Current therapeutic options for major depressive disorder (MDD) and bipolar disorder (BD) are associated with a lag of onset that can prolong distress and impairment for patients, and their antidepressant efficacy is often limited. All currently approved antidepressant medications for MDD act primarily through monoaminergic mechanisms. Glutamate is the major excitatory neurotransmitter in the central nervous system, and glutamate and its cognate receptors are implicated in the pathophysiology of MDD, and in the development of novel therapeutics for this disorder. The rapid and robust antidepressant effects of the N-methyl-d-aspartate (NMDA) antagonist ketamine were first observed in 2000. Since then, other NMDA receptor antagonists have been studied in MDD. Most have demonstrated relatively modest antidepressant effects compared to ketamine, but some have shown more favorable characteristics. This article reviews the clinical evidence supporting the use of novel glutamate receptor modulators with direct affinity for cognate receptors: (1) non-competitive NMDA receptor antagonists (ketamine, memantine, dextromethorphan, AZD6765); (2) subunit (GluN2B)-specific NMDA receptor antagonists (CP-101,606/traxoprodil, MK-0657); (3) NMDA receptor glycine-site partial agonists (GLYX-13); and (4) metabotropic glutamate receptor (mGluR) modulators (AZD2066, RO4917523/basimglurant). We also briefly discuss several other theoretical glutamate receptor targets with preclinical antidepressant-like efficacy that have yet to be studied clinically; these include α-amino-3-hydroxyl-5-methyl-4-isoxazoleproprionic acid (AMPA) agonists and mGluR2/3 negative allosteric modulators. The review also discusses other promising, non-glutamatergic targets for potential rapid antidepressant effects, including the cholinergic system (scopolamine), the opioid system (ALKS-5461), corticotropin releasing factor (CRF) receptor antagonists (CP-316,311), and others.

<h4>Background</h4>Considering the ample evidence of involvement of the glutamate system in the pathophysiology of depression, pre-clinical and clinical studies have been conducted to assess the antidepressant efficacy of glutamate inhibition, and glutamate receptor modulators in particular. This review focuses on the use of glutamate receptor modulators in unipolar depression.<h4>Objectives</h4>To assess the effects - and review the acceptability - of ketamine and other glutamate receptor modulators in comparison to placebo (or saline placebo), other pharmacologically active agents, or electroconvulsive therapy (ECT) in alleviating the acute symptoms of depression in people with unipolar major depressive disorder.<h4>Search methods</h4>We searched the Cochrane Depression, Anxiety and Neurosis Review Group's Specialised Register (CCDANCTR, to 9 January 2015). This register includes relevant randomised controlled trials (RCTs) from: the Cochrane Library (all years), MEDLINE (1950 to date), EMBASE (1974 to date), and PsycINFO (1967 to date). We did not apply any restrictions to date, language or publication status.<h4>Selection criteria</h4>Double- or single-blind RCTs comparing ketamine, memantine, or other glutamate receptor modulators with placebo (or saline placebo), other active psychotropic drugs, or electroconvulsive therapy (ECT) in adults with unipolar major depression.<h4>Data collection and analysis</h4>Three review authors independently identified studies, assessed trial quality and extracted data. The primary outcomes for this review were response rate and adverse events.<h4>Main results</h4>We included 25 studies (1242 participants) on ketamine (9 trials), memantine (3), AZD6765 (3), D-cycloserine (2), Org26576 (2), atomoxetine (1), CP-101,606 (1), MK-0657 (1), N-acetylcysteine (1), riluzole (1) and sarcosine (1). Twenty-one studies were placebo-controlled and the majority were two-arm studies (23 out of 25). Twenty-two studies defined an inclusion criteria specifying the severity of depression; 11 specified at least moderate depression; eight, severe depression; and the remaining three, mild-moderate depression. Nine studies recruited only treatment-resistant patients.We rated the risk of bias as low or unclear for most domains, though lack of detail regarding masking of treatment in the studies reduced our certainty in the effect for all outcomes. We rated three studies as having high risk for selective outcome reporting. Many trials did not provide information on all the prespecified outcomes and we found no data, or very limited data, on very important issues like suicidality, cognition, quality of life, costs to healthcare services and dropouts due to lack of efficacy.Among all glutamate receptor modulators, only ketamine (administered intravenously) proved to be more efficacious than placebo, though the quality of evidence was limited by risk of bias and small sample sizes. There was low quality evidence that treatment with ketamine increased the likelihood of response after 24 hours (odds ratio (OR) 10.77, 95% confidence interval (CI) 2.00 to 58.00; 3 RCTs, 56 participants), 72 hours (OR 12.59, 95% CI 2.38 to 66.73; 3 RCTs, 56 participants), and one week (OR 2.58, 95% CI 1.08 to 6.16; 4 RCTs, 131 participants). The effect of ketamine was even less certain at two weeks, as data were available from only one trial (OR 0.93, 95% CI 0.31 to 2.83; 51 participants, low quality evidence). This was consistent across all efficacy outcomes. Ketamine caused more confusion and emotional blunting compared to placebo. There was insufficient evidence to determine if this increased the likelihood of leaving the study early (OR 1.90, 95% CI 0.43 to 8.47; 5 RCTs, 139 participants, low quality evidence).One RCT with 72 participants reported higher numbers of responders on ketamine than midazolam at 24 hours (OR 0.36, 95% CI 0.14 to 0.58), 72 hours (OR 0.37, 95% CI 0.16 to 0.59), and one week (OR 0.29, 95% CI 0.08 to 0.49). Howe

Major depressive disorder is a severe and complex mental disorder. Impaired neurotransmission and disrupted signalling pathways may influence neuroplasticity, which is involved in the brain dysfunction in depression. Traditional neurobiological theories of depression, such as monoamine hypothesis, cannot fully explain the whole picture of depressive disorders. In this review, we discussed new treatment directions of depression, including modulation of glutamatergic system and noninvasive brain stimulation. Dysfunction of glutamatergic neurotransmission plays an important role in the pathophysiology of depression. Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has rapid and lasting antidepressive effects in previous studies. In addition to ketamine, other glutamatergic modulators, such as sarcosine, also show potential antidepressant effect in animal models or clinical trials. Noninvasive brain stimulation is another new treatment strategy beyond pharmacotherapy. Growing evidence has demonstrated that superficial brain stimulations, such as transcranial magnetic stimulation, transcranial direct current stimulation, cranial electrotherapy stimulation, and magnetic seizure therapy, can improve depressive symptoms. The antidepressive effect of these brain stimulations may be through modulating neuroplasticity. In conclusion, drugs that modulate neurotransmission via NMDA receptor and noninvasive brain stimulation may provide new directions of treatment for depression. Furthermore, exploring the underlying mechanisms will help in developing novel therapies for depression in the future.

Abstract Major depressive disorder (MDD) is a complex psychiatric condition increasingly linked to chronic neuroinflammation, particularly in the context of aging, stress, and systemic comorbidities. While microglia have traditionally been the focus of neuroimmune studies, growing evidence highlights astrocytes as central regulators in the pathogenesis of MDD. This review synthesizes current findings on the multifaceted roles of astrocytes in neuroplasticity, neurotransmission, metabolic support, and blood‐brain barrier regulation. It explores how astrocyte reactivity and the release of pro‐inflammatory cytokines are often triggered by psychosocial stress, aging, and peripheral immune activation and contribute to synaptic dysfunction and cognitive impairment. The review also examines the bidirectional crosstalk between astrocytes and microglia, astrocytic calcium signaling, epigenetic modulation via histone lactylation, and metabolic pathways involving lactate. Special attention is given to the region‐specific and phenotype‐dependent responses of astrocytes, as well as their influence on the onset and maintenance of depressive symptoms. Additionally, therapeutic strategies targeting astrocyte‐mediated pathways, including anti‐inflammatory agents, metabolic modulators, repetitive transcranial magnetic stimulation, and inflammasome inhibitors, are discussed. Finally, methodological challenges and future research directions are outlined, emphasizing the need for precision medicine approaches in developing astrocyte‐targeted interventions for MDD.

pression in rat model, and it has recently been reported to work by promoting neural plasticity through BDNF/TrkB pathway ( Cai et al., 2021 ). Besides, iridoids from Gardeniae fructus attenuates depression by enhancing synaptic plasticity via AMPAR-mTOR signaling ( Xia et al., 2021b ). Moreover, both the Danggui Buxue Decoction and Baihe Dihuang Decoction can ameliorate depression-like behaviors in rat depression models ( Wang et al., 2021a , Zhao et al., 2021 ). Xia, Hirshler and their colleagues have summarized the neuroplasticity mechanisms of Chinese herbal medicines in antidepressant actions ( Hirshler and Doron, 2017 , Xia et al., 2021a ). Once the safety, efficacy and tolerability of these traditional herbal medicines are confirmed, they can serve as natural alternatives to conventional antidepressants. 4. Conclusion and future directions Taken together, depression caused by stress and negative stimuli largely impairs neural plasticity in many ways, including volumetric changes, neurogenesis, synaptogenesis, spinogenesis, glial plasticity, network connectivity and expression of genes associated with neuroplasticity. Based on the changes of neural plasticity in depression ( Fig. 1 A), different treatments were developed to relief depressive symptoms and the effects and related neuroplastic mechanisms of the treatments were listed in Table 1 . Indeed, the etiology of depression is complex and could not be simplified by neural plasticity dysfunctions as the only targetable factor. As one of the most prevalent mental illnesses, the precise mechanism underlying depression still remains not yet clearly understood. Hence, further studies exploring the exact mechanisms about neuroplasticity changes in depression are needed to develop novel therapies for depression in the future. Table 1. Treatment of depression and the underlying mechanism of neuroplasticity. Therapy/ Treatment Neural plasticity changes Detection Approach Model Mechanism and influence of neuroplasti

The novel antidepressant ketamine has been shown to achieve what most classic antidepressants, such as Selective Serotonin Reuptake Inhibitors, have not been able to. A rapid onset of symptomatic improvement across multiple domains; mood, anhedonia, and suicidal ideation. The exact neuropsychopharmacological mechanisms of this unique phenomenon are still unknown, although many theories are emerging from human and animal studies using neuroimaging and placebo-controlled, cross-over randomised control trials. This review discusses current state-of-the-art theories of action, focussing on neurotransmitter systems, effects of ketamine at the synapse, and functional connectivity in the form of brain networks. These theories are discussed in the context of dysfunctionality in depression, concluding that a major mechanism contributing to ketamine’s antidepressant effects is the reversal of chronic stress pathology present in depression. Possible limitations of evidence presented are discussed.

Icariin, a major bioactive flavonoid extracted from Epimedium species, has demonstrated promising neuroprotective and antidepressant-like effects in preclinical research. However, the magnitude and consistency of these effects remain unclear due to substantial methodological heterogeneity across studies. Therefore, we conducted a systematic review and meta-analysis to evaluate the antidepressant efficacy of icariin in rodent models of depression. Literature searches were performed in Scopus, PubMed and Embase up to May 2025, following PRISMA 2020 guidelines. Twenty-three studies were included in the qualitative synthesis, and thirteen provided sufficient data for quantitative analysis. icariin administration significantly improved anhedonia-like behavior in the sucrose preference test (SPT), with a pooled Hedges’ g of 2.26 (95% CI: 1.56–2.96), and markedly reduced immobility in the forced swim test (FST), with a pooled Hedges’ g of 3.64 (95% CI: 2.65–4.64), indicating strong and robust antidepressant-like effects. Both findings were comparable in magnitude to conventional antidepressants. Meta-regression revealed that longer duration of depression model induction was associated with stronger behavioral improvement, whereas dose did not significantly predict efficacy. Mechanistic evidence suggests that icariin acts through multi-target neuroprotective pathways, including enhancement of BDNF-mediated neuroplasticity, inhibition of neuroinflammation, and regulation of HPA-axis dysfunction. Although methodological variability, male-biased animal selection, and pharmacokinetic limitations were identified, the overall evidence supports icariin as a promising antidepressant candidate for further translational investigation.