Pathophysiology Of Mood Disorders Research Articles

The Ketogenic Diet as a Treatment for Mood Disorders

Abstract Purpose of Review The ketogenic diet is a low carbohydrate, moderate protein, and high fat diet which results in a metabolic state known as ketosis, in which fats are broken down into ketone bodies. The ketogenic diet is a 100-year-old evidence-based treatment for epilepsy and is gaining popularity as a treatment for various mental disorders, including mood disorders. Our objective is to explain the potential mechanisms through which ketogenic diets may improve the pathophysiology of mood disorders and provide a comprehensive review of recent clinical literature on the topic Recent Findings Mood disorders are associated with several proposed pathophysiological mechanisms, including mitochondrial dysfunction, oxidative stress, inflammation, and insulin resistance. The ketogenic diet shows promise in addressing these underlying pathophysiological mechanisms and emerging clinical data suggest that ketogenic diets may improve symptoms in people with mood disorders. Summary The ketogenic diet shows promise in the treatment of mood disorders. This metabolic intervention has the potential to directly target underlying disease mechanisms, potentially reduce the need for medications, and reduce common side effects and comorbidities, such as weight gain and insulin resistance.

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.

Deciphering the interplay between psychopathological symptoms, sensorimotor, cognitive and global functioning: a transdiagnostic network analysis.

Understanding the relationship between psychopathology and major domains of human neurobehavioral functioning may identify new transdiagnostic treatment targets. However, studies examining the interrelationship between psychopathological symptoms, sensorimotor, cognitive, and global functioning in a transdiagnostic sample are lacking. We hypothesized a close relationship between sensorimotor and cognitive functioning in a transdiagnostic patient sample. We applied network analysis and community detection methods to examine the interplay and centrality [expected influence (EI) and strength] between psychopathological symptoms, sensorimotor, cognitive, and global functioning in a transdiagnostic sample consisting of 174 schizophrenia spectrum (SSD) and 38 mood disorder (MOD) patients. All patients (n = 212) were examined with the Positive and Negative Syndrome Scale (PANSS), the Heidelberg Neurological Soft Signs Scale (NSS), the Global Assessment of Functioning (GAF), and the Brief Cognitive Assessment Tool for Schizophrenia consisted of trail making test B (TMT-B), category fluency (CF) and digit symbol substitution test (DSST). NSS showed closer connections with TMT-B, CF, and DSST than with GAF and PANSS. DSST, PANSS general, and NSS motor coordination scores showed the highest EI. Sensory integration, DSST, and CF showed the highest strength. The close connection between sensorimotor and cognitive impairment as well as the high centrality of sensorimotor symptoms suggests that both domains share aspects of SSD and MOD pathophysiology. But, because the majority of the study population was diagnosed with SSD, the question as to whether sensorimotor symptoms are really a transdiagnostic therapeutic target needs to be examined in future studies including more balanced diagnostic groups.

New Light on Prions: Putative Role of PrPc in Pathophysiology of Mood Disorders.

Mood disorders are highly prevalent and heterogenous mental illnesses with devastating rates of mortality and treatment resistance. The molecular basis of those conditions involves complex interplay between genetic and environmental factors. Currently, there are no objective procedures for diagnosis, prognosis and personalization of patients' treatment. There is an urgent need to search for novel molecular targets for biomarkers in mood disorders. Cellular prion protein (PrPc) is infamous for its potential to convert its insoluble form, leading to neurodegeneration in Creutzfeldt-Jacob disease. Meanwhile, in its physiological state, PrPc presents neuroprotective features and regulates neurotransmission and synaptic plasticity. The aim of this study is to integrate the available knowledge about molecular mechanisms underlying the impact of PrPc on the pathophysiology of mood disorders. Our review indicates an important role of this protein in regulation of cognitive functions, emotions, sleep and biological rhythms, and its deficiency results in depressive-like behavior and cognitive impairment. PrPc plays a neuroprotective role against excitotoxicity, oxidative stress and inflammation, the main pathophysiological events in the course of mood disorders. Research indicates that PrPc may be a promising biomarker of cognitive decline. There is an urgent need of human studies to elucidate its potential utility in clinical practice.

Regional decreases of cortical thickness in major depressive disorder and their correlation with illness duration: a case-control study.

Alterations in brain structure and function in major depressive disorder (MDD) have been identified in a number of studies, but findings regarding cortical thickness were various and inconsistent. Our current study aims to explore the differences in cortical thickness between individuals with MDD and healthy controls (HC) in a Chinese population. We investigated T1-weighted brain magnetic resonance imaging data from 61 participants (31 MDD and 30 HC). The cortical thickness between the two groups and analyzed correlations between cortical thickness and demographic variables in the MDD group for regions with significant between-group differences were conducted. Compared with the HC group, patients with MDD had significantly decreased cortical thickness, in left pars triangularis, left pars orbitalis, left rostral middle frontal gyrus, left supramarginal gyrus, right parahippocampal gyrus, right lingual gyrus, right fusiform and right inferior parietal gyrus. The cortical thickness of left rostral middle frontal gyrus was negatively correlated (r = -0.47, p = 0.028) with the illness duration in patients with MDD. Our study distinguished that cortical thickness decreases in numerous brain regions both in the left and right hemisphere in individuals with MDD, and the negative correlation between the cortical thickness of left rostral middle frontal gyrus illness duration. Our current findings are valuable in providing neural markers to identify MDD and understanding the potential pathophysiology of mood disorders.

Targeting the Renin-Angiotensin System (RAS) for Neuropsychiatric Disorders.

Neuropsychiatric disorders, such as mood disorders, schizophrenia, and Alzheimer's disease (AD) and related dementias, are associated to significant morbidity and mortality worldwide. The pathophysiological mechanisms of neuropsychiatric disorders remain to be fully elucidated, which has hampered the development of effective therapies. The Renin Angiotensin System (RAS) is classically viewed as a key regulator of cardiovascular and renal homeostasis. The discovery that RAS components are expressed in the brain pointed out a potential role for this system in central nervous system (CNS) pathologies. The understanding of RAS involvement in the pathogenesis of neuropsychiatric disorders may contribute to identifying novel therapeutic targets. We aim to report current experimental and clinical evidence on the role of RAS in physiology and pathophysiology of mood disorders, schizophrenia, AD and related dementias. We also aim to discuss bottlenecks and future perspectives that can foster the development of new related therapeutic strategies. The available evidence supports positive therapeutic effects for neuropsychiatric disorders with the inhibition/antagonism of the ACE/Ang II/AT1 receptor axis or the activation of the ACE2/Ang-(1-7)/Mas receptor axis. Most of this evidence comes from pre-clinical studies and clinical studies lag much behind, hampering a potential translation into clinical practice.

Choroid plexus volume is increased in mood disorders and associates with circulating inflammatory cytokines

Depressed patients exhibit altered levels of immune-inflammatory markers both in the peripheral blood and in the cerebrospinal fluid (CSF) and inflammatory processes have been widely implicated in the pathophysiology of mood disorders. The Choroid Plexus (ChP), located at the base of each of the four brain ventricles, regulates the exchange of substances between the blood and CSF and several evidence supported a key role for ChP as a neuro-immunological interface between the brain and circulating immune cells. Given the role of ChP as a regulatory gate between periphery, CSF spaces and the brain, we compared ChP volumes in patients with bipolar disorder (BP) or major depressive disorder (MDD) and healthy controls, exploring their association with history of illness and levels of circulating cytokines. Plasma levels of inflammatory markers and MRI scans were acquired for 73 MDD, 79 BD and 72 age- and sex-matched healthy controls (HC). Patients with either BD or MDD had higher ChP volumes than HC. With increasing age, the bilateral ChP volume was larger in patients, an effect driven by the duration of illness; while only minor effects were observed in HC. Right ChP volumes were proportional to higher levels of circulating cytokines in the clinical groups, including IFN-γ, IL-13 and IL-17. Specific effects in the two diagnostic groups were observed when considering the left ChP, with positive association with IL-1ra, IL-13, IL-17, and CCL3 in BD, and negative associations with IL-2, IL-4, IL-1ra, and IFN-γ in MDD. These results suggest that ChP could represent a reliable and easy-to-assess biomarker to evaluate the brain effects of inflammatory status in mood disorders, contributing to personalized diagnosis and tailored treatment strategies.

Elevated Brain-Derived Neurotrophic Factor Levels During Depressive Mixed States.

Neurotrophin-like brain-derived neurotrophic factor (BDNF) and pro-inflammatory cytokines may modulate the pathophysiology of mood disorders. Although several studies show alterations in these biomarkers during the depressive, manic, and euthymic states of mood disorders, evidence is lacking for those in a mixed state. Therefore, this study aimed to investigate the relationship between the depressive mixed state (DMX) and peripheral neurobiological factors. We enrolled 136 patients with major depressive episodes. Depressive symptoms were assessed using the Quick Inventory of Depressive Symptomatology Self-Report Japanese version (QIDS-SR-J). The severity of DMX was assessed using the self-administered 12-item questionnaire (DMX-12). Categorical screening as DMX-positive (n=54) was determined by a cutoff score of 13 or more in the specific eight symptoms from the DMX-12; the remaining were DMX-negative (n=82). Serum BDNF, tumor necrosis factor-α, highsensitivity C-reactive protein, and interleukin-6 levels were measured. When comparing biomarkers between the DMX-positive and DMX-negative groups, higher serum BDNF concentration in the DMX-positive group than in the DMX-negative group was the only significant finding (p=0.009). A positive correlation existed between the total score of the eight specific symptoms of DMX-12 and the BDNF concentration (r=0.190, p=0.027). After adjustment for confounders, logistic regression analysis revealed that BDNF (odds ratio [OR]=1.07, 95% confidence interval [CI]=1.00-1.14, p=0.045), bipolar diagnosis (OR=3.43, 95% CI=1.36-8.66, p=0.009), and total QIDS-SR-J score (OR=1.29, 95% CI=1.15-1.43, p<0.001) were significantly associated with DMX positivity. BDNF was positively associated with DMX severity, suggesting that higher BDNF concentrations may be involved in the pathophysiology of DMX.

Acute effects of mifepristone on emotional processing related brain activity: A functional MRI study

The Hypothalamic-pituitary-adrenal (HPA) axis plays an important role in the pathophysiology of mood disorders, and preliminary data suggests that glucocorticoid receptor (GR) antagonism may be an important therapeutic mechanism. The effects of modulating HPA axis function on emotional processing related brain activity, which may be abnormal in depressed mood, is poorly understood. This study used a pharmacological functional magnetic resonance imaging (fMRI) design to determine the effects of the GR and progesterone receptor antagonist mifepristone on emotional faces processing task related brain activations in 19 right-handed healthy male participants. Each participant received 600 mg mifepristone or placebo on two separate imaging days and then performed an emotional processing fMRI task four hours later. The effect of mifepristone on task related brain activations was determined using Region-of-Interest (ROI) analyses and an exploratory whole brain voxel-wise analyses. No significant changes were observed in the defined ROIs (amygdala, anterior cingulate cortex, insula) or in the exploratory whole brain analyses that was associated with mifepristone administration in either the angry vs happy faces or angry and happy faces vs implicit baseline contrasts. Task reaction times and accuracy were similar in both mifepristone and placebo conditions (all p > 0.05). Our study failed to show significant evidence of modulation of emotional processing related brain activity associated with acute mifepristone administration. Future research should use fMRI to investigate the longer-term administration effects of mifepristone on mood in healthy participants and people with mood disorders to provide a deeper understanding of the potential effects on depressive symptoms.

Unipolar ve Bipolar Depresif Bozuklukta Bazı Hematolojik Parametrelerin

Background: Major depressive disorder and bipolar disorder, which are the most severe types of mood disorders, are among the diseases that cause the most disability worldwide. One of the biggest challenges in providing early and effective treatment in mood disorders is the inability to make an early differential diagnosis between UD and BD. Many studies have suggested that neuroinflammation may play a role in the pathophysiology of mood disorders. Neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), and monocyte/lymphocyte ratio (MLR) are relatively cheap hematological parameters recommended to measure the level of inflammation. This study aimed to examine the potential role of inflammatory processes in the pathogenesis of unipolar depression(UD) and bipolar depression(BD) by analyzing various hematologic markers, including NLR, PLR, and MLR Materials and Methods: The patient group comprised 54 individuals(UD: 31, BD: 23), while the healthy control(HC) group comprised 40 individuals. The study compared the values of hematologic markers between the groups. Results:The study found significant differences only in the levels of NLR among the analyzed hematologic markers(p=0.004). When the UD and BD groups were compared with HC separately, NLR was significantly higher in both the UD and BD groups compared to the HC group(p=0.002, p=0.015). When UD and BD were compared with each other, there was no significant difference in terms of NLR(P=0,416). Conclusions: In our study, although there was no significant difference between BD and UD in terms of NLR, PLR and MLR, the higher NLR in both patient groups compared to HC suggests the presence of inflammation in both BD and UD patients. More evidence is needed to evaluate it as a disease-specific marker.

Exploring the Relationship between Mood Disorders and Coexisting Health Conditions: The Focus on Nutraceuticals.

Major depressive disorder and bipolar disorder are the leading causes of global disability. Approximately 50% of patients fail to attain remission, prompting a pronounced focus on the significance of dietary patterns and specific nutrients within the pathophysiology of mood disorders. The connection between chronic diseases and mood disorders follows a bidirectional pattern: physical ailments are interrelated with affective disorders, and, concurrently, mood symptoms often precede chronic diseases and have the potential to worsen their prognosis. Nutraceuticals affect factors that could potentially impact the onset of mood disorders: monoamines and brain-derived neurotrophic factor (BDNF) concentrations, neuroinflammation, oxidative stress, and sleep quality. Furthermore, mood disorders rarely manifest in isolation. Typically, such patients concurrently experience other mental disorders or somatic comorbidities: obesity, hypertension, diabetes, polycystic ovary syndrome (PCOS), etc., where providing nutritional support is also pertinent. To optimize the therapeutic approach for individuals with mood disorders, incorporating nutritional support may not solely ameliorate symptoms stemming directly from the mental condition, but also indirectly through interventions targeting comorbidities.

Functional connectivity between the cerebellar vermis and cerebrum distinguishes early treatment response for major depressive episodes in adolescents

BackgroundThe absence of biomarkers for predicting treatment response in adolescent mood disorder calls for further research. The vermis, a component of the cerebellum, is involved in mood disorder pathophysiology and relates to clinical symptoms and treatment outcomes. We investigated vermis functional connectivity (FC) as an early marker for treatment response identification. MethodOne hundred thirty-two adolescents with mood disorders including major depressive disorder or bipolar disorder, were recruited, who were experiencing a major depressive episode. All adolescents underwent baseline and 2-week treatment resting-state MRI scans. Hamilton Rating Scale for Depression (HAMD) assessments were completed to assess the severity of symptoms. Patients were divided into treatment-responsive (≥50 % HAMD reduction, n = 75) and treatment-unresponsive subgroups (n = 57). Vermis FCs were compared between subgroups at baseline. And we compared the pre- and post-treatment FC differences within subgroups. ResultHigher vermis-left temporal lobe FC in treatment-responsive group compared to treatment-unresponsive group at baseline. The FC value showed positive prognosis for the efficacy, with the area under the curve (AUC) of 0.760 (95 % confidence interval: 0.678–0.843, p < 0.001), suggesting higher vermis-temporal FC is benefit to improve treatment-response.Furthermore, post-treatment analysis showed significant increases in the vermis-right frontal lobe FC values between in all patients, suggesting that vermis-frontal FCs were independent of treatment-outcome. LimitationSample size was relatively small, which may limit the generalizability of our results. ConclusionOur study revealed that the FC between the vermis and the cortex is not only associated with symptom alleviation but also predictive of treatment outcomes.

Increased pituitary adenylate cyclase-activating polypeptide in the central bed nucleus of the stria terminalis in mood disorders in men

The mood disorders major depressive disorder (MDD) and bipolar disorder (BD) are highly prevalent worldwide. Women are more vulnerable to these psychopathologies than men. The bed nucleus of the stria terminalis (BNST), the amygdala, and the hypothalamus are the crucial interconnected structures involved in the stress response. In mood disorders, stress systems in the brain are put into a higher gear. The BNST is implicated in mood, anxiety, and depression. The stress-related neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) is highly abundant in the central BNST (cBNST). In this study, we investigated alterations in PACAP in the cBNST of patients with mood disorders. Immunohistochemical (IHC) staining of PACAP and in situ hybridization (ISH) of PACAP mRNA were performed on the cBNST of post-mortem human brain samples. Quantitative IHC revealed elevated PACAP levels in the cBNST in both mood disorders, MDD and BD, but only in men, not in women. The PACAP ISH was negative, indicating that PACAP is not produced in the cBNST. The results support the possibility that PACAP innervation of the cBNST plays a role in mood disorder pathophysiology in men.

Neurocognitive Correlates of Cerebellar Volumetric Alterations in Youth with Pediatric Bipolar Spectrum Disorders and Bipolar Offspring.

Emerging evidence points towards the involvement of the cerebellum in the processing of emotions and pathophysiology of mood disorders. However, cerebellar and related cognitive alterations in youth with pediatric bipolar disorder (PBD) and those at high risk to develop the disorder, such as bipolar offspring (BD-OFF) are not clearly defined. To investigate cerebellar gray and white matter volumes, cognition, and their relationship in youth with PBD and BD-OFF. Thirty youth (7 to 17 years, inclusive) with PBD, 30 BD-OFF and 40 healthy controls (HC) were recruited. Study participants underwent a computer-based cognitive battery assessing affective processing, executive function, attention, psychomotor speed, and learning. Three-tesla MRI scan was performed to assess cerebellar white and gray matter volumes. Cerebellar segmentation was performed with FreeSurfer. Statistical analyses include between-group differences in cognitive domains, cerebellar gray, and white matter volumes. Relationships between cerebellar volumes and cognitive domains were examined. Youth with PBD showed greater cerebellar gray matter volumes than both BD-OFF and HC, whereas no differences were present between BD-OFF and HC. Both youth with PBD and BD-OFF showed altered processing of negative emotions and a bias towards positive emotions. In youth with PBD and BD-OFF, greater impairment in the processing of emotions correlated with greater cerebellar gray matter volumes. The present findings corroborate hypotheses on cerebellar involvement in the processing of emotions and the pathophysiology of PBD. The presence of cerebellar dysfunction in BD-OFF is unclear.

Alterations in pituitary adenylate cyclase-activating polypeptide in major depressive disorder, bipolar disorder, and comorbid depression in Alzheimer's disease in the human hypothalamus and prefrontal cortex.

Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) is involved in the stress response and may play a key role in mood disorders, but no information is available on PACAP for the human brain in relation to mood disorders. PACAP-peptide levels were determined in a major stress-response site, the hypothalamic paraventricular nucleus (PVN), of people with major depressive disorder (MDD), bipolar disorder (BD) and of a unique cohort of Alzheimer's disease (AD) patients with and without depression, all with matched controls. The expression of PACAP-(Adcyap1mRNA) and PACAP-receptors was determined in the MDD and BD patients by qPCR in presumed target sites of PACAP in stress-related disorders, the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC). PACAP cell bodies and/or fibres were localised throughout the hypothalamus with differences between immunocytochemistry and in situ hybridisation. In the controls, PACAP-immunoreactivity-(ir) in the PVN was higher in women than in men. PVN-PACAP-ir was higher in male BD compared to the matched male controls. In all AD patients, the PVN-PACAP-ir was lower compared to the controls, but higher in AD depressed patients compared to those without depression. There was a significant positive correlation between the Cornell depression score and PVN-PACAP-ir in all AD patients combined. In the ACC and DLPFC, alterations in mRNA expression of PACAP and its receptors were associated with mood disorders in a differential way depending on the type of mood disorder, suicide, and psychotic features. The results support the possibility that PACAP plays a role in mood disorder pathophysiology.

Influence of chronic stress on network states governing valence processing: Potential relevance to the risk for psychiatric illnesses.

Stress is a major risk factor for psychiatric illnesses and understanding the mechanisms through which stress disrupts behavioral states is imperative to understanding the underlying pathophysiology of mood disorders. Both chronic stress and early life stress alter valence processing, the process of assigning value to sensory inputs and experiences (positive or negative), which determines subsequent behavior and is essential for emotional processing and ultimately survival. Stress disrupts valence processing in both humans and preclinical models, favoring negative valence processing and impairing positive valence processing. Valence assignment involves neural computations performed in emotional processing hubs, including the amygdala, prefrontal cortex, and ventral hippocampus, which can be influenced by neuroendocrine mediators. Oscillations within and between these regions are critical for the neural computations necessary to perform valence processing functions. Major advances in the field have demonstrated a role for oscillatory states in valence processing under physiological conditions and emerging studies are exploring how these network states are altered under pathophysiological conditions and impacted by neuroendocrine factors. The current review highlights what is currently known regarding the impact of stress and the role of neuroendocrine mediators on network states and valence processing. Further, we propose a model in which chronic stress alters information routing through emotional processing hubs, resulting in a facilitation of negative valence processing and a suppression of positive valence processing.

Single nucleotide polymorphisms in C-reactive protein (CRP) predict response to adjunctive celecoxib treatment of resistant bipolar depression

BackgroundAffective illness has been associated with a proinflammatory state, and it is generally accepted that the immune system plays a key role in the pathophysiology of mood disorders. Since inflammatory biomarkers are elevated in bipolar disorder, anti-inflammatory combination therapies may enhance response and reverse treatment resistance. PurposeIn the present study we investigated the possible impact of single nucleotide polymorphisms (SNPs) within the CRP gene on CRP blood levels, treatment response and level-of-stress perception in our cohort of treatment-resistant bipolar-depressed patients receiving escitalopram and celecoxib, or escitalopram and placebo, as previously reported (Halaris et al., 2020). MethodsStudy design, clinical findings, and CRP blood levels have been reported previously (Halaris et al., 2020; Edberg et al., 2018). In this follow-up study we extracted DNA from blood cells collected at baseline. Genome-wide genotyping was performed for all subjects using the Infinium Multi-Ethnic Global-8 v1.0 Kit. Based on reports in the literature indicating possible associations with psychiatric conditions, ten previously reported CRP gene polymorphisms were evaluated in a preliminary analysis. We focused on rs3093059 and rs3093077 were in complete LD. Carriers were defined as those possessing at least one C allele for rs3093059, or at least one G allele for rs3093077. Additionally, we determined blood levels of the medications administered. ResultsNon-carriers of rs3093059 and rs3093077 had significantly lower baseline CRP blood levels than carriers (p = 0.03). Increased rates of HAM-D17 response (p = 0.21) and remission (p = 0.13) and lower PSS-14 scores (p = 0.13) were observed in non-carriers among subjects receiving celecoxib but they did not reach statistical significance. When examining all subjects, nominally significant associations between carrier-status and remission (p = 0.04) and PSS-14 scores (p = 0.04) were observed after correcting for treatment arm. Non-carriers receiving celecoxib had the highest rates of response and remission, and the lowest stress scores. ConclusionsCarriers of the CRP SNPs may have higher baseline CRP levels, although non-carriers appear to benefit more from celecoxib co-therapy. Determination of the carrier status in conjunction with pretreatment blood CRP level measurement may contribute to personalized psychiatric practice, but replication of the present findings is needed.

Progesterone and Its Metabolites Play a Beneficial Role in Affect Regulation in the Female Brain.

Premenstrual dysphoric disorder is a female affective disorder that is defined by mood symptoms. The condition is linked to unstable progesterone concentrations. Progestin supplementation is given in cases of threatened or recurrent miscarriage and for luteal phase support. Progesterone is essential for implantation, immune tolerance, and modulation of uterine contractility. For a long time, the administration of progestins was associated with an unfavorable impact on mood, leading to negative affect, and, therefore, was contraindicated in existing mood disorders. Establishing the role of the natural progesterone derivative allopregnanolone in advances in the treatment of postpartum depression has shed new light on the general pathophysiology of mood disorders. Allopregnanolone directly interacts with gamma-aminobutyric acid type A (GABA-A) receptors even at nanomolar concentrations and induces significant anti-depressant, anti-stress, sedative, and anxiolytic effects. Postpartum depression is caused by a rapid drop in hormones and can be instantly reversed by the administration of allopregnanolone. Premenstrual dysphoric disorder can also be considered to result from insufficient neuroactive steroid action due to low progesterone derivative concentration, unstable hormone levels, or decreased receptor sensitivity. The decrease in progesterone levels in perimenopause is also associated with affective symptoms and an exacerbation of some psychosomatic syndromes. Bioidentical progesterone supplementation encounters several obstacles, including limited absorption, first-pass effect, and rapid metabolism. Hence, non-bioidentical progestins with better bioavailability were widely applied. The paradoxical, unfavorable effect of progestins on mood can be explained by the fact that progestins suppress ovulation and disturb the endocrine function of the ovary in the luteal phase. Moreover, their distinct chemical structure prevents their metabolism to neuroactive, mood-improving derivatives. A new understanding of progesterone-related mood disorders can translate the study results from case series and observational studies to cohort studies, clinical trials, and novel, effective treatment protocols being developed.

Impaired Endogenous Neurosteroid Signaling Contributes to Behavioral Deficits Associated With Chronic Stress

BackgroundChronic stress is a major risk factor for psychiatric illnesses, including depression. However, the pathophysiological mechanisms whereby stress leads to mood disorders remain unclear. Allopregnanolone acts as a positive allosteric modulator preferentially on δ subunit–containing GABAA (gamma-aminobutyric acid A) receptors. Accumulating clinical and preclinical evidence supports the antidepressant effects of exogenous administration of allopregnanolone analogs; yet, the role of endogenous allopregnanolone in the pathophysiology of depression remains unknown. MethodsWe utilized a chronic unpredictable stress (CUS) mouse model, followed by behavioral and biochemical assays, to examine whether altered neurosteroid signaling contributes to behavioral outcomes following CUS. We subsequently performed in vivo CRISPR (clustered regularly interspaced short palindromic repeats) knockdown of rate-limiting enzymes involved in allopregnanolone synthesis, 5α-reductase type 1 and 2 (5α1/2), in addition to lentiviral overexpression of 5α1/2 in the basolateral amygdala (BLA) of mice that underwent CUS to assess the impact of 5α1/2 on behavioral outcomes. ResultsThe expression of δ subunit–containing GABAA receptors and endogenous levels of allopregnanolone were reduced in the BLA following CUS. Treatment with an exogenous allopregnanolone analog, SGE-516, was sufficient to increase allopregnanolone levels in the BLA following CUS. Knockdown of 5α1/2 in the BLA mimicked the behavioral outcomes associated with CUS. Conversely, overexpression of 5α1/2 in the BLA improved behavioral outcomes following CUS. ConclusionsOur findings demonstrate that chronic stress impairs endogenous neurosteroid signaling in the BLA, which is sufficient to induce behavioral deficits. Further, these studies suggest that allopregnanolone-based treatments may directly target the underlying pathophysiology of mood disorders suggesting that targeting endogenous neurosteroidogenesis may offer a novel therapeutic strategy.

A Scoping Review of Rodent Studies Investigating the Epigenetic Mechanisms in the Brain Underlying the Effects of Diet on Depressive-like Behaviour.

A healthy diet has been highly associated with a decreased risk for mental health problems such as major depression. Evidence from human studies shows that diet can influence mood but there is a poor understanding of the molecular mechanisms behind these effects, especially the role of epigenetic alterations in the brain. Our objective was to use the Preferred Reporting Items for Systematic Reviews and Meta-Analysis extension for Scoping Reviews (PRISMA-ScR) format to gather all recent studies using animal models that investigate direct or indirect (on the offspring) effects of diet on depressive symptoms, including studies that assess epigenetic mechanisms in the brain. In this format, two authors conducted independent database searches of PubMed, Web of Science, and Academic search premier using one search block "diet epigenetics depression" to find papers published between 2000 and 2022. Relevant studies were selected using pre-defined inclusion/exclusion criteria that were performed independently by the two authors before a subset of studies were selected for qualitative analysis. A total of 11 studies met the inclusion criteria for this systematic scoping review. We found that the literature focuses primarily on the effects of individual nutrients, instead of a specific diet, on despair-like behaviour and anxiety. Studies are heterogenous with the techniques used to asses epigenetic changes in the brain and therefore making it hard to reach common mechanistic explanations. However, all studies report diet-induced changes in the epigenome mainly by the action of DNA methylation, histone acetylation and microRNAs that are parallelel with changes in behaviour. Moreover studies show that inadequate maternal diets can make the offspring more susceptible to develop anxiety and depressive-like behaviour later in life, which is paralleled with changes in the epigenome. Overall, this systematic review shows that there is some literature suggesting a role of brain epigenetics on the diet-induced protective or detrimental effects, specifically on anxiety and depressive-like behaviour. However, studies are limited, lacking the study of some types of diets, behavioural tasks or epigenetic mechanisms. Nevertherless, it shows the importance of genome-environment interactions, bringing new insights towards mechanisms that could be involved in the pathophysiology of mood disorders as well as putative therapeutic targets.