Gia Han Le

Aperiodic electroencephalographic activity is proposed as a scalable marker of cortical population dynamics relevant to excitation–inhibition balance. However, it remains unclear whether aperiodic parameters represent disorder‐specific abnormalities or context‐sensitive indices of clinically relevant brain states. Consistent with systematic‐review guidelines and a prospectively registered protocol, Ovid databases and PubMed were searched from inception through February 9, 2026, with updated manual searching conducted through July 14, 2026. Peer‐reviewed studies reporting electroencephalography‐derived aperiodic parameters in adults with schizophrenia‐spectrum disorders, major depressive disorder, treatment‐resistant depression, and/or bipolar disorder were eligible. Studies lacking aperiodic outcomes or separable findings for eligible diagnoses were excluded. Two reviewers independently conducted study screening, data extraction, and risk‐of‐bias assessments. Findings were synthesized narratively by diagnosis, recording context, and parameter. Thirty articles ( N = 2298 aggregate participants) spanning cross‐sectional, longitudinal, and interventional designs were included. Findings in schizophrenia‐spectrum disorders were heterogeneous, with several studies reporting steeper slopes, higher offsets, or reduced temporal flexibility relative to healthy controls. Task‐related and dynamic measures often showed greater clinical relevance than static resting‐state parameters. Studies of major depressive disorder and treatment‐resistant depression more consistently reported flatter slopes and reduced offsets, particularly in central and posterior regions, with evidence from sleep and intracranial recordings. Aperiodic parameters were sensitive to treatment‐related modulation, although the direction of change differed across interventions. Bipolar disorder evidence was limited, and methodological heterogeneity precluded quantitative synthesis. Aperiodic electroencephalographic activity may be more informative as a context‐sensitive, within‐subject marker of cortical state and treatment‐related change than a fixed diagnostic signature. Methodological harmonization and direct physiological validation remain necessary before clinical implementation.

Major depressive disorder (MDD) and treatment‐resistant depression (TRD) remain leading causes of disability, providing the impetus for receptor‐level treatment strategies beyond monoamine reuptake. The serotonin 5‐HT2B receptor (5‐HT2BR) is uniquely positioned at the interface of central‐antidepressant mechanisms and peripheral cardiac risks. Herein, we reviewed preclinical, translational and clinical literature identified via PubMed and OVID (MEDLINE, Embase, AMED, PsychINFO) databases from inception to September 2025, supplemented by manual searches. Evidence converges that peripheral 5‐HT2BR agonism is mechanistically linked to valvular heart disease (VHD) through mitogenic/profibrotic signaling in valve tissue, consistent with historical signals for anorectic agents (e.g., fenfluramine) and ergot‐derived dopamine agonists, with supportive but limited data for 3,4‐methylenedioxymethamphetamine (MDMA). Classical serotonergic psychedelics bind 5‐HT2BRs; therefore, while contemporary dosing regimens are intermittent, cumulative exposure risks remain insufficiently characterized. Conversely, central 5‐HT2BR signaling appears bidirectional wherein astrocytic 5‐HT2BR activation under sustained serotonergic tone may support metabolic and plasticity programs, whereas neuronal 5‐T2BR antagonism can normalize mesolimbic dopamine output and enhance medial prefrontal glutamatergic activity. Clinically, several approved antidepressant adjuncts (e.g., aripiprazole, brexpiprazole, cariprazine) display 5‐HT2BR antagonism or inverse agonism and improve depressive symptoms without observed valvular signals in trials. The 5‐HT2BR represents a tractable augmentation target for TRD provided that peripheral agonism is rigorously avoided. Consistent with evolving scientific and regulatory safety frameworks, we propose advancing centrally selective, periphery‐sparing 5‐HT2BR antagonists into biomarker‐anchored early cardiac monitoring and preclinical exclusion of valve‐cell 5‐HT2BR agonism. This framework integrates central efficacy with defined safety boundaries, guiding development of mechanistically informed antidepressant therapies.

Background: Ketamine and esketamine produce rapid and sustained antidepressant effects in persons with treatment-resistant depression (TRD). Although it is posited that these effects are largely attributed to N -methyl-D-aspartate receptor antagonism, the potential involvement of the opioid system remains unclear. This systematic review investigates whether ketamine and esketamine antidepressant efficacy is mediated through the opioid system. Methods: We conducted a systematic search of preclinical and clinical studies investigating the potential involvement of the opioid system in the antidepressant effects of ketamine and esketamine. Database searches on PubMed, Cochrane Library, Embase and PsycINFO occurred from inception to September 27, 2025. Results: 16 studies were identified: 12 clinical ( n = 790) and 4 preclinical studies. Clinical designs included randomized controlled trials, case reports, pre-post studies and observational cohort studies. Preclinical studies utilized animal models of depression. Only one study examined esketamine. Naltrexone (nonselective opioid antagonist) attenuated ketamine’s effects in three studies, while four reported no such effect and one reported mixed evidence. Genetic markers of opioid receptor subtypes (i.e., OPRM1 and OPRD1) were examined in three studies, but results were inconclusive, potentially due to limited evidence. Separately, opioid use was not associated with ketamine response. Few studies directly examined opioid receptor subtypes. Conclusions: The reported mixed findings suggest that the opioid system may exert a partial mediating effect of ketamine in TRD. However, given the inconsistent attenuation of ketamine’s antidepressant effects by opioid receptor antagonists, the opioid system likely functions as a context-dependent modulator rather than a primary mediator, particularly at standard antidepressant doses.

Up to 50% of adults with major depressive disorder (MDD) fail to achieve remission after two or more monoaminergic antidepressants and meet criteria for treatment-resistant depression (TRD). Low-dose intravenous ketamine, intranasal esketamine, and oral dextromethorphan represent the first glutamatergic treatments to exhibit rapid and robust efficacy in persons with TRD, yet their precise mechanisms remain unclear. Herein, we amplify an existing hypothesis and integrate preclinical, pharmacological and clinical evidence implicating elevated tonic N-methyl-D-aspartate (NMDA) receptor currents, mediated predominantly by NR2C/D subunits, in the pathophysiology of TRD. We review in vivo proton magnetic resonance spectroscopy and electrophysiology studies that document sustained ambient-glutamate signaling in key limbic regions. We then synthesize mechanistic data on ketamine's dual pore-trapping and hydrophobic lateral-site binding, esketamine's preferential NR2D blockade, and dextromethorphan's pH-enhanced NR2C selectivity. Selective dampening of NR2C/D-mediated tonic currents underlie rapid and sustained antidepressant effects of ketamine, esketamine and dextromethorphan. Separately, ketamine and esketamine's affinity for NR2A/B subunits may constitute the core mechanism driving the dissociative effects which are not observed with dextromethorphan. Future drug discovery should emphasize subunit-biased ligands and allosteric modulators, guided by advanced receptor structural models and translational biomarkers, to enhance antidepressant efficacy and concurrently improve tolerability.