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1.
Artigo em Inglês | MEDLINE | ID: mdl-33618016

RESUMO

BACKGROUND: Smoking behavior during the first 24 hours of a quit attempt is a significant predictor of longer term abstinence, yet little is known about the neurobiology of early tobacco abstinence. Specifically, the effects of acute tobacco deprivation and reinstatement on brain function-particularly at the level of large-scale network dynamics and assessed across the entire brain-remain incompletely understood. To address this gap, this study uses a mixed within- and between-subjects design to assess the effects of smoking status (yes/no smoker) and state (deprived versus satiated) on whole-brain patterns of intrinsic connectivity. METHODS: Forty-two tobacco smokers participated in resting state fMRI following overnight abstinence (deprived state) and following smoking reinstatement (satiated state, randomized order across participants). Sixty healthy control non-smokers participated in a single resting state scan using the same acquisition parameters. Functional connectivity data were analyzed using both a canonical network-of-interest (NOI) approach and a whole-brain, data driven approach, intrinsic connectivity distribution (ICD). RESULTS: NOI-based analyses indicated decreased functional connectivity within frontoparietal and salience networks among smokers relative to nonsmokers, as well as effects of smoking state on default mode connectivity. In addition, ICD analyses identified novel between-group differences in subcortical-cerebellar and cortico-cerebellar networks that were largely smoking state dependent. CONCLUSIONS: These data demonstrate the importance of considering smoking state and the utility of using both theory- and data-driven analysis approaches. These data provide much needed insight into the functional neurobiology of early abstinence, which may be used in the development of novel treatments.

2.
Neuropsychopharmacology ; 46(2): 478-485, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32967000

RESUMO

Over the past decade, various N-methyl-D-aspartate modulators have failed in clinical trials, underscoring the challenges of developing novel rapid-acting antidepressants based solely on the receptor or regional targets of ketamine. Thus, identifying the effect of ketamine on the brain circuitry and networks is becoming increasingly critical. In this longitudinal functional magnetic resonance imaging study of data from 265 participants, we used a validated predictive model approach that allows the full assessment of brain functional connectivity, without the need for seed selection or connectivity summaries. First, we identified a connectome fingerprint (CFP) in healthy participants (Cohort A, n = 25) during intravenous infusion of a subanesthetic dose of ketamine, compared to normal saline. We then demonstrated the robustness and reproducibility of the discovered ketamine CFP in two separate healthy samples (Cohort B, n = 22; Cohort C, n = 18). Finally, we investigated the ketamine CFP connectivity at 1-week post treatment in major depressive disorder patients randomized to 8 weeks of sertraline or placebo (Cohort D, n = 200). We found a significant, robust, and reproducible ketamine CFP, consistent with reduced connectivity within the primary cortices and within the executive network, but increased connectivity between the executive network and the rest of the brain. Compared to placebo, the ketamine CFP connectivity changes at 1 week predicted response to sertraline at 8 weeks. In each of Cohorts A-C, ketamine significantly increased connectivity in a previously identified antidepressant CFP. Investigating the brain connectivity networks, we successfully identified a robust and reproducible ketamine biomarker that is related to the mechanisms of antidepressants.

3.
Mol Psychiatry ; 2020 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-33288872

RESUMO

Studies of posttraumatic stress disorder (PTSD) report volume abnormalities in multiple regions of the cerebral cortex. However, findings for many regions, particularly regions outside commonly studied emotion-related prefrontal, insular, and limbic regions, are inconsistent and tentative. Also, few studies address the possibility that PTSD abnormalities may be confounded by comorbid depression. A mega-analysis investigating all cortical regions in a large sample of PTSD and control subjects can potentially provide new insight into these issues. Given this perspective, our group aggregated regional volumes data of 68 cortical regions across both hemispheres from 1379 PTSD patients to 2192 controls without PTSD after data were processed by 32 international laboratories using ENIGMA standardized procedures. We examined whether regional cortical volumes were different in PTSD vs. controls, were associated with posttraumatic stress symptom (PTSS) severity, or were affected by comorbid depression. Volumes of left and right lateral orbitofrontal gyri (LOFG), left superior temporal gyrus, and right insular, lingual and superior parietal gyri were significantly smaller, on average, in PTSD patients than controls (standardized coefficients = -0.111 to -0.068, FDR corrected P values < 0.039) and were significantly negatively correlated with PTSS severity. After adjusting for depression symptoms, the PTSD findings in left and right LOFG remained significant. These findings indicate that cortical volumes in PTSD patients are smaller in prefrontal regulatory regions, as well as in broader emotion and sensory processing cortical regions.

4.
Adv Pharmacol ; 89: 163-194, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32616206

RESUMO

A paradigm shift in the conceptualization of the neurobiology of depression and the serendipitous discovery of ketamine's rapid-acting antidepressant (RAAD) effects has ushered in a new era of innovative research and novel drug development. Since the initial discovery of ketamine's RAAD effects, multiple studies have supported its short-term efficacy for fast-tracked improvements in treatment-resistant depression. Evidence from MRI studies have repeatedly demonstrated functional connectivity alterations in stress- and trauma-related disorders suggesting this may be a viable biomarker of chronic stress pathology (CSP). Human mechanistic studies further support this by coupling functional connectivity to ketamine's RAAD effects including connectivity to glutamate neurotransmission, ketamine to normalized connectivity, and these advantageous normalizations to symptom improvement/ketamine response. This review provides an abridged discussion of the suspected neurobiological underpinnings of ketamine's RAAD effects, highlighting ketamine-induced alterations in prefrontal, striatal, and anterior cingulate cortex functional connectivity in major depressive disorder. We present a model of CSP underscoring the role of synaptic loss and dysconnectivity and discuss how ketamine may be used both as (1) a treatment to restore and normalize these stress-induced neural alterations and (2) a tool to study potential biomarkers of CSP and treatment response. We conclude by noting challenges and future directions including heterogeneity, sex differences, the role of early life stress, and the need for proliferation of new methods, paradigms, and tools that will optimize signal and allow analyses at different levels of complexity, according to the needs of the question at hand, perhaps by thinking hierarchically about both clinical and biological phenotypes.


Assuntos
Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/fisiopatologia , Ketamina/uso terapêutico , Rede Nervosa/fisiopatologia , Estresse Psicológico/fisiopatologia , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Doença Crônica , Humanos , Ketamina/farmacologia
5.
Eur Neuropsychopharmacol ; 35: 71-80, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32418842

RESUMO

Early life stress (ELS) and glutamate neurotransmission have been implicated in the pathophysiology of major depressive disorder (MDD). In non-human primates, ELS was positively correlated with cortical Glx (i.e., glutamate + glutamine). However, the relationship between ELS and cortical glutamate in adult patients with MDD is not fully known. Using 1H Magnetic Resonance Spectroscopy (MRS), we conducted exploratory analyses measuring occipital cortical glutamate and glutamine levels in 36 medication-free patients with MDD. In a subsample (n=11), we measured dynamic glutamate/glutamine cycling (Vcycle) using advanced 13C MRS methods. ELS history was assessed using Early-life Trauma Inventory (ETI). Exploratory analyses suggest a relationship between ETI and glutamine as reflected by a significant positive correlation between ETI scores and occipital glutamine (rs=0.39, p=0.017) but not glutamate. Post-hoc analyses showed that the association with glutamine was driven by the ETI emotional abuse (ETI-EA) subscale (rs=0.39, p=0.02). Vcycle correlation with ETI was at trend level (rs=0.55, p=0.087) and significantly correlated with ETI-EA (rs=0.67, p=0.03). In this small sample of patients with MDD, those with childhood emotional abuse appear to have increased occipital glutamate neurotransmission as reflected by increased glutamate/glutamine cycling and glutamine level. Future studies would be needed to confirm this pilot evidence and to examine whether ELS effects on glutamate neurotransmission underlie the relationship between ELS and psychopathology.

6.
Behav Brain Res ; 390: 112628, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32407817

RESUMO

Depression is a leading cause of disability, with often chronic course of illness and high treatment resistance in a large proportion of patients. In the current short perspective paper, we present evidence supporting the presence of synaptic-based chronic stress pathology (CSP) in depression and across a number of psychiatric disorders. We summarize the synaptic connectivity model of CSP, and briefly review related preclinical and clinical evidence, while providing appropriate references for more comprehensive reviews and alternative models. We then underscore some gaps in the literature and provide various tips for future directions.

8.
Neuropsychopharmacology ; 45(6): 990-997, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32092760

RESUMO

Twenty-four hours after administration, ketamine exerts rapid and robust antidepressant effects that are thought to be mediated by activation of the mechanistic target of rapamycin complex 1 (mTORC1). To test this hypothesis, depressed patients were pretreated with rapamycin, an mTORC1 inhibitor, prior to receiving ketamine. Twenty patients suffering a major depressive episode were randomized to pretreatment with oral rapamycin (6 mg) or placebo 2 h prior to the intravenous administration of ketamine 0.5 mg/kg in a double-blind cross-over design with treatment days separated by at least 2 weeks. Depression severity was assessed using Montgomery-Åsberg Depression Rating Scale (MADRS). Rapamycin pretreatment did not alter the antidepressant effects of ketamine at the 24-h timepoint. Over the subsequent 2-weeks, we found a significant treatment by time interaction (F(8,245) = 2.02, p = 0.04), suggesting a prolongation of the antidepressant effects of ketamine by rapamycin. Two weeks following ketamine administration, we found higher response (41%) and remission rates (29%) following rapamycin + ketamine compared to placebo + ketamine (13%, p = 0.04, and 7%, p = 0.003, respectively). In summary, single dose rapamycin pretreatment failed to block the antidepressant effects of ketamine, but it prolonged ketamine's antidepressant effects. This observation raises questions about the role of systemic vs. local blockade of mTORC1 in the antidepressant effects of ketamine, provides preliminary evidence that rapamycin may extend the benefits of ketamine, and thereby potentially sheds light on mechanisms that contribute to depression relapse after ketamine administration.

9.
J Affect Disord ; 266: 655-670, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32056942

RESUMO

BACKGROUND: Posttraumatic stress disorder (PTSD) is a debilitating mental illness that is thought to be associated with brain white matter (WM) alterations. Individual diffusion tensor imaging (DTI) studies to date have reported inconsistent alterations in FA across different brain regions in patients with PTSD. Here, we aimed to investigate FA in PTSD using both region-of-interest (ROI)-based and whole-brain-based meta-analytic approaches. OBJECTIVES: Individual ROI-based meta-analysis was carried out in each eligible white matter tract and seed-based D mapping (SDM) meta-analysis was conducted in the whole brain to identify the convergence of FA alterations in PTSD relative to controls. RESULTS: Seventeen studies were included in ROI-based meta-analysis (≥ 3 studies were included for each ROI, NPTSD ≥ 80 and Ncontrol ≥ 103 per ROI). Fourteen studies with a total of 322 PTSD and 335 controls were included in whole-brain based meta-analysis. Both ROI and whole-brain meta-analyses showed that patients with PTSD have significantly higher FA in the inferior fronto-occipital fasciculus and lower FA in the genu of corpus callosum. Whole-brain meta-analyses also identified higher FA in the left inferior temporal gyrus and lower FA in the anterior cingulum and left corticospinal tract. LIMITATIONS: A small number of studies were included in some ROI tracts. Thus the results should be interpreted with caution. CONCLUSIONS: Our results suggest that PTSD patients have increased FA in areas related to visual processing, but decreased FA in anterior brain regions critical to cognition association and fear regulation.

11.
Artigo em Inglês | MEDLINE | ID: mdl-31938760

RESUMO

Background: Considering the slow-acting properties of traditional antidepressants, an important challenge in the field is the identification of early treatment response biomarkers. Reduced cortical thickness has been reported in neuroimaging studies of depression. However, little is known whether antidepressants reverse this abnormality. In this brief report, we investigated early cortical thickness changes following treatment with sertraline compared to placebo. Methods: Participants (n=215) with major depressive disorder were randomized to a selective serotonin reuptake inhibitor, sertraline, or to placebo. Structural magnetic resonance imaging scans were acquired at baseline and one week following treatment. Response was defined as at least 50% improvement in Hamilton rating scale for depression score at week 8. In a vertex-wise approach, we examined the effects of treatment, response, and treatment×response. Results: Following correction for multiple comparisons, we found a significant effect of treatment, with widespread increase in cortical thickness following sertraline compared to placebo. Clusters with increased thickness were found in the left medial prefrontal cortex, right medial and lateral prefrontal cortex, and within the right parieto-temporal lobes. There were no sertraline-induced cortical thinning, and no significant response effects or treatment×response interactions. Conclusion: Our findings suggest that cortical thickness abnormalities may be responsive to antidepressant treatment. However, a relationship between these early cortical changes and later treatment response was not demonstrated. Future studies would be needed to investigate whether those early effects are maintained at eight weeks and are associated with enhanced response.

12.
iScience ; 23(1): 100800, 2020 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-31918047

RESUMO

More than six decades have passed since the discovery of monoaminergic antidepressants. Yet, it remains a mystery why these drugs take weeks to months to achieve therapeutic effects, although their monoaminergic actions are present rapidly after treatment. In an attempt to solve this mystery, rather than studying the acute neurochemical effects of antidepressants, here we propose focusing on the early changes in the brain functional connectome using traditional statistics and machine learning approaches. Capitalizing on three independent datasets (n = 1,261) and recent developments in data and network science, we identified a specific connectome fingerprint that predates and predicts response to monoaminergic antidepressants. The discovered fingerprint appears to generalize to antidepressants with differing mechanism of action. We also established a consensus whole-brain hierarchical connectivity architecture and provided a set of model-based features engineering approaches suitable for identifying connectomic signatures of brain function in health and disease.

13.
Biol Psychiatry ; 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33568318

RESUMO

The discovery of the rapid-acting antidepressant effects of ketamine has 1) led to a paradigm shift in our perception of what is possible in treating severe depression; 2) spurred a wave of basic, translation, and clinical research; and 3) provided an unprecedented investigational tool to conduct longitudinal mechanistic studies that may capture behavioral changes as complex as clinical remission and relapse within hours and days of treatment. Unfortunately, these advances did not yet translate into clinical biomarkers or novel treatments, beyond ketamine. In contrast to slow-acting antidepressants, in which targeting monoaminergic receptors identified several efficacious drugs with comparable mechanisms, the focus on the receptor targets of ketamine has failed in several clinical trials over the past decade. Thus, it is becoming increasingly crucial that we concentrate our effort on the downstream molecular mechanisms of ketamine and their effects on the brain circuitry and networks. Honoring the legacy of our mentor, friend, and colleague Ron Duman, we provide a historical note on the discovery of ketamine and its putative mechanisms. We then detail the molecular and circuits effect of ketamine based on preclinical findings, followed by a summary of the impact of this work on our understanding of chronic stress pathology across psychiatric disorders, with particular emphasis on the role of synaptic connectivity and its brain network effects in the pathology and treatment of clinical depression.

14.
Sci Rep ; 9(1): 19290, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31848397

RESUMO

Optimal integration and segregation of neuronal connections are necessary for efficient large-scale network communication between distributed cortical regions while allowing for modular specialization. This dynamic in the cortex is enabled at the network mesoscale by the organization of nodes into communities. Previous in vivo efforts to map the mesoscale architecture in humans had several limitations. Here we characterize a consensus multiscale community organization of the functional cortical network. We derive this consensus from the clustering of subject-level networks. We applied this analysis to magnetic resonance imaging data from 1003 healthy individuals part of the Human Connectome Project. The hierarchical atlas and code will be made publicly available for future investigators.


Assuntos
Encéfalo/diagnóstico por imagem , Conectoma , Vias Neurais/fisiologia , Neurônios/fisiologia , Adulto , Encéfalo/fisiologia , Análise por Conglomerados , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Imagem por Ressonância Magnética , Masculino , Rede Nervosa/fisiologia
16.
Depress Anxiety ; 36(9): 834-845, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31385647

RESUMO

BACKGROUND: Although the ε4 allele of the apolipoprotein E (APOE) gene and posttraumatic stress disorder (PTSD) have been linked to cognitive dysfunction and dementia risk, it is unknown whether they interact to predict cognitive dysfunction. METHODS: We analyzed data from European-American (EA) veterans who participated in the National Health and Resilience in Veterans Study (NHRVS): main sample (n = 1,386) and primary replication sample (n = 509). EAs from the Yale-Penn Study cohort (n = 948) served as a second replication sample. Multivariable analyses were conducted to evaluate the predictive effects of ε4 carrier status and PTSD on cognitive functioning, with a focus on whether PTSD moderates the effect of ε4 carrier status. RESULTS: APOE ε4 allele carrier status (d = 0.15 and 0.17 in the main and primary replication NHRVS samples, respectively) and PTSD (d = 0.31 and 0.17, respectively) were independently associated with lower cognitive functioning. ε4 carriers with PTSD scored lower than those without PTSD (d = 0.68 and 1.29, respectively) with the most pronounced differences in executive function (d's = 0.75-1.50) and attention/concentration (d's = 0.62-1.33). A significant interaction was also observed in the Yale-Penn sample, with ε4 carriers with PTSD making more perseverative errors on a measure of executive function than those without PTSD (24.7% vs. 17.6%; d = 0.59). CONCLUSIONS: APOE ε4 allele carriers with PTSD have substantially greater cognitive difficulties than ε4 carriers without PTSD. These results underscore the importance of assessing, monitoring, and treating PTSD in trauma-affected individuals who are at genetic risk for cognitive decline and dementia.


Assuntos
Apolipoproteína E4/genética , Cognição , Disfunção Cognitiva/genética , Inquéritos Epidemiológicos , Polimorfismo Genético , Transtornos de Estresse Pós-Traumáticos/genética , Veteranos/psicologia , Alelos , Estudos de Coortes , Grupo com Ancestrais do Continente Europeu/psicologia , Função Executiva , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos de Estresse Pós-Traumáticos/psicologia , Estados Unidos/epidemiologia
17.
Artigo em Inglês | MEDLINE | ID: mdl-31131337

RESUMO

BACKGROUND: Better understanding of the neurobiology of posttraumatic stress disorder (PTSD) may be critical to developing novel, effective therapeutics. Here, we conducted a data-driven investigation using a well-established, graph-based topological measure of nodal strength to determine the extent of functional dysconnectivity in a cohort of active duty US Army soldiers with PTSD compared to controls. METHODS: 102 participants with (n=50) or without PTSD (n=52) completed functional magnetic resonance imaging (fMRI) at rest and during symptom provocation using subject-specific script imagery. Vertex/voxel global brain connectivity with global signal regression (GBCr), a measure of nodal strength, was calculated as the average of its functional connectivity with all other vertices/voxels in the brain gray matter. RESULTS: In contrast to during resting-state, where there were no group differences, we found a significantly higher GBCr during symptom provocation, in PTSD participants compared to controls, in areas within the right hemisphere, including anterior insula, caudal-ventrolateral prefrontal, and rostral-ventrolateral parietal cortices. Overall, these clusters overlapped with the ventral and dorsal salience networks. Post hoc analysis showed increased GBCr in these salience clusters during symptom provocation compared to resting-state. In addition, resting-state GBCr in the salience clusters predicted GBCr during symptom provocation in PTSD participants but not in controls. CONCLUSION: In PTSD, increased connectivity within the salience network has been previously hypothesized, based primarily on seed-based connectivity findings. The current results strongly support this hypothesis using whole-brain network measure in a fully data-driven approach. It remains to be seen in future studies whether these identified salience disturbances would normalize following treatment.

18.
Artigo em Inglês | MEDLINE | ID: mdl-31008419

RESUMO

BACKGROUND: In soldiers with posttraumatic stress disorder (PTSD), symptom provocation was found to induce increased connectivity within the salience network, as measured by functional magnetic resonance imaging (fMRI) and global brain connectivity with global signal regression (GBCr). However, it is unknown whether these GBCr disturbances would normalize following effective PTSD treatment. METHODS: 69 US Army soldiers with (n = 42) and without PTSD (n = 27) completed fMRI at rest and during symptom provocation using subject-specific script imagery. Then, participants with PTSD received 6 weeks (12 sessions) of group cognitive processing therapy (CPT) or present-centered therapy (PCT). At week 8, all participants repeated the fMRI scans. The primary analysis used a region-of-interest approach to determine the effect of treatment on salience GBCr. A secondary analysis was conducted to explore the pattern of GBCr alterations posttreatment in PTSD participants compared to controls. RESULTS: Over the treatment period, PCT significantly reduced salience GBCr (p = .02). Compared to controls, salience GBCr was high pretreatment (PCT, p = .01; CPT, p = .03) and normalized post-PCT (p = .53), but not post-CPT (p = .006). Whole-brain secondary analysis found high GBCr within the central executive network in PTSD participants compared to controls. Post hoc exploratory analyses showed significant increases in executive GBCr following CPT treatment (p = .01). CONCLUSION: The results support previous models relating CPT to central executive network and enhanced cognitive control while unraveling a previously unknown neurobiological mechanism of PCT treatment, demonstrating treatment-specific reduction in salience connectivity during trauma recollection.

19.
Contemp Clin Trials ; 81: 11-18, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30999057

RESUMO

Posttraumatic stress disorder (PTSD) is a debilitating disorder with limited medication treatment options. Recent reports have described the dearth of research on new drug development as a crisis in the pharmacotherapy of PTSD. There are only two PTSD medications approved by the U.S. Food and Drug Administration, and both are serotonergic antidepressants. Therefore, there is a tremendous need to identify more effective and more rapidly acting pharmacotherapies for PTSD that work through novel neural mechanisms. Pilot evidence and case reports provided preliminary evidence supporting the safety and utility of investigating the therapeutic effects of ketamine in PTSD. However, the efficacy of this drug for PTSD has not yet been tested in active duty military or veteran populations. Here, we report the design and methods of a study funded under the Consortium to Alleviate PTSD. The study is a multisite, placebo-controlled, double-blind, randomized clinical trial to examine the dose-related efficacy of ketamine, as compared to placebo, in producing a rapid and sustained reduction in PTSD symptomatology in veterans and active duty military populations with antidepressant-resistant PTSD. Approximately 198 eligible participants who meet criteria for PTSD will be randomized to the study drug (i.e., ketamine 0.5 mg/kg, ketamine 0.2 mg/kg, or placebo). The study drug will be administered intravenously twice per week for 4 weeks, followed by a 4-week follow-up period. This ongoing study is the only trial of therapeutic effects of ketamine for PTSD and the first placebo-controlled trial to determine the dose-related effects of repeated ketamine on PTSD.


Assuntos
Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Ketamina/uso terapêutico , Militares , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Veteranos , Adolescente , Adulto , Idoso , Antidepressivos/uso terapêutico , Relação Dose-Resposta a Droga , Método Duplo-Cego , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Antagonistas de Aminoácidos Excitatórios/efeitos adversos , Feminino , Humanos , Infusões Intravenosas , Ketamina/administração & dosagem , Ketamina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Projetos de Pesquisa , Adulto Jovem
20.
Neuron ; 101(5): 774-778, 2019 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-30844397

RESUMO

Ketamine is the first exemplar of a rapid-acting antidepressant with efficacy for treatment-resistant symptoms of mood disorders. Its discovery emerged from a reconceptualization of the biology of depression. Neurobiological insights into ketamine efficacy shed new light on the mechanisms underlying antidepressant efficacy.


Assuntos
Antidepressivos/uso terapêutico , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Ketamina/uso terapêutico , Animais , Antidepressivos/efeitos adversos , Antidepressivos/farmacologia , Antagonistas de Aminoácidos Excitatórios/efeitos adversos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Humanos , Ketamina/efeitos adversos , Ketamina/farmacologia , Transmissão Sináptica/efeitos dos fármacos
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