Abstract
The information on prevalence of obesity, diabetes, metabolic syndrome (MetS) and cardiovascular risk (CVR) and on sociodemographic variables available in patients with psychiatric diseases about to be treated with weight gain-associated medication (e.g., clozapine, mirtazapine, quetiapine) is limited. In a naturalistic study, psychiatric inpatients (age: 18–75) of all F diagnoses according to ICD-10, who were about to be treated with weight gain-associated medication, were included. Demographic variables were assessed as well as biological parameters to calculate the Body Mass Index (BMI), MetS, diabetes and CVR. A total of 163 inpatients were included (60.1% male; mean age: 39.8 (± 15.1, 18–75 years). The three most common disorders were depression (46.0%), bipolar disorder (20.9%) and drug addiction (20.2%). The three most common pharmacotherapeutic agents prescribed were quetiapine (29.4%), mirtazapine (20.9%) and risperidone (12.9%). Of the included inpatients 30.1% were overweight, 17.2% obese, and 26.9% and 22.4% fulfilled the criteria for a MetS according to the International Diabetes Federation (IDF) and the National Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (NCEP ATP III), respectively, 3.8% had (pre)diabetes and 8.3% had a moderate and 1.9% a high CVR according to the Prospective Cardiovascular Münster (PROCAM) score. Detailed information is reported on all assessed parameters as well as on subgroup analyses concerning sociodemographic variables. The results suggest that psychiatric patients suffer from multiple metabolic disturbances in comparison to the general population. Monitoring weight, waist circumference, blood pressure and cholesterol regularly is, therefore, highly relevant.
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References
Richmond G, Kenny C, Ahmed J, Stephenson L, Lindsay J, Earls P, Mullin D, Ryland H (2017) Health education and activity—lessening the inequalities in mental health (HEA-LTI mental health). BMJ Qual Improv Rep. https://doi.org/10.1136/bmjquality.u205156.w3484
Chang CK, Hayes RD, Perera G, Broadbent MT, Fernandes AC, Lee WE, Hotopf M, Stewart R (2011) Life expectancy at birth for people with serious mental illness and other major disorders from a secondary mental health care case register in London. PLoS One 6(5):e19590. https://doi.org/10.1371/journal.pone.0019590
Lawrence D, Hancock KJ, Kisely S (2013) The gap in life expectancy from preventable physical illness in psychiatric patients in Western Australia: retrospective analysis of population based registers. BMJ 346:f2539. https://doi.org/10.1136/bmj.f2539
Walker ER, McGee RE, Druss BG (2015) Mortality in mental disorders and global disease burden implications: a systematic review and meta-analysis. JAMA Psychiatry 72(4):334–341. https://doi.org/10.1001/jamapsychiatry.2014.2502
Russ TC, Stamatakis E, Hamer M, Starr JM, Kivimaki M, Batty GD (2012) Association between psychological distress and mortality: individual participant pooled analysis of 10 prospective cohort studies. BMJ 345:e4933. https://doi.org/10.1136/bmj.e4933
Stahl SM, Mignon L, Meyer JM (2009) Which comes first: atypical antipsychotic treatment or cardiometabolic risk? Acta Psychiatr Scand 119(3):171–179. https://doi.org/10.1111/j.1600-0447.2008.01334.x
Vancampfort D, Stubbs B, Mitchell AJ, De Hert M, Wampers M, Ward PB, Rosenbaum S, Correll CU (2015) Risk of metabolic syndrome and its components in people with schizophrenia and related psychotic disorders, bipolar disorder and major depressive disorder: a systematic review and meta-analysis. World Psychiatry 14(3):339–347. https://doi.org/10.1002/wps.20252
Wandell P, Ljunggren G, Wahlstrom L, Carlsson AC (2014) Diabetes and psychiatric illness in the total population of Stockholm. J Psychosom Res 77(3):169–173. https://doi.org/10.1016/j.jpsychores.2014.06.012
De Hert M, Correll CU, Bobes J, Cetkovich-Bakmas M, Cohen D, Asai I, Detraux J, Gautam S, Moller HJ, Ndetei DM, Newcomer JW, Uwakwe R, Leucht S (2011) Physical illness in patients with severe mental disorders. I. Prevalence, impact of medications and disparities in health care. World Psychiatry 10(1):52–77. https://doi.org/10.1002/j.2051-5545.2011.tb00014.x
Foguet-Boreu Q, Fernandez San Martin MI, Flores Mateo G, Zabaleta del Olmo E, Ayerbe García-Morzon L, Perez-Piñar López M, Martin-López LM, Montes Hidalgo J, Violán C (2016) Cardiovascular risk assessment in patients with a severe mental illness: a systematic review and meta-analysis. BMC Psychiatry 16:141. https://doi.org/10.1186/s12888-016-0833-6
Happell B, Scott D, Platania-Phung C (2012) Perceptions of barriers to physical health care for people with serious mental illness: a review of the international literature. Issues Ment Health Nurs 33(11):752–761. https://doi.org/10.3109/01612840.2012.708099
De Hert M, Cohen D, Bobes J, Cetkovich-Bakmas M, Leucht S, Ndetei DM, Newcomer JW, Uwakwe R, Asai I, Moller HJ, Gautam S, Detraux J, Correll CU (2011) Physical illness in patients with severe mental disorders. II. Barriers to care, monitoring and treatment guidelines, plus recommendations at the system and individual level. World Psychiatry 10(2):138–151. https://doi.org/10.1002/j.2051-5545.2011.tb00036.x
Lawrence D, Kisely S (2010) Inequalities in healthcare provision for people with severe mental illness. J Psychopharmacol 24(4_supplement):61–68. https://doi.org/10.1177/1359786810382058
Vancampfort D, De Hert M, Stubbs B, Ward PB, Rosenbaum S, Soundy A, Probst M (2015) Negative symptoms are associated with lower autonomous motivation towards physical activity in people with schizophrenia. Compr Psychiatry 56:128–132. https://doi.org/10.1016/j.comppsych.2014.10.007
Perez-Pinar M, Mathur R, Foguet Q, Ayis S, Robson J, Ayerbe L (2016) Cardiovascular risk factors among patients with schizophrenia, bipolar, depressive, anxiety, and personality disorders. Eur Psychiatry 35:8–15. https://doi.org/10.1016/j.eurpsy.2016.02.004
Musil R, Obermeier M, Russ P, Hamerle M (2015) Weight gain and antipsychotics: a drug safety review. Expert Opin Drug Saf 14(1):73–96. https://doi.org/10.1517/14740338.2015.974549
Haupt DW (2006) Differential metabolic effects of antipsychotic treatments. Eur Neuropsychopharmacol 16:S149–S155. https://doi.org/10.1016/j.euroneuro.2006.06.003
Dent R, Blackmore A, Peterson J, Habib R, Kay GP, Gervais A, Taylor V, Wells G (2012) Changes in body weight and psychotropic drugs: a systematic synthesis of the literature. PLoS One 7(6):e36889. https://doi.org/10.1371/journal.pone.0036889
Henderson DC, Vincenzi B, Andrea NV, Ulloa M, Copeland PM (2015) Pathophysiological mechanisms of increased cardiometabolic risk in people with schizophrenia and other severe mental illnesses. Lancet Psychiatry 2(5):452–464. https://doi.org/10.1016/s2215-0366(15)00115-7
Olfson M, Marcus SC, Corey-Lisle P, Tuomari AV, Hines P, L’Italien GJ (2006) Hyperlipidemia following treatment with antipsychotic medications. Am J Psychiatry 163(10):1821–1825. https://doi.org/10.1176/ajp.2006.163.10.1821
Birkenaes AB, Birkeland KI, Engh JA, Faerden A, Jonsdottir H, Ringen PA, Friis S, Opjordsmoen S, Andreassen OA (2008) Dyslipidemia independent of body mass in antipsychotic-treated patients under real-life conditions. J Clin Psychopharmacol 28(2):132–137. https://doi.org/10.1097/JCP.0b013e318166c4f7
Reist C, Mintz J, Albers LJ, Jamal MM, Szabo S, Ozdemir V (2007) Second-generation antipsychotic exposure and metabolic-related disorders in patients with schizophrenia: an observational pharmacoepidemiology study from 1988 to 2002. J Clin Psychopharmacol 27(1):46–51. https://doi.org/10.1097/JCP.0b013e31802e5126
Rojo LE, Gaspar PA, Silva H, Risco L, Arena P, Cubillos-Robles K, Jara B (2015) Metabolic syndrome and obesity among users of second generation antipsychotics: a global challenge for modern psychopharmacology. Pharmacol Res 101:74–85. https://doi.org/10.1016/j.phrs.2015.07.022
Kloiber S, Domschke K, Ising M, Arolt V, Baune BT, Holsboer F, Lucae S (2015) Clinical risk factors for weight gain during psychopharmacologic treatment of depression: results from 2 large German observational studies. J Clin Psychiatry 76(6):e802–e808. https://doi.org/10.4088/JCP.14m09212
Correll CU, Manu P, Olshanskiy V, Napolitano B, Kane JM, Malhotra AK (2009) Cardiometabolic risk of second-generation antipsychotic medications during first-time use in children and adolescents. JAMA 302(16):1765–1773. https://doi.org/10.1001/jama.2009.1549
Gebhardt S, Haberhausen M, Heinzel-Gutenbrunner M, Gebhardt N, Remschmidt H, Krieg JC, Hebebrand J, Theisen FM (2009) Antipsychotic-induced body weight gain: predictors and a systematic categorization of the long-term weight course. J Psychiatr Res 43(6):620–626. https://doi.org/10.1016/j.jpsychires.2008.11.001
Liu YT, Chau YL, Hsu SC, Chu CL, Chen CY (2014) Factors influencing weight gain in an Asian population of psychiatric inpatients: a retrospective study in Taiwan. Asia Pac Psychiatry 6(2):226–234. https://doi.org/10.1111/j.1758-5872.2012.00223.x
Strassnig M, Miewald J, Keshavan M, Ganguli R (2007) Weight gain in newly diagnosed first-episode psychosis patients and healthy comparisons: one-year analysis. Schizophr Res 93(1–3):90–98. https://doi.org/10.1016/j.schres.2007.02.024
Taylor VH, McIntyre RS, Remington G, Levitan RD, Stonehocker B, Sharma AM (2012) Beyond pharmacotherapy: understanding the links between obesity and chronic mental illness. Can J Psychiatry 57(1):5–12. https://doi.org/10.1177/070674371205700103
Vandenberghe F, Gholam-Rezaee M, Saigi-Morgui N, Delacretaz A, Choong E, Solida-Tozzi A, Kolly S, Thonney J, Gallo SF, Hedjal A, Ambresin AE, von Gunten A, Conus P, Eap CB (2015) Importance of early weight changes to predict long-term weight gain during psychotropic drug treatment. J Clin Psychiatry 76(11):e1417–e1423. https://doi.org/10.4088/JCP.14m09358
WHO (2016) The ICD-10 classification of mental and behavioural disorders: clinical descriptions and diagnostic guidelines, vol 10. World Health Organization, Geneva
WHO (2008) WHO STEPwise approach to surveillance (STEPS). World Health Organization (WHO), Geneva
Kerner W, Bruckel J (2014) Definition, classification and diagnosis of diabetes mellitus. Exp Clin Endocrinol Diabetes 122(7):384–386. https://doi.org/10.1055/s-0034-1366278
WHO (1997) Obesity: preventing and managing the global epidemic. Report of a WHO Consultation on Obesity. WHO/NUT/NCD/98.1, Geneva
Whelton PK, Carey RM, Aronow WS, Casey DE Jr, Collins KJ, Dennison Himmelfarb C, DePalma SM, Gidding S, Jamerson KA, Jones DW, MacLaughlin EJ, Muntner P, Ovbiagele B, Smith SC Jr, Spencer CC, Stafford RS, Taler SJ, Thomas RJ, Williams KA Sr, Williamson JD, Wright JT Jr (2018) 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: executive summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension 71(6):1269–1324. https://doi.org/10.1161/hyp.0000000000000066
Gingras V, Leroux C, Fortin A, Legault L, Rabasa-Lhoret R (2017) Predictors of cardiovascular risk among patients with type 1 diabetes: a critical analysis of the metabolic syndrome and its components. Diabetes Metab. https://doi.org/10.1016/j.diabet.2016.10.007
Assmann G, Schulte H, Cullen P, Seedorf U (2007) Assessing risk of myocardial infarction and stroke: new data from the Prospective Cardiovascular Munster (PROCAM) study. Eur J Clin Invest 37(12):925–932. https://doi.org/10.1111/j.1365-2362.2007.01888.x
Altman DG, Bland JM (2009) Parametric v non-parametric methods for data analysis. BMJ 338:a3167. https://doi.org/10.1136/bmj.a3167
Cohen J (1988) Statistical power analysis for the behavioural sciences, vol 2. Academic Press, New York
Slagter SN, van Waateringe RP, van Beek AP, van der Klauw MM, Wolffenbuttel BHR, van Vliet-Ostaptchouk JV (2017) Sex, BMI and age differences in metabolic syndrome: the Dutch Lifelines Cohort Study. Endocr Connect 6(4):278–288. https://doi.org/10.1530/ec-17-0011
Mensink GB, Schienkiewitz A, Haftenberger M, Lampert T, Ziese T, Scheidt-Nave C (2013) Overweight and obesity in Germany: results of the German Health Interview and Examination Survey for Adults (DEGS1). Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 56(5–6):786–794. https://doi.org/10.1007/s00103-012-1656-3
De Hert M, Dekker JM, Wood D, Kahl KG, Holt RI, Moller HJ (2009) Cardiovascular disease and diabetes in people with severe mental illness position statement from the European Psychiatric Association (EPA), supported by the European Association for the Study of Diabetes (EASD) and the European Society of Cardiology (ESC). Eur Psychiatry 24(6):412–424. https://doi.org/10.1016/j.eurpsy.2009.01.005
Ng M, Fleming T, Robinson M, Thomson B, Graetz N, Margono C, Mullany EC, Biryukov S, Abbafati C, Abera SF, Abraham JP, Abu-Rmeileh NME, Achoki T, AlBuhairan FS, Alemu ZA, Alfonso R, Ali MK, Ali R, Guzman NA, Ammar W, Anwari P, Banerjee A, Barquera S, Basu S, Bennett DA, Bhutta Z, Blore J, Cabral N, Nonato IC, Chang J-C, Chowdhury R, Courville KJ, Criqui MH, Cundiff DK, Dabhadkar KC, Dandona L, Davis A, Dayama A, Dharmaratne SD, Ding EL, Durrani AM, Esteghamati A, Farzadfar F, Fay DFJ, Feigin VL, Flaxman A, Forouzanfar MH, Goto A, Green MA, Gupta R, Hafezi-Nejad N, Hankey GJ, Harewood HC, Havmoeller R, Hay S, Hernandez L, Husseini A, Idrisov BT, Ikeda N, Islami F, Jahangir E, Jassal SK, Jee SH, Jeffreys M, Jonas JB, Kabagambe EK, Khalifa SEAH, Kengne AP, Khader YS, Khang Y-H, Kim D, Kimokoti RW, Kinge JM, Kokubo Y, Kosen S, Kwan G, Lai T, Leinsalu M, Li Y, Liang X, Liu S, Logroscino G, Lotufo PA, Lu Y, Ma J, Mainoo NK, Mensah GA, Merriman TR, Mokdad AH, Moschandreas J, Naghavi M, Naheed A, Nand D, Narayan KMV, Nelson EL, Neuhouser ML, Nisar MI, Ohkubo T, Oti SO, Pedroza A, Prabhakaran D, Roy N, Sampson U, Seo H, Sepanlou SG, Shibuya K, Shiri R, Shiue I, Singh GM, Singh JA, Skirbekk V, Stapelberg NJC, Sturua L, Sykes BL, Tobias M, Tran BX, Trasande L, Toyoshima H, van de Vijver S, Vasankari TJ, Veerman JL, Velasquez-Melendez G, Vlassov VV, Vollset SE, Vos T, Wang C, Wang X, Weiderpass E, Werdecker A, Wright JL, Yang YC, Yatsuya H, Yoon J, Yoon S-J, Zhao Y, Zhou M, Zhu S, Lopez AD, Murray CJL, Gakidou E (2014) Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the Global Burden of Disease Study 2013. The Lancet 384(9945):766–781. https://doi.org/10.1016/S0140-6736(14)60460-8
Moebus S, Hanisch JU, Neuhauser M, Aidelsburger P, Wasem J, Jockel KH (2006) Assessing the prevalence of the Metabolic Syndrome according to NCEP ATP III in Germany: feasibility and quality aspects of a two step approach in 1550 randomly selected primary health care practices. Ger Med Sci 4:Doc07
Hauner H, Bramlage P, Losch C, Jockel KH, Moebus S, Schunkert H, Wasem J (2008) Overweight, obesity and high waist circumference: regional differences in prevalence in primary medical care. Dtsch Arztebl Int 105(48):827–833. https://doi.org/10.3238/arztebl.2008.0827
Neuhauser H, Diederichs C, Boeing H, Felix BS, Jünger C, Lorbeer R, Meisinger C, Peters A, Völzke H, Weikert C, Wild P, Dörr M (2016) Hypertension in Germany: data from seven population-based epidemiological studies (1994–2012). Dtsch Arztebl Int 113(48):809–815. https://doi.org/10.3238/arztebl.2016.0809
Heidemann C, Scheidt-Nave C (2017) Prävalenz, Inzidenz und Mortalität von Diabetes mellitus bei Erwachsenen in Deutschland – Bestandsaufnahme zur Diabetes-Surveillance. Robert Koch-Institut, Epidemiologie und Gesundheitsberichterstattung. https://doi.org/10.17886/rki-gbe-2017-050
Osborn DP, Wright CA, Levy G, King MB, Deo R, Nazareth I (2008) Relative risk of diabetes, dyslipidaemia, hypertension and the metabolic syndrome in people with severe mental illnesses: systematic review and meta analysis. BMC Psychiatry 8:84. https://doi.org/10.1186/1471-244x-8-84
Van Hemelrijck M, Ulmer H, Nagel G, Peter RS, Fritz J, Myte R, van Guelpen B, Foger B, Concin H, Haggstrom C, Stattin P, Stocks T (2018) Longitudinal study of body mass index, dyslipidemia, hyperglycemia, and hypertension in 60,000 men and women in Sweden and Austria. PLoS One 13(6):e0197830. https://doi.org/10.1371/journal.pone.0197830
Carter P, Rai G, Aziz A, Mann J, Chandran S, Uppal H, Potluri R (2014) Trends of cardiovascular disease amongst psychiatric patients between 2001 and 2012 in Greater Manchester, UK. Int J Cardiol 173(3):573–574. https://doi.org/10.1016/j.ijcard.2014.03.116
Santini I, Stratta P, D’Onofrio S, De Lauretis I, Santarelli V, Pacitti F, Rossi A (2016) The metabolic syndrome in an Italian psychiatric sample: a retrospective chart review of inpatients treated with antipsychotics. Riv Psichiatr 51(1):37–42. https://doi.org/10.1708/2168.23452
Margari F, Lozupone M, Pisani R, Pastore A, Todarello O, Zagaria G, Minerva F, Palasciano G, Palmieri V (2013) Metabolic syndrome: differences between psychiatric and internal medicine patients. Int J Psychiatry Med 45(3):203–226. https://doi.org/10.2190/PM.45.3.a
Montano D (2017) Association between socioeconomic determinants and the metabolic syndrome in the German Health Interview and Examination Survey for Adults (DEGS1)—a mediation analysis. Rev Diabet Stud 14(2–3):279–294. https://doi.org/10.1900/rds.2017.14.279
Kouvonen A, Stafford M, De Vogli R, Shipley MJ, Marmot MG, Cox T, Vahtera J, Vaananen A, Heponiemi T, Singh-Manoux A, Kivimaki M (2011) Negative aspects of close relationships as a predictor of increased body mass index and waist circumference: the Whitehall II study. Am J Public Health 101(8):1474–1480. https://doi.org/10.2105/ajph.2010.300115
Laroche HH, Wallace RB, Snetselaar L, Hillis SL, Cai X, Steffen LM (2013) Weight gain among men and women who have a child enter their home. J Acad Nutr Diet. https://doi.org/10.1016/j.jand.2013.1005.1022
Laroche HH, Hofer TP, Davis MM (2007) Adult fat intake associated with the presence of children in households: findings from NHANES III. J Am Board Fam Med 20(1):9–15. https://doi.org/10.3122/jabfm.2007.01.060085
Bellows-Riecken KH, Rhodes RE (2008) A birth of inactivity? A review of physical activity and parenthood. Prev Med 46(2):99–110. https://doi.org/10.1016/j.ypmed.2007.08.003
Lampert T, von der Lippe E, Muters S (2013) Prevalence of smoking in the adult population of Germany: results of the German Health Interview and Examination Survey for Adults (DEGS1). Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 56(5–6):802–808. https://doi.org/10.1007/s00103-013-1698-1
Black DW, Goldstein R, Mason EE, Bell SE, Blum N (1992) Depression and other mental disorders in the relatives of morbidly obese patients. J Affect Disord 25(2):91–95. https://doi.org/10.1016/0165-0327(92)90071-D
Compas BE, Howell DC, Phares V, Williams RA, Giunta CT (1989) Risk factors for emotional/behavioral problems in young adolescents: a prospective analysis of adolescent and parental stress and symptoms. J Consult Clin Psychol 57(6):732–740. https://doi.org/10.1037/0022-006X.57.6.732
Mesgarani M, Hosseinbor M, Shafiee S, Sarkoubi R (2016) The relationship of parental mental health and dietary pattern with adolescent mental health. Int J High Risk Behav Addict 5(1):e26616. https://doi.org/10.5812/ijhrba.26616
Apter G, Bobin A, Genet M-C, Gratier M, Devouche E (2017) Update on mental health of infants and children of parents affected with mental health issues. Curr Psychiatry Rep 19(10):72. https://doi.org/10.1007/s11920-017-0820-8
Simon GE, Von Korff M, Saunders K, Miglioretti DL, Crane PK, van Belle G, Kessler RC (2006) Association between obesity and psychiatric disorders in the US adult population. Arch Gen Psychiatry 63(7):824–830. https://doi.org/10.1001/archpsyc.63.7.824
Vaughn AE, Martin CL, Ward DS (2018) What matters most—what parents model or what parents eat? Appetite 126:102–107. https://doi.org/10.1016/j.appet.2018.03.025
Tang Walfred WC, Dietmann S, Irie N, Leitch Harry G, Floros Vasileios I, Bradshaw Charles R, Hackett Jamie A, Chinnery Patrick F, Surani MA (2015) A unique gene regulatory network resets the human germline epigenome for development. Cell 161(6):1453–1467. https://doi.org/10.1016/j.cell.2015.04.053
Acknowledgements
This work was performed in partial fulfillment of the M.D. thesis requirements of the LMU Medicine faculty. We would like to thank all patients who participated in this study and our students Ann-Sophie Störmann, Gianna Heinrichs and Laura Drews for helping in the data acquisition phase. Editing of language was assisted by Thelma Coutts.
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Study concept and design: RM. Acquisition of data: AZ, KE, LR. BB. Analysis and interpretation of data: BB, AZ, RM. Drafting the manuscript: BB, AZ. Critical revision of the manuscript for important intellectual content: RM. Statistical analysis: BB, AZ.
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The authors declare that over the past three years author Dr. R. Musil has received research support from Janssen-Cilag, Speaker Honoraria from Otsuka and has been on the advisory board of Roche Pharmaceuticals. There are no other financial interests in relation to this article.
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Barton, B.B., Zagler, A., Engl, K. et al. Prevalence of obesity, metabolic syndrome, diabetes and risk of cardiovascular disease in a psychiatric inpatient sample: results of the Metabolism in Psychiatry (MiP) Study. Eur Arch Psychiatry Clin Neurosci 270, 597–609 (2020). https://doi.org/10.1007/s00406-019-01043-8
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DOI: https://doi.org/10.1007/s00406-019-01043-8