Sleep disruptions are a core feature of both major depressive disorder and treatment-resistant depression (TRD), which is defined by persistent symptoms despite multiple treatment efforts. In addition, disruptions in wakeful gamma power and sleep-related delta power have been observed in individuals with TRD. This study explored the association between gamma oscillations (30-100 Hz) occurring during wakefulness and delta power (0.5-4 Hz) in non-rapid eye movement (NREM) sleep-both of which have separately been implicated in plasticity-in healthy volunteers (HVs) and individuals with TRD. Specifically, the study explored whether a relationship exists between daytime wake gamma power and sleep NREM delta power in HVs and those with TRD.

Brain activity was measured via electroencephalography (night-time) and magnetoencephalography (daytime resting state) in 23 HVs (9M/14F; 20-56 yrs) and 40 medication-free TRD participants (20 M/20F; 18-63 yrs).

In HVs, NREM episode (NREM1) sleep delta power correlated with daytime wake gamma power (r = 0.417; p = 0.04). This correlation was absent in TRD participants (r = 0.108; p = 0.50).

The sample size of the HVs (n = 23) was smaller than the TRD participants (n = 40), and the measurement order for wake gamma power and sleep delta power varied.

These findings identify a possible link between daytime wake gamma power and NREM1 sleep delta power in HVs, supporting an association between gamma and delta power in sleep homeostasis. The lack of such a relationship in medication-free individuals with TRD suggests disrupted synaptic homeostasis that may contribute to impaired synaptic plasticity in TRD. Clinical Trials Identifiers: NCT00088699 and NCT01204918.

Approximately 30 % of patients with treatment-resistant depression (TRD) respond to ketamine; however, no replicable predictors of response have been reported. The imbalance between excitatory and inhibitory neurotransmissions may be implicated in the mechanism of action of ketamine. This study aimed to evaluate whether the ratio of glutamate and glutamine (Glx) to GABA levels at baseline in the dorsal anterior cingulate cortex (dACC) could predict ketamine response in patients with TRD.

This exploratory study analyzed data from a double-blind randomized clinical trial with an open-label extension study (jRCTs031210124). Fifteen participants in the ketamine group and 15 of 16 participants in the placebo group received repeated intravenous ketamine during the double-blind and open-label extension periods, respectively. We measured Glx and GABA levels in the dACC before and after treatment during the double-blind period using proton magnetic resonance spectroscopy. The 17-item Hamilton Depression Rating Scale (HDRS-17) was measured for depressive symptomatology. General linear models were used to examine the relationship between baseline Glx/GABA ratio and HDRS-17 score changes.

Changes in HDRS-17 scores (mean (±SD)) following ketamine treatment were -4.9 (6.5) and -4.9 (5.2) in the double-blind and open-label periods, respectively. A higher baseline dACC Glx/GABA ratio was correlated with greater improvement in HDRS-17 (β = -0.42, p = 0.040). In the ketamine group, a reduction in the dACC Glx/GABA ratio was correlated with greater HDRS-17 improvement (β = 0.74, p = 0.009) with no such association in the placebo group.

These results suggest that excitatory-inhibitory imbalance in the dACC may predict the efficacy of ketamine in TRD.

Depression and PTSD are prevalent psychiatric conditions that often co-occur and significantly impact quality of life. Ketamine has emerged as a promising rapid-acting treatment for both conditions, while traditional treatments like psychotherapy typically require weeks to show effects. This study investigated whether combining ketamine with psychotherapy produces greater symptom improvement compared to ketamine alone. We analyzed overlapping samples of N = 202, N = 470, and N = 624 help-seeking individuals (all samples ∼60 % female, mean age ∼ 42 years) who received either ketamine alone (KET) or ketamine plus psychotherapy (KET+PSY) across 4-14 treatment sessions within a 30- or 180-day period. Depression symptoms were measured using the PHQ-9, and PTSD symptoms were assessed using the PCL-5. Trajectories of symptom change were analyzed using generalized additive mixed-effects models, controlling for baseline symptoms, demographics, and treatment intervals. Both treatment groups showed substantial improvement in depression and PTSD symptoms, with similar patterns of rapid initial decline followed by stabilization. Contrary to our hypothesis, we found no significant differences in symptom trajectories between the KET and KET+PSY groups. Exploratory analyses revealed non-significant but notable patterns where younger females showed better outcomes with combined treatment, while older males showed better outcomes with ketamine alone. These findings suggest that ketamine's therapeutic effects may be robust enough that additional psychotherapy during the acute treatment phase does not significantly enhance 30-day (and possibly 180-day) outcomes. However, longer-term benefits of combined treatment and potential demographic-specific treatment responses warrant further investigation. These results have important implications for treatment planning and resource allocation in clinical settings.

Simultaneously modulating the glutamatergic and monoaminergic systems represents a promising strategy for treating depression. In this study, a series of multi-target antagonists targeting both NMDAR and monoamine transporters (SERT, DAT, and NET) was designed and evaluated for their antidepressant potential in vitro and in vivo. Among these heterocycle-fused phenylcyclohexylamine derivatives, compound A16 demonstrated potent and relatively balanced multi-target activity (A16: IC50(NMDAR): IC50(SERT): IC50(DAT): IC50(NET) = 1.8:1.0:1.9:1.3) compared to the lead compound S1. Pharmacokinetic studies revealed that A16 exhibited moderate clearance in microsomes and favorable oral brain exposure in mice. In vivo assessments showed that A16 and its R-isomer A17 exhibited significant antidepressant-like effects in the forced swim test and tail suspension test in mice. Notably, A17 demonstrated significant antidepressant-like effects at doses as low as 1 mg/kg, with no indication of addiction risk at 20 mg/kg. Collectively, these findings identify A17, a heterocycle-fused phenylcyclohexylamine as a promising scaffold for developing non-addictive, rapid-acting antidepressants.

Recent evidence suggests that the rapid-acting antidepressant ketamine has immune regulatory functions. The complement system is an important component of the innate immune response and plays a key role in synaptic plasticity. An increase in complement component 3 (C3) expression was previously found in the prefrontal cortex of individuals with depression. Given the complement system's role in depression and ketamine's potential anti-inflammatory properties, there is reason to suspect overlap between the complement system and ketamine's mechanism of action. This post-hoc study analyzed data from 39 individuals with major depressive disorder (MDD) and 25 healthy volunteers who previously participated in a randomized, double-blind trial comparing intravenous ketamine (0.5 mg/kg) to placebo. Blood was obtained at baseline, 230 min, Day 1, and Day 3. Plasma levels of C3a and C4a, two key complement proteins implicated in synaptic plasticity, were determined by ELISA. Linear mixed models were used to test baseline sex differences, whether differences varied by diagnosis, and ketamine's effects (versus placebo) on C3a and C4a levels in the MDD group only. A significant diagnosis-by-sex interaction was observed for C3a but not C4a levels. Drug effects on C3a and C4a levels did not vary over time. These results suggest that treatment strategies targeting the complement pathway may yield fruitful insights and/or advances in treatment options for MDD.

Subanesthetic-dose ketamine has recently been reported to improve hedonic pleasures associated with social interactions and altruism in individuals with treatment-resistant depression. However, whether ketamine-among other glutamate receptor modulators-also improves empathy and/or prosocial behavior in humans remains unknown. Under a framework grounded in neurobiology that proposes that prosocial behavior is preceded by empathy, this systematic review sought to: (1) explore the entactogenic effects of glutamate receptor modulators observed in clinical trials (as either primary or secondary outcomes), and (2) synthesize the findings regarding which glutamate receptor modulators produce entactogenic effects. Thirty studies that included self-reported ratings, neuroimaging, and/or behavioral task outcomes met inclusion criteria suggesting potential entactogenic effects associated with ketamine and, to less convincing extent, d-cycloserine (DCS). The findings suggest that ketamine and DCS may modulate self- and other-perception, involving changes in activity in brain regions involved in empathetic concerns and mentalizing, the ability to understand one's own and others' thoughts and feelings. These findings may guide potential therapeutic interventions for neuropsychiatric conditions associated with impaired empathy and prosocial behavior, including mood disorders, neurodevelopmental disorders, psychotic disorders, and personality disorders.

Ketamine, a dissociative compound, shows promise in treating mood disorders, including treatment-resistant depression (TRD) and bipolar disorder (BD). Despite its therapeutic potential, the neurophysiological mechanisms underlying ketamine's effects are not fully understood. This study explored acute neurophysiological changes induced by subanesthetic doses of ketamine in BD patients with depression using electroencephalography (EEG) biomarkers. A cohort of 30 BD (F = 12) inpatients with TRD undergoing ketamine treatment was included in the study. EEG recordings were performed during one of the ketamine infusions with doses ranging from 0.5 to 1 mg/kg, and subjective effects were evaluated using the Clinician-Administered Dissociative States Scale (CADSS). Both rhythmic and arrhythmic features were extrapolated from the EEG signal. Patients who exhibited a clinical response to ketamine treatment within one week were classified as early responders (ER), whereas those who responded later were categorized as late responders (LR). Ketamine reduced low-frequency spectral power density while increasing gamma oscillatory power. Additionally, ketamine flattened the slope of the power spectra, indicating altered scale-free dynamics. Ketamine also increased brain signal entropy, particularly in high-frequency bands. Notably, LR exhibited greater EEG changes compared to ER, suggesting endophenotypic differences in treatment sensitivity. These findings provide valuable insights into the neurophysiological effects of ketamine in BD depression, highlighting the utility of EEG biomarkers for assessing ketamine's therapeutic mechanisms in real-world clinical settings. Understanding the neural correlates of ketamine response may contribute to personalized treatment approaches and improved management of mood disorders.

Ketamine, a non-competitive NMDA receptor antagonist, produces antidepressant effects at subanesthetic doses. The therapeutic effect, however, is often accompanied by cognitive side effects, including memory impairments. Yet, the specific effects of ketamine on different processes of implicit and explicit memory remain to be elucidated.

We examined the effect of an antidepressant dose of ketamine (10 mg/kg, IP) on the encoding, retrieval, and modulation processes of fear memory and spatial memory in adult Wistar rats.

Ketamine was administered before the fear acquisition, retrieval, or extinction procedures in a Pavlovian fear conditioning task. In another set of experiments, it was administered before the training, probe trial, or reversal training phases of the Morris Water Maze (MWM).

The antidepressant dose of ketamine partially impaired fear extinction when administered before the acquisition or retrieval. In contrast, it facilitated memory modulation and decreased the escape latency in the first day of reversal training in the MWM when administered before the training or reversal training sessions. Encoding or retrieval performance in either type of memory was not affected.

These findings show that ketamine does not impair the acquisition or retrieval processes of cued fear or spatial memory; but exerts differential effects on memory modulation of these implicit and explicit memory paradigms, by disrupting fear extinction and facilitating reversal spatial learning.

Due to the numerous limitations of ketamine as a rapid-acting antidepressant drug (RAAD), research is still being conducted to find an effective and safe alternative to this drug. Recent studies indicate that the partial mGlu5 receptor negative allosteric modulator (NAM), 2-(2-(3-methoxyphenyl)ethynyl)-5-methylpyridine (M-5MPEP), has therapeutic potential as an antidepressant.

The study aimed to investigate the potential rapid antidepressant-like effect of M-5MPEP in a mouse model of depression and to determine the mechanism of this action.

Chronic unpredictable mild stress (CUMS) was used as an animal model of depression. The effects of single and four-day administration of M-5MPEP on CUMS-induced animal behaviors reflecting anhedonia, apathy, and helplessness were studied. Western blot was applied to measure the levels of proteins potentially involved in a rapid antidepressant effect, including mammalian target of rapamycin (mTOR), eukaryotic elongation factor 2 (eEF2), tropomyosin receptor kinase B (TrkB), and serotonin transporter (SERT), both in the hippocampus and the prefrontal cortex (PFC). Furthermore, excitatory synaptic transmission and long-term potentiation (LTP) were measured in the medial PFC (mPFC).

We showed that M-5MPEP administration for four consecutive days abolished CUMS-induced apathy- and anhedonia-like symptoms in a mouse model of depression. We also found that these effects were accompanied by changes in hippocampal TrkB levels and mTOR and eEF2 levels in the PFC. Using electrophysiological techniques, we showed that the four-day M-5MPEP treatment reversed chronic stress-induced increases in excitatory synaptic potential and CUMS-impaired LTP in the mPFC.

Partial mGlu5 receptor NAM, M-5MPEP, appears to be a potentially effective new RAAD and deserves further study.

N-methyl-D-aspartate receptors (NMDA receptors) play a crucial role as ionotropic glutamate receptors in regulating neuroplasticity, learning, memory, and a range of psychiatric disorders. Studies indicate that dysfunction of NMDA receptors is a key pathological mechanism in depression, where abnormal activation can result in neuronal excitotoxicity, excessive extracellular calcium ion accumulation, and disrupted neuroplasticity. As a non-competitive NMDA receptor antagonist, ketamine quickly relieves depressive symptoms by decreasing the activity of extracellular NMDA receptors and activating the mTOR signaling pathway. The treatment can improve severe depression and suicide thoughts within hours, but its potential for hallucinations, dissociative symptoms, and dependency restricts its broader application. Esketamine has demonstrated improvements in both side effects and efficacy and has received FDA approval, while other compounds with NMDA receptor modulating functions, such as memantine and rapastinel, are also showing potential in exploration. Future studies should concentrate on the molecular mechanisms of NMDA receptors, aiming to develop safer and more effective medications, and refine treatment strategies to offer personalized choices and longer-lasting efficacy for the treatment of depression.

Ketamine may be a novel pharmacologic approach to enhance resilience and protect against stress-related disorders, but the molecular targets underlying this response remain to be fully characterized. The multifunctional protein p11 is crucial in the pathophysiology of depression and antidepressant responses. However, it is still unclear whether p11 plays a role in the pro-resilience effects induced by ketamine. Here, we demonstrated that prophylactic administration of ketamine buffers passive stress-induced maladaptive phenotypes induced by chronic stress exposure. Spatial neurotransmitter and metabolite analysis revealed that prophylactic ketamine was also effective in blunting stress-induced disturbances of tryptophan metabolism in dorsal raphe nuclei (DRN). Additionally, we demonstrated that ketamine prevented chronic restraint stress-induced p11 reduction in DRN, a highly p11-enriched region. Furthermore, we provide novel evidence indicating that p11 deficiency regulates susceptibility to stress-induced depression-related phenotypes, and these behavioral maladaptations are dependent, at least in part, on p11 function in serotonergic neurons. Spatial neurotransmitter and metabolite analysis also showed a reduction of tryptophan and dopamine metabolism in DRN of serotonergic p11-deficient mice. Viral-mediated downregulation of p11 within DRN induced a stress-susceptible phenotype. Finally, our results also unveiled that the ability of ketamine to elicit a pro-resilience response against stress-induced maladaptive phenotypes was occluded when p11 was selectively deleted in serotonergic neurons. Altogether, we showed a previously unexplored role of the DRN circuit in regulating stress susceptibility and resilience-enhancing actions of ketamine.

The classic article by Domino et al. was the first clinical report and presented the first-in-human study of what would become the drug ketamine. Ketamine has become an analgesic, anesthetic, antidepressant, and drug of misuse. It remains today the only "dissociative anesthetic". It has challenged classical pharmacologic theory and drug development paradigms. The first report on CI-581 could never have envisioned the pharmacologic complexity or clinical utility of this molecule.

An acute increase in excitatory synaptic transmission contributes to the rapid antidepressant actions of neuroplastogens, including ketamine and its bioactive metabolite, (2R,6R)-hydroxynorketamine (HNK). It is hypothesized that drug-induced metaplastic changes in synaptic strength account for therapeutically relevant behavioral adaptations in vivo. Using the plasticity-deficient Wistar Kyoto model of treatment-resistant depression, we demonstrate that (2R,6R)-HNK potentiates glutamatergic transmission, promotes synaptic strength, restores long-term potentiation (LTP), and reverses deficits in hippocampal-dependent synaptic activity and behavior. (2R,6R)-HNK selectively potentiated CA1 pyramidal neuron activity during novelty exploration and restored Schaffer collateral-dependent spatial recognition memory. Prior experience with spatial learning partially occluded LTP in control rats, an effect mimicked in LTP-impaired rats in which spatial learning deficits were reversed by (2R,6R)-HNK. These findings demonstrate that (2R,6R)-HNK exerts rapid neuroplastogenic effects in vivo, which improve cognitive function and promote adaptive changes in synaptic strength at functionally impaired synapses.

Background/Objective: Major depressive disorder (MDD) is a common mental disorder, with a significant portion of patients developing treatment-resistant depression (TRD). Esketamine is an antagonist of the N-methyl-D-aspartate receptor indicated as a nasal spray in combination with other antidepressants for adults with TRD. Signals of suspected adverse reactions (SARs) to esketamine from the EudraVigilance database in European countries were analyzed for a more defined safety profile of this drug in the real world. Methods: SARs to esketamine reported in the data system EudraVigilance were analyzed, and disproportionality analysis for adverse reactions indicating suicidality for esketamine, in comparison to the antidepressants fluoxetine and venlafaxine, was performed. Results: Increases in blood pressure (15.4%) and dissociation (15.0%) were the most frequently reported SARs. The sex distribution indicates the prevalence of women, except for increased blood pressure and completed suicide, which were signaled in men, while adults (18-64 years) and elders (65-85 years) were the ages with the largest number of reported adverse reactions to esketamine. The results indicate the existence of a potential increase in the risk of suicide in depressed patients taking esketamine when compared with fluoxetine and venlafaxine. Conclusions: Apart from carefulness due to the known limitations of pharmacovigilance research conducted by using data systems of spontaneous signals for SARs, the analysis of data points toward the need for greater attention being paid to the potential risk of suicide following the prescription of esketamine in depressed subjects. In this regard, as regulatory agencies also recommend, patients with a history of suicide-related events or those exhibiting a significant degree of suicidal ideation prior to beginning treatment should receive more careful monitoring during treatment.

Ketamine is recognized as a rapid and sustained antidepressant, particularly for major depression unresponsive to conventional treatments. Anhedonia is a common symptom of depression for which ketamine is highly efficacious, but the underlying circuits and synaptic changes are not well understood. Here, we show that the nucleus accumbens (NAc) is essential for ketamine's effect in rescuing anhedonia in mice subjected to chronic stress. Specifically, a single exposure to ketamine rescues stress-induced decreased strength of excitatory synapses on NAc-D1 dopamine receptor-expressing medium spiny neurons (D1-MSNs). Using a cell-specific pharmacology method, we establish the necessity of this synaptic restoration for the sustained therapeutic effects of ketamine on anhedonia. Examining causal sufficiency, artificially increasing excitatory synaptic strength onto D1-MSNs recapitulates the behavioral amelioration induced by ketamine. Finally, we used opto- and chemogenetic approaches to determine the presynaptic origin of the relevant synapses, implicating monosynaptic inputs from the medial prefrontal cortex and ventral hippocampus.

The pharmacologically active (R,S)-ketamine (ketamine) metabolite (2 R,6 R)-hydroxynorketamine (HNK) maintains ketamine's preclinical antidepressant profile without adverse effects. While hypotheses have been proposed to explain how ketamine and its metabolites initiate their antidepressant-relevant effects, it remains unclear how sustained therapeutic actions arise following drug elimination. To distinguish the physiological mechanisms involved in the rapid from sustained actions of HNK, we utilized extracellular electrophysiology combined with pharmacology to develop an in vitro hippocampal slice incubation model that exhibited pharmacological fidelity to the 1) rapid synaptic potentiation induced by HNK at the Schaffer collateral-CA1 (SC-CA1) synapse during bath-application to slices collected from mice, and 2) maintenance of metaplastic (priming) activity that enhanced N-methyl-D-aspartate receptor (NMDAR) activation-dependent long-term potentiation (LTP) hours after in vivo dosing. We used this model to reveal novel mechanisms engaged in HNK's temporally-sensitive antidepressant-relevant synaptic actions, finding that the induction of synaptic potentiation by HNK did not require NMDAR activity, but NMDAR activity was necessary to maintain synaptic priming. HNK required protein kinase A (PKA) activity to rapidly potentiate SC-CA1 neurotransmission to facilitate synaptic priming that persistently promoted LTP formation. HNK's rapid actions were blocked by inhibitors of adenylyl cyclase 1 (AC1), but not an AC5 inhibitor. We conclude that HNK rapidly potentiates SC-CA1 synaptic efficacy, which then stimulates priming mechanisms that persistently favor plasticity. Targeting such priming mechanisms may be an effective antidepressant strategy, and our incubation model may aid in revealing novel pharmacological targets.

Abnormalities during rapid eye movement (REM) sleep contribute to the pathophysiology of major depressive disorder (MDD), but few studies have explored the relationship between REM sleep and treatment-resistant depression (TRD). In MDD, REM sleep abnormalities often manifest as alterations in total night REM Density (RD), RD in the first REM period (RD1), and REM Latency (RL). Among these, RD1 is notably considered a potential endophenotype of depression. This study compared REM sleep markers between 63 drug-free individuals with TRD (39 F/24 M) and 41 healthy volunteers (25 F/16 M). It also investigated the effects of ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, on these REM sleep variables. Specifically, the study investigated whether RD1 could predict antidepressant response to ketamine. TRD participants showed higher RD1 and shorter RL at baseline compared to HVs, as assessed via non-parametric tests, but Total Night RD did not differ between the two groups. Ketamine treatment decreased RD1 in TRD participants but did not affect Total Night RD or RL. As assessed via the Support Vector Machine (SVM) algorithm, baseline RD1 level moderately predicted antidepressant response to ketamine versus non-response (area under the receiver operating characteristic (ROC) curve (AUC) = 0.73, with a median accuracy of 0.75), wherein TRD participants with higher baseline RD1 were more likely to respond to ketamine. These results underscore the utility of RD1 for identifying individuals most likely to benefit from ketamine treatment, enabling more targeted and effective therapeutic strategies. Clinical Trials Identifier: NCT00088699, NCT01204918.

Since their introduction in the 1950s by Peter Dews, behavioral pharmacology laboratories have collected experimental data for discovery, approval, and regulation of many new and improved therapeutic agents across a host of therapeutic domains. The ethical use of animals in research requires evaluation of the value of animal data to justify their use. The present commentary provides a discussion of the risk-benefit analysis of the use of behavioral methods in drug discovery and drug development using antidepressants as an example. It is concluded that there are some misconceptions both within and outside drug discovery organizations as to the value of behavioral methods. We argue that there are no fully functional disease models of psychiatric disorders. The methods used in behavioral pharmacology are best viewed as whole-animal biological readouts of the actions of drugs. Behavioral pharmacology data, placed in the context of other pharmacological findings, enable the construction of confidence levels regarding the hypothesis that a new chemical entity will provide therapeutic benefit at tolerable and safe dose levels. The exclusion of behavioral pharmacology would diminish the ability of the drug discovery data set to provide needed levels of assurance that the efficacy and safety of the new chemical entity will translate into patients. New methodologies for the discovery of medicines are being developed (eg, tissue on chips and artificial intelligence paradigms). However, until nonbehavioral procedures are validated, the absence of behavioral pharmacology in drug discovery research shifts the risk of making new medicines onto the health of patients. SIGNIFICANCE STATEMENT: The pros and cons of using behavioral pharmacology in the discovery and development of new medicines are discussed.

We previously reported that a single injection of (R,S)-ketamine or its metabolite (2S,6S)-hydroxynorketamine (HNK) prior to stress attenuated learned fear. However, whether these drugs attenuate learned fear through divergent or convergent effects on neural activity remains to be determined.

129S6/SvEv male mice were injected with saline, (R,S)-ketamine, or (2S,6S)-HNK 1 week before a 3-shock contextual fear conditioning paradigm. Five days later, mice were re-exposed to the aversive context and euthanized 1 hour later to quantify active cells. Brains were processed for c-fos immunoreactivity, and neural networks were built with a novel, wide-scale imaging pipeline.

We found that (R,S)-ketamine and (2S,6S)-HNK attenuated learned fear. Fear-related neural activity was altered in dorsal CA3 following (2S,6S)-HNK; ventral CA3 and CA1, infralimbic and prelimbic regions, insular cortex, retrosplenial cortex, piriform cortex, nucleus reuniens, and periaqueductal gray following both (R,S)-ketamine and (2S,6S)-HNK; and in the paraventricular nucleus of the thalamus (PVT) following (R,S)-ketamine. Dorsal CA3 and ventral hippocampus activation correlated with freezing in the (R,S)-ketamine group, and retrosplenial cortex activation correlated with freezing in both (R,S)-ketamine and (2S,6S)-HNK groups. (R,S)-ketamine increased connectivity between cortical and subcortical regions while (2S,6S)-HNK increased connectivity within these regions.

This work identifies novel nodes in fear networks that involve the nucleus reuniens, piriform cortex, insular cortex, periaqueductal gray, and retrosplenial cortex that can be targeted with neuromodulatory strategies or pharmaceutical compounds to treat fear-induced disorders. This approach could be used to optimize target engagement and dosing strategies of existing medications.

Depressive disorder (a subclass of mental disorders) is characterized by persistent affective symptoms. Without timely therapeutic intervention, it leads to clinical deterioration manifested as reduced quality of life and may increase suicide risk in severe cases. Given its complex etiology, intertwined with intrinsic factors such as genetics and environment, and impacted by various issues such as first-pass effect and blood-brain barrier, the therapeutic efficacy of many antidepressant medications is limited for patients. Therefore, by delving into the exploration of novel antidepressant drugs and biomaterials, this review aims to offer fresh perspectives that may facilitate the discovery of innovative antidepressant medications and enhance their therapeutic outcomes. Notably, the review highlights polymers' crucial role in enhancing antidepressants' pharmacological efficacy and pharmacokinetic properties by optimizing their parameters, and they will undoubtedly become powerful tools in improving antidepressive outcomes in future research.

Oral esketamine for patients with treatment-resistant depression (TRD) could offer certain advantages over other routes, such as intravenous or intranasal, but it has not been systematically studied in a real-world setting.

Here we present results from a relatively large naturalistic study to evaluate the effectiveness, tolerability, and safety of oral esketamine in patients with TRD.

One hundred eighty-five adults with severe TRD (average of 8.1 antidepressant trials plus electroconvulsive therapy in 63% without beneficial outcome) received oral esketamine treatment twice-weekly for 6 weeks with individually titrated doses ranging from 0.5 to 3 mg/kg. Outcome measures included change from baseline to week 6 on the Hamilton Depression Rating Scale (HDRS17), Minimal Clinically Important Difference (MCID), response, remission, self-reported symptom improvement, functioning, and side effects.

Oral esketamine treatment improved depressive symptom severity on the HDRS17 from 21.2 to 15.8 (p < 0.001). MCID, response, and remission rates were 47.1%, 26.8% and 15.6% respectively. In 45.9% of participants, treatment was continued after 6 weeks to maintain initial positive effects. Side effects were reported frequently but were overall well tolerated. The drop-out rate was 7.6%. We found no significant adverse effects associated with urinary tract or cognition.

Repeated treatment with oral esketamine is effective in improving depressive symptom severity in highly treatment-resistant depressive patients. It is safe, well tolerated, and patient-friendly. Considering the level of treatment resistance, outcomes were in the range of studies investigating other routes of (es)ketamine administration.

The aim of this study was to investigate the effects of the antidepressant tianeptine on the mechanistic target of rapamycin complex 1(mTORC1)-mediated autophagy pathway in primary hippocampal neurons exposed to B27-deprived conditions. When primary hippocampal neurons were treated with tianeptine at doses of 1, 10, 50, and 100 µM for 3 days under B27-deprived conditions, we observed that it activated autophagy and increased the formation of autophagosomes through the upregulation of autophagic proteins, including autophagy-activating kinase 1 (ULK1), Beclin 1, LC3B-II/I, and p62. And at a concentration of 100 µM tianeptine, the decrease in mTORC1 phosphorylation induced by B27 deprivation was significantly reversed. Changes in the expression of autophagic proteins induced by B27 deprivation were reversed by tianeptine treatment in a concentration-dependent manner, and tianeptine significantly reduced the increase in LC3B membrane number induced by B27 deprivation, an effect that was blocked by pretreatment with rapamycin. In conclusion, tianeptine attenuated the activity of mTORC1-mediated autophagy in primary rat hippocampal neurons under B27-deprived conditions. These results may suggest a novel mechanism by which tianeptine may affect autophagy in neurons.

The probabilistic reversal learning task (PRL) is sometimes used in the context of major depressive disorder (MDD) to assess impairments in cognitive flexibility and feedback sensitivity because behavior in the task is sensitive to pharmacological interventions. Because traditional antidepressants are limited in their effectiveness, new drugs are needed to combat MDD. Ketamine has recently been investigated in the context of probabilistic reversal learning (PRL), but findings regarding its therapeutic efficacy have been mixed. One reason for this could be that almost all non-human versions of the PRL use signaled reward omission (i.e., timeout) as the punishing stimulus. It has long been known that timeout periods do not always function as punishers, and the inclusion of a known effective punishing stimulus could help to produce results of improved translational value.

The present experiment sought to examine the effects of ketamine in the PRL when electric footshocks accompanied timeout periods or not.

A baseline of PRL performance was established with 40 rats in which typical timeouts followed non-rewarded trials. In Phase 2, half the rats also received probabilistic footshock punishment for non-rewarded trials, while the other half continued under baseline conditions. Finally, a single dose of ketamine was administered to half of the rats (n = 10) in each condition (i.e., shock and no shock).

Shock punishment increased behavioral persistence and cognitive flexibility in the PRL, but ketamine had no effect beyond causing acute impairments.

These results suggest that the conditions of punishment during the PRL can have a significant impact on performance in the task and corroborate previous findings that ketamine may not impact cognitive flexibility or reward processing in healthy rats.

Ketamine is known for its rapid antidepressant effect, but its impact on affective information processing (including attentional bias [AB], a putative cognitive mechanism of depression) remains largely unexplored. We leveraged a novel measurement of AB and sought to 1) establish adequate test-retest reliability and validity among participants with depression prior to ketamine treatment and 2) harness a single dose of ketamine to assess mechanistic shifts in AB and their relationship to antidepressant efficacy.

A novel dual probe video task was used to index AB toward sad film clips. In study 1, treatment-seeking adults with moderate-to-severe depression (N = 40) completed the task at baseline, 1-week retest, and 1-month retest; a subset of participants (n = 15) also performed the task at 24 hours postketamine infusion (0.5 mg/kg over 40 minutes). In study 2, participants (N = 43) completed the task pre- and 24 hours postketamine.

Indices from the novel AB task were stable prior to ketamine, demonstrating good 1-week and 1-month test-retest reliability. Participants in both studies exhibited a robust reduction in AB from pre- to 24 hours postketamine infusion. In study 1, cross-sectional correlations were observed between AB and clinician-rated depressive symptoms at each pretreatment assessment. In study 2, changes in AB were correlated with improved symptoms from pre- to postinfusion.

Results provide evidence for the validity of a novel, psychometrically robust measure of AB among individuals with depression. Findings indicate that ketamine reliably and rapidly reduces AB, offering insight into a replicable, potential cognitive mechanism involved in its antidepressant action.

Alcohol use and major depressive disorder are frequently comorbid, with individuals diagnosed with a substance use disorder being nearly three times as likely to have major depression. Poor treatment responses are found for both disorders and are further complicated when they co-occur, underscoring the need for better therapies. One potential candidate is ketamine, which has been shown to have rapid and long-lasting effects in individuals with treatment-resistant depression and, in some studies, reduces drinking in alcohol use disorder. However, though women are more likely to have this comorbidity, few studies have examined sex-specific effects of ketamine on alcohol drinking, nor have studies assessed the potential for ketamine to reduce reinstatement of alcohol seeking.

The primary goal of the present studies was to determine the effects of ketamine on alcohol-motivated behaviors in male and female rats, including in a model of stress + cue-induced reinstatement of alcohol seeking using yohimbine (YOH).

We found a selective reduction in alcohol self-administration and YOH + cue-induced reinstatement in females, but not males at a dose of 10 mg/kg ketamine. However, the same dose of ketamine was effective in reducing YOH + cue-induced reinstatement of saccharin seeking in both sexes. In addition, a different NMDAR antagonist, memantine, was effective in reducing alcohol seeking in both sexes, while the ketamine metabolite hydroxynorketamine (HNK) had no effects.

In summary, these data suggest that antagonism of NMDARs may be effective in reducing stress-related alcohol seeking, but that ketamine has unique properties that lead to female-specific effects on alcohol seeking.

Nitrous oxide (N2O) induces rapid and durable antidepressant effects. The cellular and circuit mechanisms mediating this process are not known. Here we find that a single dose of inhaled N2O induces rapid and specific activation of layer V (L5) pyramidal neurons in the cingulate cortex of rodents exposed to chronic stress conditions. N2O-induced L5 activation rescues a stress-associated hypoactivity state, persists following exposure, and is necessary for its antidepressant-like activity. Although NMDA-receptor antagonism is believed to be a primary mechanism of action for N2O, L5 neurons activate even when NMDA-receptor function is attenuated through both pharmacological and genetic approaches. By examining different molecular and circuit targets, we identify N2O-induced inhibition of calcium-sensitive potassium (SK2) channels as a key molecular interaction responsible for driving specific L5 activity along with ensuing antidepressant-like effects. These results suggest that N2O-induced L5 activation is crucial for its fast antidepressant action and this effect involves novel and specific molecular actions in distinct cortical cell types.

To determine whether intraoperative low-dose esketamine ameliorates depression in women having breast cancer surgery.

A prospective single-center double blind randomized placebo-controlled trial.

Perioperative period, operating room, post anesthesia care unit and hospital ward.

108 women 18-65 years old who were scheduled for elective breast cancer surgery. All had preoperative depressive symptoms as defined by Montgomery-Åsberg depression scores ≥12 (range, 0-60; higher scores indicate more severe depression).

Eligible participants were randomized to esketamine 0.25 mg/kg or saline placebo. Blinded trial drugs were given intravenously over the initial 40 min of anesthesia.

Our primary outcome was the fraction of patients who had at least a 50 % reduction in the Montgomery-Åsberg depression score within 3 postoperative days. Secondary outcomes included the fraction of patients with depression remission defined as Montgomery-Åsberg scores ≤10, the numeric value of the Montgomery-Åsberg depression scores, postoperative severe pain, and anxiety as determined by the Generalized Anxiety Disorder 7-item score. Adverse events were monitored for 72 postoperative hours.

54 women each were randomized to esketamine and saline, and 104 were available for our intent-to-treat analysis. The mean age was 50 years. Esketamine non-significantly doubled the fraction of patients who had a 50 % reduction in their depressions scores: 27 % vs 13 %, odds ratio 2.4, [95 % CI 0.9 to 6.6], P = 0.087. Montgomery-Åsberg depression scores were nearly a factor-of-two and significantly lower (better) on postoperative days 1 to 5 in patients given esketamine. Montgomery-Åsberg scores decreased significantly more from baseline in patients randomized to esketamine: mean difference - 2.5 [95 % CI -4.5 to -0.6], P = 0.010. Esketamine treatment had no significant effect on other secondary outcomes or on adverse events.

Intraoperative administration of 0.25 mg/kg esketamine did not significantly improve the fraction of depressed women having breast cancer patients who had a 50 % reduction in their depression scores at 3 days postoperatively. However, the observed factor-of-two treatment effect was clinically meaningful and esketamine significantly reduced short-term postoperative depression scores without provoking complications. Robust trials are warranted. Registration Trial registry:http://www.chictr.org.cn/; Identifier: ChiCTR2300071062.

The prevalence of stress-induced disorders, including depression, anxiety, posttraumatic stress disorder, and postpartum depression, has been increasing, while current treatment approaches are limited. As a result, researchers are exploring alternative treatments that include ketamine as a prophylactic against these disorders. This review provides an overview of the current knowledge on the use of ketamine as a prophylactic for stress-induced disorders, including preclinical and clinical findings on (R,S)-ketamine, as well as (2R,6R)- and (2S,6S)-hydroxynorketamine. We also explore the potential underlying mechanisms involved in preventing these disorders, including the brain regions/circuits, as well as glutamatergic, dopaminergic, serotonergic, and inflammatory processes known to be involved, as evidenced by studies with ketamine and its metabolites. Additionally, we highlight the limitations and risks associated with ketamine use, such as age- and sex-specific efficacy, potential long-term and adverse effects, and legal and ethical considerations. Finally, we discuss future research directions, including the implications for clinical practice, integrating ketamine into current treatment approaches, and potential advancements in ketamine-based therapies. Overall, the literature emphasizes the importance of continuing research to better understand the potential benefits and risks of ketamine as a prophylactic for stress-induced disorders.

Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis and oxidative stress represent important mechanisms that have been implicated in etiopathology of depression. Although first antidepressants were introduced in clinical practice more than six decades ago, approximately 30 % of patients with a diagnosis of depression show treatment resistance. A noncompetitive N-methyl-d-aspartate receptor antagonist ketamine has shown promising rapid antidepressant effects and has been approved for treatment-resistant depression (TRD). In the present study, we investigated antioxidant and antidepressant-like activity of a single subanesthetic dose of ketamine (10 mg/kg, ip) in a rodent model of TRD induced by adrenocorticotropic hormone (10 μg ACTH/day, sc, 21 days). Behavioral assessment was performed, and plasma biomarkers of oxidative stress and DNA damage in peripheral blood lymphocytes (PBLs) were determined. We observed that ACTH produced depressive-like behavior and significant increase in superoxide anion (O2·-), advanced oxidation protein products (AOPP), malondialdehyde (MDA) and total oxidant status (TOS) in male Wistar rats. This effect was accompanied by reduced activity of antioxidant enzymes - superoxide dismutase (SOD) and paraoxonase1 (PON1) in plasma and increase in DNA damage in PBLs. In the described model of TRD, we have demonstrated antidepressant effects of ketamine for the first time. Our results reveal that ketamine was effective in reducing O2.-, AOPP, MDA and TOS, while enhancing SOD and PON1 activity in ACTH-rats. Collectively, our study sheds light on molecular mechanisms implicated in antioxidant activity of ketamine, thus incentivizing further investigation of its effects on ROS metabolism and antioxidant defenses in clinical trials, particularly in depression.

Objective: To narratively review currently available antidepressants and future potential antidepressants as monotherapy for the treatment of depressive disorders. Methods: Selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), dopamine reuptake inhibitor (bupropion), tricyclic antidepressants (TCAs), and monoamine oxidase inhibitors (MAOIs) were reviewed according to the results from Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Study and systematic reviews. For the rest of the antidepressants, a PubMed/Medline search was conducted with priority for systematic reviews. For drugs in development for depressive disorders, PubMed, Google, and Clinicaltrials.gov databases were used. Results: The STAR*D Study demonstrated that sertraline, venlafaxine, and bupropion monotherapy had similar efficacy in patients with major depressive disorder (MDD) who failed citalopram. A network meta-analyses of randomized, placebo-controlled trials found that SSRIs, SNRIs, bupropion, TCAs, mirtazapine, and agomelatine had similar relative efficacy compared to placebo, but had different acceptability. Gepirone had more failed/negative studies and smaller effect size relative to placebo compared to other antidepressants. The combination of dextromethorphan and bupropion, ketamine infusion, and intranasal esketamine had faster onset of action but similar effect size compared to monoamine-based antidepressants as monotherapy. Brexanolone and zuranolone are effective in postpartum depression (PPD), but the effect size of zuranolone in MDD as monotherapy or adjunctive therapy was very small. Psychedelics, glutamate receptor-related agents, kappa opioid receptor antagonists, orexin receptor antagonists, new anti-inflammatory agents, and biomarker-based antidepressant therapy have been under investigation for depressive disorders. Psychedelics showed faster onset of action, large effect size, and long durability. Conclusions: Monoamine-based antidepressants likely continue to be the mainstream antidepressants for depressive disorder. NMDA receptor antagonists and neurosteroid antidepressants will play a bigger role with the improvement of accessibility. Psychedelics may become a game changer if phase III studies validate their efficacy and safety in depressive disorders.

Unsuccessful response to several courses of antidepressants is a core feature of treatment-resistant depression (TRD), a severe condition that affects a third of patients with depression treated with conventional pharmacotherapy. However, the molecular mechanisms underlying TRD remain poorly understood. Here, we assessed the successful vs. unsuccessful response to ketamine (KET) in chronically stressed mice that failed to respond to initial treatment with fluoxetine (FLX) as a rodent model of TRD and characterized the associated transcriptional profiles in the nucleus accumbens (NAc) using RNA-sequencing. We observed that failed treatment with FLX exerts a priming effect that promotes behavioral and transcriptional responses to subsequent ketamine treatment. We also identified specific gene networks that are linked to both susceptibility to stress and resistance to antidepressant response. Collectively, these findings offer valuable insights into the molecular mechanisms underlying antidepressant resistance and help address a critical gap in preclinical models of TRD.

Subanesthetic doses of (R,S)-ketamine (ketamine) have demonstrated rapid and robust antidepressant effects in individuals with depression. However, individual variability in response to ketamine exists, and current biomarkers of ketamine treatment response are not entirely understood. Preclinical evidence suggests a link between hypothalamic-pituitary-adrenal (HPA) axis activation, a determinant of the stress response system, and ketamine's efficacy in stressed mice exhibiting enhanced antidepressant responses. Here, we assessed the relationship between HPA axis, major depression features, and antidepressant response to ketamine in humans.

We investigated 42 participants following medication washout with treatment-resistant depression who participated in a randomized, placebo-controlled, crossover trial receiving intravenous ketamine. Plasma levels of corticotropin-releasing factor (CRF), adrenocorticotropic hormone (ACTH), and cortisol were measured at baseline. Ketamine's antidepressant effects were assessed using the Montgomery-Asberg Depression Rating Scale.

We found that baseline HPA axis hormone levels did not significantly moderate the antidepressant effects of ketamine. However, a negative association was observed between ACTH and CRF levels and the overall duration of depressive episodes, suggesting potential biomarker implications. Also, a negative correlation between baseline depressive scores and age of onset was observed, suggesting that the severity of depression might be greater if it develops at a younger age, indicating more enduring stress on the brain and body.

Although we did not find a moderation effect of the plasma HPA axis hormones on the antidepressant effects of ketamine, moderation effects of the brain HPA axis hormones cannot be precluded and warrants further investigation. Importantly, our results implicate HPA axis components as potential biomarkers for the duration of depressive episodes.

After decades of limited progress in depression treatment, recent advancements have sparked renewed interest in developing novel antidepressants, particularly rapid-acting antidepressants (RAADs). Despite these promising developments, there remains a significant gap in research on bipolar depression. While several antipsychotics have been investigated for their efficacy in bipolar depression due to the reduced risk of mania induction, research on RAADs, such as (es)ketamine, remains scarce despite their demonstrated safety and effectiveness. In this review, we give an overview of current developments in RAADs in the context of bipolar disorder. Both published studies as well as phase II, III, and IV studies on bipolar depression (based on ClinicalTrials.gov) are reviewed in this work. The following RAAD substance classes have been or are currently being investigated as possible treatments for bipolar depression: NMDA antagonists and indirect AMPA agonists (ketamine, esketamine, riluzole, felbamate), GABAA (gamma-aminobutyric acid A) activators or positive allosteric modulators (zuranolone, pregnenolone, PEA), psychedelics (psilocybin, 5-MeO-DMT), muscarine receptor antagonists (scopolamine), and kappa opioid receptor antagonists (navacaprant). Other than the well-established efficacy and safety of (es)ketamine in treating bipolar depression, there has been little research effort in the treatment of bipolar depression. Recent research into RAADs demonstrates the growing field of novel mechanisms of action in the pharmacological treatment of bipolar depression. However, there is an urgent need for well-controlled clinical studies on RAADs in bipolar depression to expand treatment options and improve outcomes for millions of affected individuals worldwide.

Ketamine, a general anesthetic, has rapid and sustained antidepressant effects when administered at lower doses. Anesthetic levels of ketamine reduce excitatory transmission by binding deep into the pore of NMDA receptors where it blocks current influx. In contrast, the molecular targets responsible for antidepressant levels of ketamine remain controversial. We used electrophysiology, structure-based mutagenesis, and molecular and kinetic modeling to investigate the effects of ketamine on NMDA receptors across an extended range of concentrations. We report functional and structural evidence that, at nanomolar concentrations, ketamine interacts with membrane-accessible hydrophobic sites on NMDA receptors, which are distinct from the established pore-blocking site. These interactions stabilize receptors in pre-open states and produce an incomplete, voltage- and pH-dependent reduction in receptor gating. Notably, this allosteric inhibitory mechanism spares brief synaptic-like receptor activations and preferentially reduces currents from receptors activated tonically by ambient levels of neurotransmitters. We propose that the hydrophobic sites we describe here account for clinical effects of ketamine not shared by other NMDA receptor open-channel blockers such as memantine and represent promising targets for developing safe and effective neuroactive therapeutics.

Modern electroconvulsive therapy (ECT) and the approval of nasal esketamine for clinical use have significantly improved the approach to treatment-resistant depression (TRD), which is defined as non-response to at least two different courses of antidepressants with verified adherence to treatment, adequate dosage, and duration of treatment. The goal of this literature review is to present the newest evidence regarding efficacy and safety. Furthermore, we aim to provide an overview of future perspectives in this field of research, for example, regarding structural and molecular effects. Both treatment methods will be critically evaluated for their individual advantages, disadvantages, and response rates. Firstly, we will discuss the well-established method of ECT and its different treatment modalities. Secondly, we will discuss the properties of ketamine, the discovery of its antidepressive effects and the route to clinical approval of the esketamine nasal spray. We will comment on research settings which have evaluated intravenous ketamine against ECT. The decision-making process between esketamine nasal spray or ECT should include the assessment of contraindications, age, severity of disease, presence of psychotic symptoms, patient preference and treatment accessibility. We conclude that both treatment options are highly effective in TRD. If both are indicated, pragmatically esketamine will be chosen before ECT; however, ECT studies in ketamine non-responders are missing.

This analysis sought to identify potential clinical targets for the suicide crisis. Characteristics of a useful clinical target include elevation at the time of suicide crisis and responsiveness to rapid-acting interventions. Suicidal ideation (SI), depression, and hopelessness were hypothesized to meet these criteria.

Participants were 118 adults across the continuum of suicide risk, including 14 high-risk (HR) individuals who had attempted or seriously considered suicide within the last two weeks. Clinical characteristics were evaluated by: 1) comparing individuals with a recent crisis state to those whose suicide crises had resolved; 2) quantifying responses to a semi-structured interview about the time just before a suicide crisis; and 3) comparing symptomatology before and after an open-label ketamine infusion (0.5 mg/kg) in a subset of the HR group (n = 10).

As hypothesized, SI, depression, and hopelessness were elevated just after a suicide crisis and responded to ketamine, although findings were mixed depending on the assessment used. Psychological pain and traumatic stress symptoms were also associated with the suicide crisis and responded to ketamine. Participants reported high levels of SI, depression, and anxiety just before their suicide attempt.

Limitations include the small sample size, inconsistent assessments across analyses, and that ketamine was the only intervention examined.

These results underscore the importance of SI, depression, hopelessness, psychological pain, and traumatic stress in this population, all of which were elevated during the suicide crisis and responded to ketamine. A multifactorial and longitudinal approach is indicated to assess and treat suicide risk.

The N-methyl-D-aspartate receptor (NMDA-R) subunit GluN2B is abundantly expressed in brain regions critical for synaptic plasticity and cognitive processes. This study investigated the structure-activity relationships (SAR) of NMDA-R ligands using GluN2B as a molecular target. Thirty potential NMDA-R antagonists were categorized into two structural classes: 1-(1-phenylcyclohexyl) amines (series A) and α-amino-2-phenylcyclohexanone derivatives (series B). In series A compounds, the phenyl ring and R1 substituents were positioned at the carbon center of the cyclohexyl ring, with R2 substituents at the para- or meta-positions of the phenyl ring. SAR analysis revealed optimal binding affinity when R1 was carbonyl (C=O) and R2 was 4-methoxy (4-OMe). Series B compounds featured a cyclohexanone scaffold with NH-R1 at the α-position and a phenyl ring bearing R2 substituents at ortho-, meta-, or para-positions. Maximum binding affinity was achieved with R1 as hydrogen (H) and R2 as hydroxyl (OH). Compounds were assessed for GluN2B-mediated ERK activation to evaluate potential metabotropic signaling properties. Approximately 50% of the compounds demonstrated ERK activation through a non-ionotropic signaling cascade involving Src, phosphatidylinositol 3-kinase, and protein kinase C. This study elucidated key structural determinants for NMDA-R binding and characterized a novel metabotropic signaling pathway. Notably, our findings suggest that compounds acting as antagonists at the ionotropic site may simultaneously function as agonists through non-ionotropic mechanisms.