Rose C. Mantella

Salivary cortisol is associated with diagnosis and severity of late-life generalized anxiety disorder

Age-associated alterations in hypothalamic-pituitary-adrenal (HPA) axis functioning may make individuals more susceptible to HPA dysregulation in the context of mood and anxiety disorders. Little to no research has been done to examine HPA axis function in generalized anxiety disorder (GAD), particularly in late-life GAD, the most prevalent anxiety disorder in the elderly. The study sample consisted of 71 GAD subjects and 40 nonanxious comparison subjects over 60 years of age. We examined the hypotheses that elderly individuals with GAD will have elevated salivary cortisol levels compared to nonanxious subjects, and that elevated cortisol levels in GAD will be associated with measures of symptom severity. We report that late-life GAD is characterized by elevated basal salivary cortisol levels, with higher peak cortisol levels and larger areas under the curve, compared to nonanxious subjects. Additionally, severity of GAD as measured by the GAD Severity Scale and the Penn State Worry Questionnaire are positively correlated with cortisol levels. These data demonstrate HPA axis dysfunction in late-life GAD and suggest the need for additional research on the influence of aging on HPA axis function in mood and anxiety disorders.

Elevated cortisol in older adults with generalized anxiety disorder is reduced by treatment: a placebo-controlled evaluation of escitalopram.

BACKGROUND Generalized anxiety disorder (GAD) is a common disorder in older adults, which has been linked to hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis in this age group. The authors examined whether treatment of GAD in older adults with a selective serotonin reuptake inhibitor (SSRI) corrects this HPA axis hyperactivity. METHODS The authors examined adults aged 60 years and older with GAD in a 12-week randomized controlled trial comparing the SSRI escitalopram with placebo. The authors collected salivary cortisol at six daily time points for 2 consecutive days to assess peak and total (area under the curve) cortisol, both at baseline and posttreatment. RESULTS Compared with placebo-treated patients, SSRI-treated patients had a significantly greater reduction in both peak and total cortisol. This reduction in cortisol was limited to patients with elevated (above the median) baseline cortisol, in whom SSRI-treated patients showed substantially greater reduction in cortisol than did placebo-treated patients. Reductions in cortisol were associated with improvements in anxiety. Additionally, genetic variability at the serotonin transporter promoter predicted cortisol changes. CONCLUSIONS SSRI treatment of GAD in older adults reduces HPA axis hyperactivity. Further research should determine whether these treatment-attributable changes are sustained and beneficial.

Changes in neuropsychological functioning following treatment for late-life generalised anxiety disorder

BACKGROUND Generalised anxiety disorder (GAD) in older adults is associated with neuropsychological impairment. Aims We examined neuropsychological functioning in older adults with GAD in comparison with psychiatrically healthy older adults at baseline, and we examined changes following a 12-week placebo-controlled trial of escitalopram. METHOD A total of 160 participants without dementia aged ≥60 with current GAD and 37 individuals in a comparison group without psychiatric history underwent neuropsychological assessment. Of these, 129 participants with GAD were reassessed post-treatment (trial registration: NCT00105586). RESULTS The participants with GAD performed worse than the comparison group in information processing speed, working memory, inhibition, problem-solving (including concept formation and mental flexibility) and immediate and delayed memory. Neuropsychological functioning was correlated with everyday functioning. After treatment, those with low cognitive scores experienced working memory, delayed memory and visuospatial ability improvement and those who reported clinical improvement in anxiety exhibited improvement in the ability to engage inhibition and episodic recall. These improvements were modest and of similar magnitude in both treatment conditions. CONCLUSIONS Generalised anxiety disorder in older adults is associated with neuropsychological impairments, which are associated with functional impairment. Those with GAD who either have a low cognitive performance or report clinical improvement in anxiety post-treatment, show improvement in multiple cognitive domains. These findings underscore the importance of treatments that aid cognition as well as anxiety symptoms.

Corticosterone release is heightened in food or water deprived oxytocin deficient male mice.

Recent studies in female mice that cannot synthesize oxytocin (OT) suggest that central OT neural pathways attenuate the response of the hypothalamic-pituitary-adrenal (HPA) axis to certain stressors. OT deficient (OT-/-) female mice had higher plasma corticosterone concentrations than wild type (OT+/+) female mice following exposure to platform shaker (Mantella et al., 2004). The present study examined the corticosterone response of OT-/- and OT+/+ male mice that were exposed to shaker stress or other stressors (i.e., administration of cholecystokinin (CCK), dehydration, or fasting) that are known to activate central OT neurons in mice. Plasma corticosterone concentrations were higher in male mice receiving each stress than in male mice not exposed to a stressor. Plasma corticosterone concentrations were higher in OT-/- than OT+/+ male mice that were water deprived (P < 0.05) or fasted (P < 0.03), whereas corticosterone concentrations following exposure to platform shaker or CCK administration (10 microg/kg i.p.) were not different between genotypes. These findings support the hypothesis that absence of OT results in a heightened response of the HPA axis to certain stressors and that OT can attenuate the corticosterone response associated with overnight food or water deprivation in male mice.

Consumption of solutions containing sodium chloride is enhanced in female oxytocin-deficient mice

Intact and ovariectomized oxytocin (OT)-deficient (OT -/- and wild-type (OT +/+ ) mice were tested for consumption of 0.5 M NaCI solution or tap water in a 2-bottle choice test. During 3 days of acclimation, voluntary ingestion of NaCI was equal between genotypes. After overnight fluid deprivations, intact OT -/- mice ingested 2 times more NaCI solution than OT +/+ mice in the 6th hr, but not the 1st hr, after reintroduction of fluid. Ovariectomized mice consumed less than intact mice after overnight fluid deprivation. When a 0.2 M NaCI solution was administered for 6 days in ovariectomized mice, OT / mice voluntarily consumed greater amounts than OT +/+ mice. After overnight fluid deprivation. consumption by OT -/- mice was 3 times that of OT +/+ mice at I hr and 2-fold greater alter 6 hr. Enhanced intake of NaCI-containing solutions in female OT -/- mice suggests that central OT may be an important inhibitor of sodium consumption.

Treatment-related alteration of cortisol predicts change in neuropsychological function during acute treatment of late-life anxiety disorder

Older adults with anxiety disorders are burdened by impairment in neurocognition, which may be mediated by elevated circulating cortisol levels. In a randomized controlled trial of acute serotonin‐reuptake inhibitor treatment for late‐life anxiety disorder, we examined whether change in salivary cortisol concentrations during treatment predicted improvements in measures of memory and executive function.

Stress and depression

In 1992, G. P. Chrousos and P. W. Gold defined stress as a state of threatened homeostasis, or insta…