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Carmine M Pariante

Publications and source records attributed to Carmine M Pariante.

At least 19 recordsLinked to original sources
PubMed2007

Childhood maltreatment predicts adult inflammation in a life-course study.

Stress in early life has been associated with insufficient glucocorticoid signaling in adulthood, possibly affecting inflammation processes. Childhood maltreatment has been linked to increased risk of adult disease with potential inflammatory origin. However, the impact of early life stress on adult inflammation is not known in humans. We tested the life-course association between childhood maltreatment and adult inflammation in a birth cohort followed to age 32 years as part of the Dunedin Multidisciplinary Health and Development Study. Regression models were used to estimate the effect of maltreatment on inflammation, adjusting for co-occurring risk factors and potential mediating variables. Maltreated children showed a significant and graded increase in the risk for clinically relevant C-reactive protein levels 20 years later, in adulthood [risk ratio (RR)=1.80, 95% confidence interval (CI)=1.26-2.58]. The effect of childhood maltreatment on adult inflammation was independent of the influence of co-occurring early life risks (RR=1.58, 95% CI=1.08-2.31), stress in adulthood (RR=1.64, 95% CI=1.12-2.39), and adult health and health behavior (RR=1.76, 95% CI=1.23-2.51). More than 10% of cases of low-grade inflammation in the population, as indexed by high C-reactive protein, may be attributable to childhood maltreatment. The association between maltreatment and adult inflammation also generalizes to fibrinogen and white blood cell count. Childhood maltreatment is a previously undescribed, independent, and preventable risk factor for inflammation in adulthood. Inflammation may be an important developmental mediator linking adverse experiences in early life to poor adult health.

Adult↗
PubMed2006

Omega-3 fatty acids on the forced-swimming test.

OBJECTIVES: Based on the findings of epidemiological data and recent clinical trials, omega-3 fatty acids seem to have a preventive and therapeutic effect on depression. METHOD: We examined the effect of omega-3 fatty acids on the forced-swimming test (FST) in two groups of Sprague-Dawley rats after a six-week treatment with two different diets. Behavioral responses were observed and recorded during the 5-min test. The fatty acid composition from the whole brain tissue and the RBC membrane of the rats were analyzed. RESULTS: Comparing to control diet, omega-3 fatty acid diet significantly decreased the immobility time (218 +/- 16 vs. 183 +/- 19s, p = 0.001) and increased behaviors of swimming (32 +/- 7 vs. 45 +/- 9s, p = 0.012) and climbing (50 +/- 10 vs. 73 +/- 14s, p = 0.011) during the FST. The group in omega-3 fatty acid diet had higher levels of docosahexaenoic acid (DHA, 50% increase) and alpha-linolenic acid (ALA, 63% increase) in the brain, and of eicosapentaenoic acid (EPA, 27% increase) in the peripheral RBC membrane. The level of brain DHA is negatively correlated to the immobility time (r = -0.654, p = 0.006) and is positively correlated to the swimming time (r = 0.69, p = 0.003). CONCLUSION: The result shows that omega-3 fatty acids have a beneficial effect on preventing the development of depression-like behaviors in rats with the FST.

Animals↗
PubMed2006

Neuroendocrine effects of citalopram infusion in anorexia nervosa.

Because of the role of serotonin (5HT) in regulating food intake and mood, several studies have focused their attention on the assessment of serotonergic activity in eating disorders, and in particular in anorexia nervosa, but the results have been inconsistent. Citalopram, a highly selective 5HT reuptake inhibitor, has been recently reported as a neuroendocrine probe to assess the serotonergic function in physiological and pathological conditions. We evaluated the adrenocorticotropic hormone (ACTH), cortisol, prolactin (PRL) and growth hormone (GH) secretion during placebo or citalopram IV infusion (20 mg over 120 min), in six women with anorexia nervosa restricter type, and in six healthy women, in order to test the hypothesis that this neurotransmitter system is abnormal in this group of patients. ACTH and PRL secretion was higher during citalopram infusion compared to placebo (p<0.05) in both groups, while cortisol secretion was higher during citalopram infusion only in healthy controls (p<0.05), but not in anorexic patients. GH levels were unaffected by citalopram in both groups. These results demonstrate that serotonergic activation by citalopram affects corticotroph and lactotroph but not somatotroph secretion in anorexic as well as in normal subjects. Our preliminary findings do not support the existence of remarkable alterations in the serotonergic control of anterior pituitary function in anorexia nervosa, while there seems to be an impairment of the adrenal function in this group of patients.

Adrenocorticotropic Hormone↗
PubMed2006

Different responses to dexamethasone and prednisolone in the same depressed patients.

RATIONALE: Patients with major depression show hypothalamic-pituitary-adrenal (HPA) axis hyperactivity, but the mechanisms underlying this abnormality are still unclear. OBJECTIVES: We have compared two synthetic glucorticoids, dexamethasone and prednisolone, in their ability to suppress the hypothalamic-pituitary-adrenal (HPA) axis in depressed patients. Dexamethasone probes glucocorticoid receptor (GR) function, while prednisolone probes both GR and mineralocorticoid receptor (MR) function. MATERIALS AND METHODS: We used a single-blind, repeated-measure design. We administered placebo, prednisolone (5 mg) or dexamethasone (0.5 mg), at 22:00, to 18 severe, treatment-resistant depressed inpatients (15 of them with a history of childhood trauma) and 14 healthy volunteers. On the following days, we collected salivary cortisol from 9:00 to 22:00. RESULTS: Depressed patients had higher salivary cortisol levels compared with controls, at baseline and after both prednisolone and dexamethasone (p<0.001). Consistent with previous studies, depressed inpatients showed impaired suppression by dexamethasone: based on the analysis of the areas under the curve (AUCs), suppression by dexamethasone (0.5 mg) was -85% in controls vs -46% in depressed patients (p=0.018). However, the same depressed patients showed normal suppression by prednisolone (5 mg): suppression was -41% in controls and -36% in depressed patients (p=0.6). CONCLUSIONS: We suggest that the additional effects of prednisolone on the MR explain the different responses to these glucocorticoids in the same depressed patients.

Area Under Curve↗
PubMed2006

The glucocorticoid receptor: part of the solution or part of the problem?

Clinical studies have demonstrated hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis and increased levels of cortisol in patients with major depression, because of an impairment of glucocorticoid receptor (GR)-mediated negative feedback (glucocorticoid resistance). Moreover, clinical and experimental studies have shown that antidepressants increase GR function, thus leading to resolution of glucocorticoid resistance. Interestingly, a number of studies have also demonstrated that manipulating GR function with both agonists and antagonists has an antidepressant effect, and indeed that other drugs targeting the HPA axis and cortisol secretion - even drugs with opposite effects on the HPA axis - have antidepressant effects. These studies do not support the notion that cortisol has 'negative' effects on the brain. On the contrary, this paper concludes that a lack of the 'positive' effects of cortisol on the brain, because of glucocorticoid resistance, is likely to be involved in the pathogenesis of depression.

Animals↗
PubMed2005

A crossover study on lipid and weight changes associated with olanzapine and risperidone.

RATIONALE: The results from case-control and retrospective studies revealed that olanzapine might be associated with more increased risks of metabolic dysfunction than risperidone. The crossover design can minimize the influence of individual variation in metabolic profiles and demographic variables, such as age, sex, concomitant medication use and personal life styles. OBJECTIVES: We design a crossover study to evaluate the metabolic effect of olanzapine and risperidone. METHODS: Fifteen schizophrenic patients were shifted from olanzapine and risperidone or from risperidone and olanzapine due to poor treatment response. The body weights, lipid profiles and fasting glucose levels were assessed before medication switch and 3 months after crossover. RESULTS: In the seven patients taking risperidone at the time of inclusion (risperidone-first group), after shifting to olanzapine, there was a significant increase in triglyceride level (p=0.048) and body weight (p=0.008). In the other eight patients (olanzapine-first group), after shift to risperidone, there was a decrease in triglyceride level (p=0.009), body weight (p=0.049) and body mass index (BMI; p=0.04). When comparing the metabolic profiles in all patients after olanzapine and after risperidone (irrespective of the order of treatment), the mean triglyceride level (p=0.001), body weight (p=0.001) and BMI (p=0.015) were significantly higher in patients receiving olanzapine than in those receiving risperidone. Furthermore, there was a small increase in total cholesterol level (p=0.091) and a small decrease in high-density lipoprotein (HDL) level (p=0.061) in olanzapine group, but the differences did not reach a significant level. There was no significant difference between olanzapine and risperidone in fasting glucose and low-density lipoprotein (LDL). CONCLUSIONS: This study confirms that elevated levels of triglyceride and body weight could be associated with the use of olanzapine as compared with risperidone. The changes in body weights and lipid profiles should be closely monitored in patients during treatment with atypical antipsychotic drugs.

Adult↗
PubMed2005

Pituitary volume predicts future transition to psychosis in individuals at ultra-high risk of developing psychosis.

BACKGROUND: We examined pituitary volume before the onset of psychosis in subjects who were at ultra-high risk (UHR) for developing psychosis. METHODS: Pituitary volume was measured on 1.5-mm, coronal, 1.5-T magnetic resonance images in 94 UHR subjects recruited from admissions to the Personal Assessment and Crisis Evaluation Clinic in Melbourne, Australia and in 49 healthy control subjects. The UHR subjects were scanned at baseline and were followed clinically for a minimum of 1 year to detect transition to psychosis. RESULTS: Within the UHR group, a larger baseline pituitary volume was a significant predictor of future transition to psychosis. The UHR subjects who later went on to develop psychosis (UHR-P, n = 31) had a significantly larger (+12%; p = .001) baseline pituitary volume compared with UHR subjects who did not go on to develop psychosis (UHR-NP, n = 63). The survival analysis conducted by Cox regression showed that the risk of developing psychosis during the follow-up increased by 20% for every 10% increase in baseline pituitary volume (p = .002). Baseline pituitary volume of the UHR-NP subjects was smaller not only compared with UHR-P (as described above) but also compared with control subjects (-6%; p = .032). CONCLUSIONS: The phase before the onset of psychosis is associated with a larger pituitary volume, suggesting activation of the HPA axis.

Adolescent↗
PubMed2005

Increased pituitary volume in antipsychotic-free and antipsychotic-treated patients of the AEsop first-onset psychosis study.

Subjects at their first psychotic episode show an enlarged volume of the pituitary gland, but whether this is due to hypothalamic-pituitary-adrenal (HPA) axis hyperactivity, or to stimulation of the prolactin-secreting cells by antipsychotic treatment, is unclear. We measured pituitary volume, using 1.5-mm, coronal, 1.5 T, high-resolution MRI images, in 78 patients at the first psychotic episode and 78 age- and gender-matched healthy controls. In all, 18 patients were antipsychotic-free (12 of these were antipsychotic-naïve), 26 were receiving atypical antipsychotics, and 33 were receiving typical antipsychotics. As hypothesized, patients had a larger pituitary volume than controls (+22%, p< 0.001). When divided by antipsychotic treatment, and compared to controls, the pituitary volume was 15% larger in antipsychotic-free patients (p=0.028), 17% larger in patients receiving atypicals (p=0.01), and 30% larger in patients receiving typicals (p<0.001). Patients receiving typicals not only had the largest pituitary volume compared to controls but also showed a trend for a larger pituitary volume compared to the other patients grouped together (+11%, p=0.08). When divided by diagnosis, and compared to controls, the pituitary volume was 24% larger in patients with schizophrenia/schizophreniform disorder (n=40, p<0.001), 19% larger in depressed patients (n=13, p=0.022), 16% larger in bipolar patients (n=16, p=0.037), and 12% larger in those with other psychoses (n=9, p=0.2). In conclusion, the first-episode of a psychotic disorder is associated with a larger pituitary independently of the presence of antipsychotic treatment, and this could be due to activation of the HPA axis. Typical antipsychotics exert an additional enlarging effect on pituitary volume, likely to be related to activation of prolactin-secreting cells. This activation of the hormonal stress response could participate to the important metabolic abnormalities observed in patients with psychosis.

Adolescent↗
PubMed2004

[The hypothalamic pituitary adrenal axis, glucocorticoid receptor function and relevance to depression].

OBJECTIVES: Changes in the hypothalamic-pituitary-adrenocortical (HPA) system are characteristic of depression. Because the effects of glucocorticoids are mediated by intracellular receptors including, most notably, the glucocorticoid receptor (GR), several studies have examined the number and/or function of GRs in depressed patients. METHODS: Review scientific evidences have consistently demonstrated that GR function is impaired in major depression, resulting in reduced GR-mediated negative feedback on the HPA axis and increased production and secretion of CRF in various brain regions postulated to be involved in the causality of depression. RESULTS: This article summarizes the literature on GR in depression and on the impact of antidepressants on the GR in clinical and preclinical studies, and supports the concept that impaired GR signalling is a key mechanism in the pathogenesis of depression, in the absence of clear evidence of decreased GR expression. The data also indicate that antidepressants have direct effects on the GR, leading to enhanced GR function and increased GR expression. Although the effects of antidepressants on glucocorticoid hormones and their receptors are relevant for the therapeutic action of these drugs, the molecular mechanisms underlying these effects are unclear. We propose that antidepressants in humans could inhibit steroid transporters localised on the blood-brain barrier and in neurones, like the multidrug resistance p-glycoprotein, and thus increase the access of cortisol to the brain and the glucocorticoid-mediated negative feedback on the HPA axis. CONCLUSION: Enhanced cortisol action in the brain might prove to be a successful approach to maximise therapeutic antidepressant effects. Hypotheses regarding the mechanism of these receptor changes involve non-steroid compounds that regulate GR function via second messenger pathways. Research in this field will lead to new insights into the pathophysiology and treatment of affective disorders.

Antidepressive Agents↗
PubMed2004

Four days of citalopram increase suppression of cortisol secretion by prednisolone in healthy volunteers.

RATIONALE: Chronic antidepressant treatment increases glucocorticoid-mediated negative feedback on the hypothalamic-pituitary-adrenal (HPA) axis, and thus reduces HPA axis activity, in depressed patients and healthy controls. In contrast, acute antidepressant treatment induces an activation of basal HPA axis activity. OBJECTIVES: We examined the effects of 4 days of treatment with the selective serotonin reuptake inhibitor, citalopram, on basal salivary cortisol and on suppression of salivary cortisol by prednisolone. METHODS: We used a single-blind, placebo-controlled, repeated-measure design. Salivary cortisol was measured from 0900 to 1700 hours. In the first phase of the study, basal salivary cortisol secretion was measured on 2 study days, before and after 4 days of treatment with citalopram (orally, 20 mg/day). In the second phase, salivary cortisol secretion after suppression by prednisolone (5 mg, given at 2200 hours the night before) was measured on 2 study days, again before and after 4 days of treatment with citalopram (orally, 20 mg/day). Eight volunteers participated to the study. RESULTS: Citalopram increased basal salivary cortisol in the morning (0900-1100 hours) by approximately 47% (P=0.003). Moreover, citalopram increased suppression by prednisolone in the morning (0900-1100 hours): suppression was approximately 22% before citalopram and 45% after citalopram (P=0.05). CONCLUSIONS: Citalopram increases glucocorticoid-mediated negative feedback on the HPA axis after as little as 4 days of treatment. This effect could be due to an increased function of the corticosteroid receptors. Our findings further support the notion that one of the mechanisms by which antidepressants exert their therapeutic effects is by normalizing HPA axis hyperactivity in depressed patients.

Adult↗
PubMed2004

Do antidepressants regulate how cortisol affects the brain?

Although the effects of antidepressants on glucocorticoid hormones and their receptors are relevant for the therapeutic action of these drugs, the molecular mechanisms underlying these effects are unclear. Studies in depressed patients, animals and cellular models have demonstrated that antidepressants increase glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) expression and function; this, in turn, is associated with enhanced negative feedback by endogenous glucocorticoids, and thus with reduced resting and stimulated hypothalamic-pituitary-adrenal (HPA) axis activity. In a series of studies conducted over the last few years, we have shown that antidepressants modulate GR function in vitro by inhibiting membrane steroid transporters that regulate the intracellular concentration of glucocorticoids. In this paper, we will review the effects of membrane steroid transporters and antidepressants on corticosteroid receptors. We will then present our unpublished data on GR live microscopy in vitro, showing that ligand-induced translocation of the GR starts within 30 seconds and is completed within minutes. Furthermore, we will present our new data using an in situ brain perfusion model in anaesthetised guinea-pigs, showing that entry of cortisol to the brain of these animals is limited at the blood-brain barrier (BBB). Finally, we will present a comprehensive discussion of our published findings on the effects of chemically unrelated antidepressants on membrane steroid transporters, in mouse fibroblasts and rat cortical neurones. We propose that antidepressants in humans could inhibit steroid transporters localised on the BBB and in neurones, like the multidrug resistance p-glycoprotein, and thus increase the access of cortisol to the brain and the glucocorticoid-mediated negative feedback on the HPA axis. Enhanced cortisol action in the brain might prove to be a successful approach to maximise therapeutic antidepressant effects.

Animals↗
PubMed2004

Glucocorticoid receptor function in vitro in patients with major depression.

Clinical studies have demonstrated an impairment of glucocorticoid receptor (GR)-mediated negative feedback on the hypothalamic--pituitary--adrenal (HPA) axis in patients with major depression (GR resistance), and its resolution by antidepressant treatment. Interestingly, a number of studies have also demonstrated that GR function is reduced in vitro, in peripheral tissues of depressed patients, as shown by a decreased sensitivity to the effects of glucocorticoids on immune and metabolic functions. This paper reviews the in vitro studies that have examined GR function in patients with major depression, and the possible molecular mechanisms involved in GR resistance. Since several studies have demonstrated similar regulation of GR in the brain and in peripheral tissues in humans, and given limited access to brain GR in clinical populations, this review claims that in vitro studies are of particular relevance to understand the molecular mechanisms underlying GR abnormalities in patients with major depression and its regulation by antidepressant treatment.

Animals↗
PubMed2004

Psychopharmacological treatment of depression, anxiety, irritability and insomnia in patients receiving interferon-alpha: a prospective case series and a discussion of biological mechanisms.

We studied 60 patients receiving a 1-year course of interferon (IFN)-alpha therapy for chronic viral hepatitis. Patients underwent psychiatric assessment before starting the IFN-alpha therapy, and monthly throughout the therapy, using the Structured Clinical Interview for the DSM-III-R, the 17-item Hamilton Depression Rating Scale, the Beck Depression Inventory and the Spielberg State and Trait Anxiety Inventory. Five patients had a baseline diagnosis of major depression and 18 (30%) developed an IFN-alpha-induced psychiatric adverse effect; 12 of these 23 patients received psychopharmacological treatment (patients and clinicians jointly decided the need for treatment). Two of the five patients with baseline depression started an antidepressant treatment (paroxetine) together with the IFN-alpha and successfully completed the IFN-alpha therapy. Ten patients received treatment for the IFN-alpha-induced psychiatric adverse effects (depression in five patients, anxiety in two patients, severe irritability in two patients and insomnia in one patient). Depression was treated with paroxetine, amisulpride or levosulpiride; anxiety and insomnia were treated with benzodiazepines; and irritability was treated with thioridazine. Individual response to medications was measured with the Clinical Global Impression scale. Of the patients with IFN-alpha-induced depression, two received paroxetine (one showed a good response), two received amisulpride (one showed a good response) and one did not respond to levosulpiride but responded to paroxetine. The patients experiencing anxiety or insomnia responded well to benzodiazepines. One patient showed a good response, and one a poor response, to thioridazine for irritability. Only one patient interrupted the therapy because of psychiatric adverse effects. Overall, the 12 patients that received psychopharmacological treatment developed less severe psychopathological symptoms during the IFN-alpha therapy compared to the 11 patients who had untreated baseline depression or untreated IFN-alpha-induced psychiatric adverse effects. Thus, psychopharmacological management can successfully treat psychiatric symptoms in patients who are receiving IFN-alpha.

Adolescent↗
PubMed2004

Pituitary volume in psychosis.

BACKGROUND: Patients with psychosis have activation of the hypothalamic-pituitary-adrenal (HPA) axis during the acute phase of the psychosis. Whether this has any morphological consequences for the pituitary gland is currently unknown. AIMS: To examine pituitary volume variation in people at different stages of psychotic disorder. METHOD: Pituitary volume was measured using 1.5 mm, coronal magnetic resonance images in 24 people with first-episode psychosis, 51 with established schizophrenia and 59 healthy controls. RESULTS: Compared with the control group, the people with first-episode psychosis had pituitary volumes that were 10% larger, whereas those with established schizophrenia had pituitary volumes that were 17% smaller. In both of the groups with psychosis, there was no difference in pituitary volume between those receiving typical antipsychotic drugs and those receiving atypical antipsychotics. CONCLUSIONS: The first episode of a psychosis is associated with a larger pituitary volume, which we suggest is due to activation of the HPA axis. The smaller pituitary volume in the group with established schizophrenia could be the consequence of repeated episodes of HPA axis hyperactivity.

Acute Disease↗
PubMed2003

The antidepressant clomipramine regulates cortisol intracellular concentrations and glucocorticoid receptor expression in fibroblasts and rat primary neurones.

Incubation of LMCAT fibroblasts cells with antidepressants potentiates glucocorticoid receptor (GR)-mediated gene transcription in the presence of cortisol, but not of corticosterone. We have suggested that antidepressants do so by inhibiting the LMCAT cells membrane steroid transporter and thus by increasing cortisol intracellular concentrations. We now confirm and extend this model to primary neuronal cultures. Clomipramine, a tricyclic antidepressant, increased the intracellular accumulation of 3H-cortisol, but not 3H-corticosterone, in LMCAT cells (+80%) and primary rat neurones (+20%). The latter finding is the first demonstration that a membrane steroid transporter is present in neurones. Moreover, verapamil, a membrane steroid transporter inhibitor, reduced the effects of clomipramine on the intracellular accumulation of 3H-cortisol in LMCAT cells. Finally, clomipramine also decreased GR expression (whole-cell Western blot) in LMCAT cells (50% reduction) and primary rat neurones (80% reduction). This GR downregulation can explain the reduced GR-mediated gene transcription previously described under experimental conditions that do not elicit the effects on the LMCAT cells steroid transporter. This work further supports the hypothesis that membrane steroid transporters regulating the access of glucocorticoids to the brain in vivo are a fundamental target for antidepressant action.

Animals↗
PubMed2003

Antidepressant fluoxetine enhances glucocorticoid receptor function in vitro by modulating membrane steroid transporters.

1. Incubation of LMCAT fibroblast cells with antidepressants potentiates glucocorticoid receptor (GR)-mediated gene transcription in the presence of dexamethasone and cortisol, but not of corticosterone. We have shown that antidepressants do so by inhibiting the LMCAT cell membrane steroid transporter (which is virtually identical to the multidrug resistance P-glycoprotein) and thus by increasing dexamethasone or cortisol intracellular concentrations. However, previous experiments with the antidepressant fluoxetine in the presence of dexamethasone have produced negative results (Pariante et al. (2001). Br. J. Pharmacol., 134, 1335-1343). 2. We have since re-examined the effects of fluoxetine on GR-mediated gene transcription in the presence of dexamethasone. Moreover, we have examined the effects of fluoxetine on GR-mediated gene transcription in the presence of cortisol and corticosterone, and on the intracellular accumulation of radioactive cortisol and corticosterone. Finally, we have examined the effects of fluoxetine on inhibition of P-glycoprotein activity in Caco-2 cells. 3. We now find that fluoxetine (1-10 micro M) enhances GR-mediated gene transcription in the presence of dexamethasone and cortisol (+140-170%), but not of corticosterone, and increases the intracellular accumulation of (3)H-cortisol (+5-15%), but not of (3)H-corticosterone. Moreover, fluoxetine (10 micro M) induces approximately 30% inhibition of PGP activity in Caco-2 cells. 4. Our results show that fluoxetine, like other antidepressants, inhibits membrane steroid transporters.

Animals↗