Metabolic profile of adjunctive lumateperone 42 mg in major depressive disorder: A pooled analysis of 2 randomized, placebo-controlled trials

Background

Major depressive disorder (MDD) is a highly prevalent and disabling condition characterized by persistent low mood, anhedonia, and cognitive and physical symptoms that impair daily functioning. Importantly, MDD is frequently associated with comorbidities, including cardiovascular and metabolic disorders. Both antidepressant therapy (ADT) and atypical antipsychotics have been associated with weight gain and metabolic adverse effects.

Lumateperone is an atypical antipsychotic indicated for: treatment of schizophrenia in adults; treatment of depressive episodes associated with bipolar I or II disorder (bipolar depression) in adults, as monotherapy and as adjunctive therapy with lithium or valproate; and treatment of major depressive disorder (MDD) in adults as adjunct to antidepressant therapy (ADT). Two Phase 3, randomized, double-blind, placebo-controlled studies (501 [NCT04985942]; 502 [NCT05061706]) demonstrated efficacy and safety of lumateperone 42mg+ADT in patients with MDD with inadequate ADT response. A pooled analysis of these studies evaluated the metabolic profile associated with adjunctive lumateperone 42mg.

Methods

Data were pooled for Studies 501/502, which enrolled adults (18-65y) meeting DSM-5 criteria for MDD with inadequate response to 1-2 ADTs in the current depressive episode. Patients with Montgomery-Asberg Depression Rating Scale Total score ≥24, Clinical Global Impression-Severity score ≥4, and Quick Inventory of Depressive Symptomatology-Self Report-16 item score ≥14 were randomized to 6-week lumateperone 42mg+ADT or placebo+ADT. Assessments included changes in weight, body mass index (BMI), waist circumference, cardiometabolic laboratory parameters (cholesterol [total, high-density lipoprotein, low-density lipoprotein], triglycerides, glucose, insulin), and prolactin levels. Subgroups were analysed by baseline BMI category (normal weight: ≥18.5 to <25kg/m²; overweight: ≥25 to <30kg/m²; obese: ≥30kg/m²).

Results

The safety population comprised 964 patients (lumateperone+ADT, n=483; placebo+ADT, n=481). Changes from baseline to end of treatment (EOT) were minimal with lumateperone+ADT vs placebo+ADT for weight (−0.1kg vs +0.0kg), BMI (−0.0kg/m² vs +0.0kg/m²), and waist circumference (−0.2cm vs −0.3cm). Potentially clinically significant (PCS) weight increase (≥7% from baseline) was rare during treatment (lumateperone+ADT, 0.4%; placebo+ADT, 1.3%). There were no clinically meaningful changes in cardiometabolic parameters or prolactin levels.

At baseline, proportions of patients across BMI categories were similar: normal weight (lumateperone+ADT, 32.3% vs placebo+ADT, 34.3%), overweight (38.5% vs 31.8%), and obese (29.2% vs 33.9%). Changes at EOT were minimal across BMI subgroups and treatment groups for weight (−0.3kg to +0.3kg), BMI (−0.1kg/m² to +0.1kg/m²), and waist circumference (−0.6cm to +0.1cm). PCS weight increase was rare with lumateperone+ADT vs placebo+ADT (normal weight: 0.7% vs 1.2%; overweight: 0.6% vs 0%; obese: 0% vs 2.5%). Changes in cardiometabolic parameters and prolactin levels at EOT were not clinically relevant across BMI subgroups and treatment groups. Most patients remained in their BMI category by EOT (normal weight: lumateperone+ADT, 91.0% vs placebo+ADT, 95.2%; overweight: 89.8% vs 86.9%; obese: 91.5% vs 94.5%).

Conclusions

Lumateperone+ADT had a favourable safety profile with minimal changes in metabolic parameters across BMI subgroups, indicating that lumateperone may be a well-tolerated adjunctive treatment for patients with MDD with inadequate ADT response.

References

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