Schizophrenia
Conditions
Keywords
Schizophrenia, Eye movements, phenotype, biochemical, relatives
Brief summary
Schizophrenia is a complex and heritable disorder that encompasses several clinical symptom domains and functional impairments. Existing treatments of schizophrenia, although effective against positive symptoms, fail to benefit negative symptoms, the focus of the current protocol. One of the strategies of novel drug development depends on identifying heritable physiological deficits that mark the disease liability and are thought to occur along the causal pathway of negative symptoms. These heritable physiological deficits are often found in the biological relatives of schizophrenia proband; particularly those who have schizophrenia related personality styles \[defined by schizophrenia spectrum personalities (SSP) in the diagnostic system\], even though they do not have the full-blown illness. The current protocol will pilot a strategy of targeting biomarkers of negative symptoms using intranasal oxytocin in relatives of schizophrenia patients. The drug probe studies in such non-clinical sample have several advantages including the absence of other drug treatment that may modulate the response, and the lack of generalized deficits causing problems with task comprehension/engagement that may mute the therapeutic signal. In addition, finding of efficacy of the experimental drug on the target physiological deficit and the associated symptoms has clinical implications on its own rights. This is because about 25% of subjects with schizophrenia spectrum personality disorders experience serious functional impairments. Oxytocin is an extensively used drug, which is well tolerated with few serious side effects. Several lines of evidence suggest its putative role in the treatment of negatives symptoms, particularly a lack of social drive and related symptoms.
Detailed description
The current study will examine the effects of intranasal oxytocin on physiological/cognitive markers of negative symptoms in 24 participants with schizophrenia spectrum traits. Subjects will be tested in two one-day studies carried out at least a month apart. Subjects will receive a 24 IU dose of intranasal oxytocin (or placebo) followed by a battery of cognitive/neurophysiological tests administered 50 minutes later completed over the next 155 minutes. A second dose of the drug (oxytocin or placebo) will be administered 2 hours after the 1st in order to maintain therapeutic plasma levels and to complete all testing.
Interventions
DRUGOxytocin
24 IU oxytocin (or Placebo) in a total of 6 puffs (3 puffs per nostril)
DRUGPlacebo
Single dose (plus a booster dose) drug probe study using intranasal placebo
Sponsors
National Institute of Mental Health (NIMH)
University of Maryland, Baltimore
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 64 Years
Healthy volunteers
No
Inclusion criteria
* Male/Female subjects between ages of 18-64 years * The presence of 3 or more SSP symptoms (at least 2 of the SSP symptoms will be negative symptoms as defined by the schizoid traits) * The presence of visuo-spatial working memory impairment as defined by error in the oculomotor delayed response (ODR) task of more than 0.5 SD above the mean values in healthy control subjects * Relative of an individual with schizophrenia, schizo-affective, or schizophreniform disorder * Able to provide written informed consent. Females are excluded due to risk of discomfort and unblinding due to potential uterine cramps induced by oxytocin.
Exclusion criteria
* Subjects meeting criteria for a life-time diagnosis of any one of the DSM IV, Axis I psychotic disorders (exceptions being a single past episode of major depressive disorder with psychotic features or psychotic symptoms associated with substance abuse with the substance abuse ending 6-months prior to study participation) (this is for the SSP recruitment) * Subjects meeting DSM-IV criteria for current alcohol or substance dependence (other than nicotine) within the last 6 months or DSM-IV criteria for alcohol or substance abuse (other than nicotine) within the last month * Medical conditions that preclude participation in drug trials or assessments of outcome measures (including significant brain, cardiac, liver, lung, endocrinological or metabolic disorders) * Received any investigational drug in the preceding four weeks.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Social Affiliation Measured by Social Affiliative Role Play | 30 minutes | In a videotaped session, research staff engages the participant in social interaction based on a role play. The tape is rated on social skills and on Positive and Negative Affect Scale. Participants are rated on a 5 point Likert scale ranging from very poor (1) to Very Good (5). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Trust Game | 20 minutes | Participants competed in a social trust game in which they are paired with a partner (the computer program). Over the course of 24 rounds the participant can offer up to $10 to their partner. The partner can either accept the offer, in which case the total amount offered is split equally between the participant and their partner (i.e. $10 is split into $5 each). Or the partner can reject the offer and receive an portion of the total offer for themselves and give the participant nothing ($0). The total amount of money that can be offered ranges from $0-240. |
| RVIP Reaction Times | 25 minutes | Rapid Visual Information Processing (RVIP) measures primarily sustained attention but perhaps also working memory. The task was continuous stimuli presentation of a stream of single digits (from 1 to 9) presented in the center of the computer monitor at a rate of 1/600milliseconds; the subjects respond when they see a target sequence of 3 odds or 3 even digits in a consecutive sequence. Two target sequences are separated by a minimum of 5 and maximum of 30 non-target digits |
| Rapid Visual Information Processing Test (RVIP) | 25 minutes | RVIP measures primarily sustained attention but perhaps also working memory. The task was continuous stimuli presentation of a stream of single digits (from 1 to 9) presented in the center of the computer monitor at a rate of 1/600ms; the subjects respond when they see a target sequence of 3 odds or 3 even digits in a consecutive sequence. Two target sequences are separated by a minimum of 5 and maximum of 30 non-target digits. There are a total of 48 target sequences during each test block. The number of correctly Identified target sequences or hits is recorded, as well as, false alarms (incorrectly identified target sequences) and reaction times. |
| Hopkins Verbal Learning Test (HVLT) | 15 minutes | HVLT comes in 6 different forms. Forms 4 and 5 were used for this study with one form administered on the first study day and the other on the second and were counterbalanced between subjects. Each form contains 12 nouns, four words each from one of three semantic categories, to be learned over the course of three learning trials. |
| Brief Smell Identification Test | 5 minutes | The Brief Smell Identification Test (B-SIT) is a 5-minute, 12-item screening test. Participants try to identify 12 different odors with four multiple choice options given for each odor. |
| Reading the Mind in the Eyes | 10 minutes | A 30 item task presents a picture of a person's eyes and the participant is ask to determine the person's mental state from 4 multiple choice options. |
| Facial Affect Recognition | 10 minutes | This computer administered test includes 40 color photographs of four universal emotions (happy, sad, angry, and fearful) balanced for the posers gender, age, and ethnicity, including four low intensity and four high-intensity facial expressions of each emotion, plus 8 neutral faces. The stimuli are presented in random order and subjects are asked to identify which stimuli were presented to them at the end. Performance on this test correlates with negative symptom severity. |
| Brief Assessments of Cognition for Schizophrenia | 5 minutes | The BACS Symbol Coding subtest will be used to assess processing speed, and the demographically corrected T score, will be used for data analysis. This test requires less than 5 minutes to administer and provides a highly reliable measure of processing speed. There are nine symbols code 1 through 9. Participants are given 90 seconds to match a series of these symbols with their corresponding number. The total correct matches is the participants score. Scores range from 0-110. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Study Participants Participants who were screened and met inclusion/exclusion criteria for the study. | 27 |
| Total | 27 |
Baseline characteristics
| Characteristic | All Study Participants |
|---|---|
| Age, Continuous | 51.9 years STANDARD_DEVIATION 10.54 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 23 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 17 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 8 Participants |
| Sex: Female, Male Female | 21 Participants |
| Sex: Female, Male Male | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 19 | 0 / 18 |
| other Total, other adverse events | 3 / 19 | 0 / 18 |
| serious Total, serious adverse events | 0 / 19 | 0 / 18 |
Outcome results
Primary
Social Affiliation Measured by Social Affiliative Role Play
In a videotaped session, research staff engages the participant in social interaction based on a role play. The tape is rated on social skills and on Positive and Negative Affect Scale. Participants are rated on a 5 point Likert scale ranging from very poor (1) to Very Good (5).
Time frame: 30 minutes
Population: Of the 27 ppts that were screened and deemed eligible for study participation, only 19 completed testing while receiving oxytocin and only 18 complete testing while receiving placebo.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Oxytocin | Social Affiliation Measured by Social Affiliative Role Play | Overall Affect | 4.026 units on a scale | Standard Deviation 0.656 |
| Oxytocin | Social Affiliation Measured by Social Affiliative Role Play | Overall Social Skill | 4.079 units on a scale | Standard Deviation 0.854 |
| Placebo | Social Affiliation Measured by Social Affiliative Role Play | Overall Affect | 4.111 units on a scale | Standard Deviation 0.583 |
| Placebo | Social Affiliation Measured by Social Affiliative Role Play | Overall Social Skill | 4.194 units on a scale | Standard Deviation 0.622 |
Comparison: Comparison of Overall Affect Scores between Oxytocin and Placebo Armsp-value: 0.758Wilcoxon (Mann-Whitney)
Comparison: Comparison of Overall Social Skill scores between Oxytocin and Placebo armsp-value: 0.779Wilcoxon (Mann-Whitney)
Secondary
Brief Assessments of Cognition for Schizophrenia
The BACS Symbol Coding subtest will be used to assess processing speed, and the demographically corrected T score, will be used for data analysis. This test requires less than 5 minutes to administer and provides a highly reliable measure of processing speed. There are nine symbols code 1 through 9. Participants are given 90 seconds to match a series of these symbols with their corresponding number. The total correct matches is the participants score. Scores range from 0-110.
Time frame: 5 minutes
Population: Analyzable data for secondary outcomes was not available for some participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Oxytocin | Brief Assessments of Cognition for Schizophrenia | 45.6 Number of correct responses | Standard Deviation 13.8 |
| Placebo | Brief Assessments of Cognition for Schizophrenia | 47.7 Number of correct responses | Standard Deviation 14.3 |
Comparison: Comparison of Brief Assessments of Cognition for Schizophrenia scores between the Oxytocin and Placebo arms.p-value: 0.451Wilcoxon (Mann-Whitney)
Secondary
Brief Smell Identification Test
The Brief Smell Identification Test (B-SIT) is a 5-minute, 12-item screening test. Participants try to identify 12 different odors with four multiple choice options given for each odor.
Time frame: 5 minutes
Population: Analyzable data for secondary outcomes was not available for some participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Oxytocin | Brief Smell Identification Test | 10.06 Number of correct responses | Standard Deviation 1.53 |
| Placebo | Brief Smell Identification Test | 10.14 Number of correct responses | Standard Deviation 1.1 |
p-value: 0.9Wilcoxon (Mann-Whitney)
Secondary
Facial Affect Recognition
This computer administered test includes 40 color photographs of four universal emotions (happy, sad, angry, and fearful) balanced for the posers gender, age, and ethnicity, including four low intensity and four high-intensity facial expressions of each emotion, plus 8 neutral faces. The stimuli are presented in random order and subjects are asked to identify which stimuli were presented to them at the end. Performance on this test correlates with negative symptom severity.
Time frame: 10 minutes
Population: Analyzable data for secondary outcomes was not available for some participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Oxytocin | Facial Affect Recognition | Facial Affect Recognition Total | 29.79 Number of responses | Standard Deviation 4.69 |
| Oxytocin | Facial Affect Recognition | Facial Affect Recognition Hits | 12.86 Number of responses | Standard Deviation 5.36 |
| Oxytocin | Facial Affect Recognition | Facial Affect Recognition False Alarms | 6.71 Number of responses | Standard Deviation 4.51 |
| Placebo | Facial Affect Recognition | Facial Affect Recognition Total | 34.08 Number of responses | Standard Deviation 5.33 |
| Placebo | Facial Affect Recognition | Facial Affect Recognition Hits | 15.46 Number of responses | Standard Deviation 4.22 |
| Placebo | Facial Affect Recognition | Facial Affect Recognition False Alarms | 5.38 Number of responses | Standard Deviation 3.01 |
Comparison: Comparison the Facial Affect Recognition Total scores between Oxytocin and Placebo armsp-value: 0.016Wilcoxon (Mann-Whitney)
Comparison: Comparison the Facial Affect Recognition Hits between Oxytocin and Placebo armsp-value: 0.185Wilcoxon (Mann-Whitney)
Comparison: Comparison the Facial Affect Recognition False Alarms between Oxytocin and Placebo armsp-value: 0.404Wilcoxon (Mann-Whitney)
Secondary
Hopkins Verbal Learning Test (HVLT)
HVLT comes in 6 different forms. Forms 4 and 5 were used for this study with one form administered on the first study day and the other on the second and were counterbalanced between subjects. Each form contains 12 nouns, four words each from one of three semantic categories, to be learned over the course of three learning trials.
Time frame: 15 minutes
Population: Analyzable data for secondary outcomes was not available for some participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Oxytocin | Hopkins Verbal Learning Test (HVLT) | Hopkins Verbal Learning Test Trial2 | 8.56 Number of correct responses | Standard Deviation 1.93 |
| Oxytocin | Hopkins Verbal Learning Test (HVLT) | Hopkins Verbal Learning Test Trial1 | 6.19 Number of correct responses | Standard Deviation 2.23 |
| Oxytocin | Hopkins Verbal Learning Test (HVLT) | Hopkins Verbal Learning Test Trial3 | 10.12 Number of correct responses | Standard Deviation 2.03 |
| Placebo | Hopkins Verbal Learning Test (HVLT) | Hopkins Verbal Learning Test Trial1 | 6.57 Number of correct responses | Standard Deviation 1.79 |
| Placebo | Hopkins Verbal Learning Test (HVLT) | Hopkins Verbal Learning Test Trial2 | 9.36 Number of correct responses | Standard Deviation 1.78 |
| Placebo | Hopkins Verbal Learning Test (HVLT) | Hopkins Verbal Learning Test Trial3 | 10.57 Number of correct responses | Standard Deviation 1.4 |
Comparison: Comparison of HVLT Trial 1 scores between Oxytocin and Placebo Armsp-value: 0.578Wilcoxon (Mann-Whitney)
Comparison: Comparison of HVLT Trial 2 scores between Oxytocin and Placebo Armsp-value: 0.28Wilcoxon (Mann-Whitney)
Comparison: Comparison of HVLT Trial 3 scores between Oxytocin and Placebo Armsp-value: 0.707Wilcoxon (Mann-Whitney)
Secondary
Rapid Visual Information Processing Test (RVIP)
RVIP measures primarily sustained attention but perhaps also working memory. The task was continuous stimuli presentation of a stream of single digits (from 1 to 9) presented in the center of the computer monitor at a rate of 1/600ms; the subjects respond when they see a target sequence of 3 odds or 3 even digits in a consecutive sequence. Two target sequences are separated by a minimum of 5 and maximum of 30 non-target digits. There are a total of 48 target sequences during each test block. The number of correctly Identified target sequences or hits is recorded, as well as, false alarms (incorrectly identified target sequences) and reaction times.
Time frame: 25 minutes
Population: Analyzable data for secondary outcomes was not available for some participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Oxytocin | Rapid Visual Information Processing Test (RVIP) | RVIP Practice Mean Target Hits | 16.40 Number of responses | Standard Deviation 8.58 |
| Oxytocin | Rapid Visual Information Processing Test (RVIP) | RVIP First Half Mean Target Hits | 17.80 Number of responses | Standard Deviation 6.52 |
| Oxytocin | Rapid Visual Information Processing Test (RVIP) | RVIP Practice Mean False Alarms | 15.9 Number of responses | Standard Deviation 16.5 |
| Oxytocin | Rapid Visual Information Processing Test (RVIP) | RVIP First Half Mean False Alarms | 14.7 Number of responses | Standard Deviation 19.4 |
| Placebo | Rapid Visual Information Processing Test (RVIP) | RVIP First Half Mean False Alarms | 12.2 Number of responses | Standard Deviation 15.5 |
| Placebo | Rapid Visual Information Processing Test (RVIP) | RVIP Practice Mean Target Hits | 19.15 Number of responses | Standard Deviation 7.45 |
| Placebo | Rapid Visual Information Processing Test (RVIP) | RVIP Practice Mean False Alarms | 10.2 Number of responses | Standard Deviation 12 |
| Placebo | Rapid Visual Information Processing Test (RVIP) | RVIP First Half Mean Target Hits | 21.62 Number of responses | Standard Deviation 6.99 |
Comparison: Comparison of RVIP Practice Mean Target Hits between Oxytocin and Placebo arms.p-value: 0.296Wilcoxon (Mann-Whitney)
Comparison: Comparison of RVIP First Half Mean Target Hits between Oxytocin and Placebo arms.p-value: 0.136Wilcoxon (Mann-Whitney)
Comparison: Comparison of RVIP Practice Mean False Alarms between Oxytocin and Placebo arms.p-value: 0.47Wilcoxon (Mann-Whitney)
Comparison: Comparison of RVIP First Half Mean Target Hits between Oxytocin and Placebo arms.p-value: 0.702Wilcoxon (Mann-Whitney)
Secondary
Reading the Mind in the Eyes
A 30 item task presents a picture of a person's eyes and the participant is ask to determine the person's mental state from 4 multiple choice options.
Time frame: 10 minutes
Population: Analyzable data for secondary outcomes was not available for some participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Oxytocin | Reading the Mind in the Eyes | 24.40 Number of correct responses | Standard Deviation 6.06 |
| Placebo | Reading the Mind in the Eyes | 24.54 Number of correct responses | Standard Deviation 5.78 |
Comparison: Comparison of Reading the Mind in the Eyes total scores between Oxytocin and Placebo armsp-value: 0.946Wilcoxon (Mann-Whitney)
Secondary
RVIP Reaction Times
Rapid Visual Information Processing (RVIP) measures primarily sustained attention but perhaps also working memory. The task was continuous stimuli presentation of a stream of single digits (from 1 to 9) presented in the center of the computer monitor at a rate of 1/600milliseconds; the subjects respond when they see a target sequence of 3 odds or 3 even digits in a consecutive sequence. Two target sequences are separated by a minimum of 5 and maximum of 30 non-target digits
Time frame: 25 minutes
Population: Analyzable data for secondary outcomes was not available for some participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Oxytocin | RVIP Reaction Times | RVIP Practice Mean Target Reaction Time | 563 milliseconds | Standard Deviation 103 |
| Oxytocin | RVIP Reaction Times | RVIP First Half Mean Target Reaction Time | 588 milliseconds | Standard Deviation 104.7 |
| Oxytocin | RVIP Reaction Times | RVIP Practice Mean False Alarms Reaction Time | 306.9 milliseconds | Standard Deviation 49.5 |
| Oxytocin | RVIP Reaction Times | RVIP First Half Mean False Alarms Reaction Time | 302 milliseconds | Standard Deviation 115 |
| Placebo | RVIP Reaction Times | RVIP First Half Mean False Alarms Reaction Time | 228 milliseconds | Standard Deviation 138 |
| Placebo | RVIP Reaction Times | RVIP Practice Mean Target Reaction Time | 586 milliseconds | Standard Deviation 110 |
| Placebo | RVIP Reaction Times | RVIP Practice Mean False Alarms Reaction Time | 277.1 milliseconds | Standard Deviation 104.4 |
| Placebo | RVIP Reaction Times | RVIP First Half Mean Target Reaction Time | 574.4 milliseconds | Standard Deviation 82.9 |
Comparison: Comparison of RVIP Practice Mean Target Reaction Time between Oxytocin and Placebo arms.p-value: 0.559Wilcoxon (Mann-Whitney)
Comparison: Comparison of RVIP First Half Mean Target Reaction Time between Oxytocin and Placebo arms.p-value: 0.858Wilcoxon (Mann-Whitney)
Comparison: Comparison of RVIP Practice Mean False Alarms Reaction Time between Oxytocin and Placebo armsp-value: 0.514Wilcoxon (Mann-Whitney)
Comparison: Comparison of RVIP First Half Mean False Alarms Reaction Time between Oxytocin and Placebo armsp-value: 0.088Wilcoxon (Mann-Whitney)
Secondary
Trust Game
Participants competed in a social trust game in which they are paired with a partner (the computer program). Over the course of 24 rounds the participant can offer up to $10 to their partner. The partner can either accept the offer, in which case the total amount offered is split equally between the participant and their partner (i.e. $10 is split into $5 each). Or the partner can reject the offer and receive an portion of the total offer for themselves and give the participant nothing ($0). The total amount of money that can be offered ranges from $0-240.
Time frame: 20 minutes
Population: Analyzable data for secondary outcomes was not available for some participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Oxytocin | Trust Game | 112.5 Dollars | Standard Deviation 60 |
| Placebo | Trust Game | 134.5 Dollars | Standard Deviation 68.5 |
Comparison: Comparison of the total amount of money offered during the trust game between the Oxytocin and Placebo armsp-value: 0.391Wilcoxon (Mann-Whitney)