Dennis S. Charney

Noradrenergic neuronal dysregulation in panic disorder: the effects of intravenous yohimbine and clonidine in panic disorder patients

In order to evaluate possible abnormal noradrenergic neuronal functional regulation in patients with panic disorder, the behavioral, biochemical and cardiovascular effects of intravenous yohimbine (0.4 mg/kg) and clonidine (2 μg/kg) were determined in 15 healthy subjects and 38 patients with panic disorder. A subgroup of 24 panic disorder patients were observed to experience yohimbine‐induced panic attacks and had larger yohimbine‐induced increases in plasma 3‐methoxy‐4‐hydroxyphenylglycol (MHPG) than healthy subjects and other panic disorder patients. A blunted growth hormone response to clonidine and a significant clonidine‐induced decrease in plasma MHPG was also observed in this subgroup of panic disorder patients. These data replicate and extend previous investigations, which are consistent with a large body of preclinical and human data relating increased noradrenergic neuronal function to human anxiety and fear states.

Neurobiology of Post-Traumatic Stress Disorder

In the general population, post-traumatic stress disorder (PTSD) has a 1% lifetime prevalence (Heizer et al., 1987). Estimates among war veterans are much higher, with 15% of Vietnam veterans currently meeting criteria for PTSD and 30% meeting lifetime criteria. Since their tour in Vietnam, another 20% of veterans have suffered from partial PTSD, having at least some symptoms disruptive of normal social functioning (Kulka et al., 1990).

Effects of tryptophan depletion in panic disorder

Tryptophan (TRP) depletion is a useful paradigm for evaluating serotonin (5-HT) function in psychiatric disease. Primate studies have shown that plasma TRP depletion can be induced by the ingestion of an amino acid (AA) mixture lacking TRIP (Young et al ! 989). In this report the AA mixture without TRP reduced cerebrospinal fluid (CSF) TRP by 61% relative to a control AA mixture, which effect was associated with a 34% reduction in 5-hydroxyindole, acetic acid. Oral administration of this AA mixture following a Iow-TRP diet is known to reduce plasma TRP levels in healthy humans by over 80% of baseline levels (Zimmerman et a l i 993). In other clinical studies we have found that TRP depletion by this method produces a transient exacerbation of depressive symptoms in antidepressant-remitted depressed (Delgado et al 1990) and obsessive-compulsive patients (Barr et al 1994); however, to date there have been no studies utilizing TRP depletion in panic disorder (PD) patients. The norepinephrine (NE) and 5-HT systems have been implicated in the pathophysiology of PD (Kahn et al ! 988a, Charney et al 1992). Furthermore, the 5-HT system may provide inhibitory inputs to the principal NE nucleus, the locus coeruleus (AstonJones et ai ! 99 I). If TRP depletion sufficiently reduced presynaptic 5-HT inhibition of NE function in PD patients, this could lead to a transient increase in NE function with accompanying increases in anxiety, blood pressure, and the NE metabolite 3-methoxy-4hydroxyphenylglycol (MHPG).

Effects of tryptophan depletion on responses to yohimbine in healthy human subjects

There is considerable evidence that both the norepinephrine (NE) and serotonin (5-HT) systems are involved in the regulation of human anxiety and fear responses. To assess the modulating effects of central 5-HT levels on NE function, 11 healthy human subjects were studied with placebo-controlled challenge tests involving tryptophan depletion followed by administration of the alpha-2-adrenergic antagonist yohimbine 0.4 mg/kg IV. Five of the 11 subjects reported a marked increase in feelings of nervousness (> or = 25 mm on a 100 mm analog scale) following the combination test, while 1/11 had this response to yohimbine alone. No subjects had an increase in nervousness during other control tests. The increase in nervousness after the tryptophan depletion-yohimbine test was statistically significant for the whole group, but there were no other unique changes in behavioral, physiologic or biochemical (MHPG, cortisol) variables with this test. These data are discussed in terms of possible functional interactions between the 5-HT and NE neurotransmitter systems.

Effects of the serotonin reuptake inhibitor fluvoxamine on yohimbine-induced anxiety in panic disorder

To assess the effects of the selective serotonin reuptake blocker fluvoxamine on noradrenergic function in patients with panic disorder, an intravenous yohimbine challenge test was administered to eight patients with panic disorder before and after 8 weeks of fluvoxamine treatment and to a parallel group of eight patients treated with placebo. Fluvoxamine treatment reduced yohimbine-induced anxiety while placebo treatment had no effect on this variable. Both fluvoxamine and placebo treatment had little effect on biochemical or physiologic responses to yohimbine.

Personality factors in resilience to traumatic stress

Introduction The study of individual differences in resilience to traumatic stress has received unprecedented attention in recent years from investigators in the field of post-traumatic stress disorder (PTSD) but there remains a lack of consensus regarding the definition, measurement, and conceptualization of the construct. Trait personality psychologists have grappled with similar issues since the seminal work of Jack Block (1961) on the construct of ego resilience over 50 years ago. In the process, they have developed comprehensive models of personality and psychometrically sophisticated tools for the measurement of its traits that can potentially inform and advance the study of resilience. The primary purpose of this chapter is to review the literature on personality factors involved in resilience to traumatic stress and to outline a model for conceptualizing this interface. Contemporary models of personality aim to identify the structure and basis for behavioral traits – defined as individual differences in patterns of thoughts, feelings, and actions that are consistent across developmental periods and environmental contexts. Personality models differ considerably with regard to the factor structure, number, and definition of specific traits. Because of this, research on personality traits that confer risk or resilience to the development of post-traumatic psychopathology has yielded a complicated collection of studies examining disparate constructs and measures. To provide coherence and organization to this literature, this chapter will focus on three broadband personality dimensions described by Tellegen (1985, 2000) that are also represented with subtle definitional variations in most other contemporary trait models of personality. For this reason, they are known as the “big three” personality factors: positive emotionality/extraversion (PEM), negative emotionality/neuroticism (NEM), and constraint/impulsivity (CON).

Initial Clinical Evidence of Genetic Contributions to Posttraumatic Stress Disorder

There are few topics in the field of traumatic stress studies that clinicians approach more ambivalently than considerations of genetic factors associated with vulnerability or resistance to traumatization. Historically, individuals suffering from combat-related posttraumatic stress disorder (PTSD) received diagnoses including “soldier’s heart” or “neurocirculatory asthenia,” and were frequently viewed as possessing characteristics that cast them in a disparaging light, such as “constitutional inferiority” and “lack of virility” (Campbell, 1918; see Krystal et al., 1989). Early studies implicated race as an important factor influencing the vulnerability to psychological stress (cf. Dunn, 1942). However, these studies attempted to use flawed clinical data to support widely held societal prejudices against minority groups, similar to early misguided efforts to characterize the inheritance of intelligence (Gould, 1981). Similarly, German authorities abused genetic arguments to justify denying the claims of Jewish survivors of the Nazi concentration camps for reparation for long-term psychiatric sequelae of their traumatization (Eisler, 1963/1964, 1967; Kestenberg, 1980). The relatively greater progress made in characterizing the environmental factors that influence subsequent stress response, such as the importance of early childhood trauma (Herman, 1992; Krystal, 1988) and the impact of parental traumatization on parent—child relationships (Danieli, 1980; Oliver, 1993; Rosenheck, 1986), further compounds concerns about overestimating genetic factors associated with PTSD.

Textbook of Disaster Psychiatry: Neurobiology of disaster exposure: fear, anxiety, trauma, and resilience

This chapter reviews the findings of human and animal studies which have characterized normal function in the sympathetic nervous system (SNS) and the hypothalamic-pituitary-adrenal (HPA) axis, and then briefly describes post-traumatic stress disorder (PTSD)-associated abnormalities seen in each system. Neurobiological models of the structure, function and neurochemistry of the brain have evolved significantly as a result of recent input from findings of neuroimaging studies. In recent years several neurochemicals have been associated with resilience. In humans, neuroimaging studies of PTSD have primarily focused on the amygdala, the hippocampus, medial prefrontal cortex, and anterior cingulate cortex. Multidisciplinary studies that use neurochemical, neuroimaging, genetic, and psychosocial approaches may in the future clarify the complex relationships between genotype, phenotype, and psychobiological responses to stress. Pharmacological intervention aimed at treating early severe symptoms which are known to be predictive of later PTSD, such as excessive arousal, is one possible avenue of study.

CHAPTER 9:Neurocircuitry of Anxiety Disorders: Focus on Panic Disorder and Post-traumatic Stress Disorder

This chapter will provide an overview of the epidemiology, clinical features and neurocircuitry of anxiety disorders with a focus on panic disorder and post-traumatic stress disorder (PTSD). Anxiety disorders are among the most common and disabling psychiatric illnesses. Ongoing basic, clinical and translational research aimed at understanding the neurobiology underlying the disorders is shedding new light on mechanisms of disease and opening up potential new avenues for much needed therapeutic discovery. Neurocircuitry models of fear learning in animals will be described in order to provide a translational basis of human neuroimaging and therapeutic studies in anxiety disorders. Findings from human pharmacological challenge studies and other clinical studies in panic disorder and PTSD will also be reviewed. Finally, the chapter concludes with a discussion of potential novel therapeutic strategies for anxiety disorders based on the findings from preclinical and clinical studies presented.

Resilience and Mental Health: Contributors

Preface Part I. Pathways to Resilience: 1. Neurobiology of resilience Adriana Feder and Kate Collins 2. Resilience in the face of stress: emotion regulation as a protective factor Allison S. Troy and Iris Mauss 3. Cognitive factors and resilience: how self-efficacy contributes to coping with adversities Charles C. Benight and Roman Cieslak 4. Personality factors in resilience to traumatic stress Mark Miller and Kelly M. Harrington 5. Social ties and resilience in chronic disease Denise Janicki-Deverts and Sheldon Cohen 6. Religious and spiritual factors in resilience Dave W. Foy, Kent D. Drescher and Patricia J. Watson Part II. Resilience Across the Lifespan: 7. Resilience in children and adolescents Ann S. Masten, Amy R. Monn and Laura M. Supkoff 8. Toward a lifespan approach to resilience and potential trauma George A. Bonanno and Anthony D. Mancini 9. Resilience in older adults Diane L. Elmore, Lisa M. Brown and Joan M. Cook Part III. Resilience in Families, Communities, and Societies: 10. Family resilience: a collaborate approach in response to stressful life challenges Froma Walsh 11. Community resilience: concepts, assessment, and implications for intervention Fran H. Norris, Kathleen Sherrieb and Betty Pfefferbaum 12. Trauma, culture and resiliency Carl C. Bell Part IV. Specific Challenges: 13. Loss and grief: the role of individual differences Anthony D. Mancini and George Bonanno 14. Reorienting resilience: adapting resilience for post-disaster research Jennifer Johnson and Sandro Galea 15. Rape and other sexual assault Heidi S. Resnick, Constance Guille, Jenna L. McCauley and Dean G. Kilpatrick 16. The stress continuum model: a military organizational approach to resilience and recovery William P. Nash, Maria Steenkamp, Lauren Conoscenti and Brett Litz 17. Resilience in the face of terrorism: linking resource investment with engagement Stevan E. Hobfoll, Brian Hall, Katie J. Horsey and Brittain E. Lamoureux 18. Resilience in the context of poverty John C. Buckner and Jessica S. Waters 19. Resiliency in persons with serious mental illness Piper S. Meyer and Kim T. Mueser Part V. Training for Resilience 20. Interventions to enhance resilience and resilience-related constructs in adults Steven M. Southwick, Robert H. Pietrzak and Jerry White 21. Childhood resilience: adaptation, mastery and attachment Angie Torres, Steven Southwick and Linda C. Mayes 22. Military mental health training: building resilience Carl Andrew Castro and Amy B. Adler 23. Public health practice and disaster resilience: a framework integrating resilience as a worker protection strategy Dori B. Reissman, Kathleen M. Kowalski-Trakofler and Craig L. Katz Index.