Anxiety Disorders: Gottesman II

Gould TD, Gottesman II. · Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Program, National Institute of Mental Health, NIH, HHS, Bethesda, MD 20892, USA. · Genes Brain Behav. · Pubmed #16507002 No free full text.

Abstract: Endophenotypes are quantifiable components in the genes-to-behaviors pathways, distinct from psychiatric symptoms, which make genetic and biological studies of etiologies for disease categories more manageable. The endophenotype concept has emerged as a strategic tool in neuropsychiatric research. This emergence is due to many factors, including the modest reproducibility of results from studies directed toward etiologies and appreciation for the complex relationships between genes and behavior. Disease heterogeneity is often guaranteed, rather than simplified, through the current diagnostic system; inherent benefits of endophenotypes include more specific disease concepts and process definitions. Endophenotypes can be neurophysiological, biochemical, endocrine, neuroanatomical, cognitive or neuropsychological. Heritability and stability (state independence) represent key components of any useful endophenotype. Importantly, they characterize an approach that reduces the complexity of symptoms and multifaceted behaviors, resulting in units of analysis that are more amenable to being modeled in animals. We discuss the benefits of more direct interpretation of clinical endophenotypes by basic behavioral scientists. With the advent of important findings regarding the genes that predispose to psychiatric illness, we are at an important crossroads where, without anthropomorphizing, animal models may provide homologous components of psychiatric illness, rather than simply equating to similar (loosely analogized) behaviors, validators of the efficacy of current medications or models of symptoms. We conclude that there exists a need for increased collaboration between clinicians and basic scientists, the result of which should be to improve diagnosis, classification and treatment on one end and to increase the construct relevance of model organisms on the other.

Kovacsics CE, Gottesman II, Gould TD. · Department of Psychiatry, Mood and Anxiety Disorders Program, University of Maryland School of Medicine, Baltimore, Maryland, USA. · Annu Rev Pharmacol Toxicol. · Pubmed #18834309 No free full text.

Abstract: Lithium used as a drug treatment for major mental disorders such as bipolar disorder and depression is effective in reducing the risk of both attempted and completed suicide. However, the mechanisms underlying lithium's antisuicidal actions are not yet known, limiting the development of novel lithium-mimetic compounds that may help reduce suicide risk with fewer undesirable side effects. Suicide is a complex behavior, complicated to study in humans, and impossible to fully reproduce in animal models. The endophenotype approach, by which quantitative measures of neurobiological function are used to assess and subclassify psychiatric illness, may present a path to new discoveries. Aggression and impulsivity are candidate endophenotypes strongly associated with suicide; we review the evidence supporting aggression and impulsivity as suicide endophenotypes, as well as the effects of lithium on these constructs in both humans and rodents. Examining the mechanisms that contribute to lithium's antiaggressive and antiimpulsive effects may assist in understanding how lithium acts to reduce the risk of suicide and in elucidating the neurobiological underpinnings of suicidal behavior.

Hasler G, Drevets WC, Gould TD, Gottesman II, Manji HK. · Mood and Anxiety Disorders Program, National Institute of Mental Health, Bethesda, Maryland, USA. · Biol Psychiatry. · Pubmed #16406007 No free full text.

Abstract: Research aimed at elucidating the underlying neurobiology and genetics of bipolar disorder, and factors associated with treatment response, have been limited by a heterogeneous clinical phenotype and lack of knowledge about its underlying diathesis. We used a survey of clinical, epidemiological, neurobiological, and genetic studies to select and evaluate candidate endophenotypes for bipolar disorder. Numerous findings regarding brain function, brain structure, and response to pharmacological challenge in bipolar patients and their relatives deserve further investigation. Candidate brain function endophenotypes include attention deficits, deficits in verbal learning and memory, cognitive deficits after tryptophan depletion, circadian rhythm instability, and dysmodulation of motivation and reward. We selected reduced anterior cingulate volume and early-onset white matter abnormalities as candidate brain structure endophenotypes. Symptom provocation endophenotypes might be based on bipolar patients' sensitivity to sleep deprivation, psychostimulants, and cholinergic drugs. Phenotypic heterogeneity is a major impediment to the elucidation of the neurobiology and genetics of bipolar disorder. We present a strategy constructed to improve the phenotypic definition of bipolar disorder by elucidating candidate endophenotypes. Studies to evaluate candidate endophenotypes with respect to specificity, heritability, temporal stability, and prevalence in unaffected relatives are encouraged.

Manji HK, Gottesman II, Gould TD. · Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Program, NIMH, Bethesda, MD 20892, USA. · Sci STKE. · Pubmed #14600293 No free full text.

Abstract: Although psychiatric diseases are among the most common and destructive of all human illnesses, the molecular and cellular mechanisms underlying their complex origins remain to be elucidated. Dysfunction of critical intracellular signaling pathways is very likely to be involved. This conclusion is based on a number of observations, including the short- and long-term cellular effects of psychiatric drugs; the critical role signaling pathways play in neurotransmitter, neuropeptide, and neurohormone communication; and the fact that signaling pathways are principle regulators of the diverse array of behavioral symptoms experienced by patients. The genomics era has brought to psychiatry an abundance of genetic linkage and candidate gene findings. The difficult task--now under way--is to discern the functional relevance of these results. Recent evidence suggests the involvement of the ubiquitous protein phosphatase 2B (calcineurin), a critical regulator of many signal transduction pathways, as a schizophrenia susceptibility gene. It is likely that genetic findings in severe psychiatric disorders will continue to implicate direct and indirect modulation of critical intracellular signaling pathways.

Thompson WW, Gottesman II. · National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA. · Mil Med. · Pubmed #18595422 No free full text.

Abstract: OBJECTIVE: Among U.S. Vietnam War veterans, we assessed whether preinduction cognitive abilities were associated with the risk of developing combat-related post-traumatic stress disorder (PTSD). METHODS: The sample included 2,375 single-term, enlisted, male, Army, Vietnam War veterans who reported exposure to combat during the war. There were two measures of cognitive abilities obtained before military induction, the Armed Forces Qualification Test and the General Technical Examination. Associations of ability with current and lifetime diagnoses of Diagnostic and Statistical Manual of Mental Disorders, Third Edition Revised, combat-related PTSD were assessed. An index was used to grade the severity of combat exposure. RESULTS: Among low-combat exposure veterans, higher preinduction cognitive abilities decreased the risk for lifetime, Diagnostic and Statistical Manual of Mental Disorders, Third Edition Revised, combat-related PTSD. For veterans with higher levels of combat exposure, higher scores for preinduction cognitive abilities had no effect on reducing the risk for lifetime diagnosis of combat-related PTSD. For a current diagnosis of combat-related PTSD, approximately 20 years after the stressful life events, preinduction cognitive abilities had no effect on the rates of combat-related PTSD. CONCLUSIONS: We found significant interactions between preinduction cognitive abilities and severity of combat exposure for the lifetime diagnosis of combat-related PTSD among Army Vietnam War veterans. High levels of combat exposure are likely to exhaust intellectual resources available for coping with stressful life events. Lower scores for cognitive abilities are not uniformly disadvantageous, and this should be considered by military manpower policymakers.

Thompson WW, Gottesman II, Zalewski C. · Immunization Safety Office, US Centers for Disease Control and Prevention, Atlanta, GA, USA. · BMC Psychiatry. · Pubmed #16670009 links to  free full text

Abstract: BACKGROUND: Two large independent studies funded by the US government have assessed the impact of the Vietnam War on the prevalence of PTSD in US veterans. The National Vietnam Veterans Readjustment Study (NVVRS) estimated the current PTSD prevalence to be 15.2% while the Vietnam Experience Study (VES) estimated the prevalence to be 2.2%. We compared alternative criteria for estimating the prevalence of PTSD using the NVVRS and VES public use data sets collected more than 10 years after the United States withdrew troops from Vietnam. METHODS: We applied uniform diagnostic procedures to the male veterans from the NVVRS and VES to estimate PTSD prevalences based on varying criteria including one-month and lifetime prevalence estimates, combat and non-combat prevalence estimates, and prevalence estimates using both single and multiple indicator models. RESULTS: Using a narrow and specific set of criteria, we derived current prevalence estimates for combat-related PTSD of 2.5% and 2.9% for the VES and the NVVRS, respectively. Using a more broad and sensitive set of criteria, we derived current prevalence estimates for combat-related PTSD of 12.2% and 15.8% for the VES and NVVRS, respectively. CONCLUSION : When comparable methods were applied to available data we reconciled disparate results and estimated similar current prevalences for both narrow and broad definitions of combat-related diagnoses of PTSD.