Laura E. Kwako

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.

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.

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.

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 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.

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.

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.

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.

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.

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.