PF-04995274 / Pfizer - LARVOL DELTA

Effects on hippocampal activity following novel 5-HT4 receptor agonism in unmedicated patients with depression: the RESTAND study. (PubMed, Transl Psychiatry) - "In this double-blind, randomised experimental medicine study, 52 right-handed, unmedicated individuals with MDD received 6-9 days of the 5-HT4R agonist PF-04995274 (15 mg, once daily) or placebo. This replicates and extends previous findings in healthy volunteers using prucalopride, and is consistent with preclinical evidence establishing a key role for 5-HT4Rs in hippocampal-dependent learning and memory. This translational evidence supports a role for 5-HT4R activation in modulating memory-related brain circuits in MDD and previously identified beneficial effects of another 5-HT4 receptor agonist, prucalopride, on cognitive performance."

First-in-human • Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Early effects of a novel 5-HT4R agonist (PF-04995274) and the SSRI citalopram on emotional cognition in unmedicated depression: RESTAND study. (PubMed, Br J Psychiatry) - P1 | "PF-04995274 did not show the typical antidepressant profile of negative bias reductions observed with citalopram. Instead, it was associated with distinct increased medial-frontal activation during an emotional faces task, coupled with preliminary evidence of early clinical improvement, suggesting a potential alternative pathway for antidepressant effects. Findings support further clinical trials of 5-HT4R agonists and investigation of pro-cognitive and mood effects."

Journal • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Novel, small molecules targeting the 5-HT 4 receptor protect against stress-induced maladaptive behavior with efficacy across age. (PubMed, bioRxiv) - "These results characterize novel 5-HT 4 R-targeting compounds for stress-induced psychiatric disease with the potential to address unmet needs in adult and aged patients with stress-induced psychiatric illness. Future work will characterize their mechanism of action with the goal of clinical development."

Journal • CNS Disorders • Depression • Major Depressive Disorder • Mental Retardation • Mood Disorders • Psychiatry • CA3 • FOS

Effects on hippocampal activity following 5-HT4 receptor agonism in unmedicated patients with depression: the RESTAND study. (PubMed, medRxiv) - "In this double-blind, randomised study, 52 right-handed, unmedicated individuals with MDD received 6-9 days of the 5-HT 4 R agonist PF-04995274 (15mg, once daily) or placebo. This replicates and extends previous findings in healthy volunteers using prucalopride, and is consistent with preclinical evidence establishing a key role for 5-HT 4 Rs in hippocampal-dependent learning and memory. This translational evidence supports a role for 5-HT 4 R activation in modulating memory-related brain circuits in MDD and highlights its therapeutic potential for treating cognitive symptoms of depression."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Serotonin 4 Receptor agonists: A Promising New Approach for the Treatment of Cognition (ISBD 2024) - "Extending this work to clinical populations, we recently completed two clinical studies investigating the effects of another 5-HT4R agonist, PF-04995274, in depressed patients...Complementing this experimental work, we have recently completed a pharmacoepidemiology study using clinical data records, which has demonstrated associations between the use of the 5-HT4R agonist prucalopride (licensed for the treatment of refractory constipation) and real-world mental health outcomes. Taken together this evidence has established the considerable clinical potential of 5-HT4R agonists in the treatment of mood and cognition."

Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Depression • Psychiatry

RESTART: PF-04995274 and Emotional Processing in Treatment Resistant Depression (clinicaltrials.gov) - P1 | N=54 | Completed | Sponsor: University of Oxford | Recruiting ➔ Completed

Trial completion • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

RESTAND: PF-04995274 and Emotional Processing in Un-medicated Depression (clinicaltrials.gov) - P1 | N=90 | Completed | Sponsor: University of Oxford | Recruiting ➔ Completed

Trial completion • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

RESTAND: PF-04995274 and Emotional Processing in Un-medicated Depression (clinicaltrials.gov) - P1 | N=90 | Recruiting | Sponsor: University of Oxford | Unknown status ➔ Recruiting | Trial completion date: Apr 2020 ➔ Jul 2022 | Trial primary completion date: Apr 2020 ➔ Jul 2022

Enrollment open • Trial completion date • Trial primary completion date • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

RESTART: PF-04995274 and Emotional Processing in Treatment Resistant Depression (clinicaltrials.gov) - P1 | N=54 | Recruiting | Sponsor: University of Oxford | Unknown status ➔ Recruiting | Trial completion date: Apr 2020 ➔ Jul 2022 | Trial primary completion date: Apr 2020 ➔ Jul 2022

Enrollment open • Trial completion date • Trial primary completion date • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Prophylactic efficacy of 5-HTR agonists against stress. (PubMed, Neuropsychopharmacology) - "While we have shown that the selective 5-hydroxytryptamine (5-HT) (serotonin) reuptake inhibitor (SSRI) fluoxetine (Flx) is ineffective as a prophylactic, we hypothesized that other serotonergic compounds such as serotonin 4 receptor (5-HTR) agonists could act as prophylactics...Mice were administered saline, (R,S)-ketamine, Flx, RS-67,333, prucalopride, or PF-04995274 at varying doses, and then 1 week later were subjected to chronic CORT or CFC...Electrophysiological recordings following (R,S)-ketamine or prucalopride administration revealed that both drugs alter AMPA receptor-mediated synaptic transmission in CA3. These data show that in addition to (R,S)-ketamine, 5-HTR agonists are also effective prophylactics against stress, suggesting that the 5-HTR may be a novel target for prophylactic drug development."

Clinical • Journal