Antidepressant effect of psychedelic compounds and mechanisms underlying the G protein-coupled receptors activation psychedelics: Antidepressant action and GPCR signaling.

Inflammation in treatment-resistant depression: From mechanisms to therapeutics.

To evaluate the acute effects, safety, and tolerability of an open-label whole-brain transcranial photobiomodulation (tPBM) protocol in patients with treatment-resistant depression (TRD). This prospective, open-label, single-arm pilot trial enrolled 29 adult outpatients with TRD with moderate-to-severe depressive symptoms (Montgomery-Åsberg Depression Rating Scale [MADRS] score ≥20) in the intention-to-treat analysis. The intervention involved a standardized whole-brain tPBM protocol delivered via a light-emitting diode-based helmet (near-infrared light, 810 nm; 12.8 W), administered in 20-min sessions, three times weekly for 4 weeks (12 sessions). The primary outcome was clinical response at the end of the acute treatment phase (T1), defined as ≥50% reduction in MADRS scores. Safety and tolerability were evaluated throughout. In total, 22 participants completed treatment (per-protocol, n = 22): MADRS scores decreased significantly from 35.5 ± 6.9 at baseline to 22.9 ± 11.2 post-treatment, reflecting a mean change of -12.5 ± 11.3 points (p < 0.001). Clinical response was achieved in nine participants (40.9%), and remission in two (9.1%). In the intention-to-treat analysis, response and remission rates were 31.0% and 6.9%, respectively. Fourteen participants (63.6%) reported ≥1 mild-to-moderate adverse event; headache was the most common (n = 11, 50.0%). No serious adverse events occurred. A 4-week, whole-brain tPBM protocol was associated with clinically meaningful reductions in the severity of depressive symptoms in patients with TRD and was well tolerated. These findings support the feasibility and potential clinical relevance of whole-brain tPBM as a noninvasive neuromodulation strategy. Larger, randomized, sham-controlled trials are warranted to confirm efficacy and optimize stimulation parameters.

Ketamine and esketamine have emerged as effective and rapid-acting interventions for treatment-resistant depression. Nevertheless, the best-suited candidates for these treatments are not clear. As such, the ability to personalize treatment selection and parameters would likely improve therapeutic response. This systematic review synthesized the literature on clinical and demographic predictors of antidepressant response to ketamine and esketamine, including both unipolar and bipolar treatment-resistant depression. We searched the databases of PubMed, Embase, Scopus, and APA PsychINFO on 25 March, 2025, with an update on 19 November, 2025, to identify studies on the clinical and demographic predictors of ketamine or esketamine effectsin treatment-resistant depression. There were no restrictions on study design. Studies in a language other than English were excluded. Two authors, OAS and VS, independently reviewed studies and resolved conflicted judgments through a discussion. Risk of bias was assessed using the Cochrane RoB 2 for randomized studies and ROBINS-I for non-randomized studies. For each included study, the direction of effect (positive, negative, no association) for predictor variables was extracted. A total of 122 studies (n = 12,674) were included in the review, with 75 distinct samples (n = 6902), published between August 2006 and September 2025. There were 65 studies providing open-label ketamine, 47 secondary analyses of a trial, and 10 randomized controlled trials included. Studies most commonly treated both treatment-resistant unipolar and bipolar depression (k = 62) and solely administered intravenous ketamine at a fixed dosage of 0.5 mg/kg (k = 61). We examined the predictive value of 77 predictor variables, including body mass index, dissociation, and previous neuromodulation treatments. Most variables had more reports revealing no association with antidepressant outcomes than a positive or negative predictive ability.Some promising predictive factors, such as early response to treatment and a family history of substance use disorders, were identified and warrant further exploration. In a comprehensive synthesis of predictor analyses for ketamine and esketamine treatments, most demographic and clinical variables did not confer differential outcomes to ketamine and esketamine treatments, although some promising predictive variables were identified for further investigation. PROSPERO (CRD42024554316).

This systematic review and network meta-analysis (NMA) aimed to compare and rank the efficacy and acceptability of different repetitive transcranial magnetic stimulation (rTMS) modalities for major depressive disorder (MDD). The following databases were searched from inception to October 8, 2025: PubMed, Embase, the Cochrane Library, Web of Science, Chinese Biomedical Database (CBM), Chinese National Knowledge Infrastructure (CNKI), Chinese Science and Technology Periodical Database (VIP), and Wanfang Database. In order to identify relevant unpublished studies and ongoing clinical trials, gray literature and trial registries were examined. The randomized controlled trials that investigated the effect of rTMS interventions for MDD were included. We included studies involving adults (aged ≥ 18 years) with a clinical diagnosis of unipolar MDD, which utilized at least two of the following rTMS modalities: low-frequency left (LFL-) rTMS, high-frequency left (HFL-) rTMS, low-frequency right (LFR-) rTMS, high-frequency right (HFR-) rTMS, bilateral (BL-) rTMS, deep TMS (dTMS), theta burst stimulation (TBS), accelerated rTMS (aTMS), synchronized TMS (sTMS), or sham stimulation. The primary endpoints were efficacy (response rate) and acceptability (dropout rate). Additionally, the symptom remission rate was assessed as a secondary outcome. Two authors independently completed the article selection and data extraction. We also evaluated the risk of bias in the included studies with the Cochrane ROB 2.0 tool. The certainty of evidence for each outcome was assessed using the Confidence in Network Meta-Analysis (CINeMA) framework. A conventional pairwise meta-analysis was performed using RevMan software. A NMA was performed with Markov chain Monte Carlo simulations to facilitate indirect comparisons across different rTMS modalities. We applied funnel plots to examine publication bias and assessed the robustness of our findings through sensitivity analysis and subgroup analysis. A total of 141 trials comprising 10,587 participants with MDD were included. The aTMS (odds ratio [OR]: 4.14; 95% confidence interval [CI] 2.14, 8.01), TBS (OR: 4.47; 95% CI, 3.13, 6.37), BL (OR: 3.93; 95% CI, 2.56, 6.03), HFL (OR: 3.34; 95% CI, 2.80, 3.98), LFR (OR: 2.90; 95% CI, 2.13, 3.95) demonstrated significantly greater efficacy than sham control. Additionally, aTMS (OR: 4.44; 95% CI, 1.02, 19.29), TBS (OR: 4.78; 95% CI, 1.23, 18.62), BL (OR: 4.21; 95% CI, 1.06, 16.71) also showed superior efficacy compared to LFL. Furthermore, sTMS was less effective than TBS (OR: 0.27; 95% CI, 0.08, 0.94). In terms of achieving remission, TBS (OR: 4.81; 95% CI, 2.59, 8.95), BL (OR: 4.69; 95% CI, 2.27, 9.69), HFL (OR: 3.35; 95% CI, 2.34, 4.81), and LFR (OR: 3.27; 95% CI, 1.48, 7.24) were all significantly superior to sham control. The estimated relative ranking of treatments suggested that TBS (87.2%) might be the most efficacious among all rTMS modalities. The surface under the cumulative ranking curve (SUCRA) probabilities for acceptability were as follows: BL (80.1%), dTMS (78.1%), LFR (62.8%), HFL (56.5%), sham (50.0%), TBS (49.9%), sTMS (34.0%), aTMS (28.3%), LFL (10.4%). Our sensitivity analysis excluding high-risk studies yielded largely consistent results with the primary analysis. In particular, the superiority of TBS over sham stimulation remained stable. Although the effect sizes were slightly reduced, the estimates remained statistically significant. In the treatment-resistant depression (TRD) subgroup, TBS demonstrated the highest probability of response (SUCRA: 87.5%) and remission (SUCRA: 79.2%), with efficacy significantly superior to sham stimulation. In the non-TRD subgroup, aTMS ranked best for response rate (SUCRA: 83.0%), while LFR achieved the highest remission rate (SUCRA: 81.5%; OR: 7.16). No significant differences in acceptability were observed between any active intervention and sham across all subgroups. The risk-of-bias assessment categorized 87 studies as high risk, 51 as having some concerns, and only three as low risk. CINeMA results showed that the comparison of BL versus sham had moderate confidence for remission rate, while other comparisons for response, remission, and acceptability were largely rated as low or very low confidence. TBS had the highest probability of being the most effective rTMS modality for depression, but the confidence intervals overlapped across multiple comparisons, and the effect sizes were modest. High-quality head-to-head trials are needed to confirm these probabilistic rankings.

Intermittent theta burst stimulation modulates brain metabolism in treatment-resistant depression patients: Insights from PET imaging.

Short-term effects of oral ketamine for the treatment of depression: A systematic review and meta-analysis of randomized controlled trials.

Oral administration of (S)-ketamine for treatment-resistant depression (TRD), as alternative to the registered intranasal or off-label intravenous administrations, has high potential. However, it is characterized by an extensive first-pass metabolism, resulting in low (S)-ketamine exposure and high levels of active metabolites, including (S)-norketamine and (S)-hydroxynorketamine. The relative contribution of the parent and metabolites to the resulting antidepressant effects remains unclear. Therefore, this study aimed to first characterize the pharmacokinetics (PK) of (S)-ketamine and its metabolites after oral and intravenous administration in healthy participants and secondly quantify the pharmacokinetic/pharmacodynamic (PKPD) relationship of (S)-ketamine and (S)-norketamine to the subjective effects measured on the visual analogue scale (VAS) 'Feeling High'. Data from a previously conducted clinical study was used, where 17 healthy participants received oral (0.20 and 0.45 mg/kg) and intravenous (0.4mg/kg over 40 min) (S)-ketamine in a randomized, placebo-controlled, crossover clinical trial. A semi-physiological population PK model was developed to describe the first-pass metabolism and (S)-ketamine and subsequently (S)-norketamine concentrations were linked to the VAS 'Feeling High' using a bounded integer modelling approach. A significant (S)-norketamine PKPD relationship was determined alongside (S)-ketamine, but estimated variance of the bounded integer model was high warranting further investigation. Our analysis suggests that not (S)-ketamine, but its metabolite, is the main driver of subjective effects after oral administration, and as such may also contribute to antidepressant effects in TRD patients receiving oral (S)-ketamine.

Predictors of responsiveness to ketamine: An updated systematic review of neuroimaging findings.

Major depressive disorder (MDD) is aheterogeneous, debilitating disorder. Adistinct subgroup within the MDD spectrum is identified to have treatment-resistant depression (TRD). There is an impetus to find alternative treatments for TRD to reduce disease burden and improve quality of life. Psychedelics have been used in the treatment of various psychiatric disorders since the 1950s, with potential benefits in TRD. Aiming to summarize the evidence of using psychedelics for TRD by exploring mechanisms and potential benefits, we conducted aliterature search on different psychedelics with their mechanisms from clinical and preclinical evidence. Psychedelics have been examined in many preclinical studies for efficacy and mechanisms with fewer clinical studies on patients with TRD. Besides serotonergic agonism, glutamate surge and monoamine release, psychedelics promote neuroplasticity, corticolimbic function, and epigenetic changes. Psilocybin, ketamine, and esketamine are the most researched agents of psychedelics in the context of TRD. Psilocybin-assisted therapy has been shown to induce short-term improvement in symptoms that can persist for weeks and months, with some meta-analyses consolidating such findings. Ketamine, as an atypical psychedelic, in many clinical trials of intravenous, subcutaneous, and oral forms, had rapid and robust effects in reducing depressive symptoms and relapses without decreasing cognitive function. Similarly, esketamine induced early and clinically meaningful improvements in function and productivity. Ayahuasca also showed fast and sustained effects with higher remission rates and good safety. Psychedelics have significant potential in TRD with superior mechanisms over traditional antidepressants. Despite the encouraging findings of the existing studies, large, well-designed studies are needed to extend their use as part of standard recommendations.

Intrinsic excitation-inhibition imbalance in major depressive disorder.

Deep brain stimulation (DBS) is a promising therapeutic modality for managing treatment-resistant depression. Most DBS research has focused on single brain regions resulting in unclear optimal stimulation targets and vague mechanisms. Here, we introduce an experimental paradigm in which multiple graphene fiber stimulating electrodes were implanted in various brain regions of the same depressive animal for behavioral testing and DBS-functional MRI studies. We observed an instantaneous alleviation of depressive-like symptoms with a high response rate in Wistar-Kyoto rats following DBS at the medial forebrain bundle (MFB), lateral habenula (LHb), ventral tegmental area (VTA), and dorsal raphe nucleus (DRN), with a highly similar blood-oxygenation-level-dependent (BOLD) activation pattern, engaging the cortical areas, limbic, serotonin, and dopamine system where the BOLD activation levels in the medial prefrontal cortex (mPFC) and cingulate cortex showed strongest correlation with the degree of depression alleviation. No antidepressant effects were observed in DBS at the mPFC or nucleus accumbens. Lesion of VTA dopaminergic neurons resulted in a decrease in the extent of depression alleviation and BOLD activation levels. These results indicate that DBS targeting the MFB, LHb, VTA, and DRN might represent a rapid-acting antidepressant therapy by activating a highly overlapping dopamine-related neural network.

Treatment-resistant depression and chronic pain represent major global health challenges due to their high prevalence, significant disability burden, and limited response to conventional therapeutic approaches. Recent advances in neuroscience have improved understanding of the neural networks involved in emotional regulation, cognitive processing, and pain modulation, leading to the development of innovative neuromodulation strategies. This review analyzes current evidence regarding neurostimulation therapies used in the management of treatment-resistant depression and chronic pain, including repetitive transcranial magnetic stimulation, transcranial direct current stimulation, vagus nerve stimulation, deep brain stimulation, spinal cord stimulation, and dorsal root ganglion stimulation. A scientific-method-based literature review was conducted using publications indexed in major biomedical databases. The findings indicate that neurostimulation offers clinically meaningful benefits in selected patients by directly modulating dysfunctional neural circuits associated with symptom persistence. Repetitive transcranial magnetic stimulation demonstrated strong evidence in treatment-resistant depression, while spinal cord stimulation and dorsal root ganglion stimulation showed substantial effectiveness in refractory neuropathic pain conditions. The review also highlights the importance of individualized treatment selection, safety considerations, technological innovation, and multidisciplinary collaboration. Furthermore, emerging developments involving adaptive stimulation systems, artificial intelligence, biomarker-guided interventions, and precision neuromodulation may significantly influence future clinical practice. Neurostimulation is increasingly recognized as a valuable component of modern neurological, psychiatric, neurosurgical, and pain management strategies, with growing implementation across diverse healthcare systems, including Latin America. Continued research and technological advancement are expected to further expand its therapeutic potential and improve outcomes for patients with complex and refractory disorders.

Oral S-ketamine (S-KETPO) is being explored as an alternative to intravenous maintenance treatment (S-KETIV) in treatment-resistant depression (TRD). However, the first-pass effect with S-KETPO significantly alters S-ketamine's bioavailability and the systemic exposure of its active metabolites, raising potential safety and efficacy concerns. This study characterized the pharmacodynamic and safety profiles of S-KETPO related to its pharmacokinetics in healthy participants, compared head-to-head with an S-KETIV dose that had previously demonstrated antidepressant effects in TRD . In a randomized, double-blind, placebo-controlled, double-dummy, four-way cross-over study, 16 healthy participants received a single dose of S-KETPO 0.20 and 0.45 mg/kg, S-KETIV 0.40 mg/kg and placebo. Plasma concentrations of S-KET and its active metabolites norketamine (S-NOR) and S-hydroxynorketamine (S-HNK) were measured, safety assessments were conducted up to 24 hours post-dose, and central nervous system (CNS) effects were evaluated up to 6 hours post-dose. Absolute bioavailability of S-KETPO was poor (9-12%). Peak plasma concentrations for S-KETPO 0.20 mg/kg, 0.45 mg/kg and S-KETIV were 9.81, 22.7 and 146 ng/mL (S-KET); 62.0, 127 and 55.2 ng/mL (S-NOR); and 29.5, 62.1 and 32.2 ng/mL (S-HNK), respectively. S-KET and S-HNK:S-KET metabolite-to-parent compound ratios were 7.52, 6.98 and 0.42, and 3.78, 3.71 and 0.23, for KETPO 0.20 mg/kg, S-KETPO 0.45 mg/kg, and S-KETIV, respectively. S-KETIV produced sedative, psychomotor and psychotomimetic effects coinciding with reductions in quantitative electroencephalography (qEEG) alpha, beta and delta power, whereas S-KETPO 0.45 mg/kg demonstrated inconsistent effects on vigilance and arousal but clear albeit relatively smaller reductions in qEEG alpha, beta and delta power coinciding with limited psychotomimetic effects, and finally, KETPO 0.20 mg/kg lacked effects altogether. Safety was comparable across treatments. Oral administration of S-ketamine alters pharmacokinetic and pharmacodynamic profiles, resulting in poor bioavailability, increased pharmacologically active metabolite exposures, and limited CNS effects relative to intravenous administration. The current findings have implications for S-KETPO dose selection, which may impact safety and/or therapeutic outcomes in future TRD studies. The study was registered in the 'Overview of Medical Research in the Netherlands' (OMON) under NL-OMON55261.

Methodological considerations of suicide risk following antipsychotic therapy in treatment-resistant depression.

Latent class modeling of repetitive transcranial magnetic stimulation response trajectories in treatment-resistant depression.

Neuroimaging is prevalent in psychiatric research, but there is limited evidence that it improves clinical outcomes. Functional connectivity neuroimaging was recently used to target individualized brain circuits with accelerated transcranial magnetic stimulation (aTMS), with rapid antidepressant effects and US Food and Drug Administration clearance, but the importance of connectivity-based targeting remains unclear. To estimate the effect size of connectivity- vs scalp-based targeting of aTMS for treatment-resistant depression. This randomized clinical trial comparing connectivity- to scalp-based aTMS treatment was conducted between July 2023 and March 2025 with the primary outcome assessed at 1 month posttreatment and follow-up every 3 months for 1 year. Participants, TMS technicians, and study physicians were blinded. The study took place at the Center for Brain Circuit Therapeutics at Mass General Brigham and Harvard Medical School in Boston, Massachusetts. Forty adults aged 22 to 80 years with a primary diagnosis of major depressive disorder with moderate to severe depression per Montgomery-Åsberg Depression Rating Scale (MADRS) score and moderate to severe treatment resistance per Maudsley Staging Method were included. Key exclusion criteria included contraindications to TMS or magnetic resonance imaging, primary psychiatric diagnoses other than major depressive disorder or anxiety disorders, recent rapid-acting antidepressant treatments, and significant neurological or substance use disorders. All participants underwent a 41-minute multiecho resting-state functional connectivity scan prior to aTMS, and half of them received treatment guided by these data. The connectivity-based target was defined as the left dorsolateral prefrontal cortex region with the greatest correlation to a published and publicly available convergent depression circuit. This circuit includes multiple brain regions linked to depression, including negative connectivity to the subgenual cingulate cortex. The scalp-based target was identified with the Beam F3 method. MADRS score 1 month after treatment, adjusted for baseline. In total, 40 participants (22 female [55%]; mean [SD] age, 45.7 [15.2] years) were randomized and treated. The median (IQR) MADRS score reduction was 24 (19-28) vs 18 (10-23) points with connectivity- vs scalp-based targeting, respectively (P = .02). Connectivity-based targeting had an effect size of 0.8 (Cohen d analog) and 95% CI of 0.26-1.54, with a number needed to scan of 5 individuals. Individualized targets were reproducible within an individual (4.47 mm split-half distance) and different between individuals (12.97 mm) (P < .001). In this randomized clinical trial, individualized, connectivity-based targeting of the convergent depression circuit enhanced the antidepressant effects of high-dose aTMS. These results could facilitate cost-effectiveness analyses and help to power a confirmatory efficacy trial. ClinicalTrials.gov Identifier: NCT05680727.

Real-world effectiveness and safety of intranasal esketamine for treatment-resistant depression: data from the enTRD registry.

Ketamine offers rapid relief for treatment-resistant depression and severe pain in the clinic, providing immediate benefits that traditional medications often fail to deliver. While its antagonistic action at the N-methyl-D-aspartate receptor (NMDAR) is a key mechanism, ketamine's dual nature as both a promising treatment and a drug with abuse potential suggests its therapeutic effects extend beyond NMDAR inhibition. Here we provide structural evidence of human opioid receptors bound to ketamine and its parent analog phencyclidine (PCP), supporting that both ligands can directly bind and activate opioid receptors. The structures, together with site-directed mutagenesis and structure-activity relationship studies, identify key motifs involved in ketamine and PCP recognition and efficacy modulation. Furthermore, we determine the structure of the ligand-free state of human κ opioid receptor, revealing molecular details before ligand engagement. Compared to PCP, ketamine displays more notable binding dynamics in the orthosteric site that may contribute to its unique pharmacology at opioid receptors. Our findings highlight the importance of including opioid receptors to fully understand ketamine's versatility in clinical settings.

Research objective: The aim of this study was to present the current state of knowledge about bipolar affective disorder (BD) — its classification, clinical picture, pharmacological treatment and alternative methods, with particular emphasis on bipolar depression. Methodology: The study is based on a narrative review of recent scientific literature concerning bipolar affective disorder, conducted using the PubMed database with the following keywords: bipolar disorder; bipolar depression; lithium; atypical neuroleptics; ketamine; psilocybin; neuromodulation; electroconvulsive therapy; rTMS; phototherapy. Main conclusions: Bipolar affective disorder is a chronic and recurrent mood disorder characterized by alternating episodes of mania, hypomania and depression, leading to significant functional decline, increased risk of suicide and shortened life expectancy. Lithium remains the drug of first choice for the treatment and prevention of mania, while valproate and carbamazepine are effective but carry a higher risk of side effects, and atypical neuroleptics are active in both mania and depression. For treatment-resistant cases, especially refractory bipolar depression, neuromodulatory techniques (ECT, rTMS, tDCS, VNS) and the use of ketamine and psychedelics such as psilocybin show promising results. Electroconvulsive therapy is currently the best studied of these methods, rTMS and tDCS show moderate efficacy with good tolerance, ketamine provides rapid antidepressant and anti-suicidal effects despite limited long-term data, and phototherapy demonstrates beneficial effects in seasonal and non-seasonal depression with a good safety profile. Application of the study: The findings may support clinicians in improving diagnostic accuracy and optimizing treatment strategies for patients with bipolar affective disorder, particularly through a more individualized approach to the management of bipolar depression. Originality/Novelty of the study: The review integrates recent findings on emerging therapeutic perspectives in bipolar affective disorder, highlighting advances in neuromodulation, ketamine and psychedelic-assisted treatment, and their potential role in addressing treatment-resistant bipolar depression.