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07 Anxiety and Stress Disorders

07 Anxiety and Stress Disorders

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Published by Piotor.Ar
ACNP - Neuropsychopharmacology: 5th Generation of Progress. Section 7/13
ACNP - Neuropsychopharmacology: 5th Generation of Progress. Section 7/13

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Published by: Piotor.Ar on Dec 04, 2009
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The chapters in this section reflect the advances that havebeen made in our understanding of the molecular neurobi-ology and neural circuits underlying fear and anxiety statesandthepotentialforbadlyneededadvancesinthediagnosis,pathophysiology, and treatment of anxiety disorders.Many readers will be surprised by the data cited in theKessler and Greenberg chapter on the economic burden of anxiety and stress disorders. Recent surveys demonstratethat anxiety and stress disorders are the most commonly occurring of all mental disorders. Anxiety disorders are tem-porally the primary disorders in many people with a lifetimehistory of any mental disorder. Indeed the combined occur-rence of high lifetime prevalence with an early age at onsetand high chronicity makes anxiety disorders unique.The chapter by Stein and Lang reviews in detail thecourse of anxiety and stress disorders over the lifetime. Onepoint they make that is especially important to emphasizeis the critical need for further research in childhood anxiety disorders. The presence of an anxiety disorder in childhoodor adolescence is a predictor of the persistence into adult-hood of not only anxiety disorders but other psychiatricdisorders as well, particularly depression. It is not knownifearlyeffectivetreatmentofchildhoodandadolescentanxi-ety disorders will prevent the development of psychiatricdisorders later in life.Importantinsightsintothepathogenesisofanxietydisor-ders come from preclinical investigations reviewed by Davisin his chapter. The identification of the brain structures andneural circuits involved in the generation of fear and anxi-ety-related behaviors are most noteworthy. The delineationof specific neural pathways mediating conditioned and un-conditioned fear can logically guide the design and conductof clinical studies investigating the neurobiological mecha-nisms of anxiety disorders such as generalized anxiety disor-
Dennis Charney:
Mood and Anxiety Disorder Research Program, Na-tional Institute of Mental Health, Bethesda, Maryland.
der (unconditional fear) and phobic disorders (conditionedfear). Increased knowledge of the neural mechanisms andneurotransmitters involved in extinction may offer noveltherapeutic approaches. If we can discover pharmacologicmethods to enhance extinction, more effective drug treat-ments for conditioned fear or anxiety may be found. Thereis evidence of extinction being mediated by 
-aminobutyricacid (GABA) release. This suggests the possibility of aug-menting extinction-based psychotherapy with GABA ago-nist drug treatment.Determinationofthegeneticcontributiontoanxietydis-orders is critically important to progress in understandingetiology and improving treatment.Merikangas and Pine review the evidence that the majorsubtypesoftheanxietydisordersaggregateinfamilies.How-ever, the magnitude of heritability is relatively moderate,indicating a strong environmental contribution to etiology.Unfortunately, thus far linkage and association studies inanxiety disorders have not been fruitful. Future studiesshould determine if components of anxiety syndromes arecontrolled by specific genes. The revolution occurring ingenomics research as a consequence of sequencing thehuman genome and the identification of over 1
millionsingle nucleotide polymorphisms (SNPs) should make dis-covery of anxiety-related disease genes a reality. Strategiesthat are complementary to linkage analyses and utilize datafrom linkage studies are indicated. Such approaches couplethe genotyping of candidate functional SNPs with linkageand equilibrium mapping in chromosomal regions impli-cated in linkage studies. In parallel with the genetic studies,enhanced efforts to identify endophenotypic biological vul-nerability markers are indicated. The studies cited in thechapter on temperament, anxiety sensitivity, autonomicreactivity, psychophysiologicfunction, ventilatoryfunction,neurochemical, and neuroendocrine factors are good exam-ples of this approach.Bakshi and Kalin point out in their chapter the advan-
Neuropsychopharmacology: The Fifth Generation of Progress 
tages of using putative animal endophenotypes of stress andanxiety to identify genetic abnormalities associated withanxiety disorders. Rodent and nonhuman primate studiesof mother-infant interactions are particularly compelling,given the important clinical implications if these interac-tionsarefoundtobeacriticalfactorinfuturefearfuldisposi-tion. Targeted mutations leading to anxiety-like endophe-notypes in transgenic mice have suggested roles forserotonin receptor subtype 1A (5-HT
), corticotropin-releasing hormone (CRH), GABA, neuropeptide Y, chole-cystokinin,and substancePneuralsystemsinthegenerationon anxiety-fear behaviors. These studies provide clues forthe discovery of new medications and pharmacogenomicapproaches to treatment. Accelerated drug development ef-forts focusing on corticotropin-releasing factor 1 (CRF-1)receptor antagonists and benzodiazepine agonists with ananxioselective subunit profile are indicated. The feasibility of pharmacogenomicinvestigations designed toevaluate therelationships among functional polymorphisms of the5-HT
receptor, benzodiazepine receptor, and GABA syn-thesis enzymes and therapeutic responses to specific drugsshould be explored.It is imperative that these findings from the preclinicalstudies of anxiety and fear states be translated into increasedknowledge of the neural circuits and associated neuralmechanisms that can account for the signs and symptomsin patients with anxiety disorders. Rauch and Shin reviewedthe neuroimaging findings relevant to anxiety and stressdisorders. Their chapter emphasizes the areas of congruencebetweenanimalstudiesand clinicalneuroimaginginvestiga-tions. For example, imaging studies in healthy subjects sup-port a role for the amygdala in fear conditioning and thefrontal cortex in extinction. In the imaging studies of pa-tients with anxiety disorders, progress has been made inidentifying specific neural circuits. Functional relationshipsamong the amygdala, hippocampus, and medial prefrontalcortex have been reported in patients with posttraumaticstress disorder (PTSD). The imaging findings in patients with obsessive-compulsive disorder (OCD) are consistent with ‘‘pathology’’ in cortico-striatal-thalamo-cortical circui-try. Unfortunately, a critical gap in knowledge exists regard-ing the relevant neural circuits involved in panic disorder,social anxiety disorder, and generalized anxiety disorder.The neurochemical systems associated with anxiety and fearcircuitsarereviewed inthechapterbyCharneyand Drevets. As predicted from the preclinical studies, abnormalities innorepinephrine, benzodiazepine, glucocorticoid, and CRHsystems have been identified in patients with anxiety disor-ders. However, most of the findings reviewed should bedeemed preliminary, and they require replication. None of 
Neuropsychopharmacology: The Fifth Generation of Progress.
Edited by Kenneth L. Davis, Dennis Charney, Joseph T. Coyle, andCharles Nemeroff. American College of Neuropsychopharmacology 
the reported neurobiological distinctions between patientsand controls is robust enough to be of diagnostic relevance.Tallman, Cassella, and Kehne review the mechanism of action of anxiolytic drugs and the status of new and noveltherapeutic agents. They highlight the therapeutic potentialand current status of CRH antagonist drug development.They also note the potential of developing targets for theCRF-2 receptor and other peptides, such as vasoactiveintes-tinal peptide (VIP), involved in the regulation of stress. Inregard to benzodiazepine drug development, they note anideal drug might have limited effects on the
subtype with increased responsiveness at
subunits. Glu-tamate receptor agonists and modulators are proposed asviable targets for anxiety disorders. For example, pointmutations in the glycine-binding site of the NR1 subunitresult in mice that have reduced glycine affinity andan anxiolytic profile. Group II metabotrophic glutamateagonists are in early clinical development for the treatmentof anxiety disorders. Other novel drug targets includeantagonists of AMPA receptors and antagonists of strych-nine-sensitive glycine site, both of which show anxiolyticprofiles in animal models.Ultimately, the goal of research on the neurobiologicalunderpinnings of anxiety disorders is to lead to more effec-tive, morerapidly actingtreatments, toachieve amore com-plete response, and to be ableto predict responsesto specifictreatments. In their review, Gorman, Kent, and Coplanhighlight the extremely broad spectrum of action of norepi-nephrineandserotonintransportinhibitorsinanxietydisor-ders. These drugs are limited by a delayed onset and in-complete response in many patients. This suggests thatnorepinephrine and serotonin have broad modulatory ef-fects on other neuronal systems, which are more primarily related to the pathogenesis of anxiety disorders.Insummary, areading ofthese chaptersreveals that therehave not been fundamental advances in our ability to diag-nose anxiety disorders based on known etiology. The main-stayofmedicationtreatmentcontinuestobeclassesofmedi-cations that have existed for decades. There are major gapsin our knowledge of anxiety disorders in children. Themechanisms responsible for the occurrence of anxiety disor-ders in childhood and adolescence leading to increased risk for other psychiatric disorders in adulthood are unknown.However, the potential for progress is great. A multidiscipli-nary team approach utilizing the findings from preclinicalinvestigations on neural circuitry, neurochemistry, and ge-netics to inform clinical investigations of genetic vulnerabil-ity, environmental risk factors, neuroimaging, pharmaco-genomics, and novel drug design and testing will be apathway to discovery.
This chapter traces the course and trajectory of anxiety dis-ordersacross thelifespan. Thechapterdiscusses thesedisor-dersinthreeagegroups:(a)childhood,(b)youngadulthoodto middle age, and (c) older adulthood.
ANXIETY AND STRESS DISORDERS INCHILDHOODTemperamental and EnvironmentalPrecursors
Thereare anumber offactorsthat relateto thedevelopmentof anxiety in general. Although this remains a controversialarea, current evidence suggests that anxiety does not appearto be specifically heritable; what clusters in families is amore general predisposition to mood or anxiety disorders.Evidence of this comes from twin studies (1) as well asfrom studies of the incidence of disorders in the families of anxious patients (2). Specific phobia, however, may be anexception to this general heritability; family members withspecific phobias tend to be associated with increased risk only for specific phobias (3). Anybiologicalpredispositionislikelymoderatedbyenvi-ronmental factors. For example, Beidel and Turner (2)found that parental psychopathology was a risk factor forthedevelopmentofdisorderonlyamongthelowersocioeco-nomic status (STS) portion of their sample. It has beensuggested that environmental factors play a significant rolein the manifestation of specific psychopathology (1). Anxi-ety in particular is believed to be related to a combinationof negative affect, a sense of lack of control over situationsor environments, and attentional self-focus. Early experi-ences of being unable to influence or control situations,therefore, may lead to the development of anxiety (4).Specific patterns within the family may lead to increased
Murray B. Stein and Ariel J. Lang:
Department ofPsychiatry, University of California–San Diego, San Diego, California.
risk of development of childhood anxiety. Expressed emo-tion (EE), which is an interactional style composed of emo-tionaloverinvolvement and high levelsofcriticism,hasbeenassociated with an increased likelihood of childhood anxiety disorders (5) and with long-term functioning in those withanxiety disorders (6). Parents may also influence a child’sanxiety by providing positive (e.g., the child gets attention)or negative (e.g., the child is allowed to avoid anxiety-pro-voking situations) reinforcement for expressions of anxiety,by providing inadequate affection and by excessive control/overprotection (4).Can it be said that some people are born anxious? Theanswer is a qualified yes. The last decade or so of researchby JeromeKagan and colleagueshas led tothe identificationof a temperament, ‘‘behavioral inhibition’’ (BI), that ap-pears to be related to the subsequent onset of anxiety disor-ders. BI involves reacting to unfamiliar or novel situations with behavioral restraint and physiologic arousal (5). Whenconfronted with an unfamiliar person or object, a BI child will withdraw, cling, be reluctant to interact, show emo-tional distress, and stop other activities. BI has also beenassociated with physiologic differences, such as high andstable heart rate, increased salivary cortisol and urinary cate-cholamines,pupillarydilation,and laryngealmuscletension(7). These findings have led to the hypothesis that BI isrelated to a low threshold for arousal in the amygdala andhypothalamus (8). This characteristic, which appears to bepresent in 10% to 15% of children, has been identified inchildren as young as 14 months, has been shown to persistthroughout childhood (9), and is more commonly foundin offspring of anxious parents (8). The inhibited tempera-ment has been associated with risk of developing an anxiety disorder, most commonly social phobia (10).Some have suggested that childhood anxiety and depres-sion are so closely related that they are best considered aspart of the same construct, often referred to as internalizingdisorder.Thislackofdifferentiationappearstobecharacter-istic of younger children, with increased specificity develop-ing over time (11,12). At least by middle childhood, thereis support for the set of anxiety-related diagnoses in the

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