Schizophrenia; Psychosis
Conditions
Brief summary
The purpose of this study is to test whether administration of levetiracetam (LEV), a commonly used anti-epileptic that alters neurotransmitter release, can reduce hippocampal hyperactivity in people with psychotic disorders. Specifically, the investigators will utilize two functional magnetic resonance imaging (MRI) techniques: 1) blood-oxygen-level-dependent (BOLD) contrast will assess activity with a visual scene processing task that engages the anterior hippocampus and 2) arterial spin labeling (ASL) will assess baseline activity. Previous studies in people with psychotic disorders have shown that the hippocampus is hyperactive and more activity correlates with worsening of clinical symptoms. Therefore, the aim of this study is to use an intervention to further understand the underlying mechanisms of the hippocampus in psychosis.
Interventions
DRUGLevetiracetam (LEV) 500 mg
The levetiracetam pill will look just like the placebo pill.
DRUGPlacebo
The placebo pill will look just like the levetiracetam pill, but does not contain any levetiracetam.
Sponsors
Vanderbilt University Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
During Visit 2, participants will be randomly assigned to an intervention arm in which they will receive two 250mg LEV capsules or two placebo capsules. Both the participant and the research team will be blinded to which arm each participant is in. During Visit 3, the participant will undergo cross-over and receive either two 250mg LEV capsules or two placebo capsules (whichever intervention they did not receive in Visit 2).
Intervention model description
2-way crossover, double-blind, randomized controlled study
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
Inclusion criteria for psychosis subjects 1. Men and women age 18 - 65. 2. Communicative in English. 3. Provide voluntary, written informed consent. 4. Physically healthy by medical history. 5. BMI \> 17.5 and \< 45. 6. Diagnosis of a psychotic disorder confirmed by Structured Clinical Interview for Diagnostic and Statistical Manual-5 (SCID) or diagnostic interview with a trained clinician. 7. Stable medication regimen over at least the past two weeks, including the use of either an oral or intramuscular administration of an antipsychotic medication. 8. For females, no longer of child-bearing potential, or agreeing to practice effective contraception during the study (e.g., established use of oral, injected or implanted hormonal methods of contraception; placement of an intrauterine device or intrauterine system; barrier methods: condom with spermicidal foam/gel/film/cream/suppository or occlusive cap \[diaphragm or cervical/vault caps\] with spermicidal foam/gel/film/cream/suppository; male partner sterilization; or true abstinence when this is in line with the preferred and usual lifestyle of the subject); and, 9. For females of child-bearing potential, must have a negative urine pregnancy test before MRI and drug administration. 10. Not breastfeeding/nursing at time of screening or at any time during the study. Inclusion criteria for healthy controls 1\. All of the above except for subjects will be psychiatrically healthy and not taking psychotropic or potentially psychoactive prescription medication. \----
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Hippocampal Activity (Arterial Spin Labeling [ASL] Study) After Levetiracetam (LEV) | 2 hours after LEV administration | ASL signal after LEV, using Magnetic Resonance Imaging (MRI) scanning of the brain. ASL measures cerebral blood flow, which is linked to neuronal metabolism and functions as a proxy for neuronal activity. |
| Hippocampal Activity (Arterial Spin Labeling [ASL] Study) After Placebo | 2 hours after placebo administration | ASL signal after placebo, using Magnetic Resonance Imaging (MRI) scanning of the brain. ASL measures cerebral blood flow, which is linked to neuronal metabolism and functions as a proxy for neuronal activity. |
| Hippocampal Recruitment (Blood-Oxygen-Level-Dependent [BOLD] Study) After Levetiracetam (LEV) | 2 hours after LEV administration | BOLD signal after LEV, using Magnetic Resonance Imaging (MRI) scanning of the brain. This method reflects changes in oxygenation of blood in the brain during a scene-processing task that engages, or recruits, the hippocampus. |
| Hippocampal Recruitment (Blood-Oxygen-Level-Dependent [BOLD] Study) After Placebo | 2 hours after placebo administration | BOLD signal after placebo, using Magnetic Resonance Imaging (MRI) scanning of the brain. This method reflects changes in oxygenation of blood in the brain during a scene-processing task that engages, or recruits, the hippocampus. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Healthy Control Participants: Levetiracetam (LEV), Then Placebo Healthy control participants will undergo two MRI scanning sessions. Each session includes two functional magnetic resonance imaging (MRI) techniques:
1. Blood-oxygen-level-dependent (BOLD) contrast to assess activity with a visual scene processing task that engages the hippocampus.
2. Arterial spin labeling (ASL) to assess baseline activity. ASL measures cerebral blood flow, which is linked to neuronal metabolism and functions as a proxy for neuronal activity.
About 2 hours before the first imaging session, they will receive levetiracetam (LEV) 500 mg. The levetiracetam pill will look just like the placebo pill. About 2 hours before the second imaging session, they will receive the placebo pill. The placebo pill will look just like the levetiracetam pill, but does not contain any levetiracetam. | 15 |
| Healthy Control Participants: Placebo, Then Levetiracetam (LEV) Healthy control participants will undergo two MRI scanning sessions. Each session includes two functional magnetic resonance imaging (MRI) techniques:
1. Blood-oxygen-level-dependent (BOLD) contrast to assess activity with a visual scene processing task that engages the hippocampus.
2. Arterial spin labeling (ASL) to assess baseline activity. ASL measures cerebral blood flow, which is linked to neuronal metabolism and functions as a proxy for neuronal activity.
About 2 hours before the first imaging session, they will receive the placebo pill. The placebo pill will look just like the levetiracetam pill, but does not contain any levetiracetam. About 2 hours before the second imaging session, they will receive levetiracetam (LEV) 500 mg. The levetiracetam pill will look just like the placebo pill. | 15 |
| Patients With Schizophrenia: Levetiracetam (LEV), Then Placebo Patients with schizophrenia will undergo two MRI scanning sessions. Each session includes two functional magnetic resonance imaging (MRI) techniques:
1. Blood-oxygen-level-dependent (BOLD) contrast to assess activity with a visual scene processing task that engages the hippocampus.
2. Arterial spin labeling (ASL) to assess baseline activity. ASL measures cerebral blood flow, which is linked to neuronal metabolism and functions as a proxy for neuronal activity.
About 2 hours before the first imaging session, they will receive levetiracetam (LEV) 500 mg. The levetiracetam pill will look just like the placebo pill. About 2 hours before the second imaging session, they will receive the placebo pill. The placebo pill will look just like the levetiracetam pill, but does not contain any levetiracetam. | 14 |
| Patients With Schizophrenia: Placebo, Then Levetiracetam (LEV) Patients with schizophrenia will undergo two MRI scanning sessions. Each session includes two functional magnetic resonance imaging (MRI) techniques:
1. Blood-oxygen-level-dependent (BOLD) contrast to assess activity with a visual scene processing task that engages the hippocampus.
2. Arterial spin labeling (ASL) to assess baseline activity. ASL measures cerebral blood flow, which is linked to neuronal metabolism and functions as a proxy for neuronal activity.
About 2 hours before the first imaging session, they will receive the placebo pill. The placebo pill will look just like the levetiracetam pill, but does not contain any levetiracetam. About 2 hours before the second imaging session, they will receive levetiracetam (LEV) 500 mg. The levetiracetam pill will look just like the placebo pill. | 16 |
| Total | 60 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| First Intervention (1 Day) | Adverse Event | 0 | 0 | 0 | 1 |
| First Intervention (1 Day) | Withdrawn due to inability to complete imaging | 0 | 0 | 1 | 0 |
| Second Intervention (1 Day) | Lost to Follow-up | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Healthy Control Participants: Levetiracetam (LEV), Then Placebo | Total | Patients With Schizophrenia: Placebo, Then Levetiracetam (LEV) | Patients With Schizophrenia: Levetiracetam (LEV), Then Placebo | Healthy Control Participants: Placebo, Then Levetiracetam (LEV) |
|---|---|---|---|---|---|
| Age, Continuous | 32.2 years STANDARD_DEVIATION 9 | 34.7 years STANDARD_DEVIATION 11.2 | 34.8 years STANDARD_DEVIATION 12.7 | 35.7 years STANDARD_DEVIATION 12.1 | 36.0 years STANDARD_DEVIATION 11.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 4 Participants | 1 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants | 56 Participants | 15 Participants | 14 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 13 Participants | 6 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 2 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 | 12 Participants | 44 Participants | 10 Participants | 14 Participants | 8 Participants |
| Region of Enrollment United States | 15 participants | 60 participants | 16 participants | 14 participants | 15 participants |
| Sex: Female, Male Female | 5 Participants | 18 Participants | 4 Participants | 5 Participants | 4 Participants |
| Sex: Female, Male Male | 10 Participants | 42 Participants | 12 Participants | 9 Participants | 11 Participants |
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 / 30 | 0 / 30 | 0 / 31 | 0 / 30 |
| other Total, other adverse events | 0 / 30 | 0 / 30 | 0 / 31 | 1 / 30 |
| serious Total, serious adverse events | 0 / 30 | 0 / 30 | 0 / 31 | 0 / 30 |
Outcome results
Primary
Hippocampal Activity (Arterial Spin Labeling [ASL] Study) After Levetiracetam (LEV)
ASL signal after LEV, using Magnetic Resonance Imaging (MRI) scanning of the brain. ASL measures cerebral blood flow, which is linked to neuronal metabolism and functions as a proxy for neuronal activity.
Time frame: 2 hours after LEV administration
Population: The overall number of participants analyzed is inconsistent with the numbers provided in the participant flow module due to MRI scanner or participant error during the collection of the ASL sequence. However, these participants still included useful imaging data collected in other imaging sequences during the study.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Healthy Control Participants: Levetiracetam (LEV), Then Placebo | Hippocampal Activity (Arterial Spin Labeling [ASL] Study) After Levetiracetam (LEV) | 28.3 ml/100g/min |
| Healthy Control Participants: Placebo, Then Levetiracetam (LEV) | Hippocampal Activity (Arterial Spin Labeling [ASL] Study) After Levetiracetam (LEV) | 27.1 ml/100g/min |
| Patients With Schizophrenia: Levetiracetam (LEV), Then Placebo | Hippocampal Activity (Arterial Spin Labeling [ASL] Study) After Levetiracetam (LEV) | 28.0 ml/100g/min |
| Patients With Schizophrenia: Placebo, Then Levetiracetam (LEV) | Hippocampal Activity (Arterial Spin Labeling [ASL] Study) After Levetiracetam (LEV) | 28.5 ml/100g/min |
Primary
Hippocampal Activity (Arterial Spin Labeling [ASL] Study) After Placebo
ASL signal after placebo, using Magnetic Resonance Imaging (MRI) scanning of the brain. ASL measures cerebral blood flow, which is linked to neuronal metabolism and functions as a proxy for neuronal activity.
Time frame: 2 hours after placebo administration
Population: The overall number of participants analyzed is inconsistent with the numbers provided in the participant flow module due to MRI scanner or participant error during the collection of the ASL sequence. However, these participants still included useful imaging data collected in other imaging sequences during the study.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Healthy Control Participants: Levetiracetam (LEV), Then Placebo | Hippocampal Activity (Arterial Spin Labeling [ASL] Study) After Placebo | 28.1 ml/100g/min |
| Healthy Control Participants: Placebo, Then Levetiracetam (LEV) | Hippocampal Activity (Arterial Spin Labeling [ASL] Study) After Placebo | 28.3 ml/100g/min |
| Patients With Schizophrenia: Levetiracetam (LEV), Then Placebo | Hippocampal Activity (Arterial Spin Labeling [ASL] Study) After Placebo | 28.1 ml/100g/min |
| Patients With Schizophrenia: Placebo, Then Levetiracetam (LEV) | Hippocampal Activity (Arterial Spin Labeling [ASL] Study) After Placebo | 28.7 ml/100g/min |
Primary
Hippocampal Recruitment (Blood-Oxygen-Level-Dependent [BOLD] Study) After Levetiracetam (LEV)
BOLD signal after LEV, using Magnetic Resonance Imaging (MRI) scanning of the brain. This method reflects changes in oxygenation of blood in the brain during a scene-processing task that engages, or recruits, the hippocampus.
Time frame: 2 hours after LEV administration
Population: The overall number of participants analyzed is inconsistent with the numbers provided in the participant flow module due to MRI scanner or participant error during the collection of the recruitment data using the BOLD signal. However, these participants still included useful imaging data collected in other imaging sequences during the study.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Healthy Control Participants: Levetiracetam (LEV), Then Placebo | Hippocampal Recruitment (Blood-Oxygen-Level-Dependent [BOLD] Study) After Levetiracetam (LEV) | -0.0342 BOLD percent signal change |
| Healthy Control Participants: Placebo, Then Levetiracetam (LEV) | Hippocampal Recruitment (Blood-Oxygen-Level-Dependent [BOLD] Study) After Levetiracetam (LEV) | 0.1216 BOLD percent signal change |
| Patients With Schizophrenia: Levetiracetam (LEV), Then Placebo | Hippocampal Recruitment (Blood-Oxygen-Level-Dependent [BOLD] Study) After Levetiracetam (LEV) | 0.2915 BOLD percent signal change |
| Patients With Schizophrenia: Placebo, Then Levetiracetam (LEV) | Hippocampal Recruitment (Blood-Oxygen-Level-Dependent [BOLD] Study) After Levetiracetam (LEV) | 0.2381 BOLD percent signal change |
Primary
Hippocampal Recruitment (Blood-Oxygen-Level-Dependent [BOLD] Study) After Placebo
BOLD signal after placebo, using Magnetic Resonance Imaging (MRI) scanning of the brain. This method reflects changes in oxygenation of blood in the brain during a scene-processing task that engages, or recruits, the hippocampus.
Time frame: 2 hours after placebo administration
Population: The overall number of participants analyzed is inconsistent with the numbers provided in the participant flow module due to MRI scanner or participant error during the collection of the recruitment data using the BOLD signal. However, these participants still included useful imaging data collected in other imaging sequences during the study.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Healthy Control Participants: Levetiracetam (LEV), Then Placebo | Hippocampal Recruitment (Blood-Oxygen-Level-Dependent [BOLD] Study) After Placebo | 0.1908 BOLD percent signal change |
| Healthy Control Participants: Placebo, Then Levetiracetam (LEV) | Hippocampal Recruitment (Blood-Oxygen-Level-Dependent [BOLD] Study) After Placebo | 0.0507 BOLD percent signal change |
| Patients With Schizophrenia: Levetiracetam (LEV), Then Placebo | Hippocampal Recruitment (Blood-Oxygen-Level-Dependent [BOLD] Study) After Placebo | 0.1769 BOLD percent signal change |
| Patients With Schizophrenia: Placebo, Then Levetiracetam (LEV) | Hippocampal Recruitment (Blood-Oxygen-Level-Dependent [BOLD] Study) After Placebo | 0.0703 BOLD percent signal change |