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Brief Report   |    
Stress Responsivity and HPA Axis Activity in Juveniles: Results From a Home-Based CO2 Inhalation Study
Thomas A. Terleph, Ph.D.; Rachel G. Klein, Ph.D.; Roxann Roberson-Nay, Ph.D.; Salvatore Mannuzza, Ph.D.; John L. Moulton, III, Ph.D.; Girma Woldehawariat, Ph.D.; Mary Guardino; Daniel S. Pine, M.D.
Am J Psychiatry 2006;163:738-740. doi:10.1176/appi.ajp.163.4.738

Abstract

Objective: A previous laboratory-based study found elevated cortisol levels in anxious children susceptible to CO2-induced panic, but the effects of parent diagnosis were not considered. The current home-based study tested the hypothesis that parental panic disorder and offspring response to CO2 are associated with elevated cortisol levels in juvenile offspring. Method: A total of 131 offspring (ages 9–19) of parents with panic disorder, major depression, and no mental disorder underwent CO2 inhalation. Parent and child diagnoses were assessed. Salivary cortisol was assayed before and after CO2 inhalation. Results: Neither parents with panic disorder, parents with major depression, or offspring anxiety predicted offspring cortisol levels. Independent of parent and child diagnoses, anxiety response to CO2 predicted elevated cortisol levels in offspring. Conclusions: As in adults, anxiety response to CO2 in juveniles is associated with elevated cortisol levels, but elevated cortisol levels are not related to parent or child diagnoses.

Abstract Teaser
Figures in this Article

Considerable literature relates developmental perturbation in stress regulation to later diagnosis of anxiety or major depression (1, 2). However, little is known about stress regulation in children with anxiety disorders. In a laboratory paradigm that exposed anxious and normal children to 5% CO2, patients with anxiety disorders experiencing CO2-induced panic symptoms exhibited elevations in cortisol levels before and after CO2 exposure relative to patients and healthy subjects not experiencing panic symptoms. Cortisol levels did not increase further during CO2 exposure, even in subjects who developed panic (3). These results, consistent with data in adults (4), suggest a relationship in juveniles between anticipatory anxiety and hypothalamic-pituitary-adrenal (HPA) axis function.

With a family-based design, the present study addressed whether parental panic disorder relates to HPA activity in offspring during exposure to CO2 inhalation. The study also examined whether the previously noted positive relationship between anxiety response to CO2 and HPA activity could be replicated in a nonclinical group that was studied at home.

The methodological details of the study have appeared elsewhere (5). We recruited 142 offspring from 93 families, ages 9–19; 131 (92%) provided cortisol samples. The subjects included offspring of parents with panic disorder, major depression, and neither condition. The participants were diagnosed with the Structured Clinical Interview for DSM-IV (SCID) (for the parents) and the Parent as Respondent Informant Schedule (6) (for the offspring). All of the subjects provided consent or assent.

CO2 inhalation was conducted in the subjects’ homes. The subjects breathed through a face mask. Response to CO2 was assessed with the Acute Panic Inventory (3, 5) at three time points: before the procedure (baseline), immediately before CO2 inhalation (threat), and during CO2 inhalation. A technician rated the occurrence of panic attacks by applying standard criteria (3); 14 of 131 (11%) met the criteria.

Cortisol samples, obtained from saliva immediately before and after CO2 inhalation, were analyzed as described previously (3). Because the study was home based, it was not possible to standardize the time. The procedures began within 1 hour of four times: 10:00 a.m., 12:00 noon, 2:00 p.m., and 4:00 p.m.

To maintain consistency with our previous report (3), cortisol levels measured before and during CO2 administration were treated as the dependent measures. Predictors included a within-subject repeated-measure or pre-to-postsample effect as well as time of day coded from 1 to 4 to indicate procedure initiation time, Acute Panic Inventory score, CO2-induced panic attack, anxiety disorder in offspring, and panic disorder and/or major depression in parents. We used the SAS mixed-model procedure (7) to examine whether cortisol levels before and after CO2 inhalation were predicted by Acute Panic Inventory scores and by panic attacks, with control for time of day and offspring or parent diagnosis. This approach allows modeling of variability due to familial factors resulting from the inclusion of multiple offspring from the same family and of variability due to repeated measures resulting from repeated cortisol samplings. These methods account for the nonindependence of data deriving from related subjects. Predictor variables in the multivariate models included fixed effects (time of day, parent with major depression, parent with panic disorder, offspring anxiety diagnosis, Acute Panic Inventory score, and repeated measure or sample) and random effects (parent and offspring). The autoregressive covariance structure was used, and denominator degrees of freedom for F or t tests on fixed and random effects were estimated by using Satterthwaite approximation, with Bonferroni correction for post hoc tests (significance was two-tailed at alpha=0.05).

The table presented online (Data Supplement 1 at http://ajp.psychiatryonline.org) shows data for offspring dichotomized by the presence or absence of CO2-induced panic (i.e., demographic characteristics, Acute Panic Inventory ratings, diagnostic data, and offspring cortisol levels). A previous report described associations among parent diagnoses, offspring diagnoses, and offspring Acute Panic Inventory responses to CO2(5). The prior report noted that offspring anxiety diagnosis but not parent diagnosis predicted offspring Acute Panic Inventory scores during CO2 inhalation.

The mean of the two cortisol values was significantly higher in offspring who did versus those who did not experience CO2-induced panic (F=5.2, df=1, 154, p<0.05) with control for the time of day, parents with panic disorder, parents with major depression, and offspring with an anxiety diagnosis—none of which predicted cortisol level. Because the model entered these variables as covariates, the noted between-group difference was independent of time of day and parent or offspring diagnosis. Adjusted cortisol values in the entire sample were significantly higher before (mean=2.0 mg/dl, SD=0.2) than after (mean=1.8 mg/dl, SD=0.2) CO2 inhalation (F=6.0, df=1, 154, p<0.05). Cortisol values were similar in subjects with (mean=1.9 mg/d, SD=0.2) and without (mean=1.9 mg/dl, SD=0.2) parental panic disorder. No interactions with repeated measure or sample emerged for any predictor.

A second multivariate model was fit, including as predictors the two continuous Acute Panic Inventory ratings but not the categorical designation of “panic attack.” This analysis found a positive association between mean cortisol level and Acute Panic Inventory scores recorded during (F=7.2, df=1, 153, p<0.01) but not before CO2 inhalation (F=0.7, df=1, 153, p=0.42). As in the first model, time of day was controlled, but it only marginally predicted cortisol level (F=2.1, df=1, 153, p=0.10). This analysis also controlled for parental major depression, parental panic disorder, and offspring anxiety diagnosis—none of which predicted cortisol level. Again, no interactions with repeated measure or trial emerged. Thus, the relationship between mean cortisol level and Acute Panic Inventory score during CO2 exposure was independent of time of day and parent or offspring diagnosis. Acute Panic Inventory scores at baseline showed no association with cortisol level.

Parental panic disorder, parental major depression, and offspring anxiety diagnosis were not associated with offspring cortisol level. However, consistent with prior findings (3), cortisol level was elevated in juveniles susceptible to CO2-induced panic attacks.

Novel environments are known to increase cortisol levels. The previous CO2 study (5) was conducted in the laboratory—a novel setting—whereas the current study occurred in the home. Consequently, the current findings cannot be explained by an interaction between the novelty of the laboratory context and the stressor. Current and previous findings document consistent associations in juveniles between elevations in cortisol levels and anxiety response to a standard stressor. Such findings are notable, given inconsistencies in previous research on developmental psychobiology of the human HPA axis (1). Current data suggest that translational research on the HPA axis in children may benefit from the use of standard stress paradigms that produce clinically relevant changes in affect and physiology.

Study limitations should be noted. First, findings are based on at-risk offspring recruited through parents seeking treatment for panic disorder or major depression, a sampling strategy vulnerable to referral biases. Second, cortisol exhibits diurnal variations, but it was not possible to standardize the procedural timing. Of importance, analyses used multivariate models that controlled for diurnal variability. Similarly, accurate assessment of baseline HPA activity requires acquisition of multiple cortisol samples over multiple days. The study examined stress-related but not baseline cortisol activity; because of habituation, intermediate pre-CO2 cortisol value is expected to be elevated over a baseline value. Prestress cortisol level is most relevant to our study hypotheses. Because both limitations are more likely to increase type II than type I errors, they are unlikely to account for the positive findings obtained.

+Received Nov. 2, 2004; revision received Feb. 10, 2005; accepted April 25, 2005. From the Section on Development and Affective Neuroscience, Intramural Research Program, NIMH, NIH; the Child Study Center, New York University, New York; the Nathan S. Kline Institute for Psychiatric Research, Orangeburg, N.Y.; and Freedom From Fear, Staten Island, N.Y. Address correspondence to Dr. Pine, NIMH, NIH, Bldg. 15-K, Rm. 110, MSC-2670, Bethesda, MD 20817–2670; daniel.pine@nih.gov (e-mail).Supported by NIMH grant R01 MH-59171 and a National Alliance for Research on Schizophrenia and Depression Independent Investigator Award (to Dr. Pine).

1. Gunnar MR: Integrating neuroscience and psychological approaches in the study of early experiences. Ann NY Acad Sci 2003; 1008:238–247
 
2. Heim C, Nemeroff CB: Neurobiology of early life stress: clinical studies. Semin Clin Neuropsychiatry 2002; 7:147–159
 
3. Coplan JD, Moreau D, Chaput F, Martinez JM, Hoven CW, Mandell DJ, Gorman JM, Pine DS: Salivary cortisol concentrations before and after carbon-dioxide inhalations in children. Biol Psychiatry 2002; 51:326–333
 
4. Sinha SS, Coplan JD, Pine DS, Martinez JA, Klein DF, Gorman JM: Panic induced by carbon dioxide inhalation and lack of hypothalamic-pituitary-adrenal axis activation. Psychiatry Res 1999; 86:93–98
 
5. Pine DS, Klein RG, Roberson-Nay R, Mannuzza S, Moutlon JL, Woldehawariat G, Guardino M: Response to 5% CO2 in juveniles: relationship to panic disorder in parents and anxiety disorders in subjects. Arch Gen Psychiatry, 2005; 62:73–80
 
6. Kentgen LM, Klein RG, Mannuzza S, Davies M: Test-retest reliability of maternal reports of lifetime mental disorders in their children. J Abnorm Child Psychol 1997; 25:389–398
 
7. Littell RC, Milliken MG, Stroup WW, Wofinger RD: SAS System for Mixed Models. Cary, NC, SAS Institute, 1996
 
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References

1. Gunnar MR: Integrating neuroscience and psychological approaches in the study of early experiences. Ann NY Acad Sci 2003; 1008:238–247
 
2. Heim C, Nemeroff CB: Neurobiology of early life stress: clinical studies. Semin Clin Neuropsychiatry 2002; 7:147–159
 
3. Coplan JD, Moreau D, Chaput F, Martinez JM, Hoven CW, Mandell DJ, Gorman JM, Pine DS: Salivary cortisol concentrations before and after carbon-dioxide inhalations in children. Biol Psychiatry 2002; 51:326–333
 
4. Sinha SS, Coplan JD, Pine DS, Martinez JA, Klein DF, Gorman JM: Panic induced by carbon dioxide inhalation and lack of hypothalamic-pituitary-adrenal axis activation. Psychiatry Res 1999; 86:93–98
 
5. Pine DS, Klein RG, Roberson-Nay R, Mannuzza S, Moutlon JL, Woldehawariat G, Guardino M: Response to 5% CO2 in juveniles: relationship to panic disorder in parents and anxiety disorders in subjects. Arch Gen Psychiatry, 2005; 62:73–80
 
6. Kentgen LM, Klein RG, Mannuzza S, Davies M: Test-retest reliability of maternal reports of lifetime mental disorders in their children. J Abnorm Child Psychol 1997; 25:389–398
 
7. Littell RC, Milliken MG, Stroup WW, Wofinger RD: SAS System for Mixed Models. Cary, NC, SAS Institute, 1996
 
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