Lynnette A Averill

Lynnette A Averill
Yale University | YU · Department of Psychiatry

PhD

About

79
Publications
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Publications

Publications (79)
Article
Full-text available
There is mounting evidence suggesting psychedelic and entactogen medicines (namely psilocybin and 3,4-methylenedioxymethamphetamine [MDMA]), in conjunction with proper psychosocial support, hold the potential to provide safe, rapid acting, and robust clinical improvements with durable effects. In the US, both psilocybin and MDMA have been granted B...
Article
Full-text available
Background: The Rapid Acting Empathogen (RAE) 3,4-methylenedioxy-N-methylcathinone (methylone; also known as MDMC, βk-MDMA, and M1), is a phenethylamine compound with chemical and pharmacological similarities to 3,4-Methylenedioxymethamphetamine (MDMA). It has been used outside of medical settings to treat Posttraumatic Stress Disorder (PTSD) and d...
Article
Full-text available
Background Trauma and chronic stress are believed to induce and exacerbate psychopathology by disrupting glutamate synaptic strength. However, in vivo in human methods to estimate synaptic strength are limited. In this study, we established a novel putative biomarker of glutamatergic synaptic strength, termed energy-per-cycle (EPC). Then, we used E...
Article
Suicide is a public health crisis with limited treatment options. Ketamine has demonstrated rapid and robust improvements in suicidal ideation (SI). The parent study for the secondary pilot analyses presented here was a double-blind, cross-over trial that found pretreatment with the mechanistic target of rapamycin complex 1 (mTORC1) prolonged the a...
Article
This study tested the efficacy of repeated intravenous ketamine doses to reduce symptoms of posttraumatic stress disorder (PTSD). Veterans and service members with PTSD (n = 158) who failed previous antidepressant treatment were randomized to 8 infusions administered twice weekly of intravenous placebo (n = 54), low dose (0.2 mg/kg; n = 53) or stan...
Article
Full-text available
Background & aims Special Operations Forces Veterans (SOFV) have unique treatment needs stemming from multiple repeated forms of combat exposure resulting in a complex sequela of problems including alcohol misuse and post-traumatic stress symptoms. Current approved pharmacologic treatments for alcohol misuse and PTSD are lacking in adherence and ef...
Article
The STRONG STAR Consortium (South Texas Research Organizational Network Guiding Studies on Trauma and Resilience) and the Consortium to Alleviate PTSD are interdisciplinary and multi-institutional research consortia focused on the detection, diagnosis, prevention, and treatment of combat-related posttraumatic stress disorder (PTSD) and comorbid con...
Chapter
Full-text available
A vast literature demonstrates that traumatic stress has deleterious effects on the brain; however, the precise mechanisms through which these neural alterations occur is not fully elucidated. Neurocircuitry and neuroplasticity have been identified as critical components in determining an individual's stress tolerance and response In this abridged...
Preprint
Full-text available
Background: This study tested the efficacy of repeated intravenous ketamine doses to reduce antidepressant-resistant symptoms of posttraumatic stress disorder (PTSD). Methods: Veterans and service members with PTSD (n=158) who failed previous antidepressant treatment were randomized to 8 infusions administered twice weekly of intravenous placebo (n...
Preprint
Full-text available
Trauma and chronic stress are believed to induce and exacerbate psychopathology by disrupting glutamate synaptic strength. However, in vivo in human methods to estimate synaptic strength are limited. In this study, we established a novel putative biomarker of glutamatergic synaptic strength, termed energy-per-cycle (EPC). Then, we used EPC to inves...
Article
Full-text available
Background Major depressive disorder (MDD) treatment is characterized by low remission rate and often involves weeks to months of treatment. Identification of pretreatment biomarkers of response may play a critical role in novel drug development, in enhanced prognostic predictions, and perhaps in providing more personalized medicine. Using a networ...
Article
Full-text available
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 th...
Article
Full-text available
Background U.S. Special Operations Forces Veterans are at increased risk for a variety of mental health problems and cognitive impairment associated with military service. Current treatments are lacking in effectiveness and adherence. Therefore, this study examined psychedelic treatment with ibogaine and 5-methoxy-N,N-dimethyltryptamine for trauma-...
Chapter
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 effica...
Article
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. Usin...
Preprint
Full-text available
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 th...
Article
Full-text available
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 sufferi...
Article
The serendipitous discovery of ketamine’s robust antidepressant effects has served as a major catalyst to usher in new era of drug development and a paradigm shift in our understanding of the neurobiology of chronic stress pathology (CSP). This review provides a selective synthesis of (1) the historical foundations of N-methyl-D-aspartate receptor...
Article
Full-text available
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...
Article
Full-text available
Identifying brain alterations that contribute to suicidal thoughts and behaviors (STBs) are important to develop more targeted and effective strategies to prevent suicide. In the last decade, and especially in the last 5 years, there has been exponential growth in the number of neuroimaging studies reporting structural and functional brain circuitr...
Article
Full-text available
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 a...
Article
Full-text available
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 act...
Article
Full-text available
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 n...
Article
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 antidepre...
Preprint
Full-text available
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 no...
Preprint
Full-text available
BACKGROUND: Ketamine exerts rapid and robust antidepressant effects 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. METHODS: Twenty-three patients suffering a major depressive...
Article
Full-text available
The societal burden of psychiatric disorders that result after exposure to psychological trauma is enormous. The study of trauma-related disorders using neurobiological and public health approaches is often disjointed. It is critical to emphasize the translational potential of neurobiological work and its relevance to the public health burden of ps...
Preprint
Full-text available
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 act...
Article
Military sexual trauma (MST) is associated with a range of negative mental and physical health outcomes. Investigations of potential sex-based differences in outcomes in MST survivors have been inconsistent with little work evaluating psychosocial correlates of resilience (e.g., social support, humor, capacity to adapt to change). Data were analyze...
Article
Full-text available
Background: Identifying the neural correlates of ketamine treatment may facilitate and expedite the development of novel, robust, and safe rapid-acting antidepressants. Prefrontal cortex (PFC) global brain connectivity with global signal regression (GBCr) was recently identified as a putative biomarker of major depressive disorder (MDD). Accumulat...
Article
Full-text available
New approaches to the neurobiology of posttraumatic stress disorder (PTSD) are needed to address the reported crisis in PTSD drug development. These new approaches may require the field to move beyond a narrow fear-based perspective, as fear-based medications have not yet demonstrated compelling efficacy. Antidepressants, particularly recent rapid-...
Article
Full-text available
Here we present functional neuroimaging-based network data (focused on the default mode network) collected from a cohort of US Veterans with history of combat exposure, combined with clinical assessments for PTSD and other psychiatric comorbidities. The data has been processed and analyzed using several network construction methods (signed, thresho...
Article
Purpose of the study: Prior studies showed posttraumatic stress disorder (PTSD)-related alterations in white matter integrity, but most of these studies have used region-based approaches. We address this limitation by investigating the relationship between PTSD severity and fractional anisotropy (FA) using a tract-based approach. Procedures: Str...
Article
Full-text available
The ability of ketamine administration to activate prefrontal glutamate neurotransmission is thought to be a key mechanism contributing to its transient psychotomimetic effects and its delayed and sustained antidepressant effects. Rodent studies employing carbon-13 magnetic resonance spectroscopy (13C MRS) methods have shown ketamine and other N-me...
Poster
Full-text available
Manuscript Now Published at Molecular Neuropsychiatry. CITATION: Averill CL, Averill LA, Wrocklage KM, Scott JC, Akiki TJ, Schweinsburg B, Southwick SM, Krystal JH, Abdallah CG. Altered white matter diffusivity of the cingulum angular bundle in posttraumatic stress disorder. Mol Neuropsychiatry 2018;4:75–82. https://doi.org/10.1159/000490464
Article
Full-text available
Disruption in the default mode network (DMN) has been implicated in numerous neuropsychiatric disorders, including posttraumatic stress disorder (PTSD). However, studies have largely been limited to seed-based methods and involved inconsistent definitions of the DMN. Recent advances in neuroimaging and graph theory now permit the systematic explora...
Article
Full-text available
Purpose of review: This review focuses on the relationship between resilience and the ability to effectively modulate the stress response. Neurobiological and behavioral responses to stress are highly variable. Exposure to a similar stressor can lead to heterogeneous outcomes-manifesting psychopathology in one individual, but having minimal effect...
Poster
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The Methodological Question: Can fMRI-derived restricted-network biomarkers serve as robust marker of PTSD symptomatology? Can these network-analyses identify abnormalities that can potentially be targeted using circuit-based therapeutics?
Article
Full-text available
The Opioid Abuse Risk Screener was developed to support well-informed decision-making in opioid analgesic prescribing by extending the breadth of psychiatric risk factors evaluated relative to other non–clinician-administered measures. We examined the preliminary predictive validity of the Opioid Abuse Risk Screener relative to the widely used Scre...
Article
Full-text available
Background Two decades of human neuroimaging research have associated volume reductions in the hippocampus with posttraumatic stress disorder. However, little is known about the distribution of volume loss across hippocampal subfields. Recent advances in neuroimaging methods have made it possible to accurately delineate 10 gray matter hippocampal s...
Data
This manuscript (https://goo.gl/ea9UU9) includes an animated 3D video that was created (in Blender) using meshes from one of the combat control (non-PTSD) participants described in the manuscript. It demonstrates the gray matter subfields of the hippocampus, walking through each one to better visualize the more hidden areas. This video is an excell...
Poster
Full-text available
Background: The discovery of the rapid acting antidepressant effects of ketamine have generated considerable interest in academia and industry about the prospect of targeting NMDA receptors (NMDAR) in the treatment of refractory depression. However, the results from clinical trials failing to reach primary outcomes, combined with recent preclinical...
Poster
Full-text available
Abstract Background The hippocampus and amygdala have been repeatedly implicated in the psychopathology of posttraumatic stress disorder (PTSD). While numerous structural neuroimaging studies examined these two structures in PTSD, these analyses have largely been limited to volumetric measures. Recent advances in vertex-based neuroimaging methods h...
Poster
Full-text available
Abstract Background: Two decades of human neuroimaging research have associated volume reductions in the hippocampus with posttraumatic stress disorder. However, little is known about the distribution of volume loss across hippocampal subfields. Recent advances in neuroimaging methods have made it possible to accurately delineate 10 gray matter hip...
Article
Full-text available
Purpose of review: Studies of the neurobiology and treatment of PTSD have highlighted many aspects of the pathophysiology of this disorder that might be relevant to treatment. The purpose of this review is to highlight the potential clinical importance of an often-neglected consequence of stress models in animals that may be relevant to PTSD: the...
Article
Full-text available
Background: Chronic stress and related physiological responses are known to have deleterious effects on neural integrity. Combat exposure is a notoriously pathogenic stressor and with over 2 million U.S. troops deployed to active combat zones since 2001, there is an urgent need to advance our understanding of its potential neural impact. Previous...
Article
Full-text available
Background: The hippocampus and amygdala have been repeatedly implicated in the psychopathology of posttraumatic stress disorder (PTSD). While numerous structural neuroimaging studies examined these two structures in PTSD, these analyses have largely been limited to volumetric measures. Recent advances in vertex-based neuroimaging methods have mad...
Article
Full-text available
Background: Prefrontal global brain connectivity with global signal regression (GBCr) was proposed as a robust biomarker of depression, and was associated with ketamine’s mechanism of action. Here, we investigated prefrontal GBCr in treatment-resistant depression (TRD) at baseline and following treatment. Then, we conducted a set of pharmacological...
Article
Full-text available
We investigated the extent of cortical thinning in U.S. Veterans exposed to combat who varied in the severity of their posttraumatic stress disorder (PTSD) symptoms. In addition, we explored the neural correlates of PTSD symptom dimensions and the interactive effects of combat exposure and PTSD upon cortical thickness. Sixty-nine combat exposed Vet...