U.S. Department of Health and Human Services OHRP issued an FWA restriction on NYSPI research that included a pause of human subjects research as of June 23, 2023. This study will resume recruitment after OHRP has approved the resumption of research.

In the present study, 120 healthy volunteers (HV) will be randomized to one of three ketamine-induced pharmacoBOLD (phBOLD) arms: low, medium, and high. Within each ketamine arm, participants will be randomized to 4 days of "study drug" [TS-134 (1st 20 participants) or XT (remaining 100 participants)] or placebo in a 5:3 ratio (25 study drug:15 placebo per arm).

During the study, each participant will undergo a Screening Period (up to 31 days), a 4-day Treatment Period, and a total of two phBOLD sessions: a first session at Baseline and a second session on Day 4 of the Treatment Period, conducted at least 7 days apart, and a follow up visit.

Schizophrenia (Sz) is associated with psychotic symptoms, such as hearing voices and paranoid beliefs that remain partially or fully refractory to standard antipsychotic medications for ~2/3 of patients. Alternative, glutamatergic approaches for treatment development have been proposed but have not yet led to FDA-approved medications. Moreover, several glutamate-targeted medications, such as pomaglumetad (POMA), have failed in pivotal clinical trials despite robust effectiveness in preclinical models. A major barrier to effective glutamatergic treatment development is the absence of validated measures for target engagement that can identify effective compounds and guide dose selection. Target" refers to a factor that an intervention is intended to modify, leading to improvement in symptoms, and target engagement biomarkers are a measure of the ability of the intervention to "engage" the target.

As part of the recently completed NIMH multicenter FAST-PS initiative and a parallel industry sponsored project, we evaluated ketamine-induced pharmacoBOLD (phBOLD) in healthy volunteers (HV) as a potential target engagement biomarker for development of metabotropic glutamate (mGluR2/3) agonists, as a prelude to planned studies in Sz. BOLD imaging indirectly measures brain energy, as a proxy for glutamate target engagement.

The structure of the R01 grant funding this protocol was split into three studies, specific aim (SA) 1, 2 and 3. In FAST-PS, a high dose of ketamine (0.23 mg/kg) was used in order to produce robust pharmacological effects.

Under SA1, which was conducted under IRB 8063, this dose was titrated downward in across two phBOLD sessions in HV in order to determine the lowest dose of ketamine that still produces a phBOLD response of Cohen's d≥1.5, hypothesizing that this dose would provide the best signal to noise for use in SA2. The study was conducted in groups of 10 subject per dose cohort, and the analysis supports using a low dose of 0.086 mg/kg for SA2.

In the present study, 120 healthy volunteers (HV) will be randomized to one of three ketamine-induced pharmacoBOLD (phBOLD) arms: low, medium, and high. Within each ketamine arm, participants will be randomized to 4 days of "study drug" [TS-134 (1st 20 participants) or XT (remaining 100 participants)] or placebo in a 5:3 ratio (25 study drug:15 placebo per arm).

During the study, each participant will undergo a Screening Period (up to 31 days), a 4-day Treatment Period, and a total of two phBOLD sessions: a first session at Baseline and a second session on Day 4 of the Treatment Period, conducted at least 7 days apart, and a follow up visit.

Inclusion Criteria:

1. Age between 18-55 at screen
2. Medically healthy, as assessed by study physician at screen
3. Capable of understanding the study procedures and able to provide informed consent
4. Eligible men and women must agree to use a reliable method of birth control (See section 5.3) during the study. Women who are post-menopausal or otherwise not of childbearing potential are also eligible.
5. Willing and reliable to participate in XT or placebo phase as an outpatient and/or agreeable to participate as an inpatient.

Exclusion Criteria:

1. Current or past Axis I psychiatric history (including Substance Use Disorder/Alcohol Use Disorder, with the exception of nicotine use disorder) as assessed at screen

2. Positive urine toxicology or alcohol at screen

3. History of recreational ketamine use, recreational PCP use, or an adverse reaction to ketamine. Participants who have participated in prior research ketamine studies will be eligible. Participants can have infusions not more frequently than biweekly, and not more than 1/month on average, therefore participants entering the study will need to wait one month if they had a single infusion and 6 weeks if they have had two closely spaced infusions.

4. History of first-degree relative with schizophrenia

5. Pregnancy or breast-feeding. This exclusion criterion applies only to females of child-bearing potential (not surgically sterilized and between menarche and 1 year postmenopausal). Must test negative for pregnancy at the time of screening based on a serum pregnancy test.

6. History of violence, including any history of using a gun, knife, or other weapon with intent to harm someone, as well as more than one physical fight without a weapon after the age of 18 years old (not including fights that happen during sports competition).

7. Presence or positive history of significant medical illness at screen, including:

   • Contraindications to XT (urinary retention, moderate or severe hepatic impairment, gastric retention, untreated narrow-angle glaucoma, hypernasality)
   • renal problems (GFR<60)
   • high blood pressure (defined as supine systolic blood pressure (SBP) > 140 or supine diastolic blood pressure (DBP) > 90)
   • low blood pressure (defined as supine SBP < 100, DBP < 60)
   • abnormal orthostatic blood pressure (change in mean arterial pressure [1/3 systolic + 2/3 diastolic] of > 20% between supine and standing blood pressures)
   • clinically significant cardiac illness, as determined by the site physician
   • clinically significant abnormal screening labs, as determined by the site physician

8. Participants with 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 participants who represent a significant risk of suicide in the opinion of the investigator.

9. Presence or positive history of neurological illness, including seizures, mental retardation or any other disease/procedure/accident/intervention associated with significant injury to or malfunction of the central nervous system (CNS), or history of significant head injury.

10. Any material in the body that is a contraindication for MRI procedures

11. Currently taking any psychotropic medication, including antidepressant medications, benzodiazepines, antipsychotic medications, mood stabilizers, anti-epileptic medications, and stimulants. We will exclude any participant who requires treatment with any psychotropic medication from one of these classes.

NIMH Data archive

Per NIMH Data archive regulations

Qualified investigator

Double blind