The Role of Stress in the Pathogenesis and Maintenance of Obsessive-Compulsive Disorder

Individuals with obsessive-compulsive disorder often identify psychosocial stress as a factor that exacerbates their symptoms, and many trace the onset of symptoms to a stressful period of life or a discrete traumatic incident. However, the pathophysiological relationship between stress and obsessive-compulsive disorder remains poorly characterized: it is unclear whether trauma or stress is an independent cause of obsessive-compulsive disorder symptoms, a triggering factor that interacts with a preexisting diathesis, or simply a nonspecific factor that can exacerbate obsessive-compulsive disorder along with other aspects of psychiatric symptomatology. Nonetheless, preclinical research has demonstrated that stress has conspicuous effects on corticostriatal and limbic circuitry. Specifically, stress can lead to neuronal atrophy in frontal cortices (particularly the medial prefrontal cortex), the dorsomedial striatum (caudate), and the hippocampus. Stress can also result in neuronal hypertrophy in the dorsolateral striatum (putamen) and amygdala. These neurobiological effects mirror reported neural abnormalities in obsessive-compulsive disorder and may contribute to an imbalance between goal-directed and habitual behavior, an imbalance that is implicated in the pathogenesis and expression of obsessive-compulsive disorder symptomatology. The modulation of corticostriatal and limbic circuits by stress and the resultant imbalance between habit and goal-directed learning and behavior offers a framework for investigating how stress may exacerbate or trigger obsessive-compulsive disorder symptomatology

Lymphotoxin beta-activated LTBR/NIK/RELB axis drives proliferation in cholangiocarcinoma.

BACKGROUND AND AIMS Cholangiocarcinoma (CCA) is an aggressive malignancy arising from the intrahepatic (iCCA) or extrahepatic (eCCA) bile ducts with poor prognosis and limited treatment options. Prior evidence highlighted a significant contribution of the non-canonical NF-κB signalling pathway in initiation and aggressiveness of different tumour types. Lymphotoxin-β (LTβ) stimulates the NF-κB-inducing kinase (NIK), resulting in the activation of the transcription factor RelB. However, the functional contribution of the non-canonical NF-κB signalling pathway via the LTβ/NIK/RelB axis in CCA carcinogenesis and progression has not been established. METHODS Human CCA-derived cell lines and organoids were examined to determine the expression of NF-κB pathway components upon activation or inhibition. Proliferation and cell death were analysed using real-time impedance measurement and flow cytometry. Immunoblot, qRT-PCR, RNA sequencing and in situ hybridization were employed to analyse gene and protein expression. Four in vivo models of iCCA were used to probe the activation and regulation of the non-canonical NF-κB pathway. RESULTS Exposure to LTα1/β2 activates the LTβ/NIK/RelB axis and promotes proliferation in CCA. Inhibition of NIK with the small molecule inhibitor B022 efficiently suppresses RelB expression in patient-derived CCA organoids and nuclear co-translocation of RelB and p52 stimulated by LTα1/β2 in CCA cell lines. In murine CCA, RelB expression is significantly increased and LTβ is the predominant ligand of the non-canonical NF-κB signalling pathway. CONCLUSIONS Our study confirms that the non-canonical NF-κB axis LTβ/NIK/RelB drives cholangiocarcinogenesis and represents a candidate therapeutic target

Association of polymorphisms in HCN4 with mood disorders and obsessive compulsive disorder

Hyperpolarization activated cyclic nucleotide-gated (HCN) potassium channels are implicated in the control of neuronal excitability and are expressed widely in the brain. HCN4 is expressed in brain regions relevant to mood and anxiety disorders including specific thalamic nuclei, the basolateral amygdala, and the midbrain dopamine system. We therefore examined the association of HCN4 with a group of mood and anxiety disorders. We genotyped nine tag SNPs in the HCN4 gene using Sequenom iPLEX Gold technology in 285 Caucasian patients with DSM-IV mood disorders and/or obsessive compulsive disorder and 384 Caucasian controls. HCN4 polymorphisms were analyzed using single marker and haplotype-based association methods. Three SNPs showed nominal association in our population (rs12905211, rs3859014, rs498005). SNP rs12905211 maintained significance after Bonferroni correction, with allele T and haplotype CTC overrepresented in cases. These findings suggest HCN4 as a genetic susceptibility factor for mood and anxiety disorders; however, these results will require replication using a larger sample

Safety, feasibility, tolerability, and clinical effects of repeated psilocybin dosing combined with non-directive support in the treatment of obsessive-compulsive disorder: protocol for a randomized, waitlist-controlled trial with blinded ratings

BackgroundTo date, few randomized controlled trials of psilocybin with non-directive support exist for obsessive-compulsive disorder (OCD). Results and participant feedback from an interim analysis of an ongoing single-dose trial (NCT03356483) converged on the possibility of administering a higher fixed dose and/or more doses of psilocybin in future trials for presumably greater benefits.ObjectivesThis trial aims to evaluate the safety, feasibility, tolerability, and clinical effects of two doses of psilocybin paired with non-directive support in the treatment of OCD. This trial also seeks to examine whether two doses of psilocybin lead to greater OCD symptom reduction than a single dose, and to elucidate psychological mechanisms underlying the effects of psilocybin on OCD.DesignA randomized (1:1), waitlist-controlled design with blinded ratings will be used to examine the effects of two doses of oral psilocybin paired with non-directive support vs. waitlist control on OCD symptoms. An adaptive dose selection strategy will be implemented (i.e., first dose: 25 mg; second dose: 25 or 30 mg).Methods and analysisThis single-site trial will enroll 30 adult participants with treatment-refractory OCD. Aside from safety, feasibility, and tolerability metrics, primary outcomes include OCD symptoms assessed on the Yale-Brown Obsessive-Compulsive Scale – Second Edition (Y-BOCS-II). A blinded independent rater will assess primary outcomes at baseline and the primary endpoint at the end of the second dosing week. Participants will be followed up to 12 months post-second dosing. Participants randomized to waitlist will be rescreened after 7 weeks post-randomization, and begin their delayed treatment phase thereafter if still eligible.EthicsWritten informed consent will be obtained from participants. The institutional review board has approved this trial (protocol v. 1.7; HIC #2000032623).DiscussionThis study seeks to advance our ability to treat refractory OCD, and catalyze future research seeking to optimize the process of psilocybin treatment for OCD through understanding relevant psychological mechanisms.Clinical trial registration: ClinicalTrials.gov, identifier NCT05370911

Yale Program for Psychedelic Science (YPPS) Manual for Psilocybin Combined with Non-Directive Support in the Treatment of OCD

The Yale Program for Psychedelic Science (YPPS) supports a multi-disciplinary research community dedicated to investigating the effects of psychedelic substances on brain function, cognition, and behavior, including their therapeutic potential in treating neuropsychiatric conditions. In support of this mission, YPPS is testing the safety and efficacy of psilocybin, administered in conjunction with non-directive psychological support, as a treatment for certain neurological and psychiatric conditions. The current study, “Effects of repeated dosing of psilocybin on obsessive-compulsive disorder: A randomized, waitlist-controlled study” (NCT05370911), will investigate the effects of repeated dosing of oral psilocybin on obsessive-compulsive disorder (OCD) symptomatology and assess psychological mechanisms that may mediate psilocybin’s therapeutic effects on OCD. The study will employ a randomized, waitlist-controlled design with blinded ratings, with participants randomized to receive either immediate treatment (two doses of oral psilocybin separated by one week) or delayed treatment (7 weeks post-randomization). An adaptive dose selection strategy will be implemented; the first dose will be fixed at 25 mg of psilocybin, and the second dose will be 25 mg or 30 mg, depending on whether or not a clinically significant response is detected after the first dose. This manual provides background and details for facilitator-related activities at various phases – pre-dosing preparation sessions, dosing sessions, and post-dosing integration sessions. The approach for psychological support by facilitators is unstructured and non-directive. In other words, facilitators do not provide any structured therapy, but rather collaborate and support participants as they prepare for psilocybin dosing sessions, ensure their psychological safety during dosing sessions, and provide them with an unstructured, non-directive context in which to process and consolidate their experiences during and after each dosing at defined time points. In doing so, while no structured therapy program is implemented, the presence and accompaniment by facilitators throughout all study sessions in the treatment phase may be experienced as supportive or even therapeutic by participants. This manual shares several features with a previous YPPS protocol-specific session monitor manual for single-dose psilocybin paired with psychological support for OCD (Ching et al., 2022), including the primary focus on a non-directive approach for preparatory, dosing, and integration sessions. Distinctive additions in this manual include a discussion of psychological processes in OCD that serve as a context for responsive facilitation of study visits, as well as updated facilitator checklists for preparatory, dosing, and integration sessions specific to the current two-dose protocol

Yale Program for Psychedelic Science (YPPS) Manual for Psilocybin-OCD Session Monitors for Protocol HIC: 2000020355

The Yale Program for Psychedelic Science (YPPS) is testing the safety and efficacy of psilocybin, administered in conjunction with non-directive psychological support, as a treatment for certain neurological and psychiatric conditions. The study, HIC: 200020355 (Neural correlates of the effects of psilocybin in obsessive-compulsive disorder: A double-blind, placebo-controlled study), will explore the safety and efficacy of a single 0.25 mg/kg dose of psilocybin, administered in a supportive clinical environment, to eligible participants with obsessive-compulsive disorder (OCD). Monitors meet with each participant before, during, and after the dosing session. Monitors do not provide any structured therapy, but rather help participants prepare for the experience of psilocybin dosing, ensure psychological safety during dosing, and provide participants with an unstructured context in which to process their experience during and after dosing at defined timepoints. In doing so, while no structured therapy is provided, the presence and accompaniment by monitors throughout all study sessions may be experienced as supportive or even therapeutic by participants. This manual provides background and details for Monitors on the activities that are required at three points – before, during, and after the dosing session

PTSD: from neurobiology to pharmacological treatments

Posttraumatic stress disorder (PTSD) is a chronic debilitating psychiatric disorder characterized by symptoms of re-experience, avoidance, and hyperarousal that can arise immediately or many years after exposure to a traumatic event and injury. Although extensive research has been done over the past 30 years, the etiology of PTSD remains largely unknown. Several neurobiological systems have been implicated in the pathophysiology and vulnerability for developing PTSD; however, first-line pharmacotherapies are limited. Less than 30% achieve full remission, and even then, approved pharmacological treatments often take weeks for therapeutic effect. This article aims to review the pathophysiology of PTSD within multiple neurobiological systems and how these mechanisms are used as pharmacologic targets of treatment, as well as their potential for future targets of intervention

Table_1_Methylone is a rapid-acting neuroplastogen with less off-target activity than MDMA.XLSX

BackgroundPost-traumatic stress disorder (PTSD) is a highly prevalent psychiatric disorder that can become chronic and debilitating when left untreated. Available pharmacotherapies are limited, take weeks to show modest benefit and remain ineffective for up to 40% of patients. Methylone is currently in clinical development for the treatment of PTSD. Preclinical studies show rapid, robust and long-lasting antidepressant-like and anxiolytic effects. The mechanism of action underlying these effects is not yet fully understood. This study investigated the downstream gene expression changes and signaling pathways affected by methylone in key brain areas linked to PTSD and MDD. It also sought to determine whether neuroplasticity-related genes were involved. We compared effects of methylone with MDMA to explore similarities and differences in their brain effects because MDMA-assisted psychotherapy has recently shown benefit in clinical trials for PTSD and methylone is a structural analog of MDMA.MethodsMonoamine binding, uptake and release studies were performed and a high-throughput-screen evaluated agonist/antagonist activities at 168 GPCRs in vitro. We used RNA sequencing (RNA-seq) to probe drug-induced gene expression changes in the amygdala and frontal cortex, two brain areas responsible for emotional learning that are affected by PTSD and MDD. Rats were treated with methylone or MDMA (both 10 mg/kg, IP), and their responses were compared with controls. We performed functional enrichment analysis to identify which pathways were regulated by methylone and/or MDMA. We confirmed changes in gene expression using immunohistochemistry.ResultsMethylone, a monoamine uptake inhibitor and releaser, demonstrated no off-target effects at 168 GPCRs, unlike MDMA, which showed activity at 5HT2A and 5HT2C receptors. RNA-seq results revealed significant regulation of myelin-related genes in the amygdala, confirmed by immunohistochemistry. In the frontal cortex, methylone significantly upregulated genes implicated in neuroplasticity.ConclusionResults suggest that (1) methylone is a rapid-acting neuroplastogen that affects key brain substrates for PTSD and MDD and that (2) methylone appears to exhibit higher specificity and fewer off-target effects than MDMA. Together, these results are consistent with the reported clinical experiences of methylone and MDMA and bolster the potential use of methylone in the treatment of PTSD and, potentially, other neuropsychiatric disorders.</p