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.