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Neuropsychiatry of Schizophrenia

Neuropsychiatry of Schizophrenia. Prof Belinda Lennox Department of Psychiatry, University of Oxford Belinda.lennox@psych.ox.ac.uk. Oxford Neurology Course 2016. Schizophrenia – a public health crisis 1% population Cost to UK £19 billion per year (all cancers combined £6.7 billion)

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Neuropsychiatry of Schizophrenia

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  1. Neuropsychiatry of Schizophrenia Prof Belinda Lennox Department of Psychiatry, University of Oxford Belinda.lennox@psych.ox.ac.uk Oxford Neurology Course 2016

  2. Schizophrenia – a public health crisis 1% population Cost to UK £19 billion per year (all cancers combined £6.7 billion) 50% of all psychiatric inpatient beds

  3. High morbidity – onset in adolescence

  4. History of schizophrenia – a severe brain disorder of unknown cause • Emil Kraepelin – Dementia precox 1897 catatonia/hebephrenia/paranoia • Eugene Bleuler – Schizophrenia 1911 • Schneiders first rank symptoms >>>DSM-V

  5. Schneiders First rank symptoms • 3rd Person auditory hallucinations (Voices arguing or discussing) • Running commentary • Somatic passivity experiences • Thought withdrawal or thought control • Thought broadcast • Delusional perception • Made affect, made impulse

  6. ‘Dementia Praecox and Paraphrenia ‘ Emil Kraepelin 1916 ‘a seizure is not very infrequently the first sign of the approaching disease’ in 16% of observed series ‘distortion of the corners of the mouth, irregular movements of the tongue and lips’ ‘Blood pressure is as a rule lowered; it fluctuates however, considerably. Respiration shows many irregularities’ ‘consciousness is for the most part somewhat clouded in catatonic morbid states sometimes even very considerably’

  7. Not just a disorder of positive symptoms • Negative symptoms – social withdrawal, apathy, lack interest • Cognitive impairment – present at onset, persistent, most disabling symptoms • Neurological signs – movement disorder, catatonia, • Antipsychotics ineffective in treating these symptoms

  8. Attention, memory and executive tasks on 80 1st episode psychoses – CANTAB in CAMEO Green “normal” Orange 1sd below control mean Red 2 sd below control mean Barnett et al Psychol Med. 2005 Jul;35(7):1031-41 Red and orange cognitive failure far more common than it should be by chance & very disabling

  9. What if a proportion of schizophrenia was autoimmune?

  10. Schizophrenia GWAS34,241 cases and 45604 controls (Psychiatric Genomics Consortium Nature 2015) MHC CD20 CD19 CACNB2 CACNA1C CACNA1l GRIN2A GRM3 GRIA1 SRR

  11. Increased schizophrenia with other autoimmune disorder and history of infection Benros et al Am J Psychiatry. 2011;168(12):1303-1310. Incidence Rate Ratios of Schizophrenia Spectrum Disorders Associated With Autoimmune Disease and Infectionaa The linear trend between the number of infections is significant (p<0.00001).

  12. New disorders antibody mediated encephalitis • Voltage Gated Potassium Channel complex (LGI1, CASPR2, contactin-2) 2001 • N-Methyl-D-aspartate receptor (NMDA) 2008 • AMPA receptor 2009 • GABA-B 2008 • Glycine receptor 2012 • D2 receptor 2013 • GABA-A receptor 2014

  13. Neuronal cell surface antibodies = pathogenic Control: IgG Patient 1: IgG NR1/NR2B/EGFP NR1/NR2B/EGFP

  14. NMDA-receptor encephalitis: Progessive life threatening limbic encephalitis, Fits, cognitive impairment, autonomic instability, coma and dystonic movement disorder 20-50% paraneoplastic (ovarian teratomas) 66-80% women, age 5-80 (mean 23) 1% all admissions to ITU (Dalmau et al Lancet Neurology 2008, Irani et al Brain 2010 )

  15. Psychosis common as an early feature Cortical Subcortical Irani et al Brain 2010

  16. Responsive to early immunotherapy Irani et al Brain 2010

  17. NMDA dysfunction as a model for schizophrenia Pathology Genes ketamine Harrison and Weinberger 2008 Glantz and Lewis Arch Gen Psych 2000

  18. How many patients with psychosis without other features of encephalitis also have NMDAR antibodies

  19. Psychosis antibody cases identified • National psychosis screening study - MRC PPiP study Referrals to joint encephalitis clinic 2015-2016: • from psychiatric services ‘atypical’– NMDAR 30, • (ref: encephalitis referrals ‘typical’NMDAR 16)

  20. MRC PPiP study Patients • 37 sites across England Mental Health Trusts 2012-2014 • First episode psychotic illness • Aged 14-35 years • < 6 weeks medication Controls • General population (Cambridge) - Opportunity sample • No personal or family history of mental illness • Age, gender and ethnicity matched to a FEP population

  21. Neuronal cell surface antibodies in psychosis Lennox et al Lancet Psychiatry in press

  22. Treatment response to immunotherapy and not to antipsychotics in patients with NMDAR ab psychosis (n=9) Zandi et al Schiz. Research 2014

  23. No difference in Ab scores between ‘typical’ and ‘atypical’ patients. Significant drop in level after treatment in both groups Morris et al Neurology 2014

  24. Atypical patients lower mRs to start, still respond to treatment Morris et al Neurology 2014

  25. Neurological assessment and treatment needed

  26. The nature of ‘psychiatric’ disease has evolved Categories of illness (from annual report of St Lawrence's Hospital, 1877)

  27. Psychiatry – the ‘holistic medical speciality’ ‘Psychiatry’ introduced 1808 by Professor Johann Christian Reil of Halle, Germany Mental diseases are universal. Everybody can get them. An anti-stigma campaign is required, and humanity should be primary in the treatment of the mentally ill. Only the best physicians shall become psychiatrists. A medical psychology specific to the needs of the physician shall be fundamental to medical training.

  28. Summary Schizophrenia is a common mental illness with high morbidity It is a disorder of positive psychotic symptoms, negative symptoms, cognitive symptoms, movement disorder Antipsychotics do not treat the most disabling symptoms

  29. Summary (2) There is an overlap between symptoms of autoimmune encephalitis and schizophrenia There is an increased rate of neuronal cell surface antibodies in first episode psychosis Preliminary evidence suggests people with psychosis and antibodies get better with immunotherapy rather than antipsychotics An evolution in the role of psychiatrists and neurologists may be required

  30. Acknowledgements • Prof Angela Vincent, Dr Camilla Buckley, Dr M. Isabel Leite, Dr Ester Coutinho, Dr SaroshIrani, Dr Katrina Morris, Dr Leslie Jacobsen, Dr Adam Al-Diwani, Dr Tom Pollak, NeuroimmunologyGroup, NDCN, University of Oxford • Prof.Rev. Alasdair Coles, Dr Mike Zandi Therapeutic Immunology Group, University of Cambridge • Dr Emma Palmer-Cooper, Prof Paul Harrison Department of Psychiatry, University of Oxford • Prof. Peter Jones, Dr Julia Deakin, Dr Linda Scoriels Department of Psychiatry, University of Cambridge • 37 PIs and CRN: Mental Health staff across England • Funding: MRC, Stanley Medical Research Institute

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