Nadja P. Maric

Changes in Neuroendocrine and Metabolic Hormones Induced by Atypical Antipsychotics in Normal-Weight Patients with Schizophrenia

Context: Atypical antipsychotics (SGA) have the propensity to induce weight gain. Objective: The aim was to evaluateearly changes in hormones involved in neuroendocrine regulations (serum cortisol, growth hormone and prolactin) and positive energy balance (serum insulin, leptin and ghrelin) during SGA treatment in normal-weight patients with schizophrenia with the purpose of exploring the possibility to combat weight gain early through manipulation of circulating hormone levels. Design: We conducted a randomized, partly cross-sectional and partly longitudinal, prospective study. Setting and Patients: Eighteen normal-weight in-patients with schizophrenia treated with FGA (first-generation antipsychotics) were referred to the Institute of Psychiatry. Twenty age-, gender- and BMI-matched healthy subjects were investigated at the Neuroendocrine Unit, Belgrade University. Intervention: Oral glucose tolerance test (OGTT) was performed at baseline in all and then 13 patients were assigned to receive SGA (risperidone or clozapine) and OGTT was repeated after 1 and 3 months. Results: At baseline, patients with schizophrenia had higher peak glucose levels (p < 0.05), glucose area under the curve (AUC; p < 0.05), peak insulin levels (p < 0.05), insulin AUC values during OGTT (p < 0.01) and the calculated homeostasis model assessment (HOMA-IR) value than control subjects (p < 0.05). Patients with schizophrenia showed higher morning cortisol (p < 0.05) levels than control subjects. After 1 and 3 months of SGA therapy patients with schizophrenia gained bodyweight by 3.5 and 8.6%, respectively. Leptin levels steadily increased while cortisol levels decreased in the first month and remained so. Serum glucose, insulin and ghrelin levels on SGA were similar as at baseline. Circulating ghrelin levels decreased after OGTT during SGA which is consistent with a role for ghrelin in the initiation of meals. Conclusions: Treatment with SGA was associated with continuous weight gain, with an early increase in serum leptin levels and decrease in cortisol levels. Elevated circulating leptin was ineffective in the control of fat deposition. Similar plasma ghrelin levels and similar decrease pattern of ghrelin after OGTT compared to healthy subjects signify intact meal-promoting effects of ghrelin during SGA therapy, which at the same time renders anorexigenic pathways ineffective. This may lead to weight gain and further studies with a ghrelin antagonist may provide support for this hypothesis.

Bone remodeling, bone mass and weight gain in patients with stabilized schizophrenia in real-life conditions treated with long-acting injectable risperidone.

Background: Prolactin-raising antipsychotics, risperidone (antidopaminergic activity), may be associated with low bone mass. On the other hand, risperidone may cause an increase in body weight thought to be favorable for bone. Objectives: (1) To determine bone remodeling parameters and bone mass in patients with schizophrenia on long-term treatment with long-acting injectable risperidone (LAIR) in naturalistic settings, and (2) to evaluate the change in body weight, metabolic profile and neuroendocrine status in these patients. Design: This was a prospective, cross-sectional study. Patients: Patients included 26 outpatients with controlled schizophrenia in real-life conditions (age 31.3 ± 1.3 years, BMI 28.1 ± 1.0) on long-term maintenance therapy with LAIR for a mean of 18.0 ± 1.6 months (range 6–36) with a mean dose of 38 ± 2 mg. 35 subjects matched for sex, age, BMI and education served as healthy controls. Methods: Serum osteocalcin, C-terminal telopeptide of type I collagen (CTx), vitamin D, leptin, prolactin, sex steroids, and parathyroid hormone were assessed. Indices of insulin sensitivity and resistance were determined following an oral glucose tolerance test (OGTT). Bone mineral density (BMD) was measured by dual X-ray absorptiometry at the lumbar spine (LS) and femoral neck (FN). Results: Mild to moderate hyperprolactinemia (1,000–2,000 mU/l) was associated with asymptomatic hypogonadism. Prolactin values >2,000 mU/l occurred in a few female patients. Hypogonadism leads to a slight increase (upper limit of normal) in bone resorption marker (CTx) in patients with schizophrenia (p = 0.023). As for bone mass, although lower at the spine than in healthy subjects, it did not reach statistical significance (p = 0.094), while at the FN, BMD was not different from healthy subjects. Body weight increased on average 8.7 ± 1.6 kg in more than 50% of patients. Leptin levels adjusted for BMI in females were significantly higher in patients than in healthy female subjects (p = 0.018), while in males there was no difference between the groups (p = 0.833). A high prevalence of low vitamin D levels and more current smokers were found in patients with schizophrenia. As for the metabolic profile during treatment with risperidone, the low Matsuda index of insulin sensitivity (p = 0.039) confirmed insulin resistance in these patients. Conclusion: A potential long-term consequence of asymptomatic hypogonadism due to risperidone-induced hyperprolactinemia might cause a slight rise in bone resorption marker (CTx). On the other hand, by increasing body weight, risperidone could have a protective effect on the bone and thus no change in bone mass was recorded when compared with healthy controls.

Phosphorylation of leukocyte glucocorticoid receptor in patients with current episode of major depressive disorder.

The impaired glucocorticoid receptor (GR) signaling has long been considered one of the cornerstones in understanding the pathophysiology of depression. Since the phosphorylation of GR is very important for GR function, in this study we investigated whether GR phosphorylation at serine 211 (pGR-S211) and serine 226 (pGR-S226) is altered in patients with current episode of major depressive disorder (MDD). Particularly, in 30 MDD patients and 35 controls we assessed the levels of nuclear total GR (tGR), pGR-S211 and pGR-S226 in peripheral blood mononuclear cells (PBMC) using Western blot technique, along with plasma cortisol concentrations from the same blood samples. Our results demonstrated increased phosphorylation of GR at S226 (p<0.001) and, to a less extent, at S211 (p<0.05) in MDD patients compared to controls. Consequently, the pGR-S211/pGR-S226 ratio was decreased (p<0.05) implying reduced transcriptional activity of GR in MDD patients. MDD subjects had higher cortisol levels than controls and cortisol concentrations were positively correlated with PBMC pGR-S226 levels from the same blood samples. There was no difference in the levels of tGR between MDD and control subjects. The study showed that altered phosphorylation of GR could contribute to impaired GR function related to the pathophysiology of depression.

Lymphocyte levels of redox-sensitive transcription factors and antioxidative enzymes as indicators of pro-oxidative state in depressive patients.

Background: Oxidative stress is reliably observed in major depressive disorder (MDD). However, molecular data on the principal cellular redox-sensitive transcriptional factors and the levels of their downstream-regulated antioxidant enzymes in MDD are scarce. Methods: In the peripheral blood mononuclear cells (PBMC) of subjects with a current episode of MDD (n = 30) and healthy controls (n = 35), we investigated alterations in the levels of redox-sensing nuclear factor (erythroid-derived 2)-like 2 (Nrf2) protein, its inhibitor Keap1, and nuclear factor-κB (NF-κB), along with their cognate downstream effectors, the antioxidant enzymes (AOEs): manganese and copper zinc superoxide dismutase (MnSOD and CuZnSOD, respectively), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GLR). Results: MDD subjects exhibited higher levels of Nrf2 and its regulator Keap1, as well as NF-κB in the cytoplasm of PBMC compared to controls. This state was further reflected by increased levels of MnSOD, CuZnSOD and CAT proteins and by the lack of correlation between MnSOD and CAT, which could indicate impaired oxidative detoxification capacity in MDD patients. Moreover, increased levels of MnSOD, CuZnSOD and CAT in MDD patients positively correlated with levels of Nrf2, while increased levels of SODs were also positively related to NF-κB. There were no differences regarding the levels of GPx and GLR proteins, but the ratio of GLR/GPx was reduced, suggesting diminished capacity of GPx in antioxidative defence in PBMC of MDD subjects. Conclusion: These data provide evidence that MDD is characterized by up-regulation of redox-sensitive transcriptional factors (Nrf2 and NF-κB) and AOEs (MnSOD, CuZnSOD and CAT), indicating pro-oxidative state in the PBMC of MDD patients.

Stigmatization of ‘psychiatric label’ by medical and non-medical students

Backround: Stigmatization of psychiatric patients is present both in the general population and among healthcare professionals. Aim: To determine the attitudes and behaviour of medical students towards a person who goes to a psychiatrist, before and after psychiatric rotation, and to compare those attitudes between medical and non-medical students. Methods: The study included 525 medical students (second and sixth year of studies) and 154 students of law. The study instrument was a three-part self-reported questionnaire (socio-demographic data, Rosenberg Self-Esteem Scale and a vignette depicting a young, mentally healthy person). The experimental intervention consisted of ascribing a ‘psychiatric label’ to only one set of vignettes. All the vignettes (with or without the ‘psychiatric label’) were followed by 14 statements addressing the acceptance of a person described by vignette, as judged by social distance (four-point Likert scale). Results: Higher tendency to stigmatize was found in medical students in the final year, after psychiatric rotation (Z U = −3.12, p = .002), particularly in a closer relationship (Z U = −2.67, p = .007) between a student and a hypothetical person who goes to a psychiatrist. The non-medical students had a similar tendency to stigmatize as medical students before psychiatric rotation (Z U = −0.03, p = .975). Neither gender, nor the size of student’s place of origin or average academic mark was associated with the tendency to stigmatize in our sample. However, student’s elf-esteem was lower in those with a tendency to stigmatize more in a distant relationship (ρ = −0.157, p = .005). Conclusions: Psychiatric education can either reinforce stigmatization or reduce it. Therefore, detailed analyses of educational domains that reinforce stigma will be the starting point for anti-stigma action.

A preliminary evaluation of leukocyte phospho-glucocorticoid receptor as a potential biomarker of depressogenic vulnerability in healthy adults

The mechanism of maladaptive chronic stress response involves altered phosphorylation of the glucocorticoid receptor (GR). In this study, we investigated if important depressogenic vulnerability factors, such as neuroticism and self-reports of negative affective states, may be associated with alterations in levels of the GR and GR phosphoisoforms in peripheral blood mononuclear cells (PBMC) of healthy adults. In 21 women and 16 men we evaluated PMBC levels of total GR (tGR), GR phosphorylated at serine 211 (pGR-S211) and serine 226 (pGR-S226) and correlated these data with personality traits and current reports of stress, anxiety and depression. Also, we assessed plasma cortisol levels in all tested subjects. Our results showed that in women nuclear pGR-S226 was positively correlated with neuroticism and current reports of depression, anxiety and stress, while the ratio of nuclear pGR-S211/pGR-S226 was negatively correlated with reports of depression. None of the aforementioned correlations were significant in men. No significant relations between cortisol levels and any of GR parameters were observed. These preliminary findings highlight the value of GR phosphorylation-related research in identifying molecular biomarkers of depressogenic vulnerability, at least in women.

Gait characteristics in patients with major depression performing cognitive and motor tasks while walking

Depressed patients demonstrate alterations in motor and cognitive functioning that can affect their adjustments to the variations in everyday life environment. The objective was to explore gait parameters and variability of patients with major depressive disorder in dual task walking situations. Eight patients and 20 healthy controls performed motor, mental and combined motor+mental tasks while walking. Calculated parameters were cycle time, stride length, swing time, double support time and their coefficients of variation (CV). Patients demonstrated greater gait variability (swing time CV) than controls during baseline walk (t(26)=2.64, p<0.05) and motor dual task (t(26)=3.68, p<0.05). Moreover, the transition from mental to combined task decreased stride length (M=126.48±15.35 and M=121.19±13.55, p<0.001) and increased double support time (M=0.266±0.072 and M=0.287±0.076, p<0.01) only in controls. Also, gait variability increased in controls during the combined task, while remaining the same or decreasing in patients. Tasks that required greater cognitive involvement affected gait variability in patients more than controls, but only up to a certain level, after which patients׳ stability appeared unaffected by the increase of cognitive demand. This could be explained by a tendency of patients to neglect complex cognitive tasks while walking in order to preserve stability and prevent possible falls.

Accumulation of Cytoplasmic Glucocorticoid Receptor Is Related to Elevation of FKBP5 in Lymphocytes of Depressed Patients

We have previously shown that patients with the major depressive disorder (MDD) exhibited elevated phosphorylation of the lymphocyte glucocorticoid receptor (GR) at serine 226 (S226). Here, we further analyse potential alterations of GR signalization in lymphocytes of MDD patients, i.e. the cytoplasmic/nuclear distribution of GR, levels of FK506-binding protein 5 (FKBP5) and glucocorticoid-induced leucine zipper (GILZ). The FKBP5 acts as an important regulator of GR activation, by decreasing ligand binding and impeding translocation of the receptor to the nucleus, while GILZ mediates glucocorticoid anti-inflammatory effects. Our result showed that the depressed patients had significantly higher GR levels in the cytoplasm compared to controls, which was accompanied by higher FKBP5 levels. Linear regression model demonstrated significantly higher correlation between FKBP5 and cytoplasmic GR than the presence of MDD itself or phosphorylation of nuclear GR at S226. There were no differences in the levels of GILZ isoforms. Therefore, the results suggest that accumulation of the GR in cytoplasm is related to the elevation of FKBP5, adding one more step in understanding altered GR signalling in lymphocytes, and potentially brain tissue, of MDD patients.

The role of glucocorticoid receptor phosphorylation in the model of negative affective states

Abstract Objectives. To develop a structural equation model of negative affectivity (NA) that involves interaction of glucocorticoid receptor (GR) signaling, personality dimensions and recent stressful life events. Methods. Seventy participants − 35 diagnosed with major depression and 35 healthy controls, were enrolled in the study. Morning plasma cortisol levels were determined by chemiluminescent immunometric assays. Molecular parameters (total nuclear and cytoplasmatic GR, nuclear GR phosphorylated at serine 211 (pGR-211) and at serine 226 (pGR-226) and cytoplasmic FKBP51) were analysed from peripheral blood lymphocytes by Western blot. NA, personality dimensions and stressful life events were assessed by self-report instruments. Results. GR signalling parameters had direct independent effect on measures of NA, with pGR-226 levels showing the strongest correlation, followed by FKBP51 and pGR-211 levels. Neuroticism and extraversion also demonstrated strong independent effect on NA, while recent stressful events did not predict NA directly, but demonstrated a significant effect on personality dimensions. Cortisol, total nuclear GR and total cytoplasmatic GR levels were excluded from the model due to non-significant correlations with NA. Conclusions. Negative affectivity is a transdiagnostic factor in vulnerability to affective disorders and possible therapeutic target. Molecular signature of negative affectivity should incorporate GR phosphorylation with other known biological underpinnings.

Do depressive symptoms on hospital admission impact early functional outcome in elderly patients with hip fracture

Depression is the most common mood disorder in elderly people and one of the most prevalent comorbidities in older people with hip fracture. While several authors have confirmed that depressive symptoms assessed at a later stage after hip fracture impact functional outcome and mortality, the role of depressive symptoms identified at an earlier stage after hip fracture remains understudied. The aim of the present study was to determine if depressive symptoms assessed on hospital admission impact early functional outcome after hip fracture surgery.