Neuropsychopharmacology [JOURNAL]
Sun
200 papers
Mechanistic signatures of comorbid PTSD with cognitive impairment implicate cortisol-induced neural toxicity.
Kuang Z, Chesebro AG, Strey SG … +3 more , Clouston SAP, Luft BJ, Mujica-Parodi LR
Neuropsychopharmacology · 2026 Jun · PMID 41680478 · Full text
The men and women who worked in rescue and recovery operations at the 9/11 World Trade Center site are developing cognitive impairment (CI) at mid-life, decades before CI is usually detected. To date, one of the most con...
The men and women who worked in rescue and recovery operations at the 9/11 World Trade Center site are developing cognitive impairment (CI) at mid-life, decades before CI is usually detected. To date, one of the most consistent risk factors for CI in this population is symptoms of post-traumatic stress disorder (PTSD). However, little is known about the mechanistic cascade that drives stress-related neurological changes to accelerate cognitive decline in the human brain. We used machine learning to identify distinct brain signatures from functional magnetic resonance imaging between trauma-exposed healthy controls (TEHC; N = 30; 21 men), PTSD without CI (PTSD-CI; N = 19; 16 men), and PTSD with CI (PTSD + CI; N = 22; 18 men). We compared the spatial gradient of each functional signature to the distribution of mRNA expression in the brain. We applied structural equation modeling (SEM) to infer mechanistic cascades specific to each group. While modest accuracy was achieved for the PTSD-CI versus TEHC signature (0.67), clear differentiation was observed for PTSD + CI versus TEHC (0.73) and PTSD + CI versus PTSD-CI (0.85). Consistent significant correlations were found between PTSD + CI signatures and ZNF48, TOMM40, and GRIN1 expression distributions. The cortisol-induced neurotoxicity pathway was consistently found with the PTSD + CI signature, while the p53 signaling pathway was observed across all PTSD signatures. Our results reinforce peripheral biomarkers from a previous transcriptomic study and suggest functional biomarkers in PTSD and PTSD-related CI. Furthermore, our SEM results suggest that PTSD and PTSD-related CI may diverge at the mechanistic level, with neurotoxicity being specific to CI.
The sodium leak channel NALCN in Drd2 striatal neurons regulates neuronal excitability, locomotion and food-seeking in a sex-dependent manner.
Castell L, Naon C, Rogliardo A … +11 more , Ducrocq F, Makrini L, Typou A, Avrillon M, Mignon A, Bernat C, Lory P, Bertaso F, Monteil A, Bosch-Bouju C, Valjent E
Neuropsychopharmacology · 2026 Jun · PMID 41673358 · Full text
The sodium leak channel NALCN is an important modulator of cell excitability. Studies so far demonstrated the critical role of this highly conserved channel in the generation and maintenance of pacemaker activity in cell...
The sodium leak channel NALCN is an important modulator of cell excitability. Studies so far demonstrated the critical role of this highly conserved channel in the generation and maintenance of pacemaker activity in cells with spontaneous firing, such as cardiomyocytes, adrenal cells, or neurons. However, the physiological importance of NALCN for neurons with no spontaneous firing has been largely overlooked and remains unknown. Yet, Drd2-expressing striatal projection neurons (SPNs) show an enriched expression of NALCN while they are highly hyperpolarized neurons. Considering that pathogenic variants of NALCN in human result in severe pathological conditions with symptoms that include cognitive and motor impairments, we hypothesized that NALCN in Drd2-SPNs was necessary for their correct signal integration and consequently striatal-associated behaviors. Here, we investigated the impact of NALCN deletion in Drd2-SPNs in both male and female mice. Unexpectedly, we found that only male mice with deletion of NALCN in Drd2-expressing neurons exhibited enhanced locomotor responses to novel environment and reduced motivation in food-seeking tasks, while female mice were unaffected in their behavior. Similarly, electrophysiological recordings of SPNs revealed significant sex differences, with male SPNs lacking NALCN exhibiting altered membrane properties and increased excitability, while females showed only subtle changes. Finally, we found that eticlopride-induced catalepsy and signaling events were differently altered by NALCN deletion in Drd2-SPNs male and female mice. This work constitutes the first evidence that NALCN in Drd2-SPNs participates to striatal function and may be a key modulator of response to antidopaminergic treatments, with significant sex differences.
Serotonin-endocannabinoid crosstalk selectively regulates inhibitory GABAergic inputs in the medial prefrontal cortex.
Meza RC, Morales-Weil K, Ancatén-González C … +8 more , Escobar AP, Alcaino A, Sanguinetti N, Delpire E, Moya PR, Chiu CQ, Fuenzalida M, Chávez AE
Neuropsychopharmacology · 2026 Jul · PMID 41673357 · Full text
Serotonin (5-HT) plays an important role in shaping brain network dynamics by regulating excitatory synaptic function and neuronal excitability. However, much less is known about how 5-HT tunes synaptic inhibition. Here,...
Serotonin (5-HT) plays an important role in shaping brain network dynamics by regulating excitatory synaptic function and neuronal excitability. However, much less is known about how 5-HT tunes synaptic inhibition. Here, we demonstrate that transient 5-HT signaling persistently suppresses GABAergic synapses onto layer 2/3 pyramidal neurons in the medial prefrontal cortex (mPFC). Moreover, we found that 5-HT1A and 5-HT2A receptors differentially contribute to 5-HT regulation of synaptic inhibition, possibly by acting at distinct GABAergic cell subpopulations. Importantly, 5-HT2A receptor activation triggers retrograde endocannabinoid signaling to reduce GABA release selectively at synapses formed by somatostatin (SST+)- but not parvalbumin (PV+)-positive GABAergic interneurons. Altogether, our results highlight the diverse molecular and cell-type-specific mechanisms by which 5-HT signaling modulates inhibitory circuits to shape cortical function.
Galanin receptor 1 expressing neurons in hippocampal-prefrontal circuitry modulate goal directed attention and impulse control.
Messanvi F, Visocky V, Senneca C … +6 more , Berkun K, Taori M, Bradley SP, Wang H, Tejeda HA, Chudasama Y
Neuropsychopharmacology · 2026 Jul · PMID 41673356 · Full text
Neuropeptides like galanin are increasingly recognized as modulators of cognitive pathways. Galanin has been implicated in a wide range of pathological conditions in which frontal and temporal structures are compromised....
Neuropeptides like galanin are increasingly recognized as modulators of cognitive pathways. Galanin has been implicated in a wide range of pathological conditions in which frontal and temporal structures are compromised. Recently, we discovered that direct pharmacological stimulation of galanin receptor type 1 (GalR1) in the ventral prefrontal cortex (vPFC) and ventral hippocampus (vHC) caused opposing effects on attention and impulse control behaviors. In the present study, we investigate how neurons expressing GalR1 in these two areas differentially contribute to these behaviors. First, using multiplex fluorescent in situ-hybridization, we established that GalR1 is predominantly expressed in glutamatergic neurons in both the vPFC and vHC. Rats were assessed in their visuospatial attention and impulse control behaviors using the 5-Choice task. We developed a novel viral approach to gain genetic access to GalR1-expressing neurons in the vPFC and vHC and found that optogenetic excitation of GalR1 expressing neurons in the vPFC, but not vHC, selectively disrupted attention. Finally, using fiber photometry, we measured bulk calcium dynamics in GalR1-expressing neurons and discovered that GalR1- expressing neurons in the vPFC and vHC showed opposing activity; increased activity in neurons in the vPFC corresponded to correct, attentive actions, whereas activity in the vHC was associated with errors. This region- and response-specific intrinsic activity of galanin, mediated by subclasses of neurons in frontotemporal circuitry participates in shaping the expression of executive-control behaviors that often go awry in various disorders of mental health.
Moderators of treatment response in late-life depression.
Steffens DC, Diniz BS, Jain N … +3 more , Kluewer-D'Amico J, Manning KJ, Wang L
Neuropsychopharmacology · 2026 Feb · PMID 41667639 · Publisher ↗
As late-life depression is associated with a high degree of treatment resistance, understanding predictors of outcome may inform management. In this review, we examine a spectrum of factors that may moderate treatment re...
As late-life depression is associated with a high degree of treatment resistance, understanding predictors of outcome may inform management. In this review, we examine a spectrum of factors that may moderate treatment response. These include clinical moderators related to depression presentation and history, social moderators, psychosocial stressors, personality, and cognitive factors. As there has been substantial research on biological predictors of response, we also include a review of neuroimaging moderators, including markers of accelerated brain aging, as well as other peripheral or central biomarkers of response.
Neuropsychiatric illness in the later years of life: summary and synthesis.
Reynolds Iii CF, Ajilore O
Neuropsychopharmacology · 2026 Feb · PMID 41667638 · Publisher ↗
Dealing with neuropsychiatric illness in the later years of life is an immersion in complexity, born of heterogeneity in etiology, pathogenesis, clinical presentation, and response to intervention. We offer here a concep...
Dealing with neuropsychiatric illness in the later years of life is an immersion in complexity, born of heterogeneity in etiology, pathogenesis, clinical presentation, and response to intervention. We offer here a conceptual summary and synthesis of the key theme of heterogeneity, as embodied in the 20 papers that constitute this issue of Neuropsychopharmacology Reviews (NPPR's). We conclude with future scientific directions and moral imperatives for research and practice, already underway in many instances, but gaining in speed and transformative potential (especially in generative Artificial Intelligence and Large Language Models). We seek to review and to encourage research that works toward practical wisdom-- what Aristotle termed "phronesis," for promotion of resilience and wellbeing in older adults both at the individual and population levels.
Characterization of a novel female chronic social defeat stress (femCSDS) model utilizing persistently aggressive CD1 parous females.
Patel S, Kushwaha R, Anusha PV … +6 more , Arvind A, Dhaygude SS, Pattnaik SR, Kumar A, Idris M, Chakravarty S
Neuropsychopharmacology · 2026 Jul · PMID 41667637 · Full text
Depression shows significant sex differences in prevalence and neurobiological underpinnings, yet preclinical research investigating the pathophysiology of depression and the efficacy of antidepressants has predominantly...
Depression shows significant sex differences in prevalence and neurobiological underpinnings, yet preclinical research investigating the pathophysiology of depression and the efficacy of antidepressants has predominantly relied on male models. Here, we establish a novel female chronic social defeat stress paradigm by leveraging the natural aggression of parous CD1 females, co-housed with castrated males to induce aggression while eliminating confounding sexual behaviors and without hormonal or surgical manipulations. Selected aggressive females reliably displayed offensive behaviors toward C57BL/6NCrl intruders across repeated encounters. Defeated female mice exhibited pronounced depression-like behaviors, including social withdrawal, anhedonia, behavioral despair, and elevated anxiety-like responses. Biochemical analysis revealed elevated glutamate levels in Nucleus Accumbens (NAc) and caudate putamen (CPu). Alterations in EAAT1, GRIN2B, and Neurabin expression were observed in CPu, indicating excitotoxic stress and compromised synaptic integrity. Given the extensive literature on male CSDS and its established pathophysiology, we aimed and successfully developed female-specific replica model of traditional male CSDS, enabling direct comparison and elucidation of sex differences in depression pathophysiology.
Prevention of late-life depression: a framework and prospectus for research.
Okereke OI
Neuropsychopharmacology · 2026 Feb · PMID 41667636 · Publisher ↗
Depression is a leading cause of disease burden, disability, and distress for millions of older adults. Therefore, prevention of late-life depression (LLD) is a research and public health priority. Much of the research o...
Depression is a leading cause of disease burden, disability, and distress for millions of older adults. Therefore, prevention of late-life depression (LLD) is a research and public health priority. Much of the research on depression prevention has been guided by the central framework of prevention of mental disorders that was developed by the National Academies of Medicine (NAM). This framework features three modes of prevention, centered on the group or people at risk: 1) indicated prevention, which focuses on those who have symptoms but are below the threshold of clinical disease; 2) selective prevention, which focuses on persons at higher risk to develop a disease because of having key risk factors; 3) universal prevention, which focuses on the population as a whole, regardless of risk factors or risk status. This perspective will provide illustrative examples of all three NAM modes of prevention, including one example from the author's work that simultaneously addressed indicated, selective, and universal prevention of late-life depression in the VITamin D and OmegA-3 TriaL-Depression Endpoint Prevention (VITAL-DEP) study. This paper will also discuss next steps in research to advance LLD prevention, with a view toward ensuring that all older adults can benefit from the increasing range of prevention options available.
Caffeine reverses sleep deprivation-induced synaptic and social memory deficits via adenosine receptor modulation in the male mouse hippocampal CA2 region.
Wong LW, Bin Ibrahim MZ, Kannan AL … +1 more , Sajikumar S
Neuropsychopharmacology · 2026 Jul · PMID 41667635 · Full text
Sleep deprivation (SD) is a critical risk factor for cognitive decline and is closely linked to psychiatric disorders. The hippocampal CA2 region is critically involved in encoding social memory and regulating emotional...
Sleep deprivation (SD) is a critical risk factor for cognitive decline and is closely linked to psychiatric disorders. The hippocampal CA2 region is critically involved in encoding social memory and regulating emotional behavior, and it has been implicated in various neuropsychiatric conditions. However, how SD affects CA2-dependent synaptic plasticity and related behaviors remains poorly understood. Here, we subjected mice to 5 h of SD via gentle handling and examined synaptic plasticity, molecular signaling, and social recognition memory. Electrophysiological recordings revealed that SD markedly impaired long-term potentiation (LTP) in CA2 and disrupted social recognition memory, as evidenced by failure to distinguish novel from familiar conspecifics. These deficits were accompanied by upregulation of adenosine A1 receptors and PDE4A5, along with reduced expression of plasticity-related proteins including PKMζ, ERK, and BDNF. Moreover, caffeine-induced synaptic potentiation was diminished in SD mice, whereas caffeine supplementation reversed both synaptic and behavioral impairments. Together, these findings demonstrate that SD compromises CA2-dependent plasticity and social cognition through adenosine receptor signaling and identify CA2 as a vulnerable, therapeutically relevant region. Targeting adenosine pathways may represent a novel strategy to mitigate sleep loss-related cognitive dysfunction in neuropsychiatric disorders.
Hair cortisol concentrations as a putative biomarker for suicidal behavior.
Taraban L, Hone E, Jia-Richards M … +14 more , Kelly MA, Lindsay JM, Riston S, Hutchinson Z, Walko TD, Goodfriend E, Thoma BC, Sakolsky D, Chen K, Douaihy A, Brent DA, Marsland AL, Lewis DA, Melhem NM
Neuropsychopharmacology · 2026 May · PMID 41651981 · Full text
Suicide is the 2nd leading cause of death for young adults in the United States, and rates are particularly high among psychiatric patients in the year following psychiatric hospitalization. However, the prediction of su...
Suicide is the 2nd leading cause of death for young adults in the United States, and rates are particularly high among psychiatric patients in the year following psychiatric hospitalization. However, the prediction of suicidal behavior continues to be a challenge. We examined hair cortisol concentrations (HCC)-reflecting HPA axis activity over the preceding months-as an objective marker of risk for suicidal behavior across the full spectrum of suicidal behavior, including death by suicide. Participants were 238 young adults across the spectrum of suicide (i.e., suicide; suicide attempt; suicidal ideation; psychiatric comparison; 57% male) and 43 individuals who died by drug overdose (56% male). Data were collected via self-report, clinical interview, medical records review, and hair sampling (i.e., 3 cm segments). Multivariate regression models were used to examine the relationship between group and HCC, controlling for covariates. HCC was significantly lower in individuals who died by suicide compared to those with a suicide attempt [Difference in EMMs (SE) = -0.64 (0.20), p = 0.010, d = 0.73], suicidal ideation [Est. Diff (SE) = -0.89 (0.20), p < 0.0001, d = 1.02], and psychiatric comparison individuals [Est. Diff (SE) = -0.74 (0.26), p = 0.022, d = 0.85]. Lower HCC may serve as an objective marker that signals risk for death by suicide among high-risk adults, which have important clinical implications for the prediction and prevention of suicide. Future studies with larger sample sizes are needed to replicate these findings and to make assaying HCC accessible for its translation into clinical practice.
Hypocretin receptor 1 blockade early in abstinence prevents incubation of cocaine seeking and normalizes dopamine transmission.
Clark PJ, Migovich VM, Das S … +4 more , Xu W, Zhang Y, Kortagere S, España RA
Neuropsychopharmacology · 2026 May · PMID 41639572 · Full text
Abstinence from cocaine use has been shown to elicit a progressive intensification or incubation of cocaine craving/seeking that is posited to increase the likelihood of relapse. While the mechanisms underlying incubatio...
Abstinence from cocaine use has been shown to elicit a progressive intensification or incubation of cocaine craving/seeking that is posited to increase the likelihood of relapse. While the mechanisms underlying incubation of cocaine seeking remain elusive, considerable evidence suggests that abstinence from cocaine promotes mesolimbic dopamine adaptations that contribute to exaggerated cocaine seeking. Consequently, preventing these dopamine adaptations may reduce incubation of cocaine seeking and thereby decrease the likelihood of relapse. In the present studies, we first examined the relationship between incubation of cocaine seeking and dopamine transmission in the nucleus accumbens following abstinence from intermittent access to cocaine. Given the extensive evidence that hypocretins/orexins regulate motivation for cocaine, we then examined to what extent an intraperitoneal injection of a hypocretin receptor 1 antagonist on the first day of abstinence would prevent incubation of cocaine seeking and dopamine adaptations later in abstinence. Results indicated that abstinence from intermittent access to cocaine engendered robust incubation of cocaine seeking in both female and male rats. We also observed aberrant dopamine transmission, but only in rats that displayed incubation of cocaine seeking. Further, we showed that a single injection of the hypocretin receptor 1 antagonist, RTIOX-276, on the first day of abstinence prevented incubation of cocaine seeking and aberrant dopamine transmission. These findings suggest that hypocretin receptor 1 antagonism may serve as a viable therapeutic for reducing cocaine craving/seeking early in abstinence, thus reducing the likelihood of relapse.
Effects of electroconvulsive shock on the function, circuitry, and transcriptome of dentate gyrus granule neurons.
Santiago AN, Saval JC, Nguyen P … +5 more , Chung HM, Khan S, Luna VM, Hen R, Chang WL
Neuropsychopharmacology · 2026 Jun · PMID 41639571 · Full text
Therapeutic use of electroconvulsive shock (ECS) is particularly effective for treatment-resistant depression. Like other more common forms of antidepressant treatment, such as SSRIs, ECS has been shown to increase neuro...
Therapeutic use of electroconvulsive shock (ECS) is particularly effective for treatment-resistant depression. Like other more common forms of antidepressant treatment, such as SSRIs, ECS has been shown to increase neurogenesis in the hippocampal dentate gyrus of rodent models. Yet the question of how ECS-induced neurogenesis supports improvement of depressive symptoms remains unknown. Here, we show that ECS-induced neurogenesis is necessary to improve depressive-like behavior of mice exposed to chronic corticosterone (Cort). We then use slice electrophysiology to show that optogenetic stimulation of adult-born neurons produces a greater hyperpolarization in mature granule neurons after ECS vs Sham treatment. We identify that this hyperpolarization requires the activation of group II metabotropic glutamate receptors. Consistent with this finding, we observe reduced expression of the immediate early gene cFos in the granule cell layer of ECS vs Sham subjects. Using single-nucleus RNA sequencing, we reveal major transcriptomic shifts in granule neurons after treatment with ECS+Cort or fluoxetine+Cort vs. Cort alone. We identify a population of immature cells that has greater representation in both ECS+Cort and fluoxetine+Cort treated samples vs Cort alone. We also find global differences in ECS- vs fluoxetine-induced transcriptomic shifts. Together, these findings highlight a critical role for immature granule cells in the antidepressant action of ECS.
Whole brain grey matter synaptic terminal density, age and intellectual functioning in schizophrenia: an in vivo [C]UCB-J positron emission tomography study.
Onwordi EC, Whitehurst T, Shatalina E … +14 more , Mansur A, Arumuham A, Osugo M, Marques TR, Jauhar S, Mehrotra R, Ranger M, Rahaman N, Church SM, Rabiner EA, Gunn RN, Natesan S, Reichenberg A, Howes OD
Neuropsychopharmacology · 2026 May · PMID 41629634 · Full text
Converging lines of evidence implicate synaptic loss in cognitive impairment associated with schizophrenia. However, it remains unknown whether synaptic terminal density and premorbid intellectual functioning are related...
Converging lines of evidence implicate synaptic loss in cognitive impairment associated with schizophrenia. However, it remains unknown whether synaptic terminal density and premorbid intellectual functioning are related in vivo, or whether there are age-related changes in them in schizophrenia. To address this, we investigated whole brain grey matter synaptic vesicle glycoprotein 2A (SV2A) levels and examined their relationship with intellectual functioning and age, in forty-three patients with schizophrenia (SCZ) and 26 healthy volunteers (HV), using [C]UCB-J positron emission tomography (PET). Whole brain grey matter [C]UCB-J distribution volume ratio (DVR) was significantly lower in the SCZ than the HV group (Cohen's d = 0.64, p = 0.01), and negatively correlated with age in both groups (Spearman's rho = -0.46 to -0.55), with no significant group difference in magnitude of DVR-age correlations (z = 0.44, p = 0.66). Current (Cohen's d = 0.73) and premorbid IQ (Cliff's delta = 0.37) were significantly lower in the SCZ than the HV group, though DVR was not significantly associated with current or premorbid IQ in either group (including in chronic medicated and early-course unmedicated SCZ subgroups). The group differences in DVR are consistent with a global deficit in synaptic terminal density in schizophrenia, with similar age-related changes in people with schizophrenia and healthy volunteers. The lack of significant relationships between DVR and premorbid or current cognitive measures are not consistent with the hypothesis that lower levels of synaptic terminal density observed in schizophrenia underlie lower levels of intellectual functioning in the disorder.
Stereoselective, sex-dependent 5-HT receptor modulation of cortical plasticity by MDMA in mice.
Gaines-Smith MC, Silverman JM, Fiorillo M … +8 more , Younkin J, Moore KN, Maltman JL, de la Fuente Revenga M, Wolstenholme JT, Glennon RA, Dukat M, González-Maeso J
Neuropsychopharmacology · 2026 May · PMID 41629633 · Full text
The psychoactive entactogen 3,4-methylenedioxymethamphetamine (MDMA), widely known as a recreational drug, is gaining renewed attention as a potential psychotherapeutic adjunct for treatment-resistant psychiatric disorde...
The psychoactive entactogen 3,4-methylenedioxymethamphetamine (MDMA), widely known as a recreational drug, is gaining renewed attention as a potential psychotherapeutic adjunct for treatment-resistant psychiatric disorders, yet its neurobiological mechanisms - particularly those related to its stereoisomers and sex-specific effects - remain poorly understood. Here, we report stereoselective and sex-dependent actions of MDMA on serotonin (or 5-hydroxytryptamine) 2A receptor (5-HTR)-mediated signaling and dendritic structural plasticity in mouse frontal cortex. Using both in vitro and in vivo approaches, we found that racemic MDMA and S(+)-MDMA exhibit weak partial agonism at 5-HTR in HEK293 cells, whereas R(-)-MDMA shows negligible functional activity despite higher specific binding affinity. In vivo, S(+)-MDMA elicited a dose-dependent head-twitch response (HTR) in both sexes, while R(-)-MDMA-induced HTR only in females. Correspondingly, S(+)-MDMA increased inositol monophosphate (IP) accumulation in the frontal cortex of male and female mice, whereas R(-)-MDMA showed minimal effects. Structurally, S(+)-MDMA enhanced dendritic spine density in male frontal cortex in a partially 5-HTR-dependent manner, while no spine remodeling was observed in females or with R(-)-MDMA. Pharmacological blockade of the serotonin transporter (SERT) with fluoxetine fully prevented S(+)-MDMA-induced HTR and IP signaling, without affecting responses to the direct 5-HTR agonist DOI. These findings indicate that MDMA engages 5-HTR signaling indirectly via serotonin efflux and that this effect is both stereoselective and sex-dependent in mice, uncovering a previously unrecognized interaction between sex, MDMA stereochemistry, and 5-HTR-mediated cortical plasticity, with important implications for the rational design of MDMA-based therapeutics.
Medial prefrontal-thalamic white matter microstructure is associated with harm avoidance in OCD: a discovery and transdiagnostic replication study.
Lima Santos JP, Versace A, Arora M … +10 more , Bertocci MA, Chase HW, Graur S, Bonar L, Maffei C, Yendiki A, Boisseau CL, Haber SN, Rasmussen SA, Phillips ML
Neuropsychopharmacology · 2026 Jul · PMID 41620511 · Full text
Identifying neural mechanisms underlying harm avoidance and incompleteness in OCD and other psychiatric disorders is critical for improving diagnostic precision and developing targeted treatments. However, little is know...
Identifying neural mechanisms underlying harm avoidance and incompleteness in OCD and other psychiatric disorders is critical for improving diagnostic precision and developing targeted treatments. However, little is known about the neural pathways underlying these symptom dimensions across clinical populations. The goal of this study was to use diffusion MRI to replicate and extend prior findings in OCD to a transdiagnostic sample of healthy controls (HC) and individuals with Obsessive-Compulsive Disorder (OCD), Obsessive-Compulsive Personality Disorder (OCPD), and non-OCD disorders (e.g., anxiety, post-traumatic stress disorder). Connections between prefrontal (dorsomedial, dorsolateral, ventromedial, and ventrolateral) and subcortical regions (thalamus and striatum) were reconstructed using whole brain tractography in 38 HC (mean age [SD] = 30.97 [10.62), 47 OCD (mean age [SD] = 32.34 [12.23]), 21 OCPD (mean age [SD] = 35.67 [14.65]), and 20 Non-OCD (mean age [SD] = 35.90 [14.26]) participants. Fractional anisotropy (FA) was derived for each connection. Harm avoidance and incompleteness symptom dimensions were assessed using the Obsessive-Compulsive Trait Core Dimensions Questionnaire. In a first replication model, including individuals with OCD and HC, higher left (β = 0.29, P = 0.009, Q = 0.048) and right (β = 0.30, P = 0.005, Q = 0.0048) dorsomedial PFC-thalamus FA was associated with higher harm avoidance, with the left connection also associated with higher incompleteness (β = 0.29, P = 0.009, Q = 0.048). In additional models adding in OCPD and non-OCD participants, only associations among left (β = 0.20, P = 0.027, Q = 0.040) and right (β = 0.18, P = 0.035, Q = 0.045) dorsomedial PFC-thalamus FA and harm avoidance remained significant. There were no associations involving PFC-striatum connections. Dorsomedial PFC-thalamus FA was associated with harm avoidance, but less so with incompleteness. Our findings suggest that higher dorsomedial PFC-thalamic FA is associated with higher harm avoidance across diagnostic groups, providing transdiagnostic neural targets for future treatment developments.
Fundamentals of healthcare delivery science for the non-health systems scientist: the final step in translational research for late-life psychiatric and neurocognitive disorders.
Colenda CC, Forester BP, Tampi RR … +2 more , Tsegaye S, Bartels SJ
Neuropsychopharmacology · 2026 Jan · PMID 41617926 · Publisher ↗
This perspective describes why and how Healthcare Delivery Science (HDS) is the stage of translational science research necessary to answer the vexing question of clinical research: "Why is it that what we know works is...
This perspective describes why and how Healthcare Delivery Science (HDS) is the stage of translational science research necessary to answer the vexing question of clinical research: "Why is it that what we know works is frustratingly difficult to translate or 'scale' to real-world clinical practice?" Our patients with late-life psychiatric and neurocognitive disorders (PNCDs) are managed in the specialty mental health, general health and long-term care service sectors, and over their lifetimes often require complex, multifaceted and coordinated evidence-based interventions that span all three healthcare sectors to optimize their quality of life and functioning. This perspective defines core principles of HDS and summarizes key implementation and dissemination research methods to further understanding of translational research challenges in real-world settings and to facilitate their widespread dissemination. The importance of Learning Health Systems, especially Age-Friendly Health Systems, as real-world research laboratories, is also reviewed. Importantly, translation of evidence-based interventions across service sectors and large diverse patient populations requires skilled interdisciplinary teams. We characterize existing and projected geriatric professional workforce trends necessary to meet the population health service demands and will offer strategies to ensure success in the growth of the workforce that is required. Selected examples of HDS research are presented that have shown dissemination and translational promise, including a review of the "naturalistic" observational study example associated with private equity investment in the specialty mental health and long-term care service sectors. Finally, HDS's "value proposition" is offered to support the proposition that discovery science priorities could also be shaped from HDS evidence.
Large-scale behavioral characterization of oxycodone self-administration in heterogeneous stock rats reveals initial analgesic effects are associated with addiction-like behaviors.
Kallupi M, de Guglielmo G, Carrette LLG … +32 more , Simpson S, Kononoff J, Kimbrough A, Smith LC, Shankar K, Avelar A, Conlisk D, Brennan M, Tieu L, Sedighim S, Boomhower B, Maturin L, Fannon MJ, Martinez A, Crook C, Dirik S, Velarde N, Schweitzer P, Bonnet-Zahedi S, Sneddon E, Plasil S, Morgan AA, Othman DN, Sichel B, Peng B, Chitre AS, Polesskaya O, Lau J, Vang A, Solberg Woods LC, Palmer AA, George O
Neuropsychopharmacology · 2026 May · PMID 41617925 · Full text
Family and twin studies indicate that 20-60% of the vulnerability to opioid use disorder (OUD) is influenced by genetic factors, but the specific genes driving addiction-like behaviors, including sensitivity to opioid an...
Family and twin studies indicate that 20-60% of the vulnerability to opioid use disorder (OUD) is influenced by genetic factors, but the specific genes driving addiction-like behaviors, including sensitivity to opioid analgesia, tolerance, dependence, and escalation of oxycodone self-administration, remain unidentified, limiting precision medicine approaches. To address this, we phenotyped over 500 heterogeneous stock (HS) rats, an outbred population with high genetic diversity, to characterize traits associated with OUD vulnerability and resilience. Rats self-administered oxycodone (150 µg/kg/infusion) in short-access (2 h/day, 4 days) followed by long-access (12 h/day, 14 days) sessions. We assessed motivation for oxycodone using progressive ratio testing, withdrawal-induced hyperalgesia with von Frey tests, and tolerance to oxycodone's analgesic effects via tail immersion tests. Large cohorts (n = 46-60) and Z-score normalization minimized cohort-specific effects. An Addiction Index, derived from averaging Z-scores of escalation, motivation, tolerance, and hyperalgesia, revealed significant individual variability. Rats with severe addiction-like behaviors displayed higher initial analgesia, greater escalation, and more pronounced tolerance compared to resilient rats. Females showed increased escalation and motivation compared to males, but similar tolerance and hyperalgesia. Principal component analysis confirmed the Addiction Index's validity, accounting for 40% of behavioral variance. This high-throughput phenotyping in HS rats, leveraging their genetic diversity, provides a robust framework for genome-wide association studies to identify gene variants linked to OUD vulnerability, offering translational potential for discovering novel therapeutic targets and advancing pharmacogenetic strategies for OUD treatment.
The role of brain health and resilience in reshaping trajectories of late-life neuropsychiatric disorders.
Lavretsky H, Khalsa S, Oughli HA … +9 more , Ibanez A, Cruzat J, Edwards E, Newhouse P, Bassetti CLA, Begue I, Winkler AS, Jeste DV, Eyre HA
Neuropsychopharmacology · 2026 Jan · PMID 41606214 · Publisher ↗
Global population aging and increased chronic stress due to numerous mass disasters including those related to pandemics, climate change, war, displacement, and political unrest all challenge our collective resilience, w...
Global population aging and increased chronic stress due to numerous mass disasters including those related to pandemics, climate change, war, displacement, and political unrest all challenge our collective resilience, with a growing burden of late-life neuropsychiatric and neurodegenerative disorders placing unprecedented demands on health and social systems worldwide. With these considerations in mind, understanding and promoting brain health is becoming a priority for the prevention of neuropsychiatric disorders across the lifespan. Brain health represents a dynamic balance of neural, cognitive, and emotional processes that determine resilience to neuropsychiatric illness. In later life, this balance becomes particularly critical as neurobiological and psychosocial stressors converge to shape trajectories of neuropsychiatric and neurodegenerative disorders. This review synthesizes current evidence on the determinants of brain health in aging, emphasizing resilience as a modifiable pathway linking neuropsychiatric illness risk and prevention. We integrate insights from neuroscience, lifestyle medicine, geroscience, and social determinants of health to emphasize the value of a whole-person, life-course approach. Particular attention is given to the interplay between stress physiology, interoceptive regulation, emotional resilience, and cognitive and brain reserve across the aging continuum. Emerging frameworks including brain clocks, precision biomarkers, digital phenotyping, and artificial intelligence, are considered as tools for risk stratification, early detection, and personalized intervention. By linking resilience mechanisms to measurable biological indices, we argue for the integration of neurobiological, psychological, behavioral, and sociocultural domains to inform next-generation strategies in neuropsychopharmacology, prevention science, and the promotion of healthy brain aging.
The role of ovarian hormones in risk aversion in female rats.
Truckenbrod LM, Carlos N, Kelly M … +4 more , Garner M, Streifer M, Gore AC, Orsini CA
Neuropsychopharmacology · 2026 Apr · PMID 41588114 · Full text
Decision making involving risk of punishment is a cognitive process characterized by sex-specific phenotypes, with females exhibiting greater risk aversion than males. Although prior research has demonstrated that ovaria...
Decision making involving risk of punishment is a cognitive process characterized by sex-specific phenotypes, with females exhibiting greater risk aversion than males. Although prior research has demonstrated that ovarian hormones, and estradiol (E2) in particular, contribute to increased risk aversion in females, the receptor mechanisms underlying these effects remain unknown. Further, it is unclear what role the other key ovarian hormone progesterone (P4) plays in female risk aversion. Accordingly, the current set of experiments were designed to address these gaps in knowledge of the hormonal basis of female risk-taking behavior. Female rats were trained in a punishment-based risky decision-making task, ovariectomized, and then retested in the decision-making task. Rats were then treated with estradiol benzoate (Experiment 1; EB), estrogen receptor (ER) agonists (Experiment 2) or progesterone (Experiment 3; P4) after daily test sessions for 7 days. Consistent with prior work, OVX increased risk taking, and EB administration attenuated this effect. Administration of an ERα agonist, either alone or with an ERβ agonist, similarly mitigated the effects of OVX on risk taking. In contrast, the ERβ agonist alone was ineffective in restoring risk aversion in OVX females. Control tests confirmed that the effects of the ERα agonist on risk taking were not due to altered food motivation or footshock sensitivity. Finally, P4 administration did not alter risk taking in OVX females and did not inhibit EB's behavioral effects. Collectively, these data reveal that E2 is the critical ovarian hormone that promotes female risk aversion; further, they suggest that the likely mechanism by which E2 influences risk aversion in females is through activation of ERα.
Clinical staging and profiling of affective disorders.
Beekman AT, Kupka RW, van Exel E
Neuropsychopharmacology · 2026 Jan · PMID 41580569 · Publisher ↗
Clinical staging models are used to classify the stages of development of disorders across medicine. In this narrative review we explored whether staging in affective disorders may (i) improve the prediction of clinical...
Clinical staging models are used to classify the stages of development of disorders across medicine. In this narrative review we explored whether staging in affective disorders may (i) improve the prediction of clinical outcomes, (ii) provide a more precise allocation of treatments to specific patients (iii) whether staging may serve as a framework to proactively integrate prevention and early intervention in the treatment of patients, and (iv) to direct research to studies of factors determining illness progression. Finally we examined (v) why staging may be especially salient in geriatric psychiatry and whether specific staging models are necessary for older patients. Our scope with regard to affective disorders was broad, including both unipolar and bipolar disorders. Although psychiatry has been late in resuming an interest in clinical staging, empirically tested models are available, which may be reliably used to stage the development of affective disorders. Clinical staging, in combination with data about comorbidity and clinical profilers may serve to improve treatment allocation. Progression from early at-risk stages to first episodes remains understudied, but there is sufficient evidence to conclude that prevention or postponement of early progression and the recurrence of affective disorders is effective. Given the change in risk factors, increase in comorbidity and worse prognosis of depression in later life, staging may be especially helpful in older patients. However, this does not mean that other staging models need to be developed, specifically for later life.
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