Imaging suicidal thoughts and behaviors: a comprehensive review of 2 decades of neuroimaging studies

Funder: American Foundation for Suicide Prevention (AFSP); doi: https://doi.org/10.13039/100001455Funder: Brain and Behavior Research Foundation (Brain & Behavior Research Foundation); doi: https://doi.org/10.13039/100000874Funder: MQ Brighter Futures Award MQBFC/2, International Bipolar Foundation, For the Love of Travis Foundation, Women's Health Research at Yale, John and Hope Furth EndowmentFunder: U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)Funder: Brain and Behavior Research Foundation (Brain & Behavior Research Foundation)Funder: Robert E. Leet and Clara Guthrie Patterson Trust (Robert E. Leet & Clara Guthrie Patterson Trust); doi: https://doi.org/10.13039/100000938Funder: U.S. Department of Veterans Affairs (Department of Veterans Affairs); doi: https://doi.org/10.13039/100000738Abstract: 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 circuitry correlates of STBs. Within this narrative review, we conducted a comprehensive review of neuroimaging studies of STBs published to date and summarize the progress achieved on elucidating neurobiological substrates of STBs, with a focus on converging findings across studies. We review neuroimaging evidence across differing mental disorders for structural, functional, and molecular alterations in association with STBs, which converges particularly in regions of brain systems that subserve emotion and impulse regulation including the ventral prefrontal cortex (VPFC) and dorsal PFC (DPFC), insula and their mesial temporal, striatal and posterior connection sites, as well as in the connections between these brain areas. The reviewed literature suggests that impairments in medial and lateral VPFC regions and their connections may be important in the excessive negative and blunted positive internal states that can stimulate suicidal ideation, and that impairments in a DPFC and inferior frontal gyrus (IFG) system may be important in suicide attempt behaviors. A combination of VPFC and DPFC system disturbances may lead to very high risk circumstances in which suicidal ideation is converted to lethal actions via decreased top-down inhibition of behavior and/or maladaptive, inflexible decision-making and planning. The dorsal anterior cingulate cortex and insula may play important roles in switching between these VPFC and DPFC systems, which may contribute to the transition from suicide thoughts to behaviors. Future neuroimaging research of larger sample sizes, including global efforts, longitudinal designs, and careful consideration of developmental stages, and sex and gender, will facilitate more effectively targeted preventions and interventions to reduce loss of life to suicide

Neurobiological studies of trauma-related psychopathology: a public health perspective

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 psychological trauma. Applying a public health model to traumatology that includes primary, secondary, and tertiary levels, we highlight ways in which advancing the field of neurobiology can pave the way for scalable interventions that can improve outcomes and help to address the public health problem

The potential of ketamine for posttraumatic stress disorder: a review of clinical evidence.

Peer reviewed: TruePosttraumatic stress disorder (PTSD) is a devastating condition, for which there are few pharmacological agents, often with a delayed onset of action and poor efficacy. Trauma-focused psychotherapies are further limited by few trained providers and low patient engagement. This frequently results in disease chronicity as well as psychiatric and medical comorbidity, with considerable negative impact on quality of life. As such, off-label interventions are commonly used for PTSD, particularly in chronic refractory cases. Ketamine, an N-methyl-D-aspartate (NDMA) receptor antagonist, has recently been indicated for major depression, exhibiting rapid and robust antidepressant effects. It also shows transdiagnostic potential for an array of psychiatric disorders. Here, we synthesize clinical evidence on ketamine in PTSD, spanning case reports, chart reviews, open-label studies, and randomized trials. Overall, there is high heterogeneity in clinical presentation and pharmacological approach, yet encouraging signals of therapeutic safety, efficacy, and durability. Avenues for future research are discussed

The potential of ketamine for posttraumatic stress disorder: a review of clinical evidence.

Posttraumatic stress disorder (PTSD) is a devastating condition, for which there are few pharmacological agents, often with a delayed onset of action and poor efficacy. Trauma-focused psychotherapies are further limited by few trained providers and low patient engagement. This frequently results in disease chronicity as well as psychiatric and medical comorbidity, with considerable negative impact on quality of life. As such, off-label interventions are commonly used for PTSD, particularly in chronic refractory cases. Ketamine, an N-methyl-D-aspartate (NDMA) receptor antagonist, has recently been indicated for major depression, exhibiting rapid and robust antidepressant effects. It also shows transdiagnostic potential for an array of psychiatric disorders. Here, we synthesize clinical evidence on ketamine in PTSD, spanning case reports, chart reviews, open-label studies, and randomized trials. Overall, there is high heterogeneity in clinical presentation and pharmacological approach, yet encouraging signals of therapeutic safety, efficacy, and durability. Avenues for future research are discussed

The Opioid Abuse Risk Screener predicts aberrant same-day urine drug tests and 1-year controlled substance database checks: A brief report

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 Screener and Opioid Assessment for Patients with Pain–Revised in predicting aberrant urine drug tests and controlled substance database checks. The Opioid Abuse Risk Screener is significantly different from the Screener and Opioid Assessment for Patients with Pain–Revised in predicting aberrant same-day urine drug tests ( Z  = 2.912, p  = 0.0036) and controlled substance database checks within 1 year of assessment ( Z  = 3.731, p  = 0.0002). Promising preliminary analyses using machine learning methods are also discussed

Research on PTSD prevalence in OEF/OIF Veterans: expanding investigation of demographic variables

Background: A series of recent articles has reported on well-designed studies examining base rates of posttraumatic stress disorder (PTSD) screenings within the Operation Enduring Freedom (Afghanistan conflict)/Operation Iraqi Freedom (Iraq conflict) (OEF/OIF) military population. Although these studies have a number of strengths, this line of research points out several key areas in need of further examination. Objective: Many OEF/OIF Veterans do not use available Veterans Affairs (VA) services, especially mental health care. This highlights the need to understand the differences between those who use and do not use the VA, especially as research with pre-OEF/OIF Veterans suggests that these two groups differ in significant ways. The high rates of PTSD-related concerns in non-VA users also points to a need to understand whether—and where—Veterans are seeking care outside the VA and the accessibility of evidence-based, trauma-focused treatments in the community and private sectors. Careful examination of relationship status is also paramount as little research has examined relationship status or other relationship context issues. Social support, especially from a spouse, can buffer the development of PTSD; however, relationship discord has the potential to greatly exacerbate PTSD symptomatology. Furthermore, given the additional risk factors for sexual minority Veterans to be exposed to trauma, the 2011 repeal of the US Military “Don't Ask, Don't Tell” policy, and the emergence of the VA as likely the largest health care provider for sexual minority Veterans, it will be critically important to study the trauma and mental health experiences of this group. Conclusions: Studies that examine prevalence rates of PTSD in the returning cohort contribute significantly to our understanding of the US OEF/OIF military population. Further study of PTSD in relation to demographic variables such as VA and non-VA use, relationship status, and sexual orientation will provide rich data that will enhance our ability to develop policy and practice to provide the best care to this population

Ketamine, but Not the NMDAR Antagonist Lanicemine, Increases Prefrontal Global Connectivity in Depressed Patients

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. Accumulating evidence have repeatedly shown reduced PFC GBCr in major depressive disorder, an abnormality that appears to normalize following ketamine treatment. Methods Fifty-six unmedicated participants with major depressive disorder were randomized to intravenous placebo (normal saline; n = 18), ketamine (0.5 mg/kg; n = 19), or lanicemine (100 mg; n = 19). PFC GBCr was computed using time series from functional magnetic resonance imaging scans that were completed at baseline, during infusion, and at 24-h posttreatment. Results Compared to placebo, ketamine significantly increased average PFC GBCr during infusion ( p  = 0.01) and at 24-h posttreatment ( p  = 0.02). Lanicemine had no significant effects on GBCr during infusion ( p  = 0.45) and at 24-h posttreatment ( p  = 0.23) compared to placebo. Average delta PFC GBCr (during minus baseline) showed a pattern of positively predicting depression improvement in participants receiving ketamine ( r  = 0.44; p  = 0.06; d  = 1.0) or lanicemine ( r  = 0.55; p  = 0.01; d  = 1.3) but not those receiving placebo ( r  = −0.1; p  = 0.69; d  = 0.02). Follow-up vertex-wise analyses showed ketamine-induced GBCr increases in the dorsolateral, dorsomedial, and frontomedial PFC during infusion and in the dorsolateral and dorsomedial PFC at 24-h posttreatment ( corrected p  < 0.05). Exploratory vertex-wise analyses examining the relationship with depression improvement showed positive correlation with GBCr in the dorsal PFC during infusion and at 24-h posttreatment but negative correlation with GBCr in the ventral PFC during infusion ( uncorrected p  < 0.01). Conclusions In a randomized placebo-controlled approach, the results provide the first evidence in major depressive disorder of ketamine-induced increases in PFC GBCr during infusion and suggest that ketamine’s rapid-acting antidepressant properties are related to its acute effects on prefrontal connectivity. Overall, the study findings underscore the similarity and differences between ketamine and another N-methyl-D-aspartate receptor antagonist while proposing a pharmacoimaging paradigm for the optimization of novel rapid-acting antidepressants prior to testing in costly clinical trials

Prefrontal Connectivity and Glutamate Transmission: Relevance to Depression Pathophysiology and Ketamine Treatment

BackgroundPrefrontal 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 challenges in healthy subjects to investigate the glutamate neurotransmission correlates of GBCr.MethodsIn study A, we used functional magnetic resonance imaging (fMRI) to compare GBCr between 22 TRD and 29 healthy control. Then, we examined the effects of ketamine and midazolam on GBCr in TRD patients 24h post-treatment. In study B, we acquired repeated fMRI in 18 healthy subjects to determine the effects of lamotrigine (a glutamate release inhibitor), ketamine, and lamotrigine-by-ketamine interaction.ResultsIn study A, TRD patients showed significant reduction in dorsomedial and dorsolateral prefrontal GBCr compared to healthy control. In TRD patients, GBCr in the altered clusters significantly increased 24h following ketamine (effect size = 1.0 [0.3 1.8]), but not midazolam (effect size = 0.5 [-0.6 1.3]). In study B, oral lamotrigine reduced GBCr 2h post-administration, while ketamine increased medial prefrontal GBCr during infusion. Lamotrigine significantly reduced the ketamine-induced GBCr surge. Exploratory analyses showed elevated ventral prefrontal GBCr in TRD and significant reduction of ventral prefrontal GBCr during ketamine infusion in healthy subjects.ConclusionsThis study provides first replication of the ability of ketamine to normalize depression-related prefrontal dysconnectivity. It also provides indirect evidence that these effects may be triggered by the capacity of ketamine to enhance glutamate neurotransmission

The Association of PTSD Symptom Severity With Localized Hippocampus and Amygdala Abnormalities

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 made it possible to identify specific locations of subtle morphometric changes within a structure of interest. Methods In this cross-sectional study, we used high-resolution magnetic resonance imaging to examine the relationship between PTSD symptomatology, as measured using the Clinician Administered PTSD Scale for the DSM-IV, and structural shape of the hippocampus and amygdala using vertex-wise shape analyses in a group of combat-exposed U.S. Veterans (N = 69). Results Following correction for multiple comparisons and controlling for age and cranial volume, we found that participants with more severe PTSD symptoms showed an indentation in the anterior half of the right hippocampus and an indentation in the dorsal region of the right amygdala (corresponding to the centromedial amygdala). Post hoc analysis using stepwise regression suggest that among PTSD symptom clusters, arousal symptoms explain most of the variance in the hippocampal abnormality, whereas reexperiencing symptoms explain most of the variance in the amygdala abnormality. Conclusion The results provide evidence of localized abnormalities in the anterior hippocampus and centromedial amygdala in combat-exposed U.S. Veterans suffering from PTSD symptoms. This novel finding provides a more fine-grained analysis of structural abnormalities in PTSD and may be informative for understanding the neurobiology of the disorder