The impact of treatment with selective serotonin reuptake inhibitors on primate cardiovascular disease, behavior, and neuroanatomy.

Selective serotonin reuptake inhibitor (SSRI) use is ubiquitous because they are widely prescribed for a number of disorders in addition to depression. Depression increases the risk of coronary heart disease (CHD). Hence, treating depression with SSRIs could reduce CHD risk. However, the effects of long term antidepressant treatment on CHD risk, as well as other aspects of health, remain poorly understood. Thus, we undertook an investigation of multisystem effects of SSRI treatment with a physiologically relevant dose in middle-aged adult female cynomolgus monkeys, a primate species shown to be a useful model of both depression and coronary and carotid artery atherosclerosis. Sertraline had no effect on depressive behavior, reduced anxious behavior, increased affiliation, reduced aggression, changed serotonin neurotransmission and volumes of neural areas critical to mood disorders, and exacerbated coronary and carotid atherosclerosis. These data suggest that a conservative approach to prescribing SSRIs for cardiovascular or other disorders for long periods may be warranted, and that further study is critical given the widespread use of these medications.

Reduced marker of vascularization in the anterior hippocampus in a female monkey model of depression.

Depression is a common and debilitating mood disorder that impacts women more often than men. The mechanisms that result in depressive behaviors are not fully understood; however, the hippocampus has been noted as a key structure in the pathophysiology of depression. In addition to neural implications of depression, the cardiovascular system is impacted. Although not as commonly considered, the cerebrovasculature is critical to brain function, impacted by environmental stimuli, and is capable of altering neural function and thereby behavior. In the current study, we assessed the relationship between depressive behavior and a marker of vascularization of the hippocampus in adult female cynomolgus macaques (Macaca fascicularis). Similar to previously noted impacts on neuropil and glia, the depressed phenotype predicts a reduction in a marker of vascular length in the anterior hippocampus. These data reinforce the growing recognition of the effects of depression on vasculature and support further consideration of vascular endpoints in studies aimed at the elucidation of the mechanisms underlying depression.

Long term sertraline effects on neural structures in depressed and nondepressed adult female nonhuman primates.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed for mood and other disorders. However, their neural effects are difficult to study due to patient compliance and drug history variability, and rarely studied in those prescribed SSRIs for non-mood disorders. Here we evaluated SSRI effects on neural volumetrics in depressed and nondepressed monkeys. METHODS: 42 socially-housed cynomolgus monkeys were randomized to treatment balanced on pretreatment depressive behavior and body weight. Monkeys were trained for oral administration of placebo or 20 mg/kg sertraline HCl daily for 18 months and depressive and anxious behavior recorded. Volumes of neural regions of interest in depression were measured in magnetic resonance images and analyzed by 2 (depressed, nondepressed)×2 (placebo, sertraline) ANOVA. RESULTS: Sertraline reduced anxiety (p=0.04) but not depressive behavior (p=0.43). Left Brodmann's Area (BA) 32 was smaller in depressed than nondepressed monkeys (main effect of depression: p<0.05). Sertraline and depression status interacted to affect volumes of left Anterior Cingulate Cortex (ACC), left BA24, right hippocampus (HC), and right anterior HC (sertraline×depression interactions: all p's<0.05). In the Placebo group, depressed monkeys had smaller right anterior HC and left ACC than nondepressed monkeys. In nondepressed monkeys, sertraline reduced right HC volume, especially right anterior HC volume. In depressed monkeys sertraline increased left ACC volume. In nondepressed monkeys, sertraline reduced left BA24 volumes resulting in smaller BA24 volumes in nondepressed than sertraline-treated depressed monkeys. CONCLUSIONS: These observations suggest that SSRIs may differentially affect neural structures in depressed and nondepressed individuals.

Altered expression of glial and synaptic markers in the anterior hippocampus of behaviorally depressed female monkeys.

The anterior hippocampus is associated with emotional functioning and hippocampal volume is reduced in depression. We reported reduced neuropil volume and number of glia in the dentate gyrus (DG) and cornu ammonis (CA)1 of the anterior hippocampus in behaviorally depressed adult female cynomolgus macaques. To determine the biochemical correlates of morphometric and behavioral differences between behaviorally depressed and nondepressed adult female monkeys, glial and synaptic transcripts and protein levels were assessed in the DG, CA3 and CA1 of the anterior hippocampus. Glial fibrillary acidic protein (GFAP) was increased whereas spinophilin and postsynaptic density (PSD)-95 protein were decreased in the CA1 of depressed monkeys. GFAP was reciprocally related to spinophilin and PSD-95 protein in the CA1. Gene expression of GFAP paralleled the protein changes observed in the CA1 and was inversely related to serum estradiol levels in depressed monkeys. These results suggest that behavioral depression in female primates is accompanied by astrocytic and synaptic protein alterations in the CA1. Moreover, these findings indicate a potential role for estrogen in modulating astrocyte-mediated impairments in synaptic plasticity.

Sertraline effects on cerebrospinal fluid monoamines and species-typical socioemotional behavior of female cynomolgus monkeys.

RATIONALE: Although widely prescribed, little is known about the effects of selective serotonin reuptake inhibitors (SSRIs) on social behavior and cerebrospinal fluid (CSF) monoamines in female primates. OBJECTIVE: The objective of this study was to determine the effects of sertraline on agonistic and affiliative behavior. METHODS: Twenty-one adult female cynomolgus monkeys were housed in small, stable social groups, trained to participate in oral dosing, and began a 5-week cumulative dose-response study. Serial doses of 0, 5, 10, 15, and 20 mg/kg of sertraline were administered orally for 1 week each. Behavior was recorded daily during 10-min observations before and 4 h after dosing. On the seventh day of dosing, circulating sertraline/desmethylsertraline and CSF monoamines/metabolites were determined 4 h after the last dose. RESULTS: At 20 mg/kg, circulating sertraline/desmethylsertraline was in the therapeutic range. CSF 5-hydroxyindole acetic acid decreased by 33 % (p < 0.05). Overall aggression, submission, locomotion, and time alone decreased, whereas affiliative behaviors (body contact, grooming) increased (all p values <0.05). Effects of sertraline on aggression and submission were social status-dependent, reducing aggression in dominants and submission in subordinates. CONCLUSIONS: A clinically relevant oral dose of sertraline resulted in CSF metabolite changes similar to those observed in patients and altered the socioemotional behavior of female monkeys. Changes in CSF 5-HT and dopamine are novel observations that may be sex-specific. The robust effects of sertraline on aggression and affiliation may explain the efficacy of SSRIs on a range of human behavioral pathologies that share the characteristics of increased aggression and decreased sociality.

Cell number and neuropil alterations in subregions of the anterior hippocampus in a female monkey model of depression.

BACKGROUND: The anterior hippocampus is associated with emotional functioning and hippocampal volume is reduced in depression. More women are clinically depressed than men, yet the depressed female brain is little studied. We reported reduced anterior hippocampal volume in behaviorally depressed adult female cynomolgus macaques; the mechanisms contributing to that reduction are unknown. The present study represents the first systematic morphological investigation of the entire hippocampus in depressed female primates. METHODS: Cellular determinants of hippocampal size were examined in subregions of anterior and posterior hippocampus in antidepressant-naïve, adult female monkeys characterized for behavioral depression and matched on variables that influence hippocampal size (n = 8 depressed, 8 nondepressed). Unbiased stereology was used to estimate neuronal and glial numbers, neuronal soma size, and regional and layer volumes. RESULTS: Neuropil and cell layer volumes were reduced in cornu ammonis (CA)1 and dentate gyrus (DG) of the anterior but not the posterior hippocampus of depressed compared with nondepressed monkeys. Glial numbers were 30% lower in anterior CA1 and DG of depressed monkeys, with no differences observed in the posterior hippocampus. Granule neuron number tended toward a reduction in anterior DG; pyramidal neuron number was unchanged in any region. Size of pyramidal neurons and glial densities tended to be reduced throughout the whole hippocampus of depressed monkeys, whereas neuronal densities were unchanged. CONCLUSIONS: The reduced size of the anterior hippocampus in depressed female monkeys appears to arise from alterations in numbers of glia and extent of neuropil, but not numbers of neurons, in CA1 and DG.

Development of amyloid burden in African Green monkeys.

The vervet is an old world monkey increasingly being used as a model for human diseases. In addition to plaques and tangles, an additional hallmark of Alzheimer's disease is damage to neurons that synthesize noradrenaline (NA). We characterized amyloid burden in the posterior temporal lobe of young and aged vervets, and compared that with changes in NA levels and astrocyte activation. Total amyloid beta (Aß)40 and Aß42 levels were increased in the aged group, as were numbers of amyloid plaques detected using antibody 6E10. Low levels of Aß42 were detected in 1 of 5 younger animals, although diffusely stained plaques were observed in 4 of these. Increased glial fibrillary acidic protein staining and messenger RNA levels were significantly correlated with increased age, as were cortical NA levels. Levels of Aß42 and Aß40, and the number of 6E10-positive plaques, were correlated with NA levels. Interestingly messenger RNA levels of glial derived neurotrophic factor, important for noradrenergic neuronal survival, were reduced with age. These findings suggest that amyloid pathology in aged vervets is associated with astrocyte activation and higher NA levels.

Aging and physical mobility in group-housed Old World monkeys.

While indices of physical mobility such as gait speed are significant predictors of future morbidity/mortality in the elderly, mechanisms of these relationships are not understood. Relevant animal models of aging and physical mobility are needed to study these relationships. The goal of this study was to develop measures of physical mobility including activity levels and gait speed in Old World monkeys which vary with age in adults. Locomotor behaviors of 21 old ([Formula: see text] = 20 yoa) and 24 young ([Formula: see text] = 9 yoa) socially housed adult females of three species were recorded using focal sample and ad libitum behavior observation methods. Self-motivated walking speed was 17% slower in older than younger adults. Likewise, young adults climbed more frequently than older adults. Leaping and jumping were more common, on average, in young adults, but this difference did not reach significance. Overall activity levels did not vary significantly by age, and there were no significant age by species interactions in any of these behaviors. Of all the behaviors evaluated, walking speed measured in a simple and inexpensive manner appeared most sensitive to age and has the added feature of being least affected by differences in housing characteristics. Thus, walking speed may be a useful indicator of decline in physical mobility in nonhuman primate models of aging.

Behavioral and neurobiological characteristics of social stress versus depression in nonhuman primates.

The focus of the review is on the behavioral and physiological manifestations of stress versus depression. The purpose of the review is to evaluate the conceptual approach of using stress models as surrogates for depression. Social stress and depression have many characteristics in common and promote each other. Both have adverse effects on social relationships and the quality of life, and increase risk of other diseases. However, they are not the same constructs. In human and nonhuman primates, the behavior and neurobiology of stressed individuals differ from that of depressed individuals. Some similarities in stress physiology in socially stressed and depressed individuals have been used to support the use of stressed animals as models of depression, and much has been learned from stress models of depression. However, the studies reviewed here also suggest that the depressed state also has different characteristics than the stressed state, and studying the differences may be important to furthering our understanding of each of these constructs as well as their mutual relationship.

Modeling depression in adult female cynomolgus monkeys (Macaca fascicularis).

Depressive disorders are prevalent, costly, and poorly understood. Male rodents in stress paradigms are most commonly used as animal models, despite the two-fold increased prevalence of depression in women and sex differences in response to stress. Although these models have provided valuable insights, new models are needed to move the field forward. Social stress-associated behavioral depression in adult female cynomolgus macaques closely resembles human depression in physiological, neurobiological, and behavioral characteristics, including reduced body mass, hypothalamic-pituitary-adrenal axis perturbations, autonomic dysfunction, increased cardiovascular disease risk, reduced hippocampal volume, altered serotonergic function, decreased activity levels, and increased mortality. In addition, behaviorally depressed monkeys also have low ovarian steroid concentrations, even though they continue to have menstrual cycles. Although this type of ovarian dysfunction has not been reported in depressed women and is difficult to identify, it may be the key to understanding the high prevalence of depression in women. Depressive behavior in female cynomolgus monkeys is naturally occurring and not induced by experimental manipulation. Different social environmental challenges, including isolation vs. subordination, may elicit the depression-like response in some animals and not others. Similarly, social subordination is stressful and depressive behavior is more common in socially subordinate monkeys. Yet, not all subordinates exhibit behavioral depression, suggesting individual differences in sensitivity to specific environmental stressors and enhanced risk of behavioral depression in some individuals. The behavior and neurobiology of subordinates is distinctly different than that of behaviorally depressed monkeys, which affords the opportunity to differentiate between stressed and depressed states. Thus, behaviorally depressed monkeys exhibit numerous physiological, neurobiological, and behavioral characteristics same as those of depressed human beings. The nonhuman primate model represents a new animal model of depression with great promise for furthering our understanding of this prevalent and debilitating disease and identifying novel therapeutic targets.

Depression and altered serum lipids in cynomolgus monkeys consuming a Western diet.

Research over the past 15 years has suggested a high comorbidity of depression and coronary heart disease (CHD). However the mechanisms responsible for this relationship are poorly understood. This study was designed to examine the relationships between depressive behaviors and concentrations of circulating lipids and lipid signaling molecules that may be common to both CHD and depression in a cohort of cynomolgus monkeys (Macaca fascicularis) consuming a 'Western' diet, enriched with saturated fat and cholesterol. Socially-housed adult female cynomolgus monkeys (n=36) were fed the Western diet for 27 months and depressive behavior was recorded weekly. Body weight, body mass index and circulating cholesterol profiles were measured in all animals, and fatty acids (FA) and FA-based signaling molecules were measured in the 6 least and 6 most depressed monkeys. Monkeys consuming the Western diet exhibited a broad range of percent time spent in depressive behavior. The percent time spent depressed was positively correlated with total plasma and LDL cholesterol and negatively correlated with HDL cholesterol. Despite being leaner, depressed monkeys had higher concentrations of monounsaturated fats (C16:1 and C17:1), a higher ω6/ω3 polyunsaturated fatty acid (PUFA) ratio and higher concentrations of omega-6 (ω6) PUFAs, particularly C18:2ω6 and C20:3ω6. FA ratios suggest that stearoyl CoA desaturase 1 activity was increased in depressed monkeys. Depressed female cynomolgus monkeys had elevated concentrations of serum lipids and lipid signaling molecules that are typically associated with obesity, insulin resistance and cardiovascular disease, which may account in part for the comorbidity of depression and CHD.

Hippocampal volume in postmenopausal cynomolgus macaques with behavioral depression.

OBJECTIVE: Magnetic resonance imaging (MRI) studies report hippocampal (HC) volume reductions in depression. Despite observations of functional heterogeneity and ovarian steroid influence in the hippocampus, few studies report regional volume alterations or control for menstrual cycle phase. Using in vitro methods, we recently observed reduced anterior HC volume in antidepressant-naive, ovarian-intact, behaviorally depressed adult female monkeys. The purpose of this study was to confirm these findings in vivo and examine whether lack of ovarian steroids affects the relationship between depression and HC volume. METHODS: MRI was used to measure whole, anterior, and posterior HC volumes in a matched sample of antidepressant-naive, surgically postmenopausal adult female cynomolgus macaques characterized for behavioral depression (six depressed, six nondepressed). High-resolution structural MRIs were acquired, and HC regions of interest were manually segmented. HC volumes were normalized to whole brain volumes before analysis. RESULTS: Similar to the previous in vitro study, HC volume measured in vivo was associated with depression. In contrast to the previous study of ovarian-intact female monkeys, whole, anterior, and posterior volumes of both the left and right hippocampi were significantly smaller in depressed compared with nondepressed surgically postmenopausal female monkeys. CONCLUSIONS: These findings confirm and extend previous observations of smaller HC volumes in behaviorally depressed female monkeys and suggest a possible role for ovarian steroids in HC protection in depression. Further studies of the potential modulating effects of ovarian function on the relationship between depression and HC volume are warranted.

Anterior hippocampal volume is reduced in behaviorally depressed female cynomolgus macaques.

Hippocampal (HC) function and morphology have been implicated in the pathophysiology of depression. Reduced HC volume has been observed in depressed humans, although the effect is not always significant. Studies of functional differentiation of the HC have revealed that the anterior portion is associated with emotional and anxiety-related functioning, and the posterior portion with memory processing. As such, measuring whole HC volume may mask differences seen only in the anterior or posterior HC. We used unbiased stereology to measure whole, anterior, and posterior HC volumes in 12 adult female cynomolgus macaques, half of which exhibited spontaneously occurring depressive behavior defined as a slumped/collapsed body posture with open eyes, and a relative lack of responsivity to environmental stimuli. The two groups were otherwise matched on circulating estradiol, progesterone, and cortisol levels, social status, estimated age, and body weight. Frozen postmortem HC tissue from depressed and nondepressed monkeys was serially sectioned and thionin-stained. According to established neuroanatomical guidelines and with the aid of Neurolucida software (MBF Bioscience), every 10th section throughout the extent of the HC was manually traced and used to reconstruct the 3D models used to determine volumes. Anterior and posterior HC were delineated by the presence or absence of the uncus. No significant differences were found between depressed and nondepressed monkeys for whole or posterior HC volume, although the average HC volume was 4% smaller in depressed than nondepressed monkeys. Anterior HC volumes were significantly smaller (15.4%) in depressed compared to nondepressed monkeys. These results indicate that reduced volume in the anterior HC, an area previously implicated in emotional functioning, may be associated with a depressive phenotype in female cynomolgus macaques.

Stress, depression, and coronary artery disease: modeling comorbidity in female primates.

Depression and coronary heart disease (CHD) are leading contributors to disease burden in women. CHD and depression are comorbid; whether they have common etiology or depression causes CHD is unclear. The underlying pathology of CHD, coronary artery atherosclerosis (CAA), is present decades before CHD, and the temporal relationship between depression and CAA is unclear. The evidence of involvement of depression in early CAA in cynomolgus monkeys, an established model of CAA and depression, is summarized. Like people, monkeys may respond to the stress of low social status with depressive behavior accompanied by perturbations in hypothalamic-pituitary-adrenal (HPA), autonomic nervous system, lipid metabolism, ovarian, and neural serotonergic system function, all of which are associated with exacerbated CAA. The primate data are consistent with the hypothesis that depression may cause CAA, and also with the hypothesis that CAA and depression may be the result of social stress. More study is needed to discriminate between these two possibilities. The primate data paint a compelling picture of depression as a whole-body disease.

Depressive behavior and coronary artery atherogenesis in adult female cynomolgus monkeys.

OBJECTIVE: To examine depressive behavior and early coronary artery atherogenesis in 36 socially housed female cynomolgus monkeys, an established model of atherogenesis and depression. Coronary heart disease (CHD) is caused by coronary artery atherosclerosis (CAA) and its sequelae which develop over a period of decades. Thus, in prospective studies of depression and CHD, CAA was likely present at baseline in most subjects who experienced cardiac events. Little is known about the relationship between depression and CAA. METHODS: The monkeys were free of atherosclerosis before being fed a diet containing moderate amounts of fat and cholesterol for 52 months. Depressed behavior and activity levels recorded in weekly 15-minute focal samples, telemetered 24-hour heart rate, plasma total (TPC) and high-density lipoprotein cholesterol (HDLC), luteal phase serum progesterone concentrations, basal cortisol, cortisol response to corticotrophin-releasing hormone (CRH), and CAA extent were assessed. RESULTS: Time spent in depressed behavior over 4 years was significantly associated with early CAA (r = .73, p < .001), as were activity level, 24-hour heart rate, TPC, HDLC, cortisol response to CRH, and mean peak progesterone (all p < or = 0.05). Depressed females had four times the CAA compared with nondepressed females. CONCLUSIONS: Depression in primates is associated with perturbations in multiple CHD risk factors and accelerated early atherogenesis. These data are consistent with the hypotheses that depression and CAA both stem from a common mechanism and that depression may cause CAA.

Hormone therapy effects on social behavior and activity levels of surgically postmenopausal cynomolgus monkeys.

The purpose of the experiments reported here was to investigate central nervous system effects of commonly prescribed postmenopausal hormone therapies in a primate model, the cynomolgus monkey (Macaca fascicularis). The results of two experiments are reported. In the first, ovariectomized adult cynomolgus monkeys were treated for eight weeks each with oral micronized 17beta-estradiol (E2) (n=23), E2+medroxyprogesterone acetate (MPA) (n=23), E2+progesterone (P4) (n=23), and placebo (n=23) using a crossover design. In the second, ovariectomized adult cynomolgus monkeys were treated for eight weeks with oral micronized E2+oral micronized P4 (n=10), or E2+intravaginal micronized P4 delivered via a Silastic ring (n=8), or oral placebo and intravaginal placebo (n=5), using a parallel arm design. Behavior was recorded during weeks two through four. Cerebrospinal fluid (CSF) and blood were sampled, and 24h heart rate recorded by telemetry during weeks five through seven. Monoaminergic metabolites were assayed in CSF, and cortisol was assayed in serum. There were no significant effects of treatment on CSF monoaminergic metabolites or heart rate. E2+MPA increased cortisol concentrations. While there were some differences in effects between experiments, both progestogens and both routes of administration increased time spent resting, particularly resting in body contact, resulting in increased passive affiliative interaction. Thus, synthetic progestogens appear to be as sedating as progesterone, and the ring delivery system does not appear to protect the central nervous system from effects of progestogens. Further research is needed to explore social context as an important feature of behavioral response to steroid hormone regimens and to verify and extend knowledge of systemic effects of vaginal ring-delivered progestogens.

Effects of chronic moderate alcohol consumption and novel environment on heart rate variability in primates (Macaca fascicularis).

RATIONALE: The effects of chronic moderate alcohol consumption on cardiac function are not understood. Acute stress may affect cardiac function by shifting autonomic cardiac regulation in favor of the sympathetic nervous system. Although alcohol consumption often increases at times of stress, the interactive effects of stress and chronic moderate alcohol consumption on cardiac regulation have not been studied. OBJECTIVES AND METHODS: The objective was to assess the effects of long-term (1-2 years) moderate (a two-drink/day equivalent, 5 days/week) alcohol consumption on heart rate (HR) variability under normal and acutely stressful conditions in small stable groups of ovariectomized adult cynomolgus monkeys (Macaca fascicularis). Monkeys were trained to voluntarily drink their daily alcohol dose (<30 min), and blood levels were determined an hour later. The animals were acutely stressed by removal from the home cage to a novel environment for 30 min. HR in freely moving subjects was recorded via telemetry in the home cage and the novel environment. RESULTS: Acute stress increased HR, decreased HR variability, and decreased the high frequency component of the power spectrum suggesting reduced parasympathetic cardiac modulation. Chronic moderate alcohol consumption decreased HR variability and the low frequency components of the power spectrum. When stressed, monkeys with a history of chronic moderate alcohol consumption had higher HRs than the controls. CONCLUSIONS: HR dynamics in monkeys rapidly respond to acute stress. Chronic moderate alcohol consumption may be deleterious to cardiac function. HR response to stress may be exaggerated when accompanied by a history of chronic moderate alcohol consumption.