Louis Trevisan

N-methyl-D-aspartate glutamate receptors and alcoholism: reward, dependence, treatment, and vulnerability.

This review takes a translational neuroscience perspective on the role of glutamate systems in human ethanol abuse and dependence. Ethanol is a simple molecule with profound effects on many chemical systems in the brain. Glutamate is the primary excitatory neurotransmitter in the brain. Glutamatergic systems are targets for the actions of ethanol via its antagonism of the N-methyl-D-aspartate (NMDA) subtype of the glutamate receptor and other mechanisms. The modulation of glutamatergic function by ethanol contributes to both euphoric and dysphoric consequences of ethanol intoxication. Adaptations within glutamatergic systems appear to contribute to ethanol tolerance and dependence and to both acute and protracted features of ethanol withdrawal. Perhaps because of the important glutamatergic mediation of the behavioral effects of ethanol, glutamatergic systems appear to contribute to the vulnerability to alcoholism, and novel glutamatergic agents may play a role in the treatment of ethanol abuse and dependence.

Rapid Communication Chronic Ingestion of Ethanol Up‐Regulates NMDAR1 Receptor Subunit Immunoreactivity in Rat Hippocampus

We examined the effects of chronic ethanol exposure on the levels of N‐methyl‐D‐aspartate receptor subunit 1 (NMDAR1) protein, an essential component of N‐methyl‐D‐aspar‐ tate glutamate receptors, in rat brain. By immunoblotting procedures using a specific antibody for the NMDAR1 subunit, we found that ethanol dramatically up‐regulated (by 65%) NMDAR1 immunoreactivity in the hippocampus but not in the nucleus accumbens, cerebral cortex, or striatum. In contrast, ethanol did not alter the levels of glutamate receptor subunit (GLUR) 1 or GLUR2 protein, subunits that make up the α‐amino‐3‐hydroxy‐5‐methy4‐isoxazole propionic acid glutamate receptor, in the hippocampus. Because ethanol can potentially influence many different neurotransmitter systems, we examined whether chronic treatment with several psychotropic drugs with different pharmacological profiles (cocaine, haloperidol, SCH 23390, imipramine, and morphine) could mimic the effect of ethanol. None of these agents increased hippocampal NMDAR1 subunit immunoreactivity after chronic administration. Increased NMDAR1 subunit levels in the hippocampus after chronic ethanol exposure may represent an important neurochemical substrate for some of the features associated with ethanol dependence and withdrawal.

NMDA Receptor Antagonism and the Ethanol Intoxication Signal

Abstract: This paper reviews clinical evidence suggesting that antagonism of the N‐methyl‐d‐aspartate subtype of glutamate receptors by ethanol may convey an important component of the ethanol intoxication signal, that is, subjective and objective responses associated with the consumption of a large amount of ethanol. It will then review recent evidence that two phenotypes associated with increased risk for heavy alcohol consumption, recovering ethanol‐dependent patients, and healthy individuals with a family history of alcohol dependence, exhibit reduced sensitivity to the dysphoric consequences of administration of the NMDA receptor antagonist, ketamine. Each of these groups displays reduced sensitivity to a potentially important response that might normally trigger the cessation of ethanol consumption. These data raise the possibility that alterations in NMDA receptor function that reduce the response to the NMDA antagonist component of ethanol may increase the risk for heavy drinking. This hypothesis is consistent with growing evidence that NMDA receptor antagonists may play a role in the treatment of alcoholism by suppressing alcohol withdrawal, reducing the development or expression of alcohol tolerance, or preventing or reversing the sensitiziation to ethanol effects.

Altered NMDA glutamate receptor antagonist response in recovering ethanol-dependent patients.

Ethanol is an antagonist of the N-methyl-D-aspartate (NMDA) glutamate receptor. Ethanol dependence upregulates NMDA receptors and contributes to crosstolerance with selective NMDA receptor antagonists in animals. This study evaluated whether recovering ethanol-dependent patients show evidence of a reduced level of response to the effects of the NMDA receptor antagonist, ketamine. In this double-blind study, 34 recently detoxified alcohol-dependent patients and 26 healthy comparison subjects completed 3 test days involving a 40-min infusion of saline, ketamine 0.1 mg/kg, or ketamine 0.5 mg/kg in a randomized order. Recovering ethanol-dependent patients showed reduced perceptual alterations, dysphoric mood, and impairments in executive cognitive functions during ketamine infusion relative to the healthy comparison group. No attenuation of ketamine-induced amnestic effects, euphoria, or activation was observed. The alterations in NMDA receptor function observed in recovering ethanol-dependent patients may have important implications for ethanol tolerance, ethanol dependence, and the treatment of alcoholism.

Noradrenergic vs Serotonergic Antidepressant with or without Naltrexone for Veterans with PTSD and Comorbid Alcohol Dependence

The wars in Iraq and Afghanistan are associated with high rates of post-traumatic stress disorder (PTSD) and comorbid alcohol use disorders. The pharmacotherapy of these comorbid conditions has received relatively little study. The current study compared the serotonin uptake inhibitor, paroxetine, to the norepinephrine uptake inhibitor, desipramine. It also evaluated the adjunctive efficacy of the Food and Drug Administration (FDA)-approved alcoholism pharmacotherapy, naltrexone, relative to placebo. Four groups of predominately male veterans (n=88) meeting current diagnostic criteria for both alcohol dependence (AD) and PTSD were randomly assigned under double-blind conditions to one of four groups: paroxetine+naltrexone; paroxetine+placebo; desipramine+naltrexone; desipramine+placebo. Main outcome measures included standardized scales that assessed symptoms of PTSD and alcohol consumption. Paroxetine did not show statistical superiority to desipramine for the treatment of PTSD symptoms. However, desipramine was superior to paroxetine with respect to study retention and alcohol use outcomes. Naltrexone reduced alcohol craving relative to placebo, but it conferred no advantage on drinking use outcomes. Although the serotonin uptake inhibitors are the only FDA-approved medications for the treatment of PTSD, the current study suggests that norepinephrine uptake inhibitors may present clinical advantages when treating male veterans with PTSD and AD. However, naltrexone did not show evidence of efficacy in this population. This study was registered with ClinicalTrials.gov, registration number NCT00338962 and URL: http://clinicaltrials.gov/ct2/show/NCT00338962?term=desipramine+AND+alcohol+dependence+AND+depression&recr=Closed&rank=1.

Characterization of the Interactive Effects of Glycine and D -Cycloserine in Men: Further Evidence for Enhanced NMDA Receptor Function Associated with Human Alcohol Dependence

Reduced responses to N-methyl-D-aspartate (NMDA) glutamate receptor antagonists in alcohol-dependent animals and humans provided evidence that chronic alcohol consumption increased NMDA receptor function. To further probe alterations in NMDA glutamate receptor function associated with human alcohol dependence, this study examined the interactive effects of agents acting at the glycineB coagonist site of the NMDA receptor. In doing so, it tested the hypothesis that raising brain glycine concentrations would accentuate the antagonist-like effects of the glycineB partial agonist, D-cycloserine (DCS). Twenty-two alcohol-dependent men and 22 healthy individuals completed 4 test days, during which glycine 0.3 g/kg or saline were administered intravenously and DCS 1000 mg or placebo were administered orally. The study was conducted under double-blind conditions with randomized test day assignment. In this study, DCS produced alcohol-like effects in healthy subjects that were deemed similar to a single standard alcohol drink. The alcohol-like effects of DCS were blunted in alcohol-dependent patients, providing additional evidence of increased NMDA receptor function in this group. Although glycine administration reduced DCS plasma levels, glycine accentuated DCS effects previously associated with the NMDA receptor antagonists, ketamine and ethanol. Thus, this study provided evidence that raising glycine levels accentuated the NMDA receptor antagonist-like effects of DCS and that alcohol-dependent patients showed tolerance to these DCS effects.Reduced responses to N-methyl-D-aspartate (NMDA) glutamate receptor antagonists in alcohol-dependent animals and humans provided evidence that chronic alcohol consumption increased NMDA receptor function. To further probe alterations in NMDA glutamate receptor function associated with human alcohol dependence, this study examined the interactive effects of agents acting at the glycine(B) coagonist site of the NMDA receptor. In doing so, it tested the hypothesis that raising brain glycine concentrations would accentuate the antagonist-like effects of the glycine(B) partial agonist, D-cycloserine (DCS). Twenty-two alcohol-dependent men and 22 healthy individuals completed 4 test days, during which glycine 0.3 g/kg or saline were administered intravenously and DCS 1000 mg or placebo were administered orally. The study was conducted under double-blind conditions with randomized test day assignment. In this study, DCS produced alcohol-like effects in healthy subjects that were deemed similar to a single standard alcohol drink. The alcohol-like effects of DCS were blunted in alcohol-dependent patients, providing additional evidence of increased NMDA receptor function in this group. Although glycine administration reduced DCS plasma levels, glycine accentuated DCS effects previously associated with the NMDA receptor antagonists, ketamine and ethanol. Thus, this study provided evidence that raising glycine levels accentuated the NMDA receptor antagonist-like effects of DCS and that alcohol-dependent patients showed tolerance to these DCS effects.

The burden of alcohol use disorders in U.S. Military veterans: results from the National Health and Resilience in Veterans Study

AIMS To analyze data from a large, contemporary, nationally representative sample of US veterans to evaluate: (1) the prevalence of life-time alcohol use disorder (AUD) and past-year AUD; (2) common psychiatric comorbidities associated with life-time AUD; and (3) correlates of life-time and past-year probable AUD. DESIGN Data were analyzed from the National Health and Resilience in Veterans Study (NHRVS), a web-based survey of a random probability sample of a contemporary, nationally representative sample of US military veterans. SETTING United States. PARTICIPANTS Nationally representative sample of 3157 US veterans aged 21 years and older. MEASUREMENTS Life-time alcohol abuse and dependence were assessed according to DSM-IV diagnostic criteria using the Mini International Neuropsychiatric Interview, and combined into a single variable: AUD. Past-year probable AUD was assessed using the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C). Correlates of AUD, including psychiatric comorbidities, suicidality and demographic characteristics, were also assessed. FINDINGS The prevalence of life-time AUD and past-year probable AUD was 42.2% [95% confidence interval (CI) = 40.5-43.9%)] and 14.8% (95% CI = 13.6-16.0%), respectively. Compared with veterans without AUD, those with life-time AUD had substantially elevated rates of life-time and current mood and anxiety disorders [odds ratios (ORs) = 2.6-4.1], drug use disorder (OR = 10.7), life-time suicide attempt (OR = 4.1) and current suicidal ideation (OR = 2.1). Younger age, male sex, lower education, lower annual household income and greater number of life-time traumatic events were associated independently with life-time AUD. Younger age, male sex, unpartnered marital status and a life-time diagnosis of major depressive disorder were associated independently with past-year probable AUD. CONCLUSIONS More than 40% of US military veterans have a life-time history of alcohol use disorder. Veterans with a life-time history of alcohol use disorder have substantial comorbid psychiatric burden, including elevated rates of suicidal ideation and attempts. Certain socio-demographic (e.g. younger age, male sex, lower education) and clinical (e.g. trauma burden, history of depression) characteristics are associated with increased risk of AUD.

Second Messenger and Protein Phosphorylation Mechanisms Underlying Possible Genetic Vulnerability to Alcoholism

Studies of the basic neurobiology of drug addiction, including alcoholism, should be given a high priority for two reasons. First, from a clinical perspective, drug abuse continues to exact enormous human and financial costs on society, yet all currently available treatments for drug addiction are notoriously ineffective. The search for a better understanding of the neurobiological mechanisms underlying the addictive actions of drugs of abuse and of the genetic factors that contribute to addiction will result in crucial advances in our ability to treat and prevent drug addiction. Second, from a basic neuroscience perspective, study of the neurobiology of drug addiction offers a unique opportunity to establish the biological basis of a complex and clinically relevant behavioral abnormality. This is based largely on the availability of good animal models of drug addiction, which make it possible to study the detailed underlying mechanisms involved. Advances made in the field of drug addiction should provide important insights into mechanisms involved in other neuropsychiatric disorders, for which animal models are much less straightforward and much more difficult to interpret.

Transforming Systems of Care Through a Novel Resident-Led Approach to Morbidity and Mortality Conferences.

Compared to the literature from our colleagues in other medical disciplines, the literature on Morbidity and Mortality (M&M) conferences in psychiatry is limited. In 2009, Goldman et al. found only nine reports over the past 40 years of psychiatric M&M endeavors [1]. Potential explanations for this dearth of M&M activities include the stigma and blaming culture sometimes associated with these forums, the relative rarity of mortality as a result of psychiatric illness, and the difficulty in clearly defining other adverse outcomes in mental health [2]. There is an increased understanding, however, that placing greater emphasis on issues of patient safety (PS) and quality improvement (QI) leads to improved patient care [3]. Regulatory bodies that oversee hospitals and graduatemedical education have begun to place greater emphasis on PS by focusing on decreasing “medical errors” and on QI through systems-level changes at healthcare institutions [4–6]. The Accreditation Council for Graduate Medical Education (ACGME) has included proficiency in QI and PS in their residency milestones and has created the Clinical Learning Environment Review (CLER) to engage residents in QI and PS initiatives [7]. Involving residents in this process is not only educational, but also pragmatic, given their position on the front lines of care and keen awareness of the factors adversely impacting clinical decision-making [8–10]. Some residencies are implementing QI curricula by utilizing experiential learning as a component of resident education [11–13]. A select few residencies encourage trainees to take on leadership roles in developing QI initiatives [14, 15]. Further, the Veterans Affairs (VA) Office of Academic Affiliation has funded Chief Resident in Quality and Patient Safety (CRQS) positions nationally to support QI initiatives during training [16]. Ideally, M&M conferences serve as a QI endeavor, providing peer review, adverse event reporting and analysis, and relevant education [17]. Numerous factors may impede successful implementation however, including a lack of structure, inadequate time, degeneration into lecture, or a perception that great ideas are “dismissed at the door” afterwards; but perhaps most salient is their association with a culture of blame, bullying, and disrespect [6, 18–20]. In 2012, Leape and collaborators described how this dysfunctional blaming culture is “a substantial barrier to progress in patient safety” despite 30 years of evidence that improved communication and discussion of errors leads to improved patient care [21, 22]. Patient safety forums can positively influence large healthcare organizations, by promoting institutional transparency and a non-punitive culture [23]. Further, shifting focus from individual to system-level factors that lead to errors enables identification of targets for improvement in care [24]. Charles Vincent described a framework for “systems analysis,” an approach founded in root cause analysis (RCA, a systematic process for identifying “root causes” of an adverse event) [25]. We therefore initiated a resident-led M&M-style conference series for the mental health service line at VA Connecticut Healthcare System (VACHS), entitled the “Mental Health Systems Improvement Series” (MHSIS). The MHSIS was established to create a safe, interdisciplinary forum for the structured discussion of unfavorable outcomes and “near misses” (an event where an adverse clinical outcome was narrowly avoided) using an RCA framework. Here, we describe the MHSIS, highlight the systemic and cultural changes that have resulted from its implementation, and demonstrate how such a forum can improve residency * Tobias Wasser tobias.wasser@yale.edu

Addressing Veteran Homelessness to Prevent Veteran Suicides

The U.S. Department of Veterans Affairs (VA) is shifting its focus from ending veteran homelessness to preventing veteran suicides. With supporting data, this Open Forum argues that VA homelessness services also help address veteran suicides. Analysis of a nationally representative survey of U.S. veterans in 2015 shows that veterans with a history of homelessness attempted suicide in the previous two years at a rate >5.0 times higher compared with veterans without a history of homelessness (6.9% versus 1.2%), and their rates of two-week suicidal ideation were 2.5 times higher (19.8% versus 7.4%). Because the majority of veterans who die by suicide are not engaged in VA care, VA services for the homeless that include outreach efforts to engage new veterans may be reaching some of these veterans. Thus continued federal support for VA homelessness services not only may help address homelessness but also may help prevent suicide of veterans.