Factors underlying the neurofunctional domains of the Addictions Neuroclinical Assessment assessed by a standardized neurocognitive battery.

The Addictions Neuroclinical Assessment (ANA) is a neurobiologically-informed framework designed to understand the etiology and heterogeneity of Alcohol Use Disorder (AUD). Previous studies validated the three neurofunctional domains of ANA: Incentive Salience (IS), Negative Emotionality (NE) and Executive Function (EF) using secondary data. The present cross-sectional observational study assessed these domains in an independent, prospective clinical sample. Adults across the drinking spectrum (N = 300) completed the ANA battery, a standardized collection of behavioral tasks and self-report assessments. Factor analyses were used to identify latent factors underlying each domain. Associations between identified domain factors were evaluated using structural equation models. Receiver operating characteristics analyses were used to determine factors with the strongest ability to classify individuals with problematic drinking and AUD. We found (1) two factors underlie the IS domain: alcohol motivation and alcohol insensitivity. (2) Three factors were identified for the NE domain: internalizing, externalizing, and psychological strength. (3) Five factors were found for the EF domain: inhibitory control, working memory, rumination, interoception, and impulsivity. (4) These ten factors showed varying degrees of cross-correlations, with alcohol motivation, internalizing, and impulsivity exhibiting the strongest correlations. (5) Alcohol motivation, alcohol insensitivity, and impulsivity showed the greatest ability in classifying individuals with problematic drinking and AUD. Thus, the present study identified unique factors underlying each ANA domain assessed using a standardized assessment battery. These results revealed additional dimensionality to the ANA domains, bringing together different constructs from the field into a single cohesive framework and advancing the field of addiction phenotyping. Future work will focus on identifying neurobiological correlates and identifying AUD subtypes based on these factors.

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. METHODS: Participants were treated for withdrawal, if needed, and then randomized to pioglitazone (target dose 45 mg/day) or placebo. Once at target dose, they completed two experimental manipulations: guided imagery, which used personalized auditory scripts to induce alcohol cravings, and a low-dose challenge with i.v. lipopolysaccharide (LPS; 0.8 ng/kg) or placebo, on two separate sessions, in counterbalanced order. Behavioral and endocrine responses as well as CSF levels of proinflammatory cytokines were evaluated. RESULTS: The study was prematurely terminated after randomization of 16 subjects, following an independent review that established a high risk of myopathy in the active treatment group. Analysis of those who completed the study indicated that pioglitazone was associated with elevated, rather than suppressed alcohol cravings in response to alcohol-associated stimuli. LPS did not induce cravings for alcohol and thus did not lend itself to evaluating pioglitazone effects; however, pioglitazone increased the neuroendocrine stress response to LPS. CSF levels of IL-6, TNF-α, or MCP-1 were unaffected by pioglitazone treatment. CONCLUSIONS: Both safety and efficacy biomarker data suggest that pioglitazone lacks potential as a medication for the treatment of alcohol dependence. CLINICAL TRIAL REGISTRATION: NCT01631630.

History of suicidality and alcohol craving trajectories during inpatient treatment for alcohol use disorder.

BACKGROUND: Alcohol use is associated with an increased risk of completed suicide, but it is unclear whether past suicidality affects the course of alcohol use disorder (AUD). We examined whether a history of suicidal ideation or attempts is associated with treatment response in individuals with AUD. METHODS: 146 participants underwent inpatient detoxification and residential treatment for AUD. Reductions in craving during treatment were used as an index of treatment response. Participants were assessed for history of suicidality using the Columbia-Suicide Severity Rating Scale and divided into three groups: no history of suicidal ideation or attempts (N = 76), history of suicidal ideation without attempts (N = 50), and history of suicide attempts (N = 20). Alcohol craving was measured weekly during treatment using the Penn Alcohol Craving Scale and compared across groups. RESULTS: Individuals with a history of suicide attempts showed higher levels of craving throughout treatment compared to those without a history of suicidality. Associations between past suicide attempts and craving remained significant after adjusting for age, sex, alcohol use disorder severity, comorbid psychopathology, and benzodiazepine treatment. Participants in all groups had significant reductions in alcohol craving by the end of treatment. CONCLUSIONS: Our findings suggest that a history of suicide attempts is associated with higher levels of craving throughout inpatient treatment for AUD. These results support current guidelines on assessing suicidal ideation in patients with substance use disorders.

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. RESULTS: The results showed significant support for both three- and four-factor models to explain biobehavioral variation in this sample of participants with alcohol use disorder and control subjects, but the three-factor model had the best fit indices. With some nuances, including cross-correlation (lack of independence) between the three factors, the factors corresponded to incentive salience, negative emotionality, and executive function (executive control). The MIMIC model revealed that both exposure to early-life stress and sociodemographic variables predicted these factors. CONCLUSIONS: These findings suggest that three correlated neurofunctional domains are relevant for alcohol use disorder. More work is required to validate and standardize measures of neurofunctional domains in alcohol use disorder, to extend these findings to other addictive disorders, and to relate variations in them to predisposition, clinical course, treatment response, neuroimaging data, and other psychophysical indicators.

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. Examining factors that determine vulnerability as well as resilience to stress are of particular interest in the study of AUD because, in addition to increasing our understanding of the risk factors for AUD, such knowledge can be used to develop more effective treatments. Dr. Stangl presented a novel human experimental model that demonstrates, for the first time, stress-induced increases in alcohol self-administration in binge drinkers using a guided imagery paradigm combined with intravenous alcohol self-administration (IV-ASA). Dr. Blaine presented data demonstrating that glucocorticoid response to stress drives compulsive alcohol motivation and intake in binge/heavy drinkers. Dr. Plawecki presented data examining sex differences in the effect of two distinct stress paradigms - mood induction and abstinence - on IV-ASA in moderate drinkers. Dr. Schwandt presented clinical data providing a new perspective on the relationship between childhood trauma and AUD by suggesting possible underlying mechanisms that confer resilience, rather than vulnerability, to severe early life stress exposure.

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. These biomarkers, derived from both an understanding of the neurobiology of addiction and behavioral phenotypes, represent a departure from traditional markers of alcohol-relevant biomarkers, such as tests of liver function (LFTs). We posit that a potential addiction-relevant biomarker is reinforcer pathology, found to be relevant across addictions to different substances, and which may offer a target for modification through the use of episodic future thinking.

Neuroclinical Framework for the Role of Stress in Addiction.

Addiction has been conceptualized as a three-stage cycle-binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation-that worsens over time and involves allostatic changes in hedonic function via changes in the brain reward and stress systems. Using the withdrawal/negative affect stage and negative reinforcement as an important source of motivation for compulsive drug seeking, we outline the neurobiology of the stress component of the withdrawal/negative affect 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. We hypothesize that a focus on negative emotionality and stress is closely related to the acute neurobiological alterations that are experienced in addiction and may serve as a bridge to a reformulation of the addiction nosology to better capture individual differences in patients for whom the withdrawal/negative affect stage drives compulsive drug taking.

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. Herein, we focus on the translation and reverse translation of knowledge derived from animal models of addiction to the human condition via measures of neurobiological processes that are orthologous in animals and humans, and that are shared in addictions to different agents. Based on preclinical data and human studies, measures of these domains in a general framework of an Addictions Neuroclinical Assessment (ANA) can transform the assessment and nosology of addictive disorders, and can be informative for staging disease progression. We consider next steps and challenges for implementation of ANA in clinical care and research. This article is part of the Special Issue entitled "Alcoholism".

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. METHODS: Forty-nine patients with PTSD and AD were admitted for 4 weeks to an experimental medicine unit at the National Institutes of Health Clinical Center. Following detoxification, stress reactivity and peripheral endocannabinoid (eCB) levels were assessed in response to a challenge session using personalized auditory guided imagery. Over the course of the study, subjects were also evaluated for changes in PTSD symptom severity. RESULTS: FAAH C385A allele carriers showed a marked increase in serum anandamide levels at baseline and throughout the stress challenge procedure compared with C allele homozygotes, while levels of eCBs primarily metabolized through other enzymatic activity, such as 2-arachidonoylglycerol, did not differ between genotype groups. FAAH C385A carriers also had decreased subjective anxiety responses to the stress challenge. Similar effects of FAAH C385A genotype were found at the level of clinical PTSD symptom severity, in particular in the arousal domain. CONCLUSIONS: This is to our knowledge the first study showing that FAAH C385A variation modulates stress responses in subjects with disorders characterized by increased stress reactivity. These findings point to the eCB pathway as a promising target for future antistress therapeutics.

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. METHODS: Individuals (N=411, mean age=41.7±10.0years) with AD were monitored over 30days in a suburban inpatient alcohol treatment setting. Patients were evaluated to identify AD and comorbid PTSD, mood and anxiety disorders, alcohol use and dependence severity, personality, and aggression. RESULTS: Those with PTSD (19% of the sample) did not differ in the amount of alcohol consumed, but had greater: (1) severity of AD (p=0.001, d=0.44); (2) diagnosis of anxiety (p=0.000, OR=3.64) and mood (p=0.000, OR=4.83) disorders; and (3) levels of neuroticism (p<0.001, d=0.67) and aggression (p<0.001, d=0.81). CONCLUSIONS: AD patients with comorbid PTSD present a more severe phenotype across AD severity, frequency of anxiety and mood disorders, and levels of neuroticism and aggression. This group may benefit from concurrent treatment of both AD and PTSD. Future research can investigate neuroticism as a potential treatment target.

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. Anxious, alcohol-dependent women (age 21-65 years, n=39) were admitted to the NIH Clinical Center and completed withdrawal treatment before enrollment if needed. One-week single-blind placebo was followed by randomized double-blind verucerfont (350 mg per day) or placebo for 3 weeks. Verucerfont effects on the HPA axis were evaluated using the dexamethasone-CRF test. Craving was evaluated using two established protocols, one that combines a social stressor with physical alcohol cue exposure, and one that uses guided imagery to present personalized stress, alcohol, or neutral stimuli. An fMRI session examined brain responses to negative affective stimuli and alcohol cues. In contrast to our recent observations with another CRF1 antagonist, pexacerfont, verucerfont potently blocked the HPA axis response to the dexamethasone-CRF test, but left alcohol craving unaffected. Right amygdala responses to negative affective stimuli were significantly attenuated by verucerfont, but responses to alcohol-associated stimuli were increased in some brain regions, including left insula. Discontinuation rates were significantly higher in the verucerfont group. Our findings provide the first translational evidence that CRF1 antagonists with slow receptor dissociation kinetics may have increased efficacy to dampen HPA axis responses. The findings do not support a clinical efficacy of CRF1 blockade in stress-induced alcohol craving and relapse.

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. In addition, recent changes in the nosology of ADs, challenges to current classification systems, and prior attempts to subtype individuals with ADs are described. Complementary initiatives, including the Research Domain Criteria project, that have established frameworks for the neuroscience of psychiatric disorders are discussed. Three domains-executive function, incentive salience, and negative emotionality-tied to different phases in the cycle of addiction form the core functional elements of ADs. Measurement of these domains in epidemiologic, genetic, clinical, and treatment studies will provide the underpinnings for an understanding of cross-population and temporal variation in addictions, shared mechanisms in addictive disorders, impact of changing environmental influences, and gene identification. Finally, we show that it is practical to implement such a deep neuroclinical assessment using a combination of neuroimaging and performance measures. Neuroclinical assessment is key to reconceptualizing the nosology of ADs on the basis of process and etiology, an advance that can lead to improved prevention and treatment.

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). After reaching steady state, participants were assessed for alcohol craving in response to stressful or alcohol-related cues, neuroendocrine responses to these stimuli, and functional magnetic resonance imaging (fMRI) responses to alcohol-related stimuli or stimuli with positive or negative emotional valence. A separate group of 10 patients received open-label pexacerfont following the same dosing regimen and had cerebrospinal fluid sampled to estimate central nervous system exposure. Pexacerfont treatment had no effect on alcohol craving, emotional responses, or anxiety. There was no effect of pexacerfont on neural responses to alcohol-related or affective stimuli. These results were obtained despite drug levels in cerebrospinal fluid (CSF) that predict close to 90% central CRH1 receptor occupancy. CRH1 antagonists have been grouped based on their receptor dissociation kinetics, with pexacerfont falling in a category characterized by fast dissociation. Our results may indicate that antagonists with slow offset are required for therapeutic efficacy. Alternatively, the extensive preclinical data on CRH1 antagonism as a mechanism to suppress alcohol seeking may not translate to humans.

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. The present study compares two methods for induction of craving via stress and alcohol cues in individuals with co-morbid alcohol dependence (AD) and PTSD: the combined Trier social stress test and cue reactivity paradigm (Trier/CR), and a guided imagery (Scripts) paradigm. Outcomes include self-reported measures of craving, stress and anxiety as well as endocrine measures. Subjects were 52 individuals diagnosed with co-morbid AD and PTSD seeking treatment at the National Institute on Alcohol Abuse and Alcoholism inpatient research facility. They participated in a 4-week inpatient study of the efficacy of a neurokinin 1 antagonist to treat co-morbid AD and PTSD, and which included the two challenge procedures. Both the Trier/CR and Scripts induced craving for alcohol, as well as elevated levels of subjective distress and anxiety. The Trier/CR yielded significant increases in adrenocorticotropic hormone and cortisol, while the Scripts did not. Both paradigms are effective laboratory means of inducing craving for alcohol. Further research is warranted to better understand the mechanisms behind craving induced by stress versus alcohol cues, as well as to understand the impact of co-morbid PTSD and AD on craving.

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. OBJECTIVES: The aim of this study is to evaluate the efficacy of aprepitant for treatment of comorbid PTSD and alcoholism. METHODS: Fifty-three patients with PTSD and alcoholism were admitted for 4 weeks to an inpatient unit at the NIH Clinical Center and randomized to double-blind aprepitant (125 mg/day; based on PET studies reporting >90 % central receptor occupancy at this dose) or placebo. After reaching steady state, subjects were assessed for PTSD symptom severity, behavioral and neuroendocrine responses to stress and alcohol cues, and functional magnetic resonance imaging (fMRI) responses to stimuli with positive or negative emotional valence. RESULTS: Aprepitant treatment had no effect on PTSD symptoms or subjective or physiological responses to stress or alcohol cues. However, aprepitant robustly potentiated ventromedial prefrontal cortex (mPFC) fMRI responses to aversive visual stimuli. CONCLUSIONS: Despite the lack of effect on PTSD symptoms and responses to stress/alcohol cues, NK1 antagonism activated the ventral mPFC, an area considered hypoactive in PTSD, during exposure to aversive stimuli. Because this brain area is critically important for extinction of fear memories and in alcohol craving and relapse, our finding suggests that NK1 antagonism might be a useful pharmacological treatment to enhance extinction-based cue-exposure therapies.

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. Participants who experienced a trauma and had current MDD (n=38) were compared with nontraumatized healthy controls ( n=40). RESULTS: Traumatized depressed participants exhibited lower total EI, because of reductions in strategic EI ability, as well as lower levels of social support compared with the control group. CONCLUSIONS: EI and social support were significantly correlated. These findings suggest that EI may be a novel target for intervention to prevent and treat MDD.

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). The TBI sustained during IPV often occurs over time, which can increase the risk for health declines and postconcussive syndrome (PCS). Current studies have identified sequelae of cognitive dysfunction, posttraumatic stress disorder, and depression in women experiencing IPV, yet, most fail to determine the role of TBI in the onset and propagation of these disorders. Although imaging studies indicate functional differences in neuronal activation in IPV, they also have not considered the possibility of TBI contributing to these outcomes. This review highlights the significant gaps in current findings related to neuropsychological complications and medical and psychosocial symptoms that likely result in greater morbidity, as well as the societal costs of failing to acknowledge the association of IPV and TBI in women.

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. However, because both groups were at socioeconomic risk, both were typified by anxious attachment. Explanations for findings and implications for children's development are explored.