Brain Image Markers Associated With Cognitive Training and Aerobic Exercise in Schizophrenia (CORTEX-SP)

A Randomized, Open-Label, Parallel-Group Study to Investigate The Effect of Cognitive Training and Aerobic Exercise on Brain, Functional Outcome and Cognition in Schizophrenia

This study evaluates the brain correlates of Cognitive Training and Aerobic Exercise in schizophrenia. A third of participants will receive Cognitive Training plus Standard Care for schizophrenia. Another third of participants will receive Aerobic Exercise Training plus Standard Care for schizophrenia. A control group will of participants will receive Standard Care plus Occupational Activities for the same duration and frequency as the experimental groups.

Study Overview

• Status: Unknown
• Conditions: Schizophrenia
• Intervention / Treatment: Behavioral: Aerobic Exercise; Behavioral: Cognitive Training; Behavioral: Treatment as usual; Behavioral: Occupational Activities

Detailed Description

This study, randomized, open, controlled with schizophrenia-standard-care, is aimed to determine structural and functional brain changes associated to cognitive remediation and physical exercise in schizophrenia.

The study participants will be enrolled in the catchment area of the Hospital Psiquiatrico de Alava, in the province of Alava, Basque Region, Northern Spain.147 patients diagnosed with schizophrenia will be randomly assigned to Cognitive Training Group or Aerobic Exercise Group or a Control Group for a five-month period.

Both Cognitive Training Group patients and Aerobic Exercise Group patients will participate in training sessions of 60 min/d, 3 d/wk. Patients assigned to Control Group will receive the standard care for schizophrenia in this area plus occupational activities for the same duration and frequency than the two experimental groups.

Cognitive Training will be implemented through REHACOP, a cognitive remediation program for Spanish speaking patients with schizophrenia whose efficacy on cognitive performance and negative symptoms has already been demonstrated in patients with schizophrenia. REHACOP is a "paper & pencil" based cognitive remediation program that covers 8 cognitive domains including social cognition. It is based on the principles of Optimization, Restauration & Compensation.

Aerobic Exercise Training will consist of an intensive physical exercise program supervised by certified graduates and doctorate students of Physical Activity and Sport Sciences. Sessions will include 10-minute warming-up and 10-minute back exercises and stretches. The main part of the session will consist of aerobic exercise (20-minute indoor bicycle) and muscle-resistance and strength exercises for 20 minutes. The intensity of the sessions will be determined on a case by case basis according to the HR necessary to achieve the intensity ranges (R2-moderate and R3-high). During the sessions, the bicycle's power and pace will be individually adjusted to achieve the selected HR.

The assessment batteries, neuroimaging and Serum BDNF levels will be administered and determined at baseline and immediately following the completion of the Cognitive Remediation or Aerobic Exercise interventions.

Primary outcomes: Structural and functional brain changes will be assessed by MRI neuroimaging. A Philips Achieva 3.0T MRI system equipped with a modular 32-channel architecture. 3 different types of images will be acquired: a) T1-weighted MRI imaging, b) Diffusion Tensor imaging, c) fMRI imaging at rest and using a cognitive paradigm.

Secondary outcomes will be changes in cognitive performance, clinical and functional changes and Serum BDNF changes.

• Study Type: Interventional
• Enrollment (Anticipated): 150
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Pedro M Sanchez Gomez, MD; Phone Number: 6558 +34 945006555; Email: gomepe@mac.com
• Study Contact Backup: Name: Edorta J Elizagarate Zabala, MD; Phone Number: +34 945006555; Email: eduardojose.elizagaratezabala@osakidetza.eus

Study Locations

• Spain
  • Alava
    • Vitoria, Alava, Spain, 01006
      • Recruiting
      • Hospital Psiquiatrico de Alava. Red Salud Mental de Araba
      • Contact: Pedro M. S Gomez, MD; Phone Number: 6558 +34 945006555; Email: gomepe@mac.com
      • Contact: Edorta J Elizagarate Zabala, MD; Phone Number: +34 945 00 6555; Email: eduardojose.elizagaratezabala@osakidetza.eus

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Diagnosis of Schizophrenia (DSM-5 F20.9)
• More than 2 years since the onset of the disease.
• Stable cognitive impairment.
• Moderate severity of cognitive impairment in MATRICS scores (T score < 40 in, at least, 1 out of 7 cognitive domains).

Exclusion Criteria:

• Subjects clinically unstable (PANSS positive score > 19).
• Cognitive impairment due to another medical condition (neurocognitive disorders, brain injury, intellectual disability, etc.)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Aerobic Exercise; This program consists of an exercise dosage of 180 min/week administered in 3 sessions of 60 minutes. Each session includes 10 minutes of warm-up exercise before the main exercise and 10 minutes of cool-down afterwards.the principal exercise section includes 20 minutes of aerobic exercise and 20 minutes of resistance and strength exercises. The exercise intensity will be regulated according to the heart rate measured by a pulsimeter throughout the exercise. The target intensity level will be individualized according to the heart rate to set the moderate intensity level (HR values between ventilatory thresholds) and high intensity level (HR values from 2nd. ventilatory threshold to the peak threshold).	Behavioral: Aerobic Exercise; Physical exercise training consisting of aerobic exercise and strength/resistance training.
Experimental: Cognitive Training; The CT group participates in a cognitive remediation program. This program consists of 3 sessions of 60 minutes per week. CT will be administered in groups of 5-8 subjects. The cognitive domains involved in the CT are attention/concentration, memory/learning, language, executive functions, social cognition, social skills, daily living activities and psychoeducation. Cognitive Remediation will be provided by using REHACOP, a cognitive remediation training tool designed and validated for Spanish patients with schizophrenia.	Behavioral: Cognitive Training; Cognitive remediation program using REHACOP rehabilitation program.
Sham Comparator: Treatment as usual; The TaU Group receives the usual treatment that patients with schizophrenia in Spain enriched with occupational activities administered 3 times a week with a duration of 60 minutes each session.	Behavioral: Treatment as usual; Standard care for schizophrenia + Leisure and free time activities.; Behavioral: Occupational Activities; Engagement in activities aimed to keep patients actively involved in demanding tasks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Grey Matter Volume Change	Assessment of Grey Matter volume changes (T1-weighted MRI) among the 3 groups using Voxel Based Morphometry (VBM).	5 months
Fractional Anisotropy Change	Assessment of changes in fractional anisotropy of White Matter fibers by Diffusion Tensor MR Imaging and using the Tract-Based Spatial Statistics (TBSS).	5 months
Functional Magnetic Resonance Imaging (fMRI) Change at Rest	Assessment of changes in fMRI at rest with the Coon Functional Connectivity Toolbox.	5 months
Functional Magnetic Resonance Imaging (fMRI) Change during the performance of a cognitive paradigm.	Assessment of changes in fMRI during the performance of a cognitive paradigm with Statistical Parametric Mapping (SPM8).	5 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serum BDNF	Assessment of changes in serum BDNF using ELISA immuno-assay techniques. Measured in ng/ml.	5 months.
Clinical Symptoms of Schizophrenia measured by the Positive and Negative Symptoms Scale (PANSS).	Severity of the negative symptoms will be assessed with the total score of the Subscale for Negative Symptoms of the PANSS scale, which comprises 7 items, each one measuring a specific negative symptom. Each item ranges from 1 (absence of the symptom) to 7 (extreme severity of the symptom). Total score of the Negative Subscale of the PANSS ranges from 7 (minimum score) to 49 (maximum severity). Severity of positive symptoms will be assessed with the total score of the Subscale for Positive Symptoms of the PANSS, which comprises 7 items ranging from 1 (absence of the symptom) to 7 (extreme severity of the symptom). Total score of the Positive Subscale ranges from 7 (minimun score) to 49 (maximun severity). General Psychopathology will be assessed with the total score of the General Psychopathology Subscale which comprises 16 items ranging from 1(absence of the symptom) to 7 (extreme severity of the symptom).	5 months.
Negative Symptoms of Schizophrenia measured by the Brief Negative Symptoms Scale (BNSS).	Severity of negative symptoms will be assessed with the total score of the BNSS. Values ranges from 0 (total absence of negative symptoms) to 90 (maximum severity of negative symptoms).	5 months
Negative Symptoms of Schizophrenia measured by the Clinical Assessment Interview for Negative Symptoms Scale (CAINS)	Severity of negative symptoms will be assessed with the total score of the CAINS scale. Values ranges from 0 (total absence of negative symptoms) to 52 (maximum severity of negative symptoms).	5 months
Functional Outcome measured by the UCSD Performance Based Assessment of Functional Skills in Severe Mental Illness (UPSA).	The UPSA includes the following 5 subscales: Financial Skills, Communication, Comprehension/Planning, Transportation, Household Management. Total scores for each subscale are calculated by transforming raw scores into a 0- to-10 scale, yielding comparable scores on each scale. In order to have a 100-point summary score, each subscale score is multiplied by 2, yielding subscale scores ranging from 1 to 20. A summary UPSA score is calculated by summing these five scores, resulting in total scores ranging from 0 to 100. Scores of 0 represent maximum severity of functional impairment and a score of 100 represents total absence of functional disability.	5 months
Functional Outcome measured by the World Health Organization Disability Assessment Schedule (WHODAS 2.0).	The 36-item version of WHODAS 2.0 allows users to generate scores for the six domains of functioning and to calculate an overall functioning score. The scores assigned to each of the items - "none" (1), "mild" (2) "moderate" (3), "se- vere" (4) and "extreme" (5) - are summed. A score of 36 represents total absence of disability and 180 maximum severity of disability.	5 months
Functional Outcome measured by the Short Form (36) Health Survey (SF-36).	The Short Form (36) Health Survey is a 36-item, patient-reported survey of patient health. The SF-36 consists of eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. The lower the score the more disability. The higher the score the less disability i.e., a score of zero is equivalent to maximum disability and a score of 100 is equivalent to no disability.	5 months
Physical Condition measured by the Modified Shuttle Walking Test	Heart rate achieved when walking between 2 cones spaced 10 meters at an increasing rate.	5 months
Cardiorespiratory Fitness measured with the Peak Oxygen Uptake (VO2 max)	maximum rate of oxygen consumption measured during incremental exercise (exercise of increasing intensity)	5 months
Weight.	Weight in Kg	5 months
Height	Height in meters.	5 months
Body composition measured with Body Mass Index (BMI)	The BMI is defined as the body mass divided by the square of the body height, and is expressed in units of kg/m2, resulting from mass in kilograms and height in metres.	5 months.
Abdominal Perimeter	Abdominal perimeter measured in centimeters.	5 months
Body Composition measured with Total Body Water.	Percentage of Total Body Water measured by Bioimpedance.	5 months
Body Composition measured with Body Fat.	Percentage of Body Fat measured by Bioimpedance.	5 months
Blood Pressure (systolic and diastolic)	Blood Pressure (systolic and diastolic) measured in millimeters of mercury (mmHg)	5 months
Fasting Blood Glucose Levels	Fasting Blood Glucose Levels measured in mg/dl.	5 months
Fasting Cholesterol Levels	Fasting Cholesterol Levels measured in mg/dl.	5 months
Daily Physical Activity and Sedentary Behavior measured by the International Physical Activity Questionnaire.	This measure assesses the types of intensity of physical activity and sitting time that people do as part of their daily lives are considered to estimate total physical activity in MET-min/week and time spent sitting.	5 months
Level of Daytime Sleepiness measured by Epworth Sleepiness Scale (ESS)ESS-EPWORTH.	The ESS measures a person's general level of daytime sleepiness, or their average sleep propensity in daily life (ASP). The ESS is a self-administered questionnaire with 8 questions. Respondents are asked to rate, on a 4-point scale (0-3), their usual chances of dozing off or falling asleep while engaged in eight different activities. The higher the ESS score, the higher that person's average sleep propensity in daily life (ASP), or their 'daytime sleepiness'.	5 months
Intensity of Daily Physical Activity measured by the Accelerometer.	Measurement of body movement in terms of accelerations.	5 months
Cognition-Processing Speed	WAIS III test: Digit Symbol-Coding. Measured in number of symbols correctly entered in 2 minutes.	5 months
Cognition-Attention/Vigilance Stroop Test	Stroop Test: measured in the number of items read or named in 45 seconds for each of the three sheets (word, color, and color-word).	5 months
Cognition-Working Memory Digit Span Backward	WAIS IV test: Digit Span Backward subtest. Measured with the number of sequences of numbers recalled in inverse order.	5 months
Cognition-Verbal Learning/Memory	Hopkins Verbal Learning Test-Revised (HVLT-R): number of correct words recalled.	5 months
Cognition-Reasoning/Problem Solving	Modified Wisconsin Card Sorting Test (M-WCST): score achieved at the M-WCST.	5 months
Cognition-Cognitive Reserve	Spanish version of the Word Accentuation Test (TAP-E). Measured with the number of correct attempts.	5 months
Cognition-Figural Creativity	Torrance Test of Creative Thinking: Picture Completion subtest. Measured with Fluency, Originality, Elaboration, Resistance to Premature Closure, Abstractness of Titles, and Creative Strengths dimensions obtained from the drawings made in the task.	5 months
Cognition-Verbal Creativity	Torrance Test of Creative Thinking: Unusual Uses subtest. Measured with Fluency, Originality, and Flexibility dimensions obtained from the written unusual uses for cardboard boxes and tin cans.	5 months
Social Cognition-Social Attribution	Social Attribution Test (SAT). SAT is comprised of a 64 second animation with geometric figures enacting a social drama and 19 multiple-choice questions about the animation. Four possible responses are given to each question. Each correct response is scored with 1 point. Total score ranges from 0 to 19.	5 months
Social Cognition-Emotion Recognition	Bell Lysaker Emotion Recognition Task (BLERT). BLERT consists of 21 short video clips in which an actor displays one of seven emotions with three neutral monologues. The examinee is asked to indicate which emotion the actor is portraying. Each correct response is scored with 1 point. The total score is obtained from the sum of each correct emotion recognition, ranging from 0 to 21.	5 months
Social Cognition-Theory of Mind	Happe's "Strange Stories Task" Test. Strange Stories Task is comprised of 8 stories concerning double bluff, mistakes, persuasion, and white lies. Each story is scored from 0 to 2. Higher scores indicate a better performance in theory of mind.	5 months
Social Functioning measured by the Social Functioning Scale Short-Form (SFS-15)	The SFS-15 is a 15-item scale designed to measure social functioning in patients with schizophrenia. It includes items about isolation, interpersonal communication, independence-execution, independence-competence, and employment-occupation. 13 of the items range from 0 to 3 and the other 2 items range from 1 to 2. Total score is obtained from the sum of the 15 items. Total score range from 1 to 43 points. Higher scores indicate higher level of social functioning.	5 months
Self-Efficacy measured by the General Self-Efficacy Scale	General Self-Efficacy Scale is a 10-item scale that measures optimistic self-beliefs to cope with a variety of difficult demands in life. The scores assigned to each of the item - "Not at all true" (1), "Hardly true" (2), "Moderately true" (3), and "Exactly true" (4) - are summed. The final score ranges from 10 to 40, higher scores indicating a higher level of self-efficacy.	5 months
Social Anhedonia measured with the Anticipatory and Consummatory Interpersonal Pleasure Scale (ACIPS)	The ACIPS is a 17-item scale that consists of 7 anticipatory and 10 consummatory items. The scores assigned to each of the items range from 1 (very false for me) to 6 (very true for me). Total score is obtained from the sum of the 17 items. Higher scores indicate higher ability to experience interpersonal pleasure.	5 months
Handedness measured by the Edinburgh Handedness Inventory	A self-report questionnaire assessing the dominance of a person's right or left hand in ten different everyday activities.	5 months
Treatment satisfaction measured by the Spanish version of Consumer Reports Effectiveness Scale (CRES-4)	CRES-4 consists of a 4-item scale designed to evaluate patient's satisfaction with the received therapy. Its global score reflects treatment effectiveness as perceived by the patient. 3 components can be obtained: "satisfaction" (based on the first item, which ranges from 0 to 5), "problem resolution" (based on the second item, which ranges from 0 to 5), and "perceived emotional change" (obtained from the subtraction of the third from the fourth item, which range from 0 to 4). The "satisfaction" component is multiplied by 20, the "problem resolution" by 20 and the "perceived emotional change" by 12.5. Final score is obtained from the sum of the three components, ranging from 0 to 300. Higher scores indicate a greater perception of treatment efficacy.	5 months

Collaborators and Investigators

• Sponsor: Red Salud Mental Araba
• Collaborators: University of the Basque Country (UPV/EHU); University of Deusto
• Investigators: Principal Investigator: Pedro M Sanchez Gomez, MD, Hospital Psiquiatrico de Alava. Red de Salud Mental de Araba.

Publications and helpful links

General Publications

• Sanchez P, Pena J, Bengoetxea E, Ojeda N, Elizagarate E, Ezcurra J, Gutierrez M. Improvements in negative symptoms and functional outcome after a new generation cognitive remediation program: a randomized controlled trial. Schizophr Bull. 2014 May;40(3):707-15. doi: 10.1093/schbul/sbt057. Epub 2013 May 18.
• Ojeda N, Pena J, Bengoetxea E, Garcia A, Sanchez P, Elizagarate E, Segarra R, Ezcurra J, Gutierrez-Fraile M, Eguiluz JI. [REHACOP: a cognitive rehabilitation programme in psychosis]. Rev Neurol. 2012 Mar 16;54(6):337-42. Spanish.
• Pena J, Ibarretxe-Bilbao N, Sanchez P, Uriarte JJ, Elizagarate E, Gutierrez M, Ojeda N. Mechanisms of functional improvement through cognitive rehabilitation in schizophrenia. J Psychiatr Res. 2018 Jun;101:21-27. doi: 10.1016/j.jpsychires.2018.03.002. Epub 2018 Mar 6.
• Pena J, Ibarretxe-Bilbao N, Sanchez P, Iriarte MB, Elizagarate E, Garay MA, Gutierrez M, Iribarren A, Ojeda N. Combining social cognitive treatment, cognitive remediation, and functional skills training in schizophrenia: a randomized controlled trial. NPJ Schizophr. 2016 Nov 9;2:16037. doi: 10.1038/npjschz.2016.37. eCollection 2016.
• Ojeda N, Pena J, Bengoetxea E, Garcia A, Sanchez P, Elizagarate E, Segarra R, Ezcurra J, Gutierrez-Fraile M, Eguiluz JI. [Evidence of the effectiveness of cognitive rehabilitation in psychosis and schizophrenia with the REHACOP programme]. Rev Neurol. 2012 May 16;54(10):577-86. Spanish.
• Ojeda N, Pena J, Sanchez P, Bengoetxea E, Elizagarate E, Ezcurra J, Gutierrez Fraile M. Efficiency of cognitive rehabilitation with REHACOP in chronic treatment resistant Hispanic patients. NeuroRehabilitation. 2012;30(1):65-74. doi: 10.3233/NRE-2011-0728.
• Tous-Espelosin M, de Azua SR, Iriarte-Yoller N, MartinezAguirre-Betolaza A, Sanchez PM, Corres P, Arratibel-Imaz I, Sampedro A, Pena J, Maldonado-Martin S. Clinical, physical, physiological, and cardiovascular risk patterns of adults with schizophrenia: CORTEX-SP study: Characterization of adults with schizophrenia. Psychiatry Res. 2021 Jan;295:113580. doi: 10.1016/j.psychres.2020.113580. Epub 2020 Nov 18.

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2017
• Primary Completion (Anticipated): December 31, 2019
• Study Completion (Anticipated): June 1, 2020

Study Registration Dates

• First Submitted: April 11, 2018
• First Submitted That Met QC Criteria: April 25, 2018
• First Posted (Actual): April 26, 2018

Study Record Updates

• Last Update Posted (Actual): July 30, 2019
• Last Update Submitted That Met QC Criteria: July 26, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Keywords: Aerobic exercise; Cognition; Physical exercise; Negative symptoms; Cognitive remediation; Functional outcome
• Additional Relevant MeSH Terms: Mental Disorders; Schizophrenia Spectrum and Other Psychotic Disorders; Schizophrenia
• Other Study ID Numbers: CORTEX-SP Study; PI16/01022 (Other Grant/Funding Number: Instituto de Salud Carlos III (ISCIII))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No