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.

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.

Bipolar disorder (BD) is characterized by recurrent episodes of mania, hypomania, and depression and is often complicated by comorbid substance use disorders (SUDs). Up to 60% of individuals with BD experience SUDs, which exacerbate mood instability and increase the risk of rapid cycling, suicide, and poor clinical outcomes. Current treatment strategies, including lithium and valproate, show limited efficacy in treating both BD and SUD. Psychotherapeutic approaches such as cognitive behavioral therapy (CBT) offer benefits but lack a specific focus on substances such as cannabis and cocaine. Since there is still debate on how to treat this comorbidity, there is a need to find new therapeutic options; this mini-review examines the pharmacological properties of cariprazine and its emerging role in the treatment of comorbid BD and SUD. Cariprazine, an atypical antipsychotic with partial agonism at dopamine D2 and D3 receptors, has shown promise in treating both mood symptoms and cognitive dysfunction in BD. Its unique affinity for D3 receptors, which are involved in motivation and reward processing, may offer advantages in reducing drug craving. Clinical trials indicate that cariprazine effectively treats manic, depressive, and mixed episodes in BD with a favorable side effect profile, particularly at lower doses. Preliminary results suggest its potential to reduce craving and substance use in individuals with co-occurring BD and SUD. Therefore, cariprazine, with its unique pharmacodynamic mechanism, could be further studied for the treatment of BD in comorbidity with SUD. However, evidence on the role of cariprazine in the treatment of SUDs remains limited, based primarily on case reports and animal studies. Further research, including large-scale clinical trials, is needed to determine its full efficacy in this dual diagnosis.

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.