Martina Rojnic Kuzman

MDR1 gene polymorphism: therapeutic response to paroxetine among patients with major depression.

The multidrug resistance transporter, P-glycoprotein (P-gp), encoded by polymorphic MDR1 (ABCB1) gene, is involved in efflux transport of several antidepressants and acts as a barrier to different exogenous noxa in the blood-brain barrier. MDR1 gene belongs to the best understood mediators of drug resistance. Different polymorphisms in MDR1 have been found to be connected with P-gp expression and function. The aims of the study were to investigate the potential influence of MDR1 polymorphisms, exon 26 C3435T and exon 21 G2677T/A, on treatment response to paroxetine (20 mg/day) in patients with major depression. To assess and evaluate therapeutic response to paroxetine, all patients were rated weekly using the HAMD-17 scale. Responders were defined as subjects with a decrease in HAMD scale by >or=50% at week 6 of treatment. The study population included 127 patients with major depression (diagnosed by Structured Clinical Interview for DSM-IV disorders). Our results indicated that MDR1 variants G2677T and C3435T are not associated with therapeutic response to paroxetine in patients with major depressive disorder. The associations between paroxetine and P-glycoprotein still need to be clarified.

Genome-wide expression analysis of peripheral blood identifies candidate biomarkers for schizophrenia

The aim of this study was to analyze gene expression in blood of patients with newly-diagnosed schizophrenia during their first psychotic episode and subsequent remission. Whole blood samples were obtained from 32 untreated patients presenting with their first psychotic episode suggestive of schizophrenia and 32 age- and gender-matched controls. Using Affymetrix micoarrays, we identified significantly altered expression of 180 gene probes in psychotic patients compared to controls. A subset of four significantly changed genes was further confirmed with QRT-PCR. The following genes were significantly altered in patients: glucose transporter, SLC2A3 (p<0.001) and actin assembly factor DAAM2 (p<0.001) were increased, whereas translation, zinc metallopeptidase, neurolysin 1 and myosin C were significantly decreased (p<0.05). Expression of these candidate markers was also analyzed in a longitudinal study (12-24 months) in 12 patients who achieved full remission. Interestingly, expression of DAAM2 returned to control levels in patients who were in remission after their first psychotic episode, suggesting that its expression correlates with diseases progression and/or response to treatment. In summary, we identified changes of gene expression from peripheral blood which might help discriminate patients with schizophrenia from controls. While these results are promising, especially for DAAM2 whose polymorphic variants have been found significantly associated with schizophrenia, it will be important to analyze larger cohorts of patients in order to firmly establish changes in gene expression as blood markers of schizophrenia.

The influence of 5-HT2C and MDR1 genetic polymorphisms on antipsychotic-induced weight gain in female schizophrenic patients

We investigated the relationships between functional genetic variants of the 5-HT(2C) receptor and multidrug-resistant protein (MDR1), coding for P-glycoprotein, and second generation antipsychotic (SDA)-induced weight gain among 108 female schizophrenic patients treated with olanzapine or risperidone for up to 4 months. No significant differences in -759C/T allelic and genotype variants of 5-HT(2C) were found between patients who gained more than 7% of their initial weight compared with those who gained less. Haplotype-based analysis of two MDR1 loci, exon 21 G2677T and exon 26 C3435T, revealed a slightly lower representation of the G2677/C3435 haplotype in the >or=7% group. In the subgroup of patients treated with risperidone, we found borderline overrepresentation of 2677T, significant overrepresentation of 3435T variant and borderline overrepresentation of 2677T/3435T haplotype the >or=7% group, whereas G2677/C3435 haplotype was found to be less represented in the >or=7% group. Our data indicate a nonsignificant role of 759C/T 5-HT(2C) in SDA-induced weight gain, and a stronger influence of the MDR1 G2677T and C3435T polymorphisms on risperidone-induced weight gain in female schizophrenic patients. 3435T and 2677T MDR1 variants, both associated with lower P-gp function, might predispose to higher risperidone accessibility to the brain that would lead to stronger effects, including weight gain.

Association study of olanzapine-induced weight gain and therapeutic response with SERT gene polymorphisms in female schizophrenic patients

We investigated the relationships between L/S promoter (SERTPR) and l/s intron2 (SERTin2) genetic variants of serotonin transporter (SERT) polymorphisms with olanzapine-induced weight gain and treatment response in 94 female schizophrenic patients treated with olanzapine for up to 3 months. Body mass index (BMI) was calculated for each patient prior to olanzapine administration and 3 months afterwards. To assess and evaluate improvement of clinical psychotic symptoms and therapeutic response to the antipsychotic, all patients were rated using the Positive and Negative Syndrome ScaLe (PANSS). Overall, the presence of S SERTPR allelic variant and SS genotype was associated with significantly higher weight gain in subjects who were non-obese at the time of admission. The presence of L SERTPR variant was associated with significantly better treatment response measured with total PANSS and general PANSS subscale, while the presence of l SERTin2 variant determined better treatment response only in several items. No evidence of linkage disequilibrium between the two loci was found in the sample. These findings identify genetic factors associated with oLanzapine-induced weight gain and treatment response in femaLe schizophrenic patients.

Association study of MDR1 and 5-HT2C genetic polymorphisms and antipsychotic-induced metabolic disturbances in female patients with schizophrenia

The objective of this study was to determine the association of 5-HT2C (serotonin 2C receptor) and MDR1 (multidrug resistant protein) genetic polymorphisms and antipsychotic-induced metabolic abnormalities among female patients with DSM IV schizophrenia spectrum disorders. We have previously reported the associations of −759CT 5-HT2C and G2677T and C3435T MDR1 genetic polymorphisms and olanzapine/risperidone-induced weight gain in a similar sample of patients. Here, we included a total of 101 previously non-medicated female patients treated with olanzapine/risperidone over a 3-month period. The variables analyzed included fasting glucose, total cholesterol, low-density lipoprotein, high-density lipoprotein and triglyceride levels in blood, blood pressure and waist circumferences. We observed significant association of −759T 5-HT2C genetic variant and greater increase in waist circumference (P=0.03), fasting glucose level (P=0.046) and triglyceride level (P=0.045) in blood after a 3-month period. The 2677T and 3435T MDR1 genetic variants were significantly associated with the greater increase in fasting glucose level in blood when patients were using olanzapine (P<0.001 and P=0.028, respectively). Our data indicate a possible influence of −759CT 5-HT2C and MDR1 G2677T and C3435T MDR1 genetic polymorphisms on the development of metabolic abnormalities among female patients treated with olanzapine/risperidone.

Mental Health Reforms in Europe: Challenges of Postgraduate Psychiatric Training in Europe: A Trainee Perspective

The European Federation of Psychiatric Trainees (EFPT) is an umbrella organization for trainee associations in 31 countries. A survey asked member countries about the three most important issues facing postgraduate training. Qualitative analysis grouped responses in five categories: implementation of new postgraduate curricula, poor working conditions, low recruitment of psychiatric trainees, insufficient training opportunities, and inadequate psychotherapy training. Disparities between countries lead to trainee migration, which worsens conditions in their home countries. The EFPT is in a unique position to obtain feedback and work with partner organizations to improve the standards of psychiatric training for European trainees.

Challenges for trainees in psychiatry and early career psychiatrists.

Abstract Psychiatry as a discipline will undergo major changes in the coming years. Although changes can be particularly stimulating and challenging from an intellectual, scientific and social viewpoint, the new generations of psychiatrists must be prepared to face these changes and deal with them appropriately. Paradigms which have represented the foundations of psychiatry in the last century now need a major revision. In particular, both trainees in psychiatry and early career psychiatrists need to (1) (re)discover psychopathology, (2) improve mental healthcare through integrated treatments, (3) identify and treat new syndromes, (4) promote an image of psychiatry with patients at the heart of care and as advocates for each other by fighting stigma and promoting the recruitment in psychiatry by medical students. These can be achieved by increasing involvement in institutions and organizations to influence the agenda. In this paper the possible contribution of trainees and early career psychiatrists is discussed and recommendations are made in order to set a new agenda for early career psychiatrists who will still be practising 2–3 decades from now.

Association between lamotrigine concentrations and ABCB1 polymorphisms in patients with epilepsy.

Background: Epilepsy is treated with a variety of anticonvulsants that are often used concomitantly. Therefore, therapeutic drug monitoring is often necessary. Along with clinical and environmental factors, genetic predisposition has been recognized to be relevant for interindividual variability in drug response. Polymorphic transporter proteins such as P-glycoprotein significantly influence pharmacokinetics and bioavailability of many structurally unrelated drugs. The aim of the study was to evaluate the impact of polymorphisms in the P-glycoprotein–encoding gene ABCB1 (C1236T, G2677T/A, C3435T) on antiepileptic drug disposition. Methods: We recruited 222 patients with epilepsy who were prescribed lamotrigine in monotherapy or polytherapy. Lamotrigine plasma concentrations were analyzed and compared with ABCB1 gene variants. The ABCB1 genotyping was performed by real-time polymerase chain reaction methods. The therapeutic drug monitoring was performed by high-performance liquid chromatography–diode array detector (DAD) and immunoassay. Results: A significant correlation was confirmed between lamotrigine concentration and additional drugs (P < 0.001). In the whole group, statistical analysis showed correlations between lamotrigine concentrations and ABCB1 C1236T variants: 10.1 and 6.5 &mgr;mol/L for CC versus CT + TT, respectively (P = 0.021), and for dose corrected lamotrigine 0.068 and 0.053 &mgr;mol·L−1·mg−1, for CC versus CT + TT, respectively (P = 0.017). Analysis of a specific haplotype showed that 1236C–2677G–3435C carriers had higher lamotrigine concentrations than 1236T–2677G–3435T carriers (P < 0.001), followed by 1236T–2677T–3435C carriers (P < 0.001). Conclusions: ABCB1 C1236T, G2677T/A, C3435T polymorphisms have an influence on lamotrigine serum concentrations.

Metabolic syndrome in female patients with schizophrenia treated with second generation antipsychotics: a 3-month follow-up.

The objective of this study was to determine the occurrence of metabolic abnormalities among previously unmedicated female patients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition schizophrenia spectrum disorders and their associations with olanzapine and risperidone treatment. We analysed 94 female patients who were treated with olanzapine or risperidone in the period of 3 months. Analysed variables included fasting glucose, total cholesterol, low-density lipoprotein (LDL), high-density lipoproteins and triglycerides in blood, blood pressure (BP), waist and hip circumferences and body mass index (BMI). At baseline, 14 patients (15%) fulfilled criteria for metabolic syndrome. After 3 months of treatment, 25 patients (27%) fulfilled criteria for metabolic syndrome, and their baseline BMI was the only predictor for its development. Treatment with both antipsychotics was associated with significant increase in waist circumference. Positive family history of diabetes mellitus contributed to a significant greater increase in abdominal obesity, significant higher baseline levels and a borderline significant increase in fasting glucose among olanzapine-treated patients. Olanzapine admission was associated with a significant increase in LDL and risperidone with a significant increase in triglycerides. Metabolic abnormalities seem to be more prevalent in unmedicated female patients with schizophrenia spectrum disorders than expected based on results in general population (adjusted for age and sex). Olanzapine treatment might induce significant alterations in metabolic profiles, especially among patients with positive family history of diabetes, mostly by inducing abdominal obesity. The association of risperidone application and increase in triglyceride level still needs to be determined.

Development of the PICMIN (picture of mental illness in newspapers): instrument to assess mental illness stigma in print media

PurposeThe aim of this paper is to report on the development and applicability of a standardised and objective measure of stigma of mental illness in print media. Picture of mental illness in newspapers (PICMIN) instrument consists of eleven descriptive and five analytical categories. It is intended to allow comparison among countries and different studies over time.MethodsThe research team conducted a three-phase study to develop the instrument based on the principles of content analysis and test its inter-coder reliability (ICR). In the first phase, keyword search and ICR assessment was performed on articles from Croatia (75), Czech Republic (203), and Slovakia (172). The second phase consisted of instrument revision and training, along with ICR reassessment on 40 articles from USA and UK. In the third, main phase articles from Croatia (238), Czech Republic (226), and Slovakia (158) were analysed with the final version of the PICMIN instrument.ResultsAcross three countries, ICR was found acceptable to assess mental illness representations related to stigma in print media. Print media representations of the mental illness in Croatia, Czech Republic, and Slovakia significantly differed in the type of media distribution, whether headline of the article was positioned on the media cover, in the use of a sensationalistic style of writing, in the association of aggressive behaviour with persons with mental illness and in the distribution of the global impression of the headline.ConclusionsPICMIN instrument allows comparison among countries and different studies over time.