Efficacy and Safety of Iloperidone in Bipolar Mania: A Double-Blind, Placebo-Controlled Study.

Objective: To determine if iloperidone, a second-generation antipsychotic, reduces symptoms of bipolar mania.Methods: This phase 3, randomized, double-blind, placebo-controlled study was conducted in adults with bipolar mania at 27 US and international sites between April 2021 and September 2022. Participants were randomized 1:1 to iloperidone (up to 24 mg/d given twice daily) or placebo for 4 weeks. The primary efficacy endpoint was change from baseline to week 4 in Young Mania Rating Scale (YMRS) total score versus placebo. Secondary efficacy endpoints included change from baseline in the Clinical Global Impressions-Severity and Clinical Global Impression of Change scales.Results: Altogether, 414 participants were randomized and administered at least 1 dose of study medication (iloperidone, n = 206; placebo, n = 208). Overall, 139 (67.1%) iloperidone patients and 153 (72.9%) placebo patients completed the study. Iloperidone demonstrated significant improvement versus placebo at week 4 for the primary and secondary endpoints. Differences in the least-squares mean (95% CI; P value) of change from baseline for YMRS total scores were -4.0 (-5.70 to -2.25; adjusted P = .000008). The most encountered adverse events with iloperidone were tachycardia, dizziness, dry mouth, alanine aminotransferase increased, nasal congestion, increased weight, and somnolence. The incidence of akathisia and extrapyramidal symptom-related treatment-emergent adverse events was low.Conclusions: Iloperidone is effective in treating patients with bipolar mania. The tolerability and safety profile of iloperidone in bipolar mania is consistent with previous clinical studies of patients with schizophrenia, and no new safety concerns were identified.Trial Registration: ClinicalTrials.gov identifier: NCT04819776; EudraCT: 2020-000405-83.

Local Drd1-neurons input to subgroups of arcuate AgRP/NPY-neurons.

Obesity is a pandemic afflicting more than 300 million people worldwide, driven by consumption of calorically dense and highly rewarding foods. Dopamine (DA) signaling has been implicated in neural responses to highly palatable nutrients, but the exact mechanisms through which DA modulates homeostatic feeding circuits remains unknown. A subpopulation of arcuate (ARC) agouti-related peptide (AgRP)/neuropeptide Y (NPY) (ARCAgRP/NPY+) neurons express the D(1A) dopamine receptor (Drd1) and are stimulated by DA, suggesting one potential avenue for dopaminergic regulation of food intake. Using patch clamp electrophysiology, we evaluated the responses of ARC Drd1-expressing (ARCDrd1+) neurons to overnight fasting and leptin. Collectively, ARCDrd1+ neurons were less responsive to caloric deficit than ARCAgRP/NPY+ neurons; however, ARCDrd1+ neurons were inhibited by the satiety hormone leptin. Using Channelrhodopsin-2-Assisted Circuit Mapping, we identified novel subgroups of ARCDrd1+ neurons that inhibit or excite ARCAgRP/NPY+ neurons. These findings suggest dopamine receptive neurons have multimodal actions in food intake circuits.

Dopamine Signaling in the Suprachiasmatic Nucleus Enables Weight Gain Associated with Hedonic Feeding.

The widespread availability of energy-dense, rewarding foods is correlated with the increased incidence of obesity across the globe. Overeating during mealtimes and unscheduled snacking disrupts timed metabolic processes, which further contribute to weight gain. The neuronal mechanism by which the consumption of energy-dense food restructures the timing of feeding is poorly understood. Here, we demonstrate that dopaminergic signaling within the suprachiasmatic nucleus (SCN), the central circadian pacemaker, disrupts the timing of feeding, resulting in overconsumption of food. D1 dopamine receptor (Drd1)-null mice are resistant to diet-induced obesity, metabolic disease, and circadian disruption associated with energy-dense diets. Conversely, genetic rescue of Drd1 expression within the SCN restores diet-induced overconsumption, weight gain, and obesogenic symptoms. Access to rewarding food increases SCN dopamine turnover, and elevated Drd1-signaling decreases SCN neuronal activity, which we posit disinhibits downstream orexigenic responses. These findings define a connection between the reward and circadian pathways in the regulation of pathological calorie consumption.