In order to establish target engagement and identify an effective dose the investigators will conduct a placebo-controlled single-dose parallel group trial of levetiracetam 185 mg and 500 mg in 24 medication-naïve early psychosis (EP) patients, measuring hippocampal activity by pulsed arterial spin labelling (ASL) pre-dose and 2 hours post-dose. The lower dose is calculated to achieve blood levels within the range that were associated with reduced hippocampal activity and improved cognition in patients with mild cognitive impairment; the higher dose is a typical antiepileptic dose. Successful demonstration of target engagement will be defined by an effect size of 0.5 or greater compared to placebo in reduction by levetiracetam of hippocampal blood flow measured by ASL. The optimal dose will be defined by maximal reduction of hippocampal perfusion in the absence of clinically-significant adverse effects. The investigators will also study 8 healthy control subjects to verify that baseline hippocampal blood flow is elevated in the sample of EP subjects.

Inclusion Criteria:

1. Males and females 16 to 35 years of age, inclusive, at time of informed consent

2. Must have experienced a first episode of non-affective psychosis within 5 years and exhibit current psychosis, as defined by a score of ≥ 2 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

3. Must have a diagnosis of either schizophrenia, schizoaffective disorder or schizophreniform disorder as established by a Structured Clinical Interview for DSMIV TR (SCID)

4. Must not have taken an oral antipsychotic medication within the past 4 weeks prior to study enrollment or received a long acting injectable antipsychotic within 3 times the dosing interval

5. If female and of childbearing potential, patients must:

   1. Have a negative urine pregnancy test (all females regardless of childbearing potential will be required to submit a pregnancy test)
   2. Not be nursing or planning a pregnancy for the duration of the study through 30 days after the last dosing visit
   3. 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:

1. Current substance abuse or dependence for substances other than nicotine and THC (i.e., alcohol, amphetamines, barbiturates)

   1. A positive urine toxic screen (excluding THC, tricyclic antidepressants, or benzodiazepines (if prescribed))
   2. Moderate or severe cannabis use disorder
   3. Use of marijuana within the 72 hours prior to MRI scanning by self report

2. Diagnosis of major mood disorder or other Axis I disorder other than Schizophrenia, Schizoaffective Disorder or Schizophreniform Disorder

3. 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 and/or PhD or MD level clinician completing screening visit

4. Pregnant, nursing or positive urine pregnancy test

5. 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

6. Metal implants, pacemaker, or other metal in the body or medicinal patch

7. History of claustrophobia

8. Currently taking any antipsychotic medication (within 4 weeks)

The de-identified participant data from the final research dataset used in the published manuscript will be shared upon reasonable request beginning 9 months and ending 36 months following article publication or as required by a condition of awards and agreements supporting the research provided the investigator who proposes to use the data executes a data use agreement with NYU Langone Health. Requests may be directed to: donald.goff@nyulangone.org. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.

Beginning 9 months and ending 36 months following article publication or as required by a condition of awards and agreements supporting the research.

The investigator who proposed to use the data will have access to the data upon reasonable request. Requests should be directed to donald.goff@nyulangone.org. To gain access, data requestors will need to sign a data access agreement.

3 Years

Systematic assessment via administration of the Systematic Assessment for Treatment Emergent Side Effects (SAFTEE) questionnaire and follow-up phone call monitoring.