The emerging role of the FKBP5 gene polymorphisms in vulnerability-stress model of schizophrenia: further evidence from a Serbian population.

Increased reactivity to stress is observed in patients with schizophrenia spectrum disorders and their healthy siblings in comparison with the general population. Additionally, higher levels of neuroticism, as a proposed psychological measure of stress sensitivity, increase the risk of schizophrenia. HPA axis dysregulation is one of the possible mechanisms related to the vulnerability-stress model of schizophrenia, and recent studies revealed a possible role of the functional genetic variants of FK506-binding protein 51 (FKBP5) gene which modulate activity of HPA axis. The purpose of the present study was to investigate impact of FKBP5 on schizophrenia in Serbian patients and to explore relationship between genetic variants and neuroticism by using the case-sibling-control design. In 158 subjects, we measured psychotic experiences, childhood trauma and neuroticism. Nine single-nucleotide polymorphisms (rs9295158, rs3800373, rs9740080, rs737054, rs6926133, rs9380529, rs9394314, rs2766533 and rs12200498) were genotyped. The genetic influence was modeled using logistic regression, and the relationship between genetic variants and neuroticism was assessed by linear mixed model. Our results revealed genetic main effect of FKBP5 risk alleles (A allele of rs9296158 and T allele of rs3800373) and AGTC "risk" haplotype combination (rs9296158, rs3800373, rs9470080 and rs737054, respectively) on schizophrenia, particularly when childhood trauma was set as a confounding factor. We confirmed strong relationship between neuroticism and psychotic experiences in patients and siblings and further showed relationship between higher levels of neuroticism and FKBP5 risk variants suggesting potential link between biological and psychosocial risk factors. Our data support previous findings that trauma exposure shapes FKBP5 impact on schizophrenia.

Metabolic issues in psychotic disorders with the focus on first-episode patients: a review.

Before the onset of the illness, future schizophrenia patients do not weigh more comparing to their peers. However, during the later course of the illness, obesity is twice as prevalent as in general public, afflicting the half of schizophrenia patient population. There is a list of potential factors that contribute to this, including lifestyle, dietary habits, unsatisfactory monitoring of physical health etc, but nowadays side effects of antipsychotic medication become the most prominent concern when weight gain and metabolic issues in psychosis are addressed. The fact is that second generation antipsychotics (SGA) are associated with weight gain and metabolic syndrome, but that might be the case with the first generation antipsychotics (FGA) too. Besides, obesity might be evident in patients before any exposure to medications, and all that bring lot of dilemmas into the field. This paper critically reviews available data on metabolic problems in patients with psychotic disorders, raging from genetic to molecular and environmental factors, and highlights the necessity of screening for the early signs of metabolic disturbances, as well as of multidisciplinary assessment of psychiatric and medical conditions from the first psychotic episode.

Openness to experience shortens duration of untreated psychosis in Serbian clinical population.

AIM: To determine duration of untreated psychosis (DUP) in patients with schizophrenia-spectrum disorders from Serbia and to analyse factors that potentially contribute to the treatment delay, with focus on personality traits. METHODS: Fifty seven patients (males 54.4%; age = 29.9 ± 6.0 yrs; age at the illness onset = 24.9 ± 5.1 yrs; IQ = 93.5 ± 12.2) were included. The assessment consisted of Nottingham Onset Schedule (NOS), Premorbid Adjustment Scale (PAS) and NEO Personality Inventory (NEO-PI-R). We used Cox regression model to evaluate relationship between DUP and explanatory variables. RESULTS: Based on the most restrictive definition, the length of DUP in our sample was 77.8 ± 120.6 weeks (MED = 25.0 weeks). DUP was negatively associated with openness to experience (B = -0.804, P = 0.024). CONCLUSIONS: We report the first evidence of DUP in Serbia, emphasizing that the personality domains are likely to impact the use of mental health care in persons with psychosis.

Executive function in treatment-resistant depression before and after electroconvulsive therapy.

OBJECTIVES: The aim of this study was to examine executive functions (EF) in patients with treatment-resistant depression (TRD) before and after bitemporal electroconvulsive therapy (ECT) and to evaluate possible associations between the depression severity and executive tasks performances. METHODS: Patients (n = 29), treated with bitemporal ECT, underwent assessment at three time points: baseline, immediately after ECT course and 1 month later. The Stockings of Cambridge (SOC, CANTAB) was used to assess EF: (1) number of problems solved in minimum moves (SOC-P), (2) initial thinking time (SOC-I) and (3) subsequent thinking time (SOC-T). RESULTS: The scores on the Hamilton Depression Rating Scale and the Clinical Global Impression scale were significantly reduced over time, with no negative effects on the EF. Among SOC subtests, only SOC-I improved over time, which was significantly correlated with the depressive symptoms reduction. SOC-T and SOC-P remained unchanged and did not correlate with mood. Interestingly, the patients with more lifetime psychiatric hospitalisations and more ECT applications were more likely to drop-out and to have longer SOC-T while performing the test. CONCLUSIONS: Our results support the view that ECT does not produce long-lasting EF deficits, nor exacerbates the pre-existing ones. The improvement of the EF performances during and after the ECT-induced alleviation of mood symptoms in TRD is based mostly on the reduction of time needed to plan the problem solution.

Familial covariation of facial emotion recognition and IQ in schizophrenia.

Alterations in general intellectual ability and social cognition in schizophrenia are core features of the disorder, evident at the illness' onset and persistent throughout its course. However, previous studies examining cognitive alterations in siblings discordant for schizophrenia yielded inconsistent results. Present study aimed to investigate the nature of the association between facial emotion recognition and general IQ by applying genetically sensitive cross-trait cross-sibling design. Participants (total n=158; patients, unaffected siblings, controls) were assessed using the Benton Facial Recognition Test, the Degraded Facial Affect Recognition Task (DFAR) and the Wechsler Adult Intelligence Scale-III. Patients had lower IQ and altered facial emotion recognition in comparison to other groups. Healthy siblings and controls did not significantly differ in IQ and DFAR performance, but siblings exhibited intermediate angry facial expression recognition. Cross-trait within-subject analyses showed significant associations between overall DFAR performance and IQ in all participants. Within-trait cross-sibling analyses found significant associations between patients' and siblings' IQ and overall DFAR performance, suggesting their familial clustering. Finally, cross-trait cross-sibling analyses revealed familial covariation of facial emotion recognition and IQ in siblings discordant for schizophrenia, further indicating their familial etiology. Both traits are important phenotypes for genetic studies and potential early clinical markers of schizophrenia-spectrum disorders.

Neuroticism and facial emotion recognition in healthy adults.

AIM: The aim of the present study was to examine whether healthy individuals with higher levels of neuroticism, a robust independent predictor of psychopathology, exhibit altered facial emotion recognition performance. METHODS: Facial emotion recognition accuracy was investigated in 104 healthy adults using the Degraded Facial Affect Recognition Task (DFAR). Participants' degree of neuroticism was estimated using neuroticism scales extracted from the Eysenck Personality Questionnaire and the Revised NEO Personality Inventory. RESULTS: A significant negative correlation between the degree of neuroticism and the percentage of correct answers on DFAR was found only for happy facial expression (significant after applying Bonferroni correction). CONCLUSIONS: Altered sensitivity to the emotional context represents a useful and easy way to obtain cognitive phenotype that correlates strongly with inter-individual variations in neuroticism linked to stress vulnerability and subsequent psychopathology. Present findings could have implication in early intervention strategies and staging models in psychiatry.

¼Treatment Resistance« Enigma Resolved by Pharmacogenomics - A Case Study of Clozapine Therapy in Schizophrenia.

The introduction of antipsychotic medication in the 1950s forever changed the outlook on the treatment of schizophrenia, although there is still a large proportion of patients who do not reach functional recovery. At least 30% of patients do not respond to clozapine, the tricyclic dibenzodiazepine with complex pharmacological actions, which was proven to be more effective than any other antipsychotic in the treatment of schizophrenia. According to most of the therapeutic guidelines for schizophrenia, clozapine is the third line therapy for patients who did not respond to other antipsychotics. Large inter-individual variability exists for clozapine bioavailability and plasma steady-state concentrations and clearance. Clozapine is metabolized by the cytochrome P450 oxidase enzyme family (CYP450). Cytochrome P450 1A2 (CYP1A2), which is polymorphically expressed in humans, is the main enzyme of clozapine metabolism. This case report addresses the influence of CYP1A2*1F genetic polymorphism on clozapine metabolism, explains the primary non-response of a young patient with schizophrenia due to increased gene expression in homozygous genotype *1F/*1F (increased metabolism of clozapine) and underlies the importance of personalizing schizophrenia treatment by means of genetic and other molecular tools, at least in the cases of ¼treatment resistance«.

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

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.

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.