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.

Psychomotor agitation is a challenging symptom of major depressive disorder with mixed features (MDD-MF), often worsening outcomes and complicating treatment. This retrospective study assessed the efficacy and tolerability of intravenous trazodone in 97 hospitalized patients with MDE-MF. Symptom severity was evaluated using montgomery asberg depression rating Scale (MADRS), young mania rating scale, hamilton anxiety rating scale, GAD-7, and clinical global impression scale-severity of illness (CGI-S) scales, with significant reductions in agitation, anxiety, and irritability observed early during treatment. Correlation analyses revealed significant negative associations between intravenous (IV) trazodone dosage and improvements in MADRS (r = −0.23; P < 0.05), item 5 of GAD-7 (r = −0.27; P < 0.001), and CGI-S scores (r = −0.22; P < 0.05). Therapy duration also correlated negatively with improvements in GAD-7 item 5 (r = −0.29; P < 0.001) and CGI-S (r = −0.27; P < 0.001), indicating diminishing returns with prolonged treatment. Regression analyses showed that therapy duration, but not dosage, significantly influenced improvements in GAD-7 item 5 and CGI-S. Trazodone was well-tolerated, with only mild side effects in 11.3% of patients. These findings suggest that IV trazodone effectively reduces agitation and related symptoms in MDD-MF, particularly in the early treatment phase, emphasizing the importance of optimizing treatment duration. Future studies should investigate individualized dosing strategies and explore long-term outcomes in this population.

Considering the ever-increasing use of ketamine as a rapid-acting and efficacious agent for difficult-to-treat affective disorders, it is paramount that clinicians understand pharmacological interactions between ketamine and other drugs commonly used in unipolar and bipolar depression. Anticonvulsants appear of particular interest in this context, as some (valproate, lamotrigine, carbamazepine, pregabalin, gabapentin) are widely employed as mood-stabilisers and/or anxiolytics, while others are still commonly encountered due to the significant comorbidity between affective disorders and epilepsy. This is the protocol for a scoping review aiming to comprehensively collect evidence regarding pharmacodynamic and pharmacokinetic interactions between ketamine (and its enantiomers) and anticonvulsants. Our review was designed in accordance with the PRISMA Extension for Scoping Reviews (PRISMA-ScR). PubMed, Embase, PsycINFO, ProQuest and ClinicalTrials.gov will be searched for relevant papers. Primary and non-primary research of any design will be included to ensure comprehensiveness. All data will be synthetised and presented in narrative form. We anticipate that our results will provide useful insight for clinicians and highlight gaps in knowledge that may be explored in future research.

Background/Objectives: Schizophrenia is a severe psychiatric disorder, with onset typically occurring in late adolescence or early adulthood. Early identification of psychotic symptoms, especially those occurring before age 12, has been linked to better long-term outcomes. This study aims to assess the presence of psychotic spectrum symptoms before the age of 12 in adult schizophrenia patients and explore their clinical implications for early detection and intervention. Methods: This retrospective, observational study included 170 adult patients diagnosed with schizophrenia, confirmed by the SCID-5. Patients were recruited from the University of Siena Medical Center and completed the modified lifetime version of the Psychotic Spectrum Self-Report (PSY-SR) questionnaire, which assessed the onset of specific psychotic symptoms before and after age 12. Symptom severity was evaluated using the Brief Psychiatric Rating Scale (BPRS) and the Clinical Global Impression Scale (CGI). This study also examined the impact of the duration of untreated psychosis (DUP) on symptom severity. Results: In our cohort, 21% of patients exhibited prodromal symptoms before age 12 (95% CI: 15–27%). Prodromal symptoms were linked to a 9.53-point increase in the BPRS scores (p = 0.0478) and a 0.50-point increase in the CGI scores (p = 0.0347). The age of symptom onset negatively correlated with the BPRS scores (p < 0.0001), with each year of delay resulting in a 1.33-point decrease. The DUP correlated significantly with both the BPRS (ρ = 0.97) and CGI scores (ρ = 0.94). The multivariate analysis revealed that a longer DUP was associated with significant increases in both scores: a 27.16-point increase in the BPRS (p < 0.0001) for a moderate DUP and a 67.51-point increase (p < 0.0001) for a severe DUP. The CGI scores increased by 1.11 points with a moderate DUP and 3.17 points with a severe DUP (p < 0.0001). However, the interaction between the DUP and prodromal symptoms at age 12 was not significant, indicating similar impacts of the DUP regardless of early symptom onset. Conclusions: The results support the critical importance of early detection and intervention in schizophrenia. Early psychotic spectrum symptoms, particularly those occurring before age 12, are significant predictors of later severity and functional impairment. This study underscores the value of screening tools like the PSY-SR for identifying prodromal symptoms and facilitating timely intervention. Our findings highlight the need for the early identification of psychotic symptoms, particularly in at-risk populations, to improve long-term outcomes. Intervening before the onset of full-blown psychosis may reduce the severity of schizophrenia and promote better clinical outcomes.