A Study of JNJ-61393215 in the Treatment of Depression

The purpose of this study is to evaluate the efficacy of JNJ-61393215 as adjunctive treatment compared to adjunctive placebo, as assessed by the change from baseline to week 6 on a 17-item Hamilton Depression Rating Scale (HDRS-17) in participants with major depressive disorder (MDD) with anxious distress with a score greater than or equal to (\>=) 2 on item 26 or 27 of the Inventory of Depressive Symptomatology, Clinician Rating -30 (IDS-C30), who have a suboptimal response to current treatment with a standard antidepressant.


Eligibility Criteria:
Inclusion Criteria:

* Participants must have a body mass index (BMI) between 18 and 36 kilogram per meter square (kg/m\^2)
* Participants must have a primary diagnostic and statistical manual of mental disorders, 5th edition (DSM-5) diagnosis of major depressive disorder (MDD) with anxious distress, as assessed by the mini international neuropsychiatric inventory 7.0. Plus (MINI). Participants with a diagnosis of comorbid generalized anxiety disorder (GAD), post-traumatic stress disorder, persistent depressive disorder, attention deficit hyperactivity disorder (ADHD), social anxiety disorder or nicotine/caffeine dependence may be included, if MDD is primary diagnosis
* Participants must have an inventory of depressive symptomatology, clinician rating-30 (IDS-C30) total score greater than or equal to (\>=) 35 (moderate to severe depression)
* Participant must not have received more than 3 failed antidepressant treatments (of adequate dose and duration), including their current treatment, in the current episode of depression, as documented by the massachusetts general hospital antidepressant treatment history questionnaire (MGH-ATRQ)
* Participant must be currently receiving 1 of the following antidepressants for at least 6 weeks duration at screening, at an adequate therapeutic dose, as determined by the MGH-ATRQ and should remain on a stable dose throughout the study: bupropion, citalopram, escitalopram, sertraline, paroxetine, venlafaxine, desvenlafaxine, duloxetine, fluoxetine, vilazodone, vortioxetine, mirtazapine, agomelatine, nortriptyline, imipramine, amitriptyline and levomilnacipran
* Participants must have a suboptimal response (improvement \<50%) to the antidepressant used as their current treatment, as measured by the MGH-ATRQ
* A woman of childbearing potential must have a negative serum pregnancy test at screening and a negative urine pregnancy test before the first dose

Exclusion Criteria:

* Participant has any other psychiatric condition including but not limited to: MDD with current psychotic features, bipolar disorder (including lifetime diagnosis), obsessive-compulsive disorder, borderline personality disorder, eating disorder (example: bulimia, anorexia nervosa), or schizophrenia (lifetime)
* Age of onset of depression is after 55 years of age
* Participant has a history of alcohol or substance use disorder (abuse/dependence) within 6 months prior to screening (nicotine and caffeine dependence are not exclusionary)
* Participant has a current or recent (within the past year) history of clinically significant suicidal ideation (corresponding to a score of \>= 3 for ideation) or any suicidal behavior within the past year, as validated on the Colombia suicide severity rating scale (C-SSRS) at screening or baseline
* Length of current major depressive episode \>60 months
* Participant has organic brain disease or dementia or has known or suspected intellectual development disorder
* Participant has been treated with at least one of the following treatments: (a) electroconvulsive therapy in the current episode; (b) deep brain stimulation (lifetime); (c) repetitive transcranial magnetic stimulation within 4 weeks prior to baseline visit
* Participant has any clinically relevant medical condition that could potentially alter the absorption, metabolism, or excretion of the study intervention, such as liver disease or renal disease
* Participant has a relevant history of any significant and/or unstable cardiovascular, respiratory, neurological (including seizures - uncomplicated childhood febrile seizures with no sequelae are not exclusionary) or significant cerebrovascular, renal, hepatic, dermatologic, hematologic, gastrointestinal or endocrine diseases. Hospitalization for cardiovascular event (myocardial infarction, unstable angina, stroke, transient ischemic attack) within 3 months prior to the first administration of study drug is exclusionary. Diabetes mellitus be allowed when the participant is stable (HbA1c less than 7.5% or 58 mmol/mol)
* Participant has a clinically significant abnormal physical examination, vital signs or 12-lead electrocardiogram (ECG) at screening or baseline Minor deviations in ECG, which are not considered to be of clinical significance to the investigator, are acceptable.If at screening visit QTcB or QTcF interval \>=450 ms for males or \>=470 ms for females, or \>480 ms if bundle branch block and prolongation of the QTc interval are present;participant is excluded
* Participant has a history of known demyelinating diseases such as multiple sclerosis or optic neuritis