Function In Mood Disorders Research Articles

Discovery of 6,7-Dihydropyrazolo[1,5-a]pyrazin-4(5H)-one Derivatives as mGluR2 Negative Allosteric Modulators with In Vivo Activity in a Rodent's Model of Cognition.

Allosteric modulators of the metabotropic group II receptors, mGluR2 and mGluR3, have been widely explored due to their ability to modulate cognitive and neurological functions in mood disorders, although none have been approved yet. In our search for new and selective mGluR2 negative allosteric modulators (NAMs), series of 6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one derivatives were identified from our published series of 1,3,5-trisubstituted pyrazoles. SAR evolution of the initial hit resulted in 100-fold improvement in the mGluR2 NAM potency and subsequent selection of compound 11 based on its overall profile, including selectivity and ADMET properties. Further pharmacokinetic-pharmacodynamic (PK-PD) relationship built showed that compound 11 occupied the mGluR2 receptor in a dose-dependent manner. Additionally, the compound revealed in vivo activity in V-maze as a model of cognition from a dose of 0.32 mg/kg. Compound 11 was selected to be evaluated further.

Nutraceutical Capsules LL1 and Silymarin Supplementation Act on Mood and Sleep Quality Perception by Microbiota-Gut-Brain Axis: A Pilot Clinical Study.

Stress, unhealthy lifestyle, and sleep disturbance worsen cognitive function in mood disorders, prompting a rise in the development of integrative health approaches. The recent investigations in the gut-brain axis field highlight the strong interplay among microbiota, inflammation, and mental health. Thus, this study aimed to investigate a new nutraceutical formulation comprising prebiotics, minerals, and silymarin's impact on microbiota, inflammation, mood, and sleep quality. The study evaluated the LL1 + silymarin capsule supplementation over 180 days in overweight adults. We analyzed the fecal gut microbiota using partial 16S rRNA sequences, measured cytokine expression via CBA, collected anthropometric data, quality of life, and sleep questionnaire responses, and obtained plasma samples for metabolic and hormonal analysis at baseline (T0) and 180 days (T180) post-supplementation. Our findings revealed significant reshaping in gut microbiota composition at the phylum, genus, and species levels, especially in the butyrate-producer bacteria post-supplementation. These changes in gut microbiota were linked to enhancements in sleep quality, mood perception, cytokine expression, and anthropometric measures which microbiota-derived short-chain fatty acids might enhance. The supplementation tested in this study seems to be able to improve microbiota composition, reflecting anthropometrics and inflammation, as well as sleep quality and mood improvement.

Repetitive Transcranial Magnetic Stimulation Reversing Abnormal Brain Function in Mood Disorders with Early Life Stress: from preclinical models to clinical applications

BackgroundEarly life stress (ELS) significantly increases the risk of mood disorders and affects the neurodevelopment of the primary cortex. HypothesisModulating the primary cortex through neural intervention can ameliorate the impact of ELS on brain development and consequently alleviate its effects on mood disorders. MethodWe induced the chronic unpredictable mild stress (CUMS) model in adolescent rats, followed by applying repetitive transcranial magnetic stimulation (rTMS) to their primary cortex in early adulthood. To assess the applicability of primary cortex rTMS in humans, we recruited individuals aged 17–25 with mood disorders who had experienced ELS and performed primary cortex rTMS on them. Functional magnetic resonance imaging (fMRI) and depression-related behavioral and clinical symptoms were conducted in both rats and human subjects before and after the rTMS. ResultsIn animals, fMRI analysis revealed increased activation in the primary cortex of CUMS rats and decrease subcortical activation. Following the intervention of primary cortex rTMS, the abnormal functional activity was reversed. Similarly, in mood disorders patients with ELS, increased activation in the primary cortex and decreased activation in the frontal cortex were observed. During rTMS intervention, similar neuroimaging improvements were noted, particularly decreased activation in the primary cortex. This suggests that targeted rTMS in the primary cortex can reverse the abnormal neuroimaging. ConclusionThis cross-species translational study has identified the primary cortex as a key region in mood disorders patients with ELS. Targeting the primary cortex with rTMS can correct abnormal functional activity while improving symptoms. Our study provides translational evidence for therapeutics targeting the ELS factor of mood disorders patients.

Platelet Function in Mood Disorders: Interplay, Clinical Implications, and Future Perspectives – A Narrative Review

Abstract Mood disorders, encompassing major depressive disorder and bipolar disorder, present complex etiologies involving neuroanatomical, neurotransmitter, and inflammatory mechanisms. Recent research explores the role of platelets, traditionally associated with hemostasis, in the pathophysiology of mood disorders. We examine neuroanatomical insights, neurotransmitter dysregulation, and the link between inflammation and mood disorders, emphasizing the complex nature of mood disturbances. Emerging evidence of altered platelet function in mood disorders and the therapeutic potential of antiplatelet agents and serotonin reuptake inhibitors are discussed. While personalized medicine holds promise, further research is needed to fully comprehend this evolving field. This review offers comprehensive insights into mood disorder diagnosis, intervention, and pathophysiology. In this review, a comprehensive literature search was conducted using databases such as PubMed, Scopus, and Web of Science. The search focused on articles published from 2000 to 2023, using keywords like “platelet function,” “mood disorders,” and “neurotransmitter dysregulation.” We included studies that specifically investigated the role of platelets in mood disorders, encompassing various study designs and population demographics.

Neuroimmune crosstalk through brain-derived neurotrophic factor and its precursor pro-BDNF: New insights into mood disorders.

Mood disorders are the most common mental disorders, affecting approximately 350 million people globally. Recent studies have shown that neuroimmune interaction regulates mood disorders. Brain-derived neurotrophic factor (BDNF) and its precursor pro-BDNF, are involved in the neuroimmune crosstalk during the development of mood disorders. BDNF is implicated in the pathophysiology of psychiatric and neurological disorders especially in antidepressant pharmacotherapy. In this review, we describe the functions of BDNF/pro-BDNF signaling in the central nervous system in the context of mood disorders. In addition, we summarize the developments for BDNF and pro-BDNF functions in mood disorders. This review aims to provide new insights into the impact of neuroimmune interaction on mood disorders and reveal a new basis for further development of diagnostic targets and mood disorders.

Cognition Assessment in Virtual Reality: Validity and feasibility of a novel virtual reality test for real-life cognitive functions in mood disorders and psychosis spectrum disorders

There is a pressing need for measures of real-life cognitive functioning in patients with mood or psychotic disorders in clinical settings and treatment trials targeting cognition. We developed the first immersive virtual reality cognition assessment tool, the Cognition Assessment in Virtual Reality (CAVIR), which assesses verbal memory, processing speed, attention, working memory and planning skills in an interactive virtual reality kitchen scenario. This study investigates the sensitivity and validity of the CAVIR for cognitive impairments in mood and psychotic disorders and its association with functioning and neuropsychological performance. Symptomatically stable patients with mood disorders (MD; n = 40) or psychosis spectrum disorders (PSD; n = 41) and healthy control participants (HC; n = 40) completed the CAVIR and standard neuropsychological tests and were rated for clinical symptoms and daily functioning. We found that the CAVIR was sensitive to cognitive impairments across MD and PSD with large effect sizes (MD: F(73) = 11.61, p < .01, ηp2 = 0.14; PSD: F(72) = 18.24, p < .001, ηp2 = 0.19). There was a moderate to strong positive correlation between performance on the CAVIR and on neuropsychological tests (r(121) = 0.58, p < .001), which prevailed after adjustment for age, years of education and verbal IQ (B = 0.67, p < .001). Lower CAVIR scores correlated moderately with more observer-rated and performance-based functional disability (r(121) = -0.30, p < .01 and r(68) = 0.44, p < .001, respectively), also after adjustment for age, years of education and verbal IQ (B = 0.03, p < .001). In conclusion, the CAVIR is a sensitive and valid instrument for measuring real-life cognitive impairments in mood and psychotic disorders. After further psychometric assessments, the CAVIR can be implemented in clinical settings and trials targeting cognition.

Virtual reality assessment of daily life executive functions in mood disorders: associations with neuropsychological and functional measures

BackgroundMood disorders are often accompanied by cognitive difficulties that impede patients' functional capacity. However, neuropsychological tests provide limited insight into patients' ability to tackle daily life cognitive challenges. To address this challenge, we investigated the sensitivity and validity of the Jansari assessment of Executive Functions (JEF©) virtual reality test in patients with mood disorders and its associations with functional capacity. MethodsIn total, 21 patients with bipolar disorder or unipolar disorder in full or partial remission and 29 healthy control participants were recruited for the study. Participants attended one test session during which they underwent diagnostic assessments, mood ratings and assessments with JEF©, a battery of standard neuropsychological tests (RAVLT, Trial Making A and B, Fluency tests, letter-number sequencing and RBANS digit span and coding tests) and functional capacity measures (UPSA-B and FAST). ResultsPatients showed impaired executive functions on JEF© compared to the control group. Relative to the control group, patients were also impaired on neuropsychological sub-composite scores of executive function, verbal memory and processing speed as well as on a global cognition composite score. In addition, JEF© scores predicted performance on a global cognition composite based on neuropsychological tests, and a performance-based measure of functional capacity. LimitationsThis study had a relatively small sample size and included a mixed group of patients with unipolar or bipolar disorder. ConclusionsJEF© is a sensitive and valid measure of daily life executive impairments in patients with mood disorders that is associated with functional capacity.

Using network analysis to explore cognitive domains in patients with unipolar versus bipolar depression: a prospective naturalistic study.

Despite growing evidence in the field of cognitive function in mood disorders, the neurocognitive profiles of patients with unipolar and bipolar depression still need further characterization. In this study, we applied network analysis, hypothesizing this approach could highlight differences between major depressive disorder (MDD) and bipolar disorder (BD) from a cognitive perspective. The cognitive performance of 109 patients (72 unipolar and 37 bipolar depressed outpatients) was assessed through the Montreal Cognitive Assessment (MoCA), and a series of clinical variables were collected. Differences in cognitive performance between MDD and BD patients were tested using non-parametric tests. Moreover, a network graph representing MoCA domains as nodes and Spearman's rho correlation coefficients between the domains as edges was constructed for each group. The presence of mild cognitive impairment was observed in both MDD and BD patients during depression. No statistical significant difference was found between the two groups in terms of overall cognitive performance and across single domains. Nonetheless, network analytic metrics demonstrated different roles of memory and executive dysfunction in MDD versus BD patients: in particular, MDD network was more densely interconnected than BD network, and memory was the node with the highest betweenness and closeness centrality in MDD, while executive function was more central in BD. From a network analytic perspective, memory impairment displays a central role in the cognitive impairment of patients with unipolar depression, whereas executive dysfunction appears to be more central in bipolar depression. Further research is warranted to confirm our results.

Handgrip Linked to Cognition In Mood Disorders, Schizophrenia

Handgrip Linked to Cognition In Mood Disorders, Schizophrenia

Depression-resistant Phenotype in Mice Overexpressing Regulator of G Protein Signaling 8 (RGS8)

Regulator of G protein signaling (RGS) proteins are negative regulators of heterotrimeric G proteins that act by accelerating Gα-mediated GTPase activity to terminate G protein-coupled receptor-associated signaling. RGS8 is expressed in several brain regions involved with movement and mood. To investigate the role of RGS8 in vivo, we generated transgenic mice overexpressing brain RGS8 (RGS8tg). RGS8 gene and protein expressions were examined by real-time PCR and immunohistochemistry, respectively, and a significant increase in RGS8 protein was detected in the hippocampal CA1 region compared with wild-type mice (WT). We characterized the phenotypic traits, and found that RGS8tg showed decreased depressive-like behavior in the forced swimming test (FST). Previously, RGS8 was identified as a potent negative regulator of melanin-concentrating hormone receptor 1 (MCHR1), whose activation is mainly involved in energy homeostasis and emotional processing. Interestingly, acute oral administration of MCHR1 antagonist SNAP94847 did not have antidepressant-like effects on RGS8tg in the FST, but did show antidepressant effects on WT. In contrast, selective noradrenaline reuptake inhibitor desipramine had a significant effect on RGS8tg in the FST. MCHR1 is enriched in a subset of primary cilia, as sensory organelles that mediate extracellular signaling. Immunohistochemical analyses revealed significant elongation of MCHR1-positive cilia in the CA1 region of RGS8tg compared with WT. Taken together, these findings suggest that RGS8 participates in modulation of depression-like behavior through ciliary MCHR1 expressed in the CA1 region. The present study may support the possible modulation of RGS8 function in mood disorders.

Multidimensional cognitive impairment in unipolar and bipolar depression and the moderator effect of adverse childhood experiences.

Studies have demonstrated neuropsychological deficits across a variety of cognitive domains in depression. These deficits are observable both in major depressive disorder (MDD) and in bipolar disorder (BD) and are present in each phase of the illness, including euthymia. Adverse childhood experiences (ACE) have been associated with an increased risk of developing psychiatric disorders and cognitive deficits. The aim of this study was to assess neuropsychological performances in a sample of MDD and BD patients during a depressive episode compared to healthy controls (HC) and, to investigate if ACE affect the cognitive profiles in the three groups. Seventy-six BD patients, 57 MDD patients, and 57 HC underwent neuropsychological assessment for cognitive performances through the Brief Assessment of Cognition in Schizophrenia and Wisconsin Card Sorting Test. Both BD and MDD patients obtained significantly lower domain scores across the entire battery compared to HC. Splitting the sample according to exposure to ACE (high and low), the differences observed in the whole sample persisted only in the subsample of those patients exposed to high ACE. This study confirms that cognitive impairment is present both in MDD and BD, albeit in different degrees of severity, and highlights the importance of early stress as a moderator factor when investigating cognitive functions in mood disorders.

Cognitive dysfunction in major depression and bipolar disorder: Assessment and treatment options.

Cognitive dysfunction is a recognized feature of mood disorders, including major depressive disorder (MDD) and bipolar disorder (BD). Cognitive impairment is associated with poor overall functional outcome and is therefore an important feature of illness to optimize for patients' occupational and academic outcomes. While generally people with BD appear to have a greater degree of cognitive impairment than those with MDD, direct comparisons of both patient groups within a single study are lacking. There are a number of methods for the assessment of cognitive function, but few are currently used in clinical practice. Current symptoms, past course of illness, clinical features, such as the presence of psychosis and comorbid conditions, may all influence cognitive function in mood disorders. Despite the general lack of assessment of cognitive function in clinical practice, clinicians are increasingly targeting cognitive symptoms as part of comprehensive treatment strategies. Novel pharmacological agents may improve cognitive function, but most studies of standard mood stabilizers, such as lithium and the anticonvulsants, have focused on whether or not the medications impair cognition. Non-pharmacological strategies, such as cognitive remediation and exercise, are increasingly studied in patients with mood disorders. Despite the growing interest in strategies to manage cognitive function, there is a paucity of high-quality trials examining either pharmacological or non-pharmacological modes of intervention.

Nitric Oxide and Asymmetrical Dimethylarginine Levels in Acute Mania

Objective: Changes in NO synthesis have been shown in studies regarding NO function in mood disorders, schizophrenia, autism, obsessive compulsive disorder and Alzheimer's disease. The aim of this ...

Striatal structure and function in mood disorders: a comprehensive review

A large and diverse literature has implicated abnormalities of striatal structure and function in both unipolar and bipolar disorder. Recent functional imaging studies have greatly expanded this body of research. The aim of this review is to provide a comprehensive and critical appraisal of the relevant literature. A total of 331 relevant articles were reviewed to develop an integrated overview of striatal function in mood disorders. There is compelling evidence from multiple studies that functional abnormalities of the striatum and greater corticostriatal circuitry exist in at least some forms of affective illness. The literature does not yet provide data to determine whether these aberrations represent primary pathology or they contribute directly to symptom expression. Finally, there is considerable evidence that bipolar disorder may be associated with striatal hyperactivity and some suggestion that unipolar illness may be associated with hypoactivation. Additional research investigating striatal function in affective disorders will be critical to the development of comprehensive models of the neurobiology of these conditions.

A Review of Prospective Studies of Biologic Predictors of Suicidal Behavior in Mood Disorders

Predicting suicide is difficult due to the low base rate, even in high-risk groups, and the multi-causal nature of suicidal behavior. Clinical predictors have shown low specificity. Retrospective and cross-sectional studies have identified a number of biologic anomalies associated with suicide and suicide attempt. Prospective studies provide estimates of the predictive utility of biologic measures. Here we review prospective studies of suicidal behavior and serotonergic, noradrenergic, dopaminergic and hypothalamic-pituitary-adrenocortical axis function in mood disorders. The most promising biologic predictors are low CSF 5-HIAA and HPA axis dysfunction as demonstrated by dexamethasone non-suppression that are each associated with about 4.5 fold greater risk of suicide.

HPA axis function in mood disorders

Mood disorders rank among the leading causes of disability worldwide, and are characterized by biological, emotional, psychological and cognitive symptoms. The monoamine hypothesis of depression fails to provide a comprehensive theory to account for this complex symptomatology, or the therapeutic action of drugs currently available for the treatment of mood disorders. Alternative theories have focused on the function of the hypothalamic–pituitary–adrenal (HPA) axis, and particularly on the deleterious effects of hypercortisolemia on mood, cognition and neuronal architecture. This article reviews the evidence suggesting that HPA axis dysfunction and maladaptive responses to stress may have a central role in the pathophysiology of mood disorders. Recent novel therapeutic strategies that target the HPA axis are also discussed.

Beyond Monoamines: Glutamatergic Function in Mood Disorders

The monoamine theory has implicated abnormalities in serotonin and norepinephrine in the pathophysiology of major depression and bipolar illness and contributed greatly to our understanding of mood disorders and their treatment. Nevertheless, some limitations of this model still exist that require researchers and clinicians to seek further explanation and develop novel interventions that reach beyond the confines of the monoaminergic systems. Recent studies have provided strong evidence that glutamate and other amino acid neurotransmitters are involved in the pathophysiology and treatment of mood disorders. Studies employing in vivo magnetic resonance spectroscopy have revealed altered cortical glutamate levels in depressed subjects. Consistent with a model of excessive glutamate-induced excitation in mood disorders, several antiglutamatergic agents, such as riluzole and lamotrigine, have demonstrated potential antidepressant efficacy. Glial cell abnormalities commonly associated with mood disorders may at least partly account for the impairment in glutamate action since glial cells play a primary role in synaptic glutamate removal. A hypothetical model of altered glutamatergic function in mood disorders is proposed in conjunction with potential antidepressant mechanisms of antiglutamatergic agents. Further studies elucidating the role of the glutamatergic system in the pathophysiology of mood and anxiety disorders and studies exploring the efficacy and mechanism of action of antiglutamatergic agents in these disorders, are likely to provide new targets for the development of novel antidepressant agents.

The effects of an orally administered cholinergic agonist on REM sleep in major depression

Background: Centrally active cholinergic agents such as arecoline and physostigmine shorten rapid eye movement (REM) latency, reduce REM interval times, or both and do so preferentially in patients with depression. We tested an orally administered cholinergic agonist (donepezil HCL 10 mg [Aricept]) to determine whether this agent also alters REM timing in depressed patients (n = 8) compared with age- and gender-matched control subjects (n = 8).Methods: All subjects were studied for 3 consecutive nights in the sleep laboratory. The design was a fixed-order placebo-donepezil protocol to accommodate the long half-life of donepezil. Night 1 served as an adaptation night. On night 2, placebo was administered at 8:00 pm. On night 3, donepezil was administered at 8:00 pm.Results: The cholinergic challenge distinguished the groups. In depressed patients REM latency was reduced compared with baseline (47.6 vs. 64.4, p = .04) following administration of donepezil. Control subjects showed no response: REM latency after donepezil was virtually identical to baseline REM latency (71.7 vs. 69.3).Conclusions: These data indicate that donepezil is likely to be useful in testing hypotheses related to cholinergic function in mood disorders.

GABA function in mood disorders: An update and critical review

Over the past twenty years, several lines of evidence from preclinical and clinical studies has accumulated suggesting that a GABA deficit may be involved in mood disorders, particularly in depression, and that increasing GABAergic neurotransmission may exert an antidepressant effect and perhaps a mood stabilizing effect. Given that GABA has an inhibitory effect on biogenic amine neurotransmitters such as norepinephrine and serotonin and this inhibition may be involved in local circuits and interneurons, it has been suggested that the hypothesis of a GABA deficit in mood disorders does not compete with but complements the well-established hypotheses of alterations in noradrenergic and serotonergic function in mood disorders. In this paper, we systematically reviewed the results from preclinical and clinical studies of GABA function in the pathophysiology of mood disorders and in the mechanism of action of mood stabilizers, antidepressants and electroconvulsive therapy. We also discussed the unifying theory of the neurochemistry of mood disorders, which integrates the GABA hypothesis into the biogenic amine hypotheses, and indicated future directions for research.

S-44-1 - Receptor-coupled G protein function in mood disorders

S-44-1 - Receptor-coupled G protein function in mood disorders