Chronic corticosterone exposure in rats induces sex-specific alterations in hypothalamic reelin fragments, MeCP2, and DNMT3a protein levels.

Women are disproportionately affected by stress-related disorders like depression. In our prior research, we discovered that females exhibit lower basal hypothalamic reelin levels, and these levels are differentially influenced by chronic stress induced through repeated corticosterone (CORT) injections. Although epigenetic mechanisms involving DNA methylation and the formation of repressor complexes by DNA methyl-transferases (DNMTs) and Methyl-CpG binding protein 2 (MeCP2) have been recognized as regulators of reelin expression in vitro, there is limited understanding of the impact of stress on the epigenetic regulation of reelin in vivo and whether sex differences exist in these mechanisms. To address these questions, we conducted various biochemical analyses on hypothalamic brain samples obtained from male and female rats previously treated with either 21 days of CORT (40 mg/kg) or vehicle (0.9 % saline) subcutaneous injections. Upon chronic CORT treatment, a reduction in reelin fragment NR2 was noted in males, while the full-length molecule remained unaffected. This decrease paralleled with an elevation in MeCP2 and a reduction in DNMT3a protein levels only in males. Importantly, sex differences in baseline and CORT-induced reelin protein levels were not associated with changes in the methylation status of the Reln promoter. These findings suggest that CORT-induced reelin decreases in the hypothalamus may be a combination of alterations in downstream processes beyond gene transcription. This research brings novel insights into the sexually distinct consequences of chronic stress, an essential aspect to understand, particularly concerning its role in the development of depression.

Time-dependent antidepressant-like effects of reelin and ketamine in the repeated-corticosterone model of chronic stress.

There is an urgent need for novel antidepressants, given that approximately 30% of those diagnosed with depression do not respond adequately to first-line treatment. Additionally, monoaminergic-based antidepressants have a substantial therapeutic time-lag, often taking months to reach full therapeutic effect. Ketamine, an N-methyl-d-aspartate receptor (NMDAR) antagonist is the only current effective rapid-acting antidepressant, demonstrating efficacy within hours and lasting up to two weeks with an acute dose. Reelin, an extracellular matrix glycoprotein, has demonstrated rapid-acting antidepressant-like effects at 24 h, however the exact timescale of these effects has not been investigated. To determine the short and long-term effects of reelin, female Long Evans rats (n = 120) underwent a chronic corticosterone (CORT; or vehicle) paradigm (40 mg/kg, 21 days). On day 21, rats were treated with reelin (3µg; i.v.), ketamine (10 mg/kg; i.p.), both reelin and ketamine (same doses), or vehicle (saline). Behavioural and biological effects were then evaluated at 1 h, 6 h, 12 h, and 1 week after treatment. The 1-week cohort continued CORT injections to ensure the effect of chronic stress was not lost. Individually, both reelin and ketamine significantly rescued CORT-induced behaviour and hippocampal reelin expression at all timepoints. Ketamine rescued a decrease in dendritic maturity as induced by CORT. Synergistic effects of reelin and ketamine appeared at 1-week, suggesting a potential additive effect of the antidepressant-like actions. Taken together, this study provides further support for reelin-based therapeutics to develop rapid-acting antidepressant.

Molecular Mechanisms of Reelin in the Enteric Nervous System and the Microbiota-Gut-Brain Axis: Implications for Depression and Antidepressant Therapy.

Current pharmacological treatments for depression fail to produce adequate remission in a significant proportion of patients. Increasingly, other systems, such as the microbiome-gut-brain axis, are being looked at as putative novel avenues for depression treatment. Dysbiosis and dysregulation along this axis are highly comorbid with the severity of depression symptoms. The endogenous extracellular matrix protein reelin is present in all intestinal layers as well as in myenteric and submucosal ganglia, and its receptors are also present in the gut. Reelin secretion from subepithelial myofibroblasts regulates cellular migration along the crypt-villus axis in the small intestine and colon. Reelin brain expression is downregulated in mood and psychotic disorders, and reelin injections have fast antidepressant-like effects in animal models of depression. This review seeks to discuss the roles of reelin in the gastrointestinal system and propose a putative role for reelin actions in the microbiota-gut-brain axis in the pathogenesis and treatment of depression, primarily reflecting on alterations in gut epithelial cell renewal and in the clustering of serotonin transporters.

The impact of body mass index on the clinical features of bipolar disorder: A STEP-BD study.

INTRODUCTION: The effects of body mass index (BMI) on the core symptoms of bipolar disorder (BD) and its implications for disease trajectory are largely unexplored. OBJECTIVE: To examine whether BMI impacted hospitalization rate, medical and psychiatric comorbidities, and core symptom domains such as depression and suicidality in BD. METHODS: Participants (15 years and older) were 2790 BD outpatients enrolled in the longitudinal STEP-BD study; all met DSM-IV criteria for BD-I, BD-II, cyclothymia, BD NOS, or schizoaffective disorder, bipolar subtype. BMI, demographic information, psychiatric and medical comorbidities, and other clinical variables such as bipolarity index, history of electroconvulsive therapy (ECT), and history of suicide attempts were collected at baseline. Longitudinal changes in Montgomery-Åsberg Depression Rating Scale (MADRS) score, Young Mania Rating Scale (YMRS) score, and hospitalizations during the study were also assessed. Depending on the variable of interest, odds-ratios, regression analyses, factor analyses, and graph analyses were applied. RESULTS: A robust increase in psychiatric and medical comorbidities was observed, particularly for baseline BMIs >35. A significant relationship was noted between higher BMI and history of suicide attempts, and individuals with BMIs >40 had the highest prevalence of suicide attempts. Obese and overweight individuals had a higher bipolarity index (a questionnaire measuring disease severity) and were more likely to have received ECT. Higher BMIs correlated with worsening trajectory of core depression symptoms and with worsening lassitude and inability to feel. CONCLUSIONS: In BD participants, elevated BMI was associated with worsening clinical features, including higher rates of suicidality, comorbidities, and core depression symptoms.

Ketamine in neuropsychiatric disorders: an update.

The discovery of ketamine as a rapid-acting antidepressant led to a new era in the development of neuropsychiatric therapeutics, one characterized by an antidepressant response that occurred within hours or days rather than weeks or months. Considerable clinical research supports the use of-or further research with-subanesthetic-dose ketamine and its (S)-enantiomer esketamine in multiple neuropsychiatric disorders including depression, bipolar disorder, anxiety spectrum disorders, substance use disorders, and eating disorders, as well as for the management of chronic pain. In addition, ketamine often effectively targets symptom domains associated with multiple disorders, such as anxiety, anhedonia, and suicidal ideation. This manuscript: 1) reviews the literature on the pharmacology and hypothesized mechanisms of subanesthetic-dose ketamine in clinical research; 2) describes similarities and differences in the mechanism of action and antidepressant efficacy between racemic ketamine, its (S) and (R) enantiomers, and its hydroxynorketamine (HNK) metabolite; 3) discusses the day-to-day use of ketamine in the clinical setting; 4) provides an overview of ketamine use in other psychiatric disorders and depression-related comorbidities (e.g., suicidal ideation); and 5) provides insights into the mechanisms of ketamine and therapeutic response gleaned from the study of other novel therapeutics and neuroimaging modalities.

Reelin Rescues Behavioral, Electrophysiological, and Molecular Metrics of a Chronic Stress Phenotype in a Similar Manner to Ketamine.

Over the past decade, ketamine, an NMDA receptor antagonist, has demonstrated fast-acting antidepressant effects previously unseen with monoaminergic-based therapeutics. Concerns regarding psychotomimetic effects limit the use of ketamine for certain patient populations. Reelin, an extracellular matrix glycoprotein, has shown promise as a putative fast-acting antidepressant in a model of chronic stress. However, research has not yet demonstrated the changes that occur rapidly after peripheral reelin administration. To address this key gap in knowledge, male Long-Evans rats underwent a chronic corticosterone (CORT; or vehicle) paradigm (40 mg/kg, 21 d). On day 21, rats were then administered an acute dose of ketamine (10 mg/kg, i.p.), reelin (3 µg, i.v.), or vehicle. Twenty-four hours after administration, rats underwent behavioral or in vivo electrophysiological testing before killing. Immunohistochemistry was used to confirm changes in hippocampal reelin immunoreactivity. Lastly, the hippocampus was microdissected from fresh tissue to ascertain whole cell and synaptic-specific changes in protein expression through Western blotting. Chronic corticosterone induced a chronic stress phenotype in the forced swim test and sucrose preference test (SPT). Both reelin and ketamine rescued immobility and swimming, however reelin alone rescued latency to immobility. In vivo electrophysiology revealed decreases in hippocampal long-term potentiation (LTP) after chronic stress which was increased significantly by both ketamine and reelin. Reelin immunoreactivity in the dentate gyrus paralleled the behavioral and electrophysiological findings, but no significant changes were observed in synaptic-level protein expression. This exploratory research supports the putative rapid-acting antidepressant effects of an acute dose of reelin across behavioral, electrophysiological, and molecular measures.

The antidepressant actions of ketamine and its enantiomers.

Ketamine, an N-methyl-d-aspartate receptor (NMDAR) antagonist first developed as an anesthetic, has shown significant promise as a medication with rapid antidepressant properties in treatment-resistant depression. However, concerns such as adverse side effects and potential misuse liability have limited its widespread use. Racemic ketamine has two enantiomers-(S)- and (R)-ketamine-that appear to have disparate underlying mechanisms. This brief review summarizes some of the most recent preclinical and clinical research regarding the convergent and divergent prophylactic, immediate, and sustained antidepressant effects of (S)- and (R)-ketamine while addressing potential differences in their side effect and misuse liability profiles. Preclinical research suggests divergent mechanisms underlying (S)- and (R)-ketamine, with (S)-ketamine more directly affecting mechanistic target of rapamycin complex 1 (mTORC1) signaling and (R)-ketamine more directly affecting extracellular signal-related kinase (ERK) signaling. Clinical research suggests that (R)-ketamine has a milder side effect profile than (S)-ketamine and decreases depression rating scale scores, but recent randomized, controlled trials found that it had no significant antidepressant efficacy compared to placebo, suggesting that caution is warranted in interpreting its therapeutic potential. Future preclinical and clinical research is needed to maximize the efficacy of each enantiomer, either by optimizing dose, route of administration, or administration paradigm.

Intravenous Reelin Treatment Rescues Atrophy of Spleen White Pulp and Correlates to Rescue of Forced Swim Test Immobility and Neurochemical Alterations Induced by Chronic Stress.

Reelin, an extracellular matrix protein with putative antidepressant-like properties, becomes dysregulated by chronic stress. Improvement in cognitive dysfunction and depression-like behavior induced by chronic stress has been reported with both intrahippocampal and intravenous Reelin treatment but the mechanisms responsible are not clear. To determine if treatment with Reelin modifies chronic stress-induced dysfunction in immune organs and whether this relates to behavioral and/or neurochemical outcomes, spleens were collected from both male (n = 62) and female (n = 53) rats treated with daily corticosterone injections for three weeks that received Reelin or vehicle. Reelin was intravenously administered once on the final day of chronic stress, or repeatedly, with weekly treatments throughout chronic stress. Behavior was assessed during the forced swim test and the object-in-place test. Chronic corticosterone caused significant atrophy of the spleen white pulp, but treatment with a single shot of Reelin restored white pulp in both males and females. Repeated Reelin injections also resolved atrophy in females. Correlations were observed between recovery of white pulp atrophy and recovery of behavioral deficits and expression of both Reelin and glutamate receptor 1 in the hippocampus, supporting a role of the peripheral immune system in the recovery of chronic stress-induced behaviors following treatment with Reelin. Our data adds to research indicating Reelin could be a valuable therapeutic target for chronic stress-related disorders including major depression.

Inflammation, stress and depression: An exploration of ketamine's therapeutic profile.

Well-established animal models of depression have described a proximal relationship between stress and central nervous system (CNS) inflammation - a relationship mirrored in the peripheral inflammatory biomarkers of individuals with depression. Evidence also suggests that stress-induced proinflammatory states can contribute to the neurobiology of treatment-resistant depression. Interestingly, ketamine, a rapid-acting antidepressant, can partially exert its therapeutic effects via anti-inflammatory actions on the hypothalamic-pituitary adrenal (HPA) axis, the kynurenine pathway or by cytokine suppression. Further investigations into the relationship between ketamine, inflammation and stress could provide insight into ketamine's unique therapeutic mechanisms and stimulate efforts to develop rapid-acting, anti-inflammatory-based antidepressants.

κ-Opioid Receptor Plasma Levels Are Associated With Sex and Diagnosis of Major Depressive Disorder But Not Response to Ketamine.

BACKGROUND: Preclinical evidence indicates that the κ-opioid receptor (KOR)/dynorphin pathway is implicated in depressive-like behaviors. Ketamine is believed to partly exert its antidepressant effects by modulating the opioid system. This post hoc study examined the following research questions: (1) at baseline, were there differences in KOR or dynorphin plasma levels between individuals with major depressive disorder (MDD) and healthy volunteers (HVs) or between men and women? (2) in individuals with MDD, did KOR or dynorphin baseline plasma levels moderate ketamine's therapeutic effects or adverse effects? and (3) in individuals with MDD, were KOR or dynorphin plasma levels affected after treatment with ketamine compared with placebo? METHODS: Thirty-nine unmedicated individuals with MDD (23 women) and 25 HVs (16 women) received intravenous ketamine (0.5 mg/kg) and placebo in a randomized, crossover, double-blind trial. Blood was obtained from all participants at baseline and at 3 postinfusion time points (230 minutes, day 1, day 3). Linear mixed model regressions were used. RESULTS: At baseline, participants with MDD had lower KOR plasma levels than HVs ( F1,60 = 13.16, P < 0.001), and women (MDD and HVs) had higher KOR plasma levels than men ( F1,60 = 4.98, P = 0.03). Diagnosis and sex had no significant effects on baseline dynorphin levels. Baseline KOR and dynorphin levels did not moderate ketamine's therapeutic or adverse effects. Compared with placebo, ketamine was not associated with postinfusion changes in KOR or dynorphin levels. CONCLUSIONS: In humans, diagnosis of MDD and biological sex are involved with changes in components of the KOR/dynorphin pathway. Neither KOR nor dynorphin levels consistently moderated ketamine's therapeutic effects or adverse effects, nor were levels altered after ketamine infusion. TRIAL REGISTRATION: NCT00088699 ( ClinicalTrials.gov ).

Ketamine and serotonergic psychedelics: An update on the mechanisms and biosignatures underlying rapid-acting antidepressant treatment.

The discovery of ketamine as a rapid-acting antidepressant spurred significant research to understand its underlying mechanisms of action and to identify other novel compounds that may act similarly. Serotonergic psychedelics (SPs) have shown initial promise in treating depression, though the challenge of conducting randomized controlled trials with SPs and the necessity of long-term clinical observation are important limitations. This review summarizes the similarities and differences between the psychoactive effects associated with both ketamine and SPs and the mechanisms of action of these compounds, with a focus on the monoaminergic, glutamatergic, gamma-aminobutyric acid (GABA)-ergic, opioid, and inflammatory systems. Both molecular and neuroimaging aspects are considered. While their main mechanisms of action differ-SPs increase serotonergic signaling while ketamine is a glutamatergic modulator-evidence suggests that the downstream mechanisms of action of both ketamine and SPs include mechanistic target of rapamycin complex 1 (mTORC1) signaling and downstream GABAA receptor activity. The similarities in downstream mechanisms may explain why ketamine, and potentially SPs, exert rapid-acting antidepressant effects. However, research on SPs is still in its infancy compared to the ongoing research that has been conducted with ketamine. For both therapeutics, issues with regulation and proper controls should be addressed before more widespread implementation. This article is part of the Special Issue on "Ketamine and its Metabolites".

Sex differences in basal reelin levels in the paraventricular hypothalamus and in response to chronic stress induced by repeated corticosterone in rats.

Repeated exposure to the stress hormone corticosterone results in depressive-like behaviours paralleled by the downregulation of hippocampal reelin expression. Reelin is expressed in key neural populations involved in the stress response, but whether its hypothalamic expression is sex-specific or involved in sex-specific vulnerability to stress is unknown. Female and male rats were treated with either daily vehicle or corticosterone injections (40 mg/kg) for 21 days. Thereafter, they were subjected to several behavioural tasks before being sacrificed to allow the analysis of reelin expression in hypothalamic nuclei. The basal density of reelin-positive cells in males was significantly higher in the paraventricular nucleus (19 %) and in the medial preoptic area (51 %) compared to females. Chronic corticosterone injections increased the immobility time in the forced swim test in males (107 %) and females (108 %) and decreased the exploration of the elevated plus maze in males (34 %). Corticosterone also caused a significant decrease in the density of reelin-positive cells in males, in both ventrodorsal (37 %) and ventrolateral (32 %) subdivisions of the paraventricular nucleus, while not affecting females. Moreover, in the paraventricular nucleus of males, 30 % of the basal reelin-positive cells co-expressed oxytocin while only 17.5 % did in females, showing a positive correlation between reelin and oxytocin levels. Chronic corticosterone did not significantly affect co-localization levels. For the first time, this study shows that there is a sexually dimorphic subpopulation of reelin-positive neurons in the paraventricular nucleus that can be differentially affected by chronic stress.

Suicide Biomarkers to Predict Risk, Classify Diagnostic Subtypes, and Identify Novel Therapeutic Targets: 5 Years of Promising Research.

BACKGROUND: Suicide is a global health crisis. However, no objective biomarkers of suicide risk currently exist, and self-reported data can be unreliable, which limits prediction, diagnostic, and treatment efforts. Reliable biomarkers that can differentiate between diagnostic subgroups, predict worsening symptoms, or suggest novel therapeutic targets would be extremely valuable for patients, researchers, and clinicians. METHODS: MEDLINE was searched for reports published between 2016 and 2021 using search terms (suicid*) AND (biomarker*) OR (indicat*). Reports that compared biomarkers between suicidal ideation, suicide attempt, death from suicide, or any suicide subgroup against other neuropsychiatric disorders were included. Studies exclusively comparing suicidal behavior or death from suicide with healthy controls were not included to ensure that biomarkers were specific to suicide and not other psychopathology. RESULTS: This review summarizes the last 5 years of research into suicide-associated biomarkers and provides a comprehensive guide for promising and novel biomarkers that encompass varying presentations of suicidal ideation, suicide attempt, and death by suicide. The serotonergic system, inflammation, hypothalamic-pituitary-adrenal axis, lipids, and endocannabinoids emerged as the most promising diagnostic, predictive, and therapeutic indicators. CONCLUSIONS: The utility of diagnostic and predictive biomarkers is evident, particularly for suicide prevention. While larger-scale studies and further in-depth research are required, the last 5 years of research has uncovered essential biomarkers that could ultimately improve predictive strategies, aid diagnostics, and help develop future therapeutic targets.

Positive AMPA receptor modulation in the treatment of neuropsychiatric disorders: A long and winding road.

Glutamatergic transmission is widely implicated in neuropsychiatric disorders, and the discovery that ketamine elicits rapid-acting antidepressant effects by modulating α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) signaling has spurred a resurgence of interest in the field. This review explores agents in various stages of development for neuropsychiatric disorders that positively modulate AMPARs, both directly and indirectly. Despite promising preclinical research, few direct and indirect AMPAR positive modulators have progressed past early clinical development. Challenges such as low potency have created barriers to effective implementation. Nevertheless, the functional complexity of AMPARs sets them apart from other drug targets and allows for specificity in drug discovery. Additional effective treatments for neuropsychiatric disorders that work through positive AMPAR modulation may eventually be developed.

Patient oriented research in mental health: matching laboratory to life and beyond in Canada.

As patient-oriented research gains popularity in clinical research, the lack of patient input in foundational science grows more evident. Research has shown great utility in active partnerships between patient partners and scientists, yet many researchers are still hesitant about listening to the voices of those with lived experience guide and shape their experiments. Mental health has been a leading area for patient movements such as survivor-led research, however the stigma experienced by these patients creates difficulties not present in other health disciplines. The emergence of COVID-19 has also created unique circumstances that need to be addressed. Through this lens, we have taken experiences from our patient partners, students, and primary investigator to create recommendations for the better facilitation of patient-oriented research in foundational science in Canada. With these guidelines, from initial recruitment and leading to sustaining meaningful partnerships, we hope to encourage other researchers that patient-oriented research is necessary for the future of mental health research and foundational science.

Ketamine Rescues Hippocampal Reelin Expression and Synaptic Markers in the Repeated-Corticosterone Chronic Stress Paradigm.

Depression is the leading cause of disability worldwide, which necessitates novel therapeutics and biomarkers to approach treatment of this neuropsychiatric disorder. To assess potential mechanisms underlying the fast-acting antidepressant actions of ketamine we used a repeated corticosterone paradigm in adult male rats to assess the effects of ketamine on reelin-positive cells, a protein largely implicated in the pathophysiology of depression. We also assessed the effects of reelin and ketamine on hippocampal and cerebellar synpatosomes, and on serotonin transporter clustering in peripheral lymphocytes to determine reelin and ketamine's impact at the synaptic and peripheral levels. Reelin and ketamine similarly rescue synaptic expression of mTOR and p-mTOR that were decreased by corticosterone. Reelin, but not ketamine, was able to rescue patterns of serotonin transporter clustering in the periphery. These findings display ketamine as a powerful modulator of reelin expression and lend strength to further evaluation of the putative fast antidepressant-like actions of reelin.