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The review links depression pathophysiology to genetic vulnerability, chronic stress and HPA-axis dysregulation, neuroinflammation, oxidative stress, mitochondrial dysfunction, and impaired synaptic plasticity. It synthesizes evidence on pharmacological and non-pharmacological approaches, emphasizing cellular and molecular mechanisms, including ketamine-related treatments, glutamatergic/GABAergic/dopaminergic targets, and neuromodulation methods such as TMS, tDCS, and photobiomodulation.",{"@graph":14,"@context":73},[15,34,56],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/healthcare/","Healthcare",3,{"item":32,"name":10,"@type":21,"position":33},"https://docshare.wps.com/document/molecular-mechanisms-of-emerging-antidepressant-strategies-from-ketamine-to-neuromodulation/462208/",4,{"url":32,"name":10,"@type":35,"image":36,"author":41,"headline":10,"publisher":44,"fileFormat":47,"inLanguage":8,"description":12,"dateModified":48,"datePublished":49,"encodingFormat":47,"isAccessibleForFree":50,"interactionStatistic":51},"DigitalDocument",{"url":37,"@type":38,"width":39,"height":40},"https://docshare.wps.com/thumbnails/molecular-mechanisms-of-emerging-antidepressant-strategies-from-ketamine-to-neuromodulation/462208.png","ImageObject",300,407,{"name":42,"@type":43},"\tJames","Person",{"url":19,"name":45,"@type":46},"DocShare","Organization","application/pdf","2026-10-30","2026-09-30",true,{"@type":52,"interactionType":53,"userInteractionCount":55},"InteractionCounter",{"@type":54},"ViewAction",7,{"@type":57,"mainEntity":58},"FAQPage",[59,65,69],{"name":60,"@type":61,"acceptedAnswer":62},"Why is depression considered a major challenge in contemporary medicine and public health?","Question",{"text":63,"@type":64},"Depression is common, debilitating, and potentially life-threatening, affecting people across age groups. The high global prevalence and increased suicide risk in major depressive disorder make it an urgent medical and public health problem.","Answer",{"name":66,"@type":61,"acceptedAnswer":67},"Which biological mechanisms are proposed to contribute to depression and treatment resistance?",{"text":68,"@type":64},"The review highlights genetic vulnerability, chronic stress with hypothalamic–pituitary–adrenal (HPA) axis dysregulation, neuroinflammation, oxidative stress, mitochondrial dysfunction, and impaired synaptic plasticity. Together, these processes are linked to symptom heterogeneity and resistance to treatment.",{"name":70,"@type":61,"acceptedAnswer":71},"What emerging antidepressant and neuromodulation strategies are discussed?",{"text":72,"@type":64},"The review covers emerging pharmacological therapies targeting glutamatergic, GABAergic, and dopaminergic systems, including ketamine/esketamine and related agents, neurosteroids, and modulators such as cariprazine. 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Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license.  \n1 MediPsyche Medical Center, J. Kolinskiego 27, 91-849 Lodz, Poland; [mateuszjerzykowalczyk@gmail.com](mateuszjerzykowalczyk@gmail.com)  \n2 Department of Photomedicine and Physical Chemistry, Collegium Medicum, Faculty of Medicine, Rzeszów University, 35-310 Rzeszów, Poland  \n3 English Division Science Club, Collegium Medicum, Faculty of Medicine, Rzeszów University, 35-310 Rzeszów, Poland; [js126214@stud.ur.edu.pl](js126214@stud.ur.edu.pl) (J.S.); [sc126240@stud.ur.edu.pl](sc126240@stud.ur.edu.pl) (S.C.)  \n4 Department of Biochemistry and General Chemistry, Collegium Medicum, Faculty of Medicine, Rzeszów University, 35-310 Rzeszów, Poland; [dbartusikaebisher@ur.edu.pl](dbartusikaebisher@ur.edu.pl)  \n5 Department of Epidemiology and Public Health, Faculty of Medicine, Medical University of Lodz,  \nT. Kosciuszki 4, 90-419 Lodz, Poland  \n* Correspondence: [daebisher@ur.edu.pl](daebisher@ur.edu.pl) (D.A.); [gabriela.henrykowska@umed.lodz.pl](gabriela.henrykowska@umed.lodz.pl) (G.H.)  \nAbstract  \nDepression is a common, debilitating, and potentially life-threatening mental disorder affecting individuals across all age groups and populations. It represents one of the major challenges of contemporary medicine. It is estimated that more than 300 million people worldwide are affected, and patients with major depressive disorder (MDD) exhibit a significantly increased risk of suicide, underscoring the urgent need for effective and longlasting therapeutic strategies. Growing evidence indicates that the pathophysiology of depression involves a complex interplay of genetic vulnerability, chronic stress, dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, neuroinflammation, oxidative stress, mitochondrial dysfunction, and impaired synaptic plasticity, collectively contributing to symptom heterogeneity and treatment resistance. In this review, we synthesizedata derived from PubMed, Google Scholar, and ClinicalTrials.gov databases concerning pharmacological and non-pharmacological treatment strategies, with particular emphasis on their cellular and molecular mechanisms of action. We present currently used classes of antidepressant drugs, including selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and monoamine oxidase inhibitors (MAOIs), discussing their limitations in the context of contemporary pathophysiological models of depression. We then focus on emerging therapies targeting the glutamatergic, GABAergic, and dopaminergic systems, including ketamine, esketamine,(R)-ketamine, the dextromethorphan–bupropion combination (DMX–BUP), neurosteroids (zuranolone, brexanolone), as well as selective serotonin receptor modulators (gepirone ER) and dopaminergic modulators (cariprazine) . The review is complemented by a discussion of non-pharmacological neuromodulatory approaches, such as transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), and photobiomodulation. Rather than providing another summary of clinical response indicators, this article integrates the molecular underpinnings of novel antidepressant agents and neuromodulation techniques with current concepts of depression pathophysiology, highlighting their relevance for the development of precise, mechanistically targeted, and multimodal treatment strategies.  \nKeywords: depression","cbCaicgUOVGa5XPr","https://ap.wps.com/l/cbCaicgUOVGa5XPr","pdf",1487435,39,"English","# Abstract\n# Introduction\n## Epidemiology","[{\"question\":\"Why is depression considered a major challenge in contemporary medicine and public health?\",\"answer\":\"Depression is common, debilitating, and potentially life-threatening, affecting people across age groups. The high global prevalence and increased suicide risk in major depressive disorder make it an urgent medical and public health problem.\"},{\"question\":\"Which biological mechanisms are proposed to contribute to depression and treatment resistance?\",\"answer\":\"The review highlights genetic vulnerability, chronic stress with hypothalamic–pituitary–adrenal (HPA) axis dysregulation, neuroinflammation, oxidative stress, mitochondrial dysfunction, and impaired synaptic plasticity. Together, these processes are linked to symptom heterogeneity and resistance to treatment.\"},{\"question\":\"What emerging antidepressant and neuromodulation strategies are discussed?\",\"answer\":\"The review covers emerging pharmacological therapies targeting glutamatergic, GABAergic, and dopaminergic systems, including ketamine/esketamine and related agents, neurosteroids, and modulators such as cariprazine. It also discusses non-pharmacological neuromodulation approaches including TMS, tDCS, and photobiomodulation.\"}]","Molecular Mechanisms of Emerging Antidepressant Strategies - From Ketamine to Neuromodulation | PDF",1790763587,98]