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Long-term sertraline treatment and depression effects on carotid artery atherosclerosis in premenopausal female primates.
Silverstein-Metzler MG, Justice JN, Appt SE, Groban L, Kitzman DW, Carr JJ, Register TC, Shively CA
(2017) Menopause 24: 1175-1184
MeSH Terms: Animals, Carotid Artery Diseases, Carotid Artery, Common, Depression, Disease Models, Animal, Female, Hot Flashes, Humans, Longitudinal Studies, Macaca fascicularis, Premenopause, Primates, Random Allocation, Risk Factors, Serotonin Uptake Inhibitors, Sertraline
Show Abstract · Added September 11, 2017
OBJECTIVE - Atherosclerosis developed during premenopausal years predicts postmenopausal atherosclerosis burden. Selective serotonin reuptake inhibitor (SSRI) antidepressants, recently approved for hot flushes, have been associated with increased ischemic stroke risk in several observational studies; however, effects on carotid artery atherosclerosis, a strong predictor of future vascular events, are unknown.
METHODS - The effects of chronic administration of a commonly prescribed SSRI, sertraline HCl, on atherosclerosis in the carotid artery was assessed in a placebo-controlled, longitudinal, randomized study of premeonopausal depressed and nondepressed cynomolgus monkeys (Macaca fascicularis; n = 42). Physiologic and behavioral phenotypes were evaluated at baseline and after 18 months of oral sertraline (20 mg/kg, n = 21) or placebo (n = 21). Carotid artery atherosclerosis was measured post mortem via histomorphometry.
RESULTS - Atherosclerosis extent in the right common carotid artery, on average, was 60% greater in sertraline-treated depressed monkeys compared with all other groups (P = 0.028). The results of linear regression analyses suggested that sertraline and depression effects on atherosclerosis were not mediated by their effects on behavioral and physiological risk factors.
CONCLUSIONS - These findings suggest that chronic SSRI treatment is associated with the progression of carotid artery atherosclerosis, which may increase the risk for future vascular events, particularly in depressed women. The underlying mechanism remains to be determined, but does not appear to be related to SSRI effects on traditional cardiovascular risk factors.
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16 MeSH Terms
Frontocingulate cerebral blood flow and cerebrovascular reactivity associated with antidepressant response in late-life depression.
Abi Zeid Daou M, Boyd BD, Donahue MJ, Albert K, Taylor WD
(2017) J Affect Disord 215: 103-110
MeSH Terms: Adult, Aged, Aging, Antidepressive Agents, Depression, Female, Frontal Lobe, Gyrus Cinguli, Hemodynamics, Humans, Late Onset Disorders, Magnetic Resonance Imaging, Male, Middle Aged, Neuroimaging, Sertraline, Spin Labels, Treatment Outcome
Show Abstract · Added April 6, 2017
BACKGROUND - Vascular pathology is common in late-life depression (LLD) and may contribute to alterations in cerebral blood flow (CBF) and cerebrovascular reactivity (CVR). In turn, such hemodynamic deficits may adversely affect brain function and clinical course. The goal of this study was to examine whether altered cerebral hemodynamics in depressed elders predicted antidepressant response.
METHODS - 21 depressed elders completed cranial 3T MRI, including a pseudo-continuous Arterial Spin Labeling (pcASL) acquisition on both room air and during a hypercapnia challenge. Participants then completed 12 weeks of open-label sertraline. Statistical analyses examined the relationship between regional normalized CBF and CVR values and change in Montgomery-Asberg Depression Rating Scale (MADRS) and tested for differences based on remission status.
RESULTS - 10 participants remitted and 11 did not. After controlling for age and baseline MADRS, greater change in MADRS with treatment was associated with lower pre-treatment normalized CBF in the caudal anterior cingulate cortex (cACC) and lateral orbitofrontal cortex (OFC), as well as lower CVR with hypercapnia in the caudal medial frontal gyrus (cMFG). After controlling for age and baseline MADRS score, remitters exhibited lower CBF in the cACC and lower CVR in the cMFG.
LIMITATIONS - Our sample was small, did not include a placebo arm, and we examined only specific regions of interest.
CONCLUSIONS - Our findings suggest that increased perfusion of the OFC and the ACC is associated with a poor antidepressant response. They do not support that vascular pathology as measured by CBF and CVR negatively affects acute treatment outcomes.
Published by Elsevier B.V.
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18 MeSH Terms
Selective serotonin reuptake inhibitor exposure constricts the mouse ductus arteriosus in utero.
Hooper CW, Delaney C, Streeter T, Yarboro MT, Poole S, Brown N, Slaughter JC, Cotton RB, Reese J, Shelton EL
(2016) Am J Physiol Heart Circ Physiol 311: H572-81
MeSH Terms: Animals, Aorta, Ductus Arteriosus, Female, Fluoxetine, Immunohistochemistry, Mice, Myography, Persistent Fetal Circulation Syndrome, Pregnancy, RNA, Messenger, Real-Time Polymerase Chain Reaction, Receptors, Serotonin, Reverse Transcriptase Polymerase Chain Reaction, Serotonin Uptake Inhibitors, Sertraline, Vasoconstriction
Show Abstract · Added April 6, 2017
Use of selective serotonin reuptake inhibitors (SSRIs) is common during pregnancy. Fetal exposure to SSRIs is associated with persistent pulmonary hypertension of the newborn (PPHN); however, a direct link between the two has yet to be established. Conversely, it is well known that PPHN can be caused by premature constriction of the ductus arteriosus (DA), a fetal vessel connecting the pulmonary and systemic circulations. We hypothesized that SSRIs could induce in utero DA constriction. Using isolated vessels and whole-animal models, we sought to determine the effects of two commonly prescribed SSRIs, fluoxetine and sertraline, on the fetal mouse DA. Cannulated vessel myography studies demonstrated that SSRIs caused concentration-dependent DA constriction and made vessels less sensitive to prostaglandin-induced dilation. Moreover, in vivo studies showed that SSRI-exposed mice had inappropriate DA constriction in utero. Taken together, these findings establish that SSRIs promote fetal DA constriction and provide a potential mechanism by which SSRIs could contribute to PPHN.
Copyright © 2016 the American Physiological Society.
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17 MeSH Terms
Sertraline inhibits increases in body fat and carbohydrate dysregulation in adult female cynomolgus monkeys.
Silverstein-Metzler MG, Shively CA, Clarkson TB, Appt SE, Carr JJ, Kritchevsky SB, Jones SR, Register TC
(2016) Psychoneuroendocrinology 68: 29-38
MeSH Terms: Adipose Tissue, Animals, Antidepressive Agents, Body Composition, Body Weight, Carbohydrate Metabolism, Depression, Drug Administration Schedule, Female, Insulin, Longitudinal Studies, Macaca fascicularis, Models, Animal, Random Allocation, Serotonin Uptake Inhibitors, Sertraline
Show Abstract · Added September 29, 2016
Selective serotonin reuptake inhibitor (SSRI) antidepressants are widely prescribed for depression and other disorders. SSRIs have become one of the most commonly used drugs in the United States, particularly by women. Acute effects on body composition and carbohydrate metabolism have been reported, but little is known regarding the effects of chronic SSRI use. We evaluated the effects of chronic administration of a commonly prescribed SSRI, sertraline HCl, on body weight and composition, fat distribution, carbohydrate metabolism, as well as activity, in adult female depressed and nondepressed cynomolgus monkeys (Macaca fascicularis; n=42) using a placebo-controlled, longitudinal, randomized study design. Phenotypes were evaluated prior to and after 18 months of oral sertraline (20mg/kg) or placebo. Over the 18 month treatment period, the placebo group experienced increases in body weight, body fat (visceral and subcutaneous) fasting insulin concentrations, and homeostasis model assessment of insulin resistance scores (HOMA-IR). Sertraline treatment prevented increases in body weight, fat, insulin, and HOMA-IR (all p<0.05), without significantly altering activity levels. Sertraline treatment altered adiponectin in an unusual way - reducing circulating adiponectin in depressed monkeys without affecting fat mass or body weight. Deleterious effects on adiponectin, a potentially insulin-sensitizing and atheroprotective protein, may result in adverse effects on cardiovascular health despite otherwise beneficial effects on body composition and carbohydrate metabolism.
Copyright © 2016. Published by Elsevier Ltd.
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16 MeSH Terms
Acute hemodynamic effects of a selective serotonin reuptake inhibitor in postural tachycardia syndrome: a randomized, crossover trial.
Mar PL, Raj V, Black BK, Biaggioni I, Shibao CA, Paranjape SY, Dupont WD, Robertson D, Raj SR
(2014) J Psychopharmacol 28: 155-61
MeSH Terms: Adult, Blood Pressure, Cross-Over Studies, Female, Heart Rate, Hemodynamics, Humans, Male, Norepinephrine Plasma Membrane Transport Proteins, Postural Orthostatic Tachycardia Syndrome, Serotonin Uptake Inhibitors, Sertraline
Show Abstract · Added March 7, 2014
BACKGROUND - Selective serotonin reuptake inhibitors (SSRIs) are often prescribed in patients with postural tachycardia syndrome (POTS), and act at synaptic terminals to increase monoamine neurotransmitters. We hypothesized that they act to increase blood pressure and attenuate reflex tachycardia, thereby improving symptoms. Acute hemodynamic profiles after SSRI administration in POTS patients have not previously been reported.
METHODS - Patients with POTS (n=39; F=37, 39 ±9 years) underwent a randomized crossover trial with sertraline 50mg and placebo. Heart rate, systolic, diastolic, and mean blood pressure were measured with the patient seated and standing for 10 min prior to drug or placebo administration, and then hourly for 4 h. The primary endpoint was standing heart rate at 4 h.
RESULTS - At 4 h, standing heart rate and systolic blood pressure were not significantly different between sertraline and placebo. Seated systolic (106±12 mmHg vs. 101±8 mmHg; p=0.041), diastolic (72±8 mmHg vs. 69±8 mmHg; p=0.022), and mean blood pressure (86±9 mmHg vs. 81±9 mmHg; p=0.007) were significantly higher after sertraline administration than placebo. At 4 h, symptoms were worse with sertraline than placebo.
CONCLUSIONS - Sertraline had a modest pressor effect in POTS patients, but this did not translate into a reduced heart rate or improved symptoms.
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12 MeSH Terms
Treatment course with antidepressant therapy in late-life depression.
Sheline YI, Disabato BM, Hranilovich J, Morris C, D'Angelo G, Pieper C, Toffanin T, Taylor WD, MacFall JR, Wilkins C, Barch DM, Welsh-Bohmer KA, Steffens DC, Krishnan RR, Doraiswamy PM
(2012) Am J Psychiatry 169: 1185-93
MeSH Terms: Aged, Amygdala, Antidepressive Agents, Brain, Caudate Nucleus, Cerebral Cortex, Cognition Disorders, Depressive Disorder, Major, Female, Frontal Lobe, Hippocampus, Humans, Image Interpretation, Computer-Assisted, Magnetic Resonance Imaging, Male, Middle Aged, Neural Pathways, Neuropsychological Tests, Organ Size, Parahippocampal Gyrus, Personality Inventory, Prospective Studies, Psychometrics, Reaction Time, Sertraline, Treatment Outcome
Show Abstract · Added May 20, 2014
OBJECTIVE - In order to assess the effect of gray matter volumes and cortical thickness on antidepressant treatment response in late-life depression, the authors examined the relationship between brain regions identified a priori and Montgomery-Åsberg Depression Rating Scale (MADRS) scores over the course of an antidepressant treatment trial.
METHOD - In a nonrandomized prospective trial, 168 patients who were at least 60 years of age and met DSM-IV criteria for major depression underwent MRI and were enrolled in a 12-week treatment study. Exclusion criteria included cognitive impairment or severe medical disorders. The volumes or cortical thicknesses of regions of interest that differed between the depressed group and a comparison group (N=50) were determined. These regions of interest were used in analyses of the depressed group to predict antidepressant treatment outcome. Mixed-model analyses adjusting for age, education, age at depression onset, race, baseline MADRS score, scanner, and interaction with time examined predictors of MADRS scores over time.
RESULTS - Smaller hippocampal volumes predicted a slower response to treatment. With the inclusion of white matter hyper-intensity severity and neuropsychological factor scores, the best model included hippocampal volume and cognitive processing speed to predict rate of response over time. A secondary analysis showed that hippocampal volume and frontal pole thickness differed between patients who achieved remission and those who did not.
CONCLUSIONS - These data expand our understanding of the prediction of treatment course in late-life depression. The authors propose that the primary variables of hippocampal volume and cognitive processing speed, subsuming other contributing variables (episodic memory, executive function, language processing) predict antidepressant response.
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26 MeSH Terms
One-year change in anterior cingulate cortex white matter microstructure: relationship with late-life depression outcomes.
Taylor WD, Macfall JR, Boyd B, Payne ME, Sheline YI, Krishnan RR, Murali Doraiswamy P
(2011) Am J Geriatr Psychiatry 19: 43-52
MeSH Terms: Aged, Anisotropy, Antidepressive Agents, Brain, Clinical Trials as Topic, Depression, Diffusion Tensor Imaging, Female, Follow-Up Studies, Gyrus Cinguli, Humans, Male, Nerve Fibers, Myelinated, Psychiatric Status Rating Scales, Remission Induction, Sertraline
Show Abstract · Added May 20, 2014
OBJECTIVE - differences in white matter structure measured with diffusion tensor imaging (DTI) are associated with late-life depression, but results examining how these differences relate to antidepressant remission are mixed. To better describe these relationships, the authors examined how 1-year change in DTI measures are related to 1-year course of depression.
DESIGN - one-year cross-sectional follow-up to a 12-week clinical trial of sertraline.
SETTING - outpatients at an academic medical center.
PARTICIPANTS - twenty-nine depressed and 20 never-depressed elderly subjects. Over the 1-year period, 16 depressed subjects achieved and maintained remission, whereas 13 did not.
MEASUREMENTS - one-year change in fractional anisotropy (FA) and diffusivity in frontal white matter, as measured by DTI.
RESULTS - contrary to our hypotheses, depressed subjects who did not remit over the study interval exhibited significantly less change in anterior cingulate cortex (ACC) white matter FA than did never-depressed or depressed-remitted subjects. There were no group differences in other frontal or central white matter regions. Moreover, there was a significant positive relationship between change in Montgomery-Asberg Depression Rating Scale (MADRS) and change in ACC FA, wherein greater interval decline in FA was associated with greater interval decline in MADRS.
CONCLUSION - older depressed individuals who remit exhibit white matter changes comparable with what is observed in never-depressed individuals, whereas nonremitters exhibit significantly less change in ACC FA. Such a finding may be related to either antidepressant effects on brain structure or the effects of chronic stress on brain structure. Further work is needed to better understand this relationship.
2011 American Association for Geriatric Psychiatry.
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16 MeSH Terms
Frontal white matter anisotropy and antidepressant remission in late-life depression.
Taylor WD, Kuchibhatla M, Payne ME, Macfall JR, Sheline YI, Krishnan KR, Doraiswamy PM
(2008) PLoS One 3: e3267
MeSH Terms: Aged, Aged, 80 and over, Aging, Anisotropy, Antidepressive Agents, Brain, Brain Mapping, Depressive Disorder, Female, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Remission Induction, Sertraline
Show Abstract · Added May 20, 2014
INTRODUCTION - Neuroanatomic features associated with antidepressant treatment outcomes in older depressed individuals are not well established. This study used diffusion tensor imaging to examine frontal white matter structure in depressed subjects undergoing a 12-week trial of sertraline. We hypothesized that remission would be associated with higher frontal anisotropy measures, and failure to remit with lower anisotropy.
METHODS - 74 subjects with Major Depressive Disorder and age 60 years or older were enrolled in a twelve-week open-label trial of sertraline and completed clinical assessments and 1.5T magnetic resonance brain imaging. The apparent diffusion coefficient (ADC) and fractional anisotropy (FA) were measured in regions of interest placed in the white matter of the dorsolateral prefrontal cortex, anterior cingulate cortex, and corpus callosum. Differences in ADC and FA values between subjects who did and did not remit to treatment over the study period were assessed using generalized estimating equations, controlling for age, sex, medical comorbidity and baseline depression severity.
RESULTS - Subjects who did not remit to sertraline exhibited higher FA values in the superior frontal gyri and anterior cingulate cortices bilaterally. There were no statistically significant associations between ADC measures and remission.
CONCLUSIONS - Failure to remit to sertraline is associated with higher frontal FA values. Functional imaging studies demonstrate that depression is characterized by functional disconnection between frontal and limbic regions. Those individuals where this disconnection is related to structural changes as detected by DTI may be more likely to respond to antidepressants.
TRIAL REGISTRATION - ClinicalTrials.gov NCT00339066.
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15 MeSH Terms