Pharmacological Reviews最新文献

{"title":"Pathological and therapeutic roles of bile acid metabolism and signaling in hepatocellular carcinoma: Insights from human and mouse studies.","authors":"Xue Wang, Curtis D Klaassen, Xin Chen, Youcai Zhang","doi":"10.1016/j.pharmr.2025.100073","DOIUrl":"https://doi.org/10.1016/j.pharmr.2025.100073","url":null,"abstract":"<p><p>Bile acids (BAs), the end products of cholesterol catabolism, play a crucial role in various physiological and pathological processes. Defects in BA synthetic enzymes and transporters cause rare monogenic diseases. Dysregulation of BA homeostasis contributes to the pathogenesis and progression of various liver diseases, including hepatocellular carcinoma (HCC), the most common form of liver cancer. BA profiles are altered in patients with HCC and in mouse models of HCC, and their diagnostic potential is currently under clinical investigation. Growing evidence suggests that BA metabolism and signaling regulate key processes involved in HCC development. Recent advances in understanding the complex interactions between the gut microbiota and BAs have provided new insights into HCC. In this review, we summarize the current literature on BA quantification, detoxification, synthesis, transport, signaling functions, and the interplay between BAs and bacteria in the pathogenesis and progression of HCC, particularly in patients with HCC and mouse models. Furthermore, we discuss potential therapeutic strategies targeting BA metabolism and signaling as promising approaches for HCC treatment. SIGNIFICANCE STATEMENT: Bile acids hold promise as potential biomarkers for the diagnosis and prognosis of hepatocellular carcinoma. Modulating bile acid metabolism and signaling pathways represents a promising novel strategy for hepatocellular carcinoma treatment.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 5","pages":"100073"},"PeriodicalIF":19.3,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144554132","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fibroblasts-The emerging therapeutic target of the cardiovascular system?","authors":"Sebastiaan E J Asselberghs, Maurice Halder, Rafael Kramann, Judith C Sluimer","doi":"10.1016/j.pharmr.2025.100072","DOIUrl":"https://doi.org/10.1016/j.pharmr.2025.100072","url":null,"abstract":"<p><p>Recent advances in single-cell RNA sequencing have uncovered fibroblasts' heterogeneous and plastic nature across the cardiovascular system, highlighting their diverse roles beyond extracellular matrix production, including inflammatory signaling and phenotypic switching. This review synthesizes insights into fibroblast heterogeneity and modulation in healthy and diseased heart and vasculature states. It emphasizes the lack of a consensus nomenclature for fibroblast subtypes, attributing this gap to the need for large-scale meta-analyses and extensive validation studies. The emerging understanding of fibroblast subpopulations and their shared markers across cardiac and vascular tissues introduces therapeutic potential and safety concerns. Although preclinical studies targeting fibroblasts in the heart using gene silencing, editing, or epigenetic modulation show promise, comparable vascular interventions remain limited. Therapeutic strategies could benefit from improved fibroblast-specific markers to minimize off-target effects and enhance precision. Ultimately, the review advocates for refined characterization and nomenclature of fibroblast subsets to better exploit their therapeutic potential, while acknowledging the challenges posed by their overlapping phenotypes and diverse functionalities within the cardiovascular system. SIGNIFICANCE STATEMENT: Fibroblasts are a heterogeneous cell type with critical roles in cardiovascular homeostasis and disease. We explore advances in understanding fibroblast diversity and therapeutic potential. We underscore the importance of precision in cardiovascular disease through a consensus on nomenclature and marker specificity.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 4","pages":"100072"},"PeriodicalIF":19.3,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144560666","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Senotherapy for chronic lung disease.","authors":"Peter J Barnes","doi":"10.1016/j.pharmr.2025.100069","DOIUrl":"https://doi.org/10.1016/j.pharmr.2025.100069","url":null,"abstract":"<p><p>Chronic respiratory diseases are an enormous burden on healthcare and the third ranked cause of death globally. There is now compelling evidence that acceleration of lung aging and associated cellular senescence is a key driving mechanism of several chronic lung diseases, particularly chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. Senescent cells, arising from oxidative stress and unrepaired damage, can accumulate in the lung and develop a senescence-associated secretory phenotype, spreading senescence and resulting in disease progression. In addition, there is a reduction in normally protective antiaging molecules, such as sirtuins, in the lungs. The role of cellular senescence in chronic lung disease has driven interest in senotherapy that targets senescent cells as a novel approach to treating respiratory diseases, and includes repurposing of existing drugs or developing new therapies. Senomorphics, which prevent the development of senescence and inhibit senescence-associated secretory phenotype mediators, include inhibitors of phosphoinositide-3-kinase-mechanistic target of rapamycin signaling, novel antioxidants, and sirtuin activators. Senolytics remove senescent cells by inducing apoptosis and include inhibitors of antiapoptotic proteins, such as B-cell lymphoma-extra large, inhibitors of forkhead box O-4-p53 interaction, heat shock protein 90 inhibitors, and cardiac glycosides. Senotherapies have been effective in animal models of chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis, and several clinical trials are currently underway. The safety of these treatments after long-term administration requires further study, but this could potentially to be a promising approach to treating chronic lung diseases. SIGNIFICANCE STATEMENT: Cellular senescence induced by oxidative stress is a key driving mechanism in chronic lung diseases, such as chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis and may account for disease progression. Senotherapies, including senomorphics that inhibit senescent cells and senolytics that eliminate them, are promising therapeutic approaches to these common diseases, either with repurposed drugs or several new drugs that are in development.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 4","pages":"100069"},"PeriodicalIF":19.3,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144485479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The endocannabinoidomes: Pharmacological redundancy and promiscuity, and multi-kingdom variety of sources and molecular targets.","authors":"Fabio A Iannotti, Vincenzo Di Marzo","doi":"10.1016/j.pharmr.2025.100070","DOIUrl":"https://doi.org/10.1016/j.pharmr.2025.100070","url":null,"abstract":"<p><p>The endocannabinoid system (eCB) is a complex signaling network discovered in mammals during the 1980s-1990s. It conventionally revolves around two arachidonic acid-derived mediators, N-arachidonoyl-ethanolamine (anandamide) and 2-arachidonoyl-glycerol; their main receptors, the cannabinoid receptors of type 1 (CB1) and type 2 (CB2), and the transient receptor potential vanilloid-1 channels; and the enzymes responsible for their biosynthesis and degradation. However, drawing on these discoveries, numerous eCB-like signaling lipids beyond the classical eCBs, have been unveiled, together with their receptors and metabolic enzymes, thus forming a more complex signaling network known as the endocannabinoidome (eCBome). This review explores the physiology, pharmacological complexity, and molecular targets of the mammalian eCBome, highlighting its versatility and redundancy in the context of global health. Emerging mediators, metabolic pathways and mechanisms, receptors, and their implications in human physiology and pathology are described, particularly concerning metabolic disorders, pain, inflammation, neurodegenerative diseases, and cancer. The importance of other \"eCBomes\" in nonmammalian forms of life that constitute the external and internal environments of mammals is also discussed for the first time in this context. The overarching objective of this article is to gain insights into the potential of eCBome-based therapeutic strategies aimed at enhancing both human and environmental well-being. SIGNIFICANCE STATEMENT: Lipid-based signaling molecules are ubiquitous in nature, yet their study remains challenging due to intricate regulatory mechanisms. Among lipid signaling pathways, the endocannabinoid (eCB) system and its extended version, the endocannabinoidome (eCBome), are particularly remarkable. Comprising hundreds of mediators, and dozens of receptors and metabolic enzymes, the eCBome regulates critical physiological processes not only in mammals but also across diverse organisms, including plants, fungi, and bacteria. This article examines the evolutionary and functional diversity of eCBomes and highlights their untapped potential as multikingdom therapeutic targets to address pressing challenges in global health.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 4","pages":"100070"},"PeriodicalIF":19.3,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144485480","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Total-body positron emission tomography imaging to accelerate radiotracer discovery pipelines.","authors":"Andrew Sutherland, Marc R Dweck, David E Newby, Adriana A S Tavares","doi":"10.1016/j.pharmr.2025.100066","DOIUrl":"https://doi.org/10.1016/j.pharmr.2025.100066","url":null,"abstract":"<p><p>The development of the first total-body positron emission tomography (PET) clinical scanner is a transformational moment in nuclear medicine, reigniting the field by tackling 2 long-standing and critical barriers to the widespread clinical use of PET: radiation dose and patient throughput. Total-body PET also provides several other unique research and clinical opportunities, including potential to streamline radiotracer discovery and development pipelines. PET does not exist without radiotracers. However, despite decades of radiotracer development programs, the number of successful PET radiotracers adopted and approved for human use is extremely low. In neurology, an important area for nuclear medicine, only approximately 4% of all novel radiotracers that survive the radiotracer translational \"valley of death\" are adopted clinically. The potential for total-body PET technology to reverse these low numbers of radiotracer development and adoption is high. This will require the PET community to come together with the regulators to chart new frameworks for radiotracer development and translational pipelines. This article will discuss which stages of the radiotracer discovery pipeline can benefit most from the recent development of total-body PET technology. It will review the latest key developments in radiochemistry modernization and describe how these could ameliorate regulatory hurdles and deliver the groundbreaking potential of total-body PET. Finally, this article will highlight emerging radiotracer discovery opportunities that could be rapidly facilitated by total-body PET. SIGNIFICANCE STATEMENT: In addition to creating new opportunities for clinical research and patient care, total-body positron emission tomography technology can also embolden radiochemistry modernization in the clinic and break long-standing translational barriers encountered during radiotracer discovery pipelines.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 4","pages":"100066"},"PeriodicalIF":19.3,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144286078","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmaceutical perspectives on oligonucleotide therapeutics and delivery systems.","authors":"Dalton W Staller, Flobater I Gawargi, Sanjali S Panigrahi, Paras K Mishra, Ram I Mahato","doi":"10.1016/j.pharmr.2025.100065","DOIUrl":"https://doi.org/10.1016/j.pharmr.2025.100065","url":null,"abstract":"<p><p>Gene therapy has a pivotal role in treating new diseases. In addition to the recent mRNA-based COVID-19 vaccines produced by Pfizer-BioNTech and Moderna against severe acute respiratory syndrome corona virus 2, several new gene therapies have recently been approved as effective treatments for fatal genetic disorders such as Duchenne's muscular dystrophy, familial transthyretin amyloidosis, hemophilia A, hemophilia B, spinal muscle atrophy, early cerebral autoleukodystrophy, and β-thalassemia. This review provides novel insights into RNA therapeutics focusing on endogenous RNA species, RNA structure and function, and chemical modifications that improve the stability and distribution of RNAs. Furthermore, it includes updated knowledge on clinically approved gene therapies rendering a comprehensive understanding of the biochemical basis and clinical application of gene therapies. SIGNIFICANCE STATEMENT: There have recently been significant advances in clinical translation of RNA therapeutics. This review discusses the diverse types of RNA species, RNA structure and function, backbone and chemical modifications to RNAs, and every RNA therapeutic approved for clinical use at the time of writing.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 4","pages":"100065"},"PeriodicalIF":19.3,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144294765","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"International Union of Basic and Clinical Pharmacology. CXX. γ-Hydroxybutyrate protein targets in the mammalian brain-beyond classic receptors.","authors":"Petrine Wellendorph, Stine Juul Gauger, Jens Velde Andersen, Birgitte Rahbek Kornum, Sara M O Solbak, Bente Frølund","doi":"10.1016/j.pharmr.2025.100064","DOIUrl":"https://doi.org/10.1016/j.pharmr.2025.100064","url":null,"abstract":"<p><p>γ-Hydroxybutyrate (GHB) is a multifaceted compound with an intriguing, yet undeciphered, pharmacology in the mammalian brain. As a metabolite of GABA it is tightly regulated in terms of synthesis and degradation, and is found in micromolar concentrations in the brain. When GHB is taken in high pharmacological doses, it causes euphoria, relaxation, hypothermia, and sedation, and regulates sleep. Through careful pharmacological and genetic studies, this profile has been convincingly matched to the metabotropic GABA_B receptor where GHB is a weak agonist. These effects explain the illicit substance use of GHB, but also its clinically useful effects as a drug in alcoholism and narcolepsy. Additionally, GHB binds with high affinity to a discrete binding site with high expression in the forebrain, and with very well defined anatomical, biochemical, and pharmacological characteristics. Despite this clear profile, the molecular identity of this binding protein or alleged \"GHB receptor\" has remained uncertain. However, recently, prompted by the development of GHB analogs with low nanomolar affinity and selectivity for the high-affinity site, the target was revealed to be the Ca²⁺/calmodulin (CaM)-dependent protein kinase II alpha subunit-a highly important brain kinase, mediating both physiological processes in synaptic plasticity, and detrimental Ca²⁺ signaling and cell death in cases of brain ischemia. The discovery of calmodulin-dependent protein kinase II alpha subunit as the high-affinity brain target for GHB represents a major leap forward in our understanding of GHB neurobiology, and dictates new times for GHB research, suggesting a potential role for GHB and GHB analogs as integrators of inhibitory and excitatory brain signaling. SIGNIFICANCE STATEMENT: γ-Hydroxybutyrate is a molecule with a multitude of actions in the mammalian brain, and with a rather complex molecular pharmacology. A low affinity at GABA_B receptors, located mainly at inhibitory synapses, and a high affinity at the Ca2+/CaM-dependent protein kinase II alpha subunit, located at excitatory synapses, makes GHB pharmacology especially intriguing.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 4","pages":"100064"},"PeriodicalIF":19.3,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144192104","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cryoelectron microscopy as a tool for illuminating activation mechanisms of human class A orphan G protein-coupled receptors.","authors":"Isabella C Russell, Dongju Lee, Denise Wootten, Patrick M Sexton, Fabian Bumbak","doi":"10.1016/j.pharmr.2025.100056","DOIUrl":"10.1016/j.pharmr.2025.100056","url":null,"abstract":"<p><p>G protein-coupled receptors (GPCRs) are critically important medicinal targets, and the cryogenic electron microscopy (cryo-EM) revolution is providing novel high-resolution GPCR structures at a rapid pace. Orphan G protein-coupled receptors (oGPCRs) are a group of approximately 100 nonolfactory GPCRs for which endogenous ligands are unknown or not validated. The absence of modulating ligands adds difficulties to understanding the physiologic significance of oGPCRs and in the determination of high-resolution structures of isolated receptors that could facilitate drug discovery. Despite the challenges, cryo-EM structures of oGPCR-G protein complexes are emerging. This is being facilitated by numerous developments to stabilize GPCR-G protein complexes such as the use of dominant-negative G proteins, mini-G proteins, complex-stabilizing nanobodies or antibody fragments, and protein tethering methods. Moreover, many oGPCRs are constitutively active, which can facilitate complex formation in the absence of a known activating ligand. Consequently, in addition to providing templates for drug discovery, active oGPCR structures shed light on constitutive GPCR activation mechanisms. These comprise self-activation, whereby mobile extracellular portions of the receptor act as tethered agonists by occupying a canonical orthosteric-binding site in the transmembrane core, constitutive activity due to alterations to conserved molecular switches that stabilize inactive states of GPCRs, as well as receptors activated by cryptic ligands that are copurified with the receptor. Cryo-EM structures of oGPCRs are now being determined at a rapid pace and are expected to be invaluable tools for oGPCR drug discovery. SIGNIFICANCE STATEMENT: Orphan G protein-coupled receptors (GPCRs) provide large untapped potential for development of new medicines. Many of these receptors display constitutive activity, enabling structure determination and insights into observed GPCR constitutive activity including (1) self-activation by mobile receptor extracellular portions that function as tethered agonists, (2) modification of conserved motifs canonically involved in receptor quiescence and/or activation, and (3) activation by cryptic lipid ligands. Collectively, these studies advance fundamental understanding of GPCR function and provide opportunities for novel drug discovery.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 3","pages":"100056"},"PeriodicalIF":19.3,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144036362","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The microcirculation, the blood-brain barrier, and the neurovascular unit in health and Alzheimer disease: The aberrant pericyte is a central player.","authors":"Yasmin Amy Divecha, Sanketh Rampes, Sabine Tromp, Sevda T Boyanova, Alice Fleckney, Mehmet Fidanboylu, Sarah Ann Thomas","doi":"10.1016/j.pharmr.2025.100052","DOIUrl":"10.1016/j.pharmr.2025.100052","url":null,"abstract":"<p><p>High fidelity neuronal signaling is enabled by a stable local microenvironment. A high degree of homeostatic regulation of the brain microenvironment, and its separation from the variable and potentially neurotoxic contents of the blood, is brought about by the central nervous system barriers. Evidence from clinical and preclinical studies implicates brain microcirculation, cerebral hypoperfusion, blood-brain barrier dysfunction, and reduced amyloid clearance in Alzheimer pathophysiology. Studying this dysregulation is key to understanding Alzheimer disease (AD), identifying drug targets, developing treatment strategies, and improving prescribing to this vulnerable population. This review has 2 parts: part 1 describes the cerebral microcirculation, cerebral blood flow, extracellular fluid drainage, and the neurovascular unit components with an emphasis on the blood-brain barrier, and part 2 summarizes how each aspect is altered in AD. Discussing the neurovascular unit structures separately allows us to conclude that aberrant pericytes are an early contributor and central to understanding AD pathophysiology. Pericytes have multiple functions including maintenance of blood-brain barrier integrity and the control of capillary blood flow, capillary stalling, neurovascular coupling, intramural periarterial drainage, glia-lymphatic (glymphatic) drainage, and consequently amyloid and tau clearance. Pericytes are vasoactive, express cholinergic and adrenergic receptors, and exhibit apolipoprotein E isoform-specific transport pathways. Hypoperfusion in AD is linked to a pericyte-mediated response. Deficient endothelial cell-pericyte (PDGBB-PDGFRβ) signaling loops cause pericyte dysfunction, which contributes and even initiates AD degeneration. We conclude that pericytes are central to understanding AD pathophysiology, are an interesting therapeutic target in AD, and have an emerging role in regenerative therapy. SIGNIFICANCE STATEMENT: Dysregulation and dysfunction of the neurovascular unit and fluid circulation (including blood, cerebrospinal fluid, and interstitial fluid) occurs in Alzheimer disease. A central player is the aberrant pericyte. This has fundamental implications to understanding disease pathophysiology and the development of therapies.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 3","pages":"100052"},"PeriodicalIF":19.3,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12163501/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144064345","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety in treatment: Classical pharmacotherapeutics and new avenues for addressing maternal depression and anxiety during pregnancy.","authors":"Merel Dagher, Catherine M Cahill, Anne M Andrews","doi":"10.1016/j.pharmr.2025.100046","DOIUrl":"10.1016/j.pharmr.2025.100046","url":null,"abstract":"<p><p>We aimed to review clinical research on the safety profiles of antidepressant drugs and associations with maternal depression and neonatal outcomes. We focused on neuroendocrine changes during pregnancy and their effects on antidepressant pharmacokinetics. Pregnancy-induced alterations in drug disposition and metabolism impacting mothers and their fetuses are discussed. We considered evidence for the risks of antidepressant use during pregnancy. Teratogenicity associated with ongoing treatment, new prescriptions during pregnancy, or pausing medication while pregnant was examined. The Food and Drug Administration advises caution regarding prenatal exposure to most drugs, including antidepressants, largely owing to a dearth of safety studies caused by the common exclusion of pregnant individuals in clinical trials. We contrasted findings on antidepressant use with the lack of treatment where detrimental effects to mothers and children are well researched. Overall, drug classes such as selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors appear to have limited adverse effects on fetal health and child development. In the face of an increasing prevalence of major mood and anxiety disorders, we assert that individuals should be counseled before and during pregnancy about the risks and benefits of antidepressant treatment given that withholding treatment has possible negative outcomes. Moreover, newer therapeutics, such as ketamine and κ-opioid receptor antagonists, warrant further investigation for use during pregnancy. SIGNIFICANCE STATEMENT: The safety of antidepressant use during pregnancy remains controversial owing to an incomplete understanding of how drug exposure affects fetal development, brain maturation, and behavior in offspring. This leaves pregnant people especially vulnerable, as pregnancy can be a highly stressful experience for many individuals, with stress being the biggest known risk factor for developing a mood or anxiety disorder. This review focuses on perinatal pharmacotherapy for treating mood and anxiety disorders, highlighting the current knowledge and gaps in our understanding of consequences of treatment.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 3","pages":"100046"},"PeriodicalIF":19.3,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143582357","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}