Current Medicinal Chemistry - Volume 29, Issue 36, 2022

Background: The internal clock is driven by circadian genes [e.g., Clock, Bmal1, Per1-3, Cry1-2], hormones [e.g., melatonin, cortisol], as well as zeitgeber [‘synchronisers’]. Chronic disturbances in the circadian rhythm in Objectives: The aim of this review is to summarise the current knowledge and literature regarding circadian rhythms in the context of mood disorders, focussing on the role of circadian genes, hormones, and neurotransmitters. Methods: The review presents the current knowledge and literature regarding circadian rhythms in mood disorders using the Pubmed database. Articles with a focus on circadian rhythms and mood disorders [n=123], particularly from 1973 to 2020, were included. Results: The article suggests a molecular link between disruptions in the circadian rhythm and mood disorders. Circadian disturbances, caused by the dysregulation of circadian genes, hormones, and neurotransmitters, often result in a clinical picture resembling depression. Conclusion: The article suggests a molecular link between disruptions in the circadian rhythm and mood disorders. Circadian disturbances, caused by the dysregulation of circadian genes, hormones, and neurotransmitters, often result in a clinical picture resembling depression.

Background: The pathophysiology of major depressive disorder (MDD), one of the major causes of worldwide disability, is still largely unclear, despite the increasing data reporting evidence of multiple alterations of different systems. Recently, there was a renewed interest in the signalling of gamma aminobutyric acid (GABA) - the main inhibitory neurotransmitter. Objective: The aim of this study was to review and comment on the available literature about the involvement of GABA in MDD, as well as on novel GABAergic compounds possibly useful as antidepressants. Methods: We carried out a narrative review through Pubmed, Google Scholar and Scopus, by using specific keywords. Results: The results, derived from various research tools, strongly support the presence of a deficiency of the GABA system in MDD, which appears to be restored by common antidepressant treatments. More recent publications would indicate the complex interactions between GABA and all the other processes involved in MDD, such as monoamine neurotransmission, hypothalamus-pituitary adrenal axis functioning, neurotrophism, and immune response. Taken together, all these findings seem to further support the complexity of the pathophysiology of MDD, possibly reflecting the heterogeneity of the clinical pictures. Conclusion: Although further data are necessary to support the specificity of GABA deficiency in MDD, the available findings would suggest that novel GABAergic compounds might constitute innovative therapeutic strategies in MDD.

Background: Late-onset depression (LOD) is the most common neuropsychiatric disorder associated with Alzheimer's disease (AD), often associated with structural and functional brain changes, neuropsychological impairments and negative family history for affective disorders. LOD could be a risk factor or a prodromal phase of AD; this has led to the investigation of the link between depression and amyloid-β (Aβ) peptides by measuring Aβ levels in plasma, cerebrospinal fluid (CSF) and brains of elderly depressed subjects. Objective: This study aims to clarify the complex relationship between depression, Aβ peptides and AD. Methods: We evaluated all articles published up to 2019 in PubMed in which Aβ was measured in serum (or plasma), CSF or brain in elderly with Major Depressive Disorder or depressive symptoms evaluated with standard scales. Results: Low plasma Aβ42 levels are strongly associated with depression severity. Plasma Aβ40 levels are higher in younger depressed, drug-resistant and those with more severe symptoms. CSF Aβ42 levels are lower in depressed than controls. PET-detected global and region-specific increases in Aβ deposition are sometimes associated with LOD, cognitive impairment, anxiety but not with Cardiovascular Diseases (CVDs)/CVD risk factors. Elderly depressed with CVDs/CVD risk factors have more frequently high plasma Aβ40 levels and drug-resistance; those without Conclusion: Two specific Aβ profiles emerge in the depressed elderly. One is associated with Aβ42 reductions in plasma and CSF, possibly reflecting increased brain amyloid deposition and prodromal AD. The other one is characterized by high plasma Aβ40 levels, cerebrovascular disease and is clinically associated with increased AD risk.

Major depressive disorder (MDD) and bipolar disorders (BDs), the most severe types of mood disorders (MDs), are considered as among the most disabling illnesses worldwide. Several studies suggested that inflammatory neuroinflammation might be involved in the pathophysiology of MDs while reporting increasing data on the relationships between these processes and classical neurotransmitters, hypothalamus-pituitaryadrenal axis (HPA), and neurotrophic factors. The assessment of neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), and monocyte/lymphocyte ratio (MLR) in peripheral blood represents a simple method to evaluate the inflammatory status. The aim of the present paper was to review the literature on the possible relationships between NLR, PLR, and MLR in MDs and to comment on their possible wider use in clinical research. Thirty-five studies were included in the present review. The majority of them had higher values of these parameters, particularly NLR values in patients with MDs when compared to healthy subjects. The increase would appear more robust in patients with BD during a manic episode, thus indicating that it could be considered as both state and trait markers. In addition, increased NLR and PLR levels seem to represent prognostic elements for the early discovery of post-stroke depression. The findings of the present review would indicate the need to carry out further studies in this field. In particular, NLR, PLR, and MLR seem to be promising tools to detect economically and easily the activation of the inflammatory system and to perhaps evaluate the etiology and course of MDs. Again, they could suggest some information to better understand the relationship between inflammatory and cardiovascular disease and MDs, and thus, to provide clinical implications in terms of management and treatment.

Background: Brain-Derived Neurotrophic Factor (BDNF) is a promising candidate biomarker in both the development and aetiology of different neuropsychiatric conditions, including obsessive-compulsive disorder (OCD). Most of the studies in the field have been carried out in blood cells, including peripheral blood mononucleated cells (PBMCs), although DNA of high quality can be easily isolated from saliva. Objective: The objective of this study was to evaluate the epigenetic regulation of the BDNF gene in the saliva of a clinical sample of OCD patients in order to assess this source as an alternative to blood. Methods: We first analyzed DNA methylation levels at BDNF in the saliva of subjects suffering from OCD (n= 50) and healthy controls (n=50). Then, we compared these data with the results previously obtained for the same genomic region in blood samples from the same patients and controls (CTRL). Results: Our preliminary data showed a significant reduction of 5mC levels at BDNF gene (OCD: 1.23 ± 0.45; CTRL: 1.85 ± 0.64; p < 0.0001) and a significant correlation between DNA methylation in PBMCs and saliva (Spearman r = 0.2788). Conclusion: We support the perspective that saliva could be a possible, reliable source, and a substitute for blood, in search of epigenetic biomarkers in OCD.