PPARγ activation by pioglitazone does not suppress cravings for alcohol, and is associated with a risk of myopathy in treatment seeking alcohol dependent patients: a randomized controlled proof of principle study.

Rationale: Proinflammatory processes have been implicated in alcohol addiction, craving, and relapse, while studies in experimental animals have suggested that activation of peroxisome proliferator-activated receptor gamma (PPARγ) inhibits proinflammatory signaling. Accordingly, it is hypothesized that medications with PPARγ activity may have therapeutic potential in alcohol dependence.

Objectives: We conducted a double-blind, placebo-controlled mechanistic proof of principle study in alcohol-dependent inpatients to investigate the effect of pioglitazone on alcohol craving.

Neurofunctional Domains Derived From Deep Behavioral Phenotyping in Alcohol Use Disorder.

Objective: The authors evaluated whether three neurofunctional domains proposed to be critical in the addiction cycle, namely, incentive salience, negative emotionality, and executive function, could be identified through factor analysis of a deeply phenotyped clinical sample.

Methods: Clinical, behavioral, and self-report measures of addiction, personality, cognition, behavior, and exposure to early-life stress were collected as part of a screening and natural history study of alcohol use disorders in 454 individuals representing the spectrum of alcohol use and use disorders. The multiple indicators, multiple causes (MIMIC) approach was used to identify significant predictors of the latent factors identified by the analysis.

Stress vulnerability and alcohol use and consequences: From human laboratory studies to clinical outcomes.

It is well known that vulnerability to stress is a risk factor for alcohol use disorder (AUD). Chronic alcohol use can result in neuroadaptations in cortico-striatal pathways and hypothalamic pituitary adrenal (HPA) axis function that are manifested in altered behavioral and cognitive control functions contributing to alcohol craving, compulsive motivation, consumption, and consequences. This symposium brings together studies utilizing novel approaches to help improve our understanding of stress - past, acute, and chronic - on alcohol seeking and consumption and related outcomes using a combination of human laboratory models, neuroimaging, and clinical measures.

Addiction Biomarkers: Dimensional Approaches to Understanding Addiction.

Trends towards dimensional approaches in understanding psychiatric disorders may also be applied to addictive disorders. Advances in our understanding of the neurobiology of addiction can inform these efforts. Furthermore, dimensional approaches to addiction, such as the proposed Addictions Neuroclinical Assessment (ANA), may be used in identifying novel addiction biomarkers, and refining ones that currently exist.

Neuroclinical Framework for the Role of Stress in Addiction.

Addiction has been conceptualized as a three-stage cycle-, and -that worsens over time and involves allostatic changes in hedonic function via changes in the brain reward and stress systems. Using the stage and negative reinforcement as an important source of motivation for compulsive drug seeking, we outline the neurobiology of the stress component of the stage and relate it to a derivative of the Research Domain Criteria research construct for the study of psychiatric disease, known as the Addictions Neuroclinical Assessment. Using the Addictions Neuroclinical Assessment, we outline five subdomains of negative emotional states that can be operationally measured in human laboratory settings and paralleled by animal models.

Addictions Neuroclinical Assessment: A reverse translational approach.

Incentive salience, negative emotionality, and executive function are functional domains that are etiologic in the initiation and progression of addictive disorders, having been implicated in humans with addictive disorders and in animal models of addictions. Measures of these three neuroscience-based functional domains can capture much of the effects of inheritance and early exposures that lead to trait vulnerability shared across different addictive disorders. For specific addictive disorders, these measures can be supplemented by agent specific measures such as those that access pharmacodynamic and pharmacokinetic variation attributable to agent-specific gatekeeper molecules including receptors and drug-metabolizing enzymes.

FAAH Gene Variation Moderates Stress Response and Symptom Severity in Patients with Posttraumatic Stress Disorder and Comorbid Alcohol Dependence.

Background: A common single nucleotide polymorphism (C385A) in the human fatty acid amide hydrolase (FAAH) gene has been associated with decreased distress responses in healthy volunteers, but its role in psychiatric disorders remains unknown. Here, we obtained genotypes and carried out a secondary analysis of subjects from a trial of comorbid posttraumatic stress disorder (PTSD) and alcohol dependence (AD). We evaluated the effects of C385A variation on behavioral and biochemical biomarkers of distress responses.

Characterization of comorbid PTSD in treatment-seeking alcohol dependent inpatients: Severity and personality trait differences.

Background: Post-traumatic stress disorder (PTSD) is often comorbid with alcohol dependence (AD), but little is known about the characteristics of AD treatment-seeking inpatients with PTSD. We examined differences between treatment-seeking alcohol dependent inpatients with and without comorbid PTSD. We hypothesized that those with AD and PTSD would have higher levels of: (1) alcohol use and AD severity; (2) anxiety and mood disorders; (3) neuroticism.

The CRF1 Antagonist Verucerfont in Anxious Alcohol-Dependent Women: Translation of Neuroendocrine, But not of Anti-Craving Effects.

Blockade of corticotropin-releasing factor receptor 1 (CRF1) suppresses stress-induced alcohol seeking in rodents, but clinical translation remains. Here, we first showed that the CRF1 antagonist verucerfont potently blocks hypothalamic-pituitary adrenal (HPA) axis activation in adrenalectomized rats. We then evaluated verucerfont for its ability to block HPA axis activation and reduce stress-induced alcohol craving in alcohol-dependent patients.

Addictions Neuroclinical Assessment: A Neuroscience-Based Framework for Addictive Disorders.

This article proposes a heuristic framework for the Addictions Neuroclinical Assessment that incorporates key functional domains derived from the neurocircuitry of addiction. We review how addictive disorders (ADs) are presently diagnosed and the need for new neuroclinical measures to differentiate patients who meet clinical criteria for addiction to the same agent while differing in etiology, prognosis, and treatment response. The need for a better understanding of the mechanisms provoking and maintaining addiction, as evidenced by the limitations of current treatments and within-diagnosis clinical heterogeneity, is articulated.

The corticotropin releasing hormone-1 (CRH1) receptor antagonist pexacerfont in alcohol dependence: a randomized controlled experimental medicine study.

Extensive preclinical data implicate corticotropin-releasing hormone (CRH), acting through its CRH1 receptor, in stress- and dependence-induced alcohol seeking. We evaluated pexacerfont, an orally available, brain penetrant CRH1 antagonist for its ability to suppress stress-induced alcohol craving and brain responses in treatment seeking alcohol-dependent patients in early abstinence. Fifty-four anxious alcohol-dependent participants were admitted to an inpatient unit at the NIH Clinical Center, completed withdrawal treatment, and were enrolled in a double-blind, randomized, placebo-controlled study with pexacerfont (300 mg/day for 7 days, followed by 100 mg/day for 23 days).

The neurokinin-1 receptor antagonist aprepitant in co-morbid alcohol dependence and posttraumatic stress disorder: a human experimental study.

Rationale: Posttraumatic stress disorder (PTSD) and alcoholism are frequently comorbid, suggesting the possibility of overlapping neural substrates. The neurokinin 1 (NK1) receptor for substance P (SP) has been implicated in both stress- and alcohol-related behaviors. The NK1 antagonist aprepitant, clinically available as a treatment for chemotherapy-induced nausea, offers a tool to probe a potential role of the SP/NK1 system in comorbid PTSD and alcoholism.

Methods for inducing alcohol craving in individuals with co-morbid alcohol dependence and posttraumatic stress disorder: behavioral and physiological outcomes.

Alcohol addiction is a chronic relapsing disorder that presents a substantial public health problem, and is frequently co-morbid with posttraumatic stress disorder (PTSD). Craving for alcohol is a predictor of relapse to alcohol use, and is triggered by cues associated with alcohol and trauma. Identification of reliable and valid laboratory methods for craving induction is an important objective for alcoholism and PTSD research.

Major depressive disorder in persons exposed to trauma: relationship between emotional intelligence and social support.

Background: Traumatic events are often linked to the onset of major depressive disorder (MDD) and for the increase of nonremittance of symptoms; however, psychological factors that contribute to the relationship between trauma and chronic depression are not well defined.

Objective: The objective of this study is to determine if emotional intelligence (EI) and social support differ in traumatized depressed patients when compared with controls.

Method: The present study examines two psychosocial factors that may contribute to this link: EI and social support.

Traumatic brain injury in intimate partner violence: a critical review of outcomes and mechanisms.

The prevalence of intimate partner violence (IPV) is striking, as are its consequences to the lives of women. The IPV often includes physical assault, which can include injuries to the head and attempted strangulation injuries. Both types of injuries can result in traumatic brain injury (TBI).

Childhood sexual abuse and attachment: An intergenerational perspective.

Childhood sexual abuse (CSA) is a recognized risk factor for various negative outcomes in adult survivors and their offspring. We used the Dynamic-Maturational Model of attachment theory as a framework for exploring the impact of maternal CSA on children's attachment relationships in the context of a longitudinal sample of adult survivors of CSA and non-abused comparison mothers and their children. Results indicated that children of CSA survivors were more likely to have extreme strategies of attachment than the children of non-abused mothers.