Clinical improvement with fluoxetine therapy and noradrenergic function in patients with panic disorder.

BACKGROUND: Central noradrenergic (NA) dysregulation has provided a major theoretical framework for understanding the pathogenesis of panic disorder (PD). Using clonidine, an alpha 2-adrenergic receptor agonist, as a probe of NA function, we investigated the hypothesis that the antipanic efficacy of the selective serotonin reuptake inhibitors may be associated with normalization of a putatively dysregulated NA system. METHODS: We report further analyses on data from 17 subjects with PD and 16 healthy volunteers who underwent measurement of the plasma NA metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) immediately before and after oral clonidine administration. Thirteen patients with PD were rechallenged after 12 weeks during open fluoxetine hydrochloride treatment using the same clonidine paradigm; 13 healthy volunteers were rechallenged at 12 weeks, not having received treatment between challenges. RESULTS: Patients with PD, compared with healthy volunteers, have markedly elevated plasma MHPG volatility during the first clonidine challenge. Volatility describes the magnitude of within-subject plasma MHPG oscillatory activity as assessed by the root of the mean square successive difference. A greater degree of clinical global improvement was predicted by a greater magnitude of basal MHPG reduction with fluoxetine treatment. Antipanic response to fluoxetine was accompanied by a significant decrease of MHPG volatility to volunteer levels. Volunteer MHPG volatility remained unchanged from the first to second clonidine challenge. CONCLUSIONS: Further evidence is provided for the hypothesis of NA dysregulation in PD as reflected by elevations of within-subjects plasma MHPG volatility during clonidine challenge. Effective selective serotonin reuptake inhibitor-antipanic treatment in this clinical sample was paralleled by normalization of dysregulated NA function.

Neuroendocrine response to fenfluramine challenge in boys. Associations with aggressive behavior and adverse rearing.

BACKGROUND: There is evidence of relationships among serotonin, aggressive behavior, and a childhood history of socially adverse-rearing conditions. This study examines the prolactin response to fenfluramine hydrochloride challenge in young boys who show clinically significant aggressive behavior or who are raised in a social environment that is conducive to the development of chronic aggression. METHODS: A series of 34 younger brothers of convicted delinquents underwent standardized psychiatric and observation-based assessments of their social-rearing environments that were conducted during home visits. Approximately 2 years later, these boys underwent a reassessment of psychiatric status and an assessment of central serotonergic activity using the fenfluramine challenge procedure. RESULTS: Increasing degrees of aggressive behavior at either assessment were positively correlated with the prolactin response to fenfluramine challenge. Furthermore, adverse-rearing circumstances that were conducive to the development of aggressive behavior also exhibited positive correlations with the prolactin response. This association between adverse rearing and the prolactin response was statistically independent of that between aggression and the prolactin response. CONCLUSION: In young boys, aggressive behavior and social circumstances that are conducive to the development of aggressive behavior are positively correlated with a marker of central serotonergic activity.

Plasma cortisol concentrations preceding lactate-induced panic. Psychological, biochemical, and physiological correlates.

BACKGROUND: We evaluated the role of plasma cortisol levels in determining sodium lactate-induced panic by reporting psychological, physiological, and biochemical data collected from an extended sample of 214 subjects during the "placebo" infusion (isotonic saline solution) immediately preceding the lactate infusion procedure. METHODS: One hundred seventy patients with panic disorder, 101 (59%) of whom were assessed to have panicked (P group), and 69 (41%) who were assessed not to have panicked (NP group) with lactate infusion; and 44 normal healthy volunteer controls (1 of whom panicked with lactate infusion) were studied. RESULTS: Before the lactate infusion, the P group exhibited hypothalamic-pituitary-adrenal (HPA) axis activation (high plasma cortisol levels) and evidence of hyperventilation (low PCO2 levels) in comparison with NP and control groups. Self-reported fear, dyspnea, and diastolic blood pressure were highest in the P group, intermediate in the NP group, and lowest in the control group. Within the P group, baseline fear scores correlated inversely with PCO2 levels and positively with cortisol levels while PCO2 levels correlated negatively with cortisol levels. Significant predictors of lactate-induced panic were prelactate infusion fear and the interaction of high cortisol levels and low PCO2 levels. CONCLUSION: Combined data suggest that synchronized elevations of HPA axis activity, self-reported fear, and hyperventilation during the period before lactate infusion predisposes to lactate-induced panic.

Cerebrospinal fluid concentrations of somatostatin and biogenic amines in grown primates reared by mothers exposed to manipulated foraging conditions.

BACKGROUND: In an earlier study, infant primates were nursed by mothers randomly assigned to variable foraging demand (VFD) or nonvariable foraging conditions (non-VFD). A group of grown VFD-reared subjects demonstrated elevations of cisternal cerebrospinal fluid (CSF) corticotropin-releasing factor concentrations and decreased CSF cortisol levels vs non-VFD counterparts. To further characterize neurobiological sequelae of disturbed early rearing, CSF concentrations of serotonin, dopamine, and norepinephrine metabolites (5-hydroxyindoleacetic acid, homovanillic acid, and 3-methoxy-4-hydroxyphenethyleneglycol [MHPG], respectively) and of somatostatin were determined. METHODS: Second CSF taps were obtained from the previously studied cohort of 30 subjects and from 28 age-matched ad libitum-reared control subjects. Relevant assays were performed. RESULTS: All neurochemicals assayed except MHPG were elevated in the VFD-reared compared with non-VFD subjects. In the VFD group, statistically significant positive correlations between corticotropin-releasing factor and each neurochemical was found, except for MHPG. In the non-VFD subjects, no significant correlations with corticotropin-releasing factor were observed. No effect of age was evident. CONCLUSIONS: Reducing the predictability of maternal foraging demand during early rearing was associated with elevations of cisternal somatostatin and of serotonin and dopamine metabolite concentrations in grown offspring. The corticotropin-releasing factor elevations reported previously were positively correlated with all the elevated CSF parameters of the current study. The findings support the notion that adverse early rearing experiences in primates have longstanding and complex effects on a range of neurochemicals relevant to emotional regulation. Replication in prospective age-controlled studies is warranted.

Differential carbon dioxide sensitivity in childhood anxiety disorders and nonill comparison group.

BACKGROUND: To examine the relationship between respiratory regulation and childhood anxiety disorders, this study considered the relationship between anxiety disorders and symptoms during carbon dioxide (CO(2)) exposure, CO(2) sensitivity in specific childhood anxiety disorders, and the relationship between symptomatic and physiological responses to CO(2). METHODS: Following procedures established in adults, 104 children (aged 9-17 years), including 25 from a previous study, underwent 5% CO(2) inhalation. The sample included 57 probands with an anxiety disorder (social phobia, generalized anxiety disorder, separation anxiety disorder, and panic disorder) and 47 nonill comparison subjects. Symptoms of anxiety were assessed before, during, and after CO(2) inhalation. RESULTS: All children tolerated the procedure well, experiencing transient or no increases in anxiety symptoms. Children with an anxiety disorder, particularly separation anxiety disorder, exhibited greater changes in somatic symptoms during inhalation of CO(2)-enriched air, relative to the comparison group. During CO(2) inhalation, symptom ratings were positively correlated with respiratory rate increases, as well as with levels of tidal volume, minute ventilation, end-tidal CO(2), and irregularity in respiratory rate during room-air breathing. CONCLUSIONS: Childhood anxiety disorders, particularly separation anxiety disorder, are associated with CO(2) hypersensitivity, as defined by symptom reports. Carbon dioxide hypersensitivity is associated with physiological changes similar to those found in panic disorder. These and other data suggest that certain childhood anxiety disorders may share pathophysiological features with adult panic disorder.

Ventilatory physiology of children and adolescents with anxiety disorders.

BACKGROUND: Abnormalities in ventilatory physiology have been noted in adults with panic disorder. We tested the hypothesis that abnormalities in ventilatory physiology differentiate children and adolescents with anxiety disorders from psychiatrically healthy children. METHODS: Ventilatory physiology was monitored with a canopy apparatus during room-air breathing and 15 minutes of carbon dioxide exposure in 33 children and adolescents comprising 18 probands with an anxiety disorder and 15 psychiatrically healthy children. RESULTS: During room-air breathing, probands had significantly larger minute ventilation, larger tidal volumes, and more variable breathing patterns than healthy comparisons, but the groups did not differ in end-tidal carbon dioxide or respiratory rate. During carbon dioxide challenge, probands exhibited larger minute ventilation and respiratory rate responses relative to comparisons. CONCLUSION: These findings on the association between ventilatory physiology and anxiety disorders in children and adolescents are consistent with results from studies of adults with panic disorder.

Brain circuits in panic disorder.

This paper reviews the pathophysiology of panic disorder (PD), within the context of newly described "fear circuitries," which have been well characterized in preclinical models. Substantial advances in the neurosciences have made it possible for clinical neuroscientists to refine our understanding of the pathophysiology of PD and the mechanisms of currently effective treatment. These advances have in turn helped generate testable hypotheses for future neurobiological and psychopharmacologic research. Perturbation of mutual modulation ("cross talk") between key brain transmitter systems (serotonin, norepinephrine, gamma-aminobutyric acid, corticotropin-releasing factor, and others) may underlie the pathogenesis of panic-anxiety. Restoration of normal homeostasis may be an important therapeutic component of antipanic therapy and may provide information about underlying neurocircuits. Neuroimaging, an important new tool, has already begun to bridge the gap between the preclinical and clinical neurosciences through confirmation of hypothesized dysfunction of the complex human prefrontal cortex and its subcortical components. In higher species, such as humans, dysfunction of cortical inhibition or excessive cortical activation of caudal limbic structures is postulated to lead to activation of the phylogenetically conserved amygdalofugal pathways. Consistent with probable subtypes of PD, overlapping theoretical models of panic neurocircuitries are proposed, including ventilatory dysregulation, which is coupled with neurovascular instability in a critical area of the panic neurocircuitry--the amygdalohippocampus. Neuroimaging appears a critical tool in guiding further elaboration of the interaction of cortical and subcortical components of the panic neurocircuitry, whereas challenge studies appear crucial in gathering further information regarding brain stem dysfunction.

Clinical utility of the selective serotonin reuptake inhibitors in the spectrum of anxiety.

The selective serotonin reuptake inhibitors (SSRIs) are now being employed in the treatment of the full spectrum of anxiety disorders. In comparative trials, the SSRIs are proving to be equal or superior in efficacy to traditional antianxiety medications. Due to their favorable side effect profile, safety, and tolerability, they are rapidly replacing older agents in the treatment of anxiety. Neuroanatomical pathways that may be important in the antianxiety effect of the SSRIs are outline and discussed, followed by a review of the clinical evidence supporting the efficacy of this class of medications in the treatment of anxiety disorders.

Dose-response effects of oral yohimbine in unrestrained primates.

Six unrestrained bonnet macaques were each observed after oral administration of four dosages of yohimbine hydrochloride (0.10, 0.25, 0.50, and 0.75 mg/kg) and a placebo. Yohimbine significantly increased episodes of motoric activation and affective response interspersed with intervals of behavioral enervation. Yohimbine scores correlated closely with baseline levels; there was no dose-response relationship. Response to oral yohimbine differed in several ways from subcutaneous and intravenous sodium lactate infusions, including prominent enervative symptoms and the appearance of sexual arousal. In light of the appearance of cyclic enervative episodes, this study suggests limitations to primate models of panic disorder utilizing oral yohimbine.

Rebreathing tests in panic disorder.

In order to compare the ventilatory response of panic patients and normal controls, 21 panic disorder patients with agoraphobia and 21 normal controls underwent the Read rebreathing test. Panic patients panicked significantly more during the test, responded with more respiratory rate and less tidal volume, but showed no hypersensitivity to inhaled carbon dioxide compared to normal controls.

The noradrenergic system in pathological anxiety: a focus on panic with relevance to generalized anxiety and phobias.

Over the past three decades of psychiatric research, abnormalities in the noradrenergic system have been identified in particular anxiety disorders such as panic disorder. Simultaneously, neuroscience research on fear pathways and the stress response have delineated central functions for the noradrenergic system. This review focuses on the noradrenergic system in anxiety spectrum disorders such as panic disorder, generalized anxiety disorder, and phobias for the purpose of elucidating current conceptualizations of the pathophysiologies. Neuroanatomic pathways that are theoretically relevant in anxiogenesis are discussed and the implications for treatment reviewed.

Adverse early experiences affect noradrenergic and serotonergic functioning in adult primates.

It has been proposed that certain adverse early experiences may play a role in determining subsequent susceptibility to adult anxiety and affective disorders and this relationship may be the result of altered neurodevelopment of the noradrenergic and/or serotonergic systems. In this study of nonhuman primates, the predictability of foraging requirements for mothers during an early period of their infants' lives was manipulated. When the offspring were young adults, these early manipulations were related to differences in behavioral response to acute administration of two putative anxiety-provoking agents: the noradrenergic probe, yohimbine, and the serotonergic probe, mCPP. These long-term effects of the developmental environment on subsequent pharmacological responsivity suggest that both neuronal systems may be permanently altered by early experiential factors.

Premorbid polysomnographic signs in depressed adolescents: a reanalysis of EEG sleep after longitudinal follow-up in adulthood.

BACKGROUND: This is a report of a clinical follow-up study (10-15 years later as young adults) of adolescent major depressives and normal control subjects. Polysomnographic data were obtained during the original study period when the subjects were adolescent (time 1). With clinical follow-up (time 2) assessments in hand, our objective was to ascertain whether there were any premorbid polysomnographic signs associated with depression during adolescence. METHODS: Based upon initial (during adolescence) and follow-up clinical assessments (as adults), new subject groupings were generated: depression-free normal subjects and original normal subjects who experienced a depressive episode during the follow-up period (latent depressives). Suicidality and recurrence of depression were also examined. Multivariate analysis of covariance was used to analyze group differences in sleep measures and logistic regression for predicting three outcomes: lifetime depression, lifetime suicidality, and recurrence. RESULTS: Comparison of the depression-free normal subjects, the latent depressives, and the original major depressives revealed significant differences for sleep latency and sleep period time. Comparing all lifetime depressives (original major depressives and the latent depressives) to depression-free normal subjects revealed significantly more stages 3 and 4 combined (ST34) sleep and greater sleep period times among the depressives. An analysis involving the presence or absence of suicidality revealed no overall significant differences between the groups. Comparison of the lifetime depressives grouped by nonrecurrent and recurrent depressive course to the depression-free normal subjects revealed significant difference for sleep period time. Using logistic regression, we found that a longer sleep latency and sleep period time significantly predicted lifetime depression. Gender, ST34 sleep, and an interaction term for ST34 sleep and REM latency significantly predicted lifetime suicidality. CONCLUSIONS: There was evidence of premorbid sleep abnormalities during adolescence. A general pattern of sleep disruption around sleep onset and during the first 100 min of the sleep period and overall sleep was evident among the major and lifetime depressives, involving sleep latency (initial insomnia), sleep period time (hypersomnia), REM latency, and slow-wave sleep. This adds to the body of literature that highlights the importance of the first 100 min of the sleep period in depression.

Noradrenergic function in panic disorder. Effects of intravenous clonidine pretreatment on lactate induced panic.

To assess the role of noradrenergic stimulation during lactate-induced panic, ten patients with panic disorder who panicked during a standard sodium-lactate infusion underwent a repeat infusion following intravenous clonidine pretreatment. Although clonidine significantly lowered prelactate systolic blood pressure, the drug did not significantly lower prelactate anxiety levels, as reflected by the Acute Panic Inventory (API). Clonidine blocked lactate-induced panic in four of ten subjects, a significant effect. Clonidine treatment also significantly attenuated lactate-panic symptoms, as reflected by time to panic and API comparison between trials. Nevertheless, over half the subjects still panicked in response to lactate despite clonidine. This preliminary study suggests that reduction of central noradrenergic activity by clonidine, at least at the dosage levels employed in the current study, only partially attenuates panic response to lactate. Noradrenergic theories of panic may not therefore fully account for lactate panicogenesis.

Nocturnal growth hormone secretion studies in adolescents with or without major depression re-examined: integration of adult clinical follow-up data.

BACKGROUND: Early sleep is associated with an increased secretion of human growth hormone (GH) through muscarinic inhibition of somatostatin, a GH suppressant. A clinical follow-up was performed approximately 1 decade after depressed and psychiatrically "normal" control adolescents, who were now young adults, had undergone baseline serial GH measurements over a 24-hour period on the third night of sleep polysomnography studies. METHODS: The study population consisted of 77 young adults who had received a diagnosis of adolescent major depressive disorder and had participated in the adolescent sleep and neuroendocrine studies. Alternatively, the young adult subjects were assessed as normal adolescent control subjects free of any psychiatric diagnosis. Blood samples had been collected for GH every 20 min during the 24-hour period coinciding with the third consecutive night of sleep electroencephalography. Subjects, now in young adulthood, were relocated and blindly reinterviewed using the Schedule for Affective Disorders and Schizophrenia (lifetime version). The original adolescent nocturnal GH data were analyzed in light of the information obtained regarding clinical course into adulthood. RESULTS: A substantial proportion of the nominally normal control group developed at least one episode of major depression or dysthymia during the follow-up period. "Latent" depressive subjects differed from depression-free control subjects by having exhibited a significantly more rapid increase of adolescent nocturnal GH secretion following sleep onset. Of the subjects who had experienced at least one lifetime major depressive episode during the follow-up, the subgroup who would go on to make suicide attempts secreted significantly greater amounts of GH during the first 4 hours of sleep. Adults with lifetime depression exhibited significantly reduced levels of GH in the 100 min preceding sleep onset during adolescence. CONCLUSIONS: Assignment of subjects based on longitudinal clinical follow-up into adulthood revealed that the sleep-related GH secretion paradigm has predictive value for future depressive episodes and future suicide attempts. Dysfunction of complex sleep-onset mechanisms may be a premorbid marker of depression and suicidal behavior.

Effect of antipanic treatment on response to carbon dioxide.

BACKGROUND: Disordered breathing among patients with panic disorder, including hyperventilation during attacks and increased anxiogenic response to carbon dioxide (CO2) inhalation, is well established. We wished to assess whether there is a change in the physiological response to CO2 after patients have undergone antipanic therapy with either tricyclic antidepressants or cognitive behavioral therapy (CBT). METHODS: Twenty-nine patients with panic disorder underwent baseline CO2 sensitivity testing using the traditional Read rebreathing method and then received either antidepressant treatment (n = 21) or CBT (n = 8). After completing treatment, CO2 testing was repeated. A comparison sample of 14 normal volunteers also had two CO2 sensitivity tests, separated by an average of 21.6 (SD = 8.8) weeks. RESULTS: Using a liberal standard, in which all CO2 sensitivity tests whose correlations between minute ventilation and end-tidal CO2 were at least .75 were used, patients, but not controls, demonstrated a significant reduction in CO2 sensitivity between the first and second test. Using a more conservative .90 correlation standard reduced the sample size available and resulted in trend reduction in patients but no significant change in controls. There was a suggestion that the change was most pronounced in treatment responders, although the number of patient nonresponders is extremely small in this sample. CONCLUSIONS: These data indicate that treatment reduces CO2 sensitivity in patients with panic disorder. We speculate that manipulation of the serotonergic and noradrenergic neurotransmission systems, both known to play a role in the control of respiration, may have a specific effect in reducing respiratory hyperactivity in panic disorder.

Variable foraging demand rearing: sustained elevations in cisternal cerebrospinal fluid corticotropin-releasing factor concentrations in adult primates.

BACKGROUND: The authors previously reported elevated cerebrospinal fluid (CSF) corticotropin-releasing factor (CRF) concentrations in juvenile primates nursed by mothers undergoing experimentally imposed unpredictable foraging conditions in comparison to normally reared controls. The purpose of the present study was to determine if these changes would endure into young adulthood. METHODS: Cisternal CSF samples were obtained from those unpredictably reared young adult primates who had been previously studied as juveniles and age-matched ad libitum normally reared controls. Samples were assayed for CSF CRF. RESULTS: Concentrations of CSF CRF were significantly elevated in the unpredictably reared sample in comparison to the ad libitum-reared control group. A significant positive correlation was noted between juvenile and young adult CSF CRF values within the unpredictably reared cohort. CONCLUSIONS: Disturbances of maternal-infant attachment processes have an enduring impact on primate CRF function into young adulthood. The CRF elevations following unpredictable maternal foraging conditions appear traitlike in nature.

Neurobiological mechanisms of social anxiety disorder.

OBJECTIVE: The authors critically surveyed several preclinical and clinical neurobiological models of social anxiety disorder. METHOD: The authors reviewed the recent literature regarding three animal models of particular relevance to social anxiety. They then examined the recent literature concerning clinical neurobiological aspects of social anxiety disorder, including the developmental neurobiology of anxiety, the genetics of fear and social anxiety, and challenge and imaging studies. RESULTS: The available animal models are useful paradigms for understanding the features of social subordination stress, attachment behavior, and environmental rearing, but they incompletely account for the known neurobiology of human social anxiety disorder. The clinical neurobiology literature surveyed implicates specific neurotransmitter system abnormalities, most notably of the dopamine system, but largely ignores neurodevelopmental processes and the functional interactions between neurotransmitters. Both heritable factors and environmental stress factors appear to be responsible for the onset of social anxiety disorder. CONCLUSIONS: Social anxiety disorder should be conceptualized as a chronic neurodevelopmental illness that might represent a fully compensated state in adulthood. Future investigations from this perspective are discussed.

Amelioration of mitral valve prolapse after treatment for panic disorder.

Twenty panic disorder patients with mitral valve prolapse showed amelioration of prolapse on repeat echocardiogram after treatment for panic disorder. This effect was significant when compared to repeat echocardiograms in eight psychiatrically normal control subjects with mitral valve prolapse.

Neuroanatomical hypothesis of panic disorder, revised.

OBJECTIVE: In a 1989 article, the authors provided a hypothesis for the neuroanatomical basis of panic disorder that attempted to explain why both medication and cognitive behavioral psychotherapy are effective treatments. Here they revise that hypothesis to consider developments in the preclinical understanding of the neurobiology of fear and avoidance. METHOD: The authors review recent literature on the phenomenology, neurobiology, and treatment of panic disorder and impressive developments in documenting the neuroanatomy of conditioned fear in animals. RESULTS: There appears to be a remarkable similarity between the physiological and behavioral consequences of response to a conditioned fear stimulus and a panic attack. In animals, these responses are mediated by a "fear network" in the brain that is centered in the amygdala and involves its interaction with the hippocampus and medial prefrontal cortex. Projections from the amygdala to hypothalamic and brainstem sites explain many of the observed signs of conditioned fear responses. It is speculated that a similar network is involved in panic disorder. A convergence of evidence suggests that both heritable factors and stressful life events, particularly in early childhood, are responsible for the onset of panic disorder. CONCLUSIONS: Medications, particularly those that influence the serotonin system, are hypothesized to desensitize the fear network from the level of the amygdala through its projects to the hypothalamus and the brainstem. Effective psychosocial treatments may also reduce contextual fear and cognitive misattributions at the level of the prefrontal cortex and hippocampus. Neuroimaging studies should help clarify whether these hypotheses are correct.