Neuropsychopharmacology [JOURNAL]
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200 papers
Exposome and mental health across the lifespan: research and clinical perspectives.
Barzilay R, Jeste DV
Neuropsychopharmacology · 2026 Mar · PMID 41803416 · Full text
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Continued progress and innovation at Neuropsychopharmacology (NPP).
George TP, Monteggia LM
Neuropsychopharmacology · 2026 May · PMID 41796230 · Full text
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Leveraging the genetics of psychiatric disorders to prioritize potential drug targets and compounds.
Parker N, Koch E, Shadrin AA … +12 more , Fuhrer J, Hindley GFL, Stinson SE, Jaholkowski P, Tesfaye M, Dale AM, Wingo TS, Wingo AP, Frei O, O'Connell KS, Smeland OB, Andreassen OA
Neuropsychopharmacology · 2026 Jun · PMID 41795042 · Full text
Genetics can inform biologically relevant drug development and repurposing, which may improve patient care. Here, we leverage the genetics of psychiatric disorders to prioritize potential drug targets and compounds. We u...
Genetics can inform biologically relevant drug development and repurposing, which may improve patient care. Here, we leverage the genetics of psychiatric disorders to prioritize potential drug targets and compounds. We used the genome-wide association studies of four psychiatric disorders [attention deficit hyperactivity disorder (ADHD), bipolar disorder, depression, and schizophrenia] and genes encoding drug targets. We conducted drug enrichment analyses incorporating the novel and biologically specific GSA-MiXeR tool. We conducted multiple molecular trait analyses using large-scale transcriptomic and proteomic datasets sampled from brain and blood tissue. This included the novel use of the UK Biobank proteomic data for a proteome-wide association study of psychiatric disorders. With the accumulated evidence, we prioritize potential drug targets and compounds for each disorder. We reveal candidate drug targets associated with a single or multiple disorders that implicate glutamate signaling. Drug prioritization indicated genetic support for psychotropic medications, including several top-ranked antipsychotics for schizophrenia. We also observed genetic support for commonly used psychotropics for psychiatric treatment (e.g., clozapine, duloxetine, and lithium). Revealed opportunities for drug repurposing included cholinergic drugs for ADHD, estrogen modulators for depression, and matrix metalloproteinases for ADHD and depression. Our findings indicate the genetic liability to schizophrenia is associated with reduced brain and blood expression of CYP2D6, a gene encoding a metabolizer of drugs and neurotransmitters, suggesting a genetic risk for poor drug response and altered neurotransmission. Our extensive analyses highlight the utility of genetics for informing drug development and repurposing for psychiatric disorders, providing novel opportunities for improving patient outcomes. Depicted is the series of analyses conducted to generate a list of prioritized drug targets and compounds. First pairings of genome-wide association study (GWAS) traits with drugs are generated using enrichment analyses. Next, a series of molecular trait analyses is conducted to generate and rank a list of potential drug targets for each GWAS trait. Finally, enrichment and molecular trait results are combined to generate a ranked list of prioritized drugs for each GWAS trait based on supporting genetic evidence. ADHD = Attention deficit hyperactivity disorder, BIP = Bipolar disorder, DEP = Depression, SCZ = Schizophrenia, DBP = Diastolic blood pressure, T2D = Type 2 diabetes, RNA = ribonucleic acid, XWAS = both transcriptome and proteome-wide association studies, MR = Mendelian randomization, coloc = colocalization.
Sex-specific neural activation to stress and alcohol cues in high-risk drinkers: links between orbitofrontal circuits, alcohol craving, and future drinking.
Freeman C, Radoman M, Martins JS … +3 more , Lacadie C, Seo D, Sinha R
Neuropsychopharmacology · 2026 Mar · PMID 41792252 · Full text
High-risk drinking is known to disrupt stress and reward pathways including orbitofrontal cortex (OFC) circuits, which may increase cue-induced craving and alcohol use disorder (AUD) risk. Although high-risk drinking is...
High-risk drinking is known to disrupt stress and reward pathways including orbitofrontal cortex (OFC) circuits, which may increase cue-induced craving and alcohol use disorder (AUD) risk. Although high-risk drinking is more prevalent in men, it is increasing rapidly among women. It remains unclear whether sex differences in reactivity to stress and alcohol cues contribute to these trends. One hundred eighteen adults (56 high-risk drinkers, 62 low-risk drinkers; 52.5% female) completed an fMRI cue provocation task involving alcohol, stress, and neutral cues in a randomized block design with repeated craving assessments. Linear mixed-effects models tested Group (high-risk, low-risk)-by-Sex-by-Condition (Alcohol, Stress, Neutral) effects on craving and brain activation. High-risk drinkers of both sexes reported greater alcohol cue-induced craving (p < 0.001); however, only high-risk women reported increased craving during stress cues (p = 0.020). Whole-brain voxel-based analyses (p < 0.001, cluster corrected at α < 0.05) revealed alcohol cue-related hyperactivation in OFC circuits in high-risk women, but blunted activation in high-risk men. OFC activation correlated positively with craving in women, but negatively in men. During stress cues, high-risk women exhibited increased OFC and hippocampal activation, whereas high-risk men showed heightened amygdala and reduced striatal activity. Decreased stress-related salience network and striatal activity in women but increased activity in men was associated with prospective drinking frequency. These results demonstrate that risky-drinking men and women showed distinct subjective craving and OFC circuit responses to alcohol and stress cues. These sex-specific OFC circuit-related neural patterns may reflect differential risk pathways for AUD and underscore the need for sex-informed prevention and intervention strategies.
Investigational drugs in PTSD.
Obi T, Ressler KJ
Neuropsychopharmacology · 2026 Jun · PMID 41792251 · Full text
Post-traumatic stress disorder (PTSD) remains one of psychiatry's most challenging disorders, common, disabling, and biologically complex. Despite decades of research, only sertraline and paroxetine are FDA-approved, bot...
Post-traumatic stress disorder (PTSD) remains one of psychiatry's most challenging disorders, common, disabling, and biologically complex. Despite decades of research, only sertraline and paroxetine are FDA-approved, both with modest efficacy. Even first-line trauma-focused psychotherapies leave up to half of patients with persistent symptoms. However, advances in neurobiology are reframing PTSD as a disorder of maladaptive stress circuitry, neuroplasticity, and memory reconsolidation, opening new therapeutic possibilities. This comprehensive review examines current PTSD pharmacotherapy, emerging neurobiological targets, and investigational treatments, highlighting 45 actively enrolling clinical trials. Emerging approaches target the hypothalamic-pituitary-adrenal (HPA) axis, adrenergic signaling, glutamatergic/GABAergic systems, endocannabinoids, neuropeptides, and serotonergic-based psychedelics. Rapid-acting interventions represent a major advance in PTSD therapeutics. Ketamine produces symptom reductions within hours, MDMA-assisted psychotherapy has demonstrated Phase 3 efficacy, and neurosteroids offer novel approaches to targeting hyperarousal. However, questions remain regarding durability, optimal dosing, patient selection, precision approaches, and long-term safety. Several early-stage assets also show preliminary promise but require rigorous evaluation. At the same time, the development pipeline remains unforgiving: many mechanistically plausible candidates, from NK-1 antagonists to AMPA modulators, have failed in late-stage trials, often due to high placebo responses, patient heterogeneity despite subtype-specific medication targets, and translational gaps. Brexpiprazole's recent FDA rejection, despite supportive early data, underscores persistent regulatory hurdles. While traditional approaches remain standard of care, breakthrough therapies represent paradigm shifts toward disease modification. Future progress depends on biomarker-guided precision medicine, novel trial designs to mitigate placebo effects, and integration of pharmacologic innovations with evidence-based psychotherapies.
Hedonic hotspot in rat olfactory tubercle: map for mu-opioid, orexin, and muscimol enhancement of sucrose 'liking'.
Murata K, Berridge KC
Neuropsychopharmacology · 2026 May · PMID 41772180 · Full text
Pleasure plays a crucial role in positive reinforcement and motivation. Brain regions able to amplify positive hedonic reactions to sweetness, known as 'hedonic hotspots', are distributed within the mesocorticolimbic rew...
Pleasure plays a crucial role in positive reinforcement and motivation. Brain regions able to amplify positive hedonic reactions to sweetness, known as 'hedonic hotspots', are distributed within the mesocorticolimbic reward systems. The olfactory tubercle (OT), a part of the ventral striatum that receives olfactory input, contains distinct functional domains: the anteromedial domain mediates approach motivation toward odors associated with food, whereas the lateral domain mediates avoidance motivation away from odors associated with danger. However, it has remained unclear whether the OT modulates hedonic reactions to pleasant sensations. In this study, we made pharmacological microinjections in OT of rats to examine whether these OT subregions can modulate hedonic reactions, as assessed by the taste reactivity test. Sweet oral infusions of sucrose solution were delivered into the mouth via an intraoral cannula, and the rats' orofacial and somatic hedonic reactions were recorded and analyzed. We compared three pharmacological agents: mu-opioid receptor agonist DAMGO, orexin-A peptide, and GABA receptor agonist muscimol. Microinjection of any of these drugs into the anteromedial OT subregion enhanced hedonic 'liking' reactions to sucrose. Furthermore, DAMGO injection into the anteromedial OT subregion recruited distant Fos expression in other 'hedonic hotspots', including in the caudal ventral pallidum and the rostromedial orbitofrontal cortex. By contrast, the same microinjections into the anterolateral OT subregion failed to enhance 'liking' reactions and, DAMGO oppositely increased aversive 'disgust' reactions. These findings suggest that the anteromedial OT contains a 'hedonic hotspot', whereas the anterolateral OT may contain a suppressive opioid 'hedonic coldspot'. Thus, OT subregions may help causally modulate hedonic reactions to sweetness and flavor perception.
Maternal immune activation in mice recapitulates features of attention-deficit/hyperactivity disorder (ADHD) in susceptible offspring.
Schaer R, Wenger N, Steiner S … +2 more , Notter T, Meyer U
Neuropsychopharmacology · 2026 Jul · PMID 41764291 · Full text
Prenatal exposure to infectious or non-infectious maternal immune activation (MIA) represents a transdiagnostic environmental risk factor for psychiatric and neurodevelopmental disorders. Building on previous findings of...
Prenatal exposure to infectious or non-infectious maternal immune activation (MIA) represents a transdiagnostic environmental risk factor for psychiatric and neurodevelopmental disorders. Building on previous findings of locomotor hyperactivity in a subset of male MIA offspring, the present study investigated whether viral-like MIA in mice recapitulates features of attention-deficit/hyperactivity disorder (ADHD) in this subgroup. We show that 40-50% of MIA-exposed male offspring develop locomotor hyperactivity in a novel environment, which is most pronounced during early- to mid-adolescence and precedes the emergence of increased impulsive behavior and pre-attentive filtering deficits in early adulthood. We further identified subgroup-specific dopaminergic and noradrenergic alterations in cortical and subcortical brain regions of MIA offspring. These neuronal alterations were age-dependent and correlated with behavioral changes. Moreover, treatment with methylphenidate (MPH), a first-line pharmacological therapy for ADHD, normalized locomotor hyperactivity and restored abnormal mesolimbic and striatal activation patterns in susceptible MIA offspring. Collectively, our findings demonstrate that MIA in mice recapitulates key features of ADHD in a susceptible subset of offspring, supporting the notion that MIA may contribute etiologically to ADHD in some individuals. More broadly, our results suggest that the heterogeneous neurobehavioral outcomes of MIA offspring may result from distinct yet overlapping pathophysiological mechanisms across neurodevelopmental and psychiatric disorders.
Escalation of cocaine consumption: tolerance versus sensitization of incentive salience.
Kawa AB, Robinson TE
Neuropsychopharmacology · 2026 Jun · PMID 41764290 · Full text
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The association between cannabis use and brain reward anticipation: a 12-month longitudinal study of adults and adolescents who use cannabis and age-matched controls.
Skumlien M, Wang S, Freeman TP … +6 more , Eddison M, Petrilli K, Wall MB, Mokrysz C, Curran HV, Lawn W
Neuropsychopharmacology · 2026 Feb · PMID 41748910 · Publisher ↗
Substance use has been associated with blunted brain responses to non-drug rewards, but findings in people who use cannabis are mixed. Adolescents may be uniquely vulnerable to cannabis-related disruption to reward proce...
Substance use has been associated with blunted brain responses to non-drug rewards, but findings in people who use cannabis are mixed. Adolescents may be uniquely vulnerable to cannabis-related disruption to reward processing due to ongoing neuromaturation, but longitudinal research is lacking. In this longitudinal fMRI study, we compared brain measures of reward anticipation in 46 adolescents (16-17 years) and adults (26-29 years) who used cannabis (1-7 days/week) and 50 age-matched controls with the Monetary Incentive Delay task at baseline and 12-month follow-up. Region of interest (ROI) analyses adjusted for cigarette/roll-up use, depression, and risk-taking found that reward anticipation activity decreased in the right (p = 0.05, η = 0.04) and left (p = 0.02, η = 0.05) ventral striatum from baseline to follow-up in participants who used cannabis compared with control participants. These effects remained in unadjusted models and when including only participants who consistently used or abstained from cannabis during the study period. There were no significant interactions between the cannabis user-group and age-group, or between the user-group, age-group, and time. There were also no cannabis user-group main or interaction effects in full sample ROI analyses for the thalamus, insula, or supplementary motor area, or in exploratory whole-brain analyses. The current results suggest that cannabis use may be associated with reductions in non-drug reward anticipation activity in the ventral striatum, a key part of the brain's reward system. However, there was no evidence of adolescent resilience or vulnerability to cannabis-related changes in brain reward anticipation activity.
Risk calculation circuit abnormalities plus psychosocial risk variables predict problematic substance use in youth with externalizing disorders.
Mattey-Mora PP, Murray OK, Aloi J … +3 more , Dzemidzic M, Harezlak J, Hulvershorn LA
Neuropsychopharmacology · 2026 Jun · PMID 41748909 · Full text
Prior research has identified brain regions associated with problematic substance use in youth, yet it remains unclear how neural processes during decision-making contribute to later drug use. Moreover, few studies have...
Prior research has identified brain regions associated with problematic substance use in youth, yet it remains unclear how neural processes during decision-making contribute to later drug use. Moreover, few studies have integrated psychosocial and environmental risk factors into predictive frameworks. This study investigated whether brain activation during risky decision-making in drug-naïve, high-risk children predicts problematic substance use during adolescence. Youth (n = 95; 64 male, mean baseline age=11.7 years) with externalizing disorders completed the Balloon Analogue Risk Task (BART) during functional MRI. Activation contrasts from six regions of interest, identified using a regularization-based feature selection method, were incorporated into cost-sensitive logistic regression models along with psychosocial and environmental variables, including family history of substance use, parental monitoring, and violence exposure. Models were adjusted for age at conversion to drug use, sex assigned at birth, and maternal education. Psychosocial-only factors showed fair predictive accuracy (AUC = 0.76; accuracy= 0.74) with good specificity and fair sensitivity. Neural activation-only models showed poor predictive accuracy (AUCs = 0.60-0.67; accuracy = 55-78%) with good specificity but limited sensitivity. Incorporating both psychosocial and neural factors substantially improved model performance (AUCs = 0.83-0.86; accuracy up to 82%), with fair sensitivity and good specificity in the adjusted models. These findings suggest that neural activity in regions involving risk evaluation, reward response, and sensory integration, together with relevant psychosocial factors predicts later problematic substance use, emphasizing the value of multidimensional models for early identification youth at elevated risk.
Comparing affective bias modification by first- and second-generation antidepressants in male rats using a translational behavioural task.
Kamenish KA, Cahill EN, Robinson ESJ
Neuropsychopharmacology · 2026 May · PMID 41741691 · Full text
Negative affective biases influence cognitive and emotional behaviours and have been observed in patients with major depressive disorder. The neuropsychological hypothesis of antidepressant efficacy suggests direct modul...
Negative affective biases influence cognitive and emotional behaviours and have been observed in patients with major depressive disorder. The neuropsychological hypothesis of antidepressant efficacy suggests direct modulation of affective biases may contribute to efficacy. Studies have shown conventional antidepressants can positively bias emotional processing following acute administration in humans. This study employs a rat model developed to study affective biases based on associative learning and memory, and used this assay to compare selected first versus second generation antidepressants. Dose-response experiments using the tricyclic antidepressant, amitriptyline (0.3-3.0 mg/kg), monoamine oxidase inhibitor, moclobemide (3.0-10.0 mg/kg) and serotonin specific re-uptake inhibitor, sertraline (1.0-10.0 mg/kg) were performed. Specific protocols permitted quantification of affective biases associated with new learning or the acute and sustained modulation of past experiences. All treatments positively biased new learning but exhibited differences in terms of their ability to modulate negatively biased memories. Amitriptyline and sertraline attenuated negatively biases memories when administered 1 h or 24 h before testing. Moclobemide had no effects on past experiences. No treatments had effects in the control reward learning assay. Although generally considered to have similar efficacy and time course of effects, the pharmacological profiles of these antidepressants differ. Previous work has shown that variations in affective bias modification are linked to both the time course of clinical effects and their interaction with experience-dependent plasticity. Integrating understanding of these neuropsychological differences within clinical practice has the potential to improve clinical outcomes for patients.
Sensorimotor circuit connectivity as a candidate biomarker for responsiveness to sertraline in obsessive-compulsive disorder.
Bai T, Wang Y, Ruan H … +9 more , Zhang G, Gao J, Zheng Z, Li D, Zhao Q, Han H, Fan Q, Shi D, Wang Z
Neuropsychopharmacology · 2026 Feb · PMID 41741690 · Publisher ↗
Predicting selective serotonin reuptake inhibitor (SSRI) response in obsessive-compulsive disorder (OCD) remains a clinical challenge. Converging evidence implicated that the sensorimotor circuit is linked to OCD-related...
Predicting selective serotonin reuptake inhibitor (SSRI) response in obsessive-compulsive disorder (OCD) remains a clinical challenge. Converging evidence implicated that the sensorimotor circuit is linked to OCD-related sensory phenomena and repetitive motor rituals, and it is densely innervated by serotonergic projections, making it a plausible substrate of SSRI effects. We therefore hypothesized that baseline functional connectivity (FC) of this circuit could serve as a candidate neural marker of SSRI treatment response. In this exploratory single-site resting-state fMRI study, 54 drug-naïve patients with OCD and 39 matched healthy controls (HCs) underwent scanning. Patients received sertraline for 12 weeks and were classified as responders (rOCD, n = 33) or non-responders (nOCD, n = 21) based on Yale-Brown Obsessive Compulsive Scale score reductions. Seed-based FC analysis of the sensorimotor circuit was conducted across the three groups. We observed that OCD patients exhibited abnormal FC primarily within the sensorimotor circuit and in its connections with the cerebellum. The rOCD group showed generally higher FC within the sensorimotor circuit than HCs, whereas the nOCD group showed lower FC values. Cerebellar regions with altered connectivity included areas involved in sensorimotor processing and higher-level functions. In prediction analyses, the connectivity between right thalamus and cerebellar Crus I region achieved an AUC of 0.854 for distinguishing responders from non-responders under leave-one-out cross-validation. Moreover, FC-based models showed better predictive performance than clinical models. These findings suggest that baseline sensorimotor-network FC may serve as a candidate biomarker of sertraline response in OCD, pending validation in large, independent samples.
The neurobiological cravings signature (NCS) as a predictive neuromarker of clinical outcomes in alcohol use disorder.
Löfberg A, Harp N, Perini I … +5 more , Kämpe R, Karlsson H, Pietrzak M, Kober H, Heilig M
Neuropsychopharmacology · 2026 Jun · PMID 41741689 · Full text
The Neural Craving Signature (NCS), a machine learning derived neuroimaging biomarker, differentiates individuals with from those without substance use disorders (SUDs), but has not been evaluated for predicting clinical...
The Neural Craving Signature (NCS), a machine learning derived neuroimaging biomarker, differentiates individuals with from those without substance use disorders (SUDs), but has not been evaluated for predicting clinical outcomes. In a secondary analysis, we applied the NCS to fMRI cue-reactivity data from 39 participants in a published, negative RCT of repetitive transcranial magnetic stimulation (rTMS) for Alcohol Use Disorder (AUD). NCS scores predicted craving [Penn Alcohol Craving Scale (PACS)], both at the time of fMRI (R = 0.29, 95%, CI [0.27, 0.73], t(36) = 3.86, p = 0.0005), and during repeated study visits (β = 4.6, SE = 5.3, t(39.15) = 1.17, p < 0.0001). NCS also classified AUD severity (Addiction Severity Index, ASI, alcohol subscale-β = 0.14, SE = 0.04, p = 0.0016, R² = 0.24; Alcohol Use Disorder Identification Test, AUDIT, β = 5.32,SE = 1.46, p < 0.0025, R² = 0.22). Most importantly, the NCS predicted alcohol use, both measured by self-reported percent heavy drinking days (HDD%; β = 10.19, SE = 4.46, t(38.23) = 2.28, p = 0.028) and the biomarker phosphatidyl ethanol (PEth; β = 0.32, SE = 0.15, t(37.10) = 2.15, p = 0.038). Participants with below median NCS scores had a lower likelihood of relapse than those above median (Cox regression-HR = 0.35, 95% CI [0.16-0.80], p = 0.013). NCS identified relapse cases with an area under the curve of 0.79 (SE = 0.077, z = 3.8, p = 0.0001), achieving 66.7% sensitivity and 77.8% specificity at optimal NCS score. These findings provide initial support for the NCS as a predictor of clinical outcomes in AUD.
Transcriptional profiles of antidepressant resistance across the corticolimbic pathway of chronically stressed mice.
Gyles TM, Parise EM, Estill M … +5 more , Parise LF, Browne CJ, Shen L, Nestler EJ, Torres-Berrío A
Neuropsychopharmacology · 2026 Jun · PMID 41731115 · Full text
Treatment-resistant depression (TRD), defined by unsuccessful response to multiple antidepressants, affects approximately one-third of individuals with major depressive disorder, yet its underlying molecular mechanisms r...
Treatment-resistant depression (TRD), defined by unsuccessful response to multiple antidepressants, affects approximately one-third of individuals with major depressive disorder, yet its underlying molecular mechanisms remain poorly understood. Here, we developed a preclinical model of TRD in which mice exposed to chronic social defeat stress were sequentially treated with fluoxetine (FLX) and ketamine (KET), allowing behavioral stratification into antidepressant responsive and non-responsive mice. RNA sequencing of the nucleus accumbens (NAc) and prefrontal cortex (PFC) revealed transcriptional signatures associated with treatment outcomes. Prior exposure to FLX exerted a priming effect that facilitated molecular and behavioral responsiveness to KET in a subset of animals. However, this priming effect was absent in non-responders, despite identical treatment regimes, suggesting a transcriptional divergence in both the NAc and PFC in underlying differential outcomes. Gene co-expression network analysis identified modules enriched for differentially expressed genes unique to stress-susceptible and FLX-KET nonresponsive mice, as well as modules overlapping with both stress susceptibility and antidepressant resistance. These findings suggest that failed antidepressant treatment can shape the brain's molecular landscape in a way that influences subsequent treatment outcomes, and that resistance arises not simply from treatment failure but from an absence of adaptive molecular priming. This work provides insight into the gene networks contributing to antidepressant non-response and highlights a mechanistic framework for modeling antidepressant resistance in preclinical systems. By identifying molecular correlates of sequential pharmacological resistance, our findings may inform the development of novel therapeutic strategies for individuals with TRD.
Task-guided accelerated cTBS simultaneously treats depression and social dysfunction in patients with major depressive disorder: a randomized clinical trial.
Jin J, Wang Y, Wang P … +9 more , Qin Q, Wang Z, Jin Y, Chen X, Feng Y, Fitzgerald PB, Zeidman P, Zhou Y, Wang G
Neuropsychopharmacology · 2026 Jun · PMID 41721017 · Full text
Current antidepressant therapies predominately target symptom remission in major depressive disorder (MDD) but often overlook social dysfunction, which is a critical determinant of functional recovery. Individualized, ac...
Current antidepressant therapies predominately target symptom remission in major depressive disorder (MDD) but often overlook social dysfunction, which is a critical determinant of functional recovery. Individualized, accelerated continuous theta burst stimulation (cTBS) targeting the right dorsolateral prefrontal cortex (R.DLPFC) may offer a potential therapeutic approach for concurrently improving clinical and psychosocial outcomes in MDD. In this randomized, double-blind, sham-controlled trial, 70 patients with MDD were randomly assigned to receive either active (n = 37) or sham (n = 33) accelerated cTBS for 2 weeks. The treatments targeted individualized R.DLPFC sites, which were identified by task-evoked brain activation during a social interactive task (Ultimatum Game, UG). Depressive and anxiety symptoms, general social functioning, UG-derived behavioral and computational modeling indices (e.g., learning rates), and effective connectivity in social processing networks were assessed pre- and post-treatment. Active accelerated cTBS significantly outperformed sham stimulation in reducing depressive and anxiety symptoms and improving general social functioning (all ps < 0.001). The active group also demonstrated enhanced cooperation behavior (p = 0.002) and increased learning rates (89% HDI: [0.01, 0.21]). And the active group exhibited increased effective connectivity from the right insula to the R.DLPFC and stable effective connectivity from the anterior cingulate cortex (ACC) to the left insula after treatment, which was different from the sham group (Pp > 0.95). No severe adverse events occurred. Individualized, accelerated cTBS targeting task-evoked activation in the R.DLPFC safely and effectively improves clinical symptoms and social dysfunction in MDD. Altered effective connectivity among the DLPFC, insula and ACC may provide mechanistic insights into its therapeutic effects. Trial Registration: chictr.org.cn; ChiCTR2300068273.
Pharmacotherapy of major depressive disorder in older adults: from an evidence-informed stepwise algorithm to precision medicine.
Lenze EJ, Karp JF, Gebara MA … +2 more , Nicol GE, Mulsant BH
Neuropsychopharmacology · 2026 Feb · PMID 41714410 · Publisher ↗
The pharmacotherapy of late-life depression (LLD) is characterized by clinical complexity. Older adults are living longer with multimorbidity, frailty and polypharmacy, and are taking more CNS-active medications and subs...
The pharmacotherapy of late-life depression (LLD) is characterized by clinical complexity. Older adults are living longer with multimorbidity, frailty and polypharmacy, and are taking more CNS-active medications and substances. These add to the risk and complexity of adding or changing depression treatment. At the same time, there are more medication options for depression and the use of many of them entails balancing potentials risks and benefits. As a result, the pharmacotherapy of LLD should be guided by tools such as algorithms or decision trees to maximize effectiveness and minimize risks of depression treatment. We propose an evidence-informed stepwise algorithm, based on three decades of clinical trials. With this algorithm, treatment starts with serotonin-selective reuptake inhibitors because of their safety and ease of use. If the patient does not respond, the next step is switching to serotonin-norepinephrine reuptake inhibitors, followed by augmentation (with aripiprazole as the preferred agent). For older patients who do not tolerate or do not respond to traditional pharmacotherapy, treatment options include transcranial magnetic stimulation, ketamine, or electroconvulsive therapy. Psychotherapy can be used in combination with antidepressants at any point in this algorithm. We also discuss the need for precision medicine research to improve treatment outcomes in LLD, presenting two approaches. The first is a "lock and key" approach, in which some patients need a specific medication to treat their depression, which requires biotyping to predict. The second is a "simple vs. complex depression" approach, which posits that some with TRD have a more complex illness consisting of less intact brain structure and function and are unlikely to benefit from any traditional treatment; they require novel-mechanism treatments targeting their specific pathophysiology, such as impaired slow wave sleep or accelerated biological aging. In the coming years, we expect these two complementary approaches to improve the outcomes of the increasing population of older adults who suffer from depression.
Sex-dependent developmental changes in behavior, brain structure, functional connectivity, and sensory perception following exposure to psilocybin during adolescence.
Sahoo I, Masadi S, Maheswari A … +13 more , Utama R, Abeer MI, Soltanpour S, Nasseef MT, Chukwuemeka T, Sinhal N, Pandit J, Ortiz RJ, Cavallaro N, Brengel E, Kulkarni PP, Gitcho MA, Ferris CF
Neuropsychopharmacology · 2026 Jun · PMID 41708994 · Full text
Psilocybin is a hallucinogen with complex neurobiological and behavioral effects. Underlying these effects are changes in brain neuroplasticity. We hypothesized psilocybin given during adolescence, a time of heightened n...
Psilocybin is a hallucinogen with complex neurobiological and behavioral effects. Underlying these effects are changes in brain neuroplasticity. We hypothesized psilocybin given during adolescence, a time of heightened neuroplasticity, particularly in the forebrain, would affect emotional behavior and the associated underlying neuroanatomy, neurocircuitry, and epigenetics. Female and male mice were given vehicle or 3.0 mg/kg psilocybin every other day by oral gavage from postnatal days 40-50 for a total of five exposures. Between postnatal days 90-120 mice were imaged and evaluated for affective behavior and perception of rewarding and aversive stimuli. MRI data from voxel-based morphometry, diffusion weighted imaging, and BOLD resting state functional connectivity were registered to a mouse 3D MRI atlas with 139 brain regions providing site-specific differences in global brain structure and functional connectivity between experimental groups. The prefrontal cortex was measured for changes in proteins associated with epigenetics. Mice showed no significant differences in the light/dark box test, but female mice exposed to psilocybin showed reduced mobility in the open field as compared to controls. Mice with early psilocybin exposure showed reduced brain sensitivity to both rewarding and aversive odors during scanning sessions. There were regional reductions in brain volume and alteration in water diffusivity affecting males more than females. Global and regional functional connectivity were increased in both sexes with the prefrontal cortex showing enhanced connections to the hypothalamus, thalamus and midbrain. Males showed reduced levels of epigenetic and neuroplasticity protein markers in the prefrontal cortex. The pronounced changes in brain volume, water diffusivity - a surrogate marker of gray matter microarchitecture, increase in functional connectivity, altered perception of rewarding and aversive stimuli and altered levels of protein markers of neuroplasticity provide compelling evidence that exposure to psilocybin during adolescence has long term developmental consequences, particularly in males.
Disinhibition of ventral tegmental area during initial punishment learning causes enduring punishment insensitivity.
Tan SYS, Shen MH, Keevers LJ … +4 more , Williams-Spooner M, McNally GP, Killcross S, Jean-Richard-Dit-Bressel P
Neuropsychopharmacology · 2026 May · PMID 41699234 · Full text
Avoiding actions with negative consequences is fundamental to adaptive behavior. Traditional theories suggest GABAergic inhibition of midbrain dopamine neurons, including those within ventral tegmental area (VTA), mediat...
Avoiding actions with negative consequences is fundamental to adaptive behavior. Traditional theories suggest GABAergic inhibition of midbrain dopamine neurons, including those within ventral tegmental area (VTA), mediate suppression of actions that lead to aversive outcomes. However, the role of dopamine inhibition in punishment learning remains unclear. To examine this, we conducted fiber photometry, pharmacological, and chemogenetic experiments in rats to measure VTA activity and GABA input across punishment learning, and test their causal contribution to behavior. VTA activity and GABA input phasically increased to response-elicited outcomes, with VTA activity being more strongly activated by rewards, while GABA input being more strongly activated by shock punishers during initial punishment. Pharmacologically blocking GABA receptors in VTA or chemogenetically activating VTA neurons during initial, but not later, punishment sessions produced enduring deficits in punishment avoidance. These findings suggest long-term avoidance depends upon a critical window of GABA-mediated VTA inhibition during punishment learning.
The puzzle of heterogeneity: an introduction to part II.
Ajilore O, Reynolds CF
Neuropsychopharmacology · 2026 Feb · PMID 41691128 · Publisher ↗
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Psilocybin improves novel object recognition in a rat model of Fragile X Syndrome through the modulation of the BDNF/TrkB signaling pathway.
Ascone F, Buzzelli V, Mottarlini F … +10 more , Di Trapano M, Miglioranza P, Rava A, Feo A, Spano F, Hausman M, Sugaya K, Caffino L, Fumagalli F, Trezza V
Neuropsychopharmacology · 2026 Jul · PMID 41688761 · Full text
Fragile X Syndrome (FXS) is the most common inherited intellectual disability and a leading monogenic cause of autism spectrum disorder (ASD). As a synaptic disorder, FXS involves the loss of Fragile X messenger ribonucl...
Fragile X Syndrome (FXS) is the most common inherited intellectual disability and a leading monogenic cause of autism spectrum disorder (ASD). As a synaptic disorder, FXS involves the loss of Fragile X messenger ribonucleoprotein 1 (FMRP), leading to abnormal dendrite development and immature dendritic spines. Serotonergic signaling, essential for neuronal development and circuit remodeling, has been implicated in ASD and related conditions, including FXS, raising the possibility that serotonergic modulation could ameliorate neurodevelopmental impairments. This study investigated the therapeutic potential of psilocybin, a serotonergic compound, in the validated Fmr1-exon 8 rat model of FXS. Psilocybin microdosing rescued deficits in NOR. Importantly, its benefits on recognition memory persisted despite pretreatment with the 5HT2AR antagonist, volinanserin, or the 5HT1AR antagonist, WAY-100635, indicating that classical serotonergic receptor activation is not required. In contrast, pretreatment with the TrkB receptor antagonist, ANA-12, abolished psilocybin's effects, implicating BDNF/TrkB signaling as essential. At the molecular level, psilocybin normalized mature BDNF (mBDNF), increased TrkB, and restored downstream AKT signaling in the prefrontal cortex of Fmr1-exon 8 rats, pathways strongly linked to synaptic plasticity and cognitive function. These findings demonstrate that psilocybin rescues object recognition memory deficits in this rat model of FXS via BDNF/TrkB-AKT signaling rather than serotonergic receptor mechanisms. By dissociating therapeutic effects from hallucinogenic pathways, our results highlight psilocybin microdosing as a promising therapeutic strategy for neurodevelopmental disorders such as FXS and ASD.
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