Neuropsychopharmacology

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From head to tail (of the VTA): role of projections from prelimbic cortex to rostromedial tegmental nucleus in cocaine reinstatement

Jonathan J. Chow & David J. Reiner

doi : 10.1038/s41386-020-00933-z

Neuropsychopharmacology volume 46, pages1395–1396 (2021)

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Optimizing psychedelic compounds for neuropsychiatric therapy

Scott M. Thompson

doi : 10.1038/s41386-021-01004-7

Neuropsychopharmacology volume 46, pages1397–1398 (2021)

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Prelimbic cortical projections to rostromedial tegmental nucleus play a suppressive role in cue-induced reinstatement of cocaine seeking

Adelis M. Cruz, Haley F. Spencer, Tabitha H. Kim, Thomas C. Jhou & Rachel J. Smith

doi : 10.1038/s41386-020-00909-z

Neuropsychopharmacology volume 46, pages1399–1406 (2021)

The prelimbic (PL) region of prefrontal cortex has been implicated in both driving and suppressing cocaine seeking in animal models of addiction. We hypothesized that these opposing roles for PL may be supported by distinct efferent projections. While PL projections to nucleus accumbens core have been shown to be involved in driving reinstatement of cocaine seeking, PL projections to the rostromedial tegmental nucleus (RMTg) may instead suppress reinstatement of cocaine seeking, due to the role of RMTg in behavioral inhibition. Here, we used a functional disconnection approach to temporarily disrupt the PL-RMTg pathway during cue- or cocaine-induced reinstatement. Male Sprague Dawley rats self-administered cocaine during daily 2-h sessions for ?10 days and then underwent extinction training. Reinstatement of extinguished cocaine seeking was elicited by cocaine-associated cues or cocaine prime. Prior to reinstatement, rats received microinjections of the GABA agonists baclofen/muscimol (1/0.1?mM) into unilateral PL and the AMPA receptor antagonist NBQX (1?mM) into contralateral or ipsilateral RMTg. Functional disconnection of PL-RMTg via contralateral inactivation markedly increased cue-induced reinstatement, but did not increase cocaine-induced reinstatement or drive reinstatement of extinguished cocaine seeking in the absence of cues or cocaine. Enhanced cue-induced reinstatement was also observed with ipsilateral inactivation of PL and RMTg, but not with unilateral inactivation of PL or RMTg alone, indicating that both ipsilateral and contralateral projections from PL to RMTg have an inhibitory influence on behavior. These data further support a suppressive role for PL in cocaine seeking by implicating PL efferent projections to RMTg in inhibiting cue-induced reinstatement.

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Prospective randomized pharmacogenetic study of topiramate for treating alcohol use disorder

Henry R. Kranzler, Paige E. Morris, Timothy Pond, Richard C. Crist, Kyle M. Kampman, Emily E. Hartwell & Kevin G. Lynch

doi : 10.1038/s41386-020-00945-9

Neuropsychopharmacology volume 46, pages1407–1413 (2021)

In a prior study, topiramate reduced heavy drinking among individuals who sought to reduce their drinking, with the effect moderated by a single nucleotide polymorphism (SNP; rs2832407) in GRIK1, which encodes the kainate GluK1 receptor subunit (Kranzler et al. 2014). The present study sought to replicate prospectively the effect of topiramate and rs2832407 in patients with DSM-5 alcohol use disorder (AUD) who sought to reduce or stop their drinking. We stratified the randomization on genotype (rs2832407*C-allele homozygotes vs. A-allele carriers) and assigned 170 European-American participants (71.2% male) to receive 12 weeks of treatment with topiramate (N??=?85), at a maximal daily dosage of 200?mg, or matching placebo (N?=?85). At each of nine treatment visits participants received brief counseling to reduce drinking and increase abstinent days. We hypothesized that topiramate-treated patients with the rs2832407*CC genotype would reduce heavy drinking days (HDDs) more than the other three groups. The rate of treatment completion was 91.8% in both groups. The mean number of HDDs per week in the placebo group was 1.67 (95% CI?=?(1.29, 2.16), p?=?0.0001) times greater than in the topiramate group, which was confirmed by the topiramate group’s significantly greater reduction in the concentration of the liver enzyme ?-glutamyltransferase and lower alcohol-related problems score. There was no significant difference in topiramate’s effect on HDDs between genotype groups. Although consistent with other studies showing a reduction in heavy drinking with topiramate treatment, the prior finding of a moderating effect of rs2832407 genotype was not replicated in this prospective trial.

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Effects of topiramate on neural responses to alcohol cues in treatment-seeking individuals with alcohol use disorder: preliminary findings from a randomized, placebo-controlled trial

Reagan R. Wetherill, Nathaniel Spilka, Kanchana Jagannathan, Paige Morris, Danielle Romer, Timothy Pond, Kevin G. Lynch, Teresa R. Franklin & Henry R. Kranzler

doi : 10.1038/s41386-021-00968-w

Neuropsychopharmacology volume 46, pages1414–1420 (2021)

Topiramate, a GABA/glutamate modulator, is efficacious in reducing alcohol consumption, though the mechanisms underlying this effect are not well characterized. This study analyzed functional magnetic resonance imaging (fMRI) data from 22 heavy drinkers enrolled in a 12-week placebo-controlled, randomized clinical trial of topiramate to examine the effects of topiramate on alcohol cue-elicited brain responses, craving, and heavy drinking in individuals with DSM-5 alcohol use disorder. Patients were randomized to receive either topiramate (maximal daily dosage of 200?mg/day) or placebo and were administered an fMRI alcohol cue-reactivity task at baseline (before starting medication) and after 6 weeks of double-blind treatment. Analyses compared the topiramate (n?=?12) and placebo (n?=?8) groups on (1) the change in brain responses during alcohol cue exposure (vs non-alcohol cues) within five a priori regions of interest related to reward—the bilateral and medial orbitofrontal cortex (OFC) and bilateral ventral striatum (VS) and (2) change in craving and heavy drinking days (HDDs) from baseline and scan 2. Topiramate, relative to placebo, reduced alcohol cue-elicited activation of the left VS, bilateral OFC, and medial OFC, alcohol cue-elicited craving, and HDDs between baseline and 6 weeks of treatment. The reduction in alcohol cue-elicited activation in the medial OFC correlated with reductions in craving, and reduced activation in the right VS, right OFC, and medial OFC correlated with the reduction in HDD. This preliminary study provides evidence that topiramate’s attenuation of alcohol cue-elicited brain activation and craving are key elements of the drug’s neurobiological mechanism of action in reducing heavy drinking.

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Acute depletion of dopamine precursors in the human brain: effects on functional connectivity and alcohol attentional bias

Amanda Elton, Monica L. Faulkner, Donita L. Robinson & Charlotte A. Boettiger

doi : 10.1038/s41386-021-00993-9

Neuropsychopharmacology volume 46, pages1421–1431 (2021)

Individuals who abuse alcohol often show exaggerated attentional bias (AB) towards alcohol-related cues, which is thought to reflect reward conditioning processes. Rodent studies indicate that dopaminergic pathways play a key role in conditioned responses to reward- and alcohol-associated cues. However, investigation of the dopaminergic circuitry mediating this process in humans remains limited. We hypothesized that depletion of central dopamine levels in adult alcohol drinkers would attenuate AB and that these effects would be mediated by altered function in frontolimbic circuitry. Thirty-four male participants (22–38 years, including both social and heavy drinkers) underwent a two-session, placebo-controlled, double-blind dopamine precursor depletion procedure. At each visit, participants consumed either a balanced amino acid (control) beverage or an amino acid beverage lacking dopamine precursors (order counterbalanced), underwent resting-state fMRI, and completed behavioral testing on three AB tasks: an alcohol dot-probe task, an alcohol attentional blink task, and a task measuring AB to a reward-conditioned cue. Dopamine depletion significantly diminished AB in each behavioral task, with larger effects among subjects reporting higher levels of binge drinking. The depletion procedure significantly decreased resting-state functional connectivity among ventral tegmental area, striatum, amygdala, and prefrontal regions. Beverage-related AB decreases were mediated by decreases in functional connectivity between the fronto-insular cortex and striatum and, for alcohol AB only, between anterior cingulate cortex and amygdala. The results support a substantial role for dopamine in AB, and suggest specific dopamine-modulated functional connections between frontal, limbic, striatal, and brainstem regions mediate general reward AB versus alcohol AB.

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Long-term alcohol consumption alters dorsal striatal dopamine release and regulation by D2 dopamine receptors in rhesus macaques

Armando G. Salinas, Yolanda Mateo, Verginia C. Cuzon Carlson, Gwen S. Stinnett, Guoxiang Luo, Audrey F. Seasholtz, Kathleen A. Grant & David M. Lovinger

doi : 10.1038/s41386-020-00938-8

Neuropsychopharmacology volume 46, pages1432–1441 (2021)

The dorsal striatum (DS) is implicated in behavioral and neural processes including action control and reinforcement. Alcohol alters these processes in rodents, and it is believed that the development of alcohol use disorder involves changes in DS dopamine signaling. In nonhuman primates, the DS can be divided into caudate and putamen subregions. As part of a collaborative effort examining the effects of long-term alcohol self-administration in rhesus macaques, we examined DS dopamine signaling using fast-scan cyclic voltammetry. We found that chronic alcohol self-administration resulted in several dopamine system adaptations. Most notably, dopamine release was altered in a sex- and region-dependent manner. Following long-term alcohol consumption, male macaques, regardless of abstinence status, had reduced dopamine release in putamen, while only male macaques in abstinence had reduced dopamine release in caudate. In contrast, female macaques had enhanced dopamine release in the caudate, but not putamen. Dopamine uptake was also enhanced in females, but not males (regardless of abstinence state). We also found that dopamine D2/3 autoreceptor function was reduced in male, but not female, alcohol drinkers relative to control groups. Finally, we found that blockade of nicotinic acetylcholine receptors inhibited evoked dopamine release in nonhuman primates. Altogether, our findings demonstrate that long-term alcohol consumption can sex-dependently alter dopamine release, as well as its feedback control mechanisms in both DS subregions.

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Neural correlates of inhibitory control are associated with stimulant-like effects of alcohol

Jessica Weafer, Stephanie M. Gorka, Mario Dzemidzic, David A. Kareken, K. Luan Phan & Harriet de Wit

doi : 10.1038/s41386-021-01014-5

Neuropsychopharmacology volume 46, pages1442–1450 (2021)

Poor inhibitory control and heightened feelings of stimulation after alcohol are two well-established risk factors for alcohol use disorder (AUD). Although these risk factors have traditionally been viewed as orthogonal, recent evidence suggests that the two are related and may share common neurobiological mechanisms. Here we examined the degree to which neural activity during inhibition was associated with subjective reports of stimulation following alcohol. To assess neural changes during inhibition, moderate alcohol drinkers performed a stop signal task during fMRI without drug. To assess subjective responses to alcohol they ingested alcohol (0.8?g/kg) or placebo beverages under double-blind conditions and provided subjective reports of stimulation and sedation. Feelings of stimulation following alcohol were inversely associated with activity in the supplementary motor area, insula, and middle frontal gyrus during inhibition (successful stop trials compared to go trials). Feelings of sedation did not correlate with brain activation. These results extend previous findings suggesting that poor inhibitory control is associated with more positive subjective responses to alcohol. These interrelated risk factors may contribute to susceptibility to future excessive alcohol use, and ultimately lead to neurobiological targets to prevent or treat AUD.

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Within-subject, double-blinded, randomized, and placebo-controlled evaluation of the combined effects of the cannabinoid dronabinol and the opioid hydromorphone in a human laboratory pain model

Kelly E. Dunn, Cecilia L. Bergeria, Andrew S. Huhn, Traci J. Speed, Chung Jung Mun, Ryan Vandrey & Claudia M. Campbell

doi : 10.1038/s41386-021-01007-4

Neuropsychopharmacology volume 46, pages1451–1459 (2021)

This Phase II study evaluated analgesia, abuse liability, and cognitive performance of hydromorphone and oral delta-9-tetrahydrocannabinol (THC; dronabinol) using a within-subject, double-blind, randomized, placebo-controlled, human laboratory trial. Healthy adults (N?=?29) with no history of drug use disorder received combinations of placebo, hydromorphone (4?mg; oral), and dronabinol (2.5?mg, 5.0?mg, 10?mg; oral). Primary outcomes were quantitative sensory testing (QST) measures of acute (thermal, pressure pain; thermal, punctate probe temporal summation; cold pressor; conditioned pain modulation) and chronic pain (capsaicin 10% topical cream with thermal rekindling), measures of drug abuse liability, cognitive functioning, and adverse events. Subgroup analyses were conducted within opioid-responders (endorsed >20 on a Drug Effect visual analog scale during the hydromorphone-only condition) and nonresponders. A consistent dose-effect relationship of dronabinol on hydromorphone across all measures was not observed. Analgesia only improved in the hydromorphone?+?dronabinol 2.5?mg condition. Hydromorphone?+?dronabinol 2.5?mg showed the lowest and hydromorphone+dronabinol 5?mg showed the highest risk for abuse. Hydromorphone+dronabinol 10?mg produced a high rate of dysphoric effects, and hydromorphone+dronabinol 5?mg and hydromorphone?+?dronabinol 10?mg produced AEs. Subgroup analyses showed subjective effects and abuse risk was increased among opioid responders and largely absent among nonresponders. Overall, only hydromorphone+dronabinol 2.5?mg modestly enhanced hydromorphone-based analgesia and hydromorphone?+?dronabinol 5?mg and 10?mg increased risk for abuse and AEs. These data can help inform opioid-sparing efforts in clinical pain populations. Demonstration that potential opioid effects varied as a function of participant opioid sensitivity (e.g., responder status) is a novel finding that warrants additional research.

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Brain reactivity during aggressive response in women with premenstrual dysphoric disorder treated with a selective progesterone receptor modulator

Elisavet Kaltsouni, Patrick M. Fisher, Manon Dubol, Steinar Hustad, Rupert Lanzenberger, Vibe G. Frokjaer, Johan Wikstr?m, Erika Comasco & Inger Sundstr?m-Poromaa

doi : 10.1038/s41386-021-01010-9

Neuropsychopharmacology volume 46, pages1460–1467 (2021)

Premenstrual dysphoric disorder (PMDD) is a psychiatric condition characterized by late luteal phase affective, cognitive, and physical impairment. The disorder causes significant suffering in about 5% of women in their reproductive age. Altered sensitivity of cognitive-affective brain circuits to progesterone and its downstream metabolite allopregnanolone is suggested to underlie PMDD symptomatology. Core mood symptoms include irritability and anger, with aggression being the behavioral outcome of these symptoms. The present study sought to investigate the neural correlates of reactive aggression during the premenstrual phase in women with PMDD, randomized to a selective progesterone receptor modulator (SPRM) or placebo. Self-reports on the Daily Record of Severity of Problems were used to assess PMDD symptoms and gonadal hormone levels were measured by liquid chromatography tandem mass spectrometry. Functional magnetic resonance imaging was performed in 30 women with PMDD, while performing the point subtraction aggression paradigm. Overall, a high SPRM treatment response rate was attained (93%), in comparison with placebo (53.3%). Women with PMDD randomized to SPRM treatment had enhanced brain reactivity in the dorsal anterior cingulate cortex and dorsomedial prefrontal cortex during the aggressive response condition. The fronto-cingulate reactivity during aggressive responses depended on treatment, with a negative relationship between brain reactivity and task-related aggressiveness found in the placebo but not the SPRM group. The findings contribute to define the role of progesterone in PMDD symptomatology, suggesting a beneficial effect of progesterone receptor antagonism, and consequent anovulation, on top-down emotion regulation, i.e., greater fronto-cingulate activity in response to provocation stimuli.

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Interactions between hippocampal activity and striatal dopamine in people at clinical high risk for psychosis: relationship to adverse outcomes

Gemma Modinos, Anja Richter, Alice Egerton, Ilaria Bonoldi, Matilda Azis, Mathilde Antoniades, Matthijs Bossong, Nicolas Crossley, Jesus Perez, James M. Stone, Mattia Veronese, Fernando Zelaya, Anthony A. Grace, Oliver D. Howes, Paul Allen & Philip McGuire

doi : 10.1038/s41386-021-01019-0

Neuropsychopharmacology volume 46, pages1468–1474 (2021)

Preclinical models propose that increased hippocampal activity drives subcortical dopaminergic dysfunction and leads to psychosis-like symptoms and behaviors. Here, we used multimodal neuroimaging to examine the relationship between hippocampal regional cerebral blood flow (rCBF) and striatal dopamine synthesis capacity in people at clinical high risk (CHR) for psychosis and investigated its association with subsequent clinical and functional outcomes. Ninety-five participants (67 CHR and 28 healthy controls) underwent arterial spin labeling MRI and 18F-DOPA PET imaging at baseline. CHR participants were followed up for a median of 15 months to determine functional outcomes with the global assessment of function (GAF) scale and clinical outcomes using the comprehensive assessment of at-risk mental states (CAARMS). CHR participants with poor functional outcomes (follow-up GAF?<?65, n?=?25) showed higher rCBF in the right hippocampus compared to CHRs with good functional outcomes (GAF???65, n?=?25) (pfwe?=?0.026). The relationship between rCBF in this right hippocampal region and striatal dopamine synthesis capacity was also significantly different between groups (pfwe?=?0.035); the association was negative in CHR with poor outcomes (pfwe?=?0.012), but non-significant in CHR with good outcomes. Furthermore, the correlation between right hippocampal rCBF and striatal dopamine function predicted a longitudinal increase in the severity of positive psychotic symptoms within the total CHR group (p?=?0.041). There were no differences in rCBF, dopamine, or their associations in the total CHR group relative to controls. These findings indicate that altered interactions between the hippocampus and the subcortical dopamine system are implicated in the pathophysiology of adverse outcomes in the CHR state.

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Cognitive subtypes in recent onset psychosis: distinct neurobiological fingerprints?

Julian Wenzel, Shalaila S. Haas, Dominic B. Dwyer, Anne Ruef, Oemer Faruk Oeztuerk, Linda A. Antonucci, Sebastian von Saldern, Carolina Bonivento, Marco Garzitto, Adele Ferro, Marco Paolini, Janusch Blautzik, Stefan Borgwardt, Paolo Brambilla, Eva Meisenzahl, Raimo K. R. Salokangas, Rachel Upthegrove, Stephen J. Wood, Joseph Kambeitz, Nikolaos Koutsouleris, Lana Kambeitz-Ilankovic & the PRONIA consortium

doi : 10.1038/s41386-021-00963-1

Neuropsychopharmacology volume 46, pages1475–1483 (2021)

In schizophrenia, neurocognitive subtypes can be distinguished based on cognitive performance and they are associated with neuroanatomical alterations. We investigated the existence of cognitive subtypes in shortly medicated recent onset psychosis patients, their underlying gray matter volume patterns and clinical characteristics. We used a K-means algorithm to cluster 108 psychosis patients from the multi-site EU PRONIA (Prognostic tools for early psychosis management) study based on cognitive performance and validated the solution independently (N?=?53). Cognitive subgroups and healthy controls (HC; n?=?195) were classified based on gray matter volume (GMV) using Support Vector Machine classification. A cognitively spared (N?=?67) and impaired (N?=?41) subgroup were revealed and partially independently validated (Nspared?=?40, Nimpaired?=?13). Impaired patients showed significantly increased negative symptomatology (pfdr?=?0.003), reduced cognitive performance (pfdr?<?0.001) and general functioning (pfdr?<?0.035) in comparison to spared patients. Neurocognitive deficits of the impaired subgroup persist in both discovery and validation sample across several domains, including verbal memory and processing speed. A GMV pattern (balanced accuracy?=?60.1%, p?=?0.01) separating impaired patients from HC revealed increases and decreases across several fronto-temporal-parietal brain areas, including basal ganglia and cerebellum. Cognitive and functional disturbances alongside brain morphological changes in the impaired subgroup are consistent with a neurodevelopmental origin of psychosis. Our findings emphasize the relevance of tailored intervention early in the course of psychosis for patients suffering from the likely stronger neurodevelopmental character of the disease.

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Association between age of cannabis initiation and gray matter covariance networks in recent onset psychosis

Nora Penzel, Linda A. Antonucci, Linda T. Betz, Rachele Sanfelici, Johanna Weiske, Oliver Pogarell, Paul Cumming, Boris B. Quednow, Oliver Howes, Peter Falkai, Rachel Upthegrove, Alessandro Bertolino, Stefan Borgwardt, Paolo Brambilla, Rebekka Lencer, Eva Meisenzahl, Marlene Rosen, Theresa Haidl, Lana Kambeitz-Ilankovic, Stephan Ruhrmann, Raimo R. K. Salokangas, Christos Pantelis, Stephen J. Wood, Nikolaos Koutsouleris, Joseph Kambeitz & the PRONIA Consortium-Show fewer authors

doi : 10.1038/s41386-021-00977-9

Neuropsychopharmacology volume 46, pages1484–1493 (2021)

Cannabis use during adolescence is associated with an increased risk of developing psychosis. According to a current hypothesis, this results from detrimental effects of early cannabis use on brain maturation during this vulnerable period. However, studies investigating the interaction between early cannabis use and brain structural alterations hitherto reported inconclusive findings. We investigated effects of age of cannabis initiation on psychosis using data from the multicentric Personalized Prognostic Tools for Early Psychosis Management (PRONIA) and the Cannabis Induced Psychosis (CIP) studies, yielding a total sample of 102 clinically-relevant cannabis users with recent onset psychosis. GM covariance underlies shared maturational processes. Therefore, we performed source-based morphometry analysis with spatial constraints on structural brain networks showing significant alterations in schizophrenia in a previous multisite study, thus testing associations of these networks with the age of cannabis initiation and with confounding factors. Earlier cannabis initiation was associated with more severe positive symptoms in our cohort. Greater gray matter volume (GMV) in the previously identified cerebellar schizophrenia-related network had a significant association with early cannabis use, independent of several possibly confounding factors. Moreover, GMV in the cerebellar network was associated with lower volume in another network previously associated with schizophrenia, comprising the insula, superior temporal, and inferior frontal gyrus. These findings are in line with previous investigations in healthy cannabis users, and suggest that early initiation of cannabis perturbs the developmental trajectory of certain structural brain networks in a manner imparting risk for psychosis later in life.

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Differentiating the effect of antipsychotic medication and illness on brain volume reductions in first-episode psychosis: A Longitudinal, Randomised, Triple-blind, Placebo-controlled MRI Study

Sidhant Chopra, Alex Fornito, Shona M. Francey, Brian O’Donoghue, Vanessa Cropley, Barnaby Nelson, Jessica Graham, Lara Baldwin, Steven Tahtalian, Hok Pan Yuen, Kelly Allott, Mario Alvarez-Jimenez, Susy Harrigan, Kristina Sabaroedin, Christos Pantelis, Stephen J. Wood & Patrick McGorry

doi : 10.1038/s41386-021-00980-0

Neuropsychopharmacology volume 46, pages1494–1501 (2021)

Changes in brain volume are a common finding in Magnetic Resonance Imaging (MRI) studies of people with psychosis and numerous longitudinal studies suggest that volume deficits progress with illness duration. However, a major unresolved question concerns whether these changes are driven by the underlying illness or represent iatrogenic effects of antipsychotic medication. In this study, 62 antipsychotic-naïve patients with first-episode psychosis (FEP) received either a second-generation antipsychotic (risperidone or paliperidone) or a placebo pill over a treatment period of 6 months. Both FEP groups received intensive psychosocial therapy. A healthy control group (n?=?27) was also recruited. Structural MRI scans were obtained at baseline, 3 months and 12 months. Our primary aim was to differentiate illness-related brain volume changes from medication-related changes within the first 3 months of treatment. We secondarily investigated long-term effects at the 12-month timepoint. From baseline to 3 months, we observed a significant group x time interaction in the pallidum (p?<?0.05 FWE-corrected), such that patients receiving antipsychotic medication showed increased volume, patients on placebo showed decreased volume, and healthy controls showed no change. Across the entire patient sample, a greater increase in pallidal grey matter volume over 3 months was associated with a greater reduction in symptom severity. Our findings indicate that psychotic illness and antipsychotic exposure exert distinct and spatially distributed effects on brain volume. Our results align with prior work in suggesting that the therapeutic efficacy of antipsychotic medications may be primarily mediated through their effects on the basal ganglia.

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Aberrant triple-network connectivity patterns discriminate biotypes of first-episode medication-naive schizophrenia in two large independent cohorts

Sugai Liang, Qiang Wang, Andrew J. Greenshaw, Xiaojing Li, Wei Deng, Hongyan Ren, Chengcheng Zhang, Hua Yu, Wei Wei, Yamin Zhang, Mingli Li, Liansheng Zhao, Xiangdong Du, Yajing Meng, Xiaohong Ma, Chao-Gan Yan & Tao Li

doi : 10.1038/s41386-020-00926-y

Neuropsychopharmacology volume 46, pages1502–1509 (2021)

Schizophrenia is a complex disorder associated with aberrant brain functional connectivity. This study aims to demonstrate the relation of heterogeneous symptomatology in this disorder to distinct brain connectivity patterns within the triple-network model. The study sample comprised 300 first-episode antipsychotic-naive patients with schizophrenia (FES) and 301 healthy controls (HCs). At baseline, resting-state functional magnetic resonance imaging data were captured for each participant, and concomitant neurocognitive functions were evaluated outside the scanner. Clinical information of 49 FES in the discovery dataset were reevaluated at a 6-week follow-up. Differential features between FES and HCs were selected from triple-network connectivity profiles. Cutting-edge unsupervised machine learning algorithms were used to define patient subtypes. Clinical and cognitive variables were compared between patient subgroups. Two FES subgroups with differing triple-network connectivity profiles were identified in the discovery dataset and confirmed in an independent hold-out cohort. One patient subgroup appearing to have more severe clinical symptoms was distinguished by salience network (SN)-centered hypoconnectivity, which was associated with greater impairments in sustained attention. The other subgroup exhibited hyperconnectivity and manifested greater deficits in cognitive flexibility. The SN-centered hypoconnectivity subgroup had more persistent negative symptoms at the 6-week follow-up than the hyperconnectivity subgroup. The present study illustrates that clinically relevant cognitive subtypes of schizophrenia may be associated with distinct differences in connectivity in the triple-network model. This categorization may foster further analysis of the effects of therapy on these network connectivity patterns, which may help to guide therapeutic choices to effectively reach personalized treatment goals.

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Systematic misestimation of machine learning performance in neuroimaging studies of depression

Claas Flint, Micah Cearns, Nils Opel, Ronny Redlich, David M. A. Mehler, Daniel Emden, Nils R. Winter, Ramona Leenings, Simon B. Eickhoff, Tilo Kircher, Axel Krug, Igor Nenadic, Volker Arolt, Scott Clark, Bernhard T. Baune, Xiaoyi Jiang, Udo Dannlowski & Tim Hahn

doi : 10.1038/s41386-021-01020-7

Neuropsychopharmacology volume 46, pages1510–1517 (2021)

We currently observe a disconcerting phenomenon in machine learning studies in psychiatry: While we would expect larger samples to yield better results due to the availability of more data, larger machine learning studies consistently show much weaker performance than the numerous small-scale studies. Here, we systematically investigated this effect focusing on one of the most heavily studied questions in the field, namely the classification of patients suffering from Major Depressive Disorder (MDD) and healthy controls based on neuroimaging data. Drawing upon structural MRI data from a balanced sample of N?=?1868 MDD patients and healthy controls from our recent international Predictive Analytics Competition (PAC), we first trained and tested a classification model on the full dataset which yielded an accuracy of 61%. Next, we mimicked the process by which researchers would draw samples of various sizes (N?=?4 to N?=?150) from the population and showed a strong risk of misestimation. Specifically, for small sample sizes (N?=?20), we observe accuracies of up to 95%. For medium sample sizes (N?=?100) accuracies up to 75% were found. Importantly, further investigation showed that sufficiently large test sets effectively protect against performance misestimation whereas larger datasets per se do not. While these results question the validity of a substantial part of the current literature, we outline the relatively low-cost remedy of larger test sets, which is readily available in most cases.

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Long-term prenatal effects of antidepressant use on the risk of affective disorders in the offspring: a register-based cohort study

Anna-Sophie Rommel, Natalie C. Momen, Nina Maren Molenaar, Xiaoqin Liu, Trine Munk-Olsen & Veerle Bergink

doi : 10.1038/s41386-021-01005-6

Neuropsychopharmacology volume 46, pages1518–1525 (2021)

To investigate the association between intrauterine antidepressant exposure and offspring affective disorders over an 18-year follow-up period using Danish national registers. We included 42,988 singletons born during 1998–2011 and followed-up until 2016, death, emigration, or date of first affective disorder diagnosis. Children were categorised into two groups according to maternal antidepressant use within 2 years before and during pregnancy: continuation (use before and during pregnancy) or discontinuation (use before but not during pregnancy). The outcome was an affective disorders diagnosis in the offspring based on secondary/tertiary care records and primary care prescription data. Hazard ratios (HR) of affective disorders were estimated using Cox regression models. To consider confounding by shared environmental or genetic factors, we investigated the effect of paternal antidepressant use on the risk for affective disorders. Affective disorders were diagnosed in 1538 children. Children whose mothers continued antidepressants during pregnancy had an increased risk of affective disorders (HR?=?1.20, 95% CI?=?1.08–1.34), compared with children whose mothers discontinued before pregnancy. Similarly, continued paternal antidepressant use during pregnancy was associated with higher risk for offspring affective disorders (HR?=?1.29, 95% CI?=?1.12–1.49), compared to discontinuation. Based on data from primary and secondary/tertiary care, maternal antidepressant use during pregnancy was associated with an increased risk of affective disorders in the offspring. As similar associations were observed in children whose fathers continued antidepressant use across the pregnancy period, the observed association may be attributable to the underlying parental psychopathology, rather than the direct intrauterine exposure to antidepressants.

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Symptomatic and preventive effects of the novel phosphodiesterase-9 inhibitor BI 409306 in an immune-mediated model of neurodevelopmental disorders

Joseph Scarborough, Daniele Mattei, Cornelia Dorner-Ciossek, Michael Sand, Roberto Arban, Holger Rosenbrock, Juliet Richetto & Urs Meyer

doi : 10.1038/s41386-021-01016-3

Neuropsychopharmacology volume 46, pages1526–1534 (2021)

BI 409306, a phosphodiesterase-9 inhibitor under development for treatment of schizophrenia and attenuated psychosis syndrome (APS), promotes synaptic plasticity and cognition. Here, we explored the effects of BI 409306 treatment in the polyriboinosinic-polyribocytidilic acid (poly[I:C])-based mouse model of maternal immune activation (MIA), which is relevant to schizophrenia and APS. In Study 1, adult offspring received BI 409306 0.2, 0.5, or 1?mg/kg or vehicle to establish an active dose. In Study 2, adult offspring received BI 409306 1?mg/kg and/or risperidone 0.025?mg/kg, risperidone 0.05?mg/kg, or vehicle, to evaluate BI 409306 as add-on to standard therapy for schizophrenia. In Study 3, offspring received BI 409306 1?mg/kg during adolescence only, or continually into adulthood to evaluate preventive effects of BI 409306. We found that BI 409306 significantly mitigated MIA-induced social interaction deficits and amphetamine-induced hyperlocomotion, but not prepulse inhibition impairments, in a dose-dependent manner (Study 1). Furthermore, BI 409306 1?mg/kg alone or in combination with risperidone 0.025?mg/kg significantly reversed social interaction deficits and attenuated amphetamine-induced hyperlocomotion in MIA offspring (Study 2). Finally, we revealed that BI 409306 1?mg/kg treatment restricted to adolescence prevented adult deficits in social interaction, whereas continued treatment into adulthood also significantly reduced amphetamine-induced hyperlocomotion (Study 3). Taken together, our findings suggest that symptomatic treatment with BI 409306 can restore social interaction deficits and dopaminergic dysfunctions in a MIA model of neurodevelopmental disruption, lending preclinical support to current clinical trials of BI 409306 in patients with schizophrenia. Moreover, BI 409306 given during adolescence has preventive effects on adult social interaction deficits in this model, supporting its use in people with APS.

خرید پکیج و مشاهده آنلاین مقاله

Co-released norepinephrine and galanin act on different timescales to promote stress-induced anxiety-like behavior

Rachel P. Tillage, Stephanie L. Foster, Daniel Lustberg, L. Cameron Liles, Katharine E. McCann & David Weinshenker

doi : 10.1038/s41386-021-01011-8

Neuropsychopharmacology volume 46, pages1535–1543 (2021)

Both the noradrenergic and galaninergic systems have been implicated in stress-related neuropsychiatric disorders, and these two neuromodulators are co-released from the stress-responsive locus coeruleus (LC); however, the individual contributions of LC-derived norepinephrine (NE) and galanin to behavioral stress responses are unclear. Here we aimed to disentangle the functional roles of co-released NE and galanin in stress-induced behavior. We used foot shock, optogenetics, and behavioral pharmacology in wild-type (WT) mice and mice lacking either NE (Dbh?/?) or galanin (GalcKO-Dbh) specifically in noradrenergic neurons to isolate the roles of these co-transmitters in regulating anxiety-like behavior in the elevated zero maze (EZM) either immediately or 24?h following stress. Foot shock and optogenetic LC stimulation produced immediate anxiety-like behavior in WT mice, and the effects of foot shock persisted for 24?h. NE-deficient mice were resistant to the anxiogenic effects of acute stress and optogenetic LC stimulation, while mice lacking noradrenergic-derived galanin displayed typical increases in anxiety-like behavior. However, when tested 24?h after foot shock, both Dbh?/? and GalcKO-Dbh mice lacked normal expression of anxiety-like behavior. Pharmacological rescue of NE, but not galanin, in knockout mice during EZM testing was anxiogenic. In contrast, restoring galanin, but not NE, signaling during foot shock normalized stress-induced anxiety-like behavior 24?h later. These results indicate that NE and noradrenergic-derived galanin play complementary, but distinguishable roles in behavioral responses to stress. NE is required for the expression of acute stress-induced anxiety, while noradrenergic-derived galanin mediates the development of more persistent responses following a stressor.

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