Pietro Carmellini

Objective: To assess early renal and lithium‐related safety and 12‐month renal biomarker trajectories after tirzepatide initiation in lithium‐treated adults with bipolar disorder. Methods: We retrospectively studied 23 adults at one centre. The principal 12‐week renal safety measures were serum creatinine and derived CKD‐EPI 2021 creatinine‐based eGFR. Secondary outcomes included lithium, electrolytes, gastrointestinal symptoms, acute kidney injury meeting KDIGO creatinine criteria and discontinuation. Twelve‐month trajectories and body‐surface‐area‐unindexed eGFR were exploratory. Results: At 12 weeks, creatinine changed by −3 ± 12 μmol/L ( p = 0.196), indexed eGFR by +2.6 ± 15.1 mL/min/1.73 m ² ( p = 0.259) and lithium by +0.08 ± 0.17 mmol/L ( p = 0.030). Among 20 on‐treatment completers at 12 months, weight decreased by 17.7 ± 6.0%, creatinine by 12 ± 9 μmol/L, indexed eGFR increased by 13.0 ± 12.1 mL/min/1.73 m ² and unindexed eGFR by 4.5 ± 14.3 mL/min. Two patients had lithium > 1.2 mmol/L; one developed clinician‐attributed symptomatic toxicity and discontinued tirzepatide. No acute kidney injury meeting KDIGO creatinine criteria could be confirmed from available records. Conclusions: Co‐prescription warrants structured monitoring and sick‐day education. Creatinine‐based eGFR changes during major weight loss do not establish renal benefit or exclude kidney injury.

Aim: To assess the association between apical periodontitis (AP) and subclinical symptoms of anxiety, depression and disordered eating. Methodology: A total of 120 individuals were included in this case–control study. Sixty subjects were assigned to case (AP+) and 60 to control group (AP−). The periapical and dental status were assessed using radiographic images (OPT, periapical radiographs) and dental examination. The DMFT index (decayed, missing and filled teeth) and the periapical index (PAI) scores were recorded. All subjects were interviewed to compile medical history data, anxiety (Hamilton A), depression (Hamilton D) and eating disorder (EAT‐26) questionnaires. Inferential and both simple and multiple logistic regression analyses were performed. Results: Significant associations were observed between AP and higher scores on HAM‐A, HAM‐D and EAT‐26. The regression model showed that higher PAI scores were significantly associated with increased odds of anxiety, depression and disordered eating. A PAI score of 3 showed increased odds of anxiety (OR = 5.57, p = 0.004) and depression (OR = 3.65, p = 0.025). A PAI score of 4 showed even greater odds for anxiety (OR = 8.68, p = 0.001), depression (OR = 14.07, p = 0.001) and disordered eating (OR = 3.98, p = 0.032). Participants with more than one periapical lesion were 3.56 times more likely to report higher levels of anxiety ( p = 0.007), 3.59 times more likely to experience elevated depression ( p = 0.018) and 3.08 times more likely to exhibit disordered eating behaviours ( p = 0.028). Additionally, higher DMFT scores were associated with an increased likelihood of higher HAM‐A scores (OR = 1.18, p = 0.001). Conclusions: The study results show a statistically significant higher prevalence of mood disorders and mental health‐related conditions including anxiety, depression and eating disorders in patients with AP. Longitudinal studies are needed to determine the nature of the observed association. Trial Registration: ClinicalTrials.gov identifier: NCT06589076

Background/Objectives: Major depressive disorder (MDD) remains a leading cause of disability worldwide and exhibits substantial biological heterogeneity that is not adequately captured by current symptom-based diagnostic systems. While the classical monoamine hypothesis has historically guided antidepressant development, it does not fully account for variability in treatment response, delayed therapeutic onset, or the persistence of cognitive and anhedonic symptoms. Converging evidence from molecular, neuroimaging, and translational studies increasingly implicates glutamatergic dysregulation and impaired neuroplasticity as key mechanisms in depressive pathology. This narrative review aims to integrate monoaminergic and glutamatergic perspectives within a dimensional framework that may help explain clinical heterogeneity and inform mechanism-based treatment strategies. Methods: A narrative synthesis of the literature was conducted using major biomedical databases including PubMed, Scopus, and Web of Science. Preclinical studies, neuroimaging investigations, biomarker research, randomized clinical trials, and meta-analyses examining monoaminergic dysfunction, glutamatergic signaling, neuroplasticity pathways, and rapid-acting antidepressants were reviewed and thematically integrated. Results: Evidence indicates that depressive syndromes may reflect varying contributions of monoaminergic dysregulation and glutamatergic–neuroplastic impairment. Monoaminergic disturbances interact with inflammatory and neuroendocrine processes, including cytokine-driven activation of the kynurenine pathway. In parallel, alterations in glutamatergic signaling, glial function, and BDNF–TrkB–mTOR pathways contribute to synaptic atrophy and network dysfunction. Rapid-acting antidepressants such as ketamine, esketamine, and dextromethorphan–bupropion provide clinical proof-of-concept that direct engagement of synaptic plasticity mechanisms can accelerate symptom improvement, particularly in treatment-resistant depression. Conclusions: Integrating monoaminergic and glutamatergic mechanisms within a “monoamine–glutamate continuum” offers a conceptual framework for understanding depressive heterogeneity and treatment response. Multimodal approaches combining clinical phenotyping with inflammatory, neuroimaging, and molecular markers may ultimately support mechanism-informed precision psychiatry strategies in major depressive disorder.

Aims Early identification of symptoms in schizophrenia spectrum disorders (SSD) may improve clinical outcomes, yet the temporal trajectory and prognostic relevance of initial symptom dimensions remain unclear. This study aimed to identify the earliest emerging symptoms among individuals with SSD and investigate their association with illness severity using a dimensional, data-driven approach. Methods We conducted a cross-sectional observational study including 160 adults with SSD, diagnosed using the via the Structured Clinical Interview for DSM-5 (SCID-5). Participants completed the Structured Clinical Interview for the Psychotic Spectrum – Self-Report (PSY-SR) PSY-SR questionnaire, which assesses lifetime psychotic spectrum symptoms across five domains: interpersonal sensitivity, paranoid traits, schizoid traits, misperceptions, and typical psychotic symptoms, with retrospective reporting of age at symptom onset. K-means clustering classified patients by severity based on total PSY-SR scores. Multinomial logistic regression identified factors linked to the more severe cluster. Results Two clusters were identified: Cluster 1 (less severe; n = 91) and Cluster 2 (more severe; n = 69). Cluster 2 had higher PSY-SR scores (81.2 vs. 42.0) and earlier symptom onset, particularly for interpersonal sensitivity (15.7 vs. 18.8 years, p = 0.013) and typical psychotic symptoms, including hallucinations and delusions (22.0 vs. 26.5 years, p < 0.001). In contrast, age at onset of paranoid traits and misperceptions did not significantly differ between clusters. FGA use was associated with Cluster 2 membership, likely reflecting greater clinical severity. (OR = 5.10, p = 0.008). Later onset of interpersonal sensitivity and typical psychotic symptoms was associated with reduced severity, lowering the probability of Cluster 2 membership by around 50% per additional year. Conclusions In a cross-sectional sample of adults with SSD, earlier onset of interpersonal sensitivity and typical psychotic symptoms in SSD predicted worse outcomes. These findings support a dimensional understanding of symptom heterogeneity within SSD and suggest that systematic assessment of subthreshold and spectrum-level symptoms may contribute to improved early detection, risk stratification and more personalised interventions.

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.

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.

Background: Prolonged Grief Disorder (PGD) was recently included in the DSM-5-TR. Although the diagnostic criteria for PGD have been established, its prevalence among psychiatric patients and its implications remain underexplored. This study aimed to determine the rate and characteristics of PGD among psychiatric patients and assess the utility of the PG-13-R scale as a potential predictive screening tool within this population. Methods: Data were collected from 259 psychiatric patients at a University Hospital’s Psychiatry Unit. Patients completed the PG-13-R scale and provided details about the loss and its circumstances. Descriptive statistics, inferential statistics, and ROC analysis were conducted to analyze the data. Results: Overall, 15.4% of participants met the DSM-5-TR criteria for PGD, with no significant demographic differences observed. Notably, these patients were more likely to have lost a first-degree relative. The PG-13-R mean total score was 23.76 (SD 11.47). Although a cutoff score of 30 aligned with syndromal-level PGD, additional ROC analyses identified threshold scores of 24 for patients whose loss occurred less than 6 months prior (AUC 0.73) and 27 for those whose loss occurred more than 6 but less than 12 months prior (AUC 0.97), each demonstrating over 90% sensitivity in detecting high-risk cases. Patients re-evaluated 12 months post-loss showed a significant decrease in grief scores ( p < .001), yet those initially at higher risk often maintained elevated symptom levels. Conclusions: Our study highlights the significant burden of PGD among psychiatric patients and emphasizes the importance of integrating grief assessment and intervention into psychiatric care to improve outcomes for individuals at risk of PGD. The PG-13-R emerges as a valuable tool for screening and addressing prolonged grief in this population.

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.

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.