Increased immune–inflammatory activation has been repeatedly linked to etiopathogenesis and the progression of both major depressive disorder (MDD) and bipolar depression (BD). We explore the role of soluble intercellular cell adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) in diagnostic differentiation and disorder progression in patients with MDD and BD. Serum levels of sICAM-1 and sVCAM-1 were measured in 137 patients (MDD = 93 and BD = 44) and compared with 73 healthy controls. The severity of psychopathology was assessed using the Hamilton Depression Rating Scale and Clinical Global Impression Scale. After adjustment for multiple confounders, we noticed significant downregulation of sVCAM-1 and upregulation of sICAM-1 levels in both patient groups. Decreased sVCAM-1 levels were detected in patients with acute episodes of BD when compared to MDD. Immune mediators were related to indicators of progression in both mood disorders. They also followed different post-treatment normalization patterns in MDD and BD and in relation to the stage of each disorder. Adhesion molecules could potentially be useful in discriminating between patients with MDD and BD and determining the possible progression of the disorders. Future nosological methods should include time-dependent pathoplasticity and biological correlates, at least for affective disorders.

Suicide attempts are prevalent among patients with bipolar disorder (BD). Impaired serotonin (5-HT) system in the pathogenesis of suicide attempt is partially heritable. To quantify the combined effects of multiple genetic variants, we developed a dynamic model of the 5-HT presynapse with functionally integrated individual genetic variants. The model includes five genetic variants in 5-HT system genes (TPH2, SLC6A4, MAOA) and quantitatively assesses their influence on 5-HT synthesis, reuptake, and degradation. The model was validated on 140 unaffected individuals and tested on 101 BD patients. Predicted mean concentrations of 5-HT, 5-HT precursor, and degradation product were compared between BD patients with and without a history of attempted suicide, and unaffected individuals. The model consists of eight differential equations that describe the temporal concentration change of model outputs. Calculated concentrations in unaffected control individuals aligned with published experimentally measured values, validating our model. BD patients with a history of suicide attempt showed lower calculated concentrations of 5-HT degradation product 5-hydroxy-3-indolacetic acid (5-HIAA) compared to unaffected individuals (p = 0.044). Additionally, higher calculated concentrations of free cellular 5-HT (p = 0.048) and stored 5-HT (p = 0.047), with the effect size d = 0.35, were observed when comparing suicide attempters to non-attempters.. Our approach illuminated a complex interplay of genetic variants in 5-HT system genes that contributes to the risk of suicide attempt, with quantitative and personalized outputs unattainable through genetic association studies.

Depression, a major global public health concern and leading cause of disability, necessitates effective management. This paper, as part of the development of comprehensive guidelines for the treatment of depressive disorder in Serbia, delves into the pharmacological treatment of treatment-resistant depression (TRD), focusing on augmentative and switching strategies, aiming to address the lack of response to standard treatments. The focus is on the efficacy and tolerability of various pharmacological agents, aimed at facilitating informed clinical decisions. In TRD, augmentation strategies involving atypical antipsychotics, NMDA antagonists, mood stabilizers, and other compounds are examined. Finally, the importance of an individualized approach in deciding between augmentation and switching strategies is emphasized. This narrative review aims to inform treatment guidelines and encourages a collaborative approach, which considers individual patient factors, to improve the quality of care for individuals with treatment-resistant depression.

Background: Suicide attempts often co-occur with bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia (SCH). Although impairments of the serotonin (5-HT) system have been associated with suicide attempts, it remains unclear whether these alterations reflect suicidal behavior or are confounded by underlying psychiatric diagnosis. This study used a genotype-informed dynamic model of the 5-HT presynapse to disentangle the effects of suicide attempts and psychiatric diagnosis. Methods: We applied a personalized dynamic model of the 5-HT presynapse to 392 psychiatric patients (with BD, MDD, or SCH), categorized by suicide attempt status, and 140 unaffected individuals. The model incorporated five variants across TPH2, SLC6A4, and MAOA genes simulating individual-specific concentration changes of five 5-HT-related molecular species. Model outputs were summarized by six statistical measures (mean, median, maximum, standard deviation, skewness, and kurtosis) and compared across groups. Results: No significant differences were found across groups defined by suicide attempt status and unaffected individuals. However, diagnosis significantly influenced 5-hydroxyindoleacetic acid (5-HIAA) mean, median, maximum, and standard deviation (all p < 0.05). BD patients had lower 5-HIAA levels than SCH patients (mean: p = 0.013; median: p = 0.013; maximum: p = 0.014; standard deviation: p = 0.014). MDD patients also showed lower 5-HIAA levels than SCH patients for the same measures, with differences approaching significance. No significant difference was observed between BD and MDD patients. A diagnosis-by-suicide attempt status interaction was observed for 5-HIAA skewness (p = 0.013). Conclusions: Model-derived 5-HT profiles were shaped primarily by diagnosis, while temporal dynamics of 5-HIAA, rather than its absolute levels, was associated with suicide attempt status. Thus, personalized dynamic modeling incorporating genetic variants may aid in detecting subtle molecular signatures across diagnoses and suicidal behavior.

Introduction: Treatment-resistant depression (TRD) refers to a depressive episode that has not responded to treatment with two antidepressants. Pharmacological strategies for treating TRD involve a complex process, which includes several options for the use of different psychopharmaceuticals, fundamentally consisting of: (1) substituting/optimizing the dose of antidepressants, or (2) augmenting antidepressant therapy. Within the augmentation strategy, NMDA antagonists, including intranasal esketamine, play a significant role. Current research suggests that the application of intranasal esketamine as an augmentation agent is an effective pharmacological strategy in the treatment of TRD. Case report: In this paper, we present the successful application of intranasal esketamine in co-administration with a serotonin/norepinephrine reuptake inhibitor (SNRI antidepressant) in a patient with TRD. Conclusion: Further research is necessary to better understand the mechanisms of action, dosing modalities, as well as the long-term outcomes and safety profile of this approach.

Completed suicide accounts for over 700,000 deaths worldwide annually, while attempted suicide is 20 times more frequent. Genetic background is an important factor contributing to suicidal behavior, including candidate genes in glutamate, γ-aminobutyric acid (GABA), and polyamine systems. Our aim was to differentiate genetic predispositions underlying different types of suicidal behavior, attempted and completed suicide, in two Balkan populations. Analysis of variants in the genes GRIN2B (rs2268115 and rs220557), GABRG2 (rs424740), and ODC1 (rs1049500 and rs2302614) was performed on a study sample including 173 suicide attempters with comorbid psychiatric disorders, 216 non-suicidal psychiatric patients and 172 healthy controls from Serbia, and 333 suicide completers and 356 non-suicidal autopsy controls from Slovenia. CA genotype of rs220557 in GRIN2B gene increased the risk for completed suicide (P = 0.021), and violent suicide (P = 0.037), compared to controls. In ODC1 gene, CA genotype of rs2302614 decreased the risk for completed suicide compared to suicide attempt (P = 0.012). Marginally, AC haplotype for variants rs1049500-rs2302614 in ODC1 gene decreased the risk for completed suicide compared to suicide attempt (P = 0.052). Specific genetic variants of glutamate and polyamine systems are differently distributed among diverse suicidal phenotypes, providing further information on the implication of these systems in suicidality.