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Addition of the antipsychotic lumateperone (Caplyta) to an existing antidepressant improved symptoms of depression in a randomized, double-blind phase III trial.

Among 484 patients with major depressive disorder, those on adjunctive lumateperone had a significantly greater MADRS (Montgomery-Åsberg Depression Rating Scale) total score improvement from baseline to day 43 compared with placebo (least square mean difference -4.9, P<0.0001), reported Willie Earley, MD, of maker Intra-Cellular Therapies in New York City, at Psych Congress in Boston.

"The efficacy was significant as early as day 8 and continued to the end of study at day 43," said Earley in a poster presentation.

Lumateperone was first approved by the FDA for adults with schizophrenia in December 2019. In December 2021, it gained an indication for bipolar I or II-related depressive episodes as monotherapy and as adjunctive therapy with lithium or valproate. The atypical antipsychotic has a novel mechanism of action, acting as a simultaneous modulator of serotonin, dopamine, and glutamate neurotransmission.

In the current study, adults, ages 18-65, were eligible if they had a DSM-5 diagnosis for major depressive disorder and had an inadequate response to one to two courses of a prior antidepressant. Inadequate treatment response was considered to be less than a 50% improvement with 6 weeks or longer of antidepressant monotherapy measured by the Antidepressant Treatment Response Questionnaire.

All also had to be currently experiencing a major depressive episode with a MADRS total score of ≥24 and a Quick Inventory of Depressive symptomatology-Self Report-16 item (QIDS-SR-16) score of ≥14. At baseline, average MADRS total score was 30.4 (ranges from 0-60) and Clinical Global Impressions-Severity scale (CGI-S) score was 4.7 (ranges from 1-7; 7 being the most extremely ill patients).

In the treatment arm, most participants were female (66%) and white (75%) with an average age of 45. Most were on an selective serotonin reuptake inhibitor (SSRI) versus an serotonin-norepinephrine reuptake inhibitor (SNRI) during the study (65% vs 29%).

Half (n=241) were randomized to receive 42 mg of lumateperone and half received placebo. Both groups continued their baseline antidepressant.

In addition to MADRS improvement, patients on lumateperone also had significant improvements in CGI-S score (least square mean difference -0.7, P<0.0001), which was a key secondary endpoint. Lumateperone-treated patients also had a 2.4-point drop in QIDS-SR-16 total score from a baseline score of 18.1 (P<0.0001).

Around 58% of the lumateperone group experienced a treatment-emergent adverse event (TEAE) compared with 46.5% of placebo, and serious AEs were uncommon in both arms (0.4%). Reports of dry mouth, fatigue, and tremor occurred in ≥5% of lumateperone patients.

Despite some reports of tremor, there were "no notable changes" in extrapyramidal symptoms (EPS) measured by the Abnormal Involuntary Movement Scale, Barnes Akathisia Rating Scale, and Simpson-Angus Scale. As measured by broad standard Medical Dictionary for Regulatory Activities query, EPS-related TEAEs occurred in 2.9% of placebo and 6.2% of the lumateperone arms.

No deaths occurred during the study. Also, no suicidal behavior was reported during the study, according to the Columbia-Suicide Severity Rating Scale, and emergent suicidal ideation was lower in the treatment arm (1.4% vs 3.5%).

Of note with an antipsychotic, weight and BMI remained stable in both groups throughout the study. As for cardiometabolic profiles, there were no clinically relevant mean increases in any of the following measures with lumateperone from baseline versus placebo:

• Total cholesterol: -10.3 mg/dL (baseline 197.7) vs -1.3 (baseline 199.1)

• HDL cholesterol: -0.4 mg/dL (54.7) vs -0.4 (57.5)

• LDL: -9.4: mg/dL (136) vs -0.9 (136.2)

• Triglycerides: -4.7 mg/dL (138.8) vs 1.7 (131.3)

• Glucose: 0.9 mg/dL (91.3) vs 0.8 (93.8)
• Insulin: -1.5 mIU/L (15.7) vs 1.4 (13.5)

• Prolactin: 1.6 ng/mL (11) vs 0.6 (9.6)

"These results suggest lumateperone 42 mg adjunctive to antidepressant therapy is a promising new treatment option for adults with major depressive disorder with inadequate response to prior antidepressant therapy," Earley and colleagues concluded.

Intra-Cellular Therapies said in a press release that a for the adjunctive treatment of major depressive disorder is expected by the end of 2024.

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