Karl Bechter

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K. Bechter Etiopathogenesis of psychoses60 Acta Clin Croat,  Vol. 49,  (Suppl) No. 2,  2010ETIOPATHOGENESIS OF PSYCHOSESKarl BechterUlm University/BKH Guenzburg, Germany1. IntroductionFor a rather long period the known important ge-netic contribution to mental illness was understood in a framework of a common disease common variant hypothesis. In this view the genes play a major role. But according to more stringent results this now seems diff erent (Uher 2009): gene environment interactions may be more important than previously thought, in-volving especially environments that have periodically changed throughout evolution. Furthermore, a cumu-lative eff ect of multiple pleiotropic variants of recent origin under mutation selection balance could account for the persistence of harmful and heritable mental ill-ness despite the well known and strong reproductive disadvantage. Any valid hypothesis has especially to explain this latter aspect. Th e ‘evolution-informed-framework-hypothesis’ does. 2. Types of gene-environment-interactionBut what are environmental factors involved? New results support psychoimmunological mechanisms and infectious agents may be relevant. When applying modern CSF analytic methods, we found abnormal CSF in a considerable subgroup of therapy-resistant cases of both, aff ective and schizophrenic spectrum disorders, supporting or matching with the mild en-cephalitis (ME) hypothesis in a subgroup of more than 40% of patients (Bechter et al. 2010). Th e ME hypoth-esis explains various psychiatric syndromes by low level neuroinfl ammation, which may arise dependent from infections. Together with developmental and genetic factors, via common immuninfl ammatory pathoge-netic pathways, many diff erent infectious agents may contribute to or initiate an autoimmune CNS-related or CNS-specifi c process (Bechter 2001).Th e fact, that most infectious agents are char-acterized by only low pathogenicity (low number of diseased per number of infected) is also understand-able in an evolutionary framework: the less aggres-sive an agent is to its host the more likely it adapts and survives. Low pathogenicity seems especially frequent in neurotropic viruses, and CNS represents a bradytrophic tissue and therefore a preferred sur-vival niche for viruses (Johnson 1982). Now there is an increasing number of fi ndings suggesting bacteri-al, protozoal or viral agents, likely involved in mental disorders, mumps virus infection representing even the highest risk factor for psychoses found up to now (Dalman et al. 2008). Other candidates are Borna disease virus (Bechter 2001), endogenous retrovirus Herv-W (Perron and Leboyer 2009), parvovirus B19 and persistent Adeno-associated virus 2 (Grant et al. 2009), and a serious of others. An immuninfl am-matory signature was found by highly sophisticated laboratory methods in blood monocytes in psychoses (Padmos et al. 2004). Th e diagnosis of neuropsychi-atric disorders based on neuroimmunological studies, e.g. on blood cells by microRNA, is at the beginning but seems very promising (Keller et al. 2009). Shotgun proteome analysis of post-mortem tissue identifi ed 84 diff erential expressed proteins, those involving the immune system, calcium homeostasis, cytoskeleton assembly and energy metabolism (Martins-de-Souza 2009). Such fi ndings match with the ME hypothesis very well. Compare also the abstracts of the 10th Psy-choimmunology Expert Meeting 2009 (free download available on www.psychoimmunology-experts.de.Another key environmental factor to induce psy-chotic illness seems cannabis (Lutz 2009), apparently a specifi c subgroup.Acta Clin Croat,  Vol. 49,  (Suppl) No. 2,  2010 61K. Bechter Etiopathogenesis of psychoses3. SummaryPsychoimmunology is on the rise in neuropsychia-try, though not well accepted yet in the fi eld of clinical psychiatry, but may be causally involved in a consid-erable subgroup of psychoses. Completely diff ering etiological subgroups, e.g. neurodevelopmental, may nevertheless exist. Well established is neuroimmunol-ogy in clinical neurology with well working laboratory methods, especially CSF investigation, yet the gold standard to diagnose infl ammatory CNS diseases. Low level CNS infl ammation detected in subgroups of patients with endogenous psychoses by modern CSF diagnostic methods (Bechter et al. 2010; Max-einer et al. 2009) suggests, that CSF investigation plays an underestimated role in psychiatry, but can help to better understand severe or therapy-resistant psychiatric disorders.References1. BECHTER, K. (2001). Mild encephalitis underlying psychi-atric disorder - A reconsideration and hypothesis exemplifi ed on Borna disease.  Neurol Psychiatry Brain Res  9, 55-70.2. BECHTER, K., REIBER, H., HERZOG, S., FUCHS, D., TUMANI, H. & MAXEINER, H. G. (2010). Cerebro-spinal fl uid analysis in aff ective and schizophrenic spectrum disorders: identifi cation of subgroups with immune responses and blood-CSF barrier dysfunction.  J. Psychiatr. Res.  44, 321-330.3. DALMAN, C., ALLEBECK, P., GUNNELL, D., HARRISON, G., KRISTENSSON, K., LEWIS, G., LOFVING, S., RASMUSSEN, F., WICKS, S. & KARLSSON, H. (2008). Infections in the CNS during childhood and the risk of subsequent psychotic illness: a cohort study of more than one million Swedish subjects  Am. J. Psychiatry  165, 59-65.  4. GRANT, J. K., YIN, N. C., ZAYTOUN, A. M., WASEEM, H., ADAMSON, L., POLCZ, M. & HOBBS, J. A. (2009). Persistent Adeno-associated Virus 2 and Parvovirus B19 Sequences in Human Cerebellum and Th yroid. Neurol Psychiatry Brain Res  16[Suppl.1], 25.  5. JOHNSON, R. T. (1982). Viral infections of the nervous sys-tem. Raven: New York.  6. KELLER, A., LEIDINGER, P., LANGE, J., BORRIES, A., SCHROERS, H., SCHEFFLER, M., LENHOF, H. P., RUPRECHT, K. & MEESE, E. (2009). Multiple sclerosis: microRNA expression profi les accurately diff erentiate pa-tients with relapsing-remitting disease from healthy controls. PLoS. ONE.  4, e7440.  7. LUTZ, B. (2009) From molecular neurodevelopment to psy-chiatry: new insights in mechanisms underlying cannabis-induced psychosis and schizophrenia. Eur Arch Psychiatry Clin Neurosci  259, 369-370.  8. MARTINSDESOUZA, D., GATTAZ, W.F., SCHMITT, A., REWERTS, C., MACCARRONE, G., DIASNETO, E., TURCK, C.W. (2009). Prefrontal cortex shotgun proteome analysis reveals altered calcium homeo-stasis and immune system imbalance in schizophrenia. Eur Arch Psychiatry Clin Neurosci  259, 151-163.   9. MAXEINER, H. G., ROJEWSKI, M. T., SCHMITT, A., TUMANI, H., BECHTER, K. & SCHMITT, M. (2009). Flow cytometric analysis of T cell subsets in paired samples of cerebrospinal fl uid and peripheral blood from patients with neurological and psychiatric disorders.  Brain Behav. Immun. 23, 134-142.10. PADMOS, R. C., BEKRIS, L., KNIJFF, E. M., TIEMEIER, H., KUPKA, R. W., COHEN, D., NOLEN, W. A., LERNMARK, A. & DREXHAGE, H. A. (2004). A high prevalence of organ-specifi c autoimmunity in patients with bipolar disorder.  Biol. Psychiatry  56, 476-482.11. PERRON, H. & LEBOYER, M. (2009). Human Endoge-nous Retrovirus in Schizophrenia: a New Avenue of Research at the Gene-environment Interface.  Neurol Psychiatry Brain Res 16[Suppl.1], 47.12. UHER, R. (2009). Th e role of genetic variation in the cau-sation of mental illness: an evolution-informed framework. Mol. Psychiatry  14, 1072-1082.

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