Journal of Psychopharmacology

BackgroundAt present, there are no approved pharmacological treatments for people at clinical high risk for psychosis (CHR-P). We sought to assess the acceptability of cannabidiol (CBD): a promising candidate treatment for this population. MethodsCHR-P individuals completed a survey which assessed their views on the acceptability of CBD, its expected effectiveness and side effects, and on formulation preferences. ResultsThe sample comprised 55 CHR-P individuals (24.3 years and 69% female). Most (91%) were familiar with CBD, and had previously used cannabis (64%), and around half (42%) had tried over-the-counter CBD. 75% were willing to take CBD as an intervention for mental health problems. Most participants anticipated fewer side effects with CBD than with existing medications, and preferred tablet or capsule formulations over liquids. DiscussionCBD is perceived as a highly acceptable treatment among CHR-P individuals.

Esketamine is a fast-acting antidepressant drug which induces acute psychoactive effects. The most frequent is a dissociative state which seems unrelated to therapeutic efficacy. Other esketamine-induced effects, including psychedelic-like mystical experiences, have been poorly studied in terms of phenomenology and frequency, and may carry specific therapeutic relevance. In this study, we characterised esketamine-induced mystical experiences in relation with clinical outcomes. We conducted a longitudinal observational study and systematically measured acute subjective effects in patients receiving esketamine for treatment-resistant depression after each administration across the induction phase. A total of 45 patients were included, from two independent centres, totalling 352 esketamine administrations. Principal Component Analysis (PCA) supported the validity of the Mystical Experience Questionnaire (MEQ-30) for assessing esketamine-induced subjective effects, with components recovering dimensions previously validated with classic psychedelics. Mystical experiences (MEQ-30 score above 60) occurred in 58% of patients, with high inter- and intra-individual variability in frequency, intensity, and phenomenology across sessions. Higher mean and peak MEQ scores were associated with greater improvement in Montgomery-Asberg Depression Rating Scale scores from pre- to post-treatment, whereas the intensity of dissociative or other non-mystical effects was not. Positive mood and mystical MEQ dimensions in particular predicted therapeutic outcomes. Baseline spirituality also significantly predicted treatment outcomes and peak MEQ scores in the first week of treatment. These findings add to the growing body of evidence suggesting that psychedelic-like mystical experiences may be associated to therapeutic efficacy, not only in classic psychedelic-assisted therapy, but also in esketamine treatment.

BackgroundContemporary research indicates that psychedelics induce notable neurophysiological changes, some lasting weeks to months after a single dose. However, most evidence derives from acute administration studies and limited post-acute follow-ups. Long-term naturalistic psychedelic users remain critically underexamined, yet may exhibit distinct neurobiological profiles informing our understanding of persistent alterations following repeated exposure. MethodsWe recorded resting-state EEG in 57 long-term psychedelic users (abstinent [≥]30 days) and 49 matched non-users across two independent sites under eyes-open and eyes-closed conditions. We analyzed oscillatory power, signal complexity, and source-localized effective connectivity, focusing on five canonical frequency bands and regions of the Default Mode, Salience, and Central Executive Networks. Analyses included linear mixed-effects modeling for power spectra and complexity results and a rank-based approach combining ordinary least squares regression with randomization inference for effective connectivity. ResultsWe observed predominantly null findings. No significant between-group differences emerged for oscillatory power. Complexity comparison yielded results contrary to our hypothesis: psychedelic users exhibited lower complexity values in the eyes-open condition. Effective connectivity revealed no within- or between-network differences that would survive statistical corrections. Additionally, we report a few small-magnitude effects uncovered by exploratory analyses. Conclusions Long-term naturalistic psychedelic users showed largely non-significant differences in oscillatory power, complexity, and network connectivity compared to non-users -- across several measures commonly reported as altered in acute administration studies. These findings raise the question of whether psychedelics neurophysiological signatures persist during abstinence despite repeated prior use, or whether they reflect homeostatic receptor adaptation, individual variability, or contextual factors. Null, incongruous, or subtle effects contribute to the existing evidence base, yet underscore the need for replication in larger, more ecologically valid populations to advance the emerging field of psychedelic neuroscience.

BackgroundIn 2020, Oregon became the first U.S. state to establish a regulated framework for adults to access psilocybin services using naturally-derived mushroom products. No studies have examined mental health outcomes among individuals receiving psilocybin in this context. AimsTo evaluate changes in self-reported symptoms of depression, anxiety, and well-being 30-days post-psilocybin session under the Oregon state-regulated model , and document session-related adverse events and doses consumed. MethodsThis was a naturalistic study (March 2024-April 2025) among adults [&ge;]21 years participating in a legal psilocybin services program. Online surveys were completed pre-session, 1-day, and 30-days post-session. Primary outcomes were change in depression, anxiety, and well-being symptoms pre-session to 30-days post-session evaluated using linear mixed-effects models (random effect: timepoint; fixed effects: sex, concurrent psychiatric medication use, age, session dose [total psilocybin equivalents, TPE, mg: psilocybin mg + 1.39 * psilocin mg]). Adverse events (e.g., hallucinogen persisting perception disorder [HPPD]) were assessed at 1-day and 30-days post-session. ResultsParticipants (n=88; median age 43 years; 52% male) were predominantly Oregon residents (53.4%), psychedelic-experienced (64.8%), and concurrently using psychiatric medication (46.6%). All outcomes improved significantly at 30-days post-session (p<0.001), including in sensitivity analyses stratified by concurrent psychiatric medication usage (p<0.001 all outcomes, both groups). Two participants (2.3%) reported symptoms consistent with HPPD at 1-day post-session, but none at 30-days. Mean dose was 27.8 mg (SD 8.2) TPE. ConclusionsPsilocybin sessions delivered under the Oregon regulatory model were associated with clinically meaningful improvements in depression, anxiety, and well-being 30-days post-session, supporting therapeutic effectiveness of legal psilocybin services.

Voluntary ingestion is a refined method for substance administration that can replace oral gavage in rats and mice. It requires no physical restraint and has no associated risks of adverse effects, resulting in improved welfare and reduced distress for both animals and research staff. This method has been shown to be effective for a variety of compounds but is still not widely used due to concerns about accuracy and reliability. One potential issue is aversion to the taste of the compound being administered, including a common issue of bitter taste. In this study we tested compounds used in oral preparations for human medicines to mask bitter tasting drugs, including a commercial formulation designed for this purpose, Bitter Drug Powder (BDP). The masking agents were given in combination with a palatable vehicle (10% condensed milk) and the amount consumed and time to consume recorded. Animals were first habituated to the vehicle with reliable ingestion achieved within a few days. In the first studies, only BDP was fully effective at masking the bitter taste of quinine and preventing the progressive reduction in reliability of intake of the antidepressant, venlafaxine in mice and rats. We were able to replicate these effects using a combination of two different artificial sweeteners, saccharine and acesulfame K, and a thickening agent xanthan gum. These studies demonstrate that using a masking agent can improve the reliability of voluntary oral dosing in mice and rats and provide evidence to support a formulation which is readily available for researchers.

BackgroundLithium is one of the key medications for the treatment of bipolar disorder, but it requires therapeutic drug monitoring because of its narrow therapeutic window. In routine clinical practice, blood sampling is often performed outside the recommended 10-14 hour interval after the last evening dose, which distorts interpretation of the measured concentration (overestimation with early sampling and underestimation with late sampling) and may lead to inappropriate dose adjustment. ObjectiveTo develop and validate, using synthetic data, a multiplicative model (SimpLi) that standardizes a measured lithium concentration to the 12-hour level while accounting for sampling time and daily dose. Materials and MethodsA simulation study was conducted in accordance with ADEMP recommendations. A synthetic cross-sectional dataset (n = 1000) was generated with distributions of time since the last lithium dose, serum concentrations, and doses derived from the Bipolar CHOICE study, with a median sampling time of 12 hours (IQR 11-14) and a time-concentration correlation of r {approx} -0.30. The dataset was split 70/30 with stratification by time intervals, and 5-fold cross-validation was performed. Model performance was evaluated using RMSE, MAE, and R2. ResultsThe simulation closely reproduced the prespecified time distribution, achieved the target time-concentration correlation (r {approx} -0.30), and yielded a clinically plausible dose structure. A model using time as the only predictor showed limited accuracy (RMSE = 0.316; R2 = 0.108), while adding dose provided a moderate improvement (RMSE = 0.303; R2 = 0.177). When sampling occurred exactly at 12 hours, direct prediction was biased (-0.150; RMSE = 0.357), supporting the need for an individual correction factor. In a proof-of-concept analysis of five clinical cases, SimpLi produced a lower MAE than the eLi12 formula (0.042 vs 0.056 mEq/L). ConclusionsSimpLi is a practical tool (psyandneuro.ru/bekhterev-ai/simpli/) for standardizing lithium levels to 12 hours when sampling times vary. External validation on real-world data and robustness testing across clinical scenarios are needed.

Anorexia nervosa is an eating disorder disproportionately found in female human teens and young adults. It is often resistant to treatment, has a significant chance of relapse and is more lethal than other eating disorders, such as bulimia nervosa or Avoidant/Restrictive Food Intake Disorder (ARFID). There is no specific medication for the treatment of anorexia nervosa. Treatment consists of psychosocial means, psychotherapy, psychoeducation, and nutritional counseling. Medication is usually used for treating comorbidities such as anxiety or to decrease obsessive-compulsive tendencies. These medications cannot help the patient regain weight or treat core symptoms. Metabotropic 2/3-glutamate (mGluR2/3) receptor agonist (LY379268) and antagonist (LY341495) are promising pharmacological agents to treat psychiatric disorders. Both agonists and antagonists have been reported to have anxiolytic effects in different animal models of anxiety, while antagonists have shown antidepressant-like effects in preclinical studies. The activity-based anorexia (ABA) paradigm is used to model anorexia nervosa. It consists of giving mice access to a running wheel and restricting their feeding time. This causes mice to exercise more than mice without feeding time restriction and to eat less than mice without access to a moving running wheel. In this study, we subcutaneously injected female ABA model mice with a metabotropic 2/3-glutamate receptor agonist (LY379268) and antagonist (LY341495) in two experiments. Both compounds exacerbated weight loss by decreasing food intake as well as increasing physical activity. It can be concluded that the manipulation of mGluR2/3 receptors is detrimental for the ABA model and likely for anorexia nervosa as well. HighlightsO_LImGluR2/3 agonist LY379268 decreases food intake and body weight of the ABA model C_LIO_LImGluR2/3 antagonist LY341495 decreases food intake and body weight of the ABA model C_LIO_LIBoth agonist and antagonist produce the effect within 48 hours C_LIO_LIBoth the agonist and antagonist are detrimental to the ABA-model C_LI

Background and HypothesisClozapine is the only antipsychotic with protective effects against suicide in schizophrenia (SCZ). Newer third-generation antipsychotics (TGA) have better tolerability and modulate serotonin, dopamine, and N-methyl-d-aspartate neurotransmission pathways implicated in suicide. We aimed to investigate the effects of TGAs on suicide in SCZ. MethodsWe searched seven databases up to December 2023 for SCZ studies that reported suicide data. The primary outcome was suicide deaths and attempts; suicidal ideation was added as a secondary outcome. Random effects meta-analyses quantified suicide risk in randomized controlled trials (RCT) while single proportion meta-analyses assessed longitudinal suicide risk in open label extension trials (OLE). For RCTs, sensitivity analyses were conducted and subgroup analyses explored the impact of dose, drug type, and comparator arm. Study ResultsTwenty articles were included; thirteen excluded higher suicide risk participants. Compared to placebo control, TGAs did not significantly change the risk of primary [RR = 0.65, p = 0.38] or secondary [RR = 0.63, p = 0.15] suicide outcomes. Subgroup and sensitivity analyses were not statistically significant. For OLEs, there was a significant increase in the incidence of primary [Ip = 0.004, p = 0.048] and secondary [Ip = 0.024, p = 0.0013] suicide outcomes, but there was marked study heterogeneity. ConclusionThere is no current trial evidence to show that TGAs significantly impact suicide outcomes in SCZ. The signal from OLEs should be interpreted cautiously due to heterogeneity and requires replication. An effective clozapine alternative is needed for suicide prevention in SCZ.

The use of neuromodulation techniques for the treatment of alcohol use disorder is receiving increasing attention, especially non-invasive approaches, such as repetitive transcranial magnetic stimulation or transcranial direct current stimulation, while the hypothetical use of electroconvulsive therapy remains unexplored. Given our experience inducing electroconvulsive seizures (ECS) for therapeutic purposes in psychopathology rodent models, we evaluated the role of ECS on reducing the increased voluntary ethanol consumption caused by adolescent ethanol exposure in our validated preclinical model. Rats were treated in adolescence with a binge paradigm of ethanol (2 g/kg, i.p.; 3 rounds of 2 days at 48-h intervals; post-natal day, PND 29-30, PND 33-34 and PND 37-38) or saline. Following persistent withdrawal until adulthood, rats were allowed to: voluntarily drink ethanol (20%) by a two-bottle choice test, for 3 days (PND 80-82); treated with ECS (95 mA for 0.6 s, 100 Hz, pulse width 0.6 ms; ear-clip electrodes) or SHAM for 5 days (PND 86-90); re-exposed to voluntarily ethanol exposure (PND 94-96). Brains were collected on PND 97 to evaluate hippocampal markers of ethanol toxicity and/or treatment response (e.g., NeuroD, NF-L, BDNF and NF-L/BDNF ratio). Our results reproduced the increased voluntary ethanol consumption in adult rats induced by adolescent ethanol exposure and demonstrated that ECS could improve this abuse-prone response. Moreover, we suggested a possible role for BDNF in the beneficial effects induced by ECS, especially reducing the neurotoxic ratio NF-L/BDNF. Overall, we provide preclinical evidence for the potential use of ECS as an efficacious treatment for alcohol use disorder.

The misuse of opioid medications is a significant health issue in the United States. Very few studies have investigated the effect of opioids on perineuronal nets (PNNs), scaffold-like structures that surround neurons and are involved in the regulation of plasticity-dependent mechanisms such as development, learning and memory, and acquisition of addiction-like phenotypes. Regulation of PNNs in the orbitofrontal cortex (OFC) during periods of drug intoxication or withdrawal is widely unknown. In this study, male Wistar rats were injected with fentanyl (0.125 mg/kg, s.c.) or 0.9% saline twice daily for 7 days and once on day 8 (7continuous days following by 3 days of abstinence) or twice daily for 15 days (5 continuous days followed by 2 days of abstinence for more than 3 weeks) and twice on day 16. Antinociception was evaluated using the tail immersion test immediately before and 30 minutes after injections. Whole-brain coronal slices were collected, and immunohistochemistry was used to identify Wisteria Floribunda Agglutinin (WFA)-positive PNNs and parvalbumin (PV)-expressing cells. Results confirmed that repeated fentanyl injections induced tolerance to the antinociceptive effects, which normalized following acute abstinence periods. WFA intensity decreased following 8 days of injections. Analyses confirmed significant correlations between PV+ density and tail withdrawal latency following 8 days of fentanyl injections. These data confirm that repeated fentanyl injections modulate both WFA+ and PV+ expression in the rodent brain and antinociceptive tolerance in a duration-dependent manner. Overall, these data suggest that perineuronal nets may mediate opioid-induced behavioral effects, such as antinociceptive tolerance, following repeated administration and abstinence in rats.

3,4-methylenedioxymethamphetamine (MDMA) has emerged as a potential treatment for post-traumatic stress disorder (PTSD), generating considerable enthusiasm in the field. However, rapidly changing evidence in a fast-moving field can be challenging to integrate. Here, we present a living systematic review and open-data meta-analytic resource on MDMA treatment for PTSD. In this initial release, six randomized controlled trials comprising 286 participants are included in the database. Our primary model uses inverse-variance random-effects meta-analysis of standardized mean differences on primary outcomes of PTSD. Compared to control conditions, MDMA showed a greater reduction in PTSD symptoms (Hedges' g = -0.71). Meta-regression on both the number of dosing sessions and cumulative dose showed that a higher number of dosing sessions and a higher cumulative dose was related to larger effects of MDMA. Treatment with MDMA as compared to placebo also resulted in higher response (risk ratio (RR) = 1.35) and remission (RR = 2.25) rates. Most studies included in the database had a low risk of bias according to Cochrane guidelines, though these fail to capture pertinent challenges in the field such as expectancy, functional unblinding, potential issues with study conduct, and safety. The current findings were assigned an overall low certainty rating using the GRADE approach. Together, this systematic review and meta-analysis suggests that MDMA-assisted therapy results in short-term decreases in PTSD symptoms across studies to date, though more trials are needed. This living systematic review, meta-analysis, database, and online dashboard (sypres.io) will continue to be updated as evidence emerges, providing a valuable, open, and transparent resource for researchers in a rapidly evolving field.

Background and HypothesisAbnormal default mode network (DMN) connectivity was observed in both tobacco use and psychotic spectrum disorders, but it remains unknown how psychosis impacts the relationship between connectivity and tobacco use. Interventions targeting the left lateral parietal DMN node (LLPDMN) have modulated DMN connectivity and nicotine craving in psychosis. We aimed to investigate relationships between DMN connectivity, psychotic illness, and tobacco use. Study Design336 participants (psychosis: n=161, control: n=175) reported their tobacco use history and underwent resting-state functional magnetic resonance imaging. We calculated connectivity within DMN and salience network (SN), between DMN-SN, and from LLPDMN to other DMN and SN nodes. Logistic and LASSO regression with bootstrapping were performed to investigate diagnosis-by-connectivity interactions on lifetime tobacco use. Exploratory brainwide analysis was conducted by regressing brainwide connectivity to LLPDMN against daily cigarette use. Study ResultsWe observed a significant diagnosis-by-DMN connectivity interaction for lifetime tobacco use (p=0.0281, coefficient=0.457, OR=1.579, 95% CI=[1.063, 2.411]); in the psychosis group, higher DMN connectivity was associated with higher odds of lifetime tobacco use. LASSO regression yielded four predictors of lifetime tobacco use: age, diagnosis, LLPDMN connectivity to a prefrontal SN node, and the interaction between diagnosis and LLPDMN connectivity to a right parietal DMN node. Brainwide analysis identified bilateral somatomotor clusters where higher connectivity to LLPDMN correlated with higher daily cigarette use (voxel-wise p<0.001, cluster p<0.05). ConclusionsPsychosis diagnosis modified relationship between DMN connectivity and tobacco use. Modulating DMN connectivity may provide a psychosis-specific treatment target for tobacco dependence.

Major depressive disorder (MDD) is a highly prevalent psychiatric disorder with changes in motivation to work for rewards being a core symptom. Transcutaneous vagus nerve stimulation (tVNS) has emerged as a promising therapy but its effects on the core features of MDD, such as changes in motivation, remained relatively unexplored. In this randomised, single-blind, cross-over, controlled trial, we used a grip strength effort task to investigate how tVNS impacted choices to exert different levels of physical effort for varying monetary rewards in MDD patients (n=53) and a non-depressed control group (n=45). Compared to sham stimulation, tVNS enhanced the efficiency with which participants with severe depressive symptoms allocated physical effort for rewards (reward-effort efficiency). These effects were not seen in participants with less severe symptoms. Specifically, we found that the effect of tVNS on reward-effort efficiency was driven by reduced unnecessary effort, i.e., a reduction in choices to exert additional effort when this was not required to gain a larger reward. These findings suggest a potential motivational mechanism by which tVNS exerts its therapeutic effects in MDD. Determining whether the effects of tVNS are linked to broader changes in executive functioning, such as improvements in cognitive flexibility in MDD, should be a key aim for future work.

ObjectiveNicotinic acetylcholinergic receptors (nAChRs), comprising of and {beta} subunits are present in the brain and whole body. The less abundant 2-subunit is a fast-acting receptor subtype and plays an important role in cognition and learning. To understand cellular functional consequences, this study evaluated glucose metabolism using [18F]FDG PET/CT in 2 knockout (2KO) and 2 hypersensitive (2HS) mice. MethodsControl (CN; 4M, 4F), 2 knockout (2KO; 4M, 4F) and 2 hypersensitive (2HS; 4M,4F), 12-16 month old mice were used. Mice were fasted and injected with [18F]FDG (3-5 MBq) while awake. After 40 minutes they underwent whole body PET/CT. On a separate day, nicotine challenge [18F]FDG studies were done. Reconstructed images were analyzed to obtain standard uptake values (SUV) of [18F]FDG in brain and interscapular brown adipose tissue (IBAT). Statistical analysis was performed. ResultsThe 2HS male mice exhibited the largest brain increase in [18F]FDG compared to 2KO male mice. The rank order of brain [18F]FDG uptake in the 3 groups: 2HS[male]> CN[male]> 2KO[male]> CN[female]= 2KO[female][&ge;] 2HS[female]. Nicotine treatment reduced brain [18F]FDG uptake in all mice. Females had lower [18F]FDG uptake compared to males and were less sensitive to 2 nAChR. In the case of IBAT, 2KO mice had significantly higher baseline [18F]FDG uptake compared to the other two groups: 2KO[male]> 2KO[female]> 2HS[female]> 2HS[male]> CN[female]> CN[male]. Nicotine decreased IBAT in 2KO mice rather than increase as observed in CN and 2HS mice. Conclusions2 nAChRs plays a significant role in brain activation as exhibited by the increase in [18F]FDG in 2HS mice. In the absence of regulatory control by the 2 nAChR, the 2KO mice IBAT exhibited higher [18F]FDG IBAT compared to controls and 2HS mice. Female mice were less affected by nicotine compared to the male mice. Overall, 2 nAChRs played a significant role in glucose metabolism in the brain and IBAT.

Globally, about 264 million individuals across all age groups are impacted by depression, a prevalent central nervous system (CNS) condition. Chronic and enduring depression might result in significant health consequences. Numerous pharmaceutical antidepressants exist for the management of mild to severe depression, largely functioning by modifying neurotransmitter levels in the brain. Nevertheless, these drugs frequently induce a variety of side effects, such as insomnia, constipation, exhaustion, drowsiness, and anxiety. Saffron (Crocus sativus L.) is widely acknowledged as a natural antidepressant with little adverse effects. This study investigated the potential antidepressant mechanisms of saffrons principal bioactive compounds safranal, crocin, and picrocrocin via molecular docking against critical target proteins associated with depression, namely the dopamine transporter (DAT), serotonin transporter (SERT), and monoamine oxidase B (MAO-B). Molecular docking was conducted with AutoDock 4.2 to assess the binding affinity and interaction energy of these drugs with the target proteins. Furthermore, Discovery Studio facilitated the viewing and study of both interacting and non-interacting residues at the docking sites, juxtaposing these interactions with those of established inhibitors in crystal structures. The permeability of the blood-brain barrier (BBB), pharmacokinetic characteristics, and toxicity profiles of saffron components were evaluated using SWISS ADME, DataWarrior, and Osiris Molecular Property Explorer. Among the evaluated elements, safranal had the greatest potential as a competitive inhibitor of the dopamine transporter, according to its notable blood-brain barrier permeability, robust binding affinity, and analogous interaction residues in comparison to nortriptyline, a recognized inhibitor. Our findings indicate that safranal may be a viable natural alternative to traditional antidepressants, with minimized adverse effects.

Nicotine use disorder shows heterogeneity in treatment response, potentially reflecting differences in underlying neural circuitry, particularly in the presence of depression. We examined real-time neural dynamics during nicotine inhalation in two chronic users - one with depression and one without - using simultaneous hippocampal recordings from responsive neurostimulation (RNS) electrodes and scalp EEG. Oscillatory activity and hippocampal-cortical connectivity were analyzed in relation to mood and craving. Oscillatory activity tracked mood in the non-depressed individual but was attenuated or reversed in the depressed individual, suggesting reduced reward-related neural responsiveness. In contrast, both participants showed reduced alpha hippocampal-cortical connectivity following nicotine use, suggesting a shift from reward-seeking to reward and relief processing. These findings support a network-based framework of nicotine-driven neural dynamics and provide preliminary evidence that depressive status may modulate these processes. Although limited to two cases, this work highlights the potential for identifying neurophysiological subtypes of nicotine users and informs future efforts toward personalized treatment approaches.

Background: Gamma oscillation dysfunction has been implicated in neuropsychiatric disorders. Restoring gamma oscillations via brain stimulation represents an emerging therapeutic approach. However, the strength of its clinical effects and treatment moderators remain unclear. Method: We conducted a systematic review and meta-analysis to examine the clinical effects of gamma neuromodulation in neuropsychiatric disorders. A literature search for controlled trials using gamma stimulation was performed across five databases up until April 2025. Effect sizes were calculated using Hedge's g. Separate analyses using the random-effects model examined the clinical effects in schizophrenia (SZ), major depressive disorder (MDD), bipolar disorder, and autism spectrum disorder. For SZ and MDD, subgroup analyses evaluated the effects of stimulation modality, stimulation frequency, treatment duration, and pulses per session. Result: Fifty-six studies met the inclusion criteria (NSZ = 943, NMDD = 916, NBD = 175, NASD = 232). In SZ, gamma stimulation was associated with improvements in positive (k = 10, g = -0.60, p < 0.001), negative (k = 12, g = -0.37, p = 0.03), depressive (k = 8, g = -0.39, p < 0.001), anxious symptoms (k = 5, g = -0.59, p < 0.001), and overall cognitive function (k = 7, g = 0.55, p < 0.001). Stimulation frequency and treatment duration moderated therapeutic effects. In MDD, reductions in depressive symptoms were observed (k = 23, g = -0.34, p = 0.007). Conclusion: Gamma neuromodulation showed moderate therapeutic benefits in SZ and MDD. Substantial heterogeneity likely reflects protocol differences, highlighting the need for well-powered future trials.

BackgroundAntidepressants exert their therapeutic effects through ameliorating negative emotional biases that underpin depression. However, therapeutic gains may depend upon restructuring how emotional information is processed. This can be achieved through Cognitive Bias Modification (CBM), a technique for positively shifting recognition of emotional facial expressions. Here, we examined how CBM modifies emotional processing circuits in individuals with depression who were taking Selective Serotonin Reuptake Inhibitors (SSRIs). MethodsA double-blind Randomised Controlled Trial was conducted in 84 participants with depression who had recently started SSRI medication. Participants received five sessions of active or sham CBM over one week before fMRI scanning where they viewed emotional faces (happy, fearful, sad). ResultsAcross all emotional expressions, greater Blood Oxygen Level Dependent (BOLD) signal was observed in the inferior occipital gyrus for the active compared to sham CBM. Emotional-specific effects were observed in the medial Prefrontal Cortex (mPFC), with reduced BOLD signal in the active (compared to sham) group for viewing happy vs. fearful faces. Changes in BOLD signal were also associated with individual differences in response to CBM. Enhanced functional connectivity between mPFC and right Dorsolateral Prefrontal Cortex (rDLPFC) predicted improvement in depressive symptoms four weeks later. ConclusionsThese results indicate that CBM modifies the neural circuits involved in emotion processing in people with depression currently taking antidepressants. Converting these changes in emotional perception to improved depressive symptoms was related to changing mPFC-rDLPFC connectivity. Future trials are needed to test CBMs clinical utility as a simple, affordable and accessible adjunct therapy for depression.

The right superior temporal sulcus (rSTS) plays a causal role in multisensory hallucinations, is associated with audiovisual integration (AVI), and displays abnormal activity in psychotic disorders. We sought to reduce psychosis symptoms including hallucinations while modulating AVI and rSTS activity with cathodal, high-definition transcranial direct current stimulation (HD-tDCS) of the rSTS. This double-blind, randomized, sham-controlled pilot study applied HD-tDCS to the rSTS using a ring montage (-1.5 mA cathode center and three .5 mA anode surrounds). Stimulation was administered (N=6 active, N=6 sham) for 5 days with 2 20-minute sessions per day. Assessments occurred at baseline, 5-day, and 1-month timepoints. Electroencephalography (EEG) was recorded during resting state and an AVI steady state (SSR) paradigm. Given the pilot nature of this study, analyses used an alpha threshold of .10. The active group demonstrated reduced clinician-assessed symptoms at 5-days and 1-month, attenuated AVI at 5-days, enhanced auditory SSR and attenuated alpha power over the rSTS at 1-month, and reduced self-reported symptoms at 5-days. Symptom changes correlated with alpha changes. Biological motion, functioning, mood, and cognition did not significantly change. Findings suggest therapeutic effects and successful target engagement. Results provide preliminary proof-of-concept evidence supporting the initiation of a larger trial in psychotic disorders.

Background Cognitive impairment is a core feature of schizophrenia and a major determinant of functional disability. Executive deficits affect approximately 85% of patients and are associated with reduced activity in the prefrontal cortex (hypofrontality). Current pharmacological treatments show limited efficacy in improving cognition, highlighting the need for alternative therapeutic approaches. Combining non-invasive brain stimulation with cognitive remediation may enhance neuroplasticity and improve cognitive outcomes. Methods This prospective, randomized, double-blind, sham-controlled, parallel-group superiority clinical trial. A total of 120 adults aged 18-65 years with clinically stable schizophrenia diagnosed according to DSM-5 criteria will be enrolled at a single clinical center. Participants will be randomly assigned in a 1:1 ratio to receive either active transcranial direct current stimulation (tDCS) targeting the dorsolateral prefrontal cortex followed by cognitive remediation therapy (CRT) using the RehaCom system, or sham stimulation followed by the same cognitive training. Assessments will be conducted at three time points: prior to the intervention (V1), immediately after the intervention (V2), and during the follow-up visit 8 weeks after the intervention (V3). The primary outcome is change in cognitive performance measured with the CANTAB battery. Secondary outcomes include symptom severity assessed with the PANSS, global clinical status (CGI-S), and neurophysiological changes measured by EEG. Written informed consent will be obtained from all participants, and the study has received ethics committee approval. Discussion This trial will evaluate whether tDCS administered prior to cognitive training enhances cognitive improvement compared with cognitive training alone. The findings may inform the development of more effective interventions targeting cognitive deficits in schizophrenia. Trial registration ClinicalTrials.gov Identifier: NCT07273175. Registered on 25 November 2025.