Major Depressive Disorder
Restoring Cognitive Function in Depression: Exploring the 5-HT7 Story
In recent years, there has been an increased focus on the need for treatments that can restore cognitive function in patients with depression. Here, Joseph Goldberg, MD, Clinical Professor of Psychiatry at Icahn School of Medicine, Mount Sinai, New York, explores the hypothesis that vortioxetine (a multimodal antidepressant) and lurasidone (an atypical antipsychotic) may exert positive effects on cognition through a mechanism that involves 5-HT7 receptor antagonism.
Clinical Professor of Psychiatry
“Although the exact mechanisms underlying the effect of lurasidone on cognition are unknown, its high affinity for 5-HT7 receptors is hypothesized to be an important contributor. This theory is consistent with positive effects of vortioxetine, also a 5-HT7 antagonist, seen on cognition in patients with MDD.”
The 5‐HT7 receptor has been the focus of ongoing work to identify novel therapeutics to treat conditions such as depression, sleep disorders, and cognitive deficits. In the brain, there is prominent 5‐HT7 expression in the hippocampus. Two nonselective 5‐HT7 receptor antagonists have received marketing authorization for the treatment of psychiatric conditions: vortioxetine and lurasidone. Vortioxetine is a multimodal antidepressant approved for the treatment of patients with major depressive disorder (MDD). Lurasidone is an atypical antipsychotic that has been shown to be effective in treatment of acute depression in bipolar disorder (BD) type I and has been approved in this context by the US Food and Drug Administration, as monotherapy or as adjunctive therapy with lithium or valproate.
Vortioxetine has been shown to improve scores on the Rey Auditory Verbal Learning Test (RAVLT), showing improvements in acquisition time and delayed recall. In both RAVLT recall and acquisition, vortioxetine demonstrated a higher direct effect than duloxetine, whereas benefits on depressive symptom severity were similar. Duloxetine improved measures of learning and memory, while vortioxetine improved a broader range of cognitive functions (ie, executive function, learning, memory, processing speed, and concentration). The significance of these data as relates to functional outcomes is unknown. Vortioxetine is an inhibitor of serotonin (5-HT) reuptake but 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. The contribution of each of these activities to the antidepressant effect has not been established. Vortioxetine is, however, considered to be the first and only compound with this combination of pharmacodynamic activity.
Although the exact mechanisms underlying the effect of lurasidone on cognition are unknown, its high affinity for 5-HT7 receptors is hypothesized to be an important contributor. This theory is consistent with positive effects of vortioxetine, also a 5-HT7 antagonist, seen on cognition in patients with MDD.
Lurasidone is a D2 and 5-HT2A-receptor antagonist, like other atypical antipsychotics; but, additionally, lurasidone also has high affinity for serotonin 5-HT7 receptors, which have been implicated in key cognitive functions, such as learning and memory. A recent study by Yatham and colleagues demonstrated that lurasidone adjunctive therapy was more effective than treatment as usual in improving the ISBD-BANC global cognition score (International Society for Bipolar Disorders Battery for Assessment of Neurocognition). Investigators also observed improvements in favor of lurasidone in some subjective cognitive complaints and quality of life. Greater improvements were seen in the lurasidone group in some individual measures of cognitive function assessing various domains, including visual and verbal working memory and nonverbal learning memory. Although this was a pilot study, investigators were encouraged by the large magnitude of improvement in global cognition in the lurasidone, with a clinically relevant effect size—findings that suggest that cognitive impairment in BD may be treatable.
As the field moves toward a better understanding of the domains of cognition and the subserving neurobiology, there is hope that procognitive pharmacologic strategies, perhaps in combination with other treatment modalities, will help improve our ability to treat to a more complete level of functional restoration in depressed patients who have heretofore had unsatisfactory responses.
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