Ovariectomy-induced depressive-like behavior and brain glucose metabolism changes in female rats are not affected by chronic mild stress.

The increased incidence of depression in women going through peri-menopause suggests that fluctuations in estrogen levels may increase the risk of developing depression. Nonetheless, this psychiatric disorder is likely to be multifactorial and consequently an additional trigger may be needed to induce depression in this population. Stress could be such a trigger. We therefore investigated the effect of ovarian estrogen depletion and chronic mild stress (CMS) on depressive-like behavior and brain metabolism in female rats. Approximately 2 and 9 weeks after estrogen depletion by ovariectomy, behavioral changes were assessed in the open-field test and the forced swim test, and brain metabolism was measured with [18F]FDG PET imaging. A subset of animals was subjected to a 6-weeks CMS protocol starting 17 days after ovariectomy. Short-term estrogen depletion had a significant effect on brain metabolism in subcortical areas, but not on behavior. Differences in depressive-like behavior were only found after prolonged estrogen depletion, leading to an increased immobility time in the forced swim test. Prolonged estrogen depletion also resulted in an increase in glucose metabolism in frontal cortical areas and hippocampus, whereas a decrease glucose metabolism was found in temporal cortical areas, hypothalamus and brainstem. Neither short-term nor prolonged estrogen depletion caused anxiety-like behavior. Changes in body weight, behavior and brain glucose metabolism were not significantly affected by CMS. In conclusion, ovarian estrogen depletion resulted in changes in brain metabolism and depressive-like behavior, but these changes were not enhanced by CMS.

In vivo imaging of brain androgen receptors in rats: a [(18)F]FDHT PET study.

INTRODUCTION: Steroid hormones like androgens play an important role in the development and maintenance of several brain functions. Androgens can act through androgen receptors (AR) in the brain. This study aims to demonstrate the feasibility of positron emission tomography (PET) with 16ß-[(18)F]fluoro-5α-dihydrotestosterone ([(18)F]FDHT) to image AR expression in the brain. METHODS: Male Wistar rats were either orchiectomized to inhibit endogenous androgen production or underwent sham-surgery. Fifteen days after surgery, rats were subjected to a 90-min dynamic [(18)F]FDHT PET scan with arterial blood sampling. In a subset of orchiectomized rats, 1mg/kg dihydrotestosterone was co-injected with the tracer in order to saturate the AR. Plasma samples were analyzed for the presence of radioactive metabolites by radio-TLC. Pharmacokinetic modeling was performed to quantify brain kinetics of the tracer. After the PET scan, the animals were terminated for ex-vivo biodistribution. RESULTS: PET imaging and ex vivo biodistribution studies showed low [(18)F]FDHT uptake in all brain regions, except pituitary. [(18)F]FDHT uptake in the surrounding cranial bones was high and increased over time. [(18)F]FDHT was rapidly metabolized in rats. Metabolism was significantly faster in orchiectomized rats than in sham-orchiectomized rats. Quantitative analysis of PET data indicated substantial spill-over of activity from cranial bones into peripheral brain regions, which prevented further analysis of peripheral brain regions. Logan graphical analysis and kinetic modeling using 1- and 2-tissue compartment models showed reversible and homogenously distributed tracer uptake in central brain regions. [(18)F]FDHT uptake in the brain could not be blocked by endogenous androgens or administration of dihydrotestosterone. CONCLUSION: The results of this study indicate that imaging of AR availability in rat brain with [(18)F]FDHT PET is not feasible. The low AR expression in the brain, the rapid metabolism of [(18)F]FDHT in rats and the poor brain penetration of the tracer likely contributed to the poor performance of [(18)F]FDHT PET in this study.

Sex-specific associations between Neutrophil Gelatinase-Associated Lipocalin (NGAL) and cognitive domains in late-life depression.

BACKGROUND: Although it is well established that late-life depression is associated with both systemic low-graded inflammation and cognitive impairment, the relation between inflammation and cognition in depressed older persons is still equivocal. The objective of this study is to examine the association between plasma Neutrophil Gelatinase-Associated Lipocalin (NGAL) concentrations and cognitive functioning in late-life depression, including the potentially moderating role of sex. METHODS: A total of 369 depressed older persons (≥60 years) from The Netherlands study of Depression in Older persons (NESDO) were included. Four cognitive domains, i.e. verbal memory, processing speed, interference control and attention were assessed with three cognitive tests (Stroop test, Wais Digit span test, and Rey's verbal learning test). Multiple linear regression analyses were applied with the four cognitive domains as dependent variables adjusted for confounders. RESULTS: The association between NGAL levels and specific cognitive domains were sex-specific. In women, higher NGAL levels were associated with impaired verbal memory and lower processing speed. In men, higher NGAL levels were associated with worse interference control. Higher NGAL levels were not associated with attention. No sex-specific associations of either high sensitivity C-reactive protein (hsCRP) or interleukin-6 (IL-6) with cognitive functioning were found. CONCLUSION: This study shows sex-specific association of NGAL with cognitive functioning in late-life depression.

Cost-effectiveness of CBT, SSRI, and CBT+SSRI in the treatment for panic disorder.

OBJECTIVE: The objective of this study was to assess the cost-effectiveness of three empirically supported treatments for panic disorder with or without agoraphobia: cognitive behavioral therapy (CBT), pharmacotherapy using a selective serotonin reuptake inhibitor (SSRI), or the combination of both (CBT+SSRI). METHOD: Cost-effectiveness was examined based on the data from a multicenter randomized controlled trial. The Hamilton Anxiety Rating Scale was selected as a primary health outcome measure. Data on costs from a societal perspective (i.e., direct medical, direct non-medical, and indirect non-medical costs) were collected in the study sample (N=150) throughout a 24-month period in which patients received active treatment during the first twelve months and were seen twice for follow-up in the next twelve months. RESULTS: Total costs were largely influenced by costs of the interventions and productivity losses. The mean total societal costs were lower for CBT as compared to SSRI and CBT+SSRI. Costs of medication use were substantial for both SSRI and CBT+SSRI. When examining the balance between costs and health outcomes, both CBT and CBT+SSRI led to more positive outcomes than SSRI. CONCLUSION: Cognitive behavioral therapy is associated with the lowest societal costs. Cognitive behavioral therapy and CBT+SSRI are more cost-effective treatments for panic disorder with or without agoraphobia as compared to SSRI only.

Neutrophil gelatinase-associated lipocalin: a novel inflammatory marker associated with late-life depression.

OBJECTIVE: Systemic low graded inflammation has been identified as a possible biological pathway in late-life depression. Identification of inflammatory markers and their association with characteristics of depression is essential with the aim to improve diagnosis and therapeutic approaches. This study examines the determinants of plasma Neutrophil Gelatinase-Associated Lipocalin (NGAL), which is selectively triggered by TNFα receptor 1 signaling within the central nervous system, and its association with late-life depressive disorder. METHODS: Baseline data were obtained from a well-characterized prospective cohort study of 350 depressed and 129 non-depressed older persons (≥60years). Past 6month diagnosis of major depressive disorder (MDD) according to DSM-IV-TR criteria was assessed with the Composite International Diagnostic Interview (CIDI 2.0). Potential determinants of plasma NGAL included sociodemographic characteristics, lifestyle and psychiatric and physical comorbidity. RESULTS: Plasma NGAL concentrations were significantly associated with age, male gender, smoking and waist circumference. Adjusted for these determinants, depressed patients had significantly higher NGAL plasma levels compared to non-depressed comparison group. Depressed patients who did not meet full criteria for MDD in the month before sampling (partially remitted) had lower plasma NGAL levels compared with those who did. Subjects with a recurrent depression had higher plasma NGAL levels compared to those with a first episode. NGAL levels were neither related with specific symptom profiles of depression nor with antidepressant drug use. CONCLUSION: Adjusted for confounders, NGAL plasma levels are increased in depressed older persons, without any effect of antidepressant medication and age of onset.

Amygdala activation and its functional connectivity during perception of emotional faces in social phobia and panic disorder.

Social phobia (SP) and panic disorder (PD) have been associated with aberrant amygdala responses to threat-related stimuli. The aim of the present study was to examine amygdala function and its connectivity with medial prefrontal cortex (mPFC) during emotional face perception in PD and SP, and the role of illness severity. Blood oxygen level dependent responses while perceiving emotional facial expressions were compared in 14 patients with PD, 17 patients with SP, 8 patients with comorbid PD and SP, and 16 healthy controls. We found that PD, but not SP, was associated with amygdala and lingual gyrus hypoactivation during perception of angry, fearful, happy and neutral faces, compared to healthy participants. No significant effect of PD and SP diagnoses was found on amygdala-mPFC connectivity. A positive correlation of anxiety symptom severity was found on amygdala-dorsal anterior cingulate and dorsal mPFC connectivity during perception of fearful faces. Amygdala hypoactivation suggests reduced responsiveness to positive and negative emotional faces in PD. Symptom severity, but not the presence of PD and SP diagnosis per se, explains most of the abnormalities in amygdala-mPFC connectivity during perception of fearful faces.

ABCB1 gene variants influence tolerance to selective serotonin reuptake inhibitors in a large sample of Dutch cases with major depressive disorder.

P-glycoprotein (P-gp), an ATP-driven efflux pump in the blood-brain barrier, has a major impact on the delivery of antidepressant drugs in the brain. Genetic variants in the gene ABCB1 encoding for P-gp have inconsistently been associated with adverse effects. In order to resolve these inconsistencies, we conducted a study in a large cohort of patients with major depressive disorder with the aim to unravel the association of ABCB1 variants with adverse effects of antidepressants and in particular with selective serotonin reuptake inhibitors (SSRIs), which display affinity as substrate for P-gp. The Netherlands Study of Depression and Anxiety (NESDA) study was used as a clinical sample. For 424 patients data were available on drug use, side effects. We selected six ABCB1 gene variants (1236T>C, 2677G>T/A, 3435T>C, rs2032583, rs2235040 and rs2235015) and analyzed them for association with adverse drug effects using multinomial regression analysis for both single variants and haplotypes. We found a significant association between the number of SSRI-related adverse drug effects and rs2032583 (P=0.001), rs2235040 (P=0.002) and a haplotype (P=0.002). Moreover, serotonergic effects (sleeplessness, gastrointestinal complaints and sexual effects) were significantly predicted by these variants and haplotype (P=0.002/0.003). We conclude that adverse drug effects with SSRI treatment, in particular serotonergic effects, are predicted by two common polymorphisms of the ABCB1 gene.

Neural correlates of perception of emotional facial expressions in out-patients with mild-to-moderate depression and anxiety. A multicenter fMRI study.

BACKGROUND: Depression has been associated with limbic hyperactivation and frontal hypoactivation in response to negative facial stimuli. Anxiety disorders have also been associated with increased activation of emotional structures such as the amygdala and insula. This study examined to what extent activation of brain regions involved in perception of emotional faces is specific to depression and anxiety disorders in a large community-based sample of out-patients. METHOD: An event-related functional magnetic resonance imaging (fMRI) paradigm was used including angry, fearful, sad, happy and neutral facial expressions. One hundred and eighty-two out-patients (59 depressed, 57 anxiety and 66 co-morbid depression-anxiety) and 56 healthy controls selected from the Netherlands Study of Depression and Anxiety (NESDA) were included in the present study. Whole-brain analyses were conducted. The temporal profile of amygdala activation was also investigated. RESULTS: Facial expressions activated the amygdala and fusiform gyrus in depressed patients with or without anxiety and in healthy controls, relative to scrambled faces, but this was less evident in patients with anxiety disorders. The response shape of the amygdala did not differ between groups. Depressed patients showed dorsolateral prefrontal cortex (PFC) hyperactivation in response to happy faces compared to healthy controls. CONCLUSIONS: We suggest that stronger frontal activation to happy faces in depressed patients may reflect increased demands on effortful emotion regulation processes triggered by mood-incongruent stimuli. The lack of strong differences in neural activation to negative emotional faces, relative to healthy controls, may be characteristic of the mild-to-moderate severity of illness in this sample and may be indicative of a certain cognitive-emotional processing reserve.

Antidepressive effect of mirtazapine in post-myocardial infarction depression is associated with soluble TNF-R1 increase: data from the MIND-IT.

BACKGROUND: Depressive disorder after myocardial infarction (MI) is associated with increased cardiac morbidity and mortality. Immune activity such as inflammation might be implicated as an underlying mechanism. The purpose of this study is to investigate whether the response to an antidepressant in post-MI depression is associated with changes of inflammatory markers in serum. METHODS: In a double-blind placebo-controlled study with mirtazapine 30 mg/day (50 patients), the antidepressive effect was related to immune activation parameters. The cytokines interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α), the soluble cytokine receptors sIL-6R, sTNF-R1 and sTNF-R2, and the inflammation-sensitive plasma proteins C-reactive protein and neopterin were assessed. RESULTS: Subgroup analyses revealed a highly significant correlation of pronounced sTNF-R1 increase with a decrease in depressive symptoms in antidepressant responders. CONCLUSION: Significant effects on inflammation accompany the therapeutic efficacy of mirtazapine in contrast to the therapeutic efficacy of placebo and the nontherapeutic efficacy of mirtazapine.

Chronic but not acute foot-shock stress leads to temporary suppression of cell proliferation in rat hippocampus.

Stressful experiences, especially when prolonged and severe are associated with psychopathology and impaired neuronal plasticity. Among other effects on the brain, stress has been shown to negatively regulate hippocampal neurogenesis, and this effect is considered to be exerted via glucocorticoids. Here, we sought to determine the temporal dynamics of changes in hippocampal neurogenesis after acute and chronic exposure to foot-shock stress. Rats subjected to a foot-shock procedure showed strong activation of the hypothalamic-pituitary-adrenal (HPA) axis, even after exposure to daily stress for 3 weeks. Despite a robust release of corticosterone, acute foot-shock stress did not affect the rate of hippocampal cell proliferation. In contrast, exposure to foot-shock stress daily for 3 weeks led to reduced cell proliferation 2 hours after the stress procedure. Interestingly, this stress-induced effect did not persist and was no longer detected 24 hours later. Also, while chronic foot-shock stress had no impact on survival of hippocampal cells that were born before the stress procedure, it led to a decreased number of doublecortin-positive granule neurons that were born during the chronic stress period. Thus, whereas a strong activation of the HPA axis during acute foot-shock stress is not sufficient to reduce hippocampal cell proliferation, repeated exposure to stressful stimuli for prolonged period of time ultimately results in dysregulated neurogenesis. In sum, this study supports the notion that chronic stress may lead to cumulative changes in the brain that are not seen after acute stress. Such changes may indicate compromised brain plasticity and increased vulnerability to neuropathology.

Patients with obsessive-compulsive disorder are impaired in associative learning based on external feedback.

BACKGROUND: Patients with obsessive-compulsive disorder (OCD) have to repeat their actions before feeling satisfied that the action reached its intended goal. Learning theory predicts that this may be due to a failure in the processing of external feedback. METHOD: We examined the performance of 29 OCD patients and 28 healthy volunteers on an associative learning task, in which initial learning is based solely on external feedback signals. Feedback valence was manipulated with monetary gains and losses. RESULTS: As predicted, OCD patients were impaired during initial, external feedback-driven learning but not during later learning stages. The emotional salience of the feedback modulated learning during the initial stage in patients and controls alike. During later learning stages, however, patients approached near-normal performance with rewarding feedback but continued to produce deficient learning with punishing feedback. CONCLUSION: OCD patients have a fundamental impairment in updating behavior based on the external outcome of their actions, possibly mediated by faulty error signals in response selection processes.

Intra-thoracic blood volume measurement by contrast magnetic resonance imaging.

The intra-thoracic blood volume (ITBV) is a cardiovascular parameter related to the cardiac preload and left ventricular function. Its assessment is, therefore, important for diagnosis and follow-up of several cardiovascular dysfunctions. Nowadays, the ITBV can be accurately measured only by invasive indicator dilution techniques, which require a double catheterization of the patient. In this study, a novel technique is presented for ITBV assessment by dynamic magnetic resonance imaging after intravenous injection of a small bolus of gadolinium chelate. The dose was chosen on the basis of in vitro calibration. The bolus first pass is detected from a simultaneous dynamic image series of the right and left ventricles. Two indicator dilution curves are derived and used to inspect the transpulmonary dilution system. Various mathematical models for the interpretation of the measured indicator dilution curves are compared. The ITBV is assessed as the product of the transpulmonary mean transit time of the indicator and the cardiac output, obtained by phase contrast magnetic resonance angiography. In vitro measurements showed a correlation coefficient larger than 0.99 and preliminary tests with volunteers proved the feasibility of the method, opening new possibilities for noninvasive quantitative cardiovascular diagnostics.

Lymphocyte glucocorticoid receptor resistance and depressive symptoms severity: a preliminary report.

OBJECTIVE: Assessment of the temporal interrelationship of neuropsychiatric parameters requires technologies allowing frequent biological measurements. We propose glucocorticoid receptor (GR) function of lymphocytes to assess the temporal relationship between glucocorticoid resistance and the course of major depressive disorder. METHOD: Dexamethasone suppression of lymphocyte proliferation was in vitro assessed via 5-bromo-2' deoxyuridine (BrdU) incorporation in DNA. Optimal conditions were determined using blood of healthy volunteers. Thereafter the relation between depression severity (Hamilton Depression Rating Scale, HDRS, scores), lymphocyte proliferation and morning cortisol levels in blood was studied in thirteen depressed patients, mostly with a history of treatment resistance. RESULTS: Recovery from depression was not directly associated with changes in lymphocyte glucocorticoid resistance. However, a negative correlation was observed between HDRS and BrdU incorporation and a positive correlation between morning cortisol and BrdU incorporation. No significant correlation was found between cortisol and HDRS. Regression analyses showed that HDRS was related to both suppression of BrdU incorporation (beta -0.508, p<0.001) and cortisol levels (beta 0.364, p=0.001) in a highly significant model (F2,60=14,244, p<0.001) Except for one case, such relation could not be found within patients. CONCLUSION: Our preliminary results suggest a mutual relation between lymphocyte GR function, morning cortisol levels and MDD symptom severity. A direct relation between glucocorticoids resistance and recovery may not exist, but glucocorticoid resistance might attenuate or prevent recovery. It is clear that additional studies using larger and more homogenous groups of MDD patients are required to support our findings.

On the physical and stochastic representation of an indicator dilution curve as a gamma variate.

The analysis of intravascular indicator dynamics is important for cardiovascular diagnostics as well as for the assessment of tissue perfusion, aimed at the detection of ischemic regions or cancer hypervascularization. To this end, indicator dilution curves are measured after the intravenous injection of an indicator bolus and fitted by parametric models for the estimation of the hemodynamic parameters of interest. Based on heuristic reasoning, the dilution process is often modeled by a gamma variate. In this paper, we provide both a physical and stochastic interpretation of the gamma variate model. The accuracy of the model is compared with the local density random walk model, a known model based on physics principles. Dilution curves were measured by contrast ultrasonography both in vitro and in vivo (20 patients). Blood volume measurements were used to test the accuracy and clinical relevance of the estimated parameters. Both models provided accurate curve fits and volume estimates. In conclusion, the proposed interpretations of the gamma variate model describe physics aspects of the dilution process and lead to a better understanding of the observed parameters, increasing the value and credibility of the model, and possibly expanding its diagnostic applications.

Is a combined therapy more effective than either CBT or SSRI alone? Results of a multicenter trial on panic disorder with or without agoraphobia.

OBJECTIVE: To establish whether the combination of cognitive-behavioral therapy (CBT) and pharmacotherapy (SSRI) was more effective in treating panic disorder (PD) than either CBT or SSRI alone, and to evaluate any differential effects between the mono-treatments. METHOD: Patients with PD (n = 150) with or without agoraphobia received CBT, SSRI or CBT + SSRI. Outcome was assessed after 9 months, before medication taper. RESULTS: CBT + SSRI was clearly superior to CBT in both completer and intent-to-treat analysis (ITT). Completer analysis revealed superiority of CBT + SSRI over SSRI on three measures and no differences between CBT and SSRI. ITT analysis revealed superiority of SSRI over CBT on four measures and no differences between CBT + SSRI and SSRI. CONCLUSION: Both the mono-treatments (CBT and SSRI) and the combined treatment (CBT + SSRI) proved to be effective treatments for PD. At post-test, CBT + SSRI was clearly superior to CBT, but differences between CBT + SSRI and SSRI, and between SSRI and CBT, were small.

Convergent genetic modulation of the endocrine stress response involves polymorphic variations of 5-HTT, COMT and MAOA.

Highly prevalent stress-related disorders such as major depression (MD) are characterised by a dysregulation of the neuroendocrine system. Although heritability for these disorders is high, the role of genes in the underlying pathophysiology is poorly understood. Here, we show that polymorphic variations in genes coding for serotonin transporter (5-HTT), catechol-O-methyl transferase (COMT) and monoamine oxidase A (MAOA) as well as sex differences influence the regulation of hypothalamic-pituitary-adrenal (HPA)-axis response to acute psychological and endocrine challenges. In our sample, the effects of COMT on the release of adrenocorticotrophin hormone (ACTH) depend on the presence of the low-expression MAOA variant in the same individual. By including individuals varying in their degree of susceptibility to MD, we showed evidence of interactions between 5-HTT and MD susceptibility in baseline cortisol, and between MAOA and MD susceptibility in baseline ACTH measures, indicating a role for these genotypes in stable-state endocrine regulation. Collectively, these results indicate that the simultaneous investigation of multiple monoaminergic genes in interaction with gender have to be measured to understand the endocrine regulation of stress. These findings point towards a genetic susceptibility to stress-related disorders.

Detecting fearful and neutral faces: BOLD latency differences in amygdala-hippocampal junction.

Evolutionary survival and procreation are augmented if an individual organism quickly detects environmental threats and rapidly initiates defensive behavioral reactions. Thus, facial emotions signaling a potential threat, e.g., fear or anger, should be perceived rapidly and automatically, possibly through a subcortical processing route which includes the amygdala. Using event-related functional magnetic resonance imaging (fMRI), we investigated the time course of the response in the amygdala to neutral and fearful faces, which appear from dynamically decreasing random visual noise. We aimed to detect differences of the amygdala response between fearful and neutral faces by estimating the latency of the blood oxygenation level-dependent (BOLD) response. We found that bilateral amygdala-hippocampal junction activation occurred earlier for fearful than for neutral faces. Our findings support the theory of a dual route architecture in which the subcortical thalamic-hippocampal-amygdala route serves fast preconscious threat perception.

Fear conditioning and shock intensity: the choice between minimizing the stress induced and reducing the number of animals used.

Many fear conditioning studies use electric shock as the aversive stimulus. The intensity of shocks varies throughout the literature. In this study, shock intensities ranging from 0 to 1.5 mA were used, and the effects on the rats assessed by both behavioural and biochemical stress parameters. Results indicated a significant difference with respect to defaecation and freezing behaviour between controls and those animals that received a shock. Significant differences in corticosterone levels were also noted between controls and those groups that received a shock. No significant differences were found between the shock groups with regards to the stress parameters measured in our fear conditioning paradigm, indicating that the two shock groups were similarly stressed. Increased significance levels were noted for freezing behaviour as well as a lower standard error of means was found in the highest shock intensity group. We therefore recommend using the higher shock intensity (1.5 mA) as the rats in the higher shock intensity group were more homogeneously fear-conditioned and therefore the results should be more reproducible and robust than in the lower shock intensity group. This would allow for fewer rats to be used in order to gain an accurate impression of the conditioning paradigm employed.

Clinical efficacy of agomelatine in depression: the evidence.

Despite the advances of recent decades, there is still an urgent need for antidepressants with improved efficacy, safety and tolerability. Agomelatine is a new antidepressant with an innovative pharmacological profile. It is the first melatonergic antidepressant, and is a potent agonist of melatonin receptors (MT1 and MT2) with 5-HT2C antagonist properties. The efficacy of 25 mg/day agomelatine in treating major depressive disorder (MDD) has been demonstrated in a number of placebo-controlled studies. Evidence of improvement in depressive symptoms was observed in a dose-ranging study in which 25 mg/day agomelatine was significantly better than placebo, whatever the rating scale used (Hamilton Rating Scale for Depression, Clinical Global Impression, and Montgomery-Asberg Depression Rating Scale). These results have been confirmed in two similarly designed placebo-controlled studies. Agomelatine also produces a significant improvement in anxiety compared to placebo, according to Hamilton Rating Scale for Anxiety scores. The efficacy of agomelatine has been studied in subpopulations with more severe depression, demonstrating its efficacy in these difficult-to-treat patients. In view of the available data on agomelatine, this antidepressant can be regarded as an innovative treatment for MDD patients, offering a new approach in the management of depressed patients.

Unique patterns of FOS, phospho-CREB and BrdU immunoreactivity in the female rat brain following chronic stress and citalopram treatment.

Affective disorders are common psychiatric illnesses characterized by marked gender-related prevalence. Recent evidence links chronic stress and dysregulation of neurotrophin signaling with the development of depression, while novel theories suggest that antidepressants may act by promoting intracellular adaptations linked to neuroplasticity. Although selective serotonin reuptake inhibitors (SSRIs) efficaciously improve a variety of dysfunctions in males, their neuroendocrine effects and intracellular signaling patterns in females are not well determined. Here we show that chronic footshock stress (21 days) promotes HPA axis hyperactivity (as seen by the increased FOS-ir in the paraventricular hypothalamic nucleus (PVN), plasma corticosterone and adrenal hypertrophy), reduces hippocampal BrdU immunoreactivity and suppresses cortical-limbic CREB phosphorylation in female rats. Long-term citalopram treatment, in contrast, attenuates stress-induced elevation of corticosterone levels and adrenal hypertrophy, although it does not reverse footshock-mediated induction of FOS-ir in the PVN, inhibition of CREB phosphorylation and reduction of hippocampal BrdU-labeling. Moreover, citalopram administration was also associated with significant hypophagic effects and inhibition of CREB phosphorylation. These data suggest that, in female rats, normalization of chronic stress-induced HPA axis abnormalities may represent an initial phase of citalopram-mediated therapeutic actions and despite this SSRI's apparent lack of effects on neuroplasticity, we cannot exclude the possibility that some neurochemical adaptations occur in a later stage which may require more than 3 weeks of treatment to manifest.