Longitudinal effects of the SSRI paroxetine on salivary cortisol in Major Depressive Disorder

Abstract

Hypothalamic-pituitary-adrenal (HPA)-axis dysregulation is a prominent finding in more severe Major Depressive Disorder (MDD), and is characterized by increased baseline cortisol levels at awakening (BCL), blunted cortisol awakening response (CAR) and increased area under the cortisol curve (AUC). Selective serotonin reuptake inhibitors (SSRIs) appear to normalize HPA-axis dysfunction, but this is hardly investigated longitudinally.We studied salivary BCL, CAR and AUC at awakening and 30 min thereafter. We compared measurements in initially drug-free MDD-patients with healthy controls (HCs) at study-entry. In patients, we repeated measures after 6 and 12 weeks' treatment with the SSRI paroxetine. Non-responding patients received a randomized dose-escalation after six weeks' treatment.We found no significant study-entry differences in BLC, CAR or AUC between MDD-patients (n = 70) and controls (n = 51). In MDD-patients, we found general decreases of BCL and AUC during paroxetine treatment (p ≤ 0.007), especially in late and non-responders. Importantly, while overall CAR did not change significantly over time, it robustly increased over 12 weeks especially when patients achieved remission (p ≤ 0.041). The dose-escalation intervention did not significantly influence CAR or other cortisol parameters.In conclusion, paroxetine seems to interfere with HPA-axis dysregulation, reflected in significant overall decreases in BCL and AUC during treatment. Paroxetine appears to decrease HPA-axis set-point in MDD, which might result in increased HPA-axis activity over time, which is further improved when patients achieve remission (ISRCTN register nr. ISRCTN44111488).

DHEAS and cortisol/DHEAS-ratio in recurrent depression: State, or trait predicting 10-year recurrence?

“…a state effect), but are rather a proxy for (the possibility of) successful treatment (Ruhé et al, 2015). For example, as noted before (Ruhé et al, 2015), antidepressants' effect on multidrug resistance p-glycoprotein may be a prerequisite for their clinical effectiveness (Pariante, 2008;Pariante et al, 2004).…”

“…a state effect), but are rather a proxy for (the possibility of) successful treatment (Ruhé et al, 2015). For example, as noted before (Ruhé et al, 2015), antidepressants' effect on multidrug resistance p-glycoprotein may be a prerequisite for their clinical effectiveness (Pariante, 2008;Pariante et al, 2004). Given that DHEAS also is a substrate for p-glycoprotein (Bortfeld et al, 2006;Zelcer et al, 2003), the changes in DHEAS during successful antidepressant treatment may not reflect a state-effect, but rather the effective modulation of p-glycoprotein by the antidepressant (Ruhé et al, 2015).…”

The effects of six-day SSRI administration on diurnal cortisol secretion in healthy volunteers

“…This finding is supported by the work of Harmer et al (2003) who found that six-day administration of citalopram (20 mg/day) brought about significant increases in waking cortisol in healthy volunteers. Interestingly, in depressed patients, SSRIs have been found to lower waking cortisol levels (Knorr et al 2012; Ruhé et al 2015). Since waking cortisol levels may be increased in depression (Bhagwagar et al 2005), the direction of the effect of SSRIs on waking cortisol could be related to mental health status.…”

“…However, very few studies have examined this. In patients with major depressive disorder (MDD), and in first-degree relatives of depressed patients, longer-term administration of SSRIs has been found to decrease cortisol AUC and decrease waking cortisol levels (Hinkelmann et al 2012; Knorr et al 2012; Ruhé et al 2015). This small body of work suggests that SSRI treatment affects the pattern of diurnal cortisol secretion in depressed patients and those at risk of depression.…”

“…This small body of work suggests that SSRI treatment affects the pattern of diurnal cortisol secretion in depressed patients and those at risk of depression. However, some of the studies cited above report symptom remission alongside SSRI-induced alterations in diurnal cortisol secretion (Hinkelmann et al 2012; Ruhé et al 2015). In addition, studying this association in depressed patients may be confounded by symptomatic features of the disease, medications, and clinical history.…”