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The EUGEI project was supported by the European Community's Seventh Framework Program under grant agreement No. HEALTH-F2-2009-241909 (Project EU-GEI). Dr O'Donovan is supported by MRC programme grant (G08005009) and an MRC Centre grant (MR/L010305/1), Henquet, C., Van Os, J., Pries, L.K., Rauschenberg, C., Delespaul, P., Kenis, G., Luykx, J.J., Lin, B.D., Richards, A.L., Akdede, B., Binbay, T., Altlnyazar, V., Yallnçetin, B., Gümüş-Akay, G., Cihan, B., Soygür, H., Ulaş, H., Cankurtaran, E.S., Kaymak, S.U., Mihaljevic, M.M., Petrovic, S.S., Mirjanic, T., Bernardo, M., Mezquida, G., Amoretti, S., Bobes, J., Saiz, P.A., Garciá-Portilla, M.P., Sanjuan, J., Aguilar, E.J., Santos, J.L., Jiménez-López, E., Arrojo, M., Carracedo, A., López, G., González-Penãs, J., Parellada, M., Maric, N.P., Atbaşoelu, C., Ucok, A., Alptekin, K., Saka, M.C., Arango, C., O'Donovan, M., Rutten, B.P.F., Gülöksüz, S.

BackgroundThere is evidence that environmental and genetic risk factors for schizophrenia spectrum disorders are transdiagnostic and mediated in part through a generic pathway of affective dysregulation.MethodsWe analysed to what degree the impact of schizophrenia polygenic risk (PRS-SZ) and childhood adversity (CA) on psychosis outcomes was contingent on co-presence of affective dysregulation, defined as significant depressive symptoms, in (i) NEMESIS-2 (n = 6646), a representative general population sample, interviewed four times over nine years and (ii) EUGEI (n = 4068) a sample of patients with schizophrenia spectrum disorder, the siblings of these patients and controls.ResultsThe impact of PRS-SZ on psychosis showed significant dependence on co-presence of affective dysregulation in NEMESIS-2 [relative excess risk due to interaction (RERI): 1.01, p = 0.037] and in EUGEI (RERI = 3.39, p = 0.048). This was particularly evident for delusional ideation (NEMESIS-2: RERI = 1.74, p = 0.003; EUGEI: RERI = 4.16, p = 0.019) and not for hallucinatory experiences (NEMESIS-2: RERI = 0.65, p = 0.284; EUGEI: −0.37, p = 0.547). A similar and stronger pattern of results was evident for CA (RERI delusions and hallucinations: NEMESIS-2: 3.02, p < 0.001; EUGEI: 6.44, p < 0.001; RERI delusional ideation: NEMESIS-2: 3.79, p < 0.001; EUGEI: 5.43, p = 0.001; RERI hallucinatory experiences: NEMESIS-2: 2.46, p < 0.001; EUGEI: 0.54, p = 0.465).ConclusionsThe results, and internal replication, suggest that the effects of known genetic and non-genetic risk factors for psychosis are mediated in part through an affective pathway, from which early states of delusional meaning may arise.

European Community's Seventh Framework Program, European Commission [HEALTH-F2-2009-241909]; Scientific and Technological Research Council of Turkey, 2219 International Postdoctoral Research Fellowship Program; Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III (SAM16PE07CP1, PI16/02012, and PI19/024)..., Erzin, G., Pries, L.-K., van Os, J., Fusar-Poli, L., Delespaul, P., Kenis, G., Luykx, J.J., Lin, B.D., Richards, A.L., Akdede, B., Binbay, T., Altınyazar, V., Yalınçetin, B., Gümüş-Akay, G., Cihan, B., Soygür, H., Ulaş, H., Cankurtaran, E.Ş., Kaymak, S.U., Mihaljevic, M.M., Andric-Petrovic, S., Mirjanic, T., Bernardo, M., Mezquida, G., Amoretti, S., Bobes, J., Saiz, P.A., García-Portilla, M.P., Sanjuan, J., Aguilar, E.J., Santos, J.L., Jiménez-López, E., Arrojo, M., Carracedo, A., López, G., González-Peñas, J., Parellada, M., Maric, N.P., Atbaşoğlu, C., Ucok, A., Alptekin, K., Saka, M.C., Arango, C., O'Donovan, M.C., Rutten, B.P.F., Guloksuz, S., Genetic Risk and Outcome of Psychosis (GROUP) investigators

The EUGEI project was supported by the European Community’s Seventh Framework Program under grant agreement no. HEALTH-F2-2009-241909 (Project EU-GEI). Dr O’Donovan is supported by MRC programme grant (G08005009) and an MRC Centre grant (MR/ L010305/1). Dr Rutten was funded by a VIDI award number 91718336 from the Netherlands Scientific Organisation. Drs Guloksuz and van Os are supported by the Ophelia research project, ZonMw grant number: 636340001. Dr Arango was supported by the Spanish Ministry of Science and Innovation; Instituto de Salud Carlos III (SAM16PE07CP1, PI16/02012, PI19/024); CIBERSAM; Madrid Regional Government (B2017/BMD-3740, AGES-CM-2); Fundación Familia Alonso and Fundación Alicia Koplowitz., Pries, L.-K., Dal Ferro, G.A., Van Os, J., Delespaul, P., Kenis, G., Lin, B.D., Luykx, J.J., Richards, A.L., Akdede, B., Binbay, T., Altlnyazar, V., Yallnçetin, B., Gümüş-Akay, G., Cihan, B., Soygür, H., Ulaş, H., Åžahin Cankurtaran, E., Ulusoy Kaymak, S., Mihaljevic, M.M., Andric Petrovic, S., Mirjanic, T., Bernardo, M., Mezquida, G., Amoretti, S., Bobes, J., Saiz, P.A., Garciá-Portilla, M.P., Sanjuan, J., Aguilar, E.J., Santos, J.L., Jiménez-López, E., Arrojo, M., Carracedo, A., López, G., González-Penãs, J., Parellada, M., Maric, N.P., AtbaşoÄalu, C., Ucok, A., Alptekin, K., Can Saka, M., Arango, C., O'Donovan, M., Tosato, S., Rutten, B.P.F., Guloksuz, S., and Genetic Risk and Outcome of Psychosis (GROUP) investigators

The EUGEI project was supported by the European Community’s Seventh Framework Program under grant agreement No. HEALTH-F2- 2009-241909 (Project EU-GEI). Dr. Arango was supported by the Spanish Ministry of Science and Innovation; Instituto de Salud Carlos III (SAM16-PE07CP1, PI16/02012, PI19/024); CIBERSAM (...), Fusar-Poli, L; Pries, LK; van Os, J; Erzin, G; Delespaul, P; Kenis, G; Luykx, JJ; Lin, BCD; Richards, AL; Akdede, B; Binbay, T; Altinyazar, V; Yalincetin, B; Gumus-Akay, G; Cihan, B; Soygur, H; Ulas, H; Cankurtaran, ES; Kaymak, SU; Mihaljevic, MM; Andric-Petrovic, S; Mirjanic, T; Bernardo, M; Mezquida, G; Amoretti, S; Bobes, J; Saiz, PA; Garcia-Portilla, MP; Sanjuan, J; Aguilar, EJ; Santos, JL; Jimenez-Lopez, E; Arrojo, M; Carracedo, A; Lopez, G; Gonzalez-Penas, J; Parellada, M; Maric, NP; Atbasoglu, C; Ucok, A; Alptekin, K; Saka, MC; Aguglia, E; Arango, C; O'Donovan, M; Rutten, BPF; Guloksuz, S

Clozapine (CLZ) is considered the most effective antipsychotic, but its use is associated with neutropenia (CIN) and agranulocytosis (CIA). Although the exact etiology of these hazardous side effects is unknown, 4 genetic polymorphisms have been implicated by genome-wide association studies (GWAS), mostly performed in North-Western Europeans. These polymorphisms are rs113332494 (HLA-DQB1), rs41549217 (HLA-B), and rs1546308/rs149104283 (SLCO1B3/7), several of which were not directly genotyped but imputed. To test whether these 4 single-nucleotide polymorphisms (SNPs) are associated with CIN/CIA in a Turkish population and in a more extensive group of Caucasians, we directly genotyped these polymorphisms using Taqman and Sanger sequencing and performed logistic regression. We divided our participants (234 CLZ-using participants of whom 31 CIN/CIA cases) into (1) North-Western European, (2) Turkish, (3) Caucasian (=1 + 2); and (4) a total group (Caucasian + other ethnicities). Rs113332494 (HLA-DQB1) was significantly associated with CIN/CIA in the total group (P = 3.5 × 10−8), in the Caucasian group (P = 9.3 × 10−6) and in the Turkish group (P = 2.8 × 10−5). Rs41549217 (HLA-B) was nominally significant in the Caucasian group (P = .018). In meta-analysis of our results and the previously reported genome-wide results, 3 SNPs were significantly associated with CIN/CIA in participants with Caucasian ancestry: rs113332494 (P = 2.05 × 10−8), rs41549217 (P = 7.19 × 10−9), and rs149104283 (P = 5.54 × 10−9), with the result for rs1546308 (SCLO1B3/SCLO1B7) being significantly heterogeneous across studies. Our results hint at ethnicity-dependent and clinically relevant effects of genetic polymorphisms on the risk to develop CIN/CIA. Pharmacogenetic testing can complement clinical decision making and thus empower appropriate CLZ prescribing, but ancestry should be taken into account when performing such testing for CLZ.

BackgroundFirst-degree relatives of patients with psychotic disorder have higher levels of polygenic risk (PRS) for schizophrenia and higher levels of intermediate phenotypes.MethodsWe conducted, using two different samples for discovery (n = 336 controls and 649 siblings of patients with psychotic disorder) and replication (n = 1208 controls and 1106 siblings), an analysis of association between PRS on the one hand and psychopathological and cognitive intermediate phenotypes of schizophrenia on the other in a sample at average genetic risk (healthy controls) and a sample at higher than average risk (healthy siblings of patients). Two subthreshold psychosis phenotypes, as well as a standardised measure of cognitive ability, based on a short version of the WAIS-III short form, were used. In addition, a measure of jumping to conclusion bias (replication sample only) was tested for association with PRS.ResultsIn both discovery and replication sample, evidence for an association between PRS and subthreshold psychosis phenotypes was observed in the relatives of patients, whereas in the controls no association was observed. Jumping to conclusion bias was similarly only associated with PRS in the sibling group. Cognitive ability was weakly negatively and non-significantly associated with PRS in both the sibling and the control group.ConclusionsThe degree of endophenotypic expression of schizophrenia polygenic risk depends on having a sibling with psychotic disorder, suggestive of underlying gene–environment interaction. Cognitive biases may better index genetic risk of disorder than traditional measures of neurocognition, which instead may reflect the population distribution of cognitive ability impacting the prognosis of psychotic disorder.

Supported by the European Community’s Seventh Framework Program under grant agreement No. HEALTH-F2-2009-241909 (Project EU-GEI), Schepers, E., Lousberg, R., Guloksuz, S., Pries, L.-K., Delespaul, P., Kenis, G., Luykx, J.J., Lin, B.D., Richards, A.L., Akdede, B., Binbay, T., Altınyazar, V., Yalınçetin, B., Gümüş-Akay, G., Cihan, B., Soygür, H., Ulaş, H., Cankurtaran, E.Ş., Kaymak, S.U., Mihaljevic, M.M., Petrovic, S.A., Mirjanic, T., Bernardo, M., Cabrera, B., Bobes, J., Saiz, P.A., García-Portilla, M.P., Sanjuan, J., Aguilar, E.J., Santos, J.L., Jiménez-López, E., Arrojo, M., Carracedo, A., López, G., González-Peñas, J., Parellada, M., Maric, N.P., Atbaşoğlu, C., Ucok, A., Alptekin, K., Saka, M.C., Arango, C., Rutten, B.P.F., van Os, J.

Long-term exposure to organophosphate pesticides (OPs) without acute poisoning can lead to various OPs. Environmental exposure to organophosphate pesticides may be associated with depression and suicide attempts in a population living in a rural agricultural area. Patients (n = 149) suffering from major depressive disorder (with and without attempted suicide) and a control group of healthy individuals (n = 64) who had been living in the same rural district for at least 1 year were selected. Red blood cell acetylcholine esterase (RBC-AChE) activity was examined as the basis of evaluating the degree of chronic environmental exposure to OPs residues. There were negative association between RBC-AChE activity levels and suicide attempts, the number of past suicide attempts and hopelessness levels in the depressive patients. The results of the study may support the idea that environmental exposure to OPs may be associated with mental health in individuals living in agricultural districts who are not farmers or working in occupations with access to OPs.

Tinaz, Ekrem ( Aksaray, Yazar ), Objective: The dopaminergic system, especially variations in the catechol-O-methyltransferase (COMT) gene, is of major interest in the etiology of schizophrenia. The rs4680 (Val108/158Met), rs165599, and P2 promoter rs2075507 single nucleotide polymorphisms (SNPs) in the COMT gene have been shown to be associated with alteration of COMT gene expression and COMT enzyme activity. The aim of this study was to investigate a possible association between schizophrenia and the haplotypes of these polymorphisms. Methods: The sample was comprised of 181 patients with schizophrenia and 368 healthy controls. The patients' psychotic symptoms were rated using the Positive and Negative Symptom Scale (PANSS). COMT rs2075507, rs4680, and rs165599 SNPs were evaluated by a polymerase chain reaction, followed by restriction fragment length polymorphism analysis. These SNPs in the COMT gene were subjected to haplotype analyses using Haploview ver. 4.2. Results: No significant differences were found between COMT rs2075507, rs4680, and rs165599 SNPs in schizophrenic patients and controls. The patients' PANSS results were not associated with these SNPs. No associations were obtained between 2 and 3-haplotypes of rs2075507, rs4680, rs165599 SNPs and schizophrenia. Conclusion: COMT rs2075507, rs4680, rs165599 SNPs and haplotypes do not appear to be risk factors for schizophrenia in this population.

Objective: The dopaminergic and glutamatergic systems are of major interest in the etiology of schizophrenia and supposed endophenotypes such as personality traits. In the present study, we investigated the association between the catechol-O-methyltransferase (COMT) gene P2 promoter rs2075507, Val/Met (rs4680), the dopamine transporter gene (DAT1) VNTR and the glutamate transporter gene (SLC1A2) promoter -181A/C polymorphisms, and personality traits as well as symptomatic features in schizophrenia. Methods: There were 112 healthy subjects, 51 schizophrenic patients in remission for at least six months and 45 first-degree relatives of the patients enrolled in the study. The samples were genotyped for the COMT P2 promoter rs2075507, Val/Met, DAT1 VNTR and SLC1A2 promoter -181A/C polymorphisms and assessed with the Temperament and Character Inventory (TCI). Schizophrenia patients were also evaluated using the Operational Criteria Checklist for Psychotic Illness (OPCRIT) for each of the five factor-derived scales (negative symptoms, delusions, hallucinations, mania, and depression) and The Positive and Negative Symptom Scale. Results: Our findings demonstrate that schizophrenic patients, even after remission, had a different personality pattern from controls, showing higher scores in harm avoidance and self-transcendence and lower scores in novelty seeking, persistence, self-directedness and cooperativeness. First-degree relatives of patients also had profiles distinguishable from those of the patients only by intermediate levels of harm-avoidance and higher levels of cooperativeness. In the association of genotypes and personality, COMT Val/Met polymorphism was not associated with personality in patients or in healthy subjects. Another functional polymorphism in the COMT gene the P2 promoter rs2075507 G allele was associated with significantly higher novelty seeking scores in patients than was the A allele. DAT1 VNTR long alleles (10 or 11 repeats) were demonstrated to show a non-significant trend to association with higher self-transcendence scores than in those with the short alleles (3, 7, 8 or 9 repeats) in control samples and patients. In SLC1A2 promoter -181A/C polymorphism, the C allele was significantly associated with higher self-transcendence scores than in those with the A allele in healthy subjects. We did not find any associations between the psychotic symptom dimensions of patients and DAT1 VNTR, SLC1A2 promoter -181A/C and COMT Val/Met polymorphism; however, COMT P2 promoter rs2075507 polymorphism showed an association with the delusion and mania factor scores. Conclusions: Schizophrenia may be associated with different personality patterns from controls and some personality dimensions may be associated with the appearance of psychotic symptoms. The same genes may be responsible for the development of the disease, with personality patterns seen in at least one group of patients.

The treatment of sleep disorders in Alzheimer’s disease (AD) may be quite challenging in elderly patients because of drug side effects or interactions and comorbid local or systemic diseases. Here, we report a patient with AD, who was suffering from severe insomnia and depression. We ordered agomelatine for the treatment of insomnia in this patient, and it was quite helpful not only for insomnia but also for depression and for the cognitive symptoms related with dementia. Our aim was to share these observations for similar patients.

Pek cok tedavi klavuzu sizofrenide monoterapiyi onermesine karsin, klinik pratikte birden fazla antipsikotik kullanimi, ozellikle tedaviye direncli sizofrenide sik karsilasilan bir durumdur. Litera...

Objective: The aim of this study was to investigate the effect of prolactin levels, duration of disease, accompanying metabolic syndrome, use of mood stabilizer drugs, smoking and exercise on bone mineral density (BMD) in patients treated with antipsychotics. Methods: Fifty-six patients who had been diagnosed with schizophrenia, forty-one patients who had been diagnosed with schizoaffective disorder and thirty three patients who had been diagnosed with bipolar disorders were included the study. BMD was measured at the lumbar spine and femoral sites using dual energy x-ray absorptiometry (DEXA). Arterial blood pressure, waist circumference, fasting glucose, HDL cholesterol and triglyceride levels of the patients were measured for diagnosis of metabolic syndrome. The age, weight, height, smoking habits, regular physical exercise, additional mood stabilizer drugs administered and blood prolactin levels were recorded. Results: Results of 73 patients were osteopenia or osteoporosis. There was no statistically significant relationship between BMD and plasma prolactin level, using additional mood stabilizer drugs, dose of antipsychotic drugs and metabolic syndrome. There was negative correlation between duration of illness, duration of antipsychotic drug use and BMD of the femoral neck. There was negative correlation between duration of smoking and BMD of femoral intertrochanteric region. Lumbar BMD was significantly higher in patients exercising regularly than those of patients without regular physical exercise. Conclusion: Due to a sedantary lifestyle, pro-longed use of antipsychotic drugs and smoking risk of osteoporosis increases in patients with schizophrenia, schizo-affective disorder and bipolar disorder. BMD of these patients should be followed-up with regular intervals. (Ana-tolian Journal of Psychiatry 2019; 20(x):xx-xx)