The proposed investigation addresses the biology of risk for anxiety disorders. It derives from important parallel scientific concerns regarding the association between adult and child anxiety disorders, coupled with concerns regarding the mechanisms which underlie this association. The study specifically evolves from findings that link childhood separation anxiety disorder (SAD) and adult panic disorder (PD). These findings include: family studies noting elevated rates of SAD in offspring of adults with PD; longitudinal studies linking childhood SAD to adult PD; and biological studies finding CO2-hypersensitivity in children with SAD. CO2-hypersensitivity is also found in both adults with PD and non-ill adult relatives of patients with PD. Taken together, these findings point to the existence of a latent vulnerability to PD reflected in the respiratory system. We propose to examine respiratory function in children at high risk for panic disorder. Major hypotheses are that at risk children, compared to controls, exhibit more variable respiration and hypersensitivity to CO2 exposure as manifested by greater symptomatic and physiologic responses to the inhalation of 5 percent of CO2. We hypothesize that such abnormalities will occur among offspring even in the absence of an anxiety disorder.
Aims are addressed through the study of ventilatory measures in offspring, ages nine-to-17, of adults with PD, as compared to offspring of adults with a) social phobia but not panic disorder, b) major depression but neither panic disorder nor social phobia, and c) no mental disorder. A total of nearly 350 children and their parents have been systematically assessed in an ongoing diagnostic study of children at high-risk for anxiety. In the proposed work, diagnosis will be updated with separate interviewers for each family member. Children will undergo a CO2 inhalation procedure in their home with a validated apparatus. Outcome measures consist of: i) pre-experimental respiratory variability, as well as ii) the symptomatic, and iii) physiological response to CO2. A series of studies conducted by the investigative team finds that these factors distinguish adults with PD and children with SAD from relevant contrast groups. Respiratory variables will be rated blind to parental and child diagnosis. The inclusion of offspring from pathological comparison groups, together with offspring of normals, provides a rigorous test of hypothesized diagnostic specificity in the relationship between respiratory factors and anxiety in both children and adults. The proposed study follows naturally from the investigative team's prior work and capitalizes on the availability of a well-characterized sample.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Child Psychopathology and Treatment Review Committee (CPT)
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Nottelmann, Editha
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New York State Psychiatric Institute
New York
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Roberson-Nay, Roxann; Klein, Donald F; Klein, Rachel G et al. (2010) Carbon dioxide hypersensitivity in separation-anxious offspring of parents with panic disorder. Biol Psychiatry 67:1171-7
Terleph, Thomas A; Klein, Rachel G; Roberson-Nay, Roxann et al. (2006) Stress responsivity and HPA axis activity in juveniles: results from a home-based CO2 inhalation study. Am J Psychiatry 163:738-40
Pine, Daniel S; Klein, Rachel G; Roberson-Nay, Roxann et al. (2005) Response to 5% carbon dioxide in children and adolescents: relationship to panic disorder in parents and anxiety disorders in subjects. Arch Gen Psychiatry 62:73-80
Pine, Daniel S; Klein, Rachel G; Mannuzza, Salvatore et al. (2005) Face-emotion processing in offspring at risk for panic disorder. J Am Acad Child Adolesc Psychiatry 44:664-72
Pine, Daniel S; Lissek, Shmuel; Klein, Rachel G et al. (2004) Face-memory and emotion: associations with major depression in children and adolescents. J Child Psychol Psychiatry 45:1199-208