1 Medical Evaluation of first-episode psychosisPresentation to first episode schizophrenia treatment group June 27, 2017 Erik Messamore, MD, PhD Associate Professor of Psychiatry, Northeast Ohio Medical University Medical Director, Best Practices for Schizophrenia Treatment (BeST) Center Option 1

2 Best Practices in Schizophrenia Treatment (BeST) Center at NEOMEDThe BeST Center’s mission: Promote recovery and improve the lives of as many individuals with schizophrenia as quickly as possible Accelerate the use and dissemination of effective treatments and best practices Build capacity of local systems to deliver state-of-the-art care to people affected by schizophrenia and their families The BeST Center offers: Training Consultation Education and outreach activities Services research and evaluation The BeST Center was established: Department of Psychiatry, Northeast Ohio Medical University in 2009 Supported by The Margaret Clark Morgan Foundation and other private foundations and governmental agencies

3 Schizophrenia is not a single diseaseThe heterogeneity of medication response implies multiple physiologically-defined diseases within behaviorally-defined schizophrenia

4 If there are many schizophrenias, how many?Hyper-dopaminergic subtype (approximately 70% of cases) Normal-dopamine/elevated glutamate subtype (approximately 15% of cases) 3. Addison’s disease 4. Celiac disease 5. Cerebral cysts and abscesses 6. Cushing’s disease 7. Hartnup disease 8. Hashimoto’s encephalopathy 9. Homocystinuria (MTHFR reductase deficiency) 10. HIV 11. Hydrocephalus 12. Hyperparathyroidism 13. Hyperthyroidism 14. Hypoparathyroidism 15. Hypothyroidism 16. Neurosyphilis 17. NMDA receptor antibody encephalitis 18. Pellagra 19. Pernicious anemia 20. Porphyrias 21. Rheumatic chorea 22. Systemic lupus erythematosus 23. Toxicity (drugs, medications, heavy metals) 24. Tumors of the brain 25. Wilson’s disease 26. Fabry’s disease 27. Hypopituitarism 28. Vitamin A deficiency 29. Vitamin D deficiency 30. Zinc deficiency 31. Adrenomyeloneuropathy 32. Cerebral malaria 33. Cerebrovascular lesions 34. Chromosomal disorders 35. Cranial trauma 36. Encephalitis and its sequelae 37. Familial basal ganglia calcification 38. GM2 gangliosidosis 39. Huntington’s disease 40. Hydrocephalus 41. Kartagener’s syndrome 42. Klinefelter’s syndrome 43. Metachromatic leukodystrophy 44. Narcolepsy 45. Oculocutaneous albinism 46. Occult hydrocephalus 47. Pick’s disease 48. Porphyrias 49. Prenatal static encephalopathy 50. Schilder’s cerebral sclerosis 51. Tourette syndrome 52. Toxicity (drugs, heavy metals) 53. Tuberous sclerosis 54. Tumors of the brain 55. Velocardiofacial syndrome

5 If schizophrenia is a diagnosis of exclusion…“The disturbance is not attributed to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or another medical condition.”

6 then we must actively consider, and actively exclude, medical conditionsTreatable or Preventable Diseases with Possible Schizophrenia-like Initial Presentation Addison’s disease Celiac disease Cerebral cysts and abscesses Cushing’s disease Hartnup disease Hashimoto’s encephalopathy Homocystinuria (MTHFR reductase deficiency) HIV Hydrocephalus Hyperparathyroidism Hyperthyroidism Hypoparathyroidism Hypothyroidism Neurosyphilis NMDA receptor antibody encephalitis Pellagra Pernicious anemia Porphyrias Rheumatic chorea Systemic lupus erythematosus Toxicity (drugs, medications, heavy metals) Tumors of the brain Wilson’s disease Fabry’s disease Hypopituitarism Vitamin A deficiency Vitamin D deficiency Zinc deficiency

7 Additional Diseases with Possible Schizophrenia-like Initial PresentationAdrenomyeloneuropathy Cerebral malaria Cerebrovascular lesions Chromosomal disorders Cranial trauma Encephalitis and its sequelae Familial basal ganglia calcification GM2 gangliosidosis Huntington’s disease Hydrocephalus Kartagener’s syndrome Klinefelter’s syndrome Metachromatic leukodystrophy Narcolepsy Oculocutaneous albinism Occult hydrocephalus Pick’s disease Porphyrias Prenatal static encephalopathy Schilder’s cerebral sclerosis Tourette syndrome Toxicity (drugs, heavy metals) Tuberous sclerosis Tumors of the brain Velocardiofacial syndrome

8 Arguments against comprehensive medical work upScreening test for an ‘esoteric’ disease will usually be negative Should not order tests if not ‘clinically indicated’ Not sure what to do if a result comes back positive Will increase cost of medical care

9 MRI Math 0.5% rate of discovery of a treatable cause of psychosis  1 case per 200 200 MRI $2, $400,000 Cost of 30 years of ‘as if schizophrenia’ $26,000* $780,000 *Annual cost of schizophrenia care, per patient, in the USA in the year 2000 McCombs, J.S., Nichol, M.B., Johnstone, B.M., Stimmel, G.L., Shi, J., and Smith, R. (2000). Antipsychotic drug use patterns and the cost of treating schizophrenia. Psychiatr Serv 51, 525–527.

10 Why do a complete medical evaluation?To discover treatable causes of psychosis Patients have the right of accurate diagnosis Assure that no reversible of treatable physical form of schizophrenia missed To alleviate unnecessary suffering To reduce costs/burdens of misdirected treatment (Schizophrenia care in year 2000 was approx. $26,000 per year per patient McCombs et al., 2000) 40 years of misdirected care = $1,000,000 of wasted healthcare spending To discover non-treatable causes of psychosis Avoids exposure to unnecessary treatments and stigma Access to more appropriate care/resources To establish baseline status Higher rates of movement disorders and of insulin resistance occur in schizophrenia, independent of antipsychotic medication treatment To screen for other significant illness or illness risk factors Preventable disease-related mortality contributes to the reduced life expectancy of those with schizophrenia versus the general population

11 How often do psychiatrically-relevant physical conditions occur in schizophrenia?12% of 250 consecutive admissions to psychiatric inpatient service had physical disorders that were productive of their psychiatric symptoms and that caused their admission (Johnson, 1968) 80% of those were missed in the initial assessment https://www.ncbi.nlm.nih.gov/pubmed/ 5.6% of 268 first episode schizophrenia patients had organic disease of possible or probable relevance to etiology (Johnstone et al., 1987) 7.0% of 328 recently-admitted patients with psychosis had underlying organic illness (Johnstone et al., 1988) 6% to 10% of schizophrenia patients had clinically unsuspected brain lesions of etiological relevance (Falkai, 1996)

12 Causes of psychosis found in Johnstone’s 1987 FEP cohortTertiary syphilis Sarcoidosis Autoimmune disease Cancer Cerebral cysticercosis Thyrotoxicosis

13 Is it possible to distinguish “organic” cases from idiopathic ones on the basis of mental status or physical exam? No Presence/absence of psychiatric symptoms has very little predictive validity Particularly in early psychosis, where symptoms can be protean In many instances of neurological/physical disease, psychiatric symptoms may be the only initial abnormality

14 What is the recommended medical evaluation?Opinions vary

15 Differing Medical Evaluation GuidelinesCoentre et al., 2015

16 Physical exam Physical exam, including neurological exam Vital signsWeight, Height ( body mass index) Waist circumference

17 Laboratory testing Blood cells Metabolic Endocrine ToxicCBC Metabolic Electrolytes, BUN, Creatinine, Calcium, Glucose, Uric acid, Ceruloplasmin Endocrine TSH, glucose, Toxic Drug/tox screen; blood levels of medications Immune/Inflammatory Sed rate, C-reactive protein, Thyroid peroxidase antibody, Tissue transglutaminase, Anti-nuclear antibody Deficiency states B12 level; vitamin D level Safety/Screening Pregnancy screen, Syphilis screen (FTA preferred over RPR), HIV, Hepatitis screen

18 Imaging Chest X-ray (sarcoidosis and bronchial tumor were found in FEP series) Brain imagining (MRI preferred) APA guidelines say imaging “if indicated” But mental status change *is* an imaging indication. Lesions most likely to cause psychosis symptoms occur in: Frontal cortex Temporal cortex Limbic structures Internal midline structures These regions are typically neurologically silent; lesions here do not produce defects of sensation, coordination, or motion

19 EEG 17% of 122 first-episode patients had a clearly arrhythmic EEG (Manchada et al., 2005) However, it’s often hard to make journey from abnormal finding to specific diagnosis or treatment. Low sensitivity to detect epilepsy Only 59% of patients referred for epilepsy had a confirming EEG If seizure disorder/epileptiform abnormality is suspected, EEG should be in sleep-deprived state

20 NMDA Receptor EncephalitisInvolves autoantibodies against the glycine-binding NR1 subunit of the NMDA receptor  hypofunction of the NMDA receptor NMDA receptor antibodies present in 6.5% of first episode psychosis cases (Zandi et al., 2011), and immune therapies reduce psychotic symptoms in such cases. Outcomes are better with early detection. Antibody screening in young people presenting with psychosis, seizures and cognitive disturbance is now part of routine clinical practice in many neurological and intensive care settings. CSF antibody testing is 100% sensitive/specific. Serum antibody testing is 75% - 97% sensitive/specific

21 When to do a complete evaluationAt the beginning of the illness In the setting of treatment non-response With significant change in the clinical picture

22 What to do with abnormal findingsAt a “p level” of 0.05… 1 of 20 tests (5%), on average, may be abnormal However, abnormal findings – even if seemingly minor – should be explained. May require consultation with other specialists

23 Summary Up to > 10% of schizophrenias will have a physical condition that either exacerbates, or directly causes the symptoms of schizophrenia. Early detection of treatable causes of schizophrenia will save lives. Comprehensive assessment should include: physical exam, neuro exam, brain imaging, and moderately expanded initial lab testing in each new case, and all treatment-resistant cases. Psychosis is a sufficient clinical indication for imaging or other tests. Psychosis-relevant brain regions are neurologically silent, and many physical diseases can have long durations of purely psychiatric presentations