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

Major depressive disorder (MDD) is a common psychiatric condition, and many patients fail to achieve adequate improvement with antidepressant monotherapy. Adjunctive therapies are therefore needed to improve outcomes. Lurasidone, an atypical antipsychotic, has shown potential benefit when combined with antidepressants.

This study will enroll up to 364 adult outpatients aged 19-64 years who meet Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for MDD and demonstrate inadequate response to at least one antidepressant. Participants must have a MADRS score ≥24 and CGI-S score ≥4 at both screening and baseline. After a screening/washout period of up to 14 days, subjects will be randomized 1:1 to lurasidone or placebo, in addition to their ongoing antidepressant.

Treatment period: 8 weeks of double-blind therapy, with dose titration allowed in the first 2 weeks and fixed dosing thereafter.

Follow-up: 1 week safety follow-up after last dose.

Primary objective: To assess whether adjunctive lurasidone significantly improves depressive symptoms compared to placebo, measured by MADRS total score change from baseline to Week 8.

Secondary objectives: To evaluate response and remission rates, functional improvement (SDS), and changes in anxiety and depression severity scales (HAM-A, HAM-D17, CGI-S).

Safety objectives: To monitor adverse events, extrapyramidal symptoms (Abnormal Involuntary Movement Scale (AIMS), Barnes Akathisia Rating Scale (BARS), Simpson-Angus Scale (SAS)), suicidality (Columbia-Suicide Severity Rating Scale (C-SSRS)), laboratory values, electrocardiograms (ECGs), and vital signs.

This trial will provide important evidence on the role of lurasidone as adjunctive therapy for patients with MDD who do not respond adequately to antidepressant monotherapy.

Inclusion criteria

• Signed informed consent prior to participation
• Outpatients aged 19-64 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)
• Currently on one of the protocol-permitted antidepressants 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.
• Clinically significant laboratory abnormalities that may affect study participation or safety.
• Clinically significant uncontrolled cardiovascular, hepatic, renal, endocrine, neurological, psychiatric, or other medical conditions that may affect study participation or safety.
• 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