A Study to Evaluate The Effects of RO5545965 in Participants With Negative Symptoms of Schizophrenia Treated With Antipsychotics

This is a multicenter, randomized, double-blind, placebo-controlled, three period crossover study to evaluate the effects of RO5545965 on the functioning of key brain circuitry involved in negative symptoms using functional magnetic resonance imaging (fMRI) and reward-based learning in stable participants with mild to moderate negative symptoms of schizophrenia treated with antipsychotics. Participants will be randomized to one of six different sequences during which each participant will receive three 3-week treatment courses with RO5545965 5 milligrams (mg), RO5545965 15 mg and placebo. Each treatment period will be separated by a washout period of 14 days. Total duration of study will be approximately 17 weeks.


Eligibility Criteria:
Inclusion Criteria:

* A diagnostic and statistical manual of mental disorders-5 (DSM-5) diagnosis of schizophrenia as established by structured clinical interview for DSM-5-clinical trial (SCID-5-CT) at screening
* Participants with no hospitalization for worsening of schizophrenia within 3 months prior to screening
* Male and female participants with no childbearing capacity; females must be either surgically sterile or postmenopausal for at least 1 year
* Body mass index (BMI) greater than (\>) 18.5 kilograms per square meter (kg/m\^2) and less than (\<) 35 kg/m\^2
* Fluent in English, even if English is not the primary language
* Participants with clinical global impression-severity (CGI-S) score greater than or equal to (\>/=) 3 (mildly ill)
* Participants with a score of less than or equal to (\</=) 4 (moderate) on positive and negative syndrome scale (PANSS) items P7 (hostility), G8 (uncooperativeness) and G6 (depression)
* Participants with PANSS negative symptom factor score \>/=18
* Participants with calgary depression rating scale for schizophrenia (CDSS) score \</=8
* Participants on stable treatment, that is 6 weeks without change, with no more than two antipsychotics prior to screening

Exclusion Criteria:

* Moderate to severe substance use disorder within 6 months as defined by DSM-5
* Positive urine drug screen for amphetamines, methamphetamines, opiates, buprenorphine, methadone, cannabinoids, cocaine and barbiturates
* Participants at significant risk of suicide or harming him or herself or others according to the Investigator's judgment
* History of neuroleptic malignant syndrome
* A prior or current general medical condition that might be impairing cognition or other psychiatric functioning
* A movement disorder due to antipsychotic treatment not currently controlled with anti-extrapyramidal symptoms (anti-EPS) treatment or another movement disorder which might affect the ratings on the EPS scales
* Participants with a score \>2 (mild) in any of the four CGI-S items of the extrapyramidal symptom rating scale (ESRS-A)
* History of human immunodeficiency virus (HIV) infection, Hepatitis B, or Hepatitis C infection
* QTcF interval \>450 milliseconds (msec) (470 msec for females) or other significant abnormality on screening electrocardiogram (ECG) based on centralized reading
* Clinically significant abnormalities in laboratory safety test results
* Significant or unstable physical condition
* Receipt of an investigational drug within 90 days or 5 times the half-life of the investigational drug, whatever is longer, prior to screening
* Previously received RO5545965
* Electroconvulsive treatment (ECT) within 6 months prior to screening
* Current or 6 months prior to screening treatment with olanzapine or clozapine
* Change in benzodiazepine or sleep medication regimen within 2 weeks prior to screening
* Change in anti-EPS medication within two weeks prior to screening
* Use of prohibited medications taken within 14 days or within 5 times the elimination half-life of the medication before the first study drug administration
* Use of any strong or moderate inhibitor of cytochrome P 450 3A (CYP3A) or CYP2C8 and any inducer of CYP3A within 14 days or within 5 times the elimination half-life of the medication (whichever is longer) before the first study drug administration
* Use of any other nutrients known to modulate CYP3A activity within 1 week before the first study drug administration