Cortisol Stress Response and in Vivo PET Imaging of Human Brain Serotonin 1A Receptor Binding

Cortisol Stress Response and in Vivo PET Imaging of Human Brain Serotonin 1A Receptor Binding Background: Abnormalities in the hypothalamic-pituitary-adrenal axis, serotonergic system, and stress response have been linked to the pathogenesis of major depressive disorder. State-dependent hyper-reactivity of the hypothalamic-pituitary- adrenal axis is seen in major depressive disorder, and higher binding to the serotonin 1A receptor is observed as a trait in both currently depressed and remitted untreated major depressive disorder. Here, we sought to examine whether a relationship exists between cortisol secretion in response to a stressor and serotonin 1A receptor binding throughout the brain, both in healthy controls and participants with major depressive disorder. Methods: Research participants included 42 medication-free, depressed subjects and 31 healthy volunteers. Participants were exposed to either an acute, physical stressor (radial artery catheter insertion) or a psychological stressor (Trier Social Stress Test). Levels of serotonin 1A receptor binding on positron emission tomography with [C]WAY-100635 were also obtained from all participants. The relationship between [C]WAY-100635 binding and cortisol was examined using mixed linear effects models with group (major depressive disorder vs control), cortisol, brain region, and their interactions as fixed effects and subject as a random effect. Results: We found a positive correlation between post-stress cortisol measures and serotonin 1A receptor ligand binding levels across multiple cortical and subcortical regions, independent of diagnosis and with both types of stress. The relationship between [ C]WAY-100635 binding and cortisol was homogenous across all a priori brain regions. In contrast, resting cortisol levels were negatively correlated with serotonin 1A receptor ligand binding levels independently of diagnosis, except in the RN. There was no significant difference in cortisol between major depressive disorder participants and healthy volunteers with either stressor. Similarly, there was no correlation between cortisol and depression severity in either stressor group. Received: July 19, 2018; Revised: December 7, 2018; Accepted: February 15, 2019 © The Author(s) 2019. Published by Oxford University Press on behalf of CINP. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any 329 medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ijnp/article-abstract/22/5/329/5423589 by Ed 'DeepDyve' Gillespie user on 07 May 2019 330 | International Journal of Neuropsychopharmacology, 2019 Significance Statement The relationship between the body’s response to stress and the function of serotonin in the brain has been a subject of interest in depression research. Several studies have examined this by manipulating the body’s stress response system externally—either by administering medications, such as steroids, or by removing adrenal glands surgically. The data resulting from these studies has been mixed and inconclusive. Here, we show human data from healthy volunteers and participants with major depression. We studied the body’s self-generated stress response, cortisol levels, to 2 different types of stressors: a physical and a psy- chological stressor. We found that with both stressors, greater cortisol levels are associated with higher levels of serotonin 1A receptor binding throughout the brain. There is also an inverse association between resting cortisol levels and receptor binding. Both findings were independent of diagnosis. This suggests that healthy volunteers and depressed subjects are biologically on a continuum, and that individuals with a more pronounced stress response tend to have higher levels of serotonin 1A receptor throughout the brain. Our data add to the literature by demonstrating a link between acute stress responses and serotonin 1A receptor availability in humans. Conclusions: This study suggests that there may be a common underlying mechanism that links abnormalities in the serotonin system and hypothalamic-pituitary-adrenal axis hyper-reactivity to stress. Future studies need to determine how hypothalamic-pituitary-adrenal axis dysfunction affects mood to increase the risk of suicide in major depression. Keywords: cortisol, PET imaging, serotonin, stress Introduction The hypothalamic-pituitary-adrenal (HPA) axis and the sero- 5-HT receptor agonists (Lesch et  al., 1989Y ; oung et  al., 1994; 1A tonin system have a complex bidirectional relationship (Meijer Porter et al., 19982002 , ). However, overall, results are mixed and and de Kloet, 1994; Porter et  al., 2004). This relationship is of may depend on the type of corticosteroid used and the duration potential importance in the pathogenesis of mood disorders, of exposure (Porter et  al., 1999, 2002; Montgomery et  al., 2001; because major depressive episodes are associated with trait Bhagwagar et  al., 2003). Prior positron emission tomography abnormalities in the serotonin system, including 5-HT re- (PET) imaging studies in humans have failed to detect an effect 1A ceptor upregulation (Parsey et  al., 2006a), and with hyper - of acute administration of corticosteroids on 5-HT receptor 1A active HPA axis responses to stress, which are state dependent ligand binding (Montgomery et al., 2001Bha ; gwagar et al., 2003). (Cowen, 2010; Stetler and Miller, 2011). More severe depressive However, such studies did not examine stress-induced cortisol episodes, such as those characterized by psychomotor agitation release, which may differ from pharmacologically induced cor - or psychotic features, have more severely dysregulated HPA axis tisol effects and be abnormal in subgroups of patients. function as indicated by heavier adrenal glands, higher levels To better understand the relationship between stress, HPA of corticotropin releasing factor (CRF) in brain tissue and cere- axis reactivity, depression, and 5-HT receptor levels in the brain, 1A brospinal fluid, lower CRF receptor binding in prefrontal cortex we studied the relationship between the endogenous cortisol re- postmortem, a blunted cortisol suppression response to dexa- sponse to acute stress and 5-HT receptor binding as measured 1A methasone, and greater cortisol release both at baseline and by PET. We chose 2 different types of acute stressors: (1) the Trier in response to social stressors (Lindy et  al., 1985Br ; own et  al., Social Stress Task (TSST) (Kirschbaum et al., 1993), which is a psy- 1986; Nemeroff et al., 1988; Arató et al., 1989; Pfennig et al., 2005; chological stress paradigm, and (2) arterial line placement prior to Mann et  al., 2006; Melhem et  al., 2016). Genetic and epigenetic PET, a physical stressor that involves restraint and physical dis- associations with enhanced HPA axis stress responses have comfort. Cortisol was measured in healthy volunteers and med- also been observed in major depressive disorder (MDD) and in ication-free depressed subjects: (1) in a blood sample drawn just those reporting early-life stress, which is a risk factor for MDD after arterial line placement, or (2) in saliva as part of the TSST. (McGowan et al., 2009; Coplan et al., 2011 Y ; in et al., 2016). Given our finding of elevated [ C]-WAY-100635 binding and HPA The relationship between markers of serotonergic tone and hyperactivity in MDD (Parsey et  al., 2006aMiller ; et  al., 2009a; HPA axis function has been extensively studied. Cortisol induces Parsey et al., 2010; Milak et al., 2018), we predicted a positive correl- tryptophan 2,3-dioxygenase, which metabolizes L-tryptophan, ation between regional [C]-WAY-100635 binding and post-stress thereby decreasing L-tryptophan availability for serotonin syn- cortisol levels despite rodent studies that might predict an inverse thesis (Badawy et  al., 1995). Animal work has demonstrated relationship between the two. We predicted an inverse relation- that adrenalectomized rats show increased post-synaptic ship between resting cortisol and regional [ C]-WAY-100635 bind- serotonin-1A (5-HT ) receptor binding in the hippocampus, ing, as more severe depressive pathology is associated with higher 1A whereas chronic treatment with corticosterone reduces expres- 5-HT binding on PET (Sullivan et al., 2015Oquendo et  ; al., 2016) 1A sion, binding, and function of 5-HT receptors in hippocam- and lower peripheral resting cortisol levels (Pfennig et  al., 2005; 1A pal fields (Martire et  al., 1989; Mendelson and McEwen, 1992; Jokinen et al., 2010; McGirr et al., 2011Melhem et al., ; 2016). Chalmers et  al., 1993; Kuroda et  al., 1994; Meijer and de Kloet, 1994; Laaris et  al., 1995; Zhong and Ciaranello, 1995; Le Corre Methods et al., 1997; Czyrak et al., 2002), suggesting receptor upregulation in response to low serotonergic tone. Some human studies are Participants consistent with these findings, with corticosteroid treatment causing blunting of 5-HT receptor-mediated responses, includ- Seventy-three adult subjects with PET scans using C]W [ AY- 1A 100635 were included in this analysis. Participants underwent 1 ing the hypothermic and serum growth hormone responses to Downloaded from https://academic.oup.com/ijnp/article-abstract/22/5/329/5423589 by Ed 'DeepDyve' Gillespie user on 07 May 2019 Steinberg et al. | 331 of 2 stressors: (1) arterial line placement before a PET scan (n = 34) PET images were acquired with an ECAT EXACT HR+ scanner or (2) the TSST (n= 39). Participants from stress paradigm (1) had (Siemens/CTI, Knoxville, TN) as previously detailed (Parsey et al., cortisol assayed in a blood sample drawn immediately after their 2000). Briefly, after a 15-minute transmission scan, an injection arterial line was placed, while participants of paradigm (2) had of [ C]-WAY-100635 was administered over 30 seconds and then salivary cortisol assayed in samples collected at multiple time- an emission scan of 110 minutes, consisting of 20 frames of points during the TSST. The PET data presented here were pre- increasing duration (3× 20 seconds, 3 × 1 minute, 3 × 2 minutes, viously reported in published studies (Parsey et al., 2006a 2006b , , 2 × 5 minutes, 9 × 10 minutes), was obtained. 2010; Miller et al., 2009b), but the cortisol data have never been To correct for subject motion, each PET frame was registered published. Subject selection was based on the availability of us- to the eighth frame of the scan using the FMRIB linear image reg- able [ C]WAY-100635 brain binding data and either plasma cor - istration tool, version 5.0 (FMRIB Image Analysis Group, Oxford, tisol or TSST saliva cortisol stress sample measurements. UK). Brain regions of interest (ROIs) were chosen a priori based Fourty-two depressed participants (25 female, 17 male) aged on areas of abundant [ C]-WAY-100635 binding (Hall et al., 1997) 18 to 62  years who met DSM-IV criteria for MDD in a current that included raphe nuclei (RN), anterior cingulate, cingulate, major depressive episode (as assessed by doctoral- or masters’- dorsal prefrontal cortex, hippocampus, insula, medial prefrontal level psychologists and reviewed in a consensus conference of cortex, parietal cortex, parahippocampal gyrus, occipital cortex, research psychologists and psychiatrists), a 17-item Hamilton orbital cortex, temporal cortex, and amygdala. Cerebellar white Depression Rating Scale (HDRS) score REF ≥16, and capacity matter was used as a reference region. All ROIs except for RN to provide informed consent were included in the analysis. were identified on each individual’s T1-weighted MRI using a Depression severity was assessed with the 24-item HDRS and previously described automated algorithm (Milak et  al., 2010). the Beck Depression Inventory (BDI) REF. Thirty-one healthy vol- Due to their small size, RN were labeled using a standard space unteers (19 female, 12 male) aged 18 to 65 years with no history mask of the average location of the RN in 52 healthy subjects, of DSM-IV Axis I or Axis II psychiatric disorders, no psychotropic which was created using [ C]-WAY-100635 voxel binding maps medication exposure, and no family history of a mood disorder as previously described (Delorenzo et al., 2013). MRI T1 images or schizophrenia were included. Neither group had significant were transformed into standardized 3D space using Advanced medical illness, nor were they taking medications that may Normalization Tools (7), and the reverse transform was applied affect the serotonin system at the time of neuroimaging. For to the RN mask. all subjects, the Structured Clinical Interview for DSM-IV Axis PET images were co-registered to the MRI images using the I  Disorders (First et  al., 2012) as well as psychiatric and medi- FMRIB linear image registration tool, optimized as previously cal history, chart review, physical examination, routine blood described (Delorenzo et  al., 2009). The average activity meas- tests, pregnancy test, urine toxicology, and electrocardiogram ured over the voxels within each ROI over the specified time were performed to assess study eligibility. Exclusion criteria frames through the course of the acquisition generated time included presence of significant medical conditions, alcohol or activity curves. other substance use disorder unless in complete remission for >6  months, dementia, neurological disease, head injury with Outcome Measure Estimation loss of consciousness, pregnancy, first-degree family history of Distribution volumes (V) of [ C]WAY-100635 were estimated for schizophrenia if subject was <33  years old (Sham et  al., 1994), each ROI using kinetic analysis with an arterial input function and >3 lifetime exposures to 3,4-methylenedioxymethampheta- and a 2-tissue compartment constrained model as previously mine. For depressed participants specifically, exclusion criteria described (Parsey et al., 2000). Time activity curves were fit with also included fluoxetine use within 6 weeks of PET scanning, a 2-tissue compartment constrained model in which the K/k or exposure to a 5-HT receptor agonist, such as buspirone, 1 2 1A ratio was constrained to that of the reference region (cerebellar vortioxetine, vilazodone, or lysergic acid diethylamide, within white matter) for each ROI. BP was calculated as (V – V )/ 6  months of scanning. At the time of the scan all participants F T(ROI) T(REF) f , where V is the volume of distribution in a specific ROI, were unmedicated. Depressed subjects who were on ineffective P T(ROI) V is the volume of distribution in the reference region, and f antidepressant treatment at the time of evaluation underwent T(REF) P is the free fraction in plasma. a medication washout and were drug-free for at least 2 weeks prior to neuroimaging. The Institutional Review Board of the New York State Psychiatric Institute approved the protocol, and Cortisol Measurement all subjects provided informed written consent after an expla- nation of the study protocol and associated risks. Blood cortisol was measured in blood samples drawn from 34 subjects immediately prior to PET scans and just after the arte- rial line was inserted. Given the diurnal variation of cortisol, all Radiochemistry and Input Function Measurement these blood samples were drawn within a 2-hour time window between 12 pm and 2 pm. In addition, we adjusted statistically for Subjects were injected with [ C]WAY-100635 for quantification of time of day when samples were drawn. Blood cortisol levels were 5-HT binding. Details of radiotracer preparation have been previ- 1A ascertained by radioimmunoassay (Vecsei, 1979) after denatura- ously described for [ C]WAY-100635 (Parsey et al., 2000). A metab- tion of the binding proteins by heat. Both blood and saliva cor - olite-corrected arterial input function was obtained and plasma tisol levels were measured by immunoassay with antibodies free fraction (f) was assayed in triplicate (Parsey et al., 2006a). for cortisol-3-O-carboxymethyloxime-BSA (MP Biochemicals). This was compared to cortisol standards (Sigma Chemical). Free Image Acquisition and Analysis and bound fractions were separated using anti-rabbit globulin A T1-weighted magnetic resonance image (MRI) scan was serum and polyethylene glycol. All samples and standards were acquired for each subject for registration with PET images using analyzed in duplicate. a 1.5-T Signa Advantage (General Electric Medical Systems, Subjects who underwent the TSST, which took place between Milwaukee, WI) at a resolution of 1.5 × .9 × 1.0 mm. 2 pm and 6 pm, gave saliva samples approximately 10 minutes Downloaded from https://academic.oup.com/ijnp/article-abstract/22/5/329/5423589 by Ed 'DeepDyve' Gillespie user on 07 May 2019 332 | International Journal of Neuropsychopharmacology, 2019 prior to the start of the TSST (Cort ) and again at 15, 20, 30, 3-way interaction between region, group, and cortisol measure BL and 40 minutes after completion of the TSST. Time of day was was significant, brain region-wise analyses were performed to also statistically controlled for in this sample. Saliva samples test the association between cortisol, subject group, and bind- were collected in the Sarstedt Salivette Synthetic Swab collec-ing. Covariates that were not significant in any region were tion system (catalogue # 51.1534.500 Sarstedt, Newton, NC) and dropped from region-wise analyses. subsequently stored at −30°Celsius. Salivary cortisol values were Given that cortisol has a diurnal cycle (Wüst et  al., 2000), log-transformed. Cortisol response during TSST for each subject we adjusted blood cortisol measurements during the PET scan was defined as the difference between the maximum (log-trans- for time of day relative to 12:00 pm, even though the correlation formed) value after the baseline and the (log-transformed) base- between blood cortisol and time of day was not significant in line value. Baseline cortisol was also log-transformed. this dataset (P = .091). This adjustment, performed to remove the time trend, was based on fitting a linear regression model to the cortisol data with time as the only predictor. Log-transformed TSST baseline cortisol before the TSST was similarly adjusted, Salivary cortisol response to social stress was measured in although the time trend was not statistically significant. Cortisol 39 subjects not overlapping with the subjects with blood cor - response during the TSST was adjusted by a time trend that dif- tisol measures during the PET scan: 29 MDD patients and 10 fered between males and females, using an ANCOVA model with healthy volunteers. The TSST was administered as previously time, sex, and their interaction as predictors. Cortisol measure- described (Melhem et  al., 2016). In brief, subjects were asked ments were also compared between healthy volunteers and to give a 5-minute personal introduction speech, followed by 9 participants with MDD using an ANCOVA analysis, and, in MDD minutes of speeded mental arithmetic, while being watched by patients, were correlated with 24-item HDRS and BDI scores. 1 observer known to the subject and a staff member who was unknown to the subject. Results Statistical Analysis Participant Characteristics The associations between the cortisol responses to the 2 stress- Demographic and clinical data are presented in Table 1 for all ors and 5-HT binding measured in our a priori ROIs were participants combined. Demographic and clinical data are pre- 1A examined separately for each stressor, each analysis using sented for the separate samples of subjects with blood cortisol linear mixed effects models with group (MDD vs control), cor - and those who underwent the TSST in Tables 2 and 3, respec- tisol, brain region, and their interactions as fixed effects and tively. Of 42 MDD participants, 29 had previous exposure to anti- subject as a random effect. To correct a slight skew in the data, depressants and 16 had previously attempted suicide, indicating stabilize the variance across regions, and allow for estimates high illness burden. For those with previous antidepressant of proportional effects that persist across regions, the ana- exposure, the mean time off antidepressants was 49 + 74 weeks lysis was performed on log-transformed estimates of 5-HT . (range 2–312 weeks). 1A Observations were weighted inversely proportionally to squared standard errors that were calculated based on variation in PET Cortisol Stress Response in Healthy Volunteer and data, plasma data, and metabolite data (Ogden and Tarpey, Major Depression Groups 2006). Because [ C]WAY-100635 binding has been shown to be There was no statistically significant difference in blood cortisol dependent on sex (Parsey et al., 2002) and age (Tauscher et al., 2001), these covariates were also included in the model initially, levels measured following radial artery catheter placement be- tween control and MDD groups when covarying for age, sex, both as main effects and in the form of interaction with region, but interactions were dropped when not significant. When the and blood sample time of day (F = 3.70; df = 1,31; P = .064). Salivary Table 1. Demographic and Clinical Characteristics of Combined Study Sample Healthy Volunteers MDD All subjects P value (n = 31) (n = 42) (n = 73) Age ± SD 35.3 ± 13.3 38.2 ± 12.6 37 ± 12.9 0.32 Hamilton Depression Rating Scale (24-item) 2.5 ± 3.2 18.9 ± 13.5 <.001 Beck Depression Inventory 1.9 ± 3.8 20.8 ± 16 <.001 Years of Education 15.7 ± 2.1 15.2 ± 2.5 15.45 ± 3.2 n (%) n (%) n (%) P value Female 17 (54.8) 25 (59.5) 42 (57.5) .68 Tobacco users 3 (9.7) 5 (11.9) 8 (11) .76 Prior exposure to antidepressants N/A 29 (69) 29 (39.7) Suicide attempters N/A 16 (38.1) 16 (21.9) Past alcohol abuse N/A 7 (16.6) 7 (9.6) Comorbid anxiety disorder N/A 19 (45.2) 19 (26) Race/ethnicity .09 Asian 5 (16.1) 2 (4.8) 7 (8.3) .10 African American 7 (22.6) 5 (11.9) 14 (16.7) .22 Caucasian 15 (48.3) 31 (73.8) 55 (65.5) .02 Hispanic 4 (12.9) 10 (23.8) 14 (16.7) .2 2 Downloaded from https://academic.oup.com/ijnp/article-abstract/22/5/329/5423589 by Ed 'DeepDyve' Gillespie user on 07 May 2019 Steinberg et al. | 333 Table 2. Demographic Information for Blood Cortisol Subjects Only Healthy Volunteers MDD All subjects P value (n = 21) (n = 13) (n = 34) Age ± SD 34.3 ± 14.1 38.1 ± 13.6 35.8 ± 13.18 .44 Hamilton Depression Rating Scale (24-item) 1 ± 1.2 24.8 ± 8.2 <.001 Beck Depression Inventory 1.9 ± 3 28.5 ± 11.9 <.001 Years of education 15.9 ± 2.5 15.1 ± 3.3 15.6 ± 2.8 .41 n (%) n (%) n (%) P value Female 11 (52.4) 10 (76.9) 21 (61.8) .31 Tobacco users 2 (9.5) 1 (7.7) 3 (8.8) .8 Prior exposure to antidepressants N/A 9 (69.2) 9 (26.5) Suicide attempters N/A 8 (61.5) 8 (23.5) Past alcohol abuse N/A 4 (30.7) 4 (11.8) Comorbid anxiety disorder N/A 6 (46.2) 6 (17.6) Race/ethnicity .88 Asian 4 (19) 1 (7.7) 5 (14.7) .36 African American 5 (23.8) 1 (7.7) 6 (17.6) .23 Caucasian 9 (42.9) 7 (53.8) 16 (47.1) .53 Hispanic 3 (14.3) 4 (30.8) 7 (20.6) .24 Table 3. Demographics of TSST Subjects Healthy Volunteers MDD All subjects P value (n = 10) (n = 29) (n = 39) Age ± SD 38.2 ± 11.7 38.2 ± 12.6 38.8 ± 12 .85 Hamilton Depression Rating Scale (24-item) 2.6 ± 3 18.7 ± 10.7 14.6 ± 4.8 <.001 Beck Depression Inventory 1.9 ± 2.4 20.5 ± 10.8 15.6 ± 12.5 <.001 Years of education 15.2 ± 0.67 15.3 ± 2.1 15 ± 1.8 .94 n (%) n (%) n (%) P value Female 6 (60) 15 (51.7) 21 (53.8) .65 Tobacco users 1 (10) 2 6.9) 3 (7.7) .75 Prior exposure to antidepressants N/A 20 (69) Suicide attempters N/A 8 (27.6) Past alcohol abuse N/A 3 (10.3) Comorbid anxiety disorder N/A 13 (44.8) Race/ethnicity .64 Asian 1 (10) 1 (3.4) 2 (5.1) .41 African American 2 (20) 4 (13.8) 6 (15.4) .63 Caucasian 6 (60) 24 (82.8) 30 (76.9) .14 Hispanic 1 (10) 6 (20.7) 7 (17.9) .44 baseline cortisol and cortisol response during the TSST also did not immediately prior to the scan, after accounting for age, sex, and differ significantly between control and MDD groups when covary- diagnosis (F = 6.40; df = 1,29; P = .017). The relationship between ing for age, sex, time of day, and the sex by time interaction (F = 0.91; cortisol levels and [C]WAY100635 binding was homogenous df = 1,33; P = .348, baseline cortisol: F = 2.51; df = 1,34; P = .122). across a priori brain regions, as the interaction term for brain re- gion was not significant (F = 0.67; df = 12,384; P = .777). For region- wise results, see supplemental Table 1. There was no significant Cortisol Stress Response and Depression Severity interaction between diagnosis and cortisol level on [ C]WAY- Within the MDD sample, we did not find a relationship between 100635 binding (F = 3.77; df = 1,28; P = .062). PET scan blood cortisol levels and the BDI score (F = 0.485; df = 1,8; Similarly, we found the time-adjusted salivary cortisol re- P = .506) or the 24-item HDRS score (F= 0.455; df = 1,8; P = .518), cova- sponse during TSST was positively related with [ C]WAY100635 rying for age, sex, and time of day in each case. The salivary corti- binding after adjusting for sex and age (Figure 2; F = 7.34; sol response to TSST, covarying for age, sex, time of day, and their df = 1,34; P = .011). This was also homogeneous across all a priori interaction, was not correlated with either 24-item HDRS score brain regions (region by cortisol response interaction: F = 0.93; (F = 0.56; df = 1,23; P = .462) or BDI score (F = 0.01; df = 1, 22; P = .936). df = 11,374; P = .516). For region-wise results, please see supple- mental Table 2. There was no significant interaction between diagnosis and cortisol response on [C]WAY-100635 binding Cortisol Stress Response and Brain [11C]WAY- (F = 0.21; df = 1,33; P = .649). There was also no main effect of diag- 100635 BP nosis after removing the interaction (F = 0.01; df = 1,34; P = .988). [ C]-WAY-100635 binding across the ROIs, selected a priori There was a significant age by region interaction (F= 2.31; (Figure 1), was positively related with blood cortisol levels drawn df = 11,396; P = .009) and a significant sex by region interaction Downloaded from https://academic.oup.com/ijnp/article-abstract/22/5/329/5423589 by Ed 'DeepDyve' Gillespie user on 07 May 2019 334 | International Journal of Neuropsychopharmacology, 2019 Figure 1. The post-stress cortisol is positively correlated with serotonin 1A (5-HT ) receptor ligand binding across multiple brain regions. Top row shows [ C]WAY- 1A 100635 BP averaged across subjects. Bottom row highlights corresponding anatomical regions of interest (ROIs) for which a significant positive correlation between [ C]WAY-100635 binding and blood cortisol levels was observed, including the raphe nuclei, cingulate cortex, dorsal prefrontal cortex, hippocampus, insula, medial prefrontal cortex, parietal cortex, parahippocampal gyrus, occipital cortex, orbital cortex, and temporal cortex. Analyses were corrected for multiple comparisons using a threshold of P < .001. Figure 2. Cortisol response during the Trier Social Stress Task (TSST) is positively 11 11 correlated with [C]WAY-100635 BP . Shown here are the residual values for [C] WAY-100635 BP in a single region of interest (ROI), the anterior cingulate (ACN), and corresponding residual values for cortisol response after controlling for age, Figure 3. Baseline cortisol response during the Trier Social Stress Task (TSST) sex, and diagnosis. is inversely correlated with [C]WAY-100635 BP . Shown here are the residual values for [ C]WAY-100635 BP in a single region of interest (ROI), the anterior cingulate (ACN), and corresponding residual values for cortisol response after (F = 3.01;df = 11,396; P = .001), indicating differential effects of controlling for age, sex, and diagnosis. these demographic variables on binding across brain regions. we ran posthoc region-wise analyses adjusted for age, sex, and Baseline Cortisol and Brain [ C]WAY-100635 BP diagnostic group. The effects of the interaction terms of diag- The association between baseline salivary cortisol measured nostic group with baseline cortisol on C]W [ AY100635 binding before the TSST and [ C]WAY100635 binding differed by region were not significant in any of the region-specific models and and diagnostic group (baseline cortisol by region by group inter - were removed. The main effect of diagnosis was not significant action: F = 2.41; df = 11,374; P = .007). To interpret the interaction, in any region. Baseline cortisol and [C]WAY100635 binding Downloaded from https://academic.oup.com/ijnp/article-abstract/22/5/329/5423589 by Ed 'DeepDyve' Gillespie user on 07 May 2019 Steinberg et al. | 335 were negatively correlated in all regions (Figure 3; see supple- However, it is important to note that in addition to possible spe- mental Table 3 for coefficients by ROI) except in the RN (b = −0.18; cies differences, the animal experiments differ markedly from SE = 0.11; t = −1.71; P = .098). our paradigm in that they were performed either in animals in the context of adrenalectomy, chronic steroid treatment, or chronic stress paradigms, or in cell culture. We did not meas- ure baseline cortisol in our blood cortisol samples, which were Discussion taken after arterial line insertion prior to PET scan. Therefore, Here we show a positive correlation between cortisol levels after the post-stress blood cortisol measures represent a combination two different types of stressors and 5-HT receptor binding on of the resting cortisol levels and the response to the stressor, 1A PET using [ C]WAY-100635. This effect was observed across mul- and they cannot be disambiguated. We considered the potential tiple brain regions. The fact that this observation held under 2 contribution of circadian fluctuations in cortisol level by adjust- different stress paradigms speaks to the strength of this rela- ing TSST cortisol level for time of day in the model. tionship. Conversely, a negative correlation was found between HPA axis dysfunction has been linked to depression and sui- baseline salivary cortisol and [C]WAY-100635 binding in all a cide in many previous studies. Postmortem data from suicide priori regions, except RN. We previously reported that stress- completers shows that they tend to have heavier adrenal glands, responsive disorders like MDD and PTSD are associated with higher tissue levels of CRF, which indicates oversecretion of higher 5-HT binding (Parsey et al., 2006a, 2010; Sullivan et al., CRF, and lower expression of CRF receptors in prefrontal cortex 1A 2013), although other studies have found no difference or the (Nemeroff et  al., 1988; Arató et  al., 1989; Szigethy et  al., 1994). opposite (Yates and Ferrier, 1990; Lowther et  al., 1997; Sargent A subset of patients with depression, generally those with more et al., 2000; Bonne et al., 2005; Sullivan et al., 2015Mann et  ; al., severe illness, also demonstrate nonsuppression on dexametha- 2017). In this study, the relationship of 5-HT binding to post- sone suppression testing and are at higher risk of suicide (Caroff 1A stress cortisol in blood and salivary samples was independent et al., 1983; Dratcu and Calil, 1989Cor ; yell and Schlesser, 2001; of diagnosis, indicating a mechanism that operates compara- van Heeringen, 2003; Yerevanian et al., 2004; Pfennig et al., 2005; bly in healthy volunteers and in patients with mood disorders. Kunugi et al., 2006). HPA axis dysfunction is also linked directly Consistent with this observation, within the MDD group the to serotonergic dysfunction and specifically to changes in 5-HT 1A severity of current major depression was not correlated with receptor levels. CRF directly affects the dorsal raphe, modulating either 5-HT binding or post-stress cortisol in either blood or serotonergic tone in the prefrontal cortex and nucleus accum- 1A salivary measures. Higher brain 5-HT receptor ligand binding bens (Lowry et al., 2000; Forster et al., 2008Lukkes et  ; al., 2008; 1A is a biological trait observed in medication-free major depres- Quadros et al., 2014). Several studies in animal models show that sion during acute depression and during remission (Parsey et al., cortisol reduces 5-HT receptor expression in the hippocampus 1A 2006a, 2006b; Miller et al., 2009bP ; arsey et al., 2010) and is trans- (Martire et  al., 1989Chalmers et  ; al., 1993; Kuroda et  al., 1994; mitted in families (Milak et al., 2018). What remains to be deter - Meijer and de Kloet, 1994; Zhong and Ciaranello, 1995). Our data mined is whether there is a causal link between higher 5-HT add to this literature by demonstrating a functional relationship 1A binding and HPA axis overactivity or responsivity in depression. between 5-HT receptor binding levels and cortisol levels in 1A A negative correlation was found between baseline salivary response to an acute stressor in human subjects. cortisol and [ C]WAY-100635 binding in all a priori regions, The study had several limitations. There were modest dif- except RN. This is consistent with previous data in depression ferences in racial/ethnic composition between our healthy and social anxiety disorder (Lanzenberger et  al., 2010). That volunteers and MDD group. Subjects in this study were a con- baseline cortisol has a weaker or no correlation with 5-HT venience sample, included on the grounds of having undergone 1A binding in RN may be explained by RN being a small structure [ C]WAY-100635 imaging and having either a blood or salivary with noisier quantification. Moreover, because of this small size, measure of cortisol available. We cannot determine whether RN is susceptible to partial volume effects and underestimation these serotonin system relationships to baseline and post- of binding. Alternatively, presynaptic 5-HT receptors (autore- stress cortisol levels will extend to more severe MDD, which is 1A ceptors) in RN may be functionally distinct from post-synaptic characterized by cortisol hypersecretion and dexamethasone 5-HT receptors such that expression of the latter may be more resistance. However, we saw no relationship between MDD 1A strongly modulated by baseline cortisol levels. The latter expla- severity across the range that was present in our sample and nation is consistent with the observation that adrenalectomy cortisol measures. Finally, this cross-sectional study cannot has no effect on 5-HT receptor binding in RN (Le Corre et al., demonstrate causal relationships. This would be more feasible 1A 1997; van Gaalen et  al., 2002). Furthermore, animal work has to study in mouse models where pharmacological and genetic shown that different types of stressors can lead to increased manipulations of HPA axis responsiveness are possible and serotonin secretion within parts of the RN, which would then the time frame to determine the relationship of developmen- act on 5-HT autoreceptors and differentially affect serotonin tal effects on adult phenotypes much shorter. To more fully 1A release in terminal fields (Adell et al., 1997, 2002). This may also characterize the relationship of depression status to HPA axis explain why [ C]WAY-100635 binding differs between the RN reactivity, a longitudinal study with repeated measurements and terminal fields. in individual subjects during and between episodes of major Previous animal work demonstrating an inverse relation- depression would be required and would complement mouse ship between cortisol levels and 5-HT receptor expression in developmental studies. 1A cortical and hippocampal regions are consistent with our find- In summary, despite limitations, we found a positive correla- ings with basal salivary cortisol levels (Chalmers et  al., 1993; tion between 5-HT receptor and post-stress cortisol levels, inde- 1A Meijer and de Kloet, 1994; Flügge, 1995; Zhong and Ciaranello, pendent of diagnosis. This suggests an underlying mechanism 1995; Le Corre et  al., 1997; Czyrak et  al., 2002; Iyo et  al., 2009). that links 5-HT receptor overexpression with HPA axis feedback 1A It is thought that cortisol-dependent transcriptional repression dysfunction. Conversely, binding and resting cortisol are negatively of 5-HT requires coactivation of both the glucocorticoid and correlated as reported in several rodent studies and likely involve 1A mineralocorticoid receptors (Meijer et al., 2000 Ou et  ; al., 2001). different mechanisms including the mineralocorticoid receptor. Downloaded from https://academic.oup.com/ijnp/article-abstract/22/5/329/5423589 by Ed 'DeepDyve' Gillespie user on 07 May 2019 336 | International Journal of Neuropsychopharmacology, 2019 Such mechanisms are a combination of genetic vulnerability and Coplan  JD, Abdallah  CG, Kaufman  J, Gelernter  J, Smith  EL, environmental risk factors, such as early-life stress, which leads to Perera TD, Dwork AJ, Kaffman A, Gorman JM, Rosenblum LA, epigenetic changes generating this biological phenotype. Owens MJ, Nemeroff CB (2011) Early-life stress, corticotropin- releasing factor, and serotonin transporter gene: a pilot study. Psychoneuroendocrinology 36:289–293. Funding Coryell W, Schlesser M (2001) The dexamethasone suppression This work was funded by the NIH through the following grants: test and suicide prediction. Am J Psychiatry 158:748–753. Cowen  PJ (2010) Not fade away: the HPA axis and depression. MH040695, MH090964, MH062185. Psychol Med 40:1–4. Czyrak A, Maćkowiak M, Chocyk A, Fijał K, Tokarski K, Bijak M, Acknowledgments Wedzony K (2002) Prolonged corticosterone treatment alters the responsiveness of 5-HT1A receptors to 8-OH-DPAT in rat We thank Dr Ramin Parsey for sharing subject data included in CA1 hippocampal neurons. Naunyn Schmiedebergs Arch this study. The authors of this manuscript are entirely responsi- Pharmacol 366:357–367. ble for the scientific content of this paper. Delorenzo  C, Klein  A, Mikhno  A, Gray  N, Zanderigo  F, Mann  JJ (2009). A new method for assessing PET-MRI coregistration. Statement of Interest In: SPIE medical imaging, pp 72592–72598. USA. Delorenzo  C, Delaparte  L, Thapa-Chhetry  B, Miller  JM, Mann  JJ, Mr Rubin-Falcone, Dr Kaufman, Dr Sublette, Dr Miller, Mr Parsey RV (2013) Prediction of selective serotonin reuptake in- Cooper, Mr Min, and Dr Ogden declare no conflict of interest. Dr hibitor response using diffusion-weighted MRI. Front Psych- Steinberg receives compensation for consulting for Owaves, Inc. iatry 4:5. Dr Stanley receives royalties for commercial use of the C-SSRS Dratcu L, Calil HM (1989) The dexamethasone suppression test: from the Research Foundation for Mental Hygiene, as well as its relationship to diagnoses, severity of depression and re- compensation for consulting for AbbVie and Merck. Dr Galfalvy’s sponse to treatment. Prog Neuropsychopharmacol Biol family owns stocks in Illumina, Inc. Dr Mann receives royalties Psychiatry 13:99–117. for commercial use of the C-SSRS from the Research Foundation First  MB, Spitzer  RL, Gibbon  M, Williams  JB (2012). Structured for Mental Hygiene. Dr Oquendo receives royalties for commer - clinical interview for DSM-IV axis I disorders (SCID-I), clinical cial use of the C-SSRS from the Research Foundation for Mental version, administration booklet. Hygiene. Her family owns stock in Bristol Myers Squibb. 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Abstract

Background: Abnormalities in the hypothalamic-pituitary-adrenal axis, serotonergic system, and stress response have been linked to the pathogenesis of major depressive disorder. State-dependent hyper-reactivity of the hypothalamic-pituitary- adrenal axis is seen in major depressive disorder, and higher binding to the serotonin 1A receptor is observed as a trait in both currently depressed and remitted untreated major depressive disorder. Here, we sought to examine whether a relationship exists between cortisol secretion in response to a stressor and serotonin 1A receptor binding throughout the brain, both in healthy controls and participants with major depressive disorder. Methods: Research participants included 42 medication-free, depressed subjects and 31 healthy volunteers. Participants were exposed to either an acute, physical stressor (radial artery catheter insertion) or a psychological stressor (Trier Social Stress Test). Levels of serotonin 1A receptor binding on positron emission tomography with [C]WAY-100635 were also obtained from all participants. The relationship between [C]WAY-100635 binding and cortisol was examined using mixed linear effects models with group (major depressive disorder vs control), cortisol, brain region, and their interactions as fixed effects and subject as a random effect. Results: We found a positive correlation between post-stress cortisol measures and serotonin 1A receptor ligand binding levels across multiple cortical and subcortical regions, independent of diagnosis and with both types of stress. The relationship between [ C]WAY-100635 binding and cortisol was homogenous across all a priori brain regions. In contrast, resting cortisol levels were negatively correlated with serotonin 1A receptor ligand binding levels independently of diagnosis, except in the RN. There was no significant difference in cortisol between major depressive disorder participants and healthy volunteers with either stressor. Similarly, there was no correlation between cortisol and depression severity in either stressor group. Received: July 19, 2018; Revised: December 7, 2018; Accepted: February 15, 2019 © The Author(s) 2019. Published by Oxford University Press on behalf of CINP. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any 329 medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ijnp/article-abstract/22/5/329/5423589 by Ed 'DeepDyve' Gillespie user on 07 May 2019 330 | International Journal of Neuropsychopharmacology, 2019 Significance Statement The relationship between the body’s response to stress and the function of serotonin in the brain has been a subject of interest in depression research. Several studies have examined this by manipulating the body’s stress response system externally—either by administering medications, such as steroids, or by removing adrenal glands surgically. The data resulting from these studies has been mixed and inconclusive. Here, we show human data from healthy volunteers and participants with major depression. We studied the body’s self-generated stress response, cortisol levels, to 2 different types of stressors: a physical and a psy- chological stressor. We found that with both stressors, greater cortisol levels are associated with higher levels of serotonin 1A receptor binding throughout the brain. There is also an inverse association between resting cortisol levels and receptor binding. Both findings were independent of diagnosis. This suggests that healthy volunteers and depressed subjects are biologically on a continuum, and that individuals with a more pronounced stress response tend to have higher levels of serotonin 1A receptor throughout the brain. Our data add to the literature by demonstrating a link between acute stress responses and serotonin 1A receptor availability in humans. Conclusions: This study suggests that there may be a common underlying mechanism that links abnormalities in the serotonin system and hypothalamic-pituitary-adrenal axis hyper-reactivity to stress. Future studies need to determine how hypothalamic-pituitary-adrenal axis dysfunction affects mood to increase the risk of suicide in major depression. Keywords: cortisol, PET imaging, serotonin, stress Introduction The hypothalamic-pituitary-adrenal (HPA) axis and the sero- 5-HT receptor agonists (Lesch et  al., 1989Y ; oung et  al., 1994; 1A tonin system have a complex bidirectional relationship (Meijer Porter et al., 19982002 , ). However, overall, results are mixed and and de Kloet, 1994; Porter et  al., 2004). This relationship is of may depend on the type of corticosteroid used and the duration potential importance in the pathogenesis of mood disorders, of exposure (Porter et  al., 1999, 2002; Montgomery et  al., 2001; because major depressive episodes are associated with trait Bhagwagar et  al., 2003). Prior positron emission tomography abnormalities in the serotonin system, including 5-HT re- (PET) imaging studies in humans have failed to detect an effect 1A ceptor upregulation (Parsey et  al., 2006a), and with hyper - of acute administration of corticosteroids on 5-HT receptor 1A active HPA axis responses to stress, which are state dependent ligand binding (Montgomery et al., 2001Bha ; gwagar et al., 2003). (Cowen, 2010; Stetler and Miller, 2011). More severe depressive However, such studies did not examine stress-induced cortisol episodes, such as those characterized by psychomotor agitation release, which may differ from pharmacologically induced cor - or psychotic features, have more severely dysregulated HPA axis tisol effects and be abnormal in subgroups of patients. function as indicated by heavier adrenal glands, higher levels To better understand the relationship between stress, HPA of corticotropin releasing factor (CRF) in brain tissue and cere- axis reactivity, depression, and 5-HT receptor levels in the brain, 1A brospinal fluid, lower CRF receptor binding in prefrontal cortex we studied the relationship between the endogenous cortisol re- postmortem, a blunted cortisol suppression response to dexa- sponse to acute stress and 5-HT receptor binding as measured 1A methasone, and greater cortisol release both at baseline and by PET. We chose 2 different types of acute stressors: (1) the Trier in response to social stressors (Lindy et  al., 1985Br ; own et  al., Social Stress Task (TSST) (Kirschbaum et al., 1993), which is a psy- 1986; Nemeroff et al., 1988; Arató et al., 1989; Pfennig et al., 2005; chological stress paradigm, and (2) arterial line placement prior to Mann et  al., 2006; Melhem et  al., 2016). Genetic and epigenetic PET, a physical stressor that involves restraint and physical dis- associations with enhanced HPA axis stress responses have comfort. Cortisol was measured in healthy volunteers and med- also been observed in major depressive disorder (MDD) and in ication-free depressed subjects: (1) in a blood sample drawn just those reporting early-life stress, which is a risk factor for MDD after arterial line placement, or (2) in saliva as part of the TSST. (McGowan et al., 2009; Coplan et al., 2011 Y ; in et al., 2016). Given our finding of elevated [ C]-WAY-100635 binding and HPA The relationship between markers of serotonergic tone and hyperactivity in MDD (Parsey et  al., 2006aMiller ; et  al., 2009a; HPA axis function has been extensively studied. Cortisol induces Parsey et al., 2010; Milak et al., 2018), we predicted a positive correl- tryptophan 2,3-dioxygenase, which metabolizes L-tryptophan, ation between regional [C]-WAY-100635 binding and post-stress thereby decreasing L-tryptophan availability for serotonin syn- cortisol levels despite rodent studies that might predict an inverse thesis (Badawy et  al., 1995). Animal work has demonstrated relationship between the two. We predicted an inverse relation- that adrenalectomized rats show increased post-synaptic ship between resting cortisol and regional [ C]-WAY-100635 bind- serotonin-1A (5-HT ) receptor binding in the hippocampus, ing, as more severe depressive pathology is associated with higher 1A whereas chronic treatment with corticosterone reduces expres- 5-HT binding on PET (Sullivan et al., 2015Oquendo et  ; al., 2016) 1A sion, binding, and function of 5-HT receptors in hippocam- and lower peripheral resting cortisol levels (Pfennig et  al., 2005; 1A pal fields (Martire et  al., 1989; Mendelson and McEwen, 1992; Jokinen et al., 2010; McGirr et al., 2011Melhem et al., ; 2016). Chalmers et  al., 1993; Kuroda et  al., 1994; Meijer and de Kloet, 1994; Laaris et  al., 1995; Zhong and Ciaranello, 1995; Le Corre Methods et al., 1997; Czyrak et al., 2002), suggesting receptor upregulation in response to low serotonergic tone. Some human studies are Participants consistent with these findings, with corticosteroid treatment causing blunting of 5-HT receptor-mediated responses, includ- Seventy-three adult subjects with PET scans using C]W [ AY- 1A 100635 were included in this analysis. Participants underwent 1 ing the hypothermic and serum growth hormone responses to Downloaded from https://academic.oup.com/ijnp/article-abstract/22/5/329/5423589 by Ed 'DeepDyve' Gillespie user on 07 May 2019 Steinberg et al. | 331 of 2 stressors: (1) arterial line placement before a PET scan (n = 34) PET images were acquired with an ECAT EXACT HR+ scanner or (2) the TSST (n= 39). Participants from stress paradigm (1) had (Siemens/CTI, Knoxville, TN) as previously detailed (Parsey et al., cortisol assayed in a blood sample drawn immediately after their 2000). Briefly, after a 15-minute transmission scan, an injection arterial line was placed, while participants of paradigm (2) had of [ C]-WAY-100635 was administered over 30 seconds and then salivary cortisol assayed in samples collected at multiple time- an emission scan of 110 minutes, consisting of 20 frames of points during the TSST. The PET data presented here were pre- increasing duration (3× 20 seconds, 3 × 1 minute, 3 × 2 minutes, viously reported in published studies (Parsey et al., 2006a 2006b , , 2 × 5 minutes, 9 × 10 minutes), was obtained. 2010; Miller et al., 2009b), but the cortisol data have never been To correct for subject motion, each PET frame was registered published. Subject selection was based on the availability of us- to the eighth frame of the scan using the FMRIB linear image reg- able [ C]WAY-100635 brain binding data and either plasma cor - istration tool, version 5.0 (FMRIB Image Analysis Group, Oxford, tisol or TSST saliva cortisol stress sample measurements. UK). Brain regions of interest (ROIs) were chosen a priori based Fourty-two depressed participants (25 female, 17 male) aged on areas of abundant [ C]-WAY-100635 binding (Hall et al., 1997) 18 to 62  years who met DSM-IV criteria for MDD in a current that included raphe nuclei (RN), anterior cingulate, cingulate, major depressive episode (as assessed by doctoral- or masters’- dorsal prefrontal cortex, hippocampus, insula, medial prefrontal level psychologists and reviewed in a consensus conference of cortex, parietal cortex, parahippocampal gyrus, occipital cortex, research psychologists and psychiatrists), a 17-item Hamilton orbital cortex, temporal cortex, and amygdala. Cerebellar white Depression Rating Scale (HDRS) score REF ≥16, and capacity matter was used as a reference region. All ROIs except for RN to provide informed consent were included in the analysis. were identified on each individual’s T1-weighted MRI using a Depression severity was assessed with the 24-item HDRS and previously described automated algorithm (Milak et  al., 2010). the Beck Depression Inventory (BDI) REF. Thirty-one healthy vol- Due to their small size, RN were labeled using a standard space unteers (19 female, 12 male) aged 18 to 65 years with no history mask of the average location of the RN in 52 healthy subjects, of DSM-IV Axis I or Axis II psychiatric disorders, no psychotropic which was created using [ C]-WAY-100635 voxel binding maps medication exposure, and no family history of a mood disorder as previously described (Delorenzo et al., 2013). MRI T1 images or schizophrenia were included. Neither group had significant were transformed into standardized 3D space using Advanced medical illness, nor were they taking medications that may Normalization Tools (7), and the reverse transform was applied affect the serotonin system at the time of neuroimaging. For to the RN mask. all subjects, the Structured Clinical Interview for DSM-IV Axis PET images were co-registered to the MRI images using the I  Disorders (First et  al., 2012) as well as psychiatric and medi- FMRIB linear image registration tool, optimized as previously cal history, chart review, physical examination, routine blood described (Delorenzo et  al., 2009). The average activity meas- tests, pregnancy test, urine toxicology, and electrocardiogram ured over the voxels within each ROI over the specified time were performed to assess study eligibility. Exclusion criteria frames through the course of the acquisition generated time included presence of significant medical conditions, alcohol or activity curves. other substance use disorder unless in complete remission for >6  months, dementia, neurological disease, head injury with Outcome Measure Estimation loss of consciousness, pregnancy, first-degree family history of Distribution volumes (V) of [ C]WAY-100635 were estimated for schizophrenia if subject was <33  years old (Sham et  al., 1994), each ROI using kinetic analysis with an arterial input function and >3 lifetime exposures to 3,4-methylenedioxymethampheta- and a 2-tissue compartment constrained model as previously mine. For depressed participants specifically, exclusion criteria described (Parsey et al., 2000). Time activity curves were fit with also included fluoxetine use within 6 weeks of PET scanning, a 2-tissue compartment constrained model in which the K/k or exposure to a 5-HT receptor agonist, such as buspirone, 1 2 1A ratio was constrained to that of the reference region (cerebellar vortioxetine, vilazodone, or lysergic acid diethylamide, within white matter) for each ROI. BP was calculated as (V – V )/ 6  months of scanning. At the time of the scan all participants F T(ROI) T(REF) f , where V is the volume of distribution in a specific ROI, were unmedicated. Depressed subjects who were on ineffective P T(ROI) V is the volume of distribution in the reference region, and f antidepressant treatment at the time of evaluation underwent T(REF) P is the free fraction in plasma. a medication washout and were drug-free for at least 2 weeks prior to neuroimaging. The Institutional Review Board of the New York State Psychiatric Institute approved the protocol, and Cortisol Measurement all subjects provided informed written consent after an expla- nation of the study protocol and associated risks. Blood cortisol was measured in blood samples drawn from 34 subjects immediately prior to PET scans and just after the arte- rial line was inserted. Given the diurnal variation of cortisol, all Radiochemistry and Input Function Measurement these blood samples were drawn within a 2-hour time window between 12 pm and 2 pm. In addition, we adjusted statistically for Subjects were injected with [ C]WAY-100635 for quantification of time of day when samples were drawn. Blood cortisol levels were 5-HT binding. Details of radiotracer preparation have been previ- 1A ascertained by radioimmunoassay (Vecsei, 1979) after denatura- ously described for [ C]WAY-100635 (Parsey et al., 2000). A metab- tion of the binding proteins by heat. Both blood and saliva cor - olite-corrected arterial input function was obtained and plasma tisol levels were measured by immunoassay with antibodies free fraction (f) was assayed in triplicate (Parsey et al., 2006a). for cortisol-3-O-carboxymethyloxime-BSA (MP Biochemicals). This was compared to cortisol standards (Sigma Chemical). Free Image Acquisition and Analysis and bound fractions were separated using anti-rabbit globulin A T1-weighted magnetic resonance image (MRI) scan was serum and polyethylene glycol. All samples and standards were acquired for each subject for registration with PET images using analyzed in duplicate. a 1.5-T Signa Advantage (General Electric Medical Systems, Subjects who underwent the TSST, which took place between Milwaukee, WI) at a resolution of 1.5 × .9 × 1.0 mm. 2 pm and 6 pm, gave saliva samples approximately 10 minutes Downloaded from https://academic.oup.com/ijnp/article-abstract/22/5/329/5423589 by Ed 'DeepDyve' Gillespie user on 07 May 2019 332 | International Journal of Neuropsychopharmacology, 2019 prior to the start of the TSST (Cort ) and again at 15, 20, 30, 3-way interaction between region, group, and cortisol measure BL and 40 minutes after completion of the TSST. Time of day was was significant, brain region-wise analyses were performed to also statistically controlled for in this sample. Saliva samples test the association between cortisol, subject group, and bind- were collected in the Sarstedt Salivette Synthetic Swab collec-ing. Covariates that were not significant in any region were tion system (catalogue # 51.1534.500 Sarstedt, Newton, NC) and dropped from region-wise analyses. subsequently stored at −30°Celsius. Salivary cortisol values were Given that cortisol has a diurnal cycle (Wüst et  al., 2000), log-transformed. Cortisol response during TSST for each subject we adjusted blood cortisol measurements during the PET scan was defined as the difference between the maximum (log-trans- for time of day relative to 12:00 pm, even though the correlation formed) value after the baseline and the (log-transformed) base- between blood cortisol and time of day was not significant in line value. Baseline cortisol was also log-transformed. this dataset (P = .091). This adjustment, performed to remove the time trend, was based on fitting a linear regression model to the cortisol data with time as the only predictor. Log-transformed TSST baseline cortisol before the TSST was similarly adjusted, Salivary cortisol response to social stress was measured in although the time trend was not statistically significant. Cortisol 39 subjects not overlapping with the subjects with blood cor - response during the TSST was adjusted by a time trend that dif- tisol measures during the PET scan: 29 MDD patients and 10 fered between males and females, using an ANCOVA model with healthy volunteers. The TSST was administered as previously time, sex, and their interaction as predictors. Cortisol measure- described (Melhem et  al., 2016). In brief, subjects were asked ments were also compared between healthy volunteers and to give a 5-minute personal introduction speech, followed by 9 participants with MDD using an ANCOVA analysis, and, in MDD minutes of speeded mental arithmetic, while being watched by patients, were correlated with 24-item HDRS and BDI scores. 1 observer known to the subject and a staff member who was unknown to the subject. Results Statistical Analysis Participant Characteristics The associations between the cortisol responses to the 2 stress- Demographic and clinical data are presented in Table 1 for all ors and 5-HT binding measured in our a priori ROIs were participants combined. Demographic and clinical data are pre- 1A examined separately for each stressor, each analysis using sented for the separate samples of subjects with blood cortisol linear mixed effects models with group (MDD vs control), cor - and those who underwent the TSST in Tables 2 and 3, respec- tisol, brain region, and their interactions as fixed effects and tively. Of 42 MDD participants, 29 had previous exposure to anti- subject as a random effect. To correct a slight skew in the data, depressants and 16 had previously attempted suicide, indicating stabilize the variance across regions, and allow for estimates high illness burden. For those with previous antidepressant of proportional effects that persist across regions, the ana- exposure, the mean time off antidepressants was 49 + 74 weeks lysis was performed on log-transformed estimates of 5-HT . (range 2–312 weeks). 1A Observations were weighted inversely proportionally to squared standard errors that were calculated based on variation in PET Cortisol Stress Response in Healthy Volunteer and data, plasma data, and metabolite data (Ogden and Tarpey, Major Depression Groups 2006). Because [ C]WAY-100635 binding has been shown to be There was no statistically significant difference in blood cortisol dependent on sex (Parsey et al., 2002) and age (Tauscher et al., 2001), these covariates were also included in the model initially, levels measured following radial artery catheter placement be- tween control and MDD groups when covarying for age, sex, both as main effects and in the form of interaction with region, but interactions were dropped when not significant. When the and blood sample time of day (F = 3.70; df = 1,31; P = .064). Salivary Table 1. Demographic and Clinical Characteristics of Combined Study Sample Healthy Volunteers MDD All subjects P value (n = 31) (n = 42) (n = 73) Age ± SD 35.3 ± 13.3 38.2 ± 12.6 37 ± 12.9 0.32 Hamilton Depression Rating Scale (24-item) 2.5 ± 3.2 18.9 ± 13.5 <.001 Beck Depression Inventory 1.9 ± 3.8 20.8 ± 16 <.001 Years of Education 15.7 ± 2.1 15.2 ± 2.5 15.45 ± 3.2 n (%) n (%) n (%) P value Female 17 (54.8) 25 (59.5) 42 (57.5) .68 Tobacco users 3 (9.7) 5 (11.9) 8 (11) .76 Prior exposure to antidepressants N/A 29 (69) 29 (39.7) Suicide attempters N/A 16 (38.1) 16 (21.9) Past alcohol abuse N/A 7 (16.6) 7 (9.6) Comorbid anxiety disorder N/A 19 (45.2) 19 (26) Race/ethnicity .09 Asian 5 (16.1) 2 (4.8) 7 (8.3) .10 African American 7 (22.6) 5 (11.9) 14 (16.7) .22 Caucasian 15 (48.3) 31 (73.8) 55 (65.5) .02 Hispanic 4 (12.9) 10 (23.8) 14 (16.7) .2 2 Downloaded from https://academic.oup.com/ijnp/article-abstract/22/5/329/5423589 by Ed 'DeepDyve' Gillespie user on 07 May 2019 Steinberg et al. | 333 Table 2. Demographic Information for Blood Cortisol Subjects Only Healthy Volunteers MDD All subjects P value (n = 21) (n = 13) (n = 34) Age ± SD 34.3 ± 14.1 38.1 ± 13.6 35.8 ± 13.18 .44 Hamilton Depression Rating Scale (24-item) 1 ± 1.2 24.8 ± 8.2 <.001 Beck Depression Inventory 1.9 ± 3 28.5 ± 11.9 <.001 Years of education 15.9 ± 2.5 15.1 ± 3.3 15.6 ± 2.8 .41 n (%) n (%) n (%) P value Female 11 (52.4) 10 (76.9) 21 (61.8) .31 Tobacco users 2 (9.5) 1 (7.7) 3 (8.8) .8 Prior exposure to antidepressants N/A 9 (69.2) 9 (26.5) Suicide attempters N/A 8 (61.5) 8 (23.5) Past alcohol abuse N/A 4 (30.7) 4 (11.8) Comorbid anxiety disorder N/A 6 (46.2) 6 (17.6) Race/ethnicity .88 Asian 4 (19) 1 (7.7) 5 (14.7) .36 African American 5 (23.8) 1 (7.7) 6 (17.6) .23 Caucasian 9 (42.9) 7 (53.8) 16 (47.1) .53 Hispanic 3 (14.3) 4 (30.8) 7 (20.6) .24 Table 3. Demographics of TSST Subjects Healthy Volunteers MDD All subjects P value (n = 10) (n = 29) (n = 39) Age ± SD 38.2 ± 11.7 38.2 ± 12.6 38.8 ± 12 .85 Hamilton Depression Rating Scale (24-item) 2.6 ± 3 18.7 ± 10.7 14.6 ± 4.8 <.001 Beck Depression Inventory 1.9 ± 2.4 20.5 ± 10.8 15.6 ± 12.5 <.001 Years of education 15.2 ± 0.67 15.3 ± 2.1 15 ± 1.8 .94 n (%) n (%) n (%) P value Female 6 (60) 15 (51.7) 21 (53.8) .65 Tobacco users 1 (10) 2 6.9) 3 (7.7) .75 Prior exposure to antidepressants N/A 20 (69) Suicide attempters N/A 8 (27.6) Past alcohol abuse N/A 3 (10.3) Comorbid anxiety disorder N/A 13 (44.8) Race/ethnicity .64 Asian 1 (10) 1 (3.4) 2 (5.1) .41 African American 2 (20) 4 (13.8) 6 (15.4) .63 Caucasian 6 (60) 24 (82.8) 30 (76.9) .14 Hispanic 1 (10) 6 (20.7) 7 (17.9) .44 baseline cortisol and cortisol response during the TSST also did not immediately prior to the scan, after accounting for age, sex, and differ significantly between control and MDD groups when covary- diagnosis (F = 6.40; df = 1,29; P = .017). The relationship between ing for age, sex, time of day, and the sex by time interaction (F = 0.91; cortisol levels and [C]WAY100635 binding was homogenous df = 1,33; P = .348, baseline cortisol: F = 2.51; df = 1,34; P = .122). across a priori brain regions, as the interaction term for brain re- gion was not significant (F = 0.67; df = 12,384; P = .777). For region- wise results, see supplemental Table 1. There was no significant Cortisol Stress Response and Depression Severity interaction between diagnosis and cortisol level on [ C]WAY- Within the MDD sample, we did not find a relationship between 100635 binding (F = 3.77; df = 1,28; P = .062). PET scan blood cortisol levels and the BDI score (F = 0.485; df = 1,8; Similarly, we found the time-adjusted salivary cortisol re- P = .506) or the 24-item HDRS score (F= 0.455; df = 1,8; P = .518), cova- sponse during TSST was positively related with [ C]WAY100635 rying for age, sex, and time of day in each case. The salivary corti- binding after adjusting for sex and age (Figure 2; F = 7.34; sol response to TSST, covarying for age, sex, time of day, and their df = 1,34; P = .011). This was also homogeneous across all a priori interaction, was not correlated with either 24-item HDRS score brain regions (region by cortisol response interaction: F = 0.93; (F = 0.56; df = 1,23; P = .462) or BDI score (F = 0.01; df = 1, 22; P = .936). df = 11,374; P = .516). For region-wise results, please see supple- mental Table 2. There was no significant interaction between diagnosis and cortisol response on [C]WAY-100635 binding Cortisol Stress Response and Brain [11C]WAY- (F = 0.21; df = 1,33; P = .649). There was also no main effect of diag- 100635 BP nosis after removing the interaction (F = 0.01; df = 1,34; P = .988). [ C]-WAY-100635 binding across the ROIs, selected a priori There was a significant age by region interaction (F= 2.31; (Figure 1), was positively related with blood cortisol levels drawn df = 11,396; P = .009) and a significant sex by region interaction Downloaded from https://academic.oup.com/ijnp/article-abstract/22/5/329/5423589 by Ed 'DeepDyve' Gillespie user on 07 May 2019 334 | International Journal of Neuropsychopharmacology, 2019 Figure 1. The post-stress cortisol is positively correlated with serotonin 1A (5-HT ) receptor ligand binding across multiple brain regions. Top row shows [ C]WAY- 1A 100635 BP averaged across subjects. Bottom row highlights corresponding anatomical regions of interest (ROIs) for which a significant positive correlation between [ C]WAY-100635 binding and blood cortisol levels was observed, including the raphe nuclei, cingulate cortex, dorsal prefrontal cortex, hippocampus, insula, medial prefrontal cortex, parietal cortex, parahippocampal gyrus, occipital cortex, orbital cortex, and temporal cortex. Analyses were corrected for multiple comparisons using a threshold of P < .001. Figure 2. Cortisol response during the Trier Social Stress Task (TSST) is positively 11 11 correlated with [C]WAY-100635 BP . Shown here are the residual values for [C] WAY-100635 BP in a single region of interest (ROI), the anterior cingulate (ACN), and corresponding residual values for cortisol response after controlling for age, Figure 3. Baseline cortisol response during the Trier Social Stress Task (TSST) sex, and diagnosis. is inversely correlated with [C]WAY-100635 BP . Shown here are the residual values for [ C]WAY-100635 BP in a single region of interest (ROI), the anterior cingulate (ACN), and corresponding residual values for cortisol response after (F = 3.01;df = 11,396; P = .001), indicating differential effects of controlling for age, sex, and diagnosis. these demographic variables on binding across brain regions. we ran posthoc region-wise analyses adjusted for age, sex, and Baseline Cortisol and Brain [ C]WAY-100635 BP diagnostic group. The effects of the interaction terms of diag- The association between baseline salivary cortisol measured nostic group with baseline cortisol on C]W [ AY100635 binding before the TSST and [ C]WAY100635 binding differed by region were not significant in any of the region-specific models and and diagnostic group (baseline cortisol by region by group inter - were removed. The main effect of diagnosis was not significant action: F = 2.41; df = 11,374; P = .007). To interpret the interaction, in any region. Baseline cortisol and [C]WAY100635 binding Downloaded from https://academic.oup.com/ijnp/article-abstract/22/5/329/5423589 by Ed 'DeepDyve' Gillespie user on 07 May 2019 Steinberg et al. | 335 were negatively correlated in all regions (Figure 3; see supple- However, it is important to note that in addition to possible spe- mental Table 3 for coefficients by ROI) except in the RN (b = −0.18; cies differences, the animal experiments differ markedly from SE = 0.11; t = −1.71; P = .098). our paradigm in that they were performed either in animals in the context of adrenalectomy, chronic steroid treatment, or chronic stress paradigms, or in cell culture. We did not meas- ure baseline cortisol in our blood cortisol samples, which were Discussion taken after arterial line insertion prior to PET scan. Therefore, Here we show a positive correlation between cortisol levels after the post-stress blood cortisol measures represent a combination two different types of stressors and 5-HT receptor binding on of the resting cortisol levels and the response to the stressor, 1A PET using [ C]WAY-100635. This effect was observed across mul- and they cannot be disambiguated. We considered the potential tiple brain regions. The fact that this observation held under 2 contribution of circadian fluctuations in cortisol level by adjust- different stress paradigms speaks to the strength of this rela- ing TSST cortisol level for time of day in the model. tionship. Conversely, a negative correlation was found between HPA axis dysfunction has been linked to depression and sui- baseline salivary cortisol and [C]WAY-100635 binding in all a cide in many previous studies. Postmortem data from suicide priori regions, except RN. We previously reported that stress- completers shows that they tend to have heavier adrenal glands, responsive disorders like MDD and PTSD are associated with higher tissue levels of CRF, which indicates oversecretion of higher 5-HT binding (Parsey et al., 2006a, 2010; Sullivan et al., CRF, and lower expression of CRF receptors in prefrontal cortex 1A 2013), although other studies have found no difference or the (Nemeroff et  al., 1988; Arató et  al., 1989; Szigethy et  al., 1994). opposite (Yates and Ferrier, 1990; Lowther et  al., 1997; Sargent A subset of patients with depression, generally those with more et al., 2000; Bonne et al., 2005; Sullivan et al., 2015Mann et  ; al., severe illness, also demonstrate nonsuppression on dexametha- 2017). In this study, the relationship of 5-HT binding to post- sone suppression testing and are at higher risk of suicide (Caroff 1A stress cortisol in blood and salivary samples was independent et al., 1983; Dratcu and Calil, 1989Cor ; yell and Schlesser, 2001; of diagnosis, indicating a mechanism that operates compara- van Heeringen, 2003; Yerevanian et al., 2004; Pfennig et al., 2005; bly in healthy volunteers and in patients with mood disorders. Kunugi et al., 2006). HPA axis dysfunction is also linked directly Consistent with this observation, within the MDD group the to serotonergic dysfunction and specifically to changes in 5-HT 1A severity of current major depression was not correlated with receptor levels. CRF directly affects the dorsal raphe, modulating either 5-HT binding or post-stress cortisol in either blood or serotonergic tone in the prefrontal cortex and nucleus accum- 1A salivary measures. Higher brain 5-HT receptor ligand binding bens (Lowry et al., 2000; Forster et al., 2008Lukkes et  ; al., 2008; 1A is a biological trait observed in medication-free major depres- Quadros et al., 2014). Several studies in animal models show that sion during acute depression and during remission (Parsey et al., cortisol reduces 5-HT receptor expression in the hippocampus 1A 2006a, 2006b; Miller et al., 2009bP ; arsey et al., 2010) and is trans- (Martire et  al., 1989Chalmers et  ; al., 1993; Kuroda et  al., 1994; mitted in families (Milak et al., 2018). What remains to be deter - Meijer and de Kloet, 1994; Zhong and Ciaranello, 1995). Our data mined is whether there is a causal link between higher 5-HT add to this literature by demonstrating a functional relationship 1A binding and HPA axis overactivity or responsivity in depression. between 5-HT receptor binding levels and cortisol levels in 1A A negative correlation was found between baseline salivary response to an acute stressor in human subjects. cortisol and [ C]WAY-100635 binding in all a priori regions, The study had several limitations. There were modest dif- except RN. This is consistent with previous data in depression ferences in racial/ethnic composition between our healthy and social anxiety disorder (Lanzenberger et  al., 2010). That volunteers and MDD group. Subjects in this study were a con- baseline cortisol has a weaker or no correlation with 5-HT venience sample, included on the grounds of having undergone 1A binding in RN may be explained by RN being a small structure [ C]WAY-100635 imaging and having either a blood or salivary with noisier quantification. Moreover, because of this small size, measure of cortisol available. We cannot determine whether RN is susceptible to partial volume effects and underestimation these serotonin system relationships to baseline and post- of binding. Alternatively, presynaptic 5-HT receptors (autore- stress cortisol levels will extend to more severe MDD, which is 1A ceptors) in RN may be functionally distinct from post-synaptic characterized by cortisol hypersecretion and dexamethasone 5-HT receptors such that expression of the latter may be more resistance. However, we saw no relationship between MDD 1A strongly modulated by baseline cortisol levels. The latter expla- severity across the range that was present in our sample and nation is consistent with the observation that adrenalectomy cortisol measures. Finally, this cross-sectional study cannot has no effect on 5-HT receptor binding in RN (Le Corre et al., demonstrate causal relationships. This would be more feasible 1A 1997; van Gaalen et  al., 2002). Furthermore, animal work has to study in mouse models where pharmacological and genetic shown that different types of stressors can lead to increased manipulations of HPA axis responsiveness are possible and serotonin secretion within parts of the RN, which would then the time frame to determine the relationship of developmen- act on 5-HT autoreceptors and differentially affect serotonin tal effects on adult phenotypes much shorter. To more fully 1A release in terminal fields (Adell et al., 1997, 2002). This may also characterize the relationship of depression status to HPA axis explain why [ C]WAY-100635 binding differs between the RN reactivity, a longitudinal study with repeated measurements and terminal fields. in individual subjects during and between episodes of major Previous animal work demonstrating an inverse relation- depression would be required and would complement mouse ship between cortisol levels and 5-HT receptor expression in developmental studies. 1A cortical and hippocampal regions are consistent with our find- In summary, despite limitations, we found a positive correla- ings with basal salivary cortisol levels (Chalmers et  al., 1993; tion between 5-HT receptor and post-stress cortisol levels, inde- 1A Meijer and de Kloet, 1994; Flügge, 1995; Zhong and Ciaranello, pendent of diagnosis. This suggests an underlying mechanism 1995; Le Corre et  al., 1997; Czyrak et  al., 2002; Iyo et  al., 2009). that links 5-HT receptor overexpression with HPA axis feedback 1A It is thought that cortisol-dependent transcriptional repression dysfunction. Conversely, binding and resting cortisol are negatively of 5-HT requires coactivation of both the glucocorticoid and correlated as reported in several rodent studies and likely involve 1A mineralocorticoid receptors (Meijer et al., 2000 Ou et  ; al., 2001). different mechanisms including the mineralocorticoid receptor. Downloaded from https://academic.oup.com/ijnp/article-abstract/22/5/329/5423589 by Ed 'DeepDyve' Gillespie user on 07 May 2019 336 | International Journal of Neuropsychopharmacology, 2019 Such mechanisms are a combination of genetic vulnerability and Coplan  JD, Abdallah  CG, Kaufman  J, Gelernter  J, Smith  EL, environmental risk factors, such as early-life stress, which leads to Perera TD, Dwork AJ, Kaffman A, Gorman JM, Rosenblum LA, epigenetic changes generating this biological phenotype. Owens MJ, Nemeroff CB (2011) Early-life stress, corticotropin- releasing factor, and serotonin transporter gene: a pilot study. Psychoneuroendocrinology 36:289–293. Funding Coryell W, Schlesser M (2001) The dexamethasone suppression This work was funded by the NIH through the following grants: test and suicide prediction. Am J Psychiatry 158:748–753. Cowen  PJ (2010) Not fade away: the HPA axis and depression. MH040695, MH090964, MH062185. Psychol Med 40:1–4. Czyrak A, Maćkowiak M, Chocyk A, Fijał K, Tokarski K, Bijak M, Acknowledgments Wedzony K (2002) Prolonged corticosterone treatment alters the responsiveness of 5-HT1A receptors to 8-OH-DPAT in rat We thank Dr Ramin Parsey for sharing subject data included in CA1 hippocampal neurons. Naunyn Schmiedebergs Arch this study. The authors of this manuscript are entirely responsi- Pharmacol 366:357–367. ble for the scientific content of this paper. Delorenzo  C, Klein  A, Mikhno  A, Gray  N, Zanderigo  F, Mann  JJ (2009). A new method for assessing PET-MRI coregistration. Statement of Interest In: SPIE medical imaging, pp 72592–72598. USA. Delorenzo  C, Delaparte  L, Thapa-Chhetry  B, Miller  JM, Mann  JJ, Mr Rubin-Falcone, Dr Kaufman, Dr Sublette, Dr Miller, Mr Parsey RV (2013) Prediction of selective serotonin reuptake in- Cooper, Mr Min, and Dr Ogden declare no conflict of interest. Dr hibitor response using diffusion-weighted MRI. Front Psych- Steinberg receives compensation for consulting for Owaves, Inc. iatry 4:5. Dr Stanley receives royalties for commercial use of the C-SSRS Dratcu L, Calil HM (1989) The dexamethasone suppression test: from the Research Foundation for Mental Hygiene, as well as its relationship to diagnoses, severity of depression and re- compensation for consulting for AbbVie and Merck. Dr Galfalvy’s sponse to treatment. Prog Neuropsychopharmacol Biol family owns stocks in Illumina, Inc. Dr Mann receives royalties Psychiatry 13:99–117. for commercial use of the C-SSRS from the Research Foundation First  MB, Spitzer  RL, Gibbon  M, Williams  JB (2012). Structured for Mental Hygiene. Dr Oquendo receives royalties for commer - clinical interview for DSM-IV axis I disorders (SCID-I), clinical cial use of the C-SSRS from the Research Foundation for Mental version, administration booklet. Hygiene. Her family owns stock in Bristol Myers Squibb. 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Journal

International Journal of NeuropsychopharmacologyOxford University Press

Published: May 1, 2019

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