The cortisol awakening response (CAR) in treatment resistant unipolar depression

Abstract

Introduction: HPA axis dysfunction is found in some patients with depression, with preliminary evidence that it is especially prevalent in patients with treatment resistant depression (TRD). A naturalistic measure of HPA axis activity is the cortisol awakening response (CAR); this has yet to be studied in TRD. Methods: 27 patients with a primary diagnosis of unipolar TRD were recruited from a tertiary inpatient unit, all of whom were resistant to at least one prior antidepressant, along with 33 healthy controls matched for age, gender, weight/BMI and menstrual history. Salivarycortisolwasmeasuredat0,15, 30, 45, 60, 90 minutes following awakening over two consecutive days. The outcome variables used to assess the CARwere: a)mean cortisol levels at each timepoint over the two days; and b) total post-awakening cortisol output calculated using the area under the curve (AUC). Results: Patients were highly treatment resistant, having failed a mean of 4 prior antidepressants and 10 treatments in total. There was no significant difference in the mean (±SD) awakening cortisol value between patients (14.3±6.7 nmol/l) and controls (11.6± 5.1 nmol/l; p=0.09). However, all subsequent values were higher in patients: 15 minutes 16.6±6.6 vs 13.3±5.0 nmol/l, (p=0.03); 30 minutes 18.4±6.6 vs 14.7±6.3 nmol/l (p=0.04); 45 minutes 17.5±6.7 vs 13.6±6.7 nmol/l (p=0.04); 60 minutes 15.6±6.7 vs 11.6±5.4 nmol/l, (p=0.02); and 90 minutes 14.0±6.5 vs 8.9± 4.0 nmol/l, (p=0.002). The AUC was higher in patients both on Day 1 (1509±612 vs 1108±444 nmol/l.h, p=0.007) and Day 2 (1451±498 vs 1096±567 nmol/l.h, p=0.02). Conclusions: There is a heightened CAR in TRD, a previously unreported finding. TRD probably represents a biologically severe form of depression characterised by raised HPA activity. Raised HPA activity has potentially important implications in the aetiology and treatment of TRD.