Intravenous ketamine is a rapid-acting intervention for treatment-resistant depression (TRD) in adults with major depressive disorder and bipolar disorder (BD). While efficacy is established, a comprehensive integration of clinical, neurophysiological, biomarker, metabolic, and cognitive predictors remains lacking, limiting precision CNS-targeted therapy. To synthesize recent evidence on...
Background: Anhedonia and reward-processing deficits are core features of major depressive disorder (MDD) that respond poorly to traditional antidepressants.Ketamine has rapid antidepressant effects, yet its neurofunctional actions within reward circuits remain unclear.We synthesized human neuroimaging evidence on ketamine-related modulation of reward circuitry and implications for...
G protein-coupled receptors (GPCRs) are involved in many physiological and pathophysiological processes. Conventional pharmacological models categorize the typology of pharmacologic ligands as agonists or antagonists. Biased agonism is a relatively newer pharmacodynamic characteristic that has potential to optimize therapeutic efficacy while minimizing adverse effects in psychiatric and...
Ketamine, originally synthesized in 1962, has gained increasing attention due to its rapid and sustained antidepressant effects in treatment-resistant depression (TRD). Unlike traditional antidepressants, ketamine acts on multiple neurotransmitter systems, including NMDA receptor antagonism and AMPA receptor potentiation, offering a novel mechanism for mood regulation. Beyond psychiatry,...
CNS SpectrumsFebruary 19, 2025M. Koummati, J. Vrublevska, M. de Hert et al.
Background It has been reported that abnormal experiences could be common in the general “healthy” population, with the vast majority of individuals never proceeding to manifest a frank mental disorder. Aims This study aimed to quantify subthreshold psychiatric symptoms in the general population. Methods The protocol included clinicodemographic data and a mental symptoms questionnaire, and...
This chapter explores the complex and controversial path of MDMA-assisted therapy (MDMA-AT) for treating post-traumatic stress disorder (PTSD) and other behavioral disorders. It covers MDMA's history from research to recreation to medicine, the pivotal trials, and the challenges faced by researchers. Despite recent setbacks for the clinical application of MDMA, the chapter argues that it holds...
Esketamine nasal spray (ESK) is approved in combination with an oral antidepressant (OAD) for the treatment of adults with treatment-resistant depression (TRD); however, direct comparisons with atypical antipsychotics for TRD are limited. This secondary analysis of the ESCAPE-TRD study compared rates of remission and response, and improvements in depressive symptoms over time, between ESK and...
Psychoactive substances, known for their acute impact on perception and cognition, are gaining attention for their potential therapeutic applications. Many of these substances are plant-derived with deep-rooted histories of use in non-medical contexts, where they have been viewed as either tools for social cohesion or sources of discord, depending on cultural and societal contexts. This review...
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CNS Spectrums2025Ana Rodríguez Lorente, María Pilar Campos-Navarro, Ángela Gil Montoya et al.
Abstract Objectives This proof-of-concept study aimed to assess the impact of intranasal esketamine (ESK-IN) in brain volume and neurofilament light chain (sNfL) over 6-months in patients with treatment resistant depression (TDR). Methods Seven TRD patients received ESK-IN while continuing oral antidepressants. Clinical evaluations were conducted at baseline, 1, 3, and 6 months, with MRI scans...
This article presents a comprehensive neuroethical framework that seeks to deepen our understanding of human consciousness and free will, particularly in the context of psychiatric and neurological disorders. By integrating insights from neuroscience with philosophical reflections on freedom and personal identity, the paper examines how various states of consciousness from interoception to...
Psilocybin therapy has recently emerged as a promising new treatment for depression and other mental health disorders. This chapter summarizes the most recent data on its safety and efficacy. The delivery of psilocybin therapy and its subjective effects are also presented. Furthermore, this chapter outlines our current understanding of psilocybin's pharmacology and neurobiological effects....
The revival of psilocybin in psychopharmacological research heralds a potential paradigm shift for treating mood and anxiety disorders, and other psychiatric conditions beyond the psychotic spectrum. This critical review evaluates current evidence on psilocybin's efficacy, juxtaposing potential benefits with the practical aspects of psychedelic-assisted psychotherapy (PAP) and the...
Psychedelics are a group of psychoactive substances that alter consciousness and produce marked shifts in sensory perception, cognition, and mood. Although psychedelics have been used by indigenous communities for centuries, they have only recently been investigated as an adjunctive therapeutic tool in psychotherapy. Since the early twentieth century, psychedelic-assisted psychotherapy has been...
Ayahuasca is a botanical hallucinogen traditionally used for therapeutic and ritual purposes by indigenous groups from Northwestern Amazonian countries such as Brazil, Peru, Colombia, and Ecuador. Ayahuasca is made by the decoction of two plants, which are rich in the 5-HT1A/2A partial agonist dimethyltryptamine or DMT (from the leaves of the Psychotria viridis bush) and β-carbolines such as...
Inadequate response to first- and second-line pharmacological treatments for psychiatric disorders is commonly observed. Ketamine has demonstrated efficacy in treating adults with treatment-resistant depression (TRD), with additional off-label benefits reported for various psychiatric disorders. Herein, we performed a systematic review and meta-analysis to examine the therapeutic applications...
Postpartum depression (PPD), now referred to as perinatal depression, is a prevalent and debilitating mood disorder that reduces health-related quality of life (HRQoL) and psychosocial functioning. Esketamine, which is efficacious in adults with treatment-resistant depression and individuals with depression and suicidality, is also analgesic in pain management during childbirth labour. Herein,...
AbstractObjectiveDextromethorphan/bupropion (DXM/BUP) received Food and Drug Administration (FDA) approval for the treatment of adults with major depressive disorder (MDD) in August 2022. This combination is not known to have abuse liability and is not currently scheduled by the Drug Enforcement Administration (DEA). Notwithstanding, dextromethorphan is a drug of abuse. Herein, we sought to...
CNS SpectrumsOctober 1, 2024Renzo Costa, Ayyub Imtiaz, Jacob Adelman et al.
Introduction Ketamine is used off-label for suicidality and mood disorders, whereas esketamine is FDA-approved for treatment-resistant depression in adults. However, many of these studies have excluded patients with a history of or currently presenting with psychosis. A significant number of patients who have primary mood disorders with psychotic features need novel psychopharmacological...
To examine the effect of esketamine nasal spray (ESK) plus newly initiated oral antidepressant (OAD) versus OAD plus placebo nasal spray (PBO) on the association between Montgomery-Åsberg Depression Rating Scale (MADRS) and 9-item Patient Health Questionnaire (PHQ-9) scores in adults with treatment-resistant depression (TRD). Data from TRANSFORM-1 and TRANSFORM-2 (two similarly designed,...
AbstractBackgroundAXS-05 (dextromethorphan-bupropion) is a novel, oral, investigational, NMDA receptor antagonist with multimodal activity being developed for MDD. The dextromethorphan component of AXS-05 is an NMDA receptor antagonist and a sigma-1 receptor agonist. The bupropion component of AXS-05 serves primarily to increase the bioavailability of dextromethorphan.MethodsAXS-05 was...
AbstractBackgroundIn STAR*D, following non-remission with an SSRI, remission rates for second-line treatments were ~ 25%, regardless of the switch strategy employed. Antidepressants with novel mechanisms may improve outcomes in MDD. AXS-05 (dextromethorphan HBr 45 mg- bupropion HCl 105 mg) is a novel, oral, investigational, NMDA receptor antagonist with multimodal activity. The dextromethorphan...
AbstractBackgroundInnovative therapies to treat individuals with MDD, especially those with comorbid anxiety, are urgently needed.AXS-05 (dextromethorphan HBr 45 mg-bupropion HCl 105 mg) is a novel, oral, investigational NMDA receptor antagonist with multimodal activity. The dextromethorphan component of AXS-05 is an NMDA receptor antagonist and a sigma-1 receptor agonist. The bupropion...
AbstractBackgroundTreatments for MDD that can improve both overall depressive and anhedonic symptoms are urgently needed.AXS-05 (dextromethorphan-bupropion) is a novel, oral, investigational NMDA receptor antagonist with multimodal activity being developed for MDD. The dextromethorphan component of AXS-05 is an NMDA receptor antagonist and a sigma-1 receptor agonist. The bupropion component of...
Abstract Objective To assess the likelihood of attaining response/remission of depressive symptoms with esketamine nasal spray (ESK) plus standard of care (SoC) vs placebo nasal spray (PBO) plus SoC at 4 weeks in patients with major depressive disorder and active suicidal ideation with intent (MDSI) without early response. Methods A post hoc analysis of pooled data from ASPIRE I and ASPIRE II...