Translational Psychiatry
September 1, 2015
Chun Yang, Yukihiko Shirayama, J-C Zhang et al.
600 citations
R-ketamine, a stereoisomer of the anesthetic ketamine, produces a more potent and longer-lasting antidepressant effect than S-ketamine (esketamine) in mouse models of depression, without causing psychotomimetic side effects or abuse liability. In the social defeat stress and learned helplessness models, R-ketamine more effectively restored decreased dendritic spine density, brain-derived neurotrophic factor (BDNF)-TrkB signaling, and synaptogenesis in the prefrontal cortex, CA3, and dentate gyrus of the hippocampus. Neither isomer affected these measures in the nucleus accumbens. S-ketamine, but not R-ketamine, caused hyperlocomotion, prepulse inhibition deficits, rewarding effects, and loss of parvalbumin-positive cells in the medial prefrontal cortex and dentate gyrus. R-ketamine appears to be a safe, long-lasting antidepressant.
Translational Psychiatry
November 8, 2021
Manoj K. Doss, Michal Považan, Monica D Rosenberg et al.
343 citations
Psilocybin therapy increased cognitive flexibility for at least four weeks in 24 patients with major depressive disorder, though these improvements were not linked to antidepressant effects. One week after treatment, glutamate and N-acetylaspartate concentrations decreased in the anterior cingulate cortex (ACC), and functional connectivity dynamics increased between the ACC and posterior cingulate cortex. Surprisingly, larger increases in this neural flexibility were associated with smaller gains in cognitive flexibility. Baseline brain connectivity from the ACC predicted cognitive flexibility improvements, with greater baseline connectivity linked to better baseline flexibility but less improvement. The findings suggest that while some increase in neural dynamics may help shift from rigid states, larger persisting increases may be less beneficial.
Translational Psychiatry
October 14, 2014
Níall Lally, Allison C. Nugent, David A. Luckenbaugh et al.
269 citations
A single infusion of ketamine rapidly reduced anhedonia in 36 patients with treatment-resistant bipolar depression, and this effect occurred independently from reductions in general depressive symptoms. The anti-anhedonic effects were specifically related to increased glucose metabolism in the dorsal anterior cingulate cortex and putamen, highlighting the role of the glutamatergic system in treating such symptoms.
Translational Psychiatry
December 15, 2017
Chun Yang, Youge Qu, Yuko Fujita et al.
231 citations
The gut microbiota-brain axis is implicated in depression, and (R)-ketamine shows more potent and longer-lasting antidepressant effects than (S)-ketamine. In a chronic social defeat stress mouse model of depression, fecal 16S ribosomal RNA gene sequencing revealed that both enantiomers attenuated increases in Deltaproteobacteria levels. (R)-ketamine, but not (S)-ketamine, also reversed reductions in Mollicutes levels. At the genus level, both enantiomers attenuated decreases in Butyricimonas, with (R)-ketamine being more potent. These findings suggest that the antidepressant actions of ketamine enantiomers may be partly mediated by restoring gut microbiota, with (R)-ketamine's specific effects on Mollicutes and Butyricimonas potentially explaining its superior efficacy.
Translational Psychiatry
November 7, 2019
Chun Yang, Jianjun Yang, A. Luo et al.
189 citations
Ketamine's robust antidepressant effects in treatment-resistant depression are well established, but the exact molecular and cellular mechanisms remain unclear. While NMDAR inhibition and subsequent AMPAR activation have been proposed, (R)-ketamine, a weaker NMDAR antagonist than (S)-ketamine, produces more marked and longer-lasting antidepressant-like effects in animal models. Non-ketamine NMDAR antagonists lack similar effects in patients, suggesting other mechanisms are key. Evidence points to mTORC1 activation in the medial prefrontal cortex for (S)-ketamine, and extracellular signal-regulated kinase for (R)-ketamine. The BDNF–TrkB cascade is crucial for both enantiomers and their metabolites. This review discusses recent findings, questioning the primacy of NMDAR inhibition in ketamine's antidepressant action.
Translational Psychiatry
March 21, 2017
Drew D. Kiraly, Sarah R. Horn, Nicholas T. van Dam et al.
182 citations
Patients with treatment-resistant depression (TRD) show elevated levels of the pro-inflammatory cytokine interleukin-6 compared to healthy controls, supporting the immune hypothesis of depression. Analysis of 41 cytokines, chemokines, and growth factors in blood samples from 26 healthy controls and 33 unmedicated TRD patients revealed a unique pattern of increased inflammatory mediators, chemokines, and colony-stimulating factors. Following a single intravenous infusion of ketamine (0.5 mg/kg), several cytokines showed transient changes, but none correlated with treatment response. Low pretreatment levels of fibroblast growth factor 2 were associated with ketamine treatment response, suggesting novel treatment targets for TRD patients with dysregulated immune functioning.
Translational Psychiatry
September 28, 2020
José Á. Morales-García, Javier Calleja‐conde, Jose Antonio López‐moreno et al.
139 citations
N,N-dimethyltryptamine (DMT), a component of the ayahuasca brew, activates the subgranular zone of the dentate gyrus in the hippocampus, the main adult neurogenic niche, promoting the generation of new neurons. Mice treated with DMT performed better on memory tests than control animals, suggesting a functional relevance for the newly produced neurons. The neurogenic effect appears to involve sigma-1 receptor activation, as a sigma-1 receptor antagonist blocked it. These findings demonstrate that DMT treatment enhances adult neurogenesis and improves spatial learning and memory.
Translational Psychiatry
September 15, 2015
Matthew B Young, Raül Andero, Kerry J. Ressler et al.
137 citations
MDMA (ecstasy) enhances the extinction of fear memories in mice through a mechanism dependent on brain-derived neurotrophic factor (BDNF). When administered before extinction training, MDMA persistently improved long-term extinction of conditioned fear. The drug increased Fos expression in the amygdala and medial prefrontal cortex, while BDNF expression rose specifically in the amygdala after extinction training. Direct infusion of MDMA into the basolateral amygdala recapitulated the extinction enhancement, and blocking BDNF signaling abolished it. These findings suggest MDMA may be a useful adjunct to exposure-based therapies for PTSD and other anxiety disorders involving altered fear learning.
Translational Psychiatry
April 8, 2021
Natasha L. Mason, Kim P. C. Kuypers, Johannes T. Reckweg et al.
132 citations
A double-blind, placebo-controlled experiment with 0.17 mg/kg psilocybin shows that the drug affects creative thinking in time-dependent and task-specific ways. Immediately after consumption, psilocybin increased spontaneous creative insights but decreased deliberate, task-based creativity. Seven days later, participants generated more novel ideas. Brain imaging revealed that both acute and persisting effects were predicted by connectivity within and between networks of the default mode network. These results support historical claims that psychedelics can influence aspects of the creative process and may serve as tools for investigating creativity and its neural basis.
Translational Psychiatry
August 2, 2022
Federico Cavanna, Stephanie Müller, Laura Alethia de la Fuente et al.
130 citations
A double-blind placebo-controlled trial tested the effects of a low (0.5 g) dose of dried psilocybin mushrooms on 34 individuals beginning a microdosing protocol. The active dose produced more intense acute subjective effects than placebo, but only among participants who correctly guessed their condition. These effects coincided with reduced EEG theta-band power and preserved Lempel-Ziv broadband signal complexity. No evidence was found for enhanced well-being, creativity, or cognitive function; instead, small changes toward cognitive impairment appeared. The findings suggest that expectation, not the drug itself, accounts for many anecdotal benefits attributed to psilocybin microdosing.
Translational Psychiatry
April 4, 2017
Felix Mueller, Claudia Lenz, Patrick C. Dolder et al.
124 citations
Lysergic acid diethylamide (LSD) reduces reactivity in the left amygdala and right medial prefrontal cortex when processing fearful faces, compared to a placebo. In a double-blind, randomized, crossover study, 20 healthy adults received either 100 μg of LSD or a placebo before undergoing functional magnetic resonance imaging (fMRI). Plasma LSD levels were measured before and after the scan. A significant negative correlation emerged between the reduced amygdala response to fearful stimuli and the subjective drug effects reported by participants. These findings indicate that LSD alters the engagement of brain regions involved in emotional processing.
Translational Psychiatry
January 27, 2020
Kai Zhang, Chun Yang, Lijia Chang et al.
120 citations
In mice with depression-like symptoms from chronic social defeat stress, (R)-ketamine produced more potent and longer-lasting antidepressant effects than (S)-ketamine. RNA sequencing of the prefrontal cortex showed that transforming growth factor (TGF)-β signaling may explain these differences. (R)-ketamine, but not (S)-ketamine, reversed reduced expression of Tgfb1 and its receptors in the prefrontal cortex and hippocampus. Blocking TGF-β1 with inhibitors or a neutralizing antibody prevented (R)-ketamine's antidepressant effects. Depleting microglia also blocked these effects. Recombinant TGF-β1 itself produced rapid and lasting antidepressant effects in mice, suggesting a microglial TGF-β1-dependent mechanism and potential for new human antidepressants.
Translational Psychiatry
June 26, 2020
P. Shiroma, P. Thuras, J. Wels et al.
112 citations
In treatment-resistant depression, repeated ketamine infusions showed greater antidepressant effects than the active placebo midazolam after five doses, but when compared head-to-head against a single ketamine infusion added to midazolam over two weeks, the difference was not statistically significant. Fifty-four participants completed all six infusions. The primary outcome, change in depression severity measured by the Montgomery-Åsberg Depression Rating Scale at 24 hours after the last infusion, did not differ significantly between the six-ketamine group and the single-ketamine group. Remission and response rates favored six ketamine after the fourth and fifth infusions, respectively, compared to midazolam before the single ketamine.
Translational Psychiatry
February 17, 2015
James W. Murrough, Katherine A. Collins, Jessica Fields et al.
111 citations
A single low dose of ketamine increases brain activity in the right caudate when people with treatment-resistant depression view happy faces, reversing a baseline deficit compared with healthy volunteers. Twenty patients with treatment-resistant depression not taking other antidepressants underwent fMRI before and 24 hours after receiving intravenous ketamine (0.5 mg per kg of body weight). Twenty matched healthy controls were scanned once. Before ketamine, depressed patients showed reduced neural responses to happy faces in the right caudate. After ketamine, responses to happy faces increased in a similar region. Greater connectivity of the right caudate during positive emotion perception was linked to greater improvement in depression severity. No effects were seen for sad faces.
Translational Psychiatry
September 20, 2016
Daniel M. Rotroff, Daniel Corum, Alison A. Motsinger‐Reif et al.
99 citations
Sub-anesthetic doses of ketamine and its S-enantiomer, esketamine, rapidly reduce depression symptoms in patients with treatment-resistant major depressive disorder. A pharmacometabolomics approach mapped global metabolic effects in 33 patients receiving ketamine and 20 receiving esketamine, with esketamine retested after a second infusion four days later. Both drugs altered metabolites related to tryptophan metabolism (e.g., indole-3-acetate and methionine) and the urea cycle (e.g., citrulline, arginine, and ornithine) two hours post-infusion. Changes in glutamate and circulating phospholipids were significantly associated with decreases in depression severity. These findings provide new insights into the mechanisms underlying the rapid antidepressant effects of these therapies.
Translational Psychiatry
February 23, 2016
H-L Sun, Z-Q Zhou, G.-F. Zhang et al.
87 citations
Ketamine produces rapid (within 0.5 hour) and sustained (up to 72 hours) antidepressant effects in rats exposed to chronic unpredictable mild stress (CUMS), a model of depression. The antidepressant action is blocked by ANA-12, a TrkB antagonist, indicating involvement of TrkB signaling. Ketamine restores reduced levels of brain-derived neurotrophic factor (BDNF) in the hippocampus and increases the ratio of phosphorylated TrkB to total TrkB. While ketamine does not affect p11 expression shortly after administration, it normalizes reduced p11 and BDNF levels 72 hours later. Knockdown of hippocampal p11 prevents ketamine's behavioral effects, suggesting p11 is essential for the sustained antidepressant response.
Translational Psychiatry
May 23, 2023
Severin B Vogt, Laura Ley, Livio Erne et al.
85 citations
Intravenous DMT can produce a psychedelic state that is short-lasting and controllable. A double-blind, placebo-controlled crossover trial with 27 healthy participants tested five DMT regimens: low infusion (0.6 mg/min), high infusion (1 mg/min), low bolus plus low infusion (15 mg + 0.6 mg/min), and high bolus plus high infusion (25 mg + 1 mg/min). Bolus doses induced very intense effects within 2 minutes, with more negative feelings and anxiety than infusions. Infusions produced slowly increasing, dose-dependent effects that plateaued after 30 minutes. All effects subsided within 15 minutes of stopping the infusion. Acute tolerance developed, with stable subjective effects from 30 to 90 minutes despite rising plasma concentrations. Intravenous DMT infusion is a promising tool for tailored psychedelic therapy.
Translational Psychiatry
May 31, 2016
M Belgers, M Leenaars, J R Homberg et al.
64 citations
Ibogaine, a naturally occurring substance used informally to reduce craving and relapse in substance use disorders, was evaluated in a systematic review and meta-analysis of 27 animal studies. Ibogaine reduced drug self-administration, especially within the first 24 hours after dosing, but did not affect drug-induced conditioned place preference. It caused motor impairment in the first day and cerebral cell loss persisting for weeks. Data on cardiac effects and neuropharmacological mechanisms were limited. The findings support further clinical research into ibogaine's efficacy for reducing craving and substance use in patients, but close monitoring is recommended due to potential toxic effects.
Translational Psychiatry
May 9, 2023
Jared M. Kopelman, T. Keller, Benjamin Panny et al.
57 citations
A single intravenous infusion of ketamine (0.5 mg/kg) in 98 adults with unipolar depression who had not responded to at least one antidepressant was associated with rapid changes in gray matter microstructure measured by diffusion tensor imaging (DTI) 24 hours later. Greater decreases in DTI mean diffusivity, a marker of neuroplasticity enhancement, in several brain regions (left and right BA10, left amygdala) correlated with larger improvements in depression scores, particularly in the ketamine group. In the hippocampus, the relationship was reversed for one depression scale. The findings suggest that ketamine's acute antidepressant effects may involve rapid neuroplastic changes detectable with brain imaging.
Translational Psychiatry
May 10, 2023
Sandeep Singh, Alexander Botvinnik, Orr Shahar et al.
54 citations
Psilocybin reduced marble burying in mice, a behavior used to model obsessive-compulsive disorder, but this effect did not depend on the serotonin 2A or serotonin 1A receptors typically associated with psychedelic effects. The 5-HT1A agonist 8-OH-DPAT also reduced marble burying, and its effect was additive with psilocybin, while the 5-HT1A partial agonist buspirone reduced marble burying without adding to psilocybin's effect. Blocking 5-HT1A receptors with WAY100635 did not attenuate psilocybin's effect. A staggered psilocybin regimen over 3.5 hours had no effect, and the effect of a single injection was not persistent. Co-administration of buspirone blocked psilocybin's head twitch response, a rodent correlate of psychedelic effects, suggesting buspirone might block psychedelic effects without impairing anti-obsessional effects.
Translational Psychiatry
April 8, 2023
D P Effinger, S G Quadir, M C Ramage et al.
49 citations
Psilocin, the active metabolite of psilocybin, produces sex-specific and lasting changes in central amygdala (CeA) activity and reactivity to an aversive stimulus in mice. Acutely, psilocin increased CeA activity in both sexes and increased stimulus-specific CeA reactivity in females but not males. Over time, psilocin decreased CeA reactivity in males from 2 to 28 days after administration, while no such decrease occurred in females. Behavioral responses to the aversive stimulus also showed sex-dependent changes in threat responding, without affecting exploratory behavior or locomotion. These findings indicate that a single dose of psilocin induces enduring, sex-specific alterations in CeA function and threat-related behavior.
Translational Psychiatry
September 6, 2022
Tabea Schoeler, Jason Ferris, Adam Winstock
48 citations
About 1 in 200 people who use cannabis (0.47%) experience acute psychotic symptoms—hallucinations or paranoia—severe enough to require emergency medical treatment at some point in their lives, based on data from 233,475 users across multiple countries. Risk is higher among young individuals (2.66 times), those in Denmark (3.01 times), users of high-potency resin (2.11 times), those mixing cannabis with tobacco (2.15 times), and people with pre-existing mental health diagnoses: psychosis (14.01 times), bipolar disorder (4.30 times), anxiety (2.92 times), and depression (2.68 times). The findings suggest certain groups are especially vulnerable to cannabis-induced psychotic symptoms.
Translational Psychiatry
August 11, 2022
Nicole Fadahunsi, Jens Lund, Alberte Wollesen Breum et al.
47 citations
A single dose of psilocybin substantially alters the prefrontal cortex transcriptome in mice but has no acute or long-lasting effects on food intake or body weight in diet-induced obese mice or in genetic mouse models of obesity. Sub-chronic microdosing also has no metabolic effects, does not augment GLP-1-induced weight loss, and does not enhance diet-induced weight loss. A single high dose reduces sucrose preference but fails to counter binge-like eating behavior. These preclinical data discourage clinical investigation, though nuances in psychedelic drug action may require human evaluation.
Translational Psychiatry
March 21, 2021
Jennifer L. Kruse, Megha M Vasavada, Richard Olmstead et al.
47 citations
Lower baseline levels of the inflammatory marker interleukin-8 (IL-8) in females, but not males, trended toward predicting a better response to ketamine for depression. In 46 depressed patients receiving a single ketamine infusion, changes in IL-8 over time also differed by sex and treatment response: increasing IL-8 was associated with decreasing depression scores in females, while the opposite pattern appeared in males. Other inflammatory markers showed no significant relationships. These preliminary findings suggest that sex differences in IL-8 may help explain how ketamine works and could guide personalized depression treatment.
Translational Psychiatry
January 10, 2022
F. Cathomas, L. Bevilacqua, Aarthi Ramakrishnan et al.
44 citations
Ketamine rapidly and lastingly reduces depression in people with treatment-resistant depression (TRD), but how it works remains unclear. TRD is linked to inflammation, and ketamine may curb inflammatory processes. Whole blood gene expression was compared between 21 healthy controls and 26 TRD patients, and again in TRD patients 24 hours after a single ketamine infusion. Before treatment, TRD patients showed activation of interferon signaling pathways. Among TRD patients, those who later responded to ketamine had higher levels of two glutamate receptor genes (GRM2 and GRIN2D) before the infusion. Ketamine response produced a distinct gene expression signature, but no evidence of anti-inflammatory changes was found. More research is needed on the peripheral immune system's role.