score would be a 0 and the highest score would be a 96. Higher scores in the positive-self subscale indicate more positive beliefs about selves, while higher scores in the negative-self subscale indicate more negative beliefs about selves. Higher scores in the positive-others subscale indicate more positive beliefs about others, while higher scores in the negative-others subscale indicate more negative beliefs about others.
Time frame: baseline within 1-2 weeks of start of intervention, 1-2 week follow-up after intervention complete, 3-month follow up
Generalized Self-Efficacy Scale (GSES)
The GSES assess optimistic self-beliefs to cope with a variety of difficult demands in life
Time frame: baseline within 1-2 weeks of start of intervention, 1-2 week follow-up after intervention complete, 3-month follow up
Cognitive Failures Questionnaire (CFQ)
The CFQ was designed to measure perception, memory, and motor lapses in daily life
Time frame: baseline within 1-2 weeks of start of intervention, 1-2 week follow-up after intervention complete, 3-month follow up
Need for Cognition Scale (NCS)
The NCS measures the tendency for an individual to engage in and enjoy thinking
Time frame: baseline within 1-2 weeks of start of intervention, 1-2 week follow-up after intervention complete, 3-month follow up
Davos Assessment of Cognitive Biases (DACOBS)
The DACOBS is a 42-item self-report inventory measuring cognitive biases and discriminates between schizophrenia-spectrum patients and normal control subjects. The degree of agreement to each statement is scored on a 7-point Likert scale, ranging from "1 = strongly disagree" to "7 = strongly agree". The lowest score would be a 42 and the highest score would be a 294. Higher scores would indicate more cognitive biases.
Time frame: baseline within 1-2 weeks of start of intervention, 1-2 week follow-up after intervention complete, 3-month follow up
Motivation and Pleasure Scale - Self-Report (MAP-SR)
The MAP-SR assess the motivation and pleasure domains of negative symptoms.
Time frame: baseline within 1-2 weeks of start of intervention, 1-2 week follow-up after intervention complete, 3-month follow up
Electroencephalogram (EEG)
EEG will also be assessed using the Emotiv portable EEG system to assess neural synchronization to better understand how neural signatures change before and after the intervention. All EEG will be performed at Ontario Shores. Synchronization in the alpha and theta frequency bands during standard working memory and attention tests will be used to assess synchronization.
Time frame: baseline within 1-2 weeks of start of intervention, 1-2 week follow-up after intervention complete, 3-month follow up
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