Molecular psychiatry
June 1, 2025
Anderson Camargo, Anna Nilsson, Reza Shariatgorji et al.
5 citations
Prophylactic ketamine administration buffers passive stress-induced maladaptive behaviors caused by chronic stress exposure. It also prevents stress-induced disturbances of tryptophan metabolism in the dorsal raphe nuclei (DRN) and blocks the reduction of the protein p11 in that region. p11 deficiency increases susceptibility to stress-related depression-like behaviors, and these effects depend partly on p11 function in serotonergic neurons. Viral-mediated reduction of p11 in the DRN produces a stress-susceptible phenotype. The pro-resilience effect of ketamine is lost when p11 is selectively deleted in serotonergic neurons, revealing a previously unexplored role of the DRN circuit in regulating stress susceptibility and ketamine's resilience-enhancing actions.
Molecular psychiatry
April 1, 2026
Zijian Lv, Qifeng Xie, Kecan Li et al.
3 citations
Chronic stress changes behavior in both people and animals. By testing different chronic restraint stress (CRS) protocols in male mice, researchers identified that short, intense stress (6 hours/day for 3 days) caused persistent avoidance and repetitive behaviors, while longer, milder stress (2 hours/day for 10–14 days) progressively reduced reward-seeking and coping behaviors. A 10-day CRS protocol marked a threshold for reward-seeking deficits and served as a model combining avoidance and reward-processing impairments. The antidepressant ketamine reversed reward-seeking and coping deficits, while paroxetine alleviated both repetitive/avoidance behaviors and coping/reward-seeking deficits. These findings support CRS as a valid male mouse model of stress-related neuropsychiatric disorders.
Molecular psychiatry
May 1, 2026
Sixtine Fleury, Katherine M Nautiyal
2 citations
Psilocybin's persisting antidepressant-like effects in mice involve not only the serotonin 2A receptor but also the serotonin 1B receptor (5-HT1BR). Mice lacking 5-HT1BR showed altered brain-wide neural activity after psilocybin, measured by c-Fos expression in emotion- and cognition-related regions such as the amygdala. While the acute head twitch response was unaffected, 5-HT1BR absence reduced psilocybin-induced hypolocomotion. Longer-term effects on anhedonia and anxiety-like behavior depended on 5-HT1BR, with influences from sex and stress. Network analysis identified circuits through which 5-HT1BR may modulate psilocybin's effects. The findings suggest 5-HT1BR contributes to psilocybin's enduring antidepressant-like actions in mice.
Molecular psychiatry
July 1, 2026
Waki Nakajima, Tetsu Arisawa, Susumu Jitsuki et al.
1 citation
A novel compound, K-4, which positively modulates AMPA receptors, produced longer-lasting antidepressant-like effects in a rat model of treatment-resistant depression than ketamine alone. K-4 reduced expression of the enzyme NOX-1 in the medial prefrontal cortex. Blocking NOX-1, either with an inhibitor or by genetic knockdown, prolonged ketamine's antidepressant-like effects and reduced abnormal bursting in the lateral habenula, a brain region linked to depression. Suppressing NOX-1 may be a promising strategy for extending the benefits of ketamine in treatment-resistant depression.
Molecular psychiatry
April 1, 2026
Josh Allen, Mujun Sun, Tamara L Baker et al.
1 citation
In a rat model of recurrent intimate partner violence brain injury (daily mild traumatic brain injury plus non-fatal strangulation for five days followed by 16 weeks of recovery), a single dose of psilocybin (1 mg/kg) reversed injury-induced anxiety-like behavior in the elevated plus-maze, increased sucrose preference (indicating reduced anhedonia), and improved reversal learning in the water maze and spatial memory in the Y-maze. Psilocybin also prevented the increase in microglial cells in the dorsal hippocampal molecular layer and the loss of reelin-positive cells in the subgranular zone seen in saline-treated injured rats. Pre-treatment with a 5-HT2A receptor antagonist blocked psilocybin's behavioral effects, indicating these benefits depend on 5-HT2A receptor activation.
Molecular psychiatry
November 18, 2025
Cassandre Corvo, Sébastien Goutal, Indira Mendez-David et al.
1 citation
In a mouse model of anxiety/depression, a single dose of ketamine produced rapid antidepressant effects in behavior tests, but no change in synaptic density was detected by PET imaging 24 hours later. After three weekly doses, ketamine restored synaptic density to healthy control levels, an effect that coincided with delayed antidepressant effects. The PET tracer 11C-UCB-J reliably tracked these changes, and its binding correlated with levels of synaptic proteins. The findings support using SV2A PET imaging to monitor drug-induced rebuilding of brain connections as a marker of antidepressant efficacy.
Molecular psychiatry
November 1, 2024
H Nur Eken, Crystal Spotts, Benjamin Panny et al.
1 citation
A combination of ketamine infusion and a digital training program called automated self-association training (ASAT) produced more positive implicit self-associations immediately after treatment in adults with treatment-resistant depression, compared to control groups that received only one active component. These changes in implicit self-worth tracked with concurrent depression symptom improvement across all groups and specifically predicted longer-term depression relief at 30 days for the combined treatment group. The findings indicate that shifting implicit self-esteem during a post-ketamine 'plasticity window' is a key mechanism behind the combined treatment's antidepressant effect, confirming the intended cognitive target.
Molecular psychiatry
June 25, 2026
Clotilde Guidetti, Maurizio Fava, George I. Papakostas
Major depressive disorder and treatment-resistant depression affect many people, and over half of patients do not respond adequately to first-line antidepressants. This review examines promising rapid-acting treatments, including psychedelic compounds like psilocybin, which is in late-stage trials, and neuroplastogen compounds. It also discusses repetitive transcranial magnetic stimulation, including the SAINT protocol, which has shown rapid antidepressant effects and is FDA-cleared for treatment-resistant depression. The ALTO-300 trial is evaluating an adjunctive treatment guided by an EEG biomarker, and a Phase 2 study reports outcomes varying by genotype, suggesting potential for genetically personalized interventions. Challenges include unblinding in psychedelic trials, scalability of neuromodulation, and need for validated biomarkers.
Molecular psychiatry
May 29, 2026
Mickael Eskinazi, Rayan Nasserdine, Romane M Cusin et al.
A systematic review of 23 studies examined whether serotonergic psychedelics (psilocybin, LSD, mescaline, DMT/ayahuasca) or MDMA can trigger manic or hypomanic symptoms. Rates of such symptoms ranged from 5.8% in controlled trials of psilocybin-assisted therapy for depression to 30% in naturalistic studies of people with bipolar disorder. When manic symptoms occurred, they were typically acute and self-limited. Higher risks were seen in individuals with bipolar I disorder, family vulnerability, polysubstance use, or unsupervised use. Registry data showed a 4% prevalence of later transition to bipolar disorder, with little evidence for a hallucinogen-specific signal. The authors conclude that these substances pose a low but clinically meaningful relative risk of transient mood symptoms in susceptible individuals while remaining relatively safe in controlled settings.
Molecular psychiatry
April 13, 2026
Xin Zhao, Xinyu Zhang, Shiying Yuan et al.
Ketamine, a drug used for anesthesia and rapid antidepressant effects, also modulates systemic immunity and protects organs through interactions with the gut microbiota, microbial metabolites, and immune-cell trafficking. Along the gut-brain axis, ketamine restores microbial balance, normalizes short-chain fatty acid levels, and reduces migration of gut-derived immune cells to the central nervous system, correlating with reduced neuroinflammation and depressive-like behaviors. Through the gut-lung axis, ketamine limits bacterial translocation and reduces pulmonary infiltration of pro-inflammatory cells, suggesting potential relevance in acute lung injury. Arketamine appears to provide more sustained neuroprotection with fewer adverse effects than esketamine. The findings suggest broad therapeutic potential for neuropsychiatric and inflammatory diseases, but causal studies are needed.
Molecular psychiatry
July 16, 2026
Marco Taddei-Tardón, Lidia Medina-Rodríguez, Jessica L Maltman et al.
Serotonergic psychedelics recruit an integrated 5-HT2A-TrkB signaling network that drives neuroplastic changes. Using a neural stem cell-derived in vitro model, a panel of tryptamines, phenethylamines, and ergolines was tested alongside ketamine and TrkB agonists. TrkB silencing abolished dendritogenic responses to all tested compounds, while 5-HT2A receptor silencing selectively impaired psychedelic-induced plasticity. Most compounds increased synaptogenesis and induced c-Fos and Egr-2 expression, with ligand-specific differences for psilocin, DOI, and Ariadne. Gq/11 or Gi/o protein coupling differentially modified neuroplastic and transcriptional responses. Psychedelics also induced a 5-HT2A receptor-dependent lactate response sensitive to disruption of either Gq/11 or Gi/o coupling.
Molecular psychiatry
May 13, 2026
Fukang Zhang, Shuyuan Fan, Shiqi Li et al.
Exposure to 60% nitrous oxide (N2O), but not 30%, induced conditioned place preference (CPP) reward behavior in rodents and increased the excitability and glutamatergic transmission of dopamine neurons in the ventral tegmental area (VTA). N2O specifically elevated homocysteine levels in the deep cerebellar nuclei (DCN), but blocking homocysteine production did not reduce the rewarding behavior or glutamatergic transmission. Instead, N2O directly enhanced AMPA receptor-mediated glutamatergic transmission and increased activity in both DCN and VTA dopamine neurons. Inhibiting the DCN-VTA circuit via optogenetic long-term depression or chemogenetic inhibition of VTA dopamine neurons reduced N2O-induced CPP. Attenuating N2O-induced potentiation of the DCN-VTA circuit may offer a therapeutic strategy for N2O-related reward behavior.
Molecular psychiatry
September 1, 2023
Thomas Desmidt, Paul-Armand Dujardin, Frédéric Andersson et al.
A single one-hour session of a 50:50 nitrous oxide/oxygen mixture (EMONO) rapidly alters functional connectivity in the default mode network and increases brain tissue pulsations in depressed women who respond to the treatment. Among 20 women with treatment-resistant depression, 45% showed at least a 50% reduction in depression scores one week after exposure. Responders exhibited decreased connectivity between the subgenual anterior cingulate cortex and the precuneus, and a larger early increase in brain tissue pulsations, which may enhance drug delivery. Non-responders and healthy controls showed different connectivity changes. The findings suggest potential cerebral mechanisms and markers for antidepressant response to nitrous oxide.
Molecular psychiatry
January 1, 2023
Gilly Wolf, Sandeep Singh, Karin Blakolmer et al.
Negative symptoms of schizophrenia, which cause long-term disability and respond poorly to antipsychotic drugs, are linked to cortical atrophy and cell loss. Psychedelic drugs, which show promise for other psychiatric conditions and enhance neuroplasticity in preclinical studies, might help treat these pathological changes. The main risk is inducing or worsening psychosis. Strategies to mitigate this risk include using non-hallucinogenic derivatives, sub-psychedelic or microdosing, harnessing entourage effects in psychedelic mushroom extracts, and blocking 5-HT2A receptor-mediated hallucinogenic effects. Preclinical studies with appropriate animal models are needed before careful clinical trials can proceed.
Molecular psychiatry
September 1, 2005
P Seeman, F Ko, T Tallerico
Phencyclidine, ketamine, dizocilpine, and LSD all show higher affinity for the high-affinity state of the dopamine D2 receptor (D2High) than for the NMDA receptor. Phencyclidine had a Ki of 2.7 nM at D2High versus 313 nM at the NMDA receptor; ketamine had a Ki of 55 nM at D2High versus 3100 nM at NMDA sites; dizocilpine had a Ki of 0.3 nM at D2High versus a Kd of 1.8 nM at NMDA; LSD had a Ki of 2 nM at D2High. Because these psychotomimetics are more potent at D2High, their psychotomimetic action likely involves D2 agonism. In vivo, these drugs test a combined hyperdopamine and hypoglutamate theory of psychosis.