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. Author manuscript; available in PMC: 2015 Jun 15.
Published in final edited form as: Psychopharmacology (Berl). 2011 May 27;218(2):371–379. doi: 10.1007/s00213-011-2336-y

A placebo-controlled study of sertraline’s effect on cortisol response to the dexamethasone/corticotropin-releasing hormone test in healthy adults

Linda L Carpenter 1,✉, Audrey R Tyrka 2, Janet K Lee 3, Aaron P Tracy 4, Charles W Wilkinson 5, Lawrence H Price 6
PMCID: PMC4467780  NIHMSID: NIHMS698610  PMID: 21617914

Abstract

Rationale

The dexamethasone/corticotropin-releasing hormone (Dex/CRH) test is a neuroendocrine probe involving serial blood sampling of cortisol during a standardized pharmacological challenge without inducing psychological distress in humans. Some past studies in depressed patients have shown a “normalization” or decrease in cortisol response to the Dex/CRH test following successful treatment with an antidepressant. Studies in nondepressed healthy adult samples have also shown aberrant cortisol reactivity to be associated with depression risk factors. These findings prompted research into the use of the Dex/CRH test as a tool for developing antidepressant drugs.

Objectives

In this study, the Dex/CRH test was evaluated with regard to its potential utility for drug development in nonclinical samples.

Methods

The Dex/CRH test was administered before and after 6 weeks of blinded treatment with either sertraline 100 mg/day or matching placebo in 22 healthy adults (13 women, nine men).

Results

Cortisol response to the Dex/CRH test increased following treatment with standard doses of sertraline, compared to placebo, after controlling for age and sex.

Conclusions

The observed pattern of change contrasts with results from published studies in depressed patients and with our initial hypothesis.

Keywords: Sertraline, Dex/CRH test, Cortisol, HPA axis

Introduction

Many have come to associate major depression with findings of excessive output by the hypothalamic–pituitary–adrenal (HPA) system and with glucocorticoid receptor resistance. These biological correlates have been suggested by numerous studies comparing basal and provoked cortisol concentrations in patients and nondepressed controls (Holsboer 2001; Ising et al. 2007). Some research groups have demonstrated “normalization” or dampening of cortisol indices concurrent with clinical improvement, as detected by response to standardized neuroendocrine challenge tests such as the dexamethasone/corticotropin-releasing hormone (Dex/CRH) test (Hatzinger et al. 2002; Heuser et al. 1996; Horstmann et al. 2009; Nickel et al. 2003; Zobel et al. 2001). The convergence of data generated with the Dex/CRH test in depression studies has led some researchers to consider whether the Dex/CRH test cortisol response may represent a trait marker (Holsboer et al. 1995) or a useful endophenotype (Hasler et al. 2004; Ising et al. 2007) for major depression or other psychiatric disorders. Others have suggested that the Dex/CRH test could be helpful in identifying candidate drugs for development as antidepressant medications (Ising et al. 2005a).

Compared with nondepressed controls, individuals with major depressive disorder may possess a differentially reactive HPA axis, both before and during their episodes of depression. Although the amplitude of the effect of an antidepressant drug may be very different in healthy and depressed individuals, it is unlikely that the fundamental mechanism of interaction between the drug and the HPA axis differs between the two groups. The preponderance of evidence suggests that modifications of HPA function occurring in depression are ones of degree rather than of kind (Ising et al. 2005a; Paizanis et al. 2009; Pariante et al. 2003; Schule 2007). Indeed, all preclinical work investigating the effects of antidepressants on components of the HPA axis, including in vitro and animal studies, assumes that the fundamental effects of the drugs will be the same regardless of individual differences in the system being studied.

Aberrant cortisol reactivity measured with the Dex/CRH test has been reported in adults (without psychopathology) selected on the basis of depression risk factors such as family history (Ising et al. 2005b), chronic work stress (Wirtz et al. 2008), inhibited temperament (Tyrka et al. 2008b), childhood parental loss (Tyrka et al. 2008a), and exposure to trauma in adulthood (Klaassens et al. 2010). The potential utility of characterizing the nature and consequences of these HPA axis reactivity endophenotypes is not known. The paucity of data on antidepressant treatment effects in nondepressed human subjects, including data describing treatment effects on candidate biomarkers such as cortisol reactivity, limits the ability to generate hypotheses about how pharmacological interventions might mitigate risk for developing psychiatric disorders. With these considerations in mind, we examined the effects of a standard antidepressant treatment on cortisol response to the Dex/CRH test in a randomized controlled trial with nondepressed healthy adult subjects. Based on past observations that cortisol response curves were generally reduced following successful antidepressant therapy, we studied healthy individuals with relatively high baseline cortisol responses to the test and hypothesized that 6 weeks of treatment with sertraline would lead to reductions in cortisol response, relative to that observed in subjects given placebo.

Methods

Subjects

Subjects were recruited from the community via flyers and through Internet and newspaper advertisements for healthy adults. Voluntary written informed consent was obtained for the study, which was approved by the Butler Hospital Institutional Review Board.

Phone screens and diagnostic interviews at the first clinic visit were used to exclude subjects meeting diagnostic criteria for current major depression, bipolar disorder, posttraumatic stress disorder, generalized anxiety disorder, obsessive–compulsive disorder, social anxiety disorder, panic disorder, substance use disorders, and all disorders characterized by psychosis. Current and lifetime history of axis I psychiatric diagnoses were assessed using the Structured Clinical Interview for DSM-IV (SCID; First et al. 1996). The SCID is a semi-structured diagnostic interview designed to evaluate symptoms corresponding with DSM-IV axis I disorders. Individuals endorsing only symptoms consistent with a diagnosis of dysthymia or specific phobia were not excluded from participation. Subjects with remote mood or substance use disorders were also not excluded, provided the symptoms were not clinically manifest and treatment was not indicated for at least the 1 year prior to participation in this study.

Participants completed physical and neurological examinations and laboratory studies, including electrocardiogram, complete blood count, serum electrolytes, thyroid-stimulating hormone (TSH), urine toxicology, and urinalysis. Subjects were excluded from the study if they worked night shifts or if they had acute or unstable medical illness, a history of brain injury, seizure disorder, endocrine disease, or recreational use of illicit substances. Also excluded were individuals undergoing treatment with drugs which might influence HPA axis function, including psychotropic medications, beta blockers, angiotensin-converting enzyme inhibitors, ketoconazole, metyrapone, and corticosteroids. Subjects were free of these medications for at least 2 weeks (or five half-lives, if appropriate) prior to participation. Oral contraceptives and estrogen replacement therapies were allowed.

Assessment instruments

The following additional self-report measures were included to characterize the sample at baseline in terms of symptoms and overall functioning: (1) Inventory of Depressive Symptomatology—Self-Report (IDS-SR; Rush et al. 1996), (2) State–Trait Anxiety Questionnaire (STAI; Spielberger 1983), (3) Perceived Stress Scale (Cohen et al. 1983), (4) Quality of Life Enjoyment and Satisfaction Questionnaire (Endicott et al. 1993), and (5) the 28-item version of the Childhood Trauma Questionnaire (Bernstein et al. 2003).

The Dex/CRH test

During a separate clinic visit, subjects completed the Dex/CRH test. The night before the test, a single oral dose of dexamethasone 1.5 mg was self-administered at 11:00 P.M. The following day, participants arrived at 12:00 P.M. and were given lunch. Topical anesthetic cream containing lidocaine 2.5% and prilocaine 2.5% was applied to the subject’s forearm between 12:30 and 12:45 P.M. Participants were queried prior to beginning the Dex/CRH test for any excessive use of alcohol the night prior, and urine toxicology screens were required prior to and on day of test, if use was suspected for any reason. According to our standard procedures, subjects were encouraged to maintain their usual daily habits with regard to consumption of modest amounts of caffeinated and alcoholic beverages and nicotine use before the Dex/CRH tests, to avoid precipitating withdrawal symptoms. Concurrent medication use, recorded at the time of pre-treatment physical exam and at each Dex/CRH test, revealed participants were taking the following: over-the-counter vitamins (n=7), inhalers prescribed for use as-needed for mild/intermittent bronchoconstriction (n=2; none used during the test procedure), stable maintenance doses of levothyroxine with normal range TSH (n=2), and stable use of oral contraceptive tablets (n=2) or a contraceptive vaginal ring (n=1).

At 1:00 P.M., an indwelling intravenous (IV) catheter was inserted in the forearm by a research nurse with extensive experience with IV catheter placement. Subjects then remained in a semi-recumbent position throughout the procedure except to use the bathroom. They were permitted to read or watch pre-selected movies that did not contain emotionally charged material. Vital signs were monitored throughout the test. At 3:00 P.M., CRH (corticorelin ovine triflutate, Acthrel®, Ferring Pharmaceuticals, Inc.) 100 μg reconstituted in 2 ml 0.9% sodium chloride was infused intravenously over 30 s. Blood samples were drawn at 2:59 P.M. (baseline) and following the CRH infusion at 3:30 P.M. (30 min), 3:45 P.M. (45 min), 4:00 P.M. (60 min), and 4:15 P.M. (75 min), Samples were immediately stored on ice, centrifuged within 45 min, and then stored at −80°C for assay of cortisol.

Plasma cortisol concentration was measured with the double antibody DSL-2000 Cortisol Radioimmunoassay Kit (Diagnostic Systems Laboratories, Webster, TX, USA) according to the manufacturer’s instructions. The antiserum has 100% cross-reactivity with cortisol and only 0.38% cross-reactivity with dexamethasone. The intra- and inter-assay coefficients of variation are 5.3% and 7.0%, respectively. Using a 25-μl sample, the minimum detectable level of cortisol is 4.8 nmol/l. Pre-treatment and post-treatment cortisol response curves were generated for each subject and area under the curve (AUC) calculated with the trapezoidal rule.

Randomization, drug treatment, and follow-up assessments

Subjects were considered eligible, randomized, and instructed to commence study medication approximately 7–10 days following their initial Dex/CRH tests if assay results confirmed a pre-treatment cortisol AUC response of 3,000 nmol/l min or greater. As “normal” reference ranges for Dex/CRH test cortisol response are not known, this criterion for minimum cortisol response was based on descriptive (median and range values) statistics derived from our healthy subject database at the time of study initiation, as well as on practical considerations of feasibility in recruiting healthy subjects with a sufficiently high baseline cortisol response to the Dex/CRH test to permit testing of our a priori hypothesis. The (unblinded) data manager ran a computer-generated randomization procedure (SPSS) to generate a random and unpredictable sequence of allocations to two treatment groups before the trial began. The randomization list was kept in the hospital pharmacy, where prescriptions for study medication were received, assigned to drug or placebo according to serial entry on the list, and filled by the unblinded research pharmacist. The subject assignment list was released by the pharmacist following collection of all data at the end of the study.

Subjects started sertraline at 50 mg (one capsule) or matching placebo each day for 7 days. If no significant side effects occurred, the dose was titrated to 50 mg twice daily for weeks 2 through 6. Compliance, somatic symptoms, and side effects were measured at baseline and after weeks 2, 4, and 6 on drug by spontaneous report, general clinical interview, and with a self-report checklist (Symptom Checklist-90; Derogatis and Cleary 1977). Self-report forms at each assessment included the Adverse Symptoms Checklist (SAFTEE-SI; Levine and Schooler 1986). Following 6 weeks of drug or placebo treatment, the IDS-SR scale and Dex/CRH test were repeated, and cortisol assays were performed. Women were scheduled for their post-treatment Dex/CRH tests after consideration of number of days from last menses and approximate phase of menstrual cycle to enhance consistency of hormonal state across assessment times.

Statistics

Simple descriptive statistics were use to characterize treatment-emergent side effects. t test and chi-square statistics were used to compare sample characteristics, and a bivariate correlation matrix was generated to examine relationships between pre-treatment cortisol AUC and other baseline clinical characteristics. For each subject, the change in cortisol AUC from pre-treatment to post-treatment Dex/CRH test (ΔAUC) was calculated. General linear model (GLM) univariate analysis of variance was used to examine the effect of treatment group on cortisol ΔAUC, controlling for pre-treatment AUC value. Independent samples t tests were used to test for baseline sex differences in pre-treatment data, and paired t tests were used to compare within-subject data from serial assessments in each treatment group. Post hoc GLMs were constructed to examine the treatment group effect with sex and age as covariates and the durability of main findings when other potential confounds were included in the model (BMI, dichotomized nicotine use, and depression scale scores).

Results

Fifty-five subjects underwent baseline assessments, including Dex/CRH testing. Twenty-three subjects met criteria for minimum baseline cortisol AUC (AUC greater than 3,000 nmol/l min) and were randomized to treatment with either sertraline or placebo; n=22 completed the post-drug assessments and repeat neuroendocrine test. Diagnostic interviews determined that nine of the final 22 participants met criteria for “probable” or “definite” past (lifetime) axis I disorders; four of these were randomized to sertraline and five to placebo treatment. A total of three subjects had sought or received past treatment for psychiatric symptoms (two in sertraline and one in the placebo group); one had been treated for substance-induced mood disorder and remote alcohol dependence followed by nearly 10 years sustained remission of both conditions; one subject was treated for symptoms of dysthymia, and one subject was treated for a past single episode of major depression considered to be mild or moderate in severity, followed by full remission over 5 years without subsequent treatment. All previous psychiatric treatments had been undertaken over 5 years prior to the beginning to this investigation.

The distribution of sex across randomized groups included 13 women (n=6 [46%] to sertraline and n=7 [54%] to placebo) and nine men (n=5 [56%] to sertraline and n=4 [45] to placebo), a nonsignificant difference on chi-square analysis. There were no significant differences between the sertraline and placebo groups on any of the clinical and demographic variables examined (Table 1), and there were no significant correlations found between pre-treatment cortisol AUC and the other clinical symptom or demographic measures represented as continuous data. Comparison of male and female subjects with independent t tests showed pre-treatment cortisol AUC values did not differ by sex. Cortisol concentrations for “time point 0” (following dexamethasone pre-treatment but before infusion of the CRH challenge dose) did not differ between groups at the pre-treatment assessment, between groups as the post-treatment assessment, or within groups over time. There was a wide range of pre-treatment cortisol AUC response values, ranging from 4,201 to 12,393 nmol/l min, but the means did not differ significantly between groups (mean±SD, 8,089±2,363 vs 8,858±2,203; p=0.44). The post-treatment cortisol AUC ranged from 1,035 to 23,279 nmol/l min.

Table 1.

Demographic and clinical characteristics of healthy sample

Sertraline (n=11) Placebo (n=11)
Age, years
Mean (SD), range 30.18 (8.5), 20–46 28.73 (10.6), 20–54
Sex, n (%)
Female 6 (55%) 7 (63%)
 Menstrual cycle phasea
 Luteal phase, n (% of women) 1 (16.7%) 1 (14.3%)
 Follicular phase, n (% of women) 3 (50.0%) 3 (42.9%)
 Post-menopausal, n (% of women) 0 (0.0%) 1 (14.3%)
 Menses 2 (33.3%) 2 (28.6%)
Male 5 (45.5%) 4 (36.4%)
Use of estrogen
n (% of women) 3 (50.0%) 1 (14.3%)
Depression symptoms (IDS-SR score), mean (SD)
Pre-treatment 6.82 (3.28) 11.73 (9.32)
Post-treatment 8.64 (4.69) 12.55 (7.71)
State Anxiety (STAI) Scale
Mean (SD) 31.45 (9.52) 29.55 (7.20)
Trait Anxiety (STAI) Scale
Mean (SD) 32.09 (6.82) 31.72 (10.87)
Perceived Stress Scale
Mean (SD) 16.90 (3.56) 19.36 (7.33)
Childhood Trauma Questionnaire Total, 28-item version
Mean (SD) 7.02 (2.39) 7.04 (4.11)
Quality of Life and Satisfaction, Short Form Total
Mean (SD) 4.20 (0.63) 4.18 (0.75)
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No significant differences (p< 0.05) were detected between groups with chi-square and t tests

a

Steps were undertaken to enhance consistency of menstrual cycle phase at time of pre- and post-treatment Dex/CRH testing

The GLM revealed a significant effect of treatment group (F=6.7, p=0.02), such that mean cortisol ΔAUC was greater for those who took active sertraline than for those in the placebo group. As graphed in Fig. 1, sertraline treatment was associated with an overall increase in mean cortisol response to the test. Pre-treatment cortisol AUC, entered in the model as a covariate, was associated with ΔAUC (F=5.8, p=0.03) in a fashion suggesting greater changes over time among those who had relatively lower pre-treatment cortisol responses to the Dex/CRH test. A post hoc model which also included age and sex as covariates retained the significant treatment group effect (F=10.2, p=0.005), after controlling for the effect of sex (F=9.1, p=0.008). Use of estrogen was not significantly related to pre-treatment cortisol AUC values or to cortisol ΔAUC in either group.

Fig. 1.

Fig. 1

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Mean plasma cortisol concentrations (with standard error bars) during the Dex/CRH test, administered before and after 6 weeks of blinded treatment with either sertraline 100 mg/day or matching placebo in 22 healthy adults

Several other potentially confounding variables were subsequently examined. There were no statistically significant effects of age or BMI on the outcomes, and analyses re-run with nicotine use (n=1 smoker in placebo group, n= 2 smokers in sertraline) included as a covariate in the model also retained their statistically significant main finding of treatment group effect. We did not detect a significant change in (subclinical) depressive symptom scores following drug treatment in either group. The magnitude of cortisol ΔAUC with treatment did not correlate with corresponding change in IDS-SR scores over time.

Treatment-emergent side effects reported by the subjects were consistent with those reported in clinical trials and in typical clinical practice. Two of the 11 sertraline subjects rated several related adverse effects as “severe”: One participant endorsed trouble sleeping, nightmares, drowsiness, and loss of sex interest, while another reported problems with sex arousal and interest, and orgasm. One additional subject reported drowsiness and one reported trouble sleeping. Cortisol ΔAUC was not significantly different in these four subjects compared to the other sertraline subjects. There were no side effects ranked as “severe” by the placebo group, but a number of side effects were rated as “mild” or “moderate” by both groups.

Discussion

In contrast to our hypothesis, results of this study suggest that sertraline treatment at standard doses significantly increases the cortisol response to the Dex/CRH test in healthy adults with relatively high initial cortisol responses to the Dex/CRH test. A significant change in cortisol response to serial administration of the Dex/CRH test was not observed for those who received placebo.

It is unlikely that nonspecific stress effects of the test were inducing greater cortisol release at the post-treatment assessment, as all subjects were familiar with the laboratory procedure at that time and none reported subjective distress. Use of a design involving sequential within-subjects Dex/CRH tests compared across treatment groups, in conjunction with the finding that pre-infusion cortisol concentrations did not vary following the course of treatment, supports the inference that observed changes during sertra-line treatment reflect the coordinated HPA axis response to the CRH infusion challenge rather than basal concentrations or the cortisol response to dexamethasone. The dose and duration of sertraline used in this study are consistent with standard clinical practice, though the absence of plasma sertraline and dexamethasone blood levels may be considered a limitation, especially in light of the unexpected findings.

Enrichment of the sample with individuals showing relatively high baseline cortisol response to the Dex/CRH test produced a sample whose proposed HPA reactivity endophenotype was similar to that reported for other at-risk populations (Ising et al. 2005b; Zobel et al. 2004). The use of a minimal pre-treatment cortisol reactivity criterion might also represent a limitation of the current study design, since it was intended to exclude healthy subjects whose baseline cortisol response to the test was already too low to show treatment-induced reduction. However, this maneuver would not likely account for the sertraline-associated increase in cortisol we observed.

Prior studies in healthy adults have involved acute challenge with selective serotonin reuptake inhibitors (Carpenter et al. 2003; Laakmann et al. 1988; Petraglia et al. 1984; Seifritz et al. 1996; Skene et al. 1994; von Bardeleben et al. 1989), and these typically suggest stimulation of HPA axis as reflected by elevation in cortisol concentrations following a single dose administration. In healthy men, both resting state cortisol concentration and provoked cortisol response (to physical exercise challenge on a treadmill) measured 8.5 h following a single oral dose of sertraline 100 mg were greater than those following placebo administration (Ahrens et al. 2007). Increased cortisol secretion following acute sertraline challenge has also been observed in animal studies, particularly among females (Broadbear et al. 2004).

However, divergent neuroendocrine effects are commonly generated from experiments involving acute versus chronic exposure to antidepressant drugs in preclinical studies (Bano et al. 2010; O’Donnell and Grealy 1992), and enhanced cortisol reactivity is typically not seen in investigations of chronic antidepressant treatment effects in humans. A report by Heuser et al. (1996) included data from 14 age-matched healthy comparison subjects, whose pre- and post-amitriptyline treatment (6 week) cortisol data were contrasted with similar data obtained from 39 elderly patients with depression. While amitriptyline appeared to attenuate cortisol concentrations in the Dex/CRH test for a subset of depressed patients, the same pattern of change was not seen in healthy control subjects. That study did not include any controls with relatively “high” baseline cortisol reactivity, and no statistically significant relationship emerged between changes in cortisol response over time and resolution of depression symptoms.

One study of chronic sertraline treatment also examined acute HPA axis response to steroid challenge (Cooney and Dinan 2000). In six patients with melancholic depression, basal cortisol concentrations were significantly higher before 4 weeks of treatment with sertraline, compared to those obtained after treatment; all patients were considered clinical responders. Cortisol response curves (provoked by intravenous hydrocortisone infusion over 60 min) did not show change over time associated with antidepressant treatment in these patients, leading the authors to conclude that acute phase negative feedback mechanisms are intact in depression, even in the presence of relative basal hypercortisolism. A number of investigations in depressed patients have highlighted a pattern of diminished Dex/CRH test cortisol response over time as a correlate or predictor of clinical improvement during antidepressant therapy (Sagud et al. 2002; Schule et al. 2006), with persisting patterns of elevated cortisol response to the test despite clinical remission predicting enhanced risk for future relapse. Very few have found increased cortisol reactivity in depressed patients associated with chronic pharmacotherapy, though two studies reported increased cortisol reactivity following lithium augmentation of antidepressants (Adli et al. 2009; Bschor et al. 2002).

One criticism of investigations into the usefulness of the Dex/CRH test as a predictor of antidepressant response has involved the ascertainment of “baseline” neuroendocrine data from depressed inpatients that are not free of psychotropic medications. Post hoc analyses from a multicenter study (Kunugi et al. 2006) indicated that concurrent medication use did not diminish the ability of the Dex/CRH test results to predict outcome at the time of hospital discharge. The results we report here for sertraline underscore the possibility that “baseline” Dex/CRH test values could be elevated or otherwise altered as a function of the underlying drug treatment, even if the antidepressant has been unsuccessful in producing symptom relief. Furthermore, a pattern of relatively “excessive” cortisol release to this neuroendocrine challenge has not proven characteristic of all severely depressed inpatients (Carroll et al. 2007; Pfennig et al. 2005; Schule et al. 2009) and is typically not associated with depression in outpatients or in those with atypical features (Brouwer et al. 2005; Carpenter et al. 2009a; Gervasoni et al. 2004; Oshima et al. 2000; Rydmark et al. 2006; Watson et al. 2002). Additional evidence of limited or no predictive utility comes from one recent report of serial Dex/CRH tests in depressed men, which found that relatively low cortisol response values before initiation of treatment predicted best outcome with fluoxetine (Paslakis et al. 2010).

In summary, our findings indicate that cortisol response to the Dex/CRH in healthy nondepressed adults does not appear to decrease over time with chronic antidepressant treatment. While we acknowledge the potential impact of the small sample size, there are no previous controlled studies to examine this effect in healthy subjects. These findings are important, given the extensive use of the Dex/CRH test for assessing HPA axis function in a variety of pathological conditions and for studying the mechanism of action of numerous therapeutic agents. A growing literature has identified a collection of clinical and demographic variables exerting significant effects on the cortisol response to the Dex/CRH test, including age (Kunugi et al. 2006), sex (Haefner et al. 2008), temperament (Tyrka et al. 2008b), coping style (Hori et al. 2010), early life adversity (Carpenter et al. 2009b; Heim et al. 2008), quality of parental care (Tyrka et al. 2008a), adult trauma exposure (Klaassens et al. 2009), social support (Tsuru et al. 2008), psychiatric comorbidity (Veen et al. 2009), and genotype (Binder et al. 2010; Tyrka et al. 2009; Zobel et al. 2010). Assumptions about qualitatively similar cellular and system-level responses to receptor activation by sertraline across depressed and healthy subjects supported the rationale for this investigation. Our unexpected findings lead us to speculate about contributions from the many complex effects involved in HPA axis reactivity and to conclude that the Dex/CRH test cortisol response may not be a useful tool for evaluating the potential effectiveness of antidepressants on HPA axis downregulation in healthy volunteers. Recent data describing gene–gender effects on Dex/CRH test response (Haefner et al. 2008) suggest a further avenue of research inquiry for understanding our results.

Acknowledgments

The authors thank Kelly Colombo, B.A. for her assistance with data management, Ashley Clement for her research assistant support in manuscript preparation, and Daniel Gonzalez for performance of the cortisol assays. This work was supported by an investigator-initiated grant from Pfizer Inc. (LLC) and by the Department of Veterans Affairs (CWW).

Footnotes

Conflicts of interest The authors have no conflicts of interest to disclose.

Contributor Information

Linda L. Carpenter, Email: Linda_Carpenter_MD@brown.edu, Mood Disorders Research Program and Laboratory for Clinical Neuroscience, Brown Department of Psychiatry and Human Behavior, Butler Hospital, 345 Blackstone Blvd., Providence, RI 02906, USA

Audrey R. Tyrka, Mood Disorders Research Program and Laboratory for Clinical Neuroscience, Brown Department of Psychiatry and Human Behavior, Butler Hospital, 345 Blackstone Blvd., Providence, RI 02906, USA

Janet K. Lee, Mood Disorders Research Program and Laboratory for Clinical Neuroscience, Brown Department of Psychiatry and Human Behavior, Butler Hospital, 345 Blackstone Blvd., Providence, RI 02906, USA

Aaron P. Tracy, Mood Disorders Research Program and Laboratory for Clinical Neuroscience, Brown Department of Psychiatry and Human Behavior, Butler Hospital, 345 Blackstone Blvd., Providence, RI 02906, USA

Charles W. Wilkinson, Geriatric Research, Education and Clinical Center, VA Puget Sound Health Care System, 1660 S. Columbian Way, Seattle, WA 98108, USA. Department of Psychiatry and Behavioral Sciences, University of Washington, 1660 S. Columbian Way, Seattle, WA 98108, USA

Lawrence H. Price, Mood Disorders Research Program and Laboratory for Clinical Neuroscience, Brown Department of Psychiatry and Human Behavior, Butler Hospital, 345 Blackstone Blvd., Providence, RI 02906, USA

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