Neurolief’s Post

Muscarinic Receptors in the Treatment of CNS Disorders Muscarinic acetylcholine receptors (mAChRs) have rekindled interest as potential therapeutic targets in psychiatry and neurodegenerative disorders. These G protein-coupled receptors (GPCRs) are widely expressed throughout the central nervous system (CNS) and modulate diverse neuronal functions, including memory and cognition. Intriguing Preclinical and Clinical Data: mAChR dysfunction has been implicated in the pathophysiology of schizophrenia. Preclinical studies suggest that mAChR agonists may normalize glutamatergic and dopaminergic neurotransmission, potentially mitigating core symptoms. Initial clinical trials with selective mAChR agonists have demonstrated promising efficacy and tolerability profiles in patients with schizophrenia. Mitigating Dopamine Dysregulation: While current antipsychotics primarily target the dopaminergic system, mAChRs offer a distinct mechanism of action. This opens the possibility for a more comprehensive therapeutic approach in schizophrenia treatment. Cognitive Enhancement Potential and Alzheimer's Disease: mAChR agonists may also improve cognitive function, a significant unmet need in schizophrenia and other CNS disorders, particularly Alzheimer's disease (AD). In AD, cholinergic neuron loss and subsequent ACh deficiency are well-established hallmarks of the disease. mAChR agonists have the potential to compensate for this deficit and improve memory and cognitive function in AD patients. The Future of mAChRs in CNS Disorders: While further research is necessary to elucidate optimal mAChR targeting strategies, the current data paint a promising picture. mAChR agonists may represent a novel class of medications for the treatment of schizophrenia, Alzheimer's disease, and potentially other CNS disorders with cognitive dysfunction. #muscarinicreceptors #schizophrenia #CNS #neuropsychopharmacology #GPCRs #Alzheimers

OBSESSIVE-COMPULSIVE DISORDER (OCD) ➡ The greatest overlooked unmet need in Psychiatry? Next-line OCD therapy is one of the largest commercial opportunities in Psychiatry, with the least competition - and a space Evecxia’s Phase 2-ready drug candidate EVX-101 could own. BACKGROUND: At any time, Obsessive-Compulsive Disorder (OCD) affects 1.2 % of the population (NIH). Obsessions and compulsions dominate the patient’s life, often causing distress and impairment of similar magnitude to Schizophrenia (Hirschtritt 2017). Two-thirds of OCD patients are substantially disabled. OCD is chronic and requires long-term treatment (Stein 2019). SSRIs are first-line in OCD, but 50% responds inadequately (Hirschtritt 2017). There are no FDA-approved next-line drugs for OCD. No new OCD drugs have been FDA-approved since the SSRIs in the 1990s. Roche and Novartis pursued next-line OCD drugs, but failed. Only Biohaven has a current OCD program. RATIONALE FOR EVX-101: OCD symptoms are uniquely responsive to serotonin. Elevating brain serotonin activity beyond the effect of standard SSRI doses augment clinical efficacy (Hirschtritt 2017; Rasmussen 1984). Thus, adjunctive EVX-101 could augment efficacy in OCD patients responding inadequately to SSRI therapy and become the first FDA-approved next-line OCD drug. PHASE 2 RISK-MITIGATION : In addition to the clinical basis for EVX-101, OCD trials are risk-mitigated due to 60% lower placebo response than in depression trials (Bschor 2024). References 1. Hirschtritt ME, et al. (2017): Jama. 317:1358-1367. 2. Stein DJ, et al. (2019): Nat Rev Dis Primers. 5:52. 3. Rasmussen SA (1984): Am J Psychiatry. 141:1283-1285. 4. Bschor T, et al. (2024): JAMA psychiatry.

This paper, from a team pioneering the thoughtful use of biomarkers in psychiatric drug development, outlines the potential for imaging-based data to de-risk specific critical points in the process. They make the strong case for committing to prospective, rather than retrospective, biomarker development, as the path forward towards meaningful precision psychiatry. https://lnkd.in/eDr5Z83K

HOPE Therapeutics plans to acquire Kadima Neuropsychiatry Institute The move aligns with the previously signed letter of intent for expanding the HOPE network. https://lnkd.in/e_-Be4Ck

HOPE Therapeutics plans to acquire Kadima Neuropsychiatry Institute The move aligns with the previously signed letter of intent for expanding the HOPE network. https://lnkd.in/e_-Be4Ck

𝗖𝗼𝗺𝗯𝗶𝗻𝗲𝗱 𝗡𝗲𝘂𝗿𝗼𝗺𝗼𝗱𝘂𝗹𝗮𝘁𝗶𝗼𝗻 (𝘁𝗗𝗖𝗦 + 𝗿𝗧𝗠𝗦) 𝗢𝗳𝗳𝗲𝗿𝘀 𝗥𝗮𝗽𝗶𝗱 𝗥𝗲𝗹𝗶𝗲𝗳 𝗳𝗼𝗿 𝗠𝗮𝗷𝗼𝗿 𝗗𝗲𝗽𝗿𝗲𝘀𝘀𝗶𝘃𝗲 𝗗𝗶𝘀𝗼𝗿𝗱𝗲𝗿 A recent double-blind, sham-controlled randomized clinical trial, published in 𝗝𝗔𝗠𝗔 𝗣𝘀𝘆𝗰𝗵𝗶𝗮𝘁𝗿𝘆 (November 15, 2024), investigated the efficacy of combining repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) for treating major depressive disorder (MDD), revealing significant clinical benefits within 𝗷𝘂𝘀𝘁 𝟮 𝘄𝗲𝗲𝗸𝘀 of treatment. Key Findings: Patients treated with tDCS + rTMS experienced a significantly greater reduction in depressive symptoms (measured by the Hamilton Depression Rating Scale, HDRS-24) compared to other groups:  • Active tDCS + Active rTMS: 18.33  • Sham tDCS + Active rTMS: 14.86  • Active tDCS + Sham rTMS: 9.21  • Sham tDCS + Sham rTMS: 10.77  • A large effect size (η² = 0.31) demonstrated the robust effectiveness of the combined treatment. Importance: 𝗔𝗰𝗵𝗶𝗲𝘃𝗶𝗻𝗴 𝗮 𝘀𝗶𝗴𝗻𝗶𝗳𝗶𝗰𝗮𝗻𝘁 𝗿𝗲𝗱𝘂𝗰𝘁𝗶𝗼𝗻 𝗶𝗻 𝘀𝘆𝗺𝗽𝘁𝗼𝗺𝘀 𝘄𝗶𝘁𝗵𝗶𝗻 𝗷𝘂𝘀𝘁 𝟮 𝘄𝗲𝗲𝗸𝘀 𝘂𝗻𝗱𝗲𝗿𝘀𝗰𝗼𝗿𝗲𝘀 𝘁𝗵𝗲 𝗽𝗼𝘁𝗲𝗻𝘁𝗶𝗮𝗹 𝗼𝗳 𝘁𝗗𝗖𝗦 + 𝗿𝗧𝗠𝗦 𝘁𝗼 𝗽𝗿𝗼𝘃𝗶𝗱𝗲 𝗳𝗮𝘀𝘁𝗲𝗿 𝗿𝗲𝗹𝗶𝗲𝗳 𝗳𝗼𝗿 𝗽𝗮𝘁𝗶𝗲𝗻𝘁𝘀 𝗰𝗼𝗺𝗽𝗮𝗿𝗲𝗱 𝘁𝗼 𝘀𝘁𝗮𝗻𝗱𝗮𝗹𝗼𝗻𝗲 𝗼𝗿 𝘀𝗵𝗮𝗺 𝗶𝗻𝘁𝗲𝗿𝘃𝗲𝗻𝘁𝗶𝗼𝗻𝘀. Conclusion: This trial, published in JAMA Psychiatry, establishes tDCS + rTMS as a safe and highly effective treatment, offering rapid symptom improvement and paving the way for further integration of combined neuromodulation therapies in managing MDD. Read the full publication here: https://lnkd.in/gm4z7Xzn

Good read on some exciting psychiatry therapies in development as well as some challenges in bringing these meds to market. One exciting therapy on the horizon is KarXT for schizophrenia. It’s a novel mechanism that targets muscarinic receptors rather than dopamine. Wall Street expectations range from $1B in 2026 to $10B at peak. Other companies are developing assets that target orexin for narcolepsy, kappa opioid receptors for major depression, and psychedelics for anxiety, depression and psychosis. Numerous challenges to broad pharmaceutical development were cited as the complexity of the brain, difficulty bridging animal models to humans, and heterogeneity of conditions. https://lnkd.in/e8M7-TWX: 2024-04-08 BioPharma Dive %5Bissue:60850%5D&utm_term=BioPharma Dive #mentalhealth #biotech #insights

Ahead of print Building diagnostic neuroimaging biomarkers for psychiatric disorders using reverse inference approaches: A viable route? The advent of structural magnetic resonance imaging (sMRI) at the end of the 20th century opened the way toward a deeper understanding of the neurophysiology of psychiatric disorders, substantiating regional structural abnormalities underlying this group of clinical conditions. However, despite abundant and flourishing scientific research, sMRI methodologies are not currently integrated into daily diagnostic practice. One reason behind this failed translation may be the prevailing approach to logical reasoning in neuroimaging: The forward inference via frequentist-based statistics. This reasoning prevents clinicians from obtaining information about the selectivity of results, which are therefore of limited use regarding the definition of biomarkers and refinement of diagnostic processes. Recently, another type of inferential approach has started to emerge in the neuroimaging field: The reverse inference via Bayesian statistics. Here, we introduce the key concepts of this approach, with a particular emphasis on the clinical sMRI environment. We survey recent findings showing significant potential for clinical translation. Clinical opportunities and challenges for developing reverse inference-based neural markers for psychiatry are also discussed. We propose that a systematic sharing of imaging data across the human brain mapping community is an essential first step toward a paradigmatic clinical shift. We conclude that a defined synergy between forward-based and reverse-based sMRI research can illuminate current discussions on diagnostic brain markers, offering clarity on key issues and fostering new tailored diagnostic avenues. https://lnkd.in/dc8jVuMi

https://lnkd.in/gKChAT-3 To assuage my skepticism about novel psychedelic compounds, my trusted psychiatry associates tell me that a single dose injectable is a reasonable and actually preferable alternative to oral dosing. Why not just use psilocin (the psychoactive metabolite of psilocybin)? I certainly do prefer this dosing rationale to the other common rationale for novel compounds, that being to mitigate the ever-vilified side-effect 'psychedelic experience'.

FDA GRANTS FAST-TRACK STATUS TO NEW ANTI-DEPRESSANT CANDIDATE - LIAFENSINE: (check out the reported phase IIb results using a genetic biomarker). Below, is the less than a 4-minute video, I summarize the findings of this ENLIGHTEN study. If this drug and its unique biomarker work out in Phase III trials, it will be the first biomarker-driven, Precision Psychiatry Medication for Treatment-Resistant Depression (TRD). This is a 'big deal' development in psychiatric drug development. If you wish to dive in, a couple of resources - https://lnkd.in/gydcBGHv https://lnkd.in/gqvNsP9i