D. Vasile

P.2.b.020 Comparative analysis of pregabalin and buspirone as adjunctive agents in major depressive disorder partially responsive to SSRIs

The aim of the present study was to preliminarily evaluate the role of two genes involved in neuroplastic processes in early response to ADs: the Brain derived neurotrophic factor (BDNF) coding for a major prosurvival factor in the brain, and Sialyltransefarase X (ST8SIA2), which product modulates the adhesive properties of Neural cell adhesion molecule (NCAM). We also tested potential differential effect of genetic variants depending on environmental stress exposure. Methods: The sample was composed by 114 patients affected by Mood or Anxiety disorders, enrolled for treatment with ADs, with at least minor depression (scoring 8 or more at the Hamilton Rating Scale for Depression, HRSD). All patients were asked to fill out a questionnaire for stressful life events (SLEs) designed to evaluate events in young age (less than 15 years old), the year before illness onset, and the month preceding current episode. All the patients were evaluated at baseline and weekly thereafter until the fourth week by the HRSD. Subjects were genotyped for 3 single-nucleotide polymorphisms (SNPs) in BDNF and 5 in ST8SIA. Linkage disequilibrium among SNPs was calculated by Haploview software and haplotypes were obtained by the R-software. The GLM model was employed to test the effect of alleles and haplotypes, crossed with exposure to stress, on % improvement of symptoms from baseline. Results: SLEs did not impact significantly early response to ADs. Alleles in two SNPs in BDNF (rs11030101 A-allele and rs11030104 G-allele) and alleles in two SNPs in ST8SIA2 (rs11853992-A allele and rs17522085-T) were associated to a slower response to ADs only if non-exposed to onset SLEs, whilst they had a similar response compared to the carriers of the opposite variant if exposed to onset SLEs (all p< 0.007). Haplotype analyses confirmed these trends. Conclusions: According to our data, variants in BDNF and ST8SIA may influence differentially the early response to ADs depending on exposure to SLEs at illness onset. Exposure to stress may impact the transcriptional activity of genes through epigenetic mechanisms, resulting in unexpected phenotypes. Further, recent animal studies reported that an over expression of BDNF may have detrimental effects [1], and some studies in humans found heterozygous for the most investigated BDNF rs6265 SNP having a better response to ADs [2]. The complex interplay between genetic effects, environmental factors, as well as other biological systems deserves further investigation by means of sophisticated methods of investigation.

P.3.d.028 Effectiveness and tolerability of nalmefene in alcohol use dependence comorbid with schizophrenia

Background: Patients with schizophrenia have a lifetime prevalence of comorbid use disorder of 50% with alcohol having a negative effect on brain structure and function evident in this dual diagnosed population [1]. An administered as-needed drug could be provocative in a sensitive population in terms of insight like that of schizophrenia diagnosed patients. Nalmefene is associated with favorable response in alcohol use disorders and decrease the substance consumption [2] and the same drug was used as augmentation treatment in antipsychotic-stabilized schizophrenic patients with some positive results [3]. Objective: To assess the efficacy of pharmacological management with nalmefene in alcohol dependence and chronic schizophrenia dual diagnosed patients. Methods: A group of 22 patients, 12 female and 10 male, mean age 44.2, diagnosed with schizophrenia and alcohol dependence, according DSM IV TR criteria, were admitted to our department for an exacerbation of schizophrenia. After a mean duration of 2.7 weeks of psychotic symptoms stabilization under treatment with an atypical antipsychotic (olanzapine n = 13, risperidone n = 6, amisulpride n = 3), they received also treatment with nalmefene orally 18mg taken as needed. Patients’ alcohol consumption was evaluated at baseline and every 4 weeks for 6 months using Inventory of Drug Taking Situations − alcohol focused version (IDTS) and gamma-glutamyl transpeptidase level (GGT). With the same frequency we applied Positive and Negative Syndrome Scale (PANSS), Global Assessment of Functioning (GAF) and Clinical Global Impressions − Severity/Improvement (CGI-S/I). Inclusion criteria: high drinking risk level (alcohol >60 g/day for men and >40 g/day for women), IDTS score over 100, age between 18 and 65. Exclusion criteria: previous treatment with nalmefene, positive pregnancy test, alcohol withdrawal symptoms, other comorbid axis I disorder (including other drug related/induced disorders) or axis III chronic pathology. Intent-to-treat-analysis and last-observationcarried-forward were used in the statistical processing of data. Results: At week 24, patients had an overall improved PANSS score of 15.4% reported to baseline, with an IDTS score amelioration of 25.4 points at endpoint (p< 0.05) and a greater improvement was observed in the area of ‘physical discomfort’ (p = 0.032). The GGT level decrease with 70% at week 8, had a fluctuant evolution after that, but at week 24 the value was significantly lower compared to baseline (p = 0.002). CGI-S decreased from a mean value of 4.2 to 1.8 at week 24 and the GAF scores increased with 11.5% at endpoint. A number of 4 patients discontinued treatment due to either adverse events (vomiting, nausea, abdominal pains, n = 3) or non-adherence (n = 1). Mild and moderate adverse events were reported in 12 patients, especially gastro-intestinal discomfort and sedation. Conclusions: Nalmefene could be used in schizophrenia diagnosed patients with alcohol dependence, due to its efficacy and relatively low rate of adverse events. Nalmefene decreased significantly alcohol consumption in situations of ‘physical discomfort’. The psychotic symptoms features had an overall good evolution during the combined antipsychotic and nalmefene treatment.