Institute for Response-Genetics (e.V.), University of Zurich

Elevated Sensitivity to Environmental Challenges

Evidence from twin, family and adoption studies suggests that, ultimately, genetic markers may represent the most important trait-like characteristics in the etiology of major psychiatric disorders. However, genetic predisposition appears to vary across patients and to "explain" no more than 25% to 60% of the observed phenotypic variance, depending on the onset of illness, severity of illness, and long-term course of clinical syndromes. Therefore, genetic predisposition has been conceptualized as acting nonspecifically, by elevating a subject's "vulnerability" (or "sensitivity") to environmental or endogenous challenges. Vulnerability, however, is neither necessary nor sufficient for the development of psychiatric disorders.

Mechanisms that Support and Maintain Health

A subject's vulnerability is typically compensated, at least in part, by resilience factors. The term "resilience" is used here as a broader concept than just neurogenesis, encompassing all those intrinsic/endogenous mechanisms that support and maintain health, thereby enabling patients to cope with stressful situations (includes the concept of autotherapeutic capacity). This may include personality traits supporting or impeding social skills.

Molecular-Genetic Evidence

In our molecular-genetic study of 257 patients treated with antidepressants or antipsychotics and genotyped for 178 candidate genes, we found correlations as high as 0.5604 (p = 0.0000; nonimprovers included; c95 = [0.4123, 0.6797]) between the phenotype (onset of improvement) and the subjects’ coordinate on the first eigenvector of a configuration of 26 genomic loci (31% explained phenotypic variance). Positive as well as negative correlations of the same order of magnitude were detected, with the underlying configurations sharing "core" loci while differing in their "accessory" loci, thus suggesting the existence of mechanisms that can support or impede recovery. No single genomic locus seemed to be either necessary or sufficient for having the phenotype, whereas significant non-linear interactions between the genomic loci appeared to play a key role. Interestingly, there was some overlap with genomic regions independently identified as being linked to functional psychoses, again with subgroups displaying positive or negative correlations between the configuration of genomic loci and the phenotype (vulnerability to functional psychoses: affected/unaffected sib pairs).

References

Stassen HH, Bachmann S, Bridler R, Cattapan K, Seifritz E. Polypharmacy in Psychiatry and Weight Gain: Longitudinal Study of 832 Patients Hospitalized for Depression or Schizophrenia, along with Data of 3,180 Students from Europe, the U.S., South America, and China. Eur Arch Psychiatry Clin Neurosci. 2024; https://doi.org/10.1007/s00406-024-01767-2 (Epub ahead of print) [get the article]

Stassen HH, Bachmann S, Bridler R, Cattapan K, Hartmann AM, Rujescu D, Seifritz E, Weisbrod M, Scharfetter C: Genetic Determinants of Antidepressant and Antipsychotic Drug Response: A molecular-genetic study of 902 patients over 6 weeks. Psychiatry Res. 2024 [submitted for publication]

Stassen HH, Bachmann S, Bridler R, Cattapan K, Hartmann AM, Rujescu D, Seifritz E, Weisbrod M, Scharfetter C. Analysis of genetic diversity in patients with major psychiatric disorders versus healthy controls: A molecular-genetic study of 1698 subjects genotyped for 100 candidate genes (549 SNPs). Psychiatry Res. 2024; 333: 115720. doi: 10.1016/j.psychres.2024.115720 [get the article]

Stassen HH, Bachmann S, Bridler R, Cattapan K, Herzig D, Schneeberger A, Seifritz E: Detailing the Effects of Polypharmacy in Psychiatry: Longitudinal Study of 320 Patients Hospitalized for Depression or Schizophrenia. Eur Arch Psychiatry Clin Neurosci. 2022; 272(4): 603-619 [get the article]

Stassen HH, Bachmann S, Bridler R, Cattapan K, Herzig D, Schneeberger A, Seifritz E. Inflammatory Processes linked to Major Depression and Schizophrenic Disorders and the Effects of Polypharmacy in Psychiatry: Evidence from a longitudinal Study of 279 Patients under Therapy. Eur Arch Psychiatry Clin Neurosci. 2021; 271(3): 507-520 [get the article]

Pollak TA, Lennox B, Müller S, Benros ME, Prüss H, Tebartz van Elst L, Klein H, Steiner J, Frodl T, Bogerts B, Tian L, Groc L, Hasan A, Baune BT, Endres D, Haroon E, Yolken R, Benedetti F, Halaris A, Meyer J, Stassen H, Leboyer M, Fuchs D, Otto M, Brown DA, Vincent A, Najjar S, Bechter K: An international consensus on an approach to the diagnosis and management of psychosis of suspected autoimmune origin: the concept of autoimmune psychosis. Lancet Psychiatry 2020; 7(1): 93-108

Zhang M, Bridler R, Mohr C, Moragrega I, Sun N, Xu Z, Yang Z, Possenti M, Stassen HH: Early Detection of the Risk of Developing Psychiatric Disorders: A Study of 461 Chinese University Students under Chronic Stress. Psychopathology 2019; 52(6): 367-377 [get the article]

Bhake R, Kluckner V, Stassen HH, Russell GM, Leendertz J, Stevens K, Linthorst ACE, Lightman S: Continuous Free Cortisol Profiles — Circadian Rhythms in Healthy Men. J Clinical Endocrinology & Metabolism 2019; 104(12): 5935-5947

Stassen HH: Heterogeneity of schizophrenic disorders and link to chronically elevated IgM values. Neurology, psychiatry and brain research 2018; 29: 23-24

Stassen HH, Braun S, Bridler R, Seifritz E, Weisbrod M: Inflammatory Processes and Schizophrenia: Evidence from a Twin Study. Eur Neuropsychopharmacology 2017; 27 Suppl 4: S934-S935

Braun S, Bridler R, Müller N, Schwarz MJ, Seifritz E, Weisbrod M, Zgraggen A, Stassen HH: Inflammatory Processes and Schizophrenia: Two Independent Lines of Evidence from a Study of Twins Discordant and Concordant for Schizophrenic Disorders. European Archives of Psychiatry and Clinical Neuroscience 2017; 267: 377-389 [get the article]

Braun S, Annovazzi C, Botella C, Bridler B, Camussi E, Delfino JP, Mohr C, Moragrega I, Papagno C, Pisoni A, Soler C, Seifritz E, Stassen HH: Assessing Chronic Stress, Coping Skills and Mood Disorders through Speech Analysis. A Self-Assessment "Voice App" for Laptops, Tablets, and Smartphones. Psychopathology 2016; 49(6): 406-419 [get the article]

Delfino JP, Barragán E, Botella C, Braun S, Bridler R, Camussi E, Chafrat V, Lott P, Mohr C, Moragrega I, Papagno C, Sanchez S, Seifritz E, Soler C, Stassen HH: Quantifying Insufficient Coping Behavior under Chronic Stress. A cross-cultural study of 1,303 students from Italy, Spain, and Argentina. Psychopathology 2015; 48: 230-239

Mohr C, Braun S, Bridler R, Chmetz F, Delfino JP, Kluckner VJ, Lott P, Schrag Y, Seifritz E, Stassen HH: Insufficient Coping Behavior under Chronic Stress and Vulnerability to Psychiatric Disorders. Psychopathology 2014; 47: 235-243

Stassen HH, Delfino JP, Kluckner VJ, Lott P, Mohr C: Vulnerabilität und psychische Erkrankung. Swiss Archives of Neurology and Psychiatry 2014; 165(5): 152-157

Bridler R, Orosz A, Cattapan K, Stassen HH: In Need of Psychiatric Help – Leave a Message after the Beep. Psychopathology 2013; 46(3): 201-205

Stassen HH, Anghelescu IG, Angst J, Böker H, Lötscher K, Rujescu D, Szegedi A, Scharfetter C: Predicting Response to Psychopharmacological Treatment. Survey of Recent Results. Pharmacopsychiatry 2011; 44: 263-272

Lötscher K, Anghelescu IG, Braun S, Bridler R, Stassen HH: Polypharmacy in psychiatry: clinical practice versus empirical evidence. Eur Neuropsychopharmacol. 2010; 20 (Suppl. 3): 378-379

Lötscher K, Stassen HH, Hell D, Bridler R: Community-based crisis home programme – cost-efficient alternative to psychiatric hospitalization. Nervenarzt 2009; 80(7): 818-826

Stassen HH, Anghelescu IG, Braun S, Hoffmann K, Rujescu D, Scharfetter C, Szegedi A, Tadic A: Vulnerability to major psychiatric disorders, response to treatment and medical comorbidity – shared genetic factors? Eur Neuropsychopharmacol. 2009; 19 (Suppl. 3): 262

Stassen HH, Angst J, Hell D, Scharfetter C, Szegedi A: Is there a common resilience mechanism underlying antidepressant drug response? Evidence from 2848 patients. J Clin Psychiatry

Stassen HH, Scharfetter C: Vulnerability, resilience and response to psychotropic drugs: shared genetic factors? Am J Med Genetics 2006; 141: 707-708 2007; 68(8): 1195-1205

Stassen HH, Scharfetter C, Angst J: Functional Psychoses –Molecular-genetic Evidence for a Continuum. In: A. Marneros and H.S. Akiskal (eds) The overlap of affective and schizophrenic spectra. Cambridge University Press 2006; pp. 55-78

Stassen HH, Angst J, Scharfetter C: Genetik affektiver Störungen –der quantitative Ansatz syndrom-orientierter Modelle. In: M. Leuzinger-Bohleber, S. Hau, H. Deserno (hsg): Depression –Pluralismus in Praxis und Forschung, Vandenhoeck & Ruprecht, Göttingen, 2005, pp. 219-257

Stassen HH, Scharfetter C: Ethnische Zugehörigkeit und Vulnerabilität am Beispiel der Affektkrankheiten und Schizophrenien. Die Psychiatrie 2005; 2: 85-95

Stassen HH, Angst J, Scharfetter C, Szegedi A: Therapie mit Antidepressiva: Erfolg von genetischen Faktoren abhängig? Leading Opinions, Neurologie & Psychiatrie 2005; 6: 25-27

Angst J, Sellaro R, Stassen HH, Gamma A: Diagnostic conversion from depression to bipolar disorders: results of a long-term prospective study of hospital admissions. J Aff Disorders 2005; 84(2-3): 149-157

Stassen HH: Veränderungen der Sprechmotorik. In: T.Jahn (ed) Bewegungsstörungen bei psychischen Erkrankungen. Springer Heidelberg 2004: 107-125

Angst F, Stassen HH, Clayton PJ, Angst J: Mortality of patients with mood disorders: follow-up over 34 to 38 years. J Aff Disorders 2002; 68: 167-181

Angst J, Angst F, Stassen HH: Suicide risk in patients with major depressive disorder. J Clin Psychiatry 1999; 60,2: 57-62

Angst J, Stassen HH: Methodische Probleme der Prüfung von Antidepressiva. In: Stieglitz RD, Fähndrich E, Möller HJ (eds): Syndromale Diagnostik psychischer Störungen. Hogrefe, Göttingen 1998: 5-12

Stassen HH, Ragaz M, Reich T: Age-of-onset or age-cohort changes in the lifetime occurrence of depression? Psychiat Genetics 1997; 7: 27-34

Scharfetter C, Stassen HH: Psychopathological concepts. Psychopathology 1995; 28: 8-12

Stassen HH, Schmid GB, Gross G, Angst J, Huber G: Prädiktoren des langfristigen Verlaufs schizophrener Erkrankungen. In: G. Huber (ed), Idiopathische Psychosen: Psychopathologie, Neurologie, Therapie. Schattauer, Stuttgart-New York, 1990: 95-104

Angst J, Stassen HH, Gross G, Huber G, Stone MH: Suicide in affective and schizoaffective disorders. In: Marneros A. and Tsuang M.T. (eds) Affective and Schizoaffective disorders. Springer, Berlin-Heidelberg 1990: 168-185

Stassen HH, Scharfetter C, Winokur G, Angst J: Familial syndrome patterns in schizophrenia, schizoaffective disorder, mania and depression. Eur Arch Psychiatr Neurol Sci 1988; 237: 115-123

Stassen HH, Scharfetter C, Angst J: Morbid risks of subgroups of affective disorders: some methodological and empirical results. J Psychiat Research 1987; 21: 347-355

Angst J, Bänninger R, Nüsperli M, Scharfetter C, Stassen HH: Syndromale Gruppierungen endogener Psychosen in genetischer Sicht. In: Perspektiven der Schizophrenie-Forschung, ed: Pflug B., Foerster K., Straube E.; Fischer, Stuttgart New York, 1985: 25-38

Angst J, Scharfetter C, Stassen HH: Classification of Schizoaffective Patients by Multidimensional Scaling and Cluster Analysis. Psychiatria Clin 1983; 16: 254-264

Institute for Response-Genetics (e.V.)

Chairman: Prof. Dr. Hans H. Stassen

Psychiatric Hospital (KPPP), University of Zurich

Elevated Sensitivity to Environmental Challenges

Mechanisms that Support and Maintain Health

Molecular-Genetic Evidence

References

Genes code for proteins or RNA ("gene products") which may interact among each other or the immediate environment in a variety of ways, and influence the phenotype only after a cascade of intermediate steps. That is, genes act quantitatively.