Bokhan, N.

Bosker, F. J.

Ivanova, S.

Levchuk, L.

Loonen, A. J. M.

Losenkov, I.

Mikhalitskaya, E.

Ochi, T.

Osmanova, D.

Simutkin, G.

Vyalova, N.

Wilffert, B.

English

University of Groningen

   University of GroningenP.505 The potential role of BDNF and prolactin genotypes on antidepressant response indepressive patientsVyalova, N.; Ochi, T.; Losenkov, I.; Levchuk, L.; Osmanova, D.; Mikhalitskaya, E.; Loonen, A.J. M.; Bosker, F. J.; Simutkin, G.; Bokhan, N.Published in:European NeuropsychopharmacologyDOI:10.1016/j.euroneuro.2019.09.511IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2019Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Vyalova, N., Ochi, T., Losenkov, I., Levchuk, L., Osmanova, D., Mikhalitskaya, E., Loonen, A. J. M.,Bosker, F. J., Simutkin, G., Bokhan, N., Wilffert, B., & Ivanova, S. (2019). P.505 The potential role of BDNFand prolactin genotypes on antidepressant response in depressive patients. EuropeanNeuropsychopharmacology, 29(Suppl. 6), S355-S356. https://doi.org/10.1016/j.euroneuro.2019.09.511CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Abstracts S355 volved in the precipitation of suicidal behaviour. Recently variation in GABRA6 gene in interaction with stress showed an association with a constellation of phenotypes signifi- cantly increasing risk of suicide [1]. The CB1 endocannabi- noid receptor, encoded by the CNR1 gene involved in me- diating the effects of stress has been a promising obe- sity drug target, however, rimonabant, a molecule acting on this receptor significantly increased suicide risk. While suicide is a complex phenomenon with distinct risk fac- tors appearing in constellation patterns, different neuro- transmitter systems and neural elements may contribute to the modulation of suicide risk via influencing distinct related phenotypes. In our study we compared effects of two genetic variants in distinct neurochemical systems in interaction with recent stress on suicide-related risk phenotypes. Methods: Two-thousand-and-six subjects in a large gen- eral population sample participated in the study. The Brief Symptom Inventory [2] was used to evaluate symptoms re- lated to suicide risk. Life events occurring in the past one year were measured by the List of Threatening Experi- ences [3]. Participants provided buccal mucosa cells and were genotyped for GABRA6 rs3219151 and CNR1 rs776602 by Sequenom’s MassARRAY technology with IplexTM assay. Data were analysed using linear regression models testing gene-by-environment effects on each depression and anxi- ety symptom as the outcome variable with age and gender as covariates. FDR Q values were calculated to correct for multiple testing. Results: In interaction with recent stress, GABRA6 rs3219151 significantly influenced several depression- related suicide risk items in contrast to CNR1 rs7766029 (e.g. thoughts of ending life q = 0.008 vs q = 0.08; feeling hopeless about the future q = 0.024 vs q = 0.08; feelings of worthlessness q = 0.008 vs q = 0.08; feelings of guilt q = 0.007 vs q = 0.683, p values shown for GABRA6 rs3219151 and CNR1 rs7766029 respectively). In case of thoughts of death or dy- ing, however, CNR1 rs7766029 had a more pronounced ef- fect (q = 0.007 vs q < 0.001 for GABRA6 rs3219151 and CNR1 rs7766029 respectively). Only GABRA6 rs3219151 had an ef- fect on anxiety-related suicide risk factors including spells of panic (q < 0.0001), extreme restlessness (q < 0.001), or feeling tense or keyed up (q = 0.024). Discussion: Both GABRA6 rs3219151 and CNR1 rs7766029 had a strong effect on suicide risk-related phenotypes in in- teraction with recent stress, however with different symp- tom profiles. While GABRA6 rs3219151 increased risk of sev- eral phenotypes including on thoughts of ending life, feel- ings of worthlessness, hopelessness and guilt, and, unlike CNR1 rs7766029, also had a strong effect on intense rest- lessness and drive to act immediately, thoughts directly re- lated to death or dying had a more marked association with CNR1 rs7766029. Thus both GABRA6 and CNR1 are poten- tial targets for pharmacological intervention in suicide risk. Future studies should focus on distinct suicide risk profiles which may be decreased by intervention via distinct neural targets. Disclosure statement: Supported by MTA-SE Neuropsy- chopharmacology and Neurochemistry Research Group Hungarian Brain Research Program (2017-1.2.1-NKP-2017- 00002 KTIA_13_NAPA-II/14) National Development Agency (KTIA_NAP_13-1-2013-0001) MTA-SE-NAP B Genetic Brain Imaging Migraine Research Group (KTIA_NAP_13-2-2015- 0001). Xenia Gonda was supported by the Janos Bolyai Re- search Fellowship Program of the Hungarian Academy of Sci- ences, and by ÚNKP-18-4-SE-33 Peter Petschner by ÚNKP-17- 4-I-SE-8, and Nora Eszlari by ÚNKP-16-3 and ÚNKP-17-3-III- SE-2 of the New National Excellence Program of the Ministry of Human Capacities. References [1] Gonda, X., Sarginson, J., Eszlari, N., Petschner, P., Toth, Z.G., Baksa, D., Hullam, G., Anderson, I.M., Deakin, J.F.W., Juhasz, G., Bagdy, G., 2017. A new stress sensor and risk factor for suicide: the T allele of the functional genetic variant in the GABRA6 gene. Sci. Rep. 7 (1), 12887. [2] Derogatis, L.R., 1993. BSI: Brief Symptom Inventory: Admin- istration, Scoring, and Procedures Manual. National Computer Systems Pearson Inc., Minneapolis. [3] Brugha, T., Bebbington, P., Tennant, C., Hurry, J., 1985. The List of Threatening Experiences: a subset of 12 life event categories with considerable long-term contextual threat. Psychol. Med. 15 (1), 189–194. doi: 10.1016/j.euroneuro.2019.09.510 P.505 The potential role of BDNF and prolactin geno- types on antidepressant response in depressive pa- tients N. Vyalova 1 , ∗, T. Ochi 2 , I. Losenkov 3 , L. Levchuk 1 , D. Osmanova 1 , E. Mikhalitskaya 1 , A.J.M. Loonen 2 , F.J. Bosker 4 , G. Simutkin 3 , N. Bokhan 5 , B. Wilffert 2 , S. Ivanova 1 1 Mental Health Research Institute- Tomsk National Re- search Medical Center- Russian Academy of Sciences, labo- ratory of molecular genetics and biochemistry, Tomsk, Rus- sia 2 University of Groningen- Groningen Research Institute of Pharmacy, Unit of PharmacoTherapy- - Epidemiology & - Economics, Groningen, The Netherlands 3 Mental Health Research Institute- Tomsk National Re- search Medical Center- Russian Academy of Sciences, de- partment of affective disorders, Tomsk, Russia 4 University of Groningen- University Medical Centre Groningen, University Centre for Psychiatry, Groningen, The Netherlands 5 Mental Health Research Institute- Tomsk National Re- search Medical Center- Russian Academy of Sciences, de- partment of addictive states, Tomsk, Russia Background: Two-thirds of patients with major depressive disorder (MDD) do not respond optimally to the antidepres- sant medication [1]. To improve the current situation it is necessary to identify the pathological mechanisms under- lying the symptoms of a depressive episode [2,3], enabling tailored forms of antidepressant treatment. Brain-derived neurotrophic factor (BDNF) has been associated with the response to antidepressant drugs in mood and anxiety disorders. Prolactin (PRL) is a pituitary hormone with be- havioural effects which may be involved in the antidepres- sant pharmacological response acting as a neurotrophic fac- S356 Abstracts tor within the brain. With multiple factors associated with efficacy of antidepressants, investigation of the effect of genetic factors promises to limit sub-optimal treatments [4]. Aim: The aim of the study was to investigate the relation- ship of BDNF and PRL genotypes with short-term antidepres- sant drug response, comparing the first two weeks to the second two weeks of treatment in drug-naïve patients with a major depressive disorder. Methods: In a prospective inception cohort design, we in- cluded 186 Russian participants (28 men and 158 women) of 18-70 years clinically diagnosed with depressive disor- der who initiated antidepressant medication, including SS- RIs and TCAs. These patients had not been treated with an- tidepressant drugs in the preceding three months with 54.5% never been treated with antidepressant drugs. DNA poly- morphisms were genotyped for PRL rs1341239, BDNF rs6265 and rs7124442 in the Laboratory of Genetics of the Uni- versity of Groningen with the MassARRAY® System (Agena Bioscience TM ) and in the Laboratory of Molecular Genetics and Biochemistry of the Mental Health Research Institute with “StepOnePlus” (Applied Biosystems). We measured the primary clinical outcome by differ- ences in scores using the Hamilton Depression Rating Scale ( HAMD) between baseline and week two, and week two and week four for non-specific and specific antidepressant effects. Higher HAMD score denotes better clinical out- come. Paired-sample t-tests determined the statistical signifi- cance between HAMD between the two time-points. Inde- pendent T-Test determined the statistical significance be- tween polymorphisms and HAMD in baseline and week two, and week two and week four. Results: Comparisons between genotypes did not reveal any significant differences in scores during the first two weeks of treatment (all p-values > 0.05). For the latter two weeks, homozygous C BDNF rs7124442 responded sig- nificantly worse (5.60 ± 3.64) in comparison to homozygous T during this period (8.51 ± 4.26). Further analysis of homozygous C BDNF rs7124442 re- vealed significance in all women (5.57 ± 3.77) and post- menopausal ( ≥ 50 years of age) women (4.90 ± 4.06) but not in pre-menopausal ( < 50 years of age) women (7.00 ±2.34) in comparison to homozygous T. With respect to PRL rs1341239, no association between antidepressant response and genotypes was established within the patients, includ- ing within pre-menopausal and post-menopausal women. Conclusions: PRL rs1341239 genotype did not affect HAMD score differences in patients. Difference in HAMD scores for BDNF rs6265 genotypes were not found to be significant in most patients. Homozygous C BDNF rs712442 patients were found to respond significantly worse in the last two weeks of treatment, with the exception of pre-menopausal women. Disclosure statement: This work was in part supported by the Russian Foundation for Basic Research, grant №17-29- 02205 Development of a molecular-genetic panel of de- pressive disorders based on polymorphisms of the genes of neuronal kinases, neurotrophic proteins and genes of the serotonergic system References [1] Fava, M., 2000. Management of nonresponse and intolerance: switching strategies. J. Clin. Psychiatry. 61 (2), 10–12 2000. [2] Loonen, A.J.M., Ivanova, S.A., 2016. Circuits regulating plea- sure and happiness in major depression. Med. Hypotheses 87, 14–21 2016a. [3] Loonen, A.J.M., Ivanova, S.A., 2016. Circuits regulating plea- sure and happiness-mechanisms of depression. Front. Hum. Neurosci. 10, 571 2016b. [4] Laje, G., McMahon, F.J., 2007. The pharmacogenetics of major depression: past, present, and future. Biol. Psychiatry 62 (11), 1205–1207. doi: 10.1016/j.euroneuro.2019.09.511 P.506 Effects of N-acetylcysteine in autistic disorders: a systematic review and a meta-analysis R. Lowenthal 1 , ∗, I.T. Taiar 2 , J.F. Belisario Filho 3 , R. Uchida 4 , P. Shiozawa 5 1 Faculdade de Ciencias Medicas da Santa Casa SP, Mental Health, São Paulo, Brazil 2 Faculdade de Ciencias Medicas Santa Casa de São Paulo, Mental Health, São Paulo, Brazil 3 Institute Qualia, Psychiatry, Belo Horizonte, Brazil 4 Faculdade de Ciencias Medicas da Santa Casa SP, Mental Health, Sao Paulo, Brazil 5 Faculdade de Ciencias Medicas da Santa Casa de SP, Mental Health, Sao Paulo, Brazil Background: Autism Spectrum disorder isa neurodevelop- mental disorder characterized mainly by deficits in comuni- cation, social interaction and repetitive behavior patterns, as well as stereotypic patterns. Recent publications have been highlighted clinical benefits of oral N-acetylcysteine in psychiatric and neurological disorders. through mecha- nisms such as oxidative stress and glutamate and dopamine neurotransmitter systems. Therefore, N-acetylcysteine has been used in autistic symptons, such as repetitive and rit- ualized behaviors, hiperactivity, irritability and stereotypy. Although the mechanisms the efficacy of the drug in ame- liorate these symptons are not tottaly established, it can be explained by two pathways, glutamatergic modulation and antioxidative action. Objective: The aim of the present study was to realize a systematic review followed by meta analisys of all available controled clinical trials of studies assessing the effects of N- acetylcysteine over autistic symptons following recommen- dations Cochrane group. Methods: We searched MEDLINE and EMBASE databases us- ing the key words “Autistic Disorder [Mesh]”, "Autism Spec- trum Disorder [Mesh]”, “Autism”, “Child Development Dis- orders, Pervasive [Mesh]”, “Acetylcysteine [Mesh]” and “N- acetylcysteine”. We included randomized controlled trials assessing the efficacy of N-acetylcysteine for autistic symptons. It was included 4 eligible randomized clinical trials (n = 131) in the final analysis [1,2,3,4] and one study was excluded due to not contemplating a commom scale [5]. Each study was im- puted five times each one, once we assessed the follow- 

P.505 The potential role of BDNF and prolactin genotypes on antidepressant response in depressive patients

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P.505 The potential role of BDNF and prolactin genotypes on antidepressant response in depressive patients

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