Over the past two decades, immune–inflammatory dysregulation has emerged as a central paradigm in the biology of mood disorders. Patients with major depression (MDD) and bipolar disorder (BD) frequently display low-grade systemic inflammation. Elevated C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) identify clinically relevant subgroups of patients characterized by greater severity, cognitive impairment, and poor treatment response. Changes in the gut microbiota and disruptions of the blood–brain barrier (BBB) act as important gateways through which systemic immune activity can influence the brain. At the intracellular level, pattern-recognition receptors activate convergent hubs including NF-κB, JAK/STAT, and MAPK cascades, while the NLRP3 inflammasome integrates mitochondrial dysfunction and oxidative stress with IL-1β release and pyroptosis. These pathways converge on glial dysregulation, impaired BDNF/TrkB signaling, and kynurenine pathway (KP) alterations, fostering excitotoxicity and synaptic deficits. Translational studies demonstrate that elevated CRP and IL-6 predict poor antidepressant outcomes. Anti-inflammatory agents such as infliximab and celecoxib show efficacy in specific subgroups of patients. Emerging multi-omics approaches identify immuno-metabolic biotypes, supporting the rationale for biomarker-guided stratification. These findings define an ‘inflammatory biotype’ of mood disorders and highlight the need for biomarkers and precision-based trials to guide treatment.

Mood disorders, including major depressive disorder (MDD) and bipolar disorder (BD), are among the leading causes of disability worldwide and are frequently associated with treatment resistance, functional impairment, and high comorbidity with metabolic dysfunction. Increasing evidence implicates insulin resistance (IR) as a key pathophysiological factor linking metabolic and psychiatric illness. IR is associated with chronic low-grade inflammation, hypothalamic–pituitary–adrenal (HPA) axis dysregulation, impaired neuroplasticity, mitochondrial dysfunction, and altered reward processing mechanisms that may contribute to core depressive features such as anhedonia, cognitive slowing, and emotional dysregulation. These processes are further exacerbated by the metabolic side effects of many psychotropic medications, creating a self-perpetuating cycle that worsens both psychiatric and physical health outcomes. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), initially developed for type 2 diabetes and obesity, have emerged as promising candidates to address this metabolic–psychiatric interface. Beyond improving glycemic control and promoting weight loss, GLP-1 RAs exert central actions relevant to mood disorders, including modulation of dopaminergic reward pathways, enhancement of hippocampal neurogenesis, attenuation of neuroinflammation, and regulation of appetite and energy balance. Preclinical studies demonstrate that GLP-1 RAs reduce microglial activation, promote hippocampal neurogenesis, and normalize stress-induced behavioral changes. Early clinical trials in patients with metabolic disorders suggest improvements in depressive symptoms, quality of life, and cognitive function, with some effects independent of weight loss or glycemic outcomes. Observational evidence also indicates reduced antidepressant use and psychological distress in diabetic and obese populations receiving GLP-1 RAs. While these findings are promising, large randomized controlled trials in primary psychiatric populations are lacking. Key challenges include clarifying dose–response relationships, disentangling central from peripheral effects, and addressing safety and adherence concerns in individuals with comorbid psychiatric conditions. Future research should focus on biomarker-informed stratification, comparative trials with standard treatments, and integration of GLP-1 RAs into multimodal care frameworks. Overall, GLP-1 RAs represent a biologically plausible and clinically relevant approach to bridging metabolic and psychiatric care, with the potential to improve outcomes in patients with mood disorders who carry a high metabolic burden.

Major depressive disorder (MDD) is increasingly recognized as a disorder of impaired neuroplasticity and large-scale network dysfunction rather than a simple monoaminergic deficit. Converging evidence indicates that chronic stress and depression erode synaptic connectivity, reduce glial support, and destabilize functional interactions among the default mode, salience, and executive networks. Conventional antidepressants indirectly restore circuit function over weeks, but the advent of rapid-acting glutamatergic agents has opened a new path for targeting these abnormalities directly. In this narrative review, we synthesize molecular, cellular, and connectomic findings to outline a conceptual Connectomic Glutamate Framework of Depression. We first examine how NMDAR blockade and subsequent AMPAR facilitation activate mTORC1 and BDNF signaling, driving synaptogenesis and dendritic spine formation. We then highlight the role of astrocytes and microglia in shaping the “quad-partite synapse” and sustaining network integrity. Neuroimaging studies demonstrate that glutamatergic modulators remodel dysfunctional networks: dampening DMN hyperconnectivity, enhancing fronto-limbic coupling, and normalizing salience-driven switching. Integrating these domains, we propose a hypothesis-generating, two-phase model in which glutamatergic agents destabilize maladaptive attractor states and then reintegrate circuits through structural remodeling. This framework bridges molecules, cells, and networks, offering mechanistic insight into the rapid efficacy of glutamatergic antidepressants and highlighting priorities for clinical translation.

Background: Lithium is a cornerstone in the treatment of bipolar disorder (BD). However, lithium use requires careful monitoring of thyroid function due to associated dysfunctions. The aim of our real-world study is to retrospectively evaluate the impact of lithium on thyroid function and how these thyroid alterations can be measured and managed. Methods: A retrospective observational study was performed on 150 patients with BD who started lithium treatment at the University Hospital of Siena. Thyroid function was assessed at baseline and after the introduction of lithium by measuring TSH, T3, and T4 levels at baseline and after 3, 6, 9, and 12 months, during which changes in psychiatric symptoms were also evaluated using specific psychometric scales. Results: Significant increases in TSH levels were observed at 3 and 6 months, while T3 and T4 levels decreased significantly at 3 months. Transient thyroid dysfunction occurred in 36.7% of patients, but normalized without the discontinuation of lithium or need for thyroid replacement therapy in most cases; however, replacement therapy was initiated in 8.7% of patients. There were no significant differences in treatment response between patients with and without thyroid abnormalities, as the abnormalities were transient or resolved. Conclusions: In our sample, lithium induced some cases of hypothyroidism, which, being transient or corrected with replacement therapy, did not interfere with symptomatic improvement. These findings underscore the necessity for continuous thyroid function monitoring during lithium therapy. Clinicians should be prepared to initiate thyroid replacement therapy, when necessary, as timely management can prevent the interruption of lithium treatment and ensure ongoing symptomatic improvement in BD patients. Future studies could include larger and more diverse populations to validate these findings further, extending the follow-up period beyond 12 months to better observe long-term thyroid function trends and management outcomes.

Anxiety symptoms are highly prevalent in major depressive disorder (MDD) and are associated with greater severity, functional impairment, and poorer treatment outcomes. Bupropion is widely used in clinical practice and is generally considered to have a favorable tolerability profile, but its effects on comorbid anxiety remain uncertain. We conducted a PRISMA-guided systematic review of randomized controlled trials, pooled analyses, and open-label comparative studies evaluating bupropion in adults with MDD and clinically significant anxiety symptoms. Searches of PubMed, Scopus and Web of Science were performed through August 2025. Outcomes included validated measures of anxiety and depressive symptoms and reported tolerability. Risk of bias was assessed using RoB 2 and ROBINS-I, and certainty of evidence was evaluated using GRADE. Six studies (n ≈ 3700) met inclusion criteria. Anxiety was a predefined secondary outcome in some trials and a post hoc or exploratory measure in others. Across designs, bupropion was generally associated with improvements in anxiety and depressive symptoms on secondary or exploratory anxiety measures. In pooled patient-level analyses, SSRIs showed a modest advantage over bupropion in patients with high baseline anxiety, whereas individual randomized and open-label studies found no significant between-group differences. None of the included studies reported a clear signal of anxiety worsening with bupropion on the anxiety measures used. Tolerability findings indicated a lower risk of sexual dysfunction with bupropion compared with SSRIs, while insomnia occurred more frequently but was generally manageable. Low-certainty evidence suggests that bupropion may provide clinically relevant improvement in anxiety symptoms in adults with MDD, with generally comparable efficacy to SSRIs in most presentations but a modest SSRI advantage in highly anxious subgroups. Interpretation should consider that anxiety outcomes were often secondary or exploratory and that several studies were at risk of bias. Well-designed randomized trials with anxiety as a primary endpoint are needed.