TRIM32

Since the 1960s, researchers have postulated that major depression stems from disruptions in the serotonin neurotransmitter system, but the evidence for that idea, though plentiful, was indirect. In fact, a recent comprehensive analysis of existing studies concluded that there was not strong evidence to support the 'serotonin hypothesis.' In its wake, some in the field have called for a reexamination of the hypothesis. Not so fast, says a new study that provides direct evidence of disrupted serotonin release in the brains of individuals with depression. Since the 1960s, researchers have postulated that major depression stems from disruptions in the serotonin neurotransmitter system, but the evidence for that idea, though plentiful, was indirect. In fact, a recent comprehensive analysis of existing studies concluded that there was not strong evidence to support the "serotonin hypothesis." In its wake, some in the field have called for a reexamination of the hypothesis. Not so fast, says a new study that provides direct evidence of disrupted serotonin release in the brains of individuals with depression. The study appears in Biological Psychiatry, published by Elsevier. Depression is among the most common mental illnesses and causes of disability worldwide. Despite the lack of direct evidence for disrupted serotonin signaling in the depressed brain, medications used to treat depression overwhelmingly target the serotonin signaling system to increase extracellular serotonin, also known as 5-hydroxytryptamine (5-HT). Only about half of patients respond to antidepressants, and fewer than 30% experience total remission. A better understanding of 5-HT dynamics in depression could help guide more effective therapies. "Our thinking about the role of serotonin in depression has evolved significantly over the past decade. We once thought that serotonin changes could account for the entirety of depression. When this simple hypothesis could no longer be supported, some were inclined to dismiss any role for serotonin in depression," said John Krystal, MD, editor-in-chief of Biological Psychiatry. "The current study provides important new support for further exploration of the role of serotonin in depression. This is particularly timely, as drugs targeting serotonin receptors, such as psychedelics, are being explored as potential new treatments for mood disorders." The study, conducted by Invicro, a global, imaging contract research organization, in collaboration with researchers from Imperial College London, King's College London, Copenhagen University, and the University of Oxford, used a novel imaging technique to look directly at the magnitude of serotonin released from neurons in response to a pharmacological challenge. In previous work, these researchers pioneered the use of positron emission tomography (PET) with the radioligand [11C]Cimbi-36 to detect serotonin release. In the current study, the researchers applied this methodology to compare serotonin release in 17 patients with depression and 20 healthy individuals. David Erritzoe, MRCPsych, PhD, lead author of the paper, said, "This study used a new and more direct method to measure serotonin in the living human brain, and the results suggest reduced serotonin (release) functioning in depression. This imaging method, in combination with similar methods for other brain systems, has the potential to help us to better understand the varying -- sometimes limited or even lacking -- treatment responses that people with depression have to antidepressant medication." Participants with depression and healthy controls underwent PET scanning with [11C]Cimbi-36 to measure 5-HT2A receptor availability in the frontal cortex; the two groups did not differ significantly at baseline. Both groups then received a dose of d-amphetamine, a stimulant drug that works to increase 5-HT concentration outside of neurons, where it interacts with 5-HT2A receptors and reduces the binding of [11C]Cimbi-36. In a second scanning session three hours after drug administration, healthy control participants had significantly reduced 5-HT2A receptor availability, indicating an increase in serotonin levels. Participants with depression, however, did not show a significant decrease in binding potential, suggesting they had a blunted serotonin release capacity in key brain regions. The study found no relationship between the severity of depression and the extent of serotonin release capacity deficits. Of note, all patients were free of antidepressant medication, and 11 out of the 17 had never received antidepressant treatment, indicating that low serotonin release capacity is a feature of depression rather than a result of antidepressant treatment. This first direct evaluation of serotonin levels in the brain of individuals with depression is a major step forward in laying to rest the speculations questioning the involvement of serotonergic neurotransmission in the pathology of depression. Depression is a multifaceted disorder that may have multiple causes, and different subtypes may involve multiple neurotransmitter systems. Serotonergic dysfunction is unlikely to explain all the clinical features encountered in this disorder. Nevertheless, this study demonstrates that serotonergic deficits are present in unmedicated depressed individuals. Eugenii Rabiner, MBBCh, FCPsych SA, at Invicro and senior author of the paper said, "It has taken our field over 20 years to develop a method that enables the measurement of serotonin release in the living human brain. I am very pleased that we managed to develop this method and apply it to clarify this important aspect of the pathophysiology of depression. I hope that we can use this technique in future to explore the different symptoms of depression, as well as serotonergic deficits found in other conditions, such as Parkinson's disease."

LA JOLLA, CA, USA I December 05, 2022 I Longboard Pharmaceuticals, Inc. (Nasdaq: LBPH), a clinical-stage biopharmaceutical company focused on developing novel, transformative medicines for neurological diseases, today announced positive topline results from a Phase 1 clinical study evaluating the central nervous system (CNS) pharmacokinetics (PK) and pharmacodynamics (PD) of LP352, an oral, centrally acting 5-HT2C superagonist, in healthy volunteers. "We are excited to share data from our 102 study, the first known of its kind for a 5-HT2 receptor agonist, to further elucidate the potentially best-in-class profile of LP352. We believe the results of this study are encouraging as orally administered LP352 plasma and CSF PK concentration increased in a dose-dependent and consistent manner, a clear indicator that LP352 is crossing the blood brain barrier. Furthermore, the observation of demonstrated effects on qEEG activity within the first few doses and after continuous dosing suggests that LP352 engaged neurotransmitter systems and altered the EEG spectrum. We are pleased to see favorable safety and tolerability results in this study, consistent with previous work we have conducted," stated Dr. Randall Kaye, Longboard’s Chief Medical Officer. "We anticipate sharing additional data to substantiate our belief that LP352 has the potential to be a safer and more efficacious treatment of seizures in a broad range of developmental and epileptic encephalopathies (DEEs), and we look forward to providing updates on the ongoing Phase 1b/2a PACIFIC study as they become available." Study Design & Objectives: The primary objectives of this open-label, Phase 1 study are to assess the CNS PK and PD of orally administered LP352 in healthy adult male and female participants (n=10 in each Cohort). Objectives include the characterization of plasma and CSF PK, the characterization of safety and tolerability of doses with titration and taper, and the assessment of the PK-PD relationships between plasma and CSF exposure, and PD endpoints of safety and efficacy, including quantitative electroencephalogram (qEEG) endpoints. Data being shared today relate to two doses (Cohort 1 = 6 mg and Cohort 2 = 12 mg) of LP352 three times daily (TID) that were tested over a 16-day period in addition to a screening and follow-up period. Additional cohorts of the study are ongoing. Plasma/CSF Results: Plasma samples were obtained on Day 1 through Day 11 (and during taper), measuring maximum concentration (Cmax), time of peak plasma concentration (Tmax), and area under the curve (AUCtau). Serial CSF samples were taken on Day 11 at multiple timepoints. At steady state, LP352 12 mg TID mean concentrations exceeded the Ki value for 5-HT2C activity throughout the dosing interval. The vast majority of participants in Cohort 2 achieved plasma and CSF levels above the relevant Ki throughout the dosing period at steady state. LP352 exhibited a strong correlation between plasma and CSF PK concentration, which increased in a dose-dependent and consistent manner. qEEG Results: Serial EEGs were taken at Days -1, 1, 3 & 10, and Day 16 (at trough). LP352 demonstrated early qEEG changes within the first few doses. LP352 also demonstrated sustained, dose-dependent effects on qEEG activity after continuous dosing, thus indicating receptor engagement. LP352 engaged neurotransmitter systems and altered the EEG spectrum. Safety / Tolerability Findings: Favorable safety and tolerability across both cohorts were observed, with AEs generally consistent with previous clinical studies of LP352. About LP352 LP352 is an oral, centrally acting 5-HT2C superagonist in development for the potential treatment of seizures associated with developmental and epileptic encephalopathies (DEEs) such as Dravet syndrome, Lennox-Gastaut syndrome (LGS), tuberous sclerosis complex (TSC), CDKL5 deficiency disorder (CDD), and other epileptic disorders. LP352 is designed to modulate GABA and, as a result, suppress the central hyperexcitability that is characteristic of seizures. LP352 has no detected activity at the 5-HT2B and 5-HT2A receptor subtypes. 5-HT2B and 5-HT2A receptor agonism have been associated with significant adverse side effects. LP352 has novel chemistry and attributes. It was designed to be more specific and selective for the 5-HT2C receptor subtype, giving it the potential to reduce seizures in patients with DEEs while overcoming the known or perceived safety limitations of available drugs in the 5-HT2 class. LP352 is currently being evaluated in an ongoing Ph 1b/2a clinical trial ( the PACIFIC Study ) in participants with DEEs, with data expected in the second half of 2023, as well as in additional supportive studies. About Longboard Pharmaceuticals Longboard Pharmaceuticals, Inc. is a clinical-stage biopharmaceutical company focused on developing novel, transformative medicines for neurological diseases. Longboard is working to advance a portfolio of centrally acting product candidates designed to be highly selective for specific G protein-coupled receptors (GPCRs). Longboard’s small molecule product candidates are based on more than 20 years of GPCR research. Longboard is evaluating LP352, an oral, centrally acting 5-hydroxytryptamine 2C (5-HT2C) receptor superagonist, with no detected activity at the 5-HT2B and 5-HT2A receptor subtypes. LP352 is currently being evaluated in a Phase 1b/2a clinical trial, the PACIFIC Study , and being developed for the potential treatment of seizures associated with a broad range of developmental and epileptic encephalopathies (DEEs). Longboard is also evaluating LP659, a centrally acting, sphingosine-1-phosphate (S1P) receptor subtypes 1 and 5 modulator, in development for the potential treatment of multiple neurological diseases. Longboard holds rights to other product candidates, including LP143 and nelotanserin, through a License Agreement with Arena Pharmaceuticals, Inc. SOURCE: Longboard Pharmaceuticals

VANCOUVER, British Columbia, Dec. 02, 2022 (GLOBE NEWSWIRE) -- BetterLife Pharma Inc. (“BetterLife” or the “Company”) (CSE: BETR / OTCQB: BETRF / FRA: NPAU), an emerging biotech company focused on the development and commercialization of cutting-edge treatments for mental disorders, today announced that one of its scientific collaborators, Dr. Argel Aguilar-Valles from Carleton University’s Department of Neuroscience (Ottawa, Canada), will present on the anti-depressant activity of 2-bromo-LSD (“BETR-001”), the Company’s lead compound, at the upcoming ACNP Conference being held December 4 to 7 at Phoenix, Arizona, USA. BETR-001 is a non-hallucinogenic Lysergic Acid Diethylamide (“LSD”) derivative molecule. Dr. Aguilar-Valles will present preclinical data supporting the acute and long-term anti-depressant activity of BETR-001 monotherapy in animal models. Furthermore, the data shows that BETR-001 promotes structural neuroplasticity in brain neurons and this effect is partly mediated by the activation of 5-HT2A receptor. Dr. Ahmad Doroudian, CEO of BetterLife commented, “BETR-001 is a uniquely positioned LSD derivative with the potential to be as effective as LSD in various neuropsychiatric and neurological disorders without the burden of being hallucinogenic. Because of its non-hallucinogenic nature, BETR-001 will not have all the LSD requirements of administration in specialized clinics under special treatment protocols, the LSD controlled substance regulatory issues which impact manufacturing, distribution and patient access, and the overall associated high treatment costs for all these parameters. Additionally, BETR-001 is protected by BetterLife’s composition, method-of-use, synthesis and formulation patents (issued and provisional).” He further added, “BETR-001 IND-enabling studies are being completed and we hope to IND and begin human trials by mid-2023.” About BetterLife Pharma BetterLife Pharma Inc. is an emerging biotechnology company primarily focused on developing and commercializing two compounds, BETR-001 and BETR-002, to treat neuro-psychiatric and neurological disorders. BETR-001, which is in preclinical and IND-enabling studies, is a non-hallucinogenic and non-controlled LSD derivative in development and it is unique in that it is unregulated and, therefore, could be self-administered. BetterLife’s synthesis patent for BETR-001 eliminates regulatory hurdles and its pending patent for composition and method of use covers treatment of depression, anxiety, post-traumatic stress disorder, neuropathic pain and other neuro-psychiatric and neurological disorders. BETR-002, which is in preclinical and IND-enabling studies, is based on honokiol, the active anxiolytic ingredient of magnolia bark. BetterLife’s pending method of use and formulations patent covers treatment of anxiety related disorders, including benzodiazepine dependency. BetterLife also owns a drug candidate for the treatment of viral infections such as COVID-19 and other respiratory viral infections. For further information, please visit BetterLife Pharma. About the Department of Neuroscience at Carleton University Carleton Neuroscience has an international reputation for research on stress and its effects on brain functioning and mental health. The department has an interdisciplinary approach to understanding the emergence, prevention and treatment of mental and physical disorders. For more information, please visit www.carleton.ca/neuroscience.