Sang Won Lee, Seungho Kim, Yongmin Chang, Hyunsil Cha, Ralph Noeske, Changho Choi, Seung Jae Lee
{"title":"Quantification of Glutathione and Its Associated Spontaneous Neuronal Activity in Major Depressive Disorder and Obsessive-Compulsive Disorder.","authors":"Sang Won Lee, Seungho Kim, Yongmin Chang, Hyunsil Cha, Ralph Noeske, Changho Choi, Seung Jae Lee","doi":"10.1016/j.biopsych.2024.08.018","DOIUrl":"10.1016/j.biopsych.2024.08.018","url":null,"abstract":"<p><strong>Background: </strong>Glutathione (GSH) is a crucial antioxidant in the human brain. Although proton magnetic resonance spectroscopy using the Mescher-Garwood point-resolved spectroscopy sequence is highly recommended, limited literature has measured cortical GSH using this method in major psychiatric disorders.</p><p><strong>Methods: </strong>By combining magnetic resonance spectroscopy and resting-state functional magnetic resonance imaging, we quantified brain GSH and glutamate in the medial prefrontal cortex and precuneus and explored relationships between GSH levels and intrinsic neuronal activity as well as clinical symptoms among healthy control (HC) participants (n = 30), people with major depressive disorder (MDD) (n = 28), and people with obsessive-compulsive disorder (OCD) (n = 28).</p><p><strong>Results: </strong>GSH concentrations were lower in the medial prefrontal cortex and precuneus in both the MDD and OCD groups than in the HC group. In the HC group, positive correlations were noted between GSH and glutamate levels and between GSH and fractional amplitude of low-frequency fluctuations in both regions. However, while these correlations were absent in both patient groups, there was a weak positive correlation between glutamate and fractional amplitude of low-frequency fluctuations. Moreover, GSH levels were negatively correlated with depressive and compulsive symptoms in MDD and OCD, respectively.</p><p><strong>Conclusions: </strong>These findings suggest that reduced GSH levels and an imbalance between GSH and glutamate could increase oxidative stress and alter neurotransmitter signaling, thereby leading to disruptions in GSH-related neurochemical-neuronal coupling and psychopathologies across MDD and OCD. Understanding these mechanisms could provide valuable insights into the processes that underlie these disorders and potentially become a springboard for future directions and advancing our knowledge of their neurobiological foundations.</p>","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142103999","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tongpeng Chu, Xiaopeng Si, Haizhu Xie, Heng Ma, Yinghong Shi, Wei Yao, Dong Xing, Feng Zhao, Fanghui Dong, Qun Gai, Kaili Che, Yuting Guo, Danni Chen, Dong Ming, Ning Mao
{"title":"Regional Structural-Functional Connectivity Coupling in Major Depressive Disorder Is Associated With Neurotransmitter and Genetic Profiles.","authors":"Tongpeng Chu, Xiaopeng Si, Haizhu Xie, Heng Ma, Yinghong Shi, Wei Yao, Dong Xing, Feng Zhao, Fanghui Dong, Qun Gai, Kaili Che, Yuting Guo, Danni Chen, Dong Ming, Ning Mao","doi":"10.1016/j.biopsych.2024.08.022","DOIUrl":"10.1016/j.biopsych.2024.08.022","url":null,"abstract":"<p><strong>Background: </strong>Abnormalities in structural-functional connectivity (SC-FC) coupling have been identified globally in patients with major depressive disorder (MDD). However, investigations have neglected the variability and hierarchical distribution of these abnormalities across different brain regions. Furthermore, the biological mechanisms that underlie regional SC-FC coupling patterns are not well understood.</p><p><strong>Methods: </strong>We enrolled 182 patients with MDD and 157 healthy control participants and quantified the intergroup differences in regional SC-FC coupling. Extreme gradient boosting (XGBoost), support vector machine, and random forest models were constructed to assess the potential of SC-FC coupling as biomarkers for MDD diagnosis and symptom prediction. Then, we examined the link between changes in regional SC-FC coupling in patients with MDD, neurotransmitter distributions, and gene expression.</p><p><strong>Results: </strong>We observed increased regional SC-FC coupling in the default mode network (t<sub>337</sub> = 3.233) and decreased coupling in the frontoparietal network (t<sub>337</sub> = -3.471) in patients with MDD compared with healthy control participants. XGBoost (area under the receiver operating characteristic curve = 0.853), support vector machine (area under the receiver operating characteristic curve = 0.832), and random forest (p < .05) models exhibited good prediction performance. The alterations in regional SC-FC coupling in patients with MDD were correlated with the distributions of 4 neurotransmitters (p < .05) and expression maps of specific genes. These enriched genes were implicated in excitatory neurons, inhibitory neurons, cellular metabolism, synapse function, and immune signaling. These findings were replicated on 2 brain atlases.</p><p><strong>Conclusions: </strong>This work enhances our understanding of MDD and paves the way for the development of additional targeted therapeutic interventions.</p>","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142104000","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Finding the Right Dose: NMDA Receptor-Modulating Treatments for Cognitive and Plasticity Deficits in Schizophrenia and the Role of Pharmacodynamic Target Engagement.","authors":"Pejman Sehatpour, Joshua T Kantrowitz","doi":"10.1016/j.biopsych.2024.08.019","DOIUrl":"10.1016/j.biopsych.2024.08.019","url":null,"abstract":"<p><p>Cognitive impairment associated with schizophrenia (CIAS) and related deficits in learning (plasticity) are among the leading causes of disability in schizophrenia. Despite this, there are no Food and Drug Administration-approved treatments for CIAS, and the development of treatments has been limited by numerous phase 2/3 failures of compounds that showed initial promise in small-scale studies. NMDA-type glutamate receptors (NMDARs) have been proposed to play an important role in schizophrenia; moreover, the NMDAR has a well-characterized role in cognition, learning, and neuroplasticity. We review previously published clinical trials in CIAS that focused on NMDAR modulator treatments, focusing on published and recent developments of the use of novel NMDAR-modulating treatments for CIAS both alone and combined with plasticity/learning paradigms to enhance learning. We use this discussion of previous studies to highlight the importance of incorporating pharmacodynamic target engagement biomarkers early in treatment development, which can help predict which compounds will succeed or fail in phase 3. A range of direct and indirect NMDAR modulators are covered, including D-serine, D-cycloserine, memantine, and glycine and first-generation glycine transport inhibitors (e.g., sarcosine and bitopertin), as well as recent positive studies of iclepertin, a novel glycine transport inhibitor, and luvadaxistat, a D-amino acid oxidase inhibitor that increases brain D-serine levels, and indirect noninvasive brain stimulation NMDAR-modulating treatments. Several examples of successful use of pharmacodynamic target engagement biomarkers for dose/drug discovery are emphasized, including the mismatch negativity, auditory steady state, and time-frequency event-related potential approaches.</p>","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142103997","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Clement Hamani, Benjamin Davidson, Jennifer S Rabin, Maged Goubran, Lyndon Boone, Kullervo Hynynen, Emmanuel De Schlichting, Ying Meng, Yuexi Huang, Ryan M Jones, Anusha Baskaran, Tulip Marawi, Margaret Anne Richter, Anthony Levitt, Sean M Nestor, Peter Giacobbe, Nir Lipsman
{"title":"Long-Term Safety and Efficacy of Focused Ultrasound Capsulotomy for Obsessive-Compulsive Disorder and Major Depressive Disorder.","authors":"Clement Hamani, Benjamin Davidson, Jennifer S Rabin, Maged Goubran, Lyndon Boone, Kullervo Hynynen, Emmanuel De Schlichting, Ying Meng, Yuexi Huang, Ryan M Jones, Anusha Baskaran, Tulip Marawi, Margaret Anne Richter, Anthony Levitt, Sean M Nestor, Peter Giacobbe, Nir Lipsman","doi":"10.1016/j.biopsych.2024.08.015","DOIUrl":"10.1016/j.biopsych.2024.08.015","url":null,"abstract":"<p><strong>Background: </strong>Magnetic resonance-guided focused ultrasound (MRgFUS) trials targeting the anterior limb of the internal capsule have shown promising results. We evaluated the long-term safety and efficacy of MRgFUS capsulotomy in patients with obsessive-compulsive disorder (OCD) and major depressive disorder (MDD).</p><p><strong>Methods: </strong>This phase 1, single-center, open-label study recruited patients with treatment-resistant OCD and MDD. Outcomes were measured 6 months, 12 months, and 18 to 24 months (long term) after MRgFUS capsulotomy. Neuropsychological testing and neuroimaging were conducted at baseline and 12 months postoperatively. The primary outcome was safety. The secondary outcome was clinical response, defined for OCD as a ≥35% improvement in Yale-Brown Obsessive Compulsive Scale scores and for MDD as a ≥50% reduction in Hamilton Depression Rating Scale scores compared with baseline.</p><p><strong>Results: </strong>No serious adverse effects were registered. In patients with OCD (n= 15), baseline Yale-Brown Obsessive Compulsive Scale scores (31.9 ± 1.2) were significantly reduced by 23% (p = .01) at 6 months and 35% (p < .0001) at 12 months. In patients with MDD (n = 12), a 26% and 25% nonsignificant reduction in Hamilton Depression Rating Scale scores (baseline 24.3 ± 1.2) was observed at 6 months and 12 months, respectively. Neuropsychological testing revealed no negative effects of capsulotomy. In the OCD and MDD cohorts, we found a correlation between clinical outcome and lesion laterality, with more medial left-placed lesions (OCD, p = .08) and more lateral right-placed lesions (MDD, p < .05) being respectively associated with a stronger response. In the MDD cohort, more ventral tracts appeared to be associated with a poorer response.</p><p><strong>Conclusions: </strong>MRgFUS capsulotomy is safe in patients with OCD and MDD and particularly effective in the former population.</p>","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2024-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142071934","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The Future of Disentangling the Heterogeneity of Autism With Neuroimaging Studies.","authors":"Xujun Duan, Xiaolong Shan, Lucina Q Uddin, Huafu Chen","doi":"10.1016/j.biopsych.2024.08.008","DOIUrl":"10.1016/j.biopsych.2024.08.008","url":null,"abstract":"<p><p>Autism spectrum disorder (ASD) is a lifelong neurodevelopmental condition. Over the past decade, a considerable number of approaches have been developed to identify potential neuroimaging-based biomarkers of ASD that have uncovered specific neural mechanisms that underlie behaviors associated with ASD. However, the substantial heterogeneity among individuals who are diagnosed with ASD hinders the development of biomarkers. Disentangling the heterogeneity of ASD is pivotal to improving the quality of life for individuals with ASD by facilitating early diagnosis and individualized interventions for those who need support. In this review, we discuss recent advances in neuroimaging that have facilitated the characterization of the heterogeneity of this condition using 3 frameworks: neurosubtyping, dimensional models, and normative models. We also discuss the challenges, possible solutions, and clinical utility of these 3 frameworks. We argue that several factors need to be considered when parsing heterogeneity using neuroimaging, including co-occurring conditions, neurodevelopment, heredity and environment, and multisite and multimodal data. We close with a discussion of future directions for achieving a better understanding of the neural mechanisms that underlie neurodevelopmental heterogeneity and the future of precision medicine in ASD.</p>","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142054845","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Charles H Schleifer, Sarah E Chang, Carolyn M Amir, Kathleen P O'Hora, Hoki Fung, Jee Won D Kang, Leila Kushan-Wells, Eileen Daly, Fabio Di Fabio, Marianna Frascarelli, Maria Gudbrandsen, Wendy R Kates, Declan Murphy, Jean Addington, Alan Anticevic, Kristin S Cadenhead, Tyrone D Cannon, Barbara A Cornblatt, Matcheri Keshavan, Daniel H Mathalon, Diana O Perkins, William S Stone, Elaine Walker, Scott W Woods, Lucina Q Uddin, Kuldeep Kumar, Gil D Hoftman, Carrie E Bearden
{"title":"Unique Functional Neuroimaging Signatures of Genetic Versus Clinical High Risk for Psychosis.","authors":"Charles H Schleifer, Sarah E Chang, Carolyn M Amir, Kathleen P O'Hora, Hoki Fung, Jee Won D Kang, Leila Kushan-Wells, Eileen Daly, Fabio Di Fabio, Marianna Frascarelli, Maria Gudbrandsen, Wendy R Kates, Declan Murphy, Jean Addington, Alan Anticevic, Kristin S Cadenhead, Tyrone D Cannon, Barbara A Cornblatt, Matcheri Keshavan, Daniel H Mathalon, Diana O Perkins, William S Stone, Elaine Walker, Scott W Woods, Lucina Q Uddin, Kuldeep Kumar, Gil D Hoftman, Carrie E Bearden","doi":"10.1016/j.biopsych.2024.08.010","DOIUrl":"10.1016/j.biopsych.2024.08.010","url":null,"abstract":"<p><strong>Background: </strong>22q11.2 deletion syndrome (22qDel) is a copy number variant that is associated with psychosis and other neurodevelopmental disorders. Adolescents who are at clinical high risk for psychosis (CHR) are identified based on the presence of subthreshold psychosis symptoms. Whether common neural substrates underlie these distinct high-risk populations is unknown. We compared functional brain measures in 22qDel and CHR cohorts and mapped the results to biological pathways.</p><p><strong>Methods: </strong>We analyzed 2 large multisite cohorts with resting-state functional magnetic resonance imaging data: 1) a 22qDel cohort (n = 164, 47% female) and typically developing (TD) control participants (n = 134, 56% female); and 2) a cohort of CHR individuals (n = 240, 41% female) and TD control participants (n = 149, 46% female) from the NAPLS-2 (North American Prodrome Longitudinal Study-2). We computed global brain connectivity (GBC), local connectivity (LC), and brain signal variability (BSV) across cortical regions and tested case-control differences for 22qDel and CHR separately. Group difference maps were related to published brain maps using autocorrelation-preserving permutation.</p><p><strong>Results: </strong>BSV, LC, and GBC were significantly disrupted in individuals with 22qDel compared with TD control participants (false discovery rate-corrected q < .05). Spatial maps of BSV and LC differences were highly correlated with each other, unlike GBC. In the CHR group, only LC was significantly altered versus the control group, with a different spatial pattern than the 22qDel group. Group differences mapped onto biological gradients, with 22qDel effects being strongest in regions with high predicted blood flow and metabolism.</p><p><strong>Conclusions: </strong>22qDel carriers and CHR individuals exhibited different effects on functional magnetic resonance imaging temporal variability and multiscale functional connectivity. In 22qDel carriers, strong and convergent disruptions in BSV and LC that were not seen in CHR individuals suggest distinct functional brain alterations.</p>","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142054847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The Mechanisms of Persisting Disability in Schizophrenia: Imprecise Predictive Coding via Corticostriatothalamic-Cortical Loop Dysfunction.","authors":"Peter F Liddle, Musa B Sami","doi":"10.1016/j.biopsych.2024.08.007","DOIUrl":"10.1016/j.biopsych.2024.08.007","url":null,"abstract":"<p><p>Persisting symptoms and disability remain a problem for an appreciable proportion of people with schizophrenia despite treatment with antipsychotic medication. Improving outcomes requires an understanding of the nature and mechanisms of the pathological processes underlying persistence. Classical features of schizophrenia, which include disorganization and impoverishment of mental activity, are well-recognized early clinical features that predict poor long-term outcome. Substantial evidence indicates that these features reflect imprecise predictive coding. Predictive coding provides an overarching framework for understanding efficient functioning of the nervous system. Imprecise predictive coding also has the potential to precipitate acute psychosis characterized by reality distortion (delusions and hallucinations) at times of stress. On the other hand, substantial evidence indicates that persistent reality distortion itself gives rise to poor occupational and social function in the long term. Furthermore, abuse of psychotomimetic drugs, which exacerbate reality distortion, contributes to poor long-term outcome in schizophrenia. Neural circuits involved in modulating volitional acts are well understood to be implicated in addiction. Plastic changes in these circuits may account for the association between psychotomimetic drug abuse and poor outcomes in schizophrenia. We propose a mechanistic model according to which unbalanced inputs to the corpus striatum disturb the precision of subcortical modulation of cortical activity supporting volitional action. This model accounts for the evidence that early classical symptoms predict poor outcome, while in some circumstances, persistent reality distortion also predicts poor outcome. This model has implications for the development of novel treatments that address the risk of persisting symptoms and disabilities in schizophrenia.</p>","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142054846","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Elizabeth A Eckenwiler, Anna E Ingebretson, Jeffrey J Stolley, Maxine A Fusaro, Alyssa M Romportl, Jack M Ross, Christopher L Petersen, Eera M Kale, Michael S Clark, Selena S Schattauer, Larry S Zweifel, Julia C Lemos
{"title":"Corticotropin-Releasing Factor Release From a Unique Subpopulation of Accumbal Neurons Constrains Action-Outcome Acquisition in Reward Learning.","authors":"Elizabeth A Eckenwiler, Anna E Ingebretson, Jeffrey J Stolley, Maxine A Fusaro, Alyssa M Romportl, Jack M Ross, Christopher L Petersen, Eera M Kale, Michael S Clark, Selena S Schattauer, Larry S Zweifel, Julia C Lemos","doi":"10.1016/j.biopsych.2024.08.006","DOIUrl":"10.1016/j.biopsych.2024.08.006","url":null,"abstract":"<p><strong>Background: </strong>The nucleus accumbens (NAc) mediates reward learning and motivation. Despite an abundance of neuropeptides, peptidergic neurotransmission from the NAc has not been integrated into current models of reward learning. The existence of a sparse population of neurons containing corticotropin-releasing factor (CRF) has been previously documented. Here, we provide a comprehensive analysis of their identity and functional role in shaping reward learning.</p><p><strong>Methods: </strong>Our multidisciplinary approach included fluorescent in situ hybridization (n = ≥3 mice), tract tracing (n = 5 mice), ex vivo electrophysiology (n = ≥30 cells), in vivo calcium imaging with fiber photometry (n = ≥4 mice), and use of viral strategies in transgenic lines to selectively delete CRF peptide from NAc neurons (n = ≥4 mice). Behaviors used were instrumental learning, sucrose preference, and spontaneous exploration in an open field.</p><p><strong>Results: </strong>We showed that the vast majority of NAc CRF-containing neurons are spiny projection neurons (SPNs) comprising dopamine D<sub>1</sub>-, D<sub>2</sub>-, or D<sub>1</sub>/D<sub>2</sub>-containing SPNs that primarily project and connect to the ventral pallidum and to a lesser extent the ventral midbrain. As a population, they display mature and immature SPN firing properties. We demonstrated that NAc CRF-containing neurons track reward outcomes during operant reward learning and that CRF release from these neurons acts to constrain initial acquisition of action-outcome learning and at the same time facilitates flexibility in the face of changing contingencies.</p><p><strong>Conclusions: </strong>CRF release from this sparse population of SPNs is critical for reward learning under normal conditions.</p>","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142054843","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Vibeke H Dam, Kristin Köhler-Forsberg, Brice Ozenne, Søren V Larsen, Cheng-Teng Ip, Anders Jorgensen, Dea S Stenbæk, Jacob Madsen, Claus Svarer, Martin B Jørgensen, Gitte M Knudsen, Vibe G Frokjaer
{"title":"Effect of Antidepressant Treatment on 5-HT<sub>4</sub> Receptor Binding and Associations With Clinical Outcomes and Verbal Memory in Major Depressive Disorder.","authors":"Vibeke H Dam, Kristin Köhler-Forsberg, Brice Ozenne, Søren V Larsen, Cheng-Teng Ip, Anders Jorgensen, Dea S Stenbæk, Jacob Madsen, Claus Svarer, Martin B Jørgensen, Gitte M Knudsen, Vibe G Frokjaer","doi":"10.1016/j.biopsych.2024.08.009","DOIUrl":"10.1016/j.biopsych.2024.08.009","url":null,"abstract":"<p><strong>Background: </strong>Brain serotonin 4 receptor (5-HT<sub>4</sub>R) levels are lower in untreated patients with major depressive disorder (MDD) and are linked to verbal memory. Here, we investigated the relationship between 5-HT<sub>4</sub>R levels, clinical outcomes, and cognitive function in patients with MDD who initiated selective serotonin reuptake inhibitor drug treatment.</p><p><strong>Methods: </strong>Ninety patients with moderate to severe depression underwent molecular brain imaging to measure 5-HT<sub>4</sub>R binding prior to antidepressant treatment with escitalopram. Pretreatment 5-HT<sub>4</sub>R binding was assessed for its ability to predict treatment outcome at weeks 4, 8, or 12. In 40 patients who were rescanned 8 weeks posttreatment, change in cerebral 5-HT<sub>4</sub>R binding was correlated with change in verbal memory and with change in depressive symptoms, as evaluated by the 6-item Hamilton Depression Rating Scale.</p><p><strong>Results: </strong>After 8 weeks of serotonergic intervention, neostriatal 5-HT<sub>4</sub>R binding was reduced by 9%. Global change in 5-HT<sub>4</sub>R binding from baseline was associated with verbal memory outcomes, but not with overall clinical depressive symptom outcomes. Pretreatment 5-HT<sub>4</sub>R binding did not predict clinical recovery status at week 8 and was not associated with change in the 6-item Hamilton Depression Rating Scale scores.</p><p><strong>Conclusions: </strong>In patients with moderate to severe MDD, treatment with selective serotonin reuptake inhibitors downregulated neostriatal 5-HT<sub>4</sub>R levels, which is consistent with the notion that the drugs increase cerebral extracellular serotonin. The less global brain 5-HT<sub>4</sub>R levels were downregulated after selective serotonin reuptake inhibitors, the more verbal memory improved, highlighting the potential importance of 5-HT<sub>4</sub>R as a treatment target in MDD. The findings offer insights into mechanisms that underlie antidepressant effects and point to new directions for precision medicine treatments for MDD.</p>","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142054844","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Decoding Depression: Integrating Brain Connectivity and Symptom Patterns to Uncover Major Depressive Disorder Subtypes","authors":"Leanne M. Williams","doi":"10.1016/j.biopsych.2024.07.002","DOIUrl":"10.1016/j.biopsych.2024.07.002","url":null,"abstract":"","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":"96 6","pages":"Pages 415-416"},"PeriodicalIF":9.6,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142006308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}