Investigating Effectiveness and Predicting Outcome and Dropout From Systems Training for Emotional Predictability and Problem Solving for Emotional Intensity Difficulties (STEPPS EI) in UK Primary Care.

Systems Training for Emotional Predictability and Problem Solving (STEPPS) for borderline personality disorder (BPD) has been adapted for a primary care setting into a 13-week group treatment for emotional intensity difficulties (STEPPS EI). This is the first study to examine the effectiveness and potential outcome and dropout predictors of STEPPS EI in a primary care setting. Severity of BPD, depression, and anxiety symptoms were measured pre- and postintervention for 148 participants. Treatment completers showed improvements in depression, anxiety, and BPD symptoms with medium to large effect sizes. A predictor of symptom improvement was higher baseline severity for each of the symptom measures. Attending a psychoeducational group prior to STEPPS EI was associated with lower odds of dropout. The findings support the use of STEPPS EI in a primary care setting, with the potential to alleviate the burden from other local services.

Recurrence of Depression in Relation to History of Childhood Trauma and Hair Cortisol Concentration in a Community-Based Sample.

BACKGROUND: Childhood trauma represents a risk factor for developing depression with increased rates of recurrence. Mechanisms involved include a disturbed regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Hair cortisol concentration (HCC) is a measure of long-term HPA axis activity with less interference from circadian and confounding factors. However, no study has so far used HCC to investigate the role of childhood trauma in recurrent pattern of depressive symptoms. METHODS: A community-based sample of 500 participants was recruited, and depression was assessed at 3 time points using the Revised Clinical Interview Schedule. The Childhood Trauma Questionnaire was administered to identify a history of childhood trauma. Hair samples were obtained from 144 participants for analysis of cortisol. RESULTS: Patients with recurrent depression had higher rates of childhood trauma compared to participants with no depression. Participants with current-only depression had increased HCC compared to the no depression group, while this was absent in participants with recurrent depression. Within the depressed group (both current-only and recurrent depression), those with a history of childhood physical abuse had lower HCC when compared to those with no such history. CONCLUSIONS: Our findings show that retrospectively reported childhood trauma is associated with protracted trajectories of depression and a distinct pattern of long-term HPA axis activity.

Sociodemographic, lifestyle, and psychosocial determinants of hair cortisol in a South London community sample.

OBJECTIVE: Hypothalamic-pituitary-adrenal (HPA) measures are crucial for research into stress and stress-related disorders. Most HPA measures fluctuate depending on diurnal rhythms and state confounders. Hair cortisol concentrations (HCC) are less susceptible to such fluctuations, but less is known about trait-like confounders. Using a community sample, we tested the relationship between HCC and a range of variables including demographic variables, hair treatment, and medication, as well as psychosocial variables, namely childhood trauma, critical life events, and depressive symptoms. METHODS: Hair samples were collected from 144 individuals from the South East London Community Health (SELCoH) study. Childhood trauma, life events, and depressive symptoms were measured, together with age, sex, ethnicity, relationship status, educational attainment, employment status, occupational social class, hair washing frequency, hair treatments, season reflected in the hair sample, hazardous drinking, smoking, medication intake, and body mass index. Hair samples reflecting the past 3 months were collected and analysed using immunoassays. First, correlations (continuous variables) and simple linear regressions (dichotomous variables) were conducted to identify sociodemographic, hair-related, and lifestyle determinants of HCC. Next, multiple linear regressions were conducted to test the relationship between psychosocial variables and HCC when controlling for the identified confounders. RESULTS: Age (r=-0.17, p=0.050), White British ethnicity (ß=-0.19, p=0.023), heat-based treatments (ß=-0.22, p=0.010), and winter season (ß=-0.18, p=0.024) were associated with lower HCC, whereas summer season (ß=0.24, p=0.024), painkillers (ß=0.25, p=0.003), anxiolytics/antidepressants (ß=0.21, p=0.014), and hormonal contraceptives (ß=0.27, p=0.006) were associated with higher HCC. Controlling for these confounders, physical neglect during childhood (ß=-0.17, p=0.057), war-related experiences (ß=0.20, p=0.027), separation (ß=0.18, p=0.054), and being the victim of a serious crime (ß=-0.17, p=0.062) were linked with altered HCC. CONCLUSION: Our findings suggest that variation in HCC occurs according to sociodemographic, hair-related, and lifestyle variables, and that certain associations between stress and altered HCC can only be revealed when accounting for these confounders.

Changes in disgust and heart rate during exposure for Obsessive Compulsive Disorder: A case series.

BACKGROUND AND OBJECTIVES: The emotion of disgust has been suggested as a factor contributing to a poor response to Cognitive Behaviour Therapy (CBT) in the treatment of Obsessive Compulsive Disorder (OCD). However, only limited information is available about the phenomenology of disgust in clinical OCD and the physiological mechanisms involved. This case series was designed to explore the phenomenology of OCD and the physiological activity associated with the emotion of disgust. METHODS: State disgust and heart rate was measured in eleven participants attending treatment for OCD during exposure relevant to their individual formulation. RESULTS: All participants with contamination and most patients with blood and injury related fears experienced a prominent increase in state disgust during exposure. These participants also had absent heart rate acceleration during exposure. Disgust response correlated with heart rate response (r = -0.63, p < 0.01) and Root Mean Square of Successive Differences (RMSSD) (r = 0.52, p < 0.01). LIMITATIONS: The design using ecologically valid stimuli and the limited number of participants did not allow between subject comparisons or more detailed analysis of relationship between trait and state disgust and between disgust and severity of OCD. CONCLUSIONS: Our findings show that a large proportion of our case series with OCD experience prominent disgust with signs of increased vagal tonus during their exposure. Such experiences differ from the concept of adrenergic activation used for psychoeducation in CBT and appraisals of harm and this may result in poorer therapeutic outcome.

The association between cortisol and neighborhood disadvantage in a U.S. population-based sample of adolescents.

The association between neighborhood conditions and cortisol is rarely studied in children or adolescents and has been hampered by small sample size and racial/ethnic and geographic homogeneity. Our objective was to estimate the association between neighborhood disadvantage and salivary cortisol levels in a large, geographically and racially/ethnically diverse sample of adolescents from the National Comorbidity Survey Replication Adolescent Supplement. Salivary cortisol was collected before and after an interview administered in the adolescent's home. We used a propensity score approach to match adolescents living in disadvantaged neighborhoods with those in non-disadvantaged neighborhoods to create two similar groups based on the time and day of cortisol collection as well as demographic characteristics. Adolescents living in disadvantaged neighborhoods had higher pre-interview cortisol levels and steeper rates of decline in cortisol levels over the course of the interview than similar adolescents in non-disadvantaged neighborhoods. This bolsters the evidence base suggesting that place may influence the stress response system.

Increased anxiety induced by listening to unpleasant music during stress exposure is associated with reduced blood pressure and ACTH responses in healthy men.

The relationship between anxiety and the neuroendocrine response to stress stimuli is still not fully understood. The aim of this study was to evaluate the contribution of an acute increase in state anxiety to neuroendocrine activation under stress conditions. To do so, it was necessary to find a stress condition of the same character and intensity with and without a rise in state anxiety. We decided to examine the effects of listening to music on anxiety and to apply a new methodological approach. A group of 14 healthy volunteers participated in a counterbalanced crossover design study. The stress procedure consisted of mental (Stroop test, mental arithmetic) and physical (handgrip exercise) tasks combined with listening to music played forward (pleasant) or backwards (unpleasant). The results confirmed our hypothesis, namely the condition with listening to unpleasant music was anxiogenic, while the other was not. In case of increased state anxiety, the rise in ACTH concentrations in response to mental challenge and the increase in systolic blood pressure induced by handgrip exercise was reduced compared to the situation with unchanged anxiety. Concentrations of testosterone, oxytocin, vasopressin and aldosterone were slightly increased in response to the stress paradigm accompanied with increased anxiety. In conclusion, the present data demonstrate that an acute increase in state anxiety contributes to neuroendocrine activation under stress conditions. Moreover, the results show that listening to music may both positively and negatively influence the perception of stress and the level of anxiety, which might have functional consequences.

Working memory performance after acute exposure to the cold pressor stress in healthy volunteers.

Effects of acute stress exposure on learning and memory have been frequently studied in both animals and humans. However, only a few studies have focused specifically on working memory performance and the available data are equivocal. The present study examined working memory performance during the Sternberg item recognition task after exposure to a predominantly adrenergic stressor. Twenty four healthy subjects were randomly assigned to a stress group or a control group. The stress group was exposed to the cold pressor stress test (CPS; i.e. insertion of the dominant hand into ice water for 60s),while 37 degrees C warm water was used with the control group. Twenty minutes after the stress exposure, working memory performance was tested with the Sternberg item recognition task with three levels of cognitive load. Sympathetic nervous system and hypothalamic pituitary adrenocortical (HPA) axis activation during CPS, were assessed by measuring heart rate and salivary cortisol before and during (heart rate) or 30 min after (cortisol) the stress procedure. Exposure to the CPS test was associated with a significant increase in heart rate but no increase in salivary cortisol. Participants exposed to the stress procedure showed significantly shorter reaction times during trials with higher cognitive load but tended to show higher false alarm rates than control subjects. The present results indicate that exposure to CPS can be associated with signs of both enhanced and impaired working memory performance. The observed behavioral pattern might represent a form of streamlined information processing advantageous in a threatening situation.

Startle reactivity in children at risk for migraine.

OBJECTIVE: Numerous studies have shown a higher responsiveness and/or a lack of habituation to sensory stimuli of various modalities in migraine. This study investigated psychophysiological responses to aversive acoustic stimuli in children at risk for migraine. METHODS: We measured eyeblink responses to acoustic stimuli (40ms bursts of white noise at 102dB) during anticipation of unpleasant stimuli in 74 adolescents (40 females, age 17.6+/-2.9). A mixed effects linear model was applied to test group differences in startle reactivity during baseline, safe and threat conditions among adolescents by maternal and personal history of migraine. RESULTS: The strongest association with migraine vulnerability emerged for baseline startle reactivity, which was significantly elevated in high risk youth with a history of maternal migraine. This group of offspring also had enhanced startle response during the threat condition and the threat-safe difference. CONCLUSION: Our findings indicate that migraine is associated with a higher acoustic startle responsiveness that is present already in children at risk for developing the disorder. SIGNIFICANCE: The significant effect of both maternal history of anxiety disorder and migraine on baseline startle indicates that these two diagnostic entities might in part share common pathophysiological mechanisms, and that the anxiety-migraine comorbidity should be considered when investigating each of these disorders.

Acute stress potentiates anxiety in humans.

BACKGROUND: Stress is an important factor in the development and maintenance of anxiety disorders. Stress also potentiates anxiety-like response in animals, but empirical evidence for a similar effect in humans is still lacking. METHODS: To test whether stress increases anxiety in humans, we examined the ability of a social stressor (speech and a counting task) to potentiate the facilitation of startle in the dark. Measures of subjective distress and of hypothalamic-pituitary-adrenal axis and autonomic nervous system activity (e.g., salivary cortisol, alpha-amylase, blood pressure, and heart rate) were also taken to confirm the effectiveness of the stress manipulation. RESULTS: Startle was significantly facilitated in the dark. This effect was potentiated by prior exposure to the social stressor. The social stressor induced increases in salivary cortisol and alpha amylase as well as increases in blood pressure, heart rate, and subjective distress. CONCLUSION: The findings indicate that stress potentiates anxiety. Animal studies suggest that such an effect might be mediated by glucocorticoid effects on corticotropin-releasing hormone in limbic structures.

Acute exposure to stress improves performance in trace eyeblink conditioning and spatial learning tasks in healthy men.

The present study investigated the effects of acute stress exposure on learning performance in humans using analogs of two paradigms frequently used in animals. Healthy male participants were exposed to the cold pressor test (CPT) procedure, i.e., insertion of the dominant hand into ice water for 60 sec. Following the CPT or the control procedure, participants completed a trace eyeblink conditioning task followed by a virtual navigation Morris water task (VNMWT). Hypothalamic-pituitary-adrenocortical (HPA) axis and sympathetic autonomic system (SAS) activity were assessed by measuring salivary cortisol, heart rate, and skin conductance at selected timepoints. Results revealed positive effects of stress on performance in both tasks. The stress group showed significantly more conditioned blinks than the control group during acquisition of trace eyeblink conditioning. The stress group also performed significantly better in the VNMWT than the control group, with the former showing significantly fewer failures to locate the hidden platform in the allotted time and smaller heading errors than the latter. Regression analyses revealed positive relationships between HPA axis and SAS activity during stress and eyeblink conditioning performance. Our results directly extend findings from animal studies and suggest potential physiological mechanisms underlying stress and learning.

Sustained low-grade pro-inflammatory state in unmedicated, remitted women with major depressive disorder as evidenced by elevated serum levels of the acute phase proteins C-reactive protein and serum amyloid A.

BACKGROUND: Major depressive disorder (MDD) shows increased coronary artery disease (CAD) risk of unknown mechanism(s). MDD is more common in women than men; CAD diagnosis can be difficult in women. Elevations of the inflammatory markers C-reactive protein (CRP) and serum amyloid A (SAA) predict increased CAD risk in populations; few data on these markers exist in MDD, particularly in remitted patients. METHODS: We measured fasting am serum CRP (high sensitivity, CRP(hs)) and SAA in 18 unmedicated, remitted women with MDD (mean age 41 +/- (SD)12, body mass index (BMI) 25.2 +/- 4.1 kg/m(2)) and 18 BMI-matched healthy control subjects (age 36 +/- 10, BMI 25.3 +/- 3.8 kg/m(2)) on 2 separate occasions, > or = 6 days apart. RESULTS: Repeat SAA and CRP(hs) measurements strongly correlated across study days (SAA: r = .83, p < .001; CRP(hs): r = .94, p < .001). Both SAA (5.30 +/- 3.39 vs. 2.84 +/- 1.87 mg/L, p < .005) and CRP(hs) (3.23 +/- 3.17 vs. 1.12 +/- 1.45 mg/L; p < .01) were significantly elevated in MDD women versus controls. CONCLUSIONS: Elevated SAA and CRP(hs) in remitted, unmedicated women with MDD indicate a pro-inflammatory state unrelated to current depressive symptoms or pharmacotherapy. These findings suggest that inflammatory mechanisms may in part underlie findings of increased CAD risk in MDD.

Altered coordination of the neuroendocrine response during psychosocial stress in subjects with high trait anxiety.

Contradicting data are available on stress responsiveness in subjects with high anxiety. In the present study we tested the hypothesis that high trait anxiety is associated with impaired coordination of the stress response, rather than global hypo- or hyper-responsiveness. The sample consisted of subjects with high (n=15) and with low (n=12) trait anxiety. Subjects with middle-range levels of anxiety were excluded from the study. After psychological characterization, the volunteers were exposed to a public speech procedure. A spectrum of neuroendocrine parameters was measured before, during and after the procedure and the results were analyzed by exploratory statistics. Psychological characterization of subjects revealed a lower preference for task-oriented but a higher one for emotion-oriented coping strategies as well as lower scores on hardiness in subjects with high trait anxiety. After the speech procedure, differences in selected mood and personality characteristics were observed, with the anxious group scoring significantly higher in scales for stress, tiredness, arousal, anxiety and depression. Factor analysis revealed that one common factor grouped blood pressure, catecholamine concentrations in blood and heart rate in non-anxious subjects, while three distinct factors separated these parameters in anxious subjects. Correlation analysis in anxious subjects showed that lower adrenocorticotropin (ACTH) and cortisol responses during stress were associated with exaggerated perception of stress and worse mental performance. Our findings indicate that subjects with high anxiety have different relationships between specific neuroendocrine parameters, subjective perception of stress and Stroop test performance.

Adrenomedullin and elements of orthostatic competence after 41 h of voluntary submersion in water as measured in four healthy males.

Four men established a new score (Guinness Book of Records) by staying submersed in thermoneutral water (average diving depth 2.5 m) for 41 h without sleeping. The aim of this study is to measure circulating hormones together with plasma mass density and total protein concentration as indices of plasma volume change to test the hypotheses that (1) blood volume and related hormones are influenced by prolonged water submersion the same way as observed after short-term water immersion, and (2) plasma adrenomedullin levels change in an opposite fashion as with orthostatic stimulation. We also studied effects on cortisol and testosterone levels. Water submersion led to a 19% increase in plasma protein concentration and a 2.5 g/l rise in plasma mass density, corresponding to a 15.6+/-1.1% plasma volume decrease (P=0.00). We therefore individually corrected (c) the observed post-submersion hormone values for plasma volume contraction. Based on this correction, we found a rise of plasma adrenomedullin from 7.9+/-0.9 to 12.5(c)+/-2.3 pg/ml. Aldosterone rose from 123+/-14 to 186(c)+/-24 ng/ml (P=0.029); plasma renin activity increased in all four persons but the type I error was >0.05. Plasma testosterone decreased from 3.5+/-0.4 to 2.2(c)+/-0.6 ng/ml (P=0.009) while plasma cortisol stayed unchanged. The daily salivary cortisol rhythm was preserved. We conclude that long-term water submersion has endocrine as well as plasma volume effects that are opposite to those seen after short-term immersion, and which increases plasma adrenomedullin. Circadian cortisol rhythm seems to be conserved even under extreme circumstances as those of this study.

Subchronic treatment with amino acid mixture of L-lysine and L-arginine modifies neuroendocrine activation during psychosocial stress in subjects with high trait anxiety.

The aim of the present study was to evaluate possible modulatory effect of the treatment with L-lysine and L-arginine on neuroendocrine activation during psychosocial stress in healthy subjects with relatively high trait anxiety in a randomized, double blind placebo controlled trial. In 29 healthy subjects at the upper limit of the normal range of a trait anxiety scale, a mixture of L-lysine and L-arginine (3 g each/day) was administered for 10 days followed by exposure to a psychosocial stress procedure based on public speech. Hormone levels, cardiovascular activation and skin conductance were measured. Amino acid treatment resulted in enhanced adrenocorticotropic hormone, cortisol, adrenaline and noradrenaline levels and galvanic skin responses during stress compared to those in placebo-treated group. Increases in the heart rate and blood pressure in response to public speaking task were not influenced by amino acid treatment. Results of the present study support the hypothesis that L-lysine in combination with L-arginine, which may induce anxiolytic effects, modify hormonal responses during psychosocial stress in humans. Such action may represent a normalization of hormone levels to the pattern observed previously in subjects with low trait anxiety.

High trait anxiety in healthy subjects is associated with low neuroendocrine activity during psychosocial stress.

Altered stress responsiveness has been repeatedly related to mood and anxiety disorders. In a traditional view, a reduction of the stress response has been thought favorable. The goal of the present study was to verify the hypothesis that high anxiety is accompanied by enhanced hormone release during stress. Healthy subjects at the upper (anxious, n = 15) and lower (non-anxious, n = 12) limits of the normal range of a trait anxiety scale (State trait anxiety inventory) were exposed to psychosocial stress procedure based on public speech. Hormone levels, cardiovascular activation and skin conductance were measured. Exposure to psychosocial stress was associated with significant increases of all parameters measured. During the stress procedure, subjects with high trait anxiety exhibited lower levels of hormones of the hypothalamo-pituitary-adrenocortical axis, namely ACTH and cortisol in plasma, as well as cortisol in saliva. Similarly, the stress-induced activation of epinephrine, norepinephrine and prolactin secretion was significantly lower in anxious subjects in comparison with that in non-anxious subjects. Thus, in contrast to the traditional view, high anxiousness was not associated with exaggerated stress response. Our findings suggest that high trait anxiety may be associated with an inability to respond with adequate hormone release to acute stress stimuli.

Prenatal immune challenge affects growth, behavior, and brain dopamine in offspring.

It is known that the development and plasticity of the neuroendocrine system can be affected by many factors, and that adverse events during the prenatal period can result in long-lasting changes in adulthood. This study was aimed at evaluating the possible consequences for offspring from chronic inflammation during pregnancy. Chronic inflammation was simulated by treatment with increasing doses of lipopolysaccharide (LPS) to dams on days 15 through 19 of pregnancy. Attempts were made to prevent possible negative alterations by keeping animals in an enriched environment (EE). Maternal exposure to LPS resulted in a significant reduction of body weight of male offspring during the weaning period. This difference remained until the age of 63 days in controls (C), but not in animals reared in EE. The content of dopamine in the nucleus accumbens was found to be lower in prenatally stressed (PS) adult males. Furthermore, prenatal exposure to maternal immune challenge was associated with lower locomotor activity in elevated plus maze and increased number of skips in the beam-walking test, as observed in female offspring. No differences in ACTH and corticosterone concentrations with regard to prenatal treatment were found; however, both groups kept in EE showed increased levels of corticosterone as well as enlarged adrenal glands. Thus, immune activation during pregnancy may induce long-term changes in brain catecholamines and behavior, but it is not harmful to basal hormone secretion in the offspring.

Modulation of neuroendocrine response and non-verbal behavior during psychosocial stress in healthy volunteers by the glutamate release-inhibiting drug lamotrigine.

The present work was aimed at verifying the following hypotheses: (a) lamotrigine, a drug used to treat mood disorders, affects regulation of stress hormone release in humans, and (b) non-verbal behavior during mental stress situations (public speech) is related to hormonal responses. To achieve these aims, we performed a controlled, double-blind study investigating hormonal responses and non-verbal behavior during public speech in healthy subjects with placebo or lamotrigine (300 mg per os) pretreatment. The stress procedure was performed in 19 young healthy males 5 h following drug or placebo administration. Data were obtained from cardiovascular monitoring, blood and saliva samples, as well as the video-recorded speech. Pre-stress hormone levels were not affected by lamotrigine treatment. Lamotrigine significantly inhibited diastolic blood pressure, growth hormone and cortisol increases during psychosocial stress. In contrast, it potentiated plasma renin activity and aldosterone responses. Non-verbal behavior analysis revealed a correlation between catecholamines and submissive or flight behavior in controls, while between catecholamines and displacement behavior following lamotrigine administration. In conclusion, effects of lamotrigine on hormone release might be of value for its mood-stabilizing action used in the treatment of bipolar disorder. The data are in support of a stimulatory role of glutamate in the control of cortisol and growth hormone release during psychosocial stress in humans; however, further studies using more selective drugs are needed to prove this suggestion. The effects on plasma renin activity and aldosterone release observed seem to be related to other actions of lamotrigine.

Altered glutamate receptor and corticoliberin gene expression in brain regions related to hedonic behavior in rats.

Present experiments in rats were aimed to verify the hypothesis that glutamatergic neurotransmission and stress hormones play a role in impairment of hedonic behavior, a sign of depression-like state. On the basis of individual variability in sucrose preference, test rats were divided into anhedonic and hedonic groups. Anhedonic animals showed higher basal concentrations of adrenocorticotropin and corticosterone but reduced hormonal responses during novelty stress compared to hedonic animals. Acute administration of citalopram (10 mg/kg ip) induced similar effects in both groups. Corticotropin-releasing hormone (CRH) mRNA levels in hypothalamic paraventricular nucleus (PVN) were higher in anhedonic rats. Oxytocin (OT) and vasopressin gene expression in the PVN and proopiomelanocortin (POMC) expression in the anterior pituitary failed to show any significant differences. Gene expression of NR1 receptor subunit of N-methyl-D-aspartate (NMDA) glutamate receptor in the ventral tegmental area (VTA) was found to be lower in anhedonic rats. In the nucleus accumbens (NAc) and the hippocampus of anhedonic animals, higher mRNA levels of NR2A subunit compared to those of hedonic rats were detected. Thus, low sucrose preference is associated with altered HPA axis activity, NMDA receptor subunits and CRH gene expression in selected brain regions. These mechanisms may operate in the disposition to develop hedonic deficit in some mental disorders.

Repeated citalopram treatment but not stress exposure attenuates hypothalamic-pituitary-adrenocortical axis response to acute citalopram injection.

Many experimental, clinical and epidemiological studies have shown a direct connection between exposure to stress or adverse life events and disease, but little is known about the effect of stress on the action of drugs. The aim of this study was to test the hypothesis that previous exposure to stress changes the action of the antidepressant drug citalopram (10 mg/kg, i.p.) on hypothalamic-pituitary-adrenocortical (HPA) axis function, gene expression of selected neuropeptides and serotonin reuptake. Three different stress models were used, which included immobilization, restraint and unpredictable stress stimuli. Samples of plasma for hormone measurement were taken from conscious cannulated animals. Changes in corticotropin-releasing hormone (CRH) and proopiomelanocortin (POMC) gene expression in the paraventricular nucleus of the hypothalamus and the anterior pituitary, respectively, and the ability of citalopram to inhibit serotonin reuptake were investigated. The exposure to three different stress models did not influence citalopram action on individual parameters of HPA axis and on serotonin reuptake. On the other hand, repeated administration of the drug led to significant attenuation of ACTH and CRH mRNA responses. The present results allow to suggest that the stressors used did not influence serotonergic neurotransmission to the extent that would modify HPA axis response to citalopram challenge. Activation of HPA axis by acute citalopram treatment was found to be accompanied by increased CRH gene expression in the hypothalamus. Repeated administration of the drug led to the development of tolerance to activation of central and peripheral components of HPA axis, but not to serotonin reuptake inhibition.

Enhancement of stress-induced pituitary hormone release and cardiovascular activation by antidepressant treatment in healthy men.

A randomized, double-blind, placebo-controlled trial was performed to verify the suggestion that (i) in accordance with the results of animal studies, treatment with antidepressants inhibits hormone release in response to stressful stimulation in humans and (ii) drugs with opposing effects on brain serotonine (citalopram and tianeptine) exert similar modulatory effects on neuroendocrine activation during stress. Healthy male volunteers were treated with citalopram (20 mg), tianeptine (37.5 mg) or placebo for 7 days. As a stress stimulus, insulin-induced hypoglycaemia was used. Measurement of hormone concentrations revealed an enhanced release of adrenocorticotropic hormone and growth hormone in response to stress of hypoglycaemia in subjects treated with both antidepressants used. A similar augmentation was observed in systolic blood pressure. Stress-induced prolactin release was potenciated by citalopram only. Plasma renin activity, epinephrine, norepinephrine and cortisol levels failed to be modified by antidepressants. The present study demonstrates that (i) repeated antidepressant treatment in healthy men does not inhibit, but enhances, neuroendocrine activation during stress and (ii) such effects were observed after treatment with antidepressants having opposing actions on brain serotonin, indicating involvement of nonserotoninergic mechanisms.