Effect of childhood emotional abuse on depression and anxiety in adulthood is partially mediated by neuroticism: Evidence from a large online sample.

Childhood trauma is widely recognized as a potential risk factor for psychiatric illness in adulthood, yet the precise mechanisms underlying this relationship remain incompletely understood. One proposed mechanism involves the impact of childhood trauma on personality development, particularly in relation to neuroticism, which may subsequently heighten susceptibility to psychiatric disorders. In this study, we aimed to investigate this hypothesis through an online survey involving 1116 participants (232 male, 21 %). Participants completed the Childhood Trauma Questionnaire (CTQ), assessing emotional abuse, physical abuse, sexual abuse, emotional neglect, and physical neglect, along with the Trait Self-Description Inventory (TSDI) for personality assessment and the PHQ-9 and GAD-7 clinical questionnaires for depression and anxiety symptoms evaluation, respectively. Our analyses revealed significant positive correlations between all facets of childhood trauma and neuroticism (all p < .01). Linear regression analysis demonstrated that emotional abuse significantly contributed to neuroticism (ß = 0.267, p < .05), openness (ß = 0.142, p < .05), and agreeableness (ß = 0.089, p < .05), while sexual abuse was associated with agreeableness (ß = 0.137, p < .01) Emotional neglect was negatively correlated with conscientiousness (ß = -0.090, p < .01), extroversion (ß = -0.109, p < .01) and agreeableness (ß = -0.154, p < .01). Furthermore, linear regression analysis revealed that emotional abuse was positively and significantly correlated with PHQ-9 and GAD-7 scores (r = 0.330, p < .01 and r = 0.327, p < .01, respectively). Mediation analysis supported a significant mediating role of neuroticism in the association between childhood emotional abuse and both depression (PHQ-9) (z = 8.681, p < .01) and anxiety (GAD-7) (z = 9.206, p < .01). Notably, the correlation between childhood emotional abuse and psychiatric symptoms was attenuated but not eliminated after controlling for neuroticism, suggesting partial mediation. While our cross-sectional design precludes causal inference, our findings support the notion that childhood emotional abuse may contribute to increased neuroticism, thereby elevating vulnerability to affective disorders in adulthood. These results underscore the importance of considering personality factors in understanding the long-term consequences of childhood trauma on mental health outcomes.

Early life stress unravels epistatic genetic associations of cortisol pathway genes with depression.

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis represents one of the most consistent pathophysiological findings in depressive disorders. Cortisol signaling is affected by proteins that mediate its cellular responses or alters its availability to mineralocorticoid and glucocorticoid receptors. In our study, we evaluated candidate genes that may influence the risk for depression and suicide due to its involvement in cortisol signaling. The aim of the study was to assess whether the genotypes of these genes are associated with the risk for depression, severity of depressive symptoms, suicidal ideation, and suicide attempts. And whether there is interaction between genes and early-life stress. In this study, 100 healthy controls and 140 individuals with depression were included. The subjects were clinically assessed using the 21-item GRID-Hamilton questionnaires (GRID-HAMD-21), Beck Scale for Suicidal Ideation (BSI), and the Childhood Trauma Questionnaire (CTQ). A robust multifactorial dimensionality reduction analysis was used to characterize the interactions between the genes HSD11B1, NR3C1, NR3C2, and MDR1 and early-life stress. It was found a significant association of the heterozygous genotype of the MDR1 gene rs1128503 polymorphism with reduced risk of at least one suicide attempt (OR: 0.08, p = 0.003*) and a reduction in the number of suicide attempts (ß = -0.79, p = 0.006*). Furthermore, it was found that the MDR1 rs1228503 and NR3C2 rs2070951 genes interact with early-life stress resulting in a strong association with depression (p = 0.001). Our findings suggest that polymorphisms in the MDR1 and NR3C2 genes and their interaction with childhood trauma may be important biomarkers for depression and suicidal behaviors.

Ketamine cystitis following ketamine therapy for treatment-resistant depression - case report.

BACKGROUND: Ketamine is a novel and exciting putative antidepressant medication for patients with treatment-resistant depression. A complication commonly seen in frequent and heavy recreational use of ketamine is ulcerative cystitis, which presents with lower urinary tract symptoms (LUTS) and upper renal tract damage and can be seen in over 25% of regular users. Although Ketamine-induced cystitis (KIC) is a recognised complication in recreational use of ketamine, its occurrence in therapeutic use of ketamine in depression has so far not been reported. The exact pathogenesis of KIC is currently unknown, making treatment and prevention advice much more difficult. Early diagnosis of KIC and immediate cessation of ketamine has been shown to improve adverse urinary tract symptoms and prevent further damage. CASE PRESENTATION: We present a case of a 28-year-old female who was started on ketamine treatment for depression, and who then developed symptoms of KIC, which was confirmed by urine microscopy, culture and analysis. CONCLUSIONS: To our knowledge, this is the first reported case of KIC in a patient receiving treatment-dose ketamine as part of their antidepressant therapy.

Biological rhythms are correlated with Na+, K+-ATPase and oxidative stress biomarkers: A translational study on bipolar disorder.

BACKGROUND: Bipolar disorder (BD) is a chronic, severe, and multifactorial psychiatric disorder. Although biological rhythms alterations, sodium potassium pump (Na+, K+-ATPase) changes, and oxidative stress appear to play a critical role in the etiology and pathophysiology of BD, the inter-connection between them has not been described. Therefore this study evaluated the association between biological rhythms, Na+, K+-ATPase, and oxidative stress parameters in BD patients and the preclinical paradoxical sleep deprivation model (PSD). METHODS: A translational study was conducted, including a case-control protocol with 36 BD and 46 healthy controls (HC). Subjects completed the Biological Rhythm Interview of Assessment in Neuropsychiatry (BRIAN). In addition, Erythrocyte Na+, K+-ATPase activity, and oxidative and nitrosative stress markers were assessed (4-hydroxynonenal [4-HNE], 8-isoprostane [8-ISO], thiobarbituric acid reactive substances [TBARS], carbonyl, 3-nitrotyrosine [3-nitro]). In the preclinical protocol, the same biomarkers were evaluated in the frontal cortex, hippocampus, and striatum from mice submitted to the PSD. RESULTS: BD patients had a significantly higher total score of BRIAN versus HCs. Additionally, individuals with BD showed decreased Na+, K+-ATPase activity and increased oxidative stress parameters compared to HC without psychiatric disorders. This difference was driven by actively depressed BD subjects. The mice submitted to the PSD also demonstrated decreased Na+, K+-ATPase activity and increased oxidative stress parameters. LIMITATIONS: BRIAN biological underpinning is less well characterized; We did not control for medication status; Sample size is limited; PSD it is not a true model of BD. CONCLUSIONS: The present study found a significant correlation between Na+, K+-ATPase and oxidative stress with changes in biological rhythms, reinforcing the importance of these parameters to BD.

Early life stress, depression and epigenetics.

Different factors are essential in increasing the vulnerability to psychiatric disorders, such as genetics. Among these factors, early life stress (ELS), including sexual, physical, emotional abuse, and emotional and physical neglect, enhances the odds of having menial conditions throughout life. Exhaustive research has shown that ELS leads to physiological changes, such as alteration in the HPA axis. During the most critical development period (childhood and adolescence), these changes increase the risk of having child-onset psychiatric disorders. Furthermore, research has suggested a relationship between early life stress and depression, particularly more prolonged episodes of depression with treatment-resistant outcomes. Molecular studies indicate that, in general, the hereditary character of psychiatric disorders is polygenic, multifactorial and highly complex, with innumerable low-effect genetic variants interacting with each other. However, whether there are independent effects among subtypes of ELS remains unclear. This article provides an overview of the interplay of epigenetics, the HPA axis, early life stress and the development of depression. Advances in our knowledge of epigenetics in the context of early life stress and depression provide a new understanding of the genetic influence on psychopathology. Furthermore, they could lead to identifying new targets for clinical intervention.

Early Clinical Experiences of Esketamine Nasal Spray in the UK in Adults with Treatment-Resistant Major Depressive Disorder: Advisory Panel Recommendations.

Purpose: Treatment-resistant depression (TRD) is associated with profound morbidity for patients, placing a significant burden on those affected, the health service and wider society. Despite this, TRD remains chronically underserved in terms of viable treatment options. To address this gap, an advisory panel of psychiatrists and clinical researchers with experience in managing TRD convened to develop best practice statements on the use of esketamine nasal spray, one of the first TRD treatments to be licensed in 30 years. Methods: During a virtual meeting held on 12th November 2020, the advisory panel shared their experiences of using esketamine nasal spray in their clinical practice. The meeting focused on developing and refining recommendations for setting up and running an efficient esketamine nasal spray clinic for patients living with TRD. At the conclusion of the meeting, agreement was reached on all recommendation statements. Results: In setting up an esketamine nasal spray clinic, it is important to consider the logistical requirements involved and put measures in place to ensure it runs as efficiently as possible. Educating patients about the treatment and maintaining their well-being is paramount for preventing discontinuation. Putting in place checklists can be a useful strategy for ensuring treatment appointments run smoothly and safely. Conclusion: Providing additional treatment options for the management of TRD, such as esketamine nasal spray, is likely to be key to improving the long-term outcomes of this underserved patient population.

Identifying the neuropsychiatric health effects of low-dose lithium interventions: A systematic review.

BACKGROUND: Lithium is widely evidenced for its neuropsychiatric benefits. Advantages of 'sub-therapeutic' doses are increasingly being reported, which is apposite given enduring concerns around adverse effects of 'therapeutic' doses. We aimed to synthesise all available evidence from interventional studies investigating low-dose lithium (LDL) across neuropsychiatric outcomes. METHODS: Electronic databases were systematically searched to include studies where a group of adult humans were treated with LDL (∼serum level ≤0.6 mmol/L), where data describing a neuropsychiatric outcome were reported either before and after treatment, and/or between lithium and a comparator. RESULTS: 18 articles were examined and grouped according to outcome domain (cognition, depression, mania, and related constructs e.g., suicidality). Significant benefits (versus placebo) were identified for attenuating cognitive decline, and potentially as an adjunctive therapy for people with depression/mania. Across studies, LDL was reported to be safe. CONCLUSIONS: Despite the paucity and heterogeneity of studies, LDL's apparent pro-cognitive effects and positive safety profile open promising avenues in the fields of neurodegeneration, and augmentation in affective disorders. We urge future examinations of LDL's potential to prevent cognitive/affective syndromes.

Increased immuno-inflammatory mediators in women with post-traumatic stress disorder after sexual assault: 1-Year follow-up.

BACKGROUND: Sexual violence is a traumatic event that can trigger post-traumatic stress disorder (PTSD) and generate biological responses to stress characterized by inhibiting the hypothalamic-pituitary axis (HPA), altering immune activity, and changing the structure and function of the brain. PTSD is associated with increased levels of inflammatory markers. This study aimed to measure differences in inflammatory markers and HPA hormone levels between women with PTSD due to sexual violence and controls at baseline and after 1-year follow-up. METHODS: Fifty-eight women with PTSD resulting from sexual assault occurring up to 6 months prior were compared to 41 female controls. The patients were followed for 1 year. At baseline (T1), we measured inflammatory biomarkers. We also applied the Mini International Neuropsychiatric Interview (MINI), the Clinician-Administered Post-Traumatic Stress Disorder Scale-5, the Beck Depression Inventory, the Beck Anxiety Inventory, and the Childhood Trauma Questionnaire. The patients were randomized to receive treatment with sertraline or interpersonal psychotherapy for 14 weeks (T2) and then continued the usual treatment if deemed necessary for 1 year. The same interviews and examinations were repeated after 1 year (T3). RESULTS: At baseline, the patients had significantly higher adrenocorticotropic hormone levels, compared to controls; however, there was no baseline difference in inflammatory markers or cortisol. After 1 year, there were significantly higher levels of interleukin-1ß (p < 0.0001), monocyte chemoattractant protein-1 (p < 0.0001), tumor necrosis factor-α (p < 0.0001), c-reactive protein (p < 0.0001), and cortisol (p = 0.046) in the patient group. In addition to PTSD, 56 patients presented with a major depressive episode at T1 (according to the MINI). At the end of 1 year, there was a significant improvement in depressive (p < 0.001), anxiety (p = 0.03), and PTSD symptoms (p < 0.001) regardless of the treatment received. DISCUSSION: The increase of the inflammatory markers after 1 year, even with symptomatic improvement, may indicate that PTSD following sexual violence is associated with high depressive symptoms. This association may have a different pattern of immunoendocrine alterations than PTSD only. Furthermore, these alterations may persist in the long term, even with the improvement of the symptoms, probably generating an immunological imprint that can lead to future clinical consequences. This study adds to the current knowledge of PTSD neurobiology and contributes to broadening approaches to this disorder.

Reply to Skokou, M. Comment on "Keeler et al. Ketamine as a Treatment for Anorexia Nervosa: A Narrative Review. Nutrients 2021, 13, 4158".

In response to our narrative review, which suggested the use of the glutamatergic n-methyl-D-aspartate (NMDA) receptor antagonist ketamine as a potential treatment for anorexia nervosa (AN) [...].

Predictive value of cardiometabolic biomarkers and depressive symptoms for symptom severity and quality of life in patients with psychotic disorders.

BACKGROUND: Patients with psychotic disorders show higher rates of the metabolic syndrome (MS) between the cluster of severe mental illnesses. Depressive symptoms can worsen outcomes of individuals with psychotic disorders. However, research on the association between MS and depression in psychotic disorders and their relevance to outcomes is lacking. METHODS: We investigated the association between depression and cardiometabolic biomarkers in psychotic disorders and the predictive value of depressive symptoms on psychopathological severity and quality of life (QoL). 406 patients with psychotic disorders were recruited as part of the Improving Physical Health and Reducing Substance Use in Severe Mental Illness randomised controlled trial. Depression, psychotic symptoms, QoL, waist circumference, triglycerides, high-density lipoprotein cholesterol (HDL-C), blood pressure, and fasting glucose of patients were assessed at baseline and 12 months. Sensitivity analyses were conducted to test the effect of treatment. RESULTS: More severe baseline symptoms of depression significantly predicted worse 12-month psychotic symptoms and lower mental health related QoL at 12 months. These associations held after controlling for alcohol use, gender, ethnicity, education, and mental health related QoL Baseline. Depressive symptoms also correlated with waist circumference at both baseline and 12 months, after controlling for multiple testing. CONCLUSION: Individuals with psychotic disorders experiencing more severe depressive symptoms are more likely to have larger waist circumference contemporaneously and 12 months later, as well as more severe psychotic symptoms and worse QoL at follow-up. This highlights the need for evaluation of strategies to address depression in the management of psychotic disorders.

Ketamine as a Treatment for Anorexia Nervosa: A Narrative Review.

Anorexia nervosa (AN) is a highly complex disorder to treat, especially in severe and enduring cases. Whilst the precise aetiology of the disorder is uncertain, malnutrition and weight loss can contribute to reductions in grey and white matter of the brain, impairments in neuroplasticity and neurogenesis and difficulties with cognitive flexibility, memory and learning. Depression is highly comorbid in AN and may be a barrier to recovery. However, traditional antidepressants are often ineffective in alleviating depressive symptoms in underweight patients with AN. There is an urgent need for new treatment approaches for AN. This review gives a conceptual overview for the treatment of AN with ketamine. Ketamine has rapid antidepressant effects, which are hypothesised to occur via increases in glutamate, with sequelae including increased neuroplasticity, neurogenesis and synaptogenesis. This article provides an overview of the use of ketamine for common psychiatric comorbidities of AN and discusses particular safety concerns and side effects. Potential avenues for future research and specific methodological considerations are explored. Overall, there appears to be ample theoretical background, via several potential mechanisms, that warrant the exploration of ketamine as a treatment for adults with AN.

Hypothalamic-Pituitary-Adrenal axis dysfunction by early life stress.

Evidence indicates that early life stress (ELS) may act as a risk factor for the development and maintenance of adulthood severe mental health disorders due to persistent dysregulation within the hypothalamic-pituitary-adrenal (HPA) axis. It is now broadly accepted that psychological stress may change the internal homeostatic state of an individual. The dysregulation seems to be a byproduct of changes noted in the HPA axis hormone's ability to bind to the glucocorticoid and mineralocorticoid receptors, crucial in maintaining homeostasis. Whenever there is an acute interruption of this balance, illness may result. The social and physical environments have an enormous impact on our physiology and behavior, and they influence the process of adaptation or 'allostasis'. The HPA axis response to stress can be thought of as a mirror of the organism's response to stress: acute responses are generally adaptive, but excessive or prolonged responses can lead to deleterious effects. Evidence indicates that early-life stress can induce persistent changes in the ability of the HPA axis to respond to stress in adulthood This review aims to examine and summarise the existing literature exploring the relationship between ELS with regards specifically to HPA axis functioning. The maintenance of the internal homeostatic state of an individual is proposed to be based on the ability of circulating glucocorticoids to exert negative feedback on the secretion of HPA hormones through binding to mineralocorticoid (MR) and glucocorticoid (GR) receptors limiting the vulnerability to diseases related to psychological stress in genetically predisposed individuals.

Posttraumatic stress disorder (PTSD) and depression severity in sexually assaulted women: hypothalamic-pituitary-adrenal (HPA) axis alterations.

BACKGROUND: Sexual assault is implicated in several adverse psychological and physical health outcomes, including posttraumatic stress disorder (PTSD) and depression. Neurobiological research has shown variations related to the hypothalamic-pituitary-adrenal (HPA) axis, immune alterations, metabolic function, and brain circuitry. Although these mechanisms have been extensively studied, the results have demonstrated different outcomes in PTSD. METHODS: We compared the plasma adrenocorticotropin (ACTH) and salivary cortisol levels of fifty-eight women with PTSD developed after sexual assault to those of forty-four female controls with no history of trauma. We also evaluated the psychiatric diagnosis and symptom severity of PTSD and depression. The participants' clinical conditions were associated with their hormonal levels to assess whether symptom severity was related to hormonal imbalance. RESULTS: A large percentage of sexually assaulted women had PTSD and comorbid depression. The ACTH levels were higher in the PTSD group than the control group and increased as PTSD severity increased, considering depressive symptoms, measured by the Beck Depression Inventory (BDI) (p < 0.0001), as well as PTSD symptoms, measured by subscale D of the Clinician-Administered PTSD Scale (CAPS-5) (p = 0.045) and the CAPS-5 total scale (p = 0.026). Cortisol levels measured at 10 pm were higher for the PTSD group than the control group (p = 0.045, p = 0.037, respectively), and the cortisol awakening response showed elevated cortisol levels for the PTSD group. CONCLUSIONS: These results show a correlation between symptom severity and HPA axis imbalance in patients with PTSD. Elevated ACTH and an elevated cortisol response in patients with comorbid depressive symptoms were the opposite of the expected response for patients with PTSD only. This association leads to the hypothesis that the neurobiological alterations of PTSD are related to the type of symptoms presented and their severity. These manifestations likely influence the disease course, prognosis and response to treatment. These outcomes highlight the need to discuss particular neurobiological alterations in patients with PTSD developed after sexual assault, mainly those with severe depressive symptoms.

New Pharmacological Interventions in Bipolar Disorder.

The biological bases of bipolar disorder include aspects related, among others, to neurohormonal pathways, neurotransmission, signal transduction, regulation of gene expression, oxidative stress, neuroplasticity, and changes in the immune system. There is still a gap in understanding its complex neurobiology and, consequently, developing new treatments. Multiple factors probably interact in this complex equation of pathophysiology of bipolar disorder, such as genetic, biochemical, psychosocial, and environmental stress events, correlating with the development and severity of the bipolar disorder. These mechanisms can interact to exacerbate inflammation, impair neurogenesis, and increase oxidative stress damage, cellular mitochondrial dysfunction, changes in neurotrophins and in epigenetic mechanisms, neuroendocrine dysfunction, activation of neuronal death pathways, and dysfunction in neurotransmission systems. In this review, we explore the up-to-date knowledge of the neurobiological underpinnings of bipolar disorders. The difficulty in developing new drugs for bipolar disorder is very much associated with the lack of knowledge about the precise pathophysiology of this disorder. Pharmacological treatment for bipolar patients is vital; to progress to effective medications, it is essential to understand the neurobiology in bipolar patients better and identify novel therapeutic targets.

Neuroendocrine Stress System in Bipolar Disorder.

Hormones have a crucial part in the progress and manifestation of a wide variety of different behaviors. The main influence of the neuroendocrine system on behavior is its action on the neurobiology of neuropsychiatric disorders and its relationship with the pharmacodynamics of medicines. Of all the neuroendocrine axes, the hypothalamic-pituitary-adrenal (HPA) axis has been the most extensively studied. There is evidence that disturbance in the HPA axis, the primary stress hormone system, could increase treatment resistance and relapse, worsen illness outcome, and cause cognitive deficits. Glucocorticoids mediate their actions in negative feedback binding in two different cytoplasmatic receptors described as mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs). Different psychopathologies underlying bipolar disorders are supposed to involve persistent dysfunctions in the expression and role of both MR and GR in the hippocampus. We review and analyze the evidence related to the correlation between bipolar disorders and the consequences and impact of stressful life events on the HPA axis, exploring the importance of these findings in bipolar disorders and as potential new targets for treatment.

The Neurobiology of Bipolar Disorder.

Bipolar disorders are severe and have a high prevalence; despite this, the neurobiological mechanisms are far from being elucidated, and this limits the development of new treatments. Although the aetiology of bipolar disorders is not yet fully understood, it is accepted that the disorder(s) may result from the interaction between genetic factors that cause susceptibility and predisposing, precipitating and perpetuating environmental factors, such as stress and traumatic events. A pathophysiological formulation of the disease suggests that dysfunctions in intracellular biochemical cascades, oxidative stress and mitochondrial dysfunction impair the processes linked to neuronal plasticity, leading to cell damage and the consequent loss of brain tissue that has been identified in post-mortem and neuroimaging studies. The data we have reviewed suggests that peripheral biomarkers related to hormones, inflammation, oxidative stress and neurotrophins are altered in bipolar disorders, especially during acute mood episodes. Together, these changes have been associated with a systemic toxicity of the disease and the damage resulting from multiple episodes. Systemic toxicity related to recurrent episodes in bipolar disorder may influence brain anatomical changes associated with the progression of stress and neuroplasticity in bipolar disorder and the response to treatment.

Epigenetics: A missing link between early life stress and depression.

Research has suggested a relationship between early life stress, and depression in particular longer episodes of depression with treatment resistant outcomes. However, the underlying mechanisms for this association remain poorly understood. Molecular studies indicate that, in general, the hereditary character of psychiatric disorders are polygenic, multifactorial and highly complex, with innumerable low-effect genetic variants interacting with each other. In addition, the importance of the environment and its interaction with genes has pointed to a fundamental role of epigenetic mechanisms in psychiatric disorders, such as methylation of deoxyribonucleic acid (DNA), alterations, histone actions and regulation of gene expression by non-coding ribonucleic acids (RNAs). This article provides an overview of the interplay of epigenetics, the HPA axis, early life stress and the development of depression. Advances in our knowledge of epigenetics in the context of early life stress and depression provide a new understanding of the genetic influence on psychopathology and could lead to the identification of new targets for clinical intervention.

The pharmacological interaction of compounds in ayahuasca: a systematic review

Ayahuasca is a South American psychoactive plant brew used as traditional medicine in spiritual and in cultural rituals. This is a review of the current understanding about the pharmacological mechanisms that may be interacting in ayahuasca. Searches were performed using PubMed, PsycINFO, and Web of Science databases and 16 papers were selected. As hypothesized, the primary narrative in existing research revolved around prevention of deamination of N,N-dimethyltryptamine (N,N-DMT, also referred to as DMT) by monoamine oxidase inhibitors (MAOIs) in ayahuasca. Two of the constituents, DMT and harmine, have been studied more than the secondary harmala alkaloids. At present, it is unclear whether the pharmacological interactions in ayahuasca act synergistically or additively to produce psychoactive drug effects. The included studies suggest that our current understanding of the preparation's synergistic mechanisms is limited and that more complex processes may be involved; there is not yet enough data to determine any potential synergistic interaction between the known compounds in ayahuasca. Our pharmacological understanding of its compounds must be increased to avoid the potential risks of ayahuasca use.