R33: Levetiracetam in Early Psychosis

Study Overview
=================
Brief Summary
-----------------
This is a 12-week study of levetiracetam added to a second generation antipsychotic in early psychosis patients who have been ill for less than 5 years and continue to experience psychotic symptoms despite at least 8 weeks of antipsychotic treatment. Levetiracetam (Keppra) is a medication approved for the treatment of epilepsy; it reduces excessive activity in the brain. This study will test the hypotheses that adding levetiracetam will improve psychotic symptoms that are unresponsive to antipsychotic treatment and will protect the brain from atrophy (volume loss). .

Detailed Description
-----------------
Participants will complete screening and baseline visits before being randomized in a 2:1 ratio to levetiracetam or placebo added to the antipsychotic medication. They will complete weekly study visits for the first 4 weeks (Baseline, Weeks 2-4) and then additional visits at Week 6, 8, and 12. Participants will be studied both by assessing change in symptom severity and cognitive performance over the 12 weeks as well as using an imaging measure of hippocampal volume integrity at baseline and week 12. After completing Week 12 or decision to withdraw prematurely from the study, participants will complete a 9 day medication tapering regimen.

Official Title
-----------------
A 12-week Randomized, Double-blind, Placebo-controlled Trial Investigating the Effects of Levetiracetam in Early Psychosis

Conditions
-----------------
Early Psychosis

Intervention / Treatment
-----------------
* Drug: Levetiracetam Pill
* Other: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria Males and females 16 to 40 years of age, inclusive, at time of informed consent Must have experienced a first episode of nonaffective psychosis within 5 years and exhibit current psychosis, as defined by a score of ≥ 4 on one of the following psychosis items on the BPRS: conceptual disorganization, suspiciousness, hallucinations, unusual thought content, or grandiosity, for at least 4 days per week for at least 4 weeks Must have a diagnosis of either schizophrenia, schizoaffective disorder or schizophreniform disorder as established by a Structured Clinical Interview for DSM-V (SCID) Must have taken antipsychotic medication for a minimum of 8 weeks and at a stable dose for at least 4 weeks prior to randomization If assigned female at birth and of childbearing potential, patients must: Have a negative urine pregnancy test (all participants assigned female at birth regardless of childbearing potential will be required to submit a pregnancy test) and Not be nursing or planning a pregnancy for the duration of the study through 30 days after the last dosing visit and Be abstinent or willing to use a reliable method of birth control from the screening visit and continue with the same method until termination from the study Exclusion Criteria Current substance abuse or dependence for substances other than nicotine and THC (i.e. alcohol, amphetamines, barbiturates) A positive urine toxic screen (excluding THC, tricyclic antidepressants, or benzodiazepines (if prescribed)) Moderate or severe cannabis use disorder Diagnosis of major mood disorder or other Axis I disorder other than Schizophrenia, Schizoaffective Disorder or Schizophreniform Disorder Current suicidal ideation. Suicidal ideation with intent or plan (indicated by affirmative answers to items 4 or 5 of the suicidal ideation section of the baseline C-SSRS) in the 6 months prior to screening or subjects who represent a significant risk of suicide in the opinion of the Principal Investigator Pregnant, nursing or positive urine pregnancy test Significant medical or neurological illness by history or physical exam including seizure disorder, history of loss of consciousness related to head trauma or developmental disorder including mental retardation Renal insufficiency (if serum creatinine is greater than laboratory limits for normal, estimated creatinine clearance must be greater than 80) Contraindications to MRI: metal implants, pacemaker, or other metal in the body, or claustrophobia. Individuals with tattoos will be excluded from imaging if tattoos cover more than 5% of the body surface, if a tattoo is greater than 20 cm, or if the tattoo is located on the face, neck or genitals. (Individuals with a contraindication to MRI may participate in the trial but will be excluded from the elective MRI component) Significant history of serious violence For both inpatient and outpatient subjects, a history of serious violence as assessed by the Buss-Perry Aggression Questionnaire For outpatient subjects only, a score of 5 (moderately severe) or higher on the BPRS hostility item at screening or baseline

Ages Eligible for Study
-----------------
Minimum Age: 16 Years
Maximum Age: 40 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Study Drug group<br>Participants in this group will receive 500 mg of levetiracetam twice daily for 12 weeks. After 12 weeks, levetiracetam will be gradually decreased and stopped over the next 9 days. Questionnaires will be administered at each visit to examine how participants are responding to the treatment. In addition, a brain scan and cognitive testing will be performed when feasible at the beginning and the end of the study. | Drug: Levetiracetam Pill<br>* Levetiracetam is an anticonvulsant that is frequently used to treat epilepsy in children and adults due to its superior tolerability, ease of use and excellent safety profile. It is rapidly absorbed and rapidly crosses the blood-brain barrier. Levetiracetam does not affect metabolism of antipsychotic drugs and may normalize hippocampal hyperactivity by decreasing excessive glutamatergic and dopaminergic transmission, thereby making it an ideal agent to test the hypothesis that reducing excessive hippocampal activity may enhance treatment of early psychosis and prevent antipsychotic toxicity. Levetiracetam will be administered in 500 mg capsules twice a day.<br>* Other names: Keppra;|
| Placebo Comparator: Placebo Group<br>Participants in this group will receive a placebo that looks like the levetiracetam pill twice daily for 12 weeks. After 12 weeks, the levetiracetam dose will be tapered for the next 9 days. Questionnaires will be administered at each visit to examine how participants are responding to the treatment. In addition, a brain scan and cognitive testing will be performed when feasible at the beginning and the end of the study. | Other: Placebo<br>* The placebo pill (sugar pill) will look just like the levetiracetam pill but does not contain levetiracetam. Placebo will be taken along with optimal antipsychotic medication selected by either the outpatient provider or the hospital staff responsible for the participant's care. Participants will be instructed to take the placebo pill twice daily for 12 weeks.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The symptoms measured by the BPRS total score | The efficacy of levetiracetam 500 mg bid vs. placebo on symptoms will be measured by the BPRS total score. Brief Psychiatric Rating Scale (BPRS) is an 24-item scale that measures positive symptoms, negative symptoms, general psychopathology and affective symptoms. Individual items are scored on a seven point likert scale. A higher score on the BPRS items indicate increased severity. | up to week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Compared to placebo, levetiracetam will improve psychotic symptoms measured by the BPRS psychosis subscale. | The efficacy of levetiracetam 500 mg bid vs. placebo on symptoms will be measured by the BPRS total score. Brief Psychiatric Rating Scale (BPRS) is an 24-item scale that measures positive symptoms, negative symptoms, general psychopathology and affective symptoms. Individual items are scored on a seven point likert scale. | Baseline visit (week 0), Week 12 visit | 
| Compared to placebo, levetiracetam will be associated with less hippocampal volume loss over 12 weeks. | Hippocampal volume loss will be measured by assessing change in cerebral blood flow (CBF) as measured by Arterial Spin Labeling (ASL). | Baseline visit (week 0), Week 12 visit | 
| Compare to placebo, levetiracetam will improve negative symptoms measured by the modified SANS total score. | Scale for Assessment of Negative Symptoms (SANS) will be the instrument for measurement of negative symptoms. Factor analysis has revealed good construct validity for all items of the SANS scale except the Attention subscale which clusters with measures of cognitive impairment rather than negative symptoms. Two, three and five domain models have been proposed based on factor analysis; this research will use the total score (minus the Attention Subscale) and the two factor solution (avolition and affective expression) to measure negative symptoms. | Baseline visit (week 0), Week 12 visit | 
| Compared to placebo, levetiracetam will improve cognitive functioning measured by the MATRICS composite score. | Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery is the standard tool for assessing cognitive change in trials of cognitive-enhancing agents in schizophrenia. It will be administered at baseline, week 6 and at week 12 to measure whether cognitive function has increased. | Baseline visit (week 0), Week 6 visit, Week 12 visit |