Sanja Andric

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.

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.

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.

Neuroticism and facial emotion recognition in healthy adults.

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.

»Treatment Resistance« Enigma Resolved by Pharmacogenomics − A Case Study of Clozapine Therapy in Schizophrenia / Enigma »Terapo-Rezistence« Razrešena Uz Pomoć Farmakogenomike - Prikaz Slućaja Terapije Klozapinom U Shizofreniji

Summary 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 steadystate 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 cloza - pine 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 »treatment resistance«. Kratak sadržaj Početak primene antipsihotika pedesetih godina prošlog veka zauvek je promenio perspektivu lečenja shizofrenije, mada značajan broj pacijenata sa ovom bolešću još uvek ne postiže funkcionalni oporavak. Klozapin, triciklični di- benzodijazepin sa kompleksnim tarmakološkim profilom, koji se u tretmanu shizofrenije pokazao efikasnijim od osta- lih antipsihotika, uglavnom je treča linija terapijskog izbora. Međutim, u najmanje 30% slučajeva obolelih od shizofreni- je stanje se ne poboljšava ni na terapiji klozapinom, pa se zbog toga pristupa polifarmaciji i odstupa od racionalne primene psihofarmaka. Postoji velika interindividualna vari- jabilnost u bioraspoloživosti klozapina, stabilnoj koncentra- ciji u plazmi i njegovom klirensu. Klozapin se metaboliše preko sistema citohrom P450 oksidaza (СYР450). Cito- hrom P450 1A2 (СYР1А2), koji se u humanoj populaciji odlikuje genskim polimorfizmima, glavni je enzim u meta- bolizmu klozapina. Aktuelni prikaz slučaja ilustruje uticaj polimorfizma CYP1A2*1F na metabolizam klozapina, gde je primarni izostanak odgovora na terapiju kod mlade paci- jentkinje sa shizofrenijom objašnjen povećanjem ekspresije gena kod homozigotnog genotipa *1F/*1F (povišen meta- bolizam klozapina), i naglašava značaj personalizacije tret- mana shizofrenije uz pomoć genetike i drugih molekularnih parametara, posebno u slučajevima »terapo-rezistence«.

Executive Function in Treatment-Resistant Depression Before and After Electroconvulsive Therapy

Abstract 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.

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

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.

FKBP5 Epigenetic Changes In Schizophrenia: Similarity To Stress-Related Conditions

Background Hypothalamic–pituitary–adrenal (HPA) axis dysregulation is a potential neurobiological mechanism proposed by vulnerability-stress model for schizophrenia. Recent studies highlighted the role of functional genetic variants of FKBP5 gene, which affect the activity of HPA axis following stress exposure, and supported the hypothesis of increased stress sensitivity in schizophrenia. Additionally, FKBP5 demethylation in Intron 7 was observed in stress-related conditions thus the purpose of this pilot study was to investigate FKBP5 methylation levels at Intron 7 in schizophrenia. Methods Ethnically homogeneous Serbian sample of 24 schizophrenia spectrum patients and 24 controls matched by age and gender with patients’ group, were analyzed regarding DNA methylation levels at three CpG sites and average methylation level in Intron 7. Accordingly, we covered the area of GRE that has been reported to be associated with altered stress responsiveness. Epigenetic changes in FKBP5 Intron 7 were measured by Sanger sequencing and compared between the groups using t test as appropriate. Results Analyses revealed decreased FKBP5 methylation at the three targeted CpG sites (CpG1, CpG2, and CpG3) in patients compared to controls (p=0.026, p=0.017, and p=0.027, respectively). Similarly, when we averaged methylation scores of the observed region in Intron 7, significant demethylation was detected in patients (p=0.003). Discussion To the best of our knowledge this is the first study which explored FKBP5 epigenetic changes in schizophrenia. Conclusively to previous stress-related conditions, our preliminary results revealed significant decrease of FKBP5 methylation levels in Intron 7 in patients with schizophrenia. FKBP5 demethylation presents further insight into the reported FKBP5 genetic influence in psychosis and could be promising terapeutic target for the prevention of the onset and the course of schizophrenia.

Is Electroconvulsive Therapy Improving Executive Functions in Unipolar Depression Patients

In an acute episode of unipolar depression, patients show lower performance on the tests which make substantial demands on executive functions. Several studies documented that the impairment sometimes remains even in remitted patient, partially due to the antidepressant side effects or ECT. The aim of the present study was to evaluate executive functions in subjects who underwent ECT for therapy-resistant depression. Methods A course of bilateral ECT (mean number of applications 8.8+/-3.2) was applied to 22 patients (age 46.3±9.8; males 45.8%;IQ 97.2±11.6) with baseline HAMD 28.5±3.6, DASS 95±15, MMSE 29.1±1,1, who were tested by Sockings of Cambridge (SOC) tests (Cambridge Automated Neuropsychological Test Battery)at baseline (T0), immediately after ECT (T1) and one month later (T2). ECT was delivered with a modern square-wave machine with EEG and ECG monitoring. Modified treatment was performed in all cases. Results The intensity of depressive symptoms (HAMD and DASS) was significantly reduced at T1 and T2in comparison to baseline (p Conclusion ECT reduced depression without impairing executive function. As it is less likely that improvement in mean thinking time on SOC is directly associated with ECT, we suggest that improved execution is rather due to the decreased individual sensitivity to negative feedback during performing the task.