Attenuated Psychosis Syndrome
Conditions
Keywords
UHR, Remediation, Exercise, Intervention, Psychosis
Brief summary
The goal of this proposal is to test the feasibility and effectiveness of cardiovascular exercise in promoting brain health and improving related symptoms (e.g., hearing sounds that are not there, feeling emotionally detached from self and others), cognitive difficulties (troubles with memory and learning), and every day social-occupational functioning in youth at imminent risk for developing a psychotic disorder such as schizophrenia. Understanding how exercise may protect or improve the health of a brain area that is implicated as a major contributing factor to the onset of psychosis may lead to a path-breaking new intervention that does not suffer from many of the side effects, costs, and other barriers that characterize treatments that are currently available for this group. Because a significant portion of high-risk youth go on to develop a psychotic disorder in a short period, intervening at this stage may help to improve the clinical course and ultimately prevent the onset of a devastating and prevalent mental illness.
Detailed description
Accumulating evidence from the animal literature, healthy populations, and schizophrenia studies suggests that regular exercise positively affects integral functions such as neurogenesis, synaptic plasticity and cognition. Likewise, preliminary evidence suggests that aerobic activity has been associated with improved quality of life and a lower level of symptoms in patients with schizophrenia. Because exercise has been found to stimulate human medial temporal neurogenesis, and related abnormalities have been widely observed in studies of schizophrenia, physical activity may be in an important intervention. During the psychosis prodrome, a period immediately proceeding formal onset of psychotic disorders, adolescents experience subtle attenuated symptoms coupled with cognitive deterioration and a global decline in socio-occupational functioning and anywhere between 10-35% go on to transition to a psychotic disorder such as schizophrenia in a two-year period. Despite the promise of exercise interventions, and the critical role medial temporal lobe abnormalities play in etiological models of psychosis, there have been no experimental studies of aerobic exercise in ultra-high risk youth (UHR). Understanding the potential benefits of aerobic exercise in UHR youth is integral as the prodrome is a viable period of intervention in which considerable brain development is still occurring. Further, as there have been challenges associated with many of the available interventions, and an increasing level of potential found in neuroplasticity-based interventions, understanding the effect of exercise on respective brain-behavior holds considerable promise. Experimental research is sorely needed to determine if prescribed aerobic exercise can stimulate medial-temporal neurogenesis and ameliorate cognition and symptoms/functioning in this vital group. In the proposed study, an expert team of experienced prodromal and exercise investigators will follow a group of 15 UHR adolescent and young adults (ages 16-24) through a 12 week exercise trial to determine which level of exercise intensity/frequency is tolerable for participants and optimal for improving aerobic fitness (65% of VO2max and 2 sessions per week versus 85% intensity and 3 sessions per peek) and if improvements in aerobic fitness (i.e., VO2max, VO2peak, ventilatory threshold) are associated with increases in medial temporal structure volume (hippocampus and parahippocampal gyrus) and accompanying improvements in cognitive function (i.e., including tasks known to recruit heavily on medial temporal structures) as well as symptomatology and social/role functioning. If the benchmarks are met, this data will be used to streamline a three-year rater-blind controlled trial (15 UHR-exercise, 15 UHR waitlist-control) to determine the efficacy of the intervention in promoting medial temporal health as well as accompanying cognitive, clinical, and socio-occupational function improvement. Participants will be followed up to 24-months to determine if the intervention has an affect on clinical course and transition to psychosis. Taken together, this study is important for understanding the lessons necessary for planning a future large-scale trial, and has the potential to shed light on a promising new treatment for UHR youth.
Interventions
BEHAVIORALExercise 1
65% of VO2max and 2 sessions per week
BEHAVIORALExercise 2
85% intensity and 3 sessions per peek
Sponsors
University of Colorado, Denver
National Institute of Mental Health (NIMH)
Northwestern University
University of Colorado, Boulder
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
16 Years to 24 Years
Healthy volunteers
Yes
Inclusion criteria
* age 16-24 * no history of brain injury or neurological disease * no contraindications to exercise training (as assessed by a Clinical Translational Research Center CTRC physician) * no history or current treatment with antipsychotics * no contraindications for being in an magnetic resonance imaging scanner. * meet criteria for a prodromal syndrome based upon the Structure Interview for Prodromal Syndromes (SIPS) interview.
Exclusion criteria
* people who are extremely claustrophobic * have a history of significant head injury * other physical disorder that could affect brain functioning * mental retardation * history of substance use disorder within 6 months of screening interview * have a psychotic disorder (at study entry) and/or have exhibited serious self-harm behaviors * pregnant females * people who have contraindications to magnetic resonance (MR) scanning including intracranial, intraorbital or intraspinal metal, pacemakers, cochlear implants or other non-MR-compatible devices * inability of the subject or their parent/guardian to understand the informed consent document * meeting criteria for an Axis I psychotic disorder
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Brain Volume | pre-trial, post-trial (3-months) | Medial temporal structures (hippocampus and parahippocampal gyrus) will be delineated automatically using the FMRIB's Integrated Registration and Segmentation Tool algorithm within the FMRIB's Software Library (FSL) image-processing suite. Secondly, the structures will be evaluated with vertex analyses (assessing changes in shape post trial on a per-vertex basis), which will also be carried out utilizing FIRST. Shape/appearance models used in FIRST are constructed from manually segmented images provided by the Center for Morphometric Analysis (CMA, Boston). This approach is different from using a whole-structure summary measure like volume, as it allows visualization of the region of the shape that is changing as well as the type of shape change. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Working Memory Assessment | pre-trial, post-trial (3-months) | Working Memory Assessment - Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) battery working memory subscale - a higher score indicates working memory better performance. The Relational and Item-Specific Encoding task includes visual object representations of word stimuli. Subjects make a two-button yes/no response to indicate whether items in each pair had been presented together.To prevent additional encoding of the relational object pairs the item recognition task precedes the associated recognition task. Higher scores reflect the familiarity and recollection performance as well as hit rates and false alarm rates following encoding - better performance. MATRICS Consensus Cognitive Battery working memory subscale using a t-score (0=population mean, standard deviation=10) and Relational and Item-Specific Encoding Task accuracy score in the RCT study using a task specific accuracy (d prime range; 0-100%). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Attenuated Psychosis Positive Symptom Subscales | pre-trial, post-trial (3-months) | The Structured Interview for Prodromal Symptoms (SIPS) will be administered to formally assess attenuated positive symptoms after inclusion in the study. It will also be administered post-trial to track changes in clinical symptoms post intervention trial. The SIPS rates the severity of relevant dimensions including positive symptoms along a 7-point scale ranging from absent (0) to severe and psychotic (6) across five symptom categories, resulting in a score that ranges from 0 (no positive symptoms) to 30 (psychosis along all symptoms dimensions). |
| Aerobic Fitness | pre-trial, post-trial (3 months) | VO2max was assessed via a modified Balke protocol by an exercise physiologist under the supervision of a physician. In this modified Balke protocol, the treadmill speed was individualized in a procedure to elicit 70% of the age-predicted max heart rate and ratings of a somewhat hard perceived exertion (RPE). Then, the speed of the treadmill remained the same throughout the test, but the incline of the treadmill belt increased 2% every 2 min (or 2.5% for speeds 6 mph or greater) to exhaustion. Tests generally lasted 8-12 minutes to attain the recommended target for VO2max testing. Measures indicate cardiovascular health with higher scores indicating greater health. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Exercise - High Impact Interval 95% VO2 Max -32 Week The exercise group participants completed a 3-month exercise treatment twice a week at moderate to intense levels of aerobic exercise (24 sessions over 12 weeks). To limit the perceived barriers to sessions,15 participants were provided with free transportation to the sessions, after the session access to healthy snacks and refreshments were provided. Participants received paid compensation after each session. All sessions were conducted as one-on-one sessions by the same exercise physiologist under the supervision of a physician to build rapport with participants and ensure consistency in the protocol. These high-intensity interval exercise sessions were tailored to the individual's exercise fitness level based on the baseline VO2max assessment. For initial tolerance, the treadmill exercise intensity was set to elicit 55% of the participant's VO2max which was increased to 80% gradually over the first 3 weeks. During the remainder of the trial (21 weeks), the 2 weekly, treadmill sessions were designed to elicit 80% of VO2max for the majority of the time with 1-min high-intensity intervals at 95% of VO2max, every 10 minutes for 3 repetitions for a total of 30 mins. This protocol was adapted from findings in the open-label pilot study, which suggested that fewer sessions and higher intensity of exercise were needed. After the exercise intervention, participants repeated the baseline visit again with separate study staff who were blinded to their exercise intervention status. | 18 |
| Wait List These individuals completed cognitive assessment, clinical assessment, and MRIs at baseline and follow up, but were not provided with exercise intervention. All assessors were blind to intervention status. | 20 |
| Dosage Study 85% Vigorous Participants were randomly assigned to 1 of 2 conditions:
moderate or vigorous. The moderate condition required exercise 2 days a week at 65% of their Vo 2max for a total of 24 sessions. of 36 sessions. Participants wore a Polar FT1 heart rate monitor (https://www.polar.com/us-en) throughout each exercise session, and an exercise physiologist monitored the participant's exercise in order to keep the participant's heart rate at ± 5% of the prescribed target intensity. Initial exercise sessions lasted 15 minutes at 55% of Vo 2max intensity and were gradually increased to 30 minutes and target intensity within the first 3 weeks. The remaining exercise sessions lasted 30 minutes and were conducted at prescribed exercise intensity. Participants were given the choice to ride stationary bikes, run/walk on treadmills, or use elliptical machines at each session. | 5 |
| Dosage Study 65%Moderate Participants were randomly assigned to 1 of 2 conditions:
moderate or vigorous. The moderate condition required exercise 2 days a week at 65% of their Vo 2max for a total of 24 sessions. Participants wore a Polar FT1 heart rate monitor (https://www.polar.com/us-en) throughout each exercise session, and an exercise physiologist monitored the participant's exercise in order to keep the participant's heart rate at ± 5% of the prescribed target intensity. Initial exercise sessions lasted 15 minutes at 55% of Vo 2max intensity and were gradually increased to 30 minutes and target intensity within the first 3 weeks. The remaining exercise sessions lasted 30 minutes and were conducted at prescribed exercise intensity. Participants were given the choice to ride stationary bikes, run/walk on treadmills, or use elliptical machines at each session. | 7 |
| Total | 50 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Emergence of Psychosis or Substance disorder during protocol | 0 | 0 | 2 | 1 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 3 |
| Overall Study | Withdrawal by Subject | 0 | 3 | 6 | 1 |
Baseline characteristics
| Characteristic | Exercise - High Impact Interval 95% VO2 Max -32 Week | Wait List | Dosage Study 85% Vigorous | Dosage Study 65%Moderate | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 18 Participants | 20 Participants | 5 Participants | 7 Participants | 50 Participants |
| Age, Continuous | 21.15 years STANDARD_DEVIATION 1.75 | 21.57 years STANDARD_DEVIATION 1.78 | 19.2 years STANDARD_DEVIATION 1.3 | 19.6 years STANDARD_DEVIATION 1.13 | 21.36 years STANDARD_DEVIATION 1.7 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 2 Participants | 1 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants | 1 Participants | 0 Participants | 0 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 8 Participants | 3 Participants | 7 Participants | 21 Participants |
| Region of Enrollment United States | 18 participants | 20 participants | 5 participants | 7 participants | 50 participants |
| Relational and Item-Specific Encoding Task | 2.75 recollection accuracy score STANDARD_DEVIATION 0.45 | 3.73 recollection accuracy score STANDARD_DEVIATION 0.44 | 47.2 recollection accuracy score STANDARD_DEVIATION 6.8 | 49.7 recollection accuracy score STANDARD_DEVIATION 7.57 | 3.24 recollection accuracy score STANDARD_DEVIATION 0.44 |
| Sex: Female, Male Female | 11 Participants | 3 Participants | 2 Participants | 4 Participants | 20 Participants |
| Sex: Female, Male Male | 2 Participants | 9 Participants | 3 Participants | 3 Participants | 17 Participants |
| Structured Interview for Psychosis-Risk Syndromes (SIPS) | 12.08 Symptom Severity Score STANDARD_DEVIATION 3.52 | 13.50 Symptom Severity Score STANDARD_DEVIATION 3.9 | 11.2 Symptom Severity Score STANDARD_DEVIATION 5.89 | 13.1 Symptom Severity Score STANDARD_DEVIATION 4.38 | 13.15 Symptom Severity Score STANDARD_DEVIATION 3.71 |
| VO2max assessment modified Balke protocol | 33.92 ml/kg/min STANDARD_DEVIATION 7.4 | 31.48 ml/kg/min STANDARD_DEVIATION 8.87 | 42 ml/kg/min STANDARD_DEVIATION 4.13 | 40.5 ml/kg/min STANDARD_DEVIATION 4.52 | 32.7 ml/kg/min STANDARD_DEVIATION 8.14 |
| Wide Range Achievement Test (WRAT) reading subscale | 105.83 Standard Score STANDARD_DEVIATION 13.38 | 114.8 Standard Score STANDARD_DEVIATION 14.97 | 50.2 Standard Score STANDARD_DEVIATION 7.92 | 48.5 Standard Score STANDARD_DEVIATION 7.4 | 110.315 Standard Score STANDARD_DEVIATION 14.17 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 7 | 0 / 2 | 0 / 13 | 0 / 12 |
| other Total, other adverse events | 0 / 7 | 0 / 2 | 0 / 13 | 0 / 12 |
| serious Total, serious adverse events | 0 / 7 | 0 / 2 | 0 / 13 | 0 / 12 |
Outcome results
Primary
Brain Volume
Medial temporal structures (hippocampus and parahippocampal gyrus) will be delineated automatically using the FMRIB's Integrated Registration and Segmentation Tool algorithm within the FMRIB's Software Library (FSL) image-processing suite. Secondly, the structures will be evaluated with vertex analyses (assessing changes in shape post trial on a per-vertex basis), which will also be carried out utilizing FIRST. Shape/appearance models used in FIRST are constructed from manually segmented images provided by the Center for Morphometric Analysis (CMA, Boston). This approach is different from using a whole-structure summary measure like volume, as it allows visualization of the region of the shape that is changing as well as the type of shape change.
Time frame: pre-trial, post-trial (3-months)
Population: Withdrew/excluded 3 Dosage (Exercise 2 group); 13 RCT (3 were excluded from the exercise group for not completing all 24 trials, 2 developed substance use disorders after baseline, 1 waitlist converted to a psychosis diagnosis during the protocol and was excluded); Final n=34; Change in hippocampal volume is reported below. On both measures negative scores indicate decreased hippocampal volumes over the study period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dosage Study Exercise | Brain Volume | 19.8 Change in mm cubed (baseline -followup) | Standard Deviation 50.8 |
| Doseage Study Exercise 2 | Brain Volume | 54.8 Change in mm cubed (baseline -followup) | Standard Deviation 323 |
| RCT High Impact Interval Exercise | Brain Volume | -0.489 Change in mm cubed (baseline -followup) | Standard Deviation 0.104 |
| RCT Wait List | Brain Volume | -6.28 Change in mm cubed (baseline -followup) | Standard Deviation 1.95 |
Secondary
Working Memory Assessment
Working Memory Assessment - Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) battery working memory subscale - a higher score indicates working memory better performance. The Relational and Item-Specific Encoding task includes visual object representations of word stimuli. Subjects make a two-button yes/no response to indicate whether items in each pair had been presented together.To prevent additional encoding of the relational object pairs the item recognition task precedes the associated recognition task. Higher scores reflect the familiarity and recollection performance as well as hit rates and false alarm rates following encoding - better performance. MATRICS Consensus Cognitive Battery working memory subscale using a t-score (0=population mean, standard deviation=10) and Relational and Item-Specific Encoding Task accuracy score in the RCT study using a task specific accuracy (d prime range; 0-100%).
Time frame: pre-trial, post-trial (3-months)
Population: Because there were few participants who completed the vigorous condition, subsequent analyses of the exercise intervention collapsed across conditions - Exercise 1 is all exercise Pre and Exercise 2 is all exercise post - Arm 2 has pre/Post for intervention group and wait list group listed for the RISE measure
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dosage Study Exercise | Working Memory Assessment | 47.5 Composite tscore/ RiSE Score | Standard Deviation 14.8 |
| Doseage Study Exercise 2 | Working Memory Assessment | 53 Composite tscore/ RiSE Score | Standard Deviation 19.8 |
| RCT High Impact Interval Exercise | Working Memory Assessment | 2.75 Composite tscore/ RiSE Score | Standard Deviation 0.45 |
| RCT Wait List | Working Memory Assessment | 3.00 Composite tscore/ RiSE Score | Standard Deviation 0.57 |
| RCT Waitlist Pre-Intervention | Working Memory Assessment | 3.73 Composite tscore/ RiSE Score | Standard Deviation 0.44 |
| RCT Waitlist Post-Intervention Period | Working Memory Assessment | 3.13 Composite tscore/ RiSE Score | Standard Deviation 0.56 |
| Pre-Intervention Moderate Dosage - 65% | Working Memory Assessment | 48.5 Composite tscore/ RiSE Score | Standard Deviation 7.4 |
| Post-Intervention Moderate Dosage - 65% | Working Memory Assessment | 52.9 Composite tscore/ RiSE Score | Standard Deviation 6.91 |
Other Pre-specified
Aerobic Fitness
VO2max was assessed via a modified Balke protocol by an exercise physiologist under the supervision of a physician. In this modified Balke protocol, the treadmill speed was individualized in a procedure to elicit 70% of the age-predicted max heart rate and ratings of a somewhat hard perceived exertion (RPE). Then, the speed of the treadmill remained the same throughout the test, but the incline of the treadmill belt increased 2% every 2 min (or 2.5% for speeds 6 mph or greater) to exhaustion. Tests generally lasted 8-12 minutes to attain the recommended target for VO2max testing. Measures indicate cardiovascular health with higher scores indicating greater health.
Time frame: pre-trial, post-trial (3 months)
Population: Because there were few participants (n=9); outcome data combine moderate (n=2) \& vigorous (n=7) groups; total outcome sample n=9; 13 RCT (3 were excluded from the exercise group for not completing all 24 trials, 2 developed substance use disorders after baseline, 1 waitlist converted to a psychosis diagnosis during the protocol and was excluded); Final n=34
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dosage Study Exercise | Aerobic Fitness | 40.5 ml/kg/min | Standard Deviation 10.9 |
| Doseage Study Exercise 2 | Aerobic Fitness | 39.0 ml/kg/min | Standard Deviation 10.1 |
| RCT High Impact Interval Exercise | Aerobic Fitness | 40.2 ml/kg/min | Standard Deviation 6.15 |
| RCT Wait List | Aerobic Fitness | 41.2 ml/kg/min | Standard Deviation 0.495 |
| RCT Waitlist Pre-Intervention | Aerobic Fitness | 33.92 ml/kg/min | Standard Deviation 7.4 |
| RCT Waitlist Post-Intervention Period | Aerobic Fitness | 38.2 ml/kg/min | Standard Deviation 7.8 |
| Pre-Intervention Moderate Dosage - 65% | Aerobic Fitness | 31.48 ml/kg/min | Standard Deviation 7.8 |
| Post-Intervention Moderate Dosage - 65% | Aerobic Fitness | 32.97 ml/kg/min | Standard Deviation 7.2 |
Other Pre-specified
Attenuated Psychosis Positive Symptom Subscales
The Structured Interview for Prodromal Symptoms (SIPS) will be administered to formally assess attenuated positive symptoms after inclusion in the study. It will also be administered post-trial to track changes in clinical symptoms post intervention trial. The SIPS rates the severity of relevant dimensions including positive symptoms along a 7-point scale ranging from absent (0) to severe and psychotic (6) across five symptom categories, resulting in a score that ranges from 0 (no positive symptoms) to 30 (psychosis along all symptoms dimensions).
Time frame: pre-trial, post-trial (3-months)
Population: Withdrew/excluded 3 Dosage (85% VO2 Max group); 13 RCT (3 were excluded from the exercise group for not completing all 24 trials, 2 developed substance use disorders after baseline, 1 waitlist converted to a psychosis diagnosis during the protocol and was excluded); Final n=34
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dosage Study Exercise | Attenuated Psychosis Positive Symptom Subscales | 13.1 score on a scale | Standard Deviation 4.38 |
| Doseage Study Exercise 2 | Attenuated Psychosis Positive Symptom Subscales | 9.29 score on a scale | Standard Deviation 3.82 |
| RCT High Impact Interval Exercise | Attenuated Psychosis Positive Symptom Subscales | 12.08 score on a scale | Standard Deviation 3.52 |
| RCT Wait List | Attenuated Psychosis Positive Symptom Subscales | 13.50 score on a scale | Standard Deviation 3.9 |
| RCT Waitlist Pre-Intervention | Attenuated Psychosis Positive Symptom Subscales | 8 score on a scale | Standard Deviation 3.46 |
| RCT Waitlist Post-Intervention Period | Attenuated Psychosis Positive Symptom Subscales | 11.38 score on a scale | Standard Deviation 3.82 |
| Pre-Intervention Moderate Dosage - 65% | Attenuated Psychosis Positive Symptom Subscales | 14 score on a scale | Standard Deviation 8.49 |
| Post-Intervention Moderate Dosage - 65% | Attenuated Psychosis Positive Symptom Subscales | 12 score on a scale | Standard Deviation 5.66 |