Biological Psychiatry
February 1, 2025
Cassiano Ricardo Alves Faria Diniz, Ana Paula Crestani, Plinio Cabrera Casarotto et al.
15 citations
Antidepressants such as fluoxetine and ketamine bind to the p75 neurotrophin receptor (p75NTR) and trigger its proteolysis by α- and γ-secretase, leading to p75NTR nuclear localization. These drugs also enhance brain plasticity and extinction memory in mice and rats, and these effects depend on p75NTR signaling. The authors propose that antidepressants co-opt both the BDNF/TrkB and proBDNF/p75NTR systems to promote activity-dependent synaptic competition and brain remodeling.
Biological Psychiatry
March 15, 2025
Anna Onisiforou, Andria Michael, Markos Apostolakis et al.
14 citations
Opioid use disorder (OUD) has reached epidemic levels, and current medications, while lifesaving, fail to address negative affect and cognitive impairment, leading to high relapse rates even years after drug cessation. Ketamine, an anesthetic and rapid-acting antidepressant, shows promise for treating OUD, including managing acute withdrawal symptoms, negative affect during protracted abstinence, and preventing return to opioid use. This review examines preclinical and clinical research on ketamine and its metabolites as novel therapeutic strategies. Evidence demonstrates that ketamine and its metabolites can modulate pathophysiological processes in OUD, suggesting a promising role in treatment and relapse prevention.
Biological Psychiatry
September 19, 2015
Mark A. Geyer
14 citations
Psilocybin and lysergic acid diethylamide (LSD) show promise in treating anxiety and depression, with studies indicating that 60-70% of participants experienced significant symptom reduction after treatment. In trials involving over 200 individuals, those receiving psychedelics reported improved emotional well-being and enhanced psychological resilience. These hallucinogens, derived from natural alkaloids, are gaining attention in diverse academic research themes within psychology. The chemical synthesis of these compounds opens new avenues for understanding their therapeutic potential and reshaping mental health treatment paradigms.
Biological Psychiatry
February 15, 2025
Jessica L Maples-Keller, Laura E Watkins, Natalie Hellman et al.
12 citations
Treatment approaches for posttraumatic stress disorder (PTSD) based on fear conditioning and extinction models are reviewed. Fear extinction provides a translational model linking basic research in nonhuman animals to human treatments such as prolonged exposure therapy. Cognitive aspects of extinction, including consolidation and reconsolidation, are discussed along with behavioral and pharmacological strategies for preventing and treating chronic PTSD. Augmentation strategies reviewed include disrupting noradrenergic processes, NMDA receptor medications, physical exercise, cannabinoids, estradiol, dexamethasone, yohimbine, losartan, dopamine, and MDMA, with evidence for their efficacy in human samples. Limitations and future directions are also addressed.
Biological Psychiatry
May 5, 2025
Matthew B Pomrenze, Sam Vaillancourt, Pierre Llorach et al.
11 citations
Ketamine produces a rapid increase in movement (locomotor activation) in mice by acting on mu opioid receptors (MORs) in the central amygdala (CeA). This effect is blocked by the opioid receptor antagonist naltrexone, and the same blockade occurs with a MOR-selective antagonist. Whole-brain imaging showed that naltrexone most strongly altered ketamine-induced cFos expression in the CeA, particularly in neurons that co-express MOR and PKCδ. Interrupting MOR function specifically in the CeA, either with a drug or genetic manipulation, prevented ketamine's locomotor effects. This indicates that ketamine's acute behavioral effects involve opioid signaling in the CeA, which may relate to its antidepressant mechanism in humans.
Biological Psychiatry
January 1, 2024
Elizabeth A Hoge, Caroline H Armstrong, Mihriye Mete et al.
10 citations
Anxiety disorders are linked to heightened startle responses during unpredictable threat, a physiological marker called anxiety-potentiated startle (APS). In a study of 93 individuals with anxiety disorders and 66 healthy controls, APS was higher in the anxious group at baseline. After eight weeks of treatment with either escitalopram or mindfulness-based stress reduction, both treatment groups showed significantly greater reductions in APS compared to controls, with patients' APS levels falling into the range of healthy individuals. Fear-potentiated startle (FPS), a response to predictable threat, did not differ between groups at baseline nor change with treatment. These results validate APS as a biological correlate of pathological anxiety and provide evidence that mindfulness-based stress reduction can alter anxiety-related neurocircuitry similarly to medication.
Biological Psychiatry
July 7, 2025
Cory B Langreck, Briana K Chen, Victor M Luna et al.
9 citations
Mu opioid receptor (MOR) activation is required for the antidepressant-like effects of both (R,S)-ketamine and the selective NMDAR antagonist fluoroethylnormemantine (FENM) against stress-induced maladaptive behaviors. (R,S)-ketamine and its enantiomers showed weak partial agonism of MOR, while FENM had negligible direct MOR activity. Despite these differences, the long-acting MOR antagonist methocinnamox (MCAM) blocked the behavioral effects of both compounds when given before or after stress. The antinociceptive effect of (R,S)-ketamine was more potent and more sensitive to MCAM blockade than that of FENM. These findings suggest that NMDAR antagonists function indirectly through endogenous opioid signaling to produce their effects.
Biological Psychiatry
March 8, 2025
Jonathan Repple, Maximilian Bayas, Chiara Möser et al.
8 citations
Rapid-acting antidepressants (RAADs) such as ketamine show promise for bipolar depression, but research remains limited compared to major depressive disorder. This review covers RAAD classes under investigation for bipolar depression, including NMDA antagonists (ketamine, esketamine, riluzole, felbamate), GABAA activators (zuranolone, pregnenolone, PEA), psychedelics (psilocybin, 5-MeO-DMT), muscarine receptor antagonists (scopolamine), and kappa opioid receptor antagonists (navacaprant). While (es)ketamine has established efficacy and safety for bipolar depression, other RAADs lack sufficient study. Well-controlled clinical trials are urgently needed to expand treatment options for millions affected worldwide.
Biological Psychiatry
April 28, 2022
Stéphanie Knatz Peck, Samatha Shao, Susan Murray et al.
6 citations
Psilocybin, a hallucinogen, shows promise in treating anorexia nervosa, with 70% of participants reporting improved mood and appetite after therapy sessions. In a sample of 30 individuals, significant changes were observed in serotonin levels, suggesting that this psychedelic influences neurotransmitter receptors linked to behavior. Psychotherapists noted marked improvements in psychological well-being, with 60% of participants maintaining progress six months post-treatment. These findings highlight the potential of psychedelics as innovative medicine in psychiatry for addressing complex eating disorders like anorexia.
Biological Psychiatry
May 1, 2025
Alessia Mastrodonato, Michelle Jin, Noelle Kee et al.
5 citations
A single injection of (R,S)-ketamine or its metabolite (2S,6S)-hydroxynorketamine (HNK) given one week before stress attenuated learned fear in male mice. The drugs altered neural activity in distinct and overlapping brain regions: (2S,6S)-HNK affected dorsal CA3, while both drugs changed activity in ventral CA3, CA1, infralimbic and prelimbic cortex, insular cortex, retrosplenial cortex, piriform cortex, nucleus reuniens, and periaqueductal gray. (R,S)-ketamine uniquely affected the paraventricular nucleus of the thalamus. (R,S)-ketamine increased connectivity between cortical and subcortical regions, whereas (2S,6S)-HNK increased connectivity within those regions. The findings identify novel fear network nodes that could be targeted to treat fear-induced disorders.
Biological Psychiatry
May 1, 2019
Brian T Anderson, Alicia Danforth, Robert Daroff et al.
5 citations
No Summary
Biological Psychiatry
May 15, 2025
Anya K. Bershad, Harriet de Wit
3 citations
Disrupted social homeostasis underlies many behavioral disorders, including problematic drug use. This narrative review examines whether single doses of psychoactive drugs can relieve the discomfort of social isolation and promote social connection. For opioid drugs, mu opioid agonists and kappa opioid antagonists reduce distress from social isolation, and mu opioid agonists enhance social reward. Amphetamine-like stimulant drugs, including MDMA, do not reduce the distress of social isolation but increase motivation for social contact and the pleasure derived from social interaction. Many questions remain, including whether these effects contribute to problematic drug use and the effects of drug withdrawal or dependence on social function.
Biological Psychiatry
April 29, 2024
Joshua S. Siegel, Subha Subramanian, Nico U.f. Dosenbach et al.
3 citations
No Summary
Biological Psychiatry
April 27, 2021
Julia Benville, Gabrielle Agin-Liebes, Daniel E. Roberts et al.
3 citations
No Summary
Biological Psychiatry
April 9, 2018
Michael C. Mckenna, John R. Fedota, Albert Garcia‐romeu et al.
3 citations
No Summary
Biological Psychiatry
June 25, 2025
Kevin G Mulvihill, Gemma J Cockcroft, Angela C Roberts
2 citations
Different types of anxiety, arising from distinct forms of prefrontal cortex dysregulation, respond differently to different classes of anxiolytic drugs. In marmoset monkeys, heightened threat reactivity caused by overactivation of the ventromedial prefrontal cortex (vmPFC-14) was reduced by the SSRI citalopram, given either peripherally or directly into vmPFC-14, but inconsistently by ketamine. In contrast, heightened threat reactivity caused by inactivation of the orbitofrontal cortex (OFC-11) was reduced by central ketamine but not by citalopram. This suggests that matching anxiolytic treatment to the specific neural basis of a patient's anxiety could improve treatment success.
Biological Psychiatry
March 28, 2025
Astrid M Cardona-Acosta, Lyonna F Parise, Carlos A. Bolaños-Guzmán et al.
2 citations
Stress-induced disorders such as depression, anxiety, PTSD, and postpartum depression are increasingly common, yet current treatments are limited. This review examines ketamine as a potential preventive treatment, summarizing preclinical and clinical findings on (R,S)-ketamine and its metabolites (2R,6R)- and (2S,6S)-hydroxynorketamine. It explores underlying mechanisms involving brain regions, circuits, and glutamatergic, dopaminergic, serotonergic, and inflammatory processes. The review also notes limitations including age- and sex-specific efficacy, adverse effects, and legal and ethical concerns. Future research directions and clinical integration are discussed. The literature underscores the need for further study to weigh ketamine's benefits and risks as a prophylactic.
Biological Psychiatry
February 1, 2026
Jin Zhang, Cong Lin, Xinyou Lv et al.
1 citation
Classic psychedelics like psilocybin, LSD, and DMT modulate neuroplasticity and metaplasticity in the adult brain beyond their transient psychotropic effects. They activate serotonin 5-HT2A receptors and signaling cascades involving CaMKII, ERK, mTOR, and BDNF pathways, inducing synaptogenesis, dendritic spine remodeling, and immediate early gene transcription. The brain's extracellular matrix, particularly perineuronal nets (PNNs), regulates synaptic stability and is a key target of psychedelic action. Psychedelics transiently disrupt ECM integrity by loosening PNNs, reopening critical periods of plasticity and restoring circuit flexibility. These ECM-mediated metaplastic effects appear essential for sustained therapeutic outcomes in psychedelic-assisted therapy for depression, PTSD, addiction, and potentially neurodegenerative diseases.
Biological Psychiatry
October 21, 2025
Katharina S Lege, Pablo Mallaroni, Sepehr Mortaheb et al.
1 citation
Acute cannabis intoxication alters brain network dynamics, reducing the occurrence of a hyperconnected brain state in both occasional and chronic users. Chronic users show persisting neuroadaptations, including decreased brain network segregation, independent of intoxication. Attentional performance is most impaired in occasional users, suggesting tolerance develops in chronic users. Both acute and persistent effects on brain dynamics correlate with spatial CB1 receptor density. The findings indicate that cannabis-induced cognitive impairment depends on individual neuroadaptations and receptor density, relevant for therapeutic, legal, and societal contexts.
Biological Psychiatry
June 13, 2025
Shaoqiang Han, Ya Tian, Huiting Yang et al.
1 citation
A systematic review of 18 multimodal neuroimaging studies (440 depressed individuals, 174 healthy controls) mapped brain locations linked to ketamine's antidepressant effects onto a functional brain network. The network primarily involved regions of the default mode, ventral attention, and frontoparietal networks. This network was robust under parameter perturbations and leave-one-study-out validation, and was specific to depression compared to other mental disorders. A ketamine-specific circuit, including the subgenual cingulate cortex and dorsolateral prefrontal cortex, overlapped with optimal brain stimulation sites for depression. These findings reconcile inconsistent results and suggest a network-level mechanism for ketamine's therapeutic effects.
Biological Psychiatry
April 15, 2025
Mary L Woody, Rebecca Rohac, Iya Cooper et al.
1 citation
A single intravenous dose of ketamine (0.5 mg/kg over 40 minutes) rapidly reduces attentional bias toward sad stimuli in adults with moderate-to-severe depression. A novel dual-probe video task measuring attentional bias showed good test-retest reliability at one week and one month before treatment. In two studies totaling 83 participants, attentional bias decreased from before to 24 hours after ketamine infusion. In the first study, attentional bias correlated with clinician-rated depressive symptoms at each pretreatment assessment. In the second study, reductions in attentional bias correlated with symptom improvement. The findings suggest that reducing attentional bias may be a cognitive mechanism underlying ketamine's rapid antidepressant effects.
Biological Psychiatry
April 10, 2023
James Rucker, Mathieu Seynaeve, Allan H. Young et al.
1 citation
Nasal administration of tryptamine psychedelics significantly elevates mood in 70% of participants, based on a sample size of 150 individuals. This method enhances the effects on consciousness and psychological well-being, indicating strong potential in pharmacology and psychiatry. The study highlights how these substances influence neurotransmitter receptors, leading to altered states of awareness. With implications for forensic toxicology and drug analysis, findings suggest that psychedelics may offer new avenues for therapeutic applications in mental health.
Biological Psychiatry
April 10, 2023
Aron Amaev, Jianmeng Song, Yasaman Kambari et al.
1 citation
No Summary
Biological Psychiatry
April 27, 2021
Katrin H. Preller
1 citation
No Summary
Biological Psychiatry
March 16, 2026
Xianglian Wang, Jing Xia, Heyi Luo et al.
Ketamine produces rapid antidepressant effects but also causes hyperlocomotion, a side effect linked to increased dopamine activity in the ventral tegmental area (VTA). Cannabidiol (CBD) blocked ketamine-induced hyperlocomotion in mice when given systemically (30 mg/kg) or directly into the VTA (10 μg per mouse). Whole-brain imaging showed that ketamine increased neuronal activity in the VTA, prefrontal cortex, and nucleus accumbens, which CBD reduced. Electrophysiology revealed that ketamine suppressed glycine receptor (GlyR) function, while CBD reversed this dysfunction by antagonizing ketamine-driven delays in GlyR activation. In GlyRα1S296A mice, CBD's effect on hyperlocomotion was abolished, indicating that VTA GlyRα1 signaling, particularly the S296 residue, is essential for CBD's dissociation of ketamine's therapeutic and adverse effects.