Neuroplasticity in Major Depressive Disorder: A Systematic Review of Current Insights and Treatment Implications

Deep brain stimulation and neuroimmune mechanisms in major depressive disorder.

Major depressive disorder (MDD) is increasingly associated with neuroinflammation, hypothalamic-pituitary-adrenal (HPA) axis dysregulation, and disrupted neuroimmune interactions mediated by cytokine signaling aberrations, glial dysfunction, inflammasome activation, and impaired neuroplasticity. Within this pathophysiological context, deep brain stimulation (DBS) has emerged as a promising neuromodulatory intervention for treatment-resistant depression (TRD), though its underlying biological mechanisms remain poorly elucidated. This review systematically examines the role of neuroinflammation in MDD, with a specific focus on HPA axis-immune crosstalk, cytokine- and inflammasome-dependent signaling pathways, and the regulatory contributions of neuroglial cells to inflammatory cascades and neuroplastic remodeling. We further evaluate the multifaceted biological effects of DBS in depression beyond conventional neural circuit modulation, encompassing its potential modulatory impacts on glial function, neuroplasticity, stress endocrine homeostasis, and neuroimmune signaling. Current preclinical and clinical evidence supports a biologically plausible, clinically testable role of DBS in regulating neuroinflammatory processes in MDD; however, direct clinical evidence validating its anti-inflammatory efficacy remains limited and methodologically heterogeneous. Notably, implantation-induced tissue responses, stimulation-dependent biological alterations, and long-term clinical outcomes represent distinct biological and clinical processes that require differentiated interpretation. By synthesizing empirical findings from preclinical depression models, clinical DBS studies, and convergent neuromodulation research, this review proposes that neuroimmune modulation constitutes a plausible candidate mechanism and potential biomarker framework for DBS efficacy in MDD, rather than a fully established therapeutic pathway. Future longitudinal studies incorporating disease-relevant experimental models, standardized neuroimmune biomarkers, and rigorous clinical trial designs are warranted to clarify whether DBS-associated neuroimmune alterations mediate therapeutic responses, reflect secondary treatment improvements, or arise as nonspecific biological correlates of clinical remission.

Brain Network and Synaptic Plasticity Changes Associated with Electroconvulsive Therapy for Depression: A Multilevel Review

Electroconvulsive therapy (ECT) is an important treatment for severe, treatment-resistant, or high-risk depression, yet the relationship between its antidepressant effects, brain network changes, and cellular and molecular processes remains incompletely understood. Recent advances in multimodal magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), molecular biology, and animal electroconvulsive stimulation models have provided multilevel evidence for understanding the neurobiological mechanisms of ECT in depression. Current studies suggest that ECT is accompanied by changes in functional connectivity within large-scale brain networks, including the default mode network (DMN), the frontoparietal control network (FPCN), and prefrontal-limbic circuits. In parallel, processes involving neurotransmission, brain metabolism, neurotrophic factors, inflammatory responses, and synaptic plasticity may provide biological clues for interpreting these network-level changes. This review summarizes evidence related to brain network reorganization and synaptic plasticity-associated regulation in ECT for depression, and discusses how findings across levels may be integrated to inform future mechanistic research and treatment-response prediction.

Exercise-induced BDNF signaling mediates neuroplasticity in depression

Background.Major depressive disorder (MDD) is increasingly recognized as a disorder of impaired neuroplasticity. Brain-derived neurotrophic factor (BDNF) plays a central role in neuronal survival, synaptic plasticity, and antidepressant mechanisms [1–4]. Physical exercise has emerged as an effective non-pharmacological intervention capable of enhancing BDNF signaling and promoting neuroplastic adaptations [20–27]. Aim.To summarize current evidence on the role of exercise-induced BDNF signaling in mediating neuroplastic adaptations and antidepressant effects in depression. Material and methods.A narrative review of peer-reviewed studies, including mechanistic research, randomized controlled trials, cohort studies, and meta-analyses, was conducted. Evidence from neuroscience, exercise physiology, and clinical psychiatry was integrated. Results.Exercise increases BDNF expression through multiple biological pathways, including lactate signaling, muscle–brain crosstalk, and kynurenine metabolism [8–10]. These adaptations promote neurogenesis, synaptic plasticity, and improvements in brain connectivity [11,12,16,17]. Meta-analyses demonstrate that exercise increases circulating BDNF levels and reduces depressive symptoms [14,15,22]. Epidemiological and clinical studies indicate that higher physical activity is associated with a lower risk of depression and improved mental health outcomes [20–30]. Conclusions.BDNF appears to be a key mediator of the antidepressant effects of exercise. Current evidence supports the inclusion of structured physical activity as an evidence-based component of depression treatment, although further research is needed to optimize exercise protocols and clarify individual differences in BDNF responsiveness.

Pharmacological Insights in to Schizophrenia: Neurochemical Dysregulation, Disease Mechanisms and Future Therapeutic Strategies

Current understanding of the clinical features, etiological factors, biological mechanisms, and pharmacological management of schizophrenia is summarized, while emerging therapeutic targets that may guide future research and drug development are outlined.

Neuroinflammation in major depressive disorder: Mechanisms, biomarkers, and emerging therapeutic targets

Major depressive disorder (MDD) affects an estimated 280 million people worldwide and remains a leading cause of disability. The monoamine hypothesis, and later the neuroplasticity hypothesis, transformed treatment but leave a substantial share of patients with delayed response, partial remission, or outright treatment resistance. Over the past two decades, evidence has accumulated that a subset of MDD is driven by chronic, low-grade neuroinflammation rather than, or in addition to, monoaminergic deficits. This review synthesizes current evidence on the neuroimmune mechanisms involved in MDD microglial activation, pro-inflammatory cytokine signaling, blood–brain barrier disruption, oxidative stress, kynurenine pathway dysregulation, and impaired neuroplasticity and examines how these mechanisms are captured by peripheral, central, neuroimaging, and emerging molecular biomarkers. It then reviews therapeutic strategies that target inflammation directly (minocycline, celecoxib, TNF-α antagonists), indirectly (selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), ketamine), or through lifestyle modification (exercise, diet, sleep), with attention to why inflammation-stratified trials have outperformed unstratified ones. Across mechanisms, biomarkers, and treatment response, a consistent pattern emerges: neuroinflammation does not simply co-occur with depression, it may mark a biologically distinct, identifiable subtype roughly a quarter to a third of patients with elevated high-sensitivity C-reactive protein (hsCRP) or IL-6 for whom anti-inflammatory or immune-modulating strategies produce disproportionate benefit. Overall, the findings suggest that neuroinflammation represents a promising and increasingly actionable target for biomarker-guided, personalized psychiatric care.

Advances in the Treatment of Cognitive Impairment in Major Depressive Disorder: Innovations and Research Challenges