Indira Mendez-David

Aims: Prucalopride, a 5‐HT ₄ receptor agonist, has shown potential for rapid anxiolytic and antidepressant effects in preclinical studies. This meta‐analysis aims to evaluate changes in anxiety and depressive symptoms after prucalopride treatment in chronically constipated adults. Methods: A systematic search of PubMed, the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov , and reports from the Food and Drug Administration and European Medicines Agency was conducted from inception to 1 March 2026. Included studies were double‐blind randomized controlled trials originally designed to assess effectiveness in treating chronic constipation in adults. As preplanned, the primary endpoint was the change in anxiety and depressive symptoms. Standardized mean differences (SMDs) were pooled and analyzed using a random‐effects model. This study is registered with PROSPERO, number CRD42024602454. Results: Five randomized controlled trials, including 2,404 participants, were included. The meta‐analysis revealed a significantly greater improvement in anxiety and depressive symptoms derived from quality‐of‐life scores with prucalopride compared with placebo in the random‐effects model (SMD = −0.19, 95% confidence interval [CI] [−0.3117; −0.0707]; P = 0.0019; I ² = 52%). Improvement in anxiety and depressive symptoms was associated with improvement of constipation, but not with the daily dose of prucalopride. All studies were rated as having some concerns for biais in selection of the reported result. Conclusions: Prucalopride improves anxiety and depressive symptoms in chronic constipation. Further studies are needed to explore the potential repurposing of prucalopride for anxiety and depressive disorders.

Les inhibiteurs sélectifs de recapture de la sérotonine (ISRS), agonistes indirects des récepteurs de la sérotonine (5-HT), ont un début d'effet antidépresseur retardé de plusieurs semaines. Des travaux antérieurs suggèrent que le récepteur 5-HT4 de la sérotonine serait une cible directe pour traiter la dépression et un nouvel espoir pour traiter plus rapidement ces pathologies anxio-dépressives. Toutefois, l'hypothèse « 5-HT4 » doit encore être validée dans des modèles animaux d'anxiété/dépression. Les questions posées étaient : la stimulation des récepteurs 5-HT4 centraux est-elle nécessaire aux effets comportementaux des ISRS ? la neurogenèse hippocampique adulte contribue-t-elle à ces effets ? En utilisant le modèle de stress chronique à la corticostérone (CORT) chez la souris, nous avons évalué les effets sur ces paramètres d’un traitement chronique avec un agoniste du récepteur 5-HT4 (RS67333, 1,5 mg/kg/jour pendant 4 semaines) comparé à un traitement à la fluoxétine (18 mg/kg/jour). Nous avons ensuite utilisé ce modèle murin combiné à l’ablation de la neurogenèse hippocampique par rayons-X afin d’examiner si la neurogenèse est nécessaire aux effets comportementaux d’un traitement subchronique (7 jours) ou chronique (28 jours) avec le RS67333. Nous avons également évalué le blocage des effets de la fluoxétine par un antagoniste du récepteur 5-HT4 (GR125487, 1 mg/kg/jour). Le traitement chronique avec RS67333, comme celui de la fluoxétine, induit une activité anxiolytique/antidépressive et stimule la neurogenèse hippocampique adulte. Cependant, contrairement à la fluoxétine , les effets anxiolytiques du RS67333 sont déjà présents après 7 jours de traitement, sans nécessité l’activation de la neurogenèse. Le traitement chronique avec le GR125487 empêche les deux effets anxiolytique/antidépresseur et neurogènique de la fluoxétine, indiquant que l'activation du récepteur 5-HT4 est nécessaire à ces effets de l’ISRS. Nous avons ensuite cherché à savoir si le court délai d’action antidépresseur du RS67333 peut être prédit par l'expression d'un biomarqueur périphérique. Des données de la littérature indiquent que la cascade de signalisation de β-arrestine 1 (impliquée dans la désensibilisation et l’internalisation du récepteur 5-HT4) serait un biomarqueur potentiel pré-clinique/clinique des états dépressifs et des effets d’un traitement antidépresseur. À cette fin, nous avons développé une nouvelle méthode d’évaluation des taux de protéines circulantes grâce à une analyse par immunoblot des leucocytes (PBMC) isolés à partir du sang total de souris. Les taux de β-arrestine 1 sont diminués dans les leucocytes des souris pré-traitées à la CORT. Il faut 7 jours de traitement avec le RS67333, mais 28 jours avec la fluoxétine chez ces animaux pour restaurer un taux de β-arrestine 1 comparable à celui des animaux contrôles. Ces résultats suggèrent que le taux sanguin de β-arrestine 1 est un biomarqueur de la rapidité de la réponse antidépressive. Enfin, l'activation du récepteur 5-HT4 dans le cerveau peut représenter une approche thérapeutique innovante d’apparition pour traiter plus rapidement des symptômes dépressifs associés à l’anxiété.

BACKGROUND: Serotonin (5-HT) receptors and N -methyl-D-aspartate receptors (NMDARs) have both been implicated in the pathophysiology of depression and anxiety disorders. Here, we evaluated whether targeting both receptors through combined dosing of ( R , S )-ketamine, an NMDAR antagonist, and prucalopride, a serotonin type IV receptor (5-HT ₄ R) agonist, would have additive effects, resulting in reductions in stress-induced fear, behavioral despair, and hyponeophagia. METHODS: A single injection of saline (Sal), ( R , S )-ketamine (K), prucalopride (P), or a combined dose of ( R , S )-ketamine and prucalopride (K+P) was administered before or after contextual fear conditioning (CFC) stress in both sexes. Drug efficacy was assayed using the forced swim test (FST), elevated plus maze (EPM), open field (OF), marble burying (MB), and novelty-suppressed feeding (NSF). Patch clamp electrophysiology was used to measure the effects of combined drug on neural activity in hippocampal CA3. c-fos and parvalbumin (PV) expression in the hippocampus (HPC) and medial prefrontal cortex (mPFC) was examined using immunohistochemistry and network analysis. RESULTS: We found that a combination of K+P, given before or after stress, exerted additive effects, compared to either drug alone, in reducing a variety of stress-induced behaviors in both sexes. Combined K+P administration significantly altered c-fos and PV expression and network activity in the HPC and mPFC. CONCLUSIONS: Our results indicate that combined K+P has additive benefits for combating stress-induced pathophysiology, both at the behavioral and neural level. Our findings provide preliminary evidence that future clinical studies using this combined treatment strategy may prove advantageous in protecting against a broader range of stress-induced psychiatric disorders.

We investigated the mechanisms underlying the effects of the antidepressant fluoxetine on behavior and adult hippocampal neurogenesis (AHN). After confirming our earlier report that the signaling molecule β‐arrestin‐2 (β‐Arr2) is required for the antidepressant‐like effects of fluoxetine, we found that the effects of fluoxetine on proliferation of neural progenitors and survival of adult‐born granule cells are absent in the β‐Arr2 knockout (KO) mice. To our surprise, fluoxetine induced a dramatic upregulation of the number of doublecortin (DCX)‐expressing cells in the β‐Arr2 KO mice, indicating that this marker can be increased even though AHN is not. We discovered two other conditions where a complex relationship occurs between the number of DCX‐expressing cells compared to levels of AHN: a chronic antidepressant model where DCX is upregulated and an inflammation model where DCX is downregulated. We concluded that assessing the number of DCX‐expressing cells alone to quantify levels of AHN can be complex and that caution should be applied when label retention techniques are unavailable.

Major depressive disorder (MDD) is a serious public health problem, as it is the most common psychiatric disorder worldwide. Antidepressant drugs increase adult hippocampal neurogenesis, which is required to induce some behavioral effects of antidepressants. Adult‐born granule cells in the dentate gyrus (DG) and the glutamate receptors subunits 2 (GluN2B) subunit of N‐methyl‐D‐aspartate (NMDA) ionotropic receptors play an important role in these effects. However, the precise neurochemical role of the GluN2B subunit of the NMDA receptor on adult‐born GCs for antidepressant‐like effects has yet to be elucidated. The present study aims to explore the contribution of the GluN2B‐containing NMDA receptors in the ventral dentate gyrus (vDG) to the antidepressant drug treatment using a pharmacological approach. Thus, (αR)‐(4‐hydroxyphenyl)‐(βS)‐methyl‐4‐(phenylmethyl)‐1‐piperidinepropanol (Ro25‐6981), a selective antagonist of the GluN2B subunit, was acutely administered locally into the ventral DG (vDG, 1 μg each side) following a chronic fluoxetine (18 mg/kg/day) treatment—known to increase adult hippocampal neurogenesis—in a mouse model of anxiety/depression. Responses in a neurogenesis‐dependent task, the novelty suppressed feeding (NSF), and neurochemical consequences on extracellular glutamate and gamma‐aminobutyric acid (GABA) levels in the vDG were measured. Here, we show a rapid‐acting antidepressant‐like effect of local Ro25‐6981 administration in the NSF independent of fluoxetine treatment. Furthermore, we revealed a fluoxetine‐independent increase in the glutamatergic transmission in the vDG. Our results suggest behavioral and neurochemical effects of GluN2B subunit independent of serotonin reuptake inhibition.

We investigated the mechanisms underlying the effects of the antidepressant fluoxetine on behavior and adult hippocampal neurogenesis (AHN). After confirming our earlier report that the signaling molecule β2-arrestin is required for the antidepressant-like effects of fluoxetine, we found that the effects of fluoxetine on proliferation of neural progenitors and on survival of adult-born granule cells are absent in the β2-arrestin knockout (β2-Arr KO) mice. To our surprise fluoxetine induced a dramatic upregulation of doublecortin (DCX) in the β2-Arr KO mice, indicating that DCX expression can be increased even though AHN is not. We discovered two other conditions where DCX expression is regulated non linearly compared to levels of AHN: a chronic stress model where DCX is upregulated and an inflammation model where DCX is down regulated. We conclude that assessing DCX expression alone to quantify levels of AHN can be misleading and that caution should be applied when label retention techniques are not available. HIGHLIGHTS β2-arrestin (β-Arr2) is required for the antidepressant-like effects of fluoxetine. A dramatic upregulation of doublecortin (DCX) is observed in the β2-Arr KO mice after antidepressant treatment whereas its effects on proliferation of neural progenitors and on survival of adult-born granule cells are absent. DCX is more upregulated than the number of young neurons in a mouse model of depression. DCX is more down regulated than the number of young neurons in a model of inflammation. microRNAs (miRs) may contribute to the regulation of DCX mRNA expression.

Enhancing stress resilience could protect against stress-induced psychiatric disorders in at-risk populations. We and others have previously reported that ( R , S )-ketamine acts as a resilience enhancing drug (e.g., prophylactic) against stress when administered 1 week before stress. While we have shown that the selective 5-hydroxytryptamine (5-HT) (serotonin) reuptake inhibitor (SSRI) fluoxetine (Flx) is ineffective as a prophylactic, it remains to be determined if other serotonergic drugs could be effective prophylactics. Here, we hypothesized that serotonin 4 receptor (5-HT ₄ R) agonists could be prophylactic against fear, depressive-like, and/or anxiety-like behavior. We tested if three 5-HT ₄ R agonists with varying affinity (e.g., partial or selective agonists) could protect against stress in two mouse strains by utilizing a chronic corticosterone (CORT) administration or a contextual fear conditioning (CFC) paradigm. Mice were administered RS-67,333, prucalopride, or PF-04995274 at varying doses and then 1 week later were subjected to chronic CORT or CFC. Chronic administration of RS-67,333, but not Flx was efficacious as a prophylactic against CORT in C57BL/6NTac mice. A single injection of RS-67,333 attenuated learned fear in male, but not female 129S6/SvEv mice. RS-67,333 was ineffective against stress-induced depressive-like behavior in the forced swim test (FST). A single injection of either prucalopride or PF-04995274 attenuated learned fear and decreased stress-induced depressive-like behavior. These data show that in addition to ( R , S )-ketamine, 5-HT ₄ R agonists are also effective prophylactics against stress, suggesting that the 5-HT ₄ R may be a novel target for prophylactic drug development.

Major Depressive Disorders (MDD) patients may exhibit cognitive deficits and it is currently unclear to which degree treatment with antidepressants may affect cognitive function. Preclinical and clinical observations showed that vortioxetine (VORT, an antidepressant with multimodal activity), presents beneficial effects on aspects of cognitive function. In addition, VORT treatment increases adult hippocampal neurogenesis (AHN) in rodents, a candidate mechanism for antidepressant activity. Pattern separation (PS) is the ability to discriminate between two similar contexts/events generating two distinct and non-overlapping representations. Impaired PS may lead to overgeneralization and anxiety disorders. If PS impairments were described in depressed patients, the consequences of antidepressant treatment on context discrimination (CD) are still in its infancy. We hypothesized that VORT-increased AHN may improve CD. Thus, in an attempt to elucidate the molecular mechanism underpinning VORT treatment effects on CD, a rodent model of PS, the role of AHN and stress-induced c-Fos activation was evaluated in the adult mouse hippocampus. Chronic treatment with VORT (1.8 g/kg of food weight; corresponding to a daily dose of 10 mg/kg, 3 weeks) improved CD in mice. Interestingly, chronic treatment with VORT reversed ablation of AHN-induced delay in CD and freezing behavior. VORT treatment decreased stress-induced c-Fos activation in the dorsal but not ventral dentate gyrus. VORT treatment did not affect c-Fos activity in the hippocampus of mice with ablated neurogenesis. This study highlights a role of VORT in CD, which may be independent from AHN and hippocampal c-Fos activation. Further studies elucidating the mechanisms underlying VORT’s effects in CD could contribute to future strategies for alleviating the disease burden for individuals suffering from depression and/or anxiety disorders.