Takeda and Lundbeck announced that the Food and Drug Administration (FDA)’s Psychopharmacologic Drug Advisory Committee (PDAC) voted to support the efficacy of vortioxetine (Brintellix) for treating cognitive dysfunction in adults with major depressive disorder (MDD).
The advisory committee also reviewed evidence to suggest that cognitive dysfunction in people with major depressive disorder was an appropriate target for treatment. Several recent conferences on the topic were referenced:
June, 2014: American Society of Clinical Psychopharmacology Annual Meeting – Workshop on Cognitive Dysfunction in MDD
October, 2014: Massachusetts General Hospital Psychiatry Academy Workshop – Cognition in Depression: What Do We Know?
February, 2015: Institute of Medicine – Enabling Discovery, Development, and Translation of Treatments for Cognitive Dysfunction in Depression
The committee noted that cognitive dysfunction in Major Depressive Disorder is a core feature of MDD along with mood and behavior disturbances. It occurs in about two-thirds of individuals with MDD. And it may persist even when the mood symptoms are in remission.
The Advisory Committee reviewed data from two 8-week, randomized, double-blind, placebo-controlled studies, FOCUS and CONNECT, that evaluated the ability of vortioxetine to improve cognitive dysfunction in adults with depression. These trials evaluated vortioxetine at doses of 10 mg/day and 20 mg/day using a neuropsychological test of cognitive performance (The Digit Symbol Substitution Test – a test of complex attention). The DSST has been shown to be associated other neuropsychological tests that assess attention, working memory, and executive function.
Vortioxetine is an inhibitor of serotonin (5-HT) reuptake and that is thought to be a mechanism of its action. It is also an agonist at 5-HT1A receptors, a partial agonist at 5-HT1B receptors and an antagonist at 5-HT3, 5-HT1D and 5-HT7 receptors.
Preclinical studies showed that vortioxetine enhances memory in rats and increases extracellular acetylcholine and histamine in rat medial prefrontal cortex.
In a small study of patients age 65 and over with major depression, VORTIOXETINE was associated with improvement in cognitive function (Katona et al). In this study those patients treated with vortioxetine performed better than the placebo group in cognitive tests measuring processing speed, verbal learning, and memory.
McIntyre replicated the finding in a large adult population and reported that it was a direct effect of vortioxetine on cognition, in other words, it was not dependent on the presence or absence of an antidepressant response to vortioxetine.
The Advisory Committee presents the FDA with independent expert advice and recommendations but the FDA is not bound by the committee’s guidance. The Agency is expected to make a decision by March 28, 2016.
Psychopharmacologic Drugs Advisory Committee Meeting Tiffany R. Farchione, MD Deputy Director, Division of Psychiatry Products NDA 204447/S-006 Brintellix (vortioxetine): Treatment of Cognitive Dysfunction in Major Depressive Disorder
Mørk A, Montezinho LP, Miller S, et al. Vortioxetine (Lu AA21004), a novel multimodal antidepressant, enhances memory in rats. Pharmacol Biochem Behav. 2013;105:41–50.
Katona C, Hansen T, Olsen CK. A randomized, double-blind, placebo-controlled, duloxetine-referenced, fixed-dose study comparing the efficacy and safety of Lu AA21004 in elderly patients with major depressive disorder. Int Clin Psychopharmacol. 2012;27(4):215–223.
McIntyre RS, Lophaven S, Olsen CK. A randomized, double-blind, placebo-controlled study of vortioxetine on cognitive function in depressed adults. Int J Neuropsychopharmacol. 2014;17(10):1557–1567.