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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 statesand the potential for badly needed advances in thediagnosis,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 the

course 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 knownif early effective treatment of childhood and adolescent anxi-ety disorders will prevent the development of psychiatricdisorders later in life.

Important insights into thepathogenesis of anxietydisor-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 and

neurotransmitters 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.

Determination of the genetic contribution to anxiety dis-orders is critically important to progress in understanding etiology and improving treatment.

Merikangas and Pine review the evidence that the majorsubtypes of theanxiety disorders aggregate in families. 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 11 2 millionsingle nucleotide polymorphisms (SNPs) should make dis-covery of anxiety-related disease genes a reality. Strategiesthat are complementary to linkage analyses and utilize data from linkage studies are indicated. Such approaches couple

the 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, psychophysiologic function, ventilatory function,neurochemical, and neuroendocrine factors are good exam-ples of this approach.

Bakshi and Kalin point out in their chapter the advan-

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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-tionsare found to be a critical factor in future fearfuldisposi-tion. Targeted mutations leading to anxiety-like endophe-notypes in transgenic mice have suggested roles forserotonin receptor subtype 1A (5-HT1A ), corticotropin-releasing hormone (CRH), GABA, neuropeptide Y, chole-cystokinin, and substance P neural systems in the generationon 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 pharmacogenomic investigations designed to evaluate therelationships among functional polymorphisms of the5-HT 1A 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 congruencebetween animal studies and clinical neuroimaging investiga-tions. For example, imaging studies in healthy subjects sup-port a role for the amygdala in fear conditioning and the

frontal 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 fearcircuits are reviewed in the chapter by Charney and 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 2002.

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 vasoactive intes-tinal peptide (VIP), involved in the regulation of stress. Inregard to benzodiazepine drug development, they note anideal drug might have limited effects on the 1 subtype with increased responsiveness at 2 and 3 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, more rapidly acting treatments, to achieve a more com-plete response, and to be able to predict responses to specifictreatments. In their review, Gorman, Kent, and Coplanhighlight the extremely broad spectrum of action of norepi-nephrine and serotonin transport inhibitors in anxiety disor-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.In summary, a reading of these chapters reveals that there

have not been fundamental advances in our ability to diag-nose anxiety disorders based on known etiology. The main-stay of medication treatmentcontinues to be classes of medi-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 preclinical

investigations 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 a pathway to discovery.