Neuropsychiatry of Schizophrenia Prof Belinda Lennox Department of

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) 50% of all psychiatric inpatient beds

High morbidity – onset in adolescence

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

Schneiders First rank symptoms • 3 rd 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

‘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’

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

Attention, memory and executive tasks on 80 1 st episode psychoses – CANTAB in CAMEO Green “normal” Orange 1 sd 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

What if a proportion of schizophrenia was autoimmune?

Schizophrenia GWAS 34, 241 cases and 45604 controls (Psychiatric Genomics Consortium Nature 2015) MHC CD 20 CD 19 CACNB 2 CACNA 1 C GRIA 1 GRM 3 CACNA 1 l GRIN 2 A SRR

Increased schizophrenia with other autoimmune disorder and history of infection Benros et al Am J Psychiatry. 2011; 168(12): 1303 -1310. Incidence Ratios of Schizophrenia Spectrum Disorders Associated With Autoimmune Disease and Infectiona a The linear trend between the number of infections is significant (p<0. 00001).

New disorders antibody mediated encephalitis • Voltage Gated Potassium Channel complex (LGI 1, CASPR 2, contactin-2) 2001 • N-Methyl-D-aspartate receptor (NMDA) 2008 • AMPA receptor 2009 • GABA-B 2008 • Glycine receptor 2012 • D 2 receptor 2013 • GABA-A receptor 2014

Neuronal cell surface antibodies = pathogenic Control: Ig. G NR 1/NR 2 B/EGFP Patient 1: Ig. G NR 1/NR 2 B/EGFP

• • • 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 )

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

Responsive to early immunotherapy Irani et al Brain 2010

symptom of AE Occurrence in schizophrenia Seizures OR 11. 1 (Makikyro, et al. , 1998) Cognitive dysfunction Associated with poor function and clinical outcome. Movement disorders 9% of antipsychotic-naive patients spontaneous dyskinesias; 17% have spontaneous parkinsonism (Pappa and Dazzan, 2009) Catatonia 7. 6% - 38% (Taylor and Fink, 2003). Language disorders Formal thought disorder Autonomic dysfunction reduced body temperature of 0. 2 degrees C. (Shiloh et al. (2009)). reduced heart rate variability in psychotic disorders (Alvares et al. , 2016) Hyponatraemia Occurs in 6% (Elmsley et al. , 1990); polydipsia present in 3 -17% (de Leon et al. , 1994); Antipsychotic sensitivity including rhabdomyolysis Neuroleptic malignant syndrome in 0. 07 to 2. 2%. Sleep dysfunction 30 to 80% of patients with schizophrenia (Cohr, 2008).

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

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

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

MRC PPi. P 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

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

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

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

Atypical patients lower m. Rs to start, still respond to treatment Morris et al Neurology 2014

Neurological assessment and treatment needed

The nature of ‘psychiatric’ disease has evolved Categories of illness (from annual report of St Lawrence's Hospital, 1877 ) Cause Moral Domestic trouble Religious excitement Business and pecuniary Mental anxiety and worry Fright and various shocks Physical Intemperance Accident and injury Puerperal Brain disease and general paralysis Brain disease with epilepsy Other forms of brain disease Sunstroke Hereditary Congenital No. 3 8 4 8 3 8 1 5 6 10 4 2 7 1

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.

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

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

Acknowledgements • Prof Angela Vincent, Dr Camilla Buckley, Dr M. Isabel Leite, Dr Ester Coutinho, Dr Sarosh Irani, Dr Katrina Morris, Dr Leslie Jacobsen, Dr Adam Al-Diwani, Dr Tom Pollak, Neuroimmunology Group, 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