Jul 2026· Current pharmaceutical design· 0 citations
Medicine
TL;DR
When conventional treatments are ineffective for treating treatment-resistant depression, ketamine offers quick and strong results, marking a paradigm change in psychiatric care.
Abstract
Background
Major depressive disorder (MDD) is one of the leading causes of disability globally, and conventional monoaminergic antidepressants often have a slow onset and limited efficacy. About onethird of patients suffer from treatment-resistant depression (TRD), which emphasizes the urgent need for alternative therapies. This review aims to systematically evaluate the available data about ketamine's involvement in depression, with particular attention to its pharmacological properties, modes of action, clinical effectiveness, safety profile, and potential as a next-generation antidepressant treatment.
Methods
The databases ScienceDirect and PubMed/MEDLINE were searched extensively for relevant literature. Ketamine's pharmacodynamics, clinical results, safety, and mechanistic insights in Major depressive disorder (MDD) and treatment-resistant depression (TRD) were all investigated in eligible studies. Particular focus was given to its reported side effects and molecular mechanisms.
Results
The FDA's 2019 clearance of intranasal esketamine further cemented the paradigm shift in treatment for treatment-resistant depression (TRD), which has been revolutionized by ketamine's ability to provide quick and long-lasting symptom relief. A strong neurobiological cascade underlies its therapeutic impact: NMDA receptor antagonistic action causes glutamate-AMPA activation to spike, which in turn activates the BDNF-mTORC1 signalling pathway, promoting fast synaptogenesis and reversing neuronal atrophy in the prefrontal cortex. Although dissociative side effects and cardiovascular risks now limit clinical use, the field is moving toward next-generation drugs like (2R,6R)-hydroxynorketamine. In order to create safer and more easily accessible rapid-acting antidepressants, these metabolites seek to eliminate the negative psychoactive character of ketamine while using its transformative neuroplasticity.
Conclusion
When conventional treatments are ineffective for treating treatment-resistant depression, ketamine offers quick and strong results, marking a paradigm change in psychiatric care. To optimise longitudinal dosage regimens, assess long-term safety profiles, and develop next-generation analogues that maintain neuroplastic benefits while reducing side effects, further investigation is necessary.
Treatment-resistant depression (TRD) represents one of the most severe forms of major depressive disorder and is associated with high morbidity and mortality, functional impairment, increased suicidal ideation, and significant socioeconomic impacts. In this context, ketamine and esketamine have emerged as innovative therapeutic alternatives due to their rapid antidepressant effect and their potential to reduce suicidal ideation within a few hours of administration. The aim of this study was to critically analyze the available scientific evidence regarding the therapeutic use of ketamine and esketamine in treatment-resistant depression, emphasizing their clinical efficacy, mechanisms of action, safety profile, and future prospects. A systematic literature review was conducted in accordance with the PRISMA 2020 guidelines. Searches were conducted in the PubMed/MEDLINE, Embase, Scopus, Web of Science, Cochrane Library, and PsycINFO databases, using search terms related to treatment-resistant depression, ketamine, esketamine, NMDA receptors, neuroplasticity, and suicidal ideation. After applying the eligibility criteria, 92 studies were included for qualitative analysis. The evidence demonstrated that both intravenous ketamine and intranasal esketamine promote a rapid and significant reduction in depressive symptoms and suicidal ideation, especially in patients with multiple treatment failures. The mechanisms of action involve modulation of glutamatergic neurotransmission, activation of AMPA receptors, increased expression of brain-derived neurotrophic factor (BDNF), and restoration of brain neuroplasticity. The main adverse events were transient dissociative symptoms, temporary elevation of blood pressure, nausea, and dizziness, presenting a favorable safety profile when used under specialized monitoring. It is concluded that ketamine and esketamine represent important therapeutic advances in the treatment of treatment-resistant depression, particularly due to the rapid clinical response and the potential to reduce the risk of suicide. However, further studies are needed to define optimal maintenance protocols, assess long-term safety, and expand the use of these therapies in evidence-based clinical practice.
Marcos A. Couto, Flávia Eduarda Pereira Januário, Gabriela de Luna Costa Pinheiro et al.· International Journal of Pha...· 0 citations
Abstract Background Major depressive disorder (MDD) affects more than 50 million people worldwide and remains a leading cause of disability. Approximately 50% of patients show insufficient response to at least two pharmacological or psychotherapeutic interventions, a condition known as treatment-resistant depression (TRD). In this context, members of the galanin (GAL) neuropeptide family have been implicated in depression, offering a promising opportunity to enhance antidepressant efficacy. The N-terminal fragment GAL(1–15) is particularly active in mood regulation, and our previous studies have explored its potential as an adjunct treatment with selective serotonin reuptake inhibitor (SSRIs) in both naïve and depressive models. In this study, we will investigate whether GAL(1–15) can potentiate the antidepressant effects of Fluoxetine (FLX), a SSRI, in Wistar Kyoto (WKY) rats, a genetic model displaying features of endogenous and treatment-resistant depression. Aims & Objectives The objective was to evaluate the antidepressant potential of combined FLX and GAL(1–15) administration in WKY rats. Specific aims were to: (1) characterize behavioral effects of the combination FLX+GAL(1–15), on despair and anhedonia; (2) determine the role of the GAL receptor subtype GALR2 using the antagonist M871; (3) assess the involvement of 5-HT1A receptor mechanisms through siRNA knockdown and autoradiographic analyses; and (4) examine neuroendocrine regulation by measuring corticosterone levels and performing a dexamethasone-suppressed corticotropin-releasing hormone (CRH) stimulation test. Method Adult male WKY rats were divided into groups receiving vehicle, FLX, GAL(1–15), or FLX+GAL(1–15). Behavioral effects were assessed using the forced swim test and sucrose preference test. GALR2 involvement was examined with M871 pretreatment, and 5-HT1A mechanisms were studied through intracerebral siRNA-mediated knockdown and autoradiographic receptor binding in the prefrontal cortex (PFC) and hippocampus. Plasma corticosterone levels were quantified, and HPA axis regulation was evaluated using dexamethasone/CRH tests to assess feedback sensitivity. Results Neither FLX nor GAL(1–15) alone produced significant antidepressant-like effects in WKY rats. However, co-administration of FLX+GAL(1–15) markedly reduced immobility in the forced swim test and restored sucrose preference, indicating reversal of despair and anhedonia. These effects were abolished by GALR2 blockade with M871, implicating GALR2 receptor involvement. Autoradiographic studies revealed altered 5-HT1A receptor binding in the PFC following combination treatment, suggesting a modulatory effect on serotonergic function. Furthermore, the combination therapy normalized elevated corticosterone levels while not affecting HPA axis feedback induced by the dexamethasone/CRH test. Discussion & Conclusions This study demonstrates that GAL(1–15) significantly enhances FLX’s antidepressant efficacy in a treatment-resistant depression model. The results support a synergistic interaction between galanin and serotonergic systems involving GALR2 and 5-HT1A receptor modulation, particularly within the PFC. Behavioral and neuroendocrine normalization following combination therapy highlights a novel mechanistic pathway for overcoming SSRI resistance. Targeting galanin fragments such as GAL(1–15) may therefore represent a promising augmentation strategy for patients with TRD. These findings open new avenues for translational research exploring galanin-based modulators as adjunctive treatments in refractory depression.
J. P. Pineda-Gómez, C. Millón, N. Cantero-García et al.· International Journal of Neu...· 0 citations
It is concluded that the management of ESRD should be individualized, based on up-to-date scientific evidence, and integrated with multidisciplinary approaches, aiming at symptom remission, functional recovery, and improvement of patients' quality of life.
Samuel Cândido Freres, M. A. F. Cançado, Aline Ferreira Catrolio et al.· International Health Science...· 0 citations
Depression remains a leading cause of disability worldwide with a rapidly escalating disease burden, yet current pharmacotherapies are limited by delayed onset of action, insufficient efficacy in treatment-resistant depression, and troublesome adverse effects. This review provides a systematic and critical evaluation of pharmacological mechanisms in depression and related therapeutic targets. We examine established targets spanning the neurotransmitters corresponding to serotonergic, glutamatergic, GABAergic, and dopaminergic systems, alongside emerging glial gap junctions and inflammatory perspectives. For each target, we assess the quality of evidence from preclinical studies and clinical trials, discuss corresponding antidepressant drug classes, and identify knowledge gaps. Finally, we propose future directions for antidepressant drug development, including novel target discovery, rational multi-target design, and optimization of preclinical-to-clinical translation. By providing a pharmacology-driven roadmap of druggable targets and their therapeutic mechanisms, this review aims to inform both mechanistic understanding and drug discovery efforts in depression.
Hui-Qin Wang, Shi-Fen Dong, Suo Liu et al.· Pharmacology and Therapeutic...· 0 citations
INTRODUCTION
Major depressive disorder is a leading cause of disability, with a significant rate of patients responding inadequately to antidepressants, and residual symptoms, including insomnia, worsening overall outcomes. Current adjunctive options display partial efficacy and tolerability, motivating the search for different strategies. Beyond regulating the sleep-wake cycle, orexin systems are implicated in reward and cognition, and have emerged as new targets for depressive disorders.
AREAS COVERED
This Drug Profile summarizes the published peer-reviewed evidence on seltorexant (JNJ-42847922; MIN-202), a selective orexin-2 receptor antagonist, for adjunctive treatment of MDD, covering its pharmacological, preclinical, and clinical profile, efficacy, safety and tolerability, head-to-head comparisons with current adjunctive treatments, regulatory status, and competitive landscape. Relevant literature was identified through structured searches of PubMed/MEDLINE and ClinicalTrials.gov (from database inception to April 2026), complemented by Google Scholar employed solely to identify conference proceedings, using combinations of terms related to seltorexant and depression.
EXPERT OPINION
Seltorexant 20 mg has shown a promising antidepressant effect, particularly in patients with clinically significant insomnia, and a favorable tolerability profile. The mixed phase-3 results, the modest effect sizes, and gaps on core symptoms of depression, including anhedonia and suicidality, and on long-term safety warrant a measured positive view, pending confirmatory data.
M. Di Nicola, M. Pepe, I. Marcelli et al.· Expert Review of Neurotherap...· 0 citations
Major depressive disorder (MDD) is a common health disorders characterized by anhedonia along with physical changes. MDD is a leading cause of disability worldwide. MDD treatment mainly focuses on improving the quality of life of the patients suffering from this disorder. Various modalities of treatment include initiating pharmacotherapy, focussed psychotherapy, or electroconvulsive therapies. The current treatment modalities focus on the monoamine hypothesis with a wide range of drugs available from tricyclic antidepressants (TCAs) to selective serotonin reuptake inhibitors (SSRIs). Despite therapy with the currently available drugs a substantial proportion of patients do not achieve full remission with full-dose titration and there is still persistence of treatment-resistant depression (TRD). The currently available antidepressants drugs are associated with frequent adverse effects with tolerance limiting their long-term adherence. Delivery of psychotherapy has its own set of limitation and one of them is in form of delivery of psychotherapy. As many patients despite optimal therapy of currently available antidepressant drugs one-third of the patients do not respond to the currently available forms of therapy. The understanding of the pathophysiology has increased our knowledge with role of neuroplasticity, disrupted signalling pathway, decreased neurotropic factor expressions and altered functional connectivity of neurocircuitry also playing its role apart from the neurotransmission theory of depression. Opening up avenues for treatment of currently unanswered area for depression which include lag in onset of effect, tolerance to therapy, treatment resistant depression and delay in achieving remission. The current review tries to highlight the various options for treatment of depression for effective treatment of depression.
International Journal of Human and Health Sciences Vol. 10 No. 04 Oct’26 Page: 217-226
Jaspreet Kaur, Deepika Puri, K. Sachdeva et al.· International Journal of Hum...· 0 citations
We use cookies to run the site and, with your consent, for analytics and to show ads.
See our Cookie Policy.
