Cognitive effects of intravenous hydrocortisone in subjects with PTSD and healthy control subjects.
On the basis of peripheral (nonbrain) neuroendocrine findings in subjects with posttraumatic stress disorder (PTSD), it has been hypothesized that these individuals also have a greater central (brain) sensitivity to glucocorticoids. In nonpsychiatric subjects, it has been found that working and declarative memory performance is selectively impaired by acute glucocorticoid administration. We hypothesized that subjects with PTSD, as compared to nonpsychiatric controls, would show greater impairments in verbal declarative memory and working memory, but not attention, following exogenous glucocorticoid administration. These data are part of a larger study using functional neuroimaging and peripheral HPA axis measures in these same subjects. Subjects underwent a 0.5-mg dexamethasone suppression test and measurement of basal cortisol, basal plasma lymphocyte glucocorticoid receptor number, and postdexamethasone cortisol on a separate day. Under double-blind randomized crossover conditions, 17-mg hydrocortisone or placebo was administered by intravenous (i.v.) bolus to 15 medication-free PTSD subjects (4 female) and 12 nonpsychiatric control subjects (4 female) matched by age, sex, and education level. Participants then underwent positron emission tomography (PET) scanning and 90 min after the initial drug/placebo administration, cognitive testing was then performed. By repeated measures ANCOVA (covaried for baseline performance on that neuropsychological test), neither attention tasks of digit span forward nor backward showed significant change. However, there were significant drug (F = 17.644, df = 1,25 P < 0.001), group (F = 4.383, df = 1,25 P = 0.048), and drug by group interactions (F = 4.756, df = 1,25 P = 0.040) for verbal declarative memory. By t-test, there was not a difference in baseline performance on this measure between subject groups. The subject group with PTSD experienced a greater decline in verbal declarative memory performance following hydrocortisone administration. For working memory, there were significant group (F = 6.048, df = 1,25 P = 0.022) and drug by group interactions (F = 6.048, df = 1,25 P = 0.022) for verbal declarative memory. By t-test, there was not a difference in baseline performance on this measure between subject groups. The hydrocortisone administration led to impairment in working memory in the group of subjects with PTSD, but not in the control subject group. Exploratory correlations between percent cortisol suppression following dexamethasone and baseline plasma lymphocyte glucocorticoid receptor number with declarative and working memory measures among subject groups separately and in a combined way revealed a negative correlation between lymphocyte glucocorticoid receptor density and working memory (r = -0.54, df = 25, P = 0.008). Brain sensitivity to glucocorticoids appears to be greater in subjects with PTSD. Heightened vulnerability of declarative memory in subjects with PTSD may indicate hippocampal involvement, whereas working memory vulnerability suggests additional brain regions (prefrontal, cingulate, temporal, and parietal cortices) and neurotransmitter systems (dopamine and serotonin) particularly sensitive to glucocorticoids in persons with PTSD.
Grossman
Robert
R
Department of Psychiatry, Mount Sinai School of Medicine, New York, New York 10029-6574, USA. robertgrossman@yahoo.com
Yehuda
Rachel
R
Golier
Julia
J
McEwen
Bruce
B
Harvey
Philip
P
Maria
Nelly Sta
NS
D000328:Adult; D001288:Attention / Q000187:drug effects; D003071:Cognition / Q000187:drug effects*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000008:administration & dosage / Q000627:therapeutic use*; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects; D007275:Injections, Intravenous; D008214:Lymphocytes / Q000187:drug effects; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects; D008875:Middle Aged; D009483:Neuropsychological Tests; D011965:Receptors, Glucocorticoid / Q000187:drug effects; D013313:Stress Disorders, Post-Traumatic / Q000188:drug therapy* / Q000523:psychology*
D011965:Receptors, Glucocorticoid; D006854:Hydrocortisone