E
DITORIAL
Genetics and Brain Function: Implications for the
Treatment of Anxiety
In March 2000, the Anxiety Disorders Association of America (ADAA), jointly with the National Institute of Mental Health (NIMH), sponsored a conference entitled “Genetics and Brain Function: Implications for the Treatment of Anxiety.” With a focus on genetic impli-cations for the understanding of anxiety and develop-ment of new treatdevelop-ments for the anxiety disorders, leading researchers presented advances on a spectrum of topics, with perspectives from basic science and clinical research.
This meeting, as reflected in the compendium of articles in this issue (Bakshi and Kalin 2000; Caldji et al 2000; Goldsmith and Lemery 2000; Gross et al 2000; Rosenberg and Hanna 2000; Watson et al 2000), underscored two compelling realities regarding the field of anxiety (i.e., behavioral neuroscience) research. On the one hand, the human genome project, combined with emerging tools such as DNA microassays (Watson et al 2000), opens heretofore incomprehensible pathways of discovery into the role of genes in the important biological functions of anxiety, startle, fearful temperament, alarm, and arousal. On the other hand, the notion that the pathophysiology of any DMS-IV anxiety disorder might be exclusively linked to a single gene seems implausible. Nonetheless, the intellectual attractiveness of single gene hypotheses un-derlying pathologic anxiety is reminiscent of earlier sin-gle-neurotransmitter or single-receptor or receptor subtype theories of the anxiety disorders (Uhde et al 1990). With the advent of any new research tool (e.g., the “chip” [Watson et al 2000]; functional magnetic resonance imag-ing [fMRI] [Rosenberg and Hanna 2000]; gene targetimag-ing and tissue specific receptor manipulations [Bakshi and Kalin 2000; Gross et al 2000]), the evolution of scientific inquiry predictably moves from reductionist to integrative models of pathophysiology. Thus, though the biological targets of our research have become more discreet (organ to neurotransmitter, to receptor, to cellular, to molecular, etc.), the discovery of a final common pathway has so far eluded detection.
It is probable that fear and anxiety are inevitably mediated by an interplay of factors. Using different terminology, the age-old question of “nature versus nur-ture” in the mediation of the anxiety disorders may not be elucidated by candidate gene or related methodologies. In fact, asking the nature versus nurture question itself may have delayed more relevant investigations into the rela-tionships among mind, brain, and behavior.
Several lines of evidence, as collectively represented in this issue (Bakshi and Kalin 2000; Caldji et al 2000; Goldsmith and Lemery 2000; Moldin 2000) and else-where, highlight that it is increasingly difficult to separate “Chicken– egg” types of causation when it comes to gene– environment interactions, perhaps especially in re-lation to complex emotions such as anxiety and behavioral inhibition. Genes present at birth shape later life experi-ences (e.g., trauma), behavioral traits (e.g., risk taking), environmental context (e.g., socioeconomic status, food consumption), and interpersonal dynamics (e.g., maternal bonding), factors that themselves collectively and sepa-rately affect gene expression. That genes and environment determine who we are as individuals is self-evident; more interestingly, perhaps, is how these same forces at one point in time may affect individuals across generations. A provocative and emerging area of study might be coined
genomic sociology(i.e., how the impact of gene– environ-mental factors influences emotions and behavior across generations). This has a familiar ring, albeit using a distinctly different construct, similar to Carl Jung’s no-tions of archetypes and the collective unconscious (Jung 1968). How do genetic– environmental interactions influ-ence human behavior at a single time point and over time (within individuals) as well as across generations and divergent cultures? How do both genomic and non-genomic factors influence the risks for the emergence of anxiety disorders across generations (Francis et al 1999; Yehuda et al 1998)? It appears that we have the tools to begin to unravel such mysteries.
Although the data presented at the ADAA/NIMH meet-ing do not exclude the importance of smeet-ingle genes in regulating some “seminal” feature(s) of anyanxiety dis-order, there is striking evidence to suggest that the functions of alarm, stress, and arousal in humans and animals are the result of multiple genes working in concert with environmental factors. Nonetheless, even a single susceptibility gene, which influences a key feature of a “polygenetic” anxiety disorder, may serve as a useful target for drug discovery and the development of thera-peutic agents that improve a subset of symptoms and/or course of illness (Anderson and Cook 2000; Gray et al 2000; Kola 1999).
The major reason for investigating the etiology of the anxiety disorders is to improve treatment. Tomorrow’s physician theoretically will have knowledge about anx-iety susceptibility genes and, together with other
mation (e.g., endocrine status, fMRI and magnetic resonance spectroscopy), will be able to individualize and monitor drug and psychosocial treatments, both acute and prophylactic. I challenged Drs. Rosenberg and Hanna to “wildly” speculate about the future role of pharmacogenetics and imaging genomics to diagnose and treat patients with obsessive– compulsive disorder, which offers the best body of scientific data (in terms of our understanding of anatomic structures, molecular biology, neuronal pathways, specificity of drug re-sponse, and biochemical correlates underlying core features of the syndrome [Greenberg et al 2000; Martin et al 1998]) to form such speculations. Rosenberg and Hanna (2000) provide an elegant peek into the future, although their approach was conservative and risk adversive in quality.
There is a major deficiency in the scope of topics covered in this issue ofBiological Psychiatry. As chair of the ADAA/NIMH satellite conference I failed to elicit presentations on the political, scientific, and sociologic impact of genetic testing. The role of genetic testing in the diagnosis and treatment of neurologic disorders is already a highly contentious issue. Mental health professionals and genetic counselors can antici-pate more poignant questions about the merits and morality of identifying people at risk for anxiety disor-ders once such technology becomes available. The lay public, and even practicing physicians, express appre-hension about the use of information made possible by medical research. Recently, there have been increased efforts to regulate the conduct of both basic and clinical research. Beyond the inherent value of conducting research and providing clinical care in an ethical man-ner, these external forces demand that the scientific community “take up the challenge” and engage the lay, religious, consumer, and advocacy public, government agencies, and individuals involved in diagnosis and treatment of mental disorders in an ongoing dialogue about the nature and limits of, and realistic implications for, genetic testing.
Thomas W. Uhde
Wayne State University School of Medicine 540 E. Canfield
Scott Hall of Basic Science Room 1261
Detroit MI 48201
References
Anderson GM, Cook EH (2000): Pharmacogenetics: Promise and potential in child and adolescent psychiatry.Child Adolesc Psychiatr Clin North Am9:23– 42.
Bakshi VP, Kalin NH (2000): Corticotropin-releasing hormone and animal models of anxiety: Gene– environment interac-tions.Biol Psychiatry48:1175–1198.
Caldji C, Diorio J, Meaney M (2000): Variations in maternal care in infancy regulate the development of stress reactivity.Biol Psychiatry48:1164 –1174.
Francis D, Diorio J, Liu D, Meany MJ (1999): Nongenomic transmission across generations of maternal behavior and stress response in the rat.Science286:1155–1158.
Goldsmith HH, Lemery KS (2000): Linking temperatmental fearfulness and anxiety symptoms: A behavior– genetic per-spective.Biol Psychiatry48:1199 –1209.
Gray IC, Campbell DA, Spurr NK (2000): Single nucleotide polymorphisms as tools in human genetics.Hum Mol Genet
9:2403–2408.
Greenberg BD, Murphy DL, Rasmussen SA (2000): Neuroana-tomically based approaches to obsessive-compulsive disor-der. Neurosurgery and transcranial magnetic stimulation.
Psychiatr Clin North Am23:671– 686.
Gross C, Santarelli L, Brunner D, Zhuang X, Hen R (2000): Altered fear circuits in 5-HT1A receptor KO mice. Biol
Psychiatry48:1157–1163.
Jung CG (1968): Archetypes of the collective unconscious. In: Jung C.Collected Works of C. G. Jung,Vol 9, Part 1, 2nd ed. Princeton, NJ: Princeton University Press.
Kola I (1999): Complex traits, genes, polymorphisms and the drug discovery/development process. Curr Opin Biotechnol
10:589 –592.
Martin A, State M, Anderson GM, Kaye W, Hanchett JM, McConaha CW, et al (1998): Cerebrospinal fluid levels of oxytocin in Prader-Willi syndrome: A preliminary report.
Biol Psychiatry44:1349 –1352.
Moldin S (2000): Neurobiology of anxiety and fear: Challenges for genomic science of the new millennium.Biol Psychiatry
48:1144 –1146.
Rosenberg DR, Hanna GL (2000): Genetic and imaging strate-gies in obsessive– compulsive disorder: Potential implications for treatment development.Biol Psychiatry48:1210 –1222. Uhde TW, Tancer ME, Gurguis GNM (1990): Chemical models
of anxiety: Evidence for diagnostic and neurotransmitter specificity.Int Rev Psychiatry2:367–384.
Watson SJ, Meng F, Thompson RC, Akil H (2000): The “chip” as a specific genetic tool.Biol Psychiatry48:1147–1156. Yehuda R, Schmeidler J, Giller EL Jr, Siever LJ,
Binders-Brtynes K (1998): Relationship between posttraumatic stress disorder characteristics of Holocaust survivors and their adult offspring.Am J Psychiatry155:841– 843.
Editorial BIOL PSYCHIATRY 1143
