In recent decades, mental health research has increasingly emphasized the role of inflammation in the pathogenesis, course, and treatment of mental disorders such as depression and affective disorders [1]. Several studies outlined recent developments and provided an overview of the inflammatory profiles associated with depression, psychosis, and bipolar disorder, including variations within these conditions [2,3]. Furthermore, factors such as social environment and childhood experiences have been examined for their potential to clarify the intricate interplay between inflammation and other closely related biological systems, while also considering the potentially confounding influence of various lifestyle factors. Several dietary compounds have been implicated in the onset, persistence, and severity of depressive disorders and related conditions such as obesity and diabetes [4]. Unipolar and bipolar depression are prevalent and recurrent mental illnesses affecting millions worldwide. Recently, ketamine has demonstrated a unique rapid neuroprotective and antidepressant effect through its action on the glutamatergic system. Consequently, there has been a growing body of evidence supporting the role of the excitatory amino acid neurotransmitter glutamate in depression treatment in recent years. Emerging research indicates that N-methyl-D-aspartate (NMDA) receptor antagonists, group 1 metabotropic glutamate receptor antagonists, and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor agonists possess antidepressant properties. NMDA receptor antagonists have been shown to promote synaptic plasticity and reverse neuronal changes induced by stress [5]. Recent research has identified new mediators involved in both energy balance and mood regulation, including insulin growth hormone (IGF-1), neuropeptide Y (NPY), brain-derived neurotrophic factor (BDNF), ghrelin, leptin, cholecystokinin (CCK), glucagon-like peptide 1 (GLP-1), advanced glycosylation end-products (AGEs), glucose metabolism, and the gut microbiota [6]. Changes in inflammatory markers, calcium levels, and thyroid function have been noted in patients experiencing symptoms such as anxiety, depression, fluctuations in thymic axis toward both ends, mental pain and suicidal thoughts [7]. Several studies have investigated the potential interconnections among these factors, impacting both physical homeostasis and mental well-being [2]. Inflammation plays a critical role in defense mechanisms. However, there are hypotheses suggesting that chronic inflammation could disrupt calcium metabolism, affecting neuronal function and contributing to the development of psychiatric disorders such as mood disorders and depression. Elevated levels of pro-inflammatory cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α), observed in individuals with major depression, lend support to the notion that these cytokines might influence brain function through mechanisms such as altering neurotransmission, reducing neurogenesis, and increasing oxidative stress [8]. Furthermore, inflammation has been associated with an increased risk of anxiety and suicidal thoughts. This inflammatory response may impact brain function and behavior through the gut-brain axis, altering neurotransmitter production and the permeability of the blood-brain barrier. Calcium is essential for various bodily functions, including the regulation of nerve transmission and neurotransmitter activity. Abnormal levels of calcium in the blood or brain have been linked to neuropsychiatric disorders. Research indicates that intracellular calcium levels may be disrupted in patients with depression or mood disorders, potentially affecting the release of neurotransmitters like serotonin and norepinephrine, which are critical for mood regulation. Moreover, calcium plays a fundamental role in brain neuroplasticity, known as the brain's ability to adapt and reorganize in response to experiences and learning. Imbalances in calcium levels can disrupt synaptic plasticity and brain function, potentially contributing to conditions such as anxiety and depression. The potential correlation between inflammation, calcium metabolism, and mental disorders suggests promising avenues for diagnostic and therapeutic interventions. For example, emerging research is exploring the use of anti-inflammatory treatments to manage depression and other mood disorders. Additionally, identifying and correcting imbalances in calcium metabolism could lead to targeted strategies aimed at improving mental health outcomes. Any therapeutic approach should be grounded in a comprehensive understanding of the underlying biological mechanisms and supported by robust clinical evidence. A multidisciplinary approach to these complex pathologies, integrating clinical and laboratory data, is essential for clinicians to develop precise hypotheses and effectively manage these conditions, enhancing both prevention and treatment strategies. In this context, our focus has been on observing patients with symptoms across the spectrum of unipolar and bipolar depressive disorders, assessing them clinically and based on bio-humoral indicators. The prospective study aimed to compare unipolar and bipolar depression samples in terms of socio-demographic and clinical characteristics, evaluating potential correlations with calcium levels, thyrotropin (TSH), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) values. Specifically, the study aims to:

The relationship between the immune system and alterations in the thymic axis has long been recognized, particularly the immune system's role in depressive spectrum disorders. This prospective study aimed to evaluate the relationship between several biomarkers which are routinely investigated in clinical settings, depressive symptoms and suicidal ideation, highlighting potential differences between patients with unipolar spectrum disorders and those with bipolar depression. This study was designed to assess a potential correlation between inflammation indices (ESR and CRP), TSH, and calcium, and the manifestation of depressive symptoms with or without suicidal ideation. Additionally, interactions with sociodemographic, clinical, and psychometric factors were evaluated to better understand the applicability of these biomarkers as screening methods in the context of differential diagnosis, suicide prevention, and personalized treatment strategies. The sample was evenly distributed between the sexes, with a low number of married and employed patients. This could be attributed to the predominantly young age group (N=17) and the fact that depressive symptoms often lead to relational poverty and reduced socio-occupational functioning [20]. A noteworthy observation was the early onset of mood disorders reported by patients (N=15), consistent with current literature describing an increasingly earlier onset of mood disorders, especially bipolar spectrum disorders [21]. About 30% of patients had organic and endocrinological comorbidities, predominantly type II diabetes, obesity, and hypertension. Considering the young age of the sample, this high frequency is significant. Extensive literature exists on comorbidities in psychiatric and mood disorders, suggesting multifactorial etiopathogenic mechanisms, including lifestyle habits, sedentary behavior, smoking, poor diet, and the role of polypharmacotherapy or inadequate hormonal treatments that can induce psychiatric symptoms. The role of glucocorticoids produced by the adrenal gland in regulating immune processes and metabolism is well documented. Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has been noted in mood disorders, with chronic stress leading to elevated glucocorticoid levels, particularly cortisol, triggering an inflammatory response mediated by pro-inflammatory cytokines, especially IL-1β. This HPA axis hyperactivation, potentially due to defective neuroendocrine control, could explain the increased prevalence of metabolic disorders and central obesity in bipolar patients [8]. Half of the sample had a positive family history of psychiatric disorders, particularly anxiety disorders, especially among bipolar patients. Familial predisposition is common in mood disorders, particularly in the bipolar spectrum, where patients often have a positive family history of psychiatric conditions [22]. Polypharmacotherapy was more prevalent than monotherapy, suggesting more severe and complex psychopathological conditions often necessitate the use of multiple psychotropic drugs, despite potential side effects and drug-drug interactions that can negatively impact patient compliance [23]. Suicidal ideation was present in 50% of the total population at recruitment, with 72.2% having attempted suicide before admission. The strong association between suicidal ideation and depression, particularly bipolar spectrum depression and mixed states, is well-documented [24]. Interestingly, suicidal ideation negatively correlated with substance abuse, suggesting those with current suicidal ideation were less likely to engage in substance abuse (p=0.0275). This relationship is complex and varies with individual patient contexts and substance use patterns [25]. Comparing unipolar and bipolar depression, significant alterations in calcium levels were observed in bipolar patients (p=0.050). Calcium role in the pathogenesis of bipolar spectrum disorders is acknowledged but not fully understood, with alterations linked to hypervigilance and thymic axis oscillations [26]. TSH levels showed weak alterations across both patient groups, without significant differences, reflecting the well-known relationship between thyroid hormones and mood disorders [27]. CRP levels were significantly altered, particularly in bipolar depression (p=0.028), supporting existing literature on immune system alterations in bipolar disorder [8]. The primary limitation of this study is the small sample size, which may not be representative of the broader population and lacks statistical power. Additionally, the inability to follow up with patients for repeated psychometric assessments and biochemical evaluations limits the study to a cross-sectional analysis. By integrating sociodemographic, clinical, and biomarker data, this study underscores the importance of a multidisciplinary approach in understanding and treating mood disorders, aiming to improve diagnostic precision and therapeutic outcomes.

In conclusion, this work highlights the comprehensiveness of the psychophysical aspects of the patient, moving towards an increasingly comprehensive approach to psychopathological disorders and the individual. This approach, increasingly present in international literature, aims to enhance understanding of physio-pathogenetic processes, as well as progress in diagnostic framing, differential diagnoses, and greater accuracy and personalization of therapeutic approaches. The primary endpoint of the study was to evaluate potential correlations between unipolar and bipolar depression and suicidal ideation with levels of calcium, TSH, ESR, and CRP. The results demonstrated that calcium and CRP levels are correlated with depressive symptoms, predominantly within the bipolar spectrum. Furthermore, based on the results, it is reasonable to state that among the psychometric scales used, the BRLF was the most effective in identifying patients at higher suicidal risk at the time of evaluation, particularly those with bipolar depression. The second endpoint was to compare the two subgroups of patients with unipolar and bipolar depression and analyze potential differences in clinical and socio-demographic characteristics, highlighting the main etiopathogenic factors and associated risk factors. Among these socio-demographic and clinical characteristics, current substance abuse emerged as the most interesting and worthy of further investigation, having a protective role against suicidal ideation within the sample. However, this data should be interpreted cautiously, as the tendency to deny the problem, factors related to social tolerance of alcohol consumption, and the mode of alcohol intake might have led to underestimating the phenomenon. These preliminary results need further investigation to clarify the underlying biochemical mechanisms and the clinical implications. Understanding these phenomena is crucial for developing effective preventive and therapeutic strategies and reducing the resulting individual and social burden. Future perspectives emphasize the importance of confirming our findings, enriching them with second-level investigations on inflammatory parameters such as IL-1B, IL-6, and IL-2 to identify factors useful in differential diagnosis and the identification of additional diagnostic subtypes and increasingly targeted therapeutic frameworks.