A Randomized, Double-Blind, Placebo Controlled, Two-Period Cross-Over, Proof of Activity Study to Evaluate the Effects of TAK-041 on Motivational Anhedonia as Add-On to Antipsychotics in Participants With Stable Schizophrenia

The purpose of the study is to determine whether motivation/reward deficits observed in schizophrenia are attenuated and whether cognitive impairment associated with schizophrenia is improved by add-on TAK-041 administration to antipsychotics in participants with stable schizophrenia.

The drug being tested in this study is called TAK-041. TAK-041 is being tested to treat people who have stable schizophrenia. This study will look whether motivation/reward deficits observed in schizophrenia are attenuated and whether cognitive impairment associated with schizophrenia is improved in people who take TAK-041 in addition to standard care.

The study will enroll approximately 32 patients. Participants will be randomly assigned (by chance, like flipping a coin) in 1:1 ratio to one of the two treatment sequences -which will remain undisclosed to the patient and study doctor during the study (unless there is an urgent medical need) to receive either TAK-041 40 mg or Placebo first and then will be crossed over to receive the opposite Intervention.

All participants will be asked to take oral suspension on Day 1 of each Period. There will be a wash-out Period of 35 days between the dosing days in Period 1 and 2.

This single-center trial will be conducted in the United Kingdom. The overall time to participate in this study is approximately 126 to 154 days. Participants will make multiple visits to the clinic plus a final visit 77 days after receiving their last dose of drug for a follow-up assessment.

Eligibility Criteria:
Inclusion Criteria:

1. Is on a stable dose of antipsychotics for at least 2 months as documented by medical history and assessed by site staff (other than those on the excluded medication list).
2. Meets schizophrenia criteria as defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) by the Mini International Neuropsychiatric Interview (MINI).
3. Have Positive and Negative Syndrome Scale (PANSS) total score less than or equal to (\<=) 90 and PANSS Negative Symptom Factor Score (\[NSFS\]; Sum of PANSS N1, N2, N3, N4, N6, G7, and G16) greater than or equal to (\>=) 15 at screening and baseline (Day -1).
4. Has stable Screening and baseline (Day-1) PANSS and NSFS total scores (less than \[\<\] 20 percent \[%\] change).
5. Have had a structural brain magnetic resonance imaging (MRI) within the preceding year or during screening indicating no concerning structural brain abnormalities or other abnormalities that would interfere with interpretation of functional brain imaging results.

Exclusion Criteria:

1. Has a history of cancer (malignancy).
2. Has a positive alcohol and/ or positive drug screen at Screening or Day -1.
3. Is positive for hepatitis B surface antigen (HBsAg), hepatitis C (HCV) antibody, or human immunodeficiency virus (HIV) antibody/antigen (confirmatory testing is allowed; most sensitive test should take precedence).
4. Had major surgery, or donated or lost 1 unit of blood (approximately 500 milliliters \[mL\]) within 4 weeks prior to the pretrial/Screening Visit.
5. Has abnormal Screening or baseline laboratory values (\>upper limit of normal \[ULN\] for the respective serum chemistries) of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBILI), alkaline phosphatase (ALP), γ-glutamyl transferase (GGT) confirmed upon repeat testing, 5'-nucleotidase (Screening only), and/or abnormal urine osmolality, confirmed upon repeat testing.
6. Meets DSM-5 criteria for substance use disorder or history of alcohol abuse within 1 month prior to Screening Visit.
7. Has a history of claustrophobia or inability to tolerate mock scanner environment during habituation/screening session.
8. Fulfills any of the MRI contraindications on the site standard radiography screening document.
9. Has a history in the last year from the randomization visit or is currently receiving treatment with clozapine.
10. Has a current diagnosis of a significant psychiatric illness other than schizophrenia, per DSM-5 and is in an acute phase or episode.
11. Has a risk of suicide according to the investigator's clinical judgment (example, per C-SSRS positive answers on questions 4 or 5 or has made a suicide attempt within 6 months prior to screening visit).