Study of Lurasidone as Adjunctive Treatment in Patients With Major Depressive Disorder With Inadequate Response to Antidepressant Monotherapy

Evaluating the Efficacy and Safety of Lurasidone as Adjunctive Therapy in Adult Patients Diagnosed With Major Depressive Disorder Who Have an Inadequate Response to Antidepressant Monotherapy: A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Trial

This Phase 3, multicenter, randomized, double-blind, placebo-controlled clinical trial is designed to evaluate the efficacy and safety of lurasidone as adjunctive therapy in adult patients with major depressive disorder (MDD) who show an inadequate response to antidepressant monotherapy. Eligible participants will continue their background antidepressant treatment and be randomized to receive either lurasidone (20, 40, or 60 mg/day) or placebo for 8 weeks. The primary endpoint is the change from baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score at Week 8. Secondary endpoints include response and remission rates, changes in Clinical Global Impression-Severity (CGI-S), 17-item Hamilton Depression Rating Scale (HAM-D17), Hamilton Anxiety Rating Scale (HAM-A), and Sheehan Disability Scale (SDS) scores. Safety assessments will include adverse events, laboratory tests, electrocardiograms (ECGs), vital signs, and suicidality monitoring Columbia-Suicide Severity Rating Scale (C-SSRS).

Inclusion Criteria:

• Signed informed consent prior to participation
• Outpatients aged 19-65 years
• Diagnosis of Major Depressive Disorder (MDD) per DSM-5 using MINI; psychotic features allowed
• Current major depressive episode lasting ≥8 weeks at baseline
• MADRS total score ≥24 at both screening and baseline
• CGI-S score ≥4 at both screening and baseline
• Documented history of antidepressant treatment (ADT) with inadequate response (<50% improvement), confirmed by ATRQ
• Currently on one of the allowed antidepressants (SSRI: citalopram, escitalopram, fluoxetine, paroxetine, sertraline; SNRI: duloxetine, venlafaxine, desvenlafaxine, milnacipran; Others: bupropion, vortioxetine, amitriptyline, tianeptine, agomelatine) at minimum effective dose for ≥6 weeks
• Agreement to maintain the same background ADT regimen until study completion
• BMI between 16-40 kg/m²
• Willingness to discontinue prohibited psychotropic medications during washout
• Stable doses of permitted concomitant medications (oral hypoglycemics ≥30 days, thyroid replacement ≥90 days, antihypertensives ≥30 days, lipid-lowering agents ≥30 days before baseline)

Exclusion Criteria:

• Lifetime diagnosis of schizophrenia, schizoaffective disorder, bipolar disorder, or other psychotic disorders
• Diagnosis within past 6 months of panic disorder, generalized anxiety disorder, OCD, PTSD, eating disorder, substance abuse/dependence (except caffeine/nicotine), or clinically significant personality disorder
• ≥25% reduction in MADRS score between screening and baseline
• Significant suicide risk (per C-SSRS, MADRS item 10 ≥5, recent suicide attempt, or investigator judgment)
• First major depressive episode onset after age 60
• Treatment resistance: ≥3 adequate ADT trials without remission, or non-response to antipsychotic augmentation
• Prior ECT, VNS, rTMS within 5 years or history of ECT failure
• Known hypersensitivity to lurasidone or excipients
• Use of prohibited medications (strong CYP3A4 inhibitors/inducers, QTc-prolonging drugs) within 14 days before randomization
• Prior exposure to lurasidone or investigational CNS drugs (per protocol limits)
• Pregnancy, breastfeeding, or unwillingness to use effective contraception; positive pregnancy test at screening or baseline
• Clinically significant ECG abnormalities (QTcB ≥460 ms in men, ≥480 ms in women)
• Clinically significant lab abnormalities: ALT/AST >2× ULN, bilirubin >1.5× ULN, Hb <8 g/dL (women) or <9 g/dL (men), ANC <1,200/µL, HbA1c >8%, HBsAg or HCV antibody positive (unless HCV RNA negative), CrCl <50 mL/min, abnormal thyroid function (TSH, free T3/T4)
• History of serious medical conditions: uncontrolled cardiovascular disease, recent MI, arrhythmia, active cancer (within 5 years, except basal/squamous cell skin cancer), GI surgery affecting absorption, uncontrolled endocrine disease, moderate/severe hepatic impairment, untreated sleep apnea, seizure disorders, dementia, HIV infection
• Prolactin >100 ng/mL or pituitary adenoma history
• Investigator/site staff or family members of study personnel
• Inability to comply with study procedures or anticipated relocation during study
• More than 2 prior attempts at screening/washout for this study