A Safety, Tolerability, and Pharmacokinetics Study of MK-8189 in Participants With Schizophrenia and in Healthy Participants (MK-8189-007)

Exclusion Criteria

• •Panel A (Healthy Participants)
• •Has a history of clinically diagnosed depression, anxiety disorder, or any history of psychiatric disorders having required drug treatment or hospitalization. Participants who have had situational depression more than 5 years before the start of the study may be enrolled in the study at the discretion of the investigator.
• •Has a history of stroke, chronic seizures, or major neurological disorder.
• •Has a history of dystonic reaction to antipsychotic, anti-emetic or related medication.
• •Is at imminent risk of self-harm, based on clinical interview and responses on the Columbia Suicide Severity Rating Scale (C-SSRS), or of harm to others in the opinion of the investigator. Participants must be excluded if they report suicidal ideation with intent, with or without a plan or method (e.g., positive response to item 4 or 5 in assessment of suicidal ideation on the C-SSRS) in the past 5 years or suicidal behavior in their lifetime.
• •Has a history of clinically significant endocrine, gastrointestinal, cardiovascular, hematological, hepatic, immunological, renal, respiratory, genitourinary, or major neurological (including stroke and chronic seizures) abnormalities or diseases. Participants with a remote history of uncomplicated medical events may be enrolled in the study at the discretion of the investigator.
• •Is mentally or legally incapacitated, has a history of clinically significant psychiatric disorder of the last 5 years. Participants who have had situational depression may be enrolled in the study at the discretion of the investigator.
• •Is unable to refrain from or anticipates the use of any medication, including prescription and nonprescription drugs or herbal remedies, beginning approximately 2 weeks (or 5 half-lives) prior to administration of the initial dose of study drug, throughout the study (including washout intervals between treatment periods), until the poststudy visit.
• •Is a smoker and/or has used nicotine or nicotine-containing products (e.g., nicotine patch and electronic cigarette) within 3 months of screening.
• •Panels B, C, and D (Participants with Schizophrenia; MK-8189 or Placebo Monotherapy / Add-on Therapy / 15-Day Titration Monotherapy)
• •Has evidence or history of a primary DSM-5 axis I psychiatric diagnosis other than schizophrenia or schizoaffective disorder per the allowed DSM-5 criteria within 1 month of screening.
• •Has evidence or history of mental retardation, borderline personality disorder, anxiety disorder, or organic brain syndrome.
• •Has a history of neuroleptic malignant syndrome or moderate to severe tardive dyskinesia (TD).
• •Has a substance-induced psychotic disorder or behavioral disturbance thought to be due to substance abuse.
• •Has a DSM-5 defined substance abuse or dependence disorder (excluding nicotine and caffeine) within three months of screening.
• •Has a history of seizure disorder beyond childhood or is receiving treatment with any anticonvulsant to prevent seizures.
• •Is at imminent risk of self-harm, based on clinical interview and responses on the C-SSRS, or of harm to others in the opinion of the investigator. Participants must be excluded if they report suicidal ideation with intent, with or without a plan or method (e.g., positive response to item 4 or 5 in assessment of suicidal ideation on the C-SSRS) in the past 2 months or suicidal behavior in the past 6 months.
• •Has received treatment with clozapine for schizophrenia or treatment with monoamine oxidase inhibitors within 3 months of screening. For Panel C participants, has received a total daily dose of risperidone \> 6 mg.
• •Is unable to refrain from the use of co-medication with a moderate or strong inhibiting or inducing effect on cytochrome P450 (CYP) 3A (CYP3A) and/or CYP2C9 beginning approximately 2 weeks or 5 half- lives, whichever is longer, prior to administration of the initial dose of trial drug and throughout the trial or is unable to refrain from the use of sensitive substrates of CYP2B6. Unable to refrain from cyclic hormone replacement therapy. There may be certain medications that are permitted
• •Has received a parenteral depot antipsychotic medication within 3 months of pre-trial (screening).
• •Panels A, B, C, and D
• •Is a woman of childbearing potential (WOCBP) who has a positive serum pregnancy test at the screening visit or a positive urine pregnancy test within 48 hours before the first dose of study intervention. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
• •Has a clinically significant history or presence of sick sinus syndrome, first, second, or third degree atrioventricular (AV) block, myocardial infarction, pulmonary congestion, cardiac arrhythmia, prolonged QTc interval, or conduction abnormalities.
• •Has history of repeated or frequent syncope, vasovagal episodes, or epileptic seizures.
• •Has a family history of sudden death.
• •Has a history of any illness that, in the opinion of the study investigator, might confound the results of the study or poses an additional risk to the participant by their participation in the study.
• •Has a history of significant multiple and/or severe allergies (e.g., food, drug, latex allergy), or has had an anaphylactic reaction or significant intolerability (i.e., systemic allergic reaction) to prescription or non-prescription drugs or food.
• •Has Hepatitis B, Hepatitis C or Human Immunodeficiency Virus (HIV) infection.
• •Had major surgery, donated or lost 1 unit of blood (approximately 500 mL) within 4 weeks prior to the prestudy (screening) visit.
• •Has participated in another investigational study within 4 weeks (or 5 half-lives, whichever is greater) prior to the prestudy (screening) visit. The window will be derived from the date of the last visit in the previous study.
• •Has history or presence of risk factors for Torsade de Pointes (e.g., cardiac disease, heart failure, hypokalaemia or hypomagnesaemia, hypertrophy, cardiomyopathy, or family history of long QT syndrome). Plasma calcium must be within normal limits at screening and serum calcium must be within normal limits prior to dosing.
• •Is under the age of legal consent.
• •Has been in incarceration or imprisonment within 3 months prior to screening.
• •Consumes greater than 3 glasses of alcoholic beverages per day. Participants who consume 4 glasses of alcoholic beverages per day may be enrolled at the discretion of the investigator.
• •Consumes excessive amounts, defined as greater than 6 servings (1 serving is approximately equivalent to 120 mg of caffeine) of coffee, tea, cola, energy drinks, or other caffeinated beverages per day.
• •Is a regular user of cannabis, any illicit drugs or has a history of drug (including alcohol) abuse within approximately 3 years.