The Prodrome of Schizophrenia

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This is a presentation done on 4/6/11 for the Grand Rounds at Wayne State university by Pallav Pareek M.D.
This presentation talks about the concept of prdrome as it is(if?) applicable to schizophrenia, and if schizophrenia is becoming more of a preventable illness as science progresses. If so what are the various ways and means in which we can accomplish this prevention.
Amidst so much controversy on the issue , whether there is a prodrome for this illness or not, here I have tried to present the recent advances in this field and the recent scientific literature in this regard.

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  • hello sir,
    Its very good presentation. It will surely helpful in my project 'Schizophrenia; epidemiology to molecular epidemiology
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  • Even if the illness can not be prevented altogether, early intervention will help the patient. The idea is to prevent the first psychotic breakdown and so to keep the patient well.
  • Last 15 years have seen a systematic, international collaborative movement of clinicians and researchers has sought to modify and apply the principles and practice of early diagnosis and staged treatment akin to other areas of medicine such as cancer and cardiovascular diseases.
  • Schizophrenia is a debilitating and
  • Pandys maturation : Abnormal timing and pattern of acquisitions of milestones and growth retardation among high risk group. The limitation of Gnentic HR study is its inability to generalize the findings to all those who develop the diease.
  • C
  • The damage starts long before the patient comes to medical attention. So we want to shift the point far back to the point even before first psychotic episode. We want to Model is similar to the Framingham heart The Framingham Heart Study identified risk factors for coronary heart disease and developed an algorithm based on demographic variables
  • The Framingham Heart Study identified risk factors for coronary heart disease. Current criteria, based on demographic and clinical features, are not yet sensitive enough to reliably predict future psychosis, nor are we able to predict future schizophrenia versus other Axis I disorders
  • Yes, people with these severe mental illnesses can recover
  • The Prodrome of Schizophrenia

    1. 1. The Schizophrenia Prodrome <ul><li>Pallav Pareek M.D. </li></ul>
    2. 2. Aims & Objectives <ul><li>Understand the clinical features that suggest the early stages of schizophrenia and receive an overview of the prodrome. </li></ul><ul><li>Recognize the symptomatology of psychotic prodrome and b e able to discuss with patients & families the various treatment options and their associated risks/benefits. </li></ul><ul><li>Understand the background of early intervention during the initial phases leading to psychosis. </li></ul>
    3. 3. Schizophrenia & it’s societal burden <ul><li>Greek roots skhizein ( σχίζειν , &quot;to split&quot;) and phrēn- ( φρήν, φρεν- ; &quot;mind&quot;) </li></ul><ul><li>Term: Eugen Bleuler, 1908, intended to describe the separation of function between personality, thinking, memory, and perception. </li></ul><ul><li>Schizophrenia is a result of a complex interplay between genetic, epigenetic, neurodevelopmental, environmental and psychosocial factors. </li></ul><ul><li>Schizophrenia affects around 0.3–0.7% of people at some point in their life </li></ul><ul><li>Prevalence is 1.1% (NIMH) </li></ul><ul><li>51 million people worldwide as of 2011 </li></ul><ul><li>The total cost of schizophrenia in the U.S. is estimated to be $62.7 billion </li></ul><ul><li>In the U.S., schizophrenia costs more than all cancers combined </li></ul>
    4. 4. Natural History of Schizophrenia <ul><li>Enhancing Outcomes by Addressing Critical Challenges in the Treatment of Schizophrenia Chairperson: Diana O. Perkins, MD, MPH; Faculty: Richard S.E. Keefe, PhD; Leslie Citrome, MD, MPH; John B. Buse, MD, PhD; Thomas F. Liffick, MD Medscape: 2003 </li></ul>
    5. 5. The early psychosis movement <ul><li>IN THIS DAY & AGE </li></ul><ul><li>Last 2 decades: systematic collaborative international efforts </li></ul><ul><li>Focus on timely recognition, diagnosis and phase specific treatment of first episode </li></ul><ul><li>An earlier clinical stage is known to exist, where much of the collateral psychosocial damage occurs </li></ul><ul><li>From one ->Multicenter efforts NAPLS, EPOS, EDIE-2 </li></ul><ul><li>IS THIS NEW? </li></ul><ul><li>Kraepelin 1909 4,5 : The onset of a mental illness is generally a gradual one; far rarely, the disorder befalls the human all of the sudden, without any precursors……. </li></ul><ul><li>Blueler 1911 39 : Described a prephase with deterioration & called it “latent schizophrenia” </li></ul><ul><li>Wilhelm Geisinger 1861 39 </li></ul><ul><li>Harry Stack Sullivan 1927 39 </li></ul>
    6. 6. Prevention of a disease <ul><li>Universal (General Population) </li></ul><ul><li>Selective/Targeted (risk factors) </li></ul><ul><li>Indicated/prodromal </li></ul><ul><li>Early intervention (As soon as diagnosed) </li></ul><ul><li>No “gold standard” Depends on- Research/disease in question - Strategy employed- Phases of prevention- Population targeted 4 </li></ul>Prevention Universal Selective Indicated Early
    7. 7. What is Prodrome <ul><li>Greek word prodromos </li></ul><ul><li>Webster’s Definition : An early symptom indicating the onset of a disorder, e.g., fever is prodromal to measles </li></ul><ul><li>Blakiston’s Gould Medical Dictionary : An early or premonitory manifestation of impending disease before specific symptoms begin </li></ul><ul><li>Prodromal Definition in Relation to Psychosis: </li></ul><ul><li>NIMH: Period preceding the onset of the first florid psychotic episode, when there is increasing symptomatic presentation and functional deterioration </li></ul><ul><li>Controversy regarding the use of word “prodrome” </li></ul>
    8. 8. Universal prevention <ul><li>Addresses the entire population viz. national, local community, school, district </li></ul><ul><li>All individuals, without screening, are provided with information and skills necessary to prevent the problem. </li></ul><ul><li>Birth cohort studies 9-16 : Cohorts from general population -> study childhood development e.g. UK: Millennium cohort study 2000 </li></ul><ul><li>Adoption studies: Tienari et al 2002 37 . Finnish adoption study: family environment is a protective factor. </li></ul><ul><li>Warner et al 38 : damage during pregnancy, birth or early infancy. Factors to control: expensive and unavoidable </li></ul><ul><li>Can we identify risk factors that can be intervened? </li></ul><ul><ul><li>Targeted education? </li></ul></ul><ul><ul><li>Drug awareness – especially in middle school </li></ul></ul><ul><li>A universal prevention, not appropriate for a rare disorder of yet unknown, but certainly multi-factorial etiology 8 </li></ul>
    9. 9. Genetic risk in Schizophrenia?
    10. 10. SELECTIVE: Genetically at risk <ul><li>Gross and fine motor impairment </li></ul><ul><li>DISC1 locus -> alterations in prefrontal cortical function & altered working memory performance </li></ul><ul><li>Edinburgh HR study: lower IQ (specific alterations in global memory and sentence completion -> exec. fn) </li></ul><ul><li>CNV: Normal in neuroleptic naïve vs. psychosis </li></ul><ul><li>Reductions in temporal cortical and hippocampal volumes patients & healthy biological relatives -> Impaired declarative memory </li></ul><ul><li>Axis I diagnoses </li></ul><ul><li>Volume reductions amygdala, hippocampus, STG </li></ul><ul><li>Decreased prefrontal fMRI activation with executive function and at STG with listening </li></ul><ul><li>Biomarkers & endophenotypes </li></ul>
    11. 11. “ I don’t do any hard drugs” <ul><li>You will typically hear teens/patients saying “I don’t do any hard drugs” trying to support heir use of cannabis </li></ul><ul><li>Typical cannabis cigarette (joint): 19-43 mg Cannabis, 10-25% -> circulation 34 </li></ul><ul><li>Endocannabinoids play an important role in neurodevelopment which is occurring into mid 20’s, exogenous cannabinoids interfere with that system </li></ul><ul><li>The psychotropic effects of ∆-9-THC are mediated by partial agonist effects at CB-1 receptors (CB-1R) </li></ul><ul><li>Individuals with SCZ have a greater density of CB-1 receptors in the prefrontal cortex. </li></ul><ul><li>Elevated levels of anandamide (Sanskrit: आन ̇ द ), an endogenous CB receptor agonist, in the CSF of people with SCZ </li></ul>
    12. 12. Can Marijuana cause Schizophrenia: The Daithesis Stress Model <ul><li>A biological vulnerability or pre-disposition (diathesis) x environment -> disorder. Meehl </li></ul><ul><li>Zubin et. al. 1977 32 proposed &quot;Vulnerability--a new view of schizophrenia“ </li></ul><ul><li>Pelayo-Teran et al 2010: Functional polymorphism of COMT gene, where Cannabis + Val/Val has greater risk & earlier onset than Met/Val or Met/Met allele. 33 </li></ul>
    13. 13. Cannabis as a causal factor <ul><li>Meta analysis: Large M 2011 2 . </li></ul><ul><li>83 studies: AAO and cannabis </li></ul><ul><li>8,167 users vs. 14,352 non-users </li></ul><ul><li>Age at onset 2.00 yrs earlier substance vs. non-substance </li></ul><ul><li>2.70 yrs earlier cannabis vs. non-users </li></ul><ul><li>Alcohol not associated -> age of onset </li></ul><ul><li>Conclusions: </li></ul><ul><li>- Is one modifiable factor </li></ul><ul><li>- 2-3 years of psychosis free, dev milestones for better coping later </li></ul><ul><li>- Need for a renewed public health warning for Cannabis and psychosis </li></ul><ul><li>D’souza DC et al 2005 34 </li></ul><ul><li>Setting: Neurobiological Studies Unit, VA Connecticut, West Haven, CT </li></ul><ul><li>Method 3-day, double-blind, RCT: behavioral, cognitive, motor, and endocrine effects of 0 mg, 2.5 mg, and 5 mg intravenous ∆-9-THC </li></ul><ul><li>Findings : </li></ul><ul><li>- Transient exacerbation in psychotic and cognitive deficits in SCZ </li></ul><ul><li>- Pts more vulnerable to ∆-9-THC effects on recall relative to control subjects </li></ul><ul><li>Further studies: Brain cannabinoid receptor dysfunction contributes to the pathophysiology of the cognitive deficits in schizophrenia, alone/via DA </li></ul>
    14. 14. Resources for Teens <ul><li>You cannot convince teens with logical argument </li></ul><ul><li>The following is a great compilation of educational/scientific videos by the Australian Broadcasting Corporation called “Four Corners….” http://www.abc.net.au/4corners/special_eds/20050321/default_3.htm </li></ul><ul><li>You can let your teen using marijuana watch this and let them decide on their own. </li></ul>
    15. 15. Why the Prodromal approach <ul><li>Distribution of genetic risk is known </li></ul><ul><li>Genes with most research: Dysbindin, Neuregulin, DAOA=G72, DAAO </li></ul><ul><li>Each risk factor contributes <4% </li></ul><ul><li>Combined, genetic and risk factor(s) don’t explain or predict </li></ul><ul><li>Klosterkötter J: Indicated prevention of Schizophrenia. Deutsches Ärzteblatt International Dtsch Arztebl Int 2008; 105(30): 532–9 </li></ul>
    16. 16. Risks & benefits of prodromal approach <ul><li>BENEFITS 30 </li></ul><ul><li>Avenue for help, irrespective of transition </li></ul><ul><li>Engagement & trust easier to develop </li></ul><ul><li>Minimizing DUP </li></ul><ul><li>Comorbidities -> addressed (depression, SA) </li></ul><ul><li>Onset -> averted/delayed </li></ul><ul><li>If onset is inevitable, less Cognitive & emotional impairment, more likely to give informed consent </li></ul><ul><li>RISKS 30 </li></ul><ul><li>High false + </li></ul><ul><li>Psychotropics </li></ul><ul><li>Curtailment of involvement/activities </li></ul><ul><li>Social Stigma </li></ul><ul><li>Self-stigmatization </li></ul><ul><li>Mathematical conundrum: promote help Seeking vs. sacrificing sensitivity </li></ul><ul><li>False + can’t be distinguished from FF+ </li></ul>
    17. 17. Early intervention
    18. 18. Progression of Prodrome <ul><li>Unspecific Symptoms </li></ul><ul><li>(Poor diagnostic accuracy) </li></ul><ul><li>Basic Symptoms </li></ul><ul><li>Attenuated Positive symptoms </li></ul><ul><li>Brief limited intermittent psychotic symptoms </li></ul><ul><li>Klosterkotter: EIPS & LIPS </li></ul>2/3=BS 2/3=APS 4=BLIPS Psychosis 1=UN
    19. 19. Predictive Basic Symptoms <ul><li>At least one several times weekly during the last 3 mo </li></ul><ul><li>Thought interference </li></ul><ul><li>Perseveration </li></ul><ul><li>Thought pressure </li></ul><ul><li>Thought blockages </li></ul><ul><li>Disturbance of receptive speech (either heard or read) </li></ul><ul><li>Decreased ability to discriminate between ideas and perception, fantasy and true memories </li></ul><ul><li>Unstable ideas of reference </li></ul><ul><li>Derealization </li></ul><ul><li>Visual perception disturbances </li></ul><ul><li>Acoustic perception disturbances </li></ul><ul><li>COGDIS as mentioned above -> EPOS; Based on BSABS 2/3mo </li></ul>
    20. 20. Closed-in Approach or the UHR <ul><li>Most current trials use AR, HR, ARMS, UHR, Putative prodrome, CHR </li></ul><ul><li>Generally involve 3 intake criteria </li></ul><ul><li>Attenuated positive symptoms (APS) </li></ul><ul><li>Brief limited intermittent psychotic symptoms (BLIPS) </li></ul><ul><li>State and Trait risk factor: combined genetic risk factor with recent functional deterioration </li></ul>
    21. 21. Attenuated positive symptoms <ul><ul><li>One or more sub threshold positive symptoms, not fully psychotic in intensity: Unusual thought content /delusional ideas, suspiciousness/ persecutory ideas, grandiosity, perceptual abnormalities or distortions, conceptual disorganization. </li></ul></ul><ul><ul><li>Currently present at a frequency of at least once per week, onset or worsening in the past year. </li></ul></ul>
    22. 22. Brief Limited Intermittent Psychotic symptoms (BLIPS) <ul><ul><li>One or more fully psychotic symptoms: </li></ul></ul><ul><ul><ul><li>Hallucinations (auditory, visual, tactile, etc.), </li></ul></ul></ul><ul><ul><ul><li>Delusions (thought broadcasting, thought insertion, paranoia, grandeur, etc.) and </li></ul></ul></ul><ul><ul><ul><li>Formal thought disorder (loosening of associations, flight of ideas, etc.) </li></ul></ul></ul><ul><ul><li>Present intermittently for at least several minutes per day at least once per month, </li></ul></ul><ul><ul><li>but less than 1 hour/ day, </li></ul></ul><ul><ul><li>4 days/week over 1 month. </li></ul></ul>
    23. 23. State and Trait Risk factors <ul><li>CAARMS * </li></ul><ul><li>1 st degree relative with hx any psychotic d/o OR </li></ul><ul><li>Schizotypal personality d/o identified in patient or relative </li></ul><ul><li>& </li></ul><ul><li>GAF drop of 30% from premorbid level sustained for 1 mo </li></ul><ul><li>* Comprehensive assessment of at risk mental states: Yung et al 2002 </li></ul><ul><li>COPS * </li></ul><ul><li>1 st degree relative with hx of any psychotic d/o OR </li></ul><ul><li>Criteria of schizotypal personality d/o identified in patient </li></ul><ul><li>& </li></ul><ul><li>GAF drop of at least 30% over the last month v/s 1 year ago </li></ul><ul><li>* Criteria for prodromal symptoms from SIPS version 4.0, 2003 </li></ul>
    24. 24. Rationale for Preventive Intervention <ul><li>Indicated prevention: the most promising strategy to attenuate, delay, or even avert psychosis. </li></ul><ul><li>Prevent (or postpone) first psychotic episode. </li></ul><ul><li>Postponement : even a few years of psychosis free functioning can help pts achieve important developmental milestones </li></ul><ul><li>Better education, work and relationship </li></ul><ul><li>Reduce the duration of untreated illness/psychosis </li></ul><ul><li>Figure: Tandon et al 2010 43 </li></ul>
    25. 25. Duration of Untreated Psychosis <ul><li>Lower levels of symptomatic and functional recovery from FEP 3 </li></ul><ul><li>Associated with severity of negative symptoms 3 </li></ul><ul><li>Need for more protracted treatment 6 </li></ul><ul><li>Greater risk of relapse, lower compliance, greater burden to the family, and a higher level of &quot;expressed emotion,“ 6 </li></ul><ul><li>Increased risk of depression and suicide, 6 </li></ul><ul><li>Greater burden on work training 6 </li></ul><ul><li>Increased drug abuse and delinquent behavior, costs of treatment 6 </li></ul><ul><li>Higher temporal grey matter reductions, proportional to UP 1 </li></ul><ul><li>More pronounced structural brain abnormalities, while this is less prominent earlier in the course of the disorder 18 </li></ul><ul><li>DUP: directly proportional to service utilized. Norwegian TIPS 19 study 5w vs 16w </li></ul><ul><li>BUT is a potentially modifiable prognostic factor. </li></ul>
    26. 26. The Cochrane review <ul><li>Early intervention for psychosis. 29 </li></ul><ul><li>Objectives: To evaluate the effects of </li></ul><ul><li>Early detection, Phase specific treatments & Specialized early intervention teams for prodrome </li></ul><ul><li>All randomized trials were included </li></ul><ul><li>Included 7 studies with 941 subjects </li></ul><ul><li>3 Classic studies, goal to “prevent onset of psychosis”: PACE, PRIME & EDIE 28 </li></ul><ul><li>4 studies with goal to “improve outcome of FEP” </li></ul><ul><li>LifeSPAN Australia, utilized LifeSPAN therapy based on COPE </li></ul><ul><li>Linszen Amsterdam, used Behavioral FT </li></ul><ul><li>OPUS Scandinavia: Integrated Rx vs. Standard care </li></ul><ul><li>Zhang-Suzhou: Group or individual family therapy sessios. </li></ul>
    27. 27. The Cochrane review, contd: <ul><li>Conclusions: </li></ul><ul><li>1. Prodrome: Unclear whether treating the prodrome has benefits </li></ul><ul><li>2. FEP: Use of Specialized teams for FEP is ethical, but no evidence </li></ul><ul><li>3. Clinicians: Need to keep up to date with recent developments </li></ul><ul><li>4. Policy makers: Premature to implement wide-spread Rx programs </li></ul><ul><li>Questions raised: </li></ul><ul><li>1. Can phase specific interventions prevent prodrome -> psychosis? </li></ul><ul><li>2. Can early detection reduce DUP? </li></ul><ul><li>3. Do FEP interventions improve outcome? </li></ul><ul><li>Bottom Line : “ We identified insufficient trials to draw any definitive conclusions. The substantial international interest in early intervention offers an opportunity to make major positive changes in psychiatric practice, but making the most of this opportunity requires a concerted international programme of research to address key unanswered questions.” </li></ul>
    28. 28. PACE @ EPPIC <ul><li>Randomized, No Blinding, 59 UHR 26 </li></ul><ul><li>PACE is an extension of the EPPIC, Melbourne, Australia </li></ul><ul><li>SPI: n=31, Specific preventive intervention; Risperidone mean dose 1.3 mg/d, and CBT. 3,6,10/31 </li></ul><ul><li>NBI: n=28, Need based intervention. 10,10,12/28 </li></ul><ul><li>Diagnosis: SANS, HAM-D, YMRS, CAARMS , QLI, GAF </li></ul><ul><li>Outcome: Supra-threshold Psychosis: assessed using BPRS & CASH </li></ul>
    29. 29. PRIME Study <ul><li>1 st Double blind RCT 35 </li></ul><ul><li>4 PRIME sites: New Haven; Chapel Hill; Toronto; Calgary </li></ul><ul><li>60 UHR patients </li></ul><ul><li>Specific Intervention: n=31, received olanzapine 5-15 mg/ 1-year -> no Rx 1 y-f/u, Dropout 14/31 </li></ul><ul><li>Control: n=29, PBO/1 year, no Rx f/u 1 year. Dropout 19/29 </li></ul><ul><li>Diagnosis: SOPS , embedded within SIPS , PANSS, CGI, MADRS, YMRS and GAF </li></ul><ul><li>Outcome: conversion to psychosis; POPS </li></ul>
    30. 30. PRIME Contd: <ul><li>Attrition rate, slightly higher in OLZ, but overall rate 65%(high) </li></ul><ul><li>OLZ did not alter the number of people converting to psychosis. </li></ul><ul><li>EPS, and weight gain high in OLZ group </li></ul><ul><li>Hawkins et al 2008 36 : </li></ul><ul><li>- Participants who converted to psychosis did not differ from placebo non-converters in pre-randomization global neuropsychological status </li></ul><ul><li>- Neither the onset of psychosis nor olanzapine alters neuropsychological course in persons considered to be at high risk at their initial assessment. </li></ul>
    31. 31. EDIE <ul><li>Single Blinded </li></ul><ul><li>Department of Psychology, Manchester UK </li></ul><ul><li>Subjects: 58 UHR </li></ul><ul><li>CT group: n=35 26/w CT sessions & monitoring Conversion:2/35 -> 7/35 Dropout: 9/35 ->18/35 </li></ul><ul><li>Control: n=23 monitoring Conversion:5/23 -> 7/23 dropout: 7/23 ->13/23 </li></ul>
    32. 32. EDIE-2 <ul><li>A second in series single blind multi-site trial in the UK 40 </li></ul><ul><li>Sample: 288 UHR for state or state+trait </li></ul><ul><li>Sites: 5 sites in UK: Manchester, Birmingham/ Worcestershire, Glasgow, Cambridgeshire and Norfolk </li></ul><ul><li>Monitoring:144 receive treatment as needed + regular monitoring </li></ul><ul><li>CT: 144 treatment as needed+ Monitoring +weekly 6 months of CT & 4 booster sessions </li></ul><ul><li>Follow up period: min 1 year to max 2 years </li></ul><ul><li>Primary outcome Measure: Diagnostic criteria CAARMS </li></ul><ul><li>(i) time to transition to psychosis; </li></ul><ul><li>(ii) the reduction in the severity of ARMS experiences; and </li></ul><ul><li>(iii) the reduction in distress caused by ARMS experiences. </li></ul><ul><li>Secondary outcome: Conversion to psychosis using SCID </li></ul>
    33. 33. Call for early CBT interventions <ul><li>McGlashan 2003: Clinical example of a prodromal “unusual thought content” can be: Patient reports considering the possibility, but clearly not believing, that others might be able to read their minds….. </li></ul><ul><li>Impact is greatest in early stages of illness 20, 21 </li></ul><ul><li>Reduces persistent positive symptoms 21 </li></ul><ul><li>Hastens recovery from acute episodes 21 </li></ul><ul><li>Increased adaptation to the illness 22 </li></ul><ul><li>Better acceptance over psychopharmacological interventions, and treatment if needed and accepted 23 </li></ul><ul><li>Reduces co-morbid substance abuse 24 </li></ul>
    34. 34. Vienna ω -3 PUFA Study <ul><li>Setting: Double blind RCT 45 Public Hospital in Vienna Austria </li></ul><ul><li>Subjects: 81 help seeking/UHR patients </li></ul><ul><li>Intervention: 12wk 1.2g/d ω -3 PUFA/PBO </li></ul><ul><li>F/U 40 wks, total duration 52 weeks </li></ul><ul><li>Later 3-4 year f/u NA </li></ul>
    35. 35. Omega-3 Fatty Acids <ul><li>Ω -3FA reduce free radicals, improve antioxidant defense, reduce cell injury. </li></ul><ul><li>Stabilize the serotonergic and dopaminergic systems </li></ul><ul><li>Reduced levels of FA in individuals with SCZ </li></ul><ul><li>Membrane enhancement in neurons, fortification of myelin sheaths </li></ul><ul><li>Randomized, placebo-controlled trial of 1200 mg of ω -3 FA for 12 weeks </li></ul><ul><li>RESULTS: </li></ul><ul><ul><li>4.9% of Rx group vs. 27.5 % PBO -> Psychosis </li></ul></ul><ul><ul><li>PUFA significantly reduced positive and negative symptoms and improved overall functioning </li></ul></ul><ul><ul><li>Results were sustained after one year </li></ul></ul>
    36. 36. The North American Prodromal Longitudinal Study (NAPLS) <ul><li>The largest longitudinal study: 8 sites </li></ul><ul><li>304 CHR, 52 FHR (non-CHR), 193 controls </li></ul><ul><li>Longitudinal : 2½ years f/u </li></ul><ul><li>Outcome(s): neurocognitive composite score, 8 individual neuropsychological measures </li></ul><ul><li>Criteria: SIPS , NNAP </li></ul><ul><li>Findings: </li></ul><ul><li>1. 89/304 CHR (29.5%) </li></ul><ul><li>2. Composite score FHR=CHR </li></ul><ul><li>3. Profiles of 8 variables varied in groups </li></ul><ul><li>Bottom Line: Neuropsychological functioning did not contribute uniquely to the prediction of psychosis </li></ul>
    37. 37. European Prediction of Psychosis Study (EPOS) <ul><li>245 UHR </li></ul><ul><li>Prospective naturalistic field study 46 </li></ul><ul><li>Sites: 6 sites in Europe </li></ul><ul><li>Outcome : iIR or Conversion to psychosis </li></ul><ul><li>7/6, 11/9, 14/12, 19/18 </li></ul><ul><li>Prediction Model has been developed: + symptoms, bizarre thinking, sleep disturbance, SZTYPL, GAF, yrs in Education </li></ul><ul><li>Results: </li></ul><ul><li>- Combining UHR and COGDIS increases sensitivity </li></ul><ul><li>- 4 level prognostic risk indicator, category IV can have predicted iIR up to 85% </li></ul>
    38. 38. Case for diagnostic criteria in DSM-5 <ul><li>The patients are currently ill 44 </li></ul><ul><li>They are at high risk for getting worse </li></ul><ul><li>Young people who are highly distressed and functionally impaired, but not previously recognized as having a diagnosable condition </li></ul><ul><li>The diagnosis is now reliable & valid?? </li></ul><ul><li>A DSM-5 Diagnosis would help </li></ul><ul><ul><li>Promote Rx and prevention research </li></ul></ul><ul><ul><li>Benefit the UHR patients. </li></ul></ul><ul><li>Problems: </li></ul><ul><li>- The amount of training and time required to reliably assess and rate </li></ul><ul><li>- The implications of the lack of an accepted standard treatment, </li></ul>
    39. 39. Attenuated Psychosis Syndrome DSM-V <ul><li>All six of the following: </li></ul><ul><li>a)  Characteristic symptoms: at least one of the following in attenuated form with intact reality testing, but of sufficient severity and/or frequency that it is not discounted or ignored; </li></ul><ul><li>(i)  delusions </li></ul><ul><li>(ii)  hallucinations </li></ul><ul><li>(iii) disorganized speech  </li></ul><ul><li>b)   Frequency/Currency: symptoms meeting criterion A must be present in the past month and occur at an average frequency of at least once per week in past month  </li></ul><ul><li>c)   Progression: symptoms meeting criterion A must have begun in or significantly worsened in the past year </li></ul><ul><li>d)   Distress/Disability/Treatment Seeking:  symptoms meeting criterion A are sufficiently distressing and disabling to the patient and/or parent/guardian to lead them to seek help </li></ul><ul><li>e)   Symptoms meeting criterion A are not better explained by any DSM-5 diagnosis, including substance-related disorder </li></ul><ul><li>f)   Clinical criteria for any DSM-V psychotic disorder have never been met </li></ul>
    40. 40. Deterministic to Probabilistic approach(es) <ul><li>The extension of early intervention from mainstream medicine to psychiatry has generated anxiety and controversy </li></ul><ul><li>Opponents of intervention are concerned about </li></ul><ul><li>1. Psychopharmacological interventions: Drug side effects. </li></ul><ul><li>2. Psychosocial interventions: educating and psychotherapy for psychosis: Stigma, anxiety, self stigmatization, curtailment, needless alarm </li></ul><ul><li>3. False Positive individuals. </li></ul><ul><li>Aim is future incidence reduction </li></ul><ul><li>Lessons from early intervention in cancer, stroke, DM and CAD are not yet translated to psychosis. </li></ul><ul><li>McGlashan (2006) olanzapine vs. placebo. The NNT was 4.5 </li></ul><ul><li>NNT=4 in the Vienna ω -3 PUFA study </li></ul><ul><li>Compare to NNT 14 for Stroke prevention with ASA 41 </li></ul>
    41. 41. Recommendations <ul><li>Preventive approach -> target specific symptoms and not the potential future </li></ul><ul><li>Psychoeducation: Issues to be addressed are &quot;meaning&quot;, &quot;mastery&quot; and &quot;self-esteem“ 42 </li></ul><ul><li>Family involvement can be the key 25 </li></ul><ul><li>Use of non-stigmatizing ‘psychosis’ vs. ‘schizophrenia’ </li></ul><ul><li>Closer monitoring and tailored crisis plans. </li></ul><ul><li>Role of antipsychotics? </li></ul><ul><li>Fish oil for everyone? </li></ul><ul><li>(Adapted from the BCU Mental Health Evaluation &Community Consultation Early Psychosis Guide & guidelines for early psychosis 2005.) </li></ul>
    42. 42. Concept of recovery then to now…. <ul><li>DSM III (1980): “a complete return to premorbid levels of functioning in individuals with schizophrenia is so rare as to cast doubt upon the accuracy of the diagnosis” </li></ul><ul><li>DSM IV (2000): Complete remission… is not common in this disorder </li></ul><ul><li>DSM-5 : HOPE…for HOPE </li></ul>
    43. 43. Elyn Saks <ul><li>Elyn Saks is Associate Dean and Professor of Law, Psychology, and Psychiatry @ University of Southern California Gould Law School and an expert in mental health law. </li></ul><ul><li>Sporadic symptoms of schizophrenia that were undiagnosed during high school, symptoms escalated during college. In graduate school at Oxford, England she suffered a full-blown psychotic episode. Symptoms erupted later as she studied law at Yale. Admitted to New Haven Hospital (was restrained). With therapy and pharmaceuticals, she successfully manages her schizophrenia </li></ul><ul><li>The Center Cannot Hold: My Journey Through Madness :Hyperion Books, 2007. </li></ul><ul><li>Dr. Saks is in training as a psychoanalyst in Southern California </li></ul><ul><li>2009: Robert H. MacArthur Award a.k.a “Genius Award” </li></ul>
    44. 44. Carol. S. North M.D. <ul><li>Dr. North currently serves as Professor of Psychiatry at UTSW </li></ul><ul><li>First break: late in high school </li></ul><ul><li>Freshman year: Hospitalized Dx with SCZ </li></ul><ul><li>Medical school at the University of Iowa. illness worsened…expelled </li></ul><ul><li>Reapplied to WUSOM, accepted </li></ul><ul><li>Faculty @ WU- 18 years </li></ul><ul><li>&quot;I see myself as blessed with a sort of personal miracle, It was just against all odds because we know from experience in the field that few people recover or do as well as I've done. </li></ul>
    45. 45. Fall seven times, stand up eight. Japanese proverb <ul><li>John Nash : An eccentric mathematical genius whose sudden youthful plunge into schizophrenia could have ended in obscurity or tragedy. Instead, his 30-year battle against crippling mental disease ended in triumph--and winning the 1994 Nobel Prize in economics, as recounted in the blockbuster 2001 film, A Beautiful Mind. </li></ul><ul><li>Tom Harrell has been called the John Forbes Nash, Jr. of jazz. Against considerable odds, Harrell has successfully struggled with schizophrenia and become one of the most respected trumpeters and composers of the past 30 years. </li></ul><ul><li>Andy Goram - Scottish Soccer Player/Goal Keeper - His superb reaction saves and bravery have earned him World Cup recognition since earning his first Scotland cap while an Oldham Athletic player in 1986. </li></ul><ul><li>Roger Keith ‘Syd’ Barrett : Vocalist, guitarist Pink Floyd 1946-2006 </li></ul>
    46. 46. Future directions & Challanges <ul><li>Are specific treatments superior to non-specific </li></ul><ul><li>How acceptable are treatments to patients/families </li></ul><ul><li>What is the optimal sequence of treatments & for how long </li></ul><ul><li>What factors in what phase of illness predict treatment response </li></ul><ul><li>ω -3 PUFA, CBT, CET : Promise </li></ul><ul><li>EPOS: evaluation of delays and obstacles to adequate treatment </li></ul><ul><li>Produce awareness and prevention programs for the community </li></ul><ul><li>False False Positives </li></ul><ul><li>Only help seeking patients come to specialized clinics </li></ul><ul><li>Minimal awareness amongst PCP </li></ul><ul><li>Depression, withdrawal, and psychotic like experiences are commonly reported amongst adolescents and young adults </li></ul><ul><li>Diagnostic criteria are still not clearly defined. </li></ul><ul><li>Bigger catchment areas, multicenter studies & international collaboration are needed. </li></ul>
    47. 47. Early intervention Clinics in USA <ul><li>UCLA: The Staglin Music Festival Center for the Assessment and Prevention of Prodromal States (CAPPS) </li></ul><ul><li>PART (Prodrome Assessment Research and Treatment) Program - at University of California, San Francisco (UCSF) </li></ul><ul><li>Cognitive Assessment and Risk Evaluation (CARE) Program at the University of California, San Diego (UCSD) </li></ul><ul><li>Sacramento , California - EDAPT (Early Diagnosis and Preventive Treatment) </li></ul><ul><li>PRIME (Prevention through Risk Identification, Management & Education) Research Clinic - Yale University Medical School </li></ul><ul><li>First Episode Psychosis Program at the University of Illinois Medical Center at Chicago </li></ul><ul><li>Portland, Maine - The Portland Identification and Early Referral (PIER) program </li></ul><ul><li>First Episode Clinic - Maryland Psychiatric Research Center at University of Maryland School of Medicine. </li></ul><ul><li>First Episode and Early Psychosis Program (FEPP) at Massachusetts General Hospital. </li></ul><ul><li>Boston/Jamaica Plain Neighborhood Prevention and Recovery in Early Psychosis (PREP) </li></ul><ul><li>Services for the Treatment in Early Psychoses (STEP) at Wayne State University </li></ul><ul><li>The Center of Prevention & Evaluation (COPE) – Columbia University Department of Psychiatry/ New York State Psychiatric Institute   </li></ul><ul><li>Recognition and Prevention (RAP) Program - Lake Success, New York </li></ul><ul><li>PRIME @ the University of North Carolina at Chapel Hill </li></ul><ul><li> Oregon Salem, Oregon Early Assessment and Support Team (EAST) </li></ul>
    48. 48. Dr. Ashok. R. Shah Dr. David. R. Rosenberg Dr. Rajaprabhakaran Rajarethinam Acknowledgements
    49. 49. Questions ???? <ul><li>“ The statistics [ …... ] are that one out of every four Americans is suffering from some form of mental illness. Think of your three </li></ul><ul><li>best friends. If they're okay, then it's you.” Rita Mae Brown </li></ul>
    50. 50. References <ul><li>1. Lappin JM, Morgan K, Morgan C, Hutchison G, Chitnis X,Suckling J, et al. Gray matter abnormalities associatedwith duration of untreated psychosis. Schizophr Res 2006;/83:/14553. </li></ul><ul><li>2. Large M, Sharma S, Compton MT, Slade T, Nielssen O.Cannabis Use and Earlier Onset of Psychosis: A Systematic Meta-analysis: Arch Gen Psychiatry. 2011 Feb 7. [Epub ahead of print] </li></ul><ul><li>3. Perkins DO, Gu H, Boteva K, Lieberman JA. Relationship between duration of untreated psychosis and outcome in first-episode schizophrenia: a critical review and meta-analysis: Am J Psychiatry. 2005 Oct </li></ul><ul><li>4. Joachim Klosterko¨tter,Frauke Schultze-Lutter,Stephan Ruhrmann: Kraepelin and psychotic prodromal conditions: Eur Arch Psychiatry Clin Neurosci (2008) 258 </li></ul><ul><li>5. Kraepelin E (1909) Psychiatrie. Ein Lehrbuch fu¨r Studierendeund A¨ rzte. Achte, vollsta¨ndig umgearbeitete Auflage. I. Band. Allgemeine Psychiatrie. Barth Verlag, Leipzig </li></ul><ul><li>6. Ruhrmann S, Schultze-Lutter F, Klosterkötter J: Early detection and intervention in the initial prodromal phase of schizophrenia. Pharmacopsychiatry 2003; 3: 162–7. </li></ul><ul><li>7. Kellam SG, Langevin DJ A framework for understanding evidence in prevention research and programs. Prev Sci. 2003 Sep;4(3):137-53. </li></ul><ul><li>8. Medical Research Council National Survey of Health and Development.(1946 British Birth cohort). </li></ul><ul><li>9. The National Child Development Study(1958 British birth cohort study). </li></ul><ul><li>10. BCS-70, British cohort study 1970 </li></ul><ul><li>11. Millenium cohort study 200 </li></ul><ul><li>12.. 1966 Northern Finland Birth Cohort. </li></ul><ul><li>13. Helsinki 1951-1960 Birth cohort. </li></ul><ul><li>14. Swedish Conscript Cohort. </li></ul><ul><li>15. Israeli Draft Board Conscript Cohort. </li></ul><ul><li>16. The Philadelphia Cohort. </li></ul>
    51. 51. References <ul><li>17. The Dunedin Multidisciplinary Health and Developmental Survey. </li></ul><ul><li>18. M.S. Keshavan and A. Amirsadri, Early intervention in schizophrenia: current and future perspectives, Curr. Psychiatry Rep. 9 (4) (2007),325–328 </li></ul><ul><li>19. Melle et al., 2004 I. Melle, T.K. Larsen, U. Haahr, S. Friis, J.O. Johannessen and S. Opjordsmoen et al. , Reducing the duration of untreated first-episode psychosis: effects on clinical presentation, Arch. Gen. Psychiatry 61 (2) (2004),. 143–150 </li></ul><ul><li>20. J. Scott, E. Paykel, R. Morriss, R. Bentall, P. Kinderman and T. Johnson et al. , Cognitive-behavioural therapy for severe and recurrent bipolar disorders: randomised controlled trial, Br. J. Psychiatry 188 (2006), pp. 313–320 </li></ul><ul><li>21. N. Tarrier, Cognitive behaviour therapy for schizophrenia — a review of development, evidence and implementation, Psychother. Psychosom. 74 (2005), pp. 136–144 </li></ul><ul><li>22. H. Jackson, P. McGorry, L. Henry, J. Edwards, C. Hulbert and S. Harrigan et al. , Cognitively oriented psychotherapy for early psychosis (COPE): a 1-year follow-up, Br. J. Clin. Psychol. 40 (Pt 1) (2001), pp. 57–70. </li></ul><ul><li>23. G. Haddock and S. Lewis, Psychological interventions in early psychosis, Schizophr. Bull. 31 (3) (2005), pp. 697–704. </li></ul><ul><li>24. J. Edwards, K. Elkins, M. Hinton, S.M. Harrigan, K. Donovan and O. Athanasopoulos et al. , Randomized controlled trial of a cannabis-focused intervention for young people with first-episode psychosis, Acta Psychiatr. Scand. 114 (2) (2006), pp. 109–117 </li></ul><ul><li>25. D. Addington and J. Addington, First-episode psychosis. In: K.T. Mueser and D.V. Jeste, Editors, Clinical Handbook of Schizophrenia , Guildford Press, New York (2008), pp. 367–379. </li></ul><ul><li>26. McGorry PD, Yung AR, Phillips LJ, Yuen HP, Francey S, Cosgrave EM, Germano D, Bravin J, McDonald T, Blair A, Adlard S, Jackson H. Randomized controlled trial of interventions designed to reduce the risk of progression to first-episode psychosis in a clinical sample with subthreshold symptoms. Arch Gen Psychiatry. 2002 Oct;59(10):921-8. </li></ul><ul><li>27. Morrison AP, French P, Walford L, Lewis SW, Kilcommons A, Green J, Parker S, Bentall RP. Cognitive therapy for the prevention of psychosis in people at ultra-high risk: randomised controlled trial; Br J Psychiatry. 2004 Oct;185:291-7 </li></ul><ul><li>28. Anthony P. Morrison, Paul French, Sophie Parker,Morwenna Roberts, Helen Stevens2, Richard P. Bentall,and Shoˆn W. Lewis:Three-Year Follow-up of a Randomized Controlled Trial of Cognitive Therapy for the Prevention of Psychosis in People at Ultrahigh Risk: Schizophrenia Bulletin vol. 33 no. 3 pp. 682–687, 2007 </li></ul><ul><li>29. Marshall M and Rathbone J; Cochrane Database Syst Rev. 2006 Oct 18;(4):CD004718 </li></ul>
    52. 52. References <ul><li>30. McGorry PD, Yung AR, Phillips LJ; The &quot;close-in&quot; or ultra high-risk model: a safe and effective strategy for research and clinical intervention in prepsychotic mental disorder; Schizophr Bull. 2003;29(4):771-90. </li></ul><ul><li>31. Klosterkötter J: Indicated prevention of Schizophrenia. Deutsches Ärzteblatt International Dtsch Arztebl Int 2008; 105(30): 532–9 </li></ul><ul><li>32. Zubin J, Spring B (April 1977). &quot;Vulnerability--a new view of schizophrenia&quot;. J Abnorm Psychol 86 (2): 103–26 </li></ul><ul><li>33. Pelayo-Tera´n JM, Pe´rez-Iglesias R, Mata I, Carrasco-Marı´n E, Va´zquez-Barquero JL, Crespo-Facorro B. Catechol-O-Methyltransferase (COMT) ValMet variations and cannabis use in first-episode non-affective psychosis: clinical-onset implications. Psychiatry Res . 2010;179(3):291-296. </li></ul><ul><li>34. D'Souza DC, Abi-Saab WM, Madonick S, Forselius-Bielen K, Doersch A, Braley G, Gueorguieva R, Cooper TB, Krystal JH: Delta-9-tetrahydrocannabinol effects in schizophrenia: implications for cognition, psychosis, and addiction. Biol Psychiatry. 2005 Mar 15;57(6):594-608 </li></ul><ul><li>35. McGlashan TH, Zipursky RB, Perkins D, Addington J, Miller T, Woods SW, Hawkins KA, Hoffman RE, Preda A, Epstein I, Addington D, Lindborg S, Trzaskoma Q, Tohen M, Breier A. Randomized, double-blind trial of olanzapine versus placebo in patients prodromally symptomatic for psychosis.Am J Psychiatry. 2006 May;163(5):790-9. </li></ul><ul><li>36. Hawkins KA, Keefe RS, Christensen BK, Addington J, Woods SW, Callahan J, Zipursky RB, Perkins DO, Tohen M, Breier A, McGlashan TH. Neuropsychological course in the prodrome and first episode of psychosis: findings from the PRIME North America Double Blind Treatment Study.Schizophr Res. 2008 Oct;105(1-3):1-9 </li></ul><ul><li>37. Tienari P,Wynne LC, Sorri A, Lahti I, Läksy K,Moring J,Naarala M,Nieminen P, Eahlberg K-E, Miettunen J (2002) Genotype-environment interaction in the Finnish adoptive family study – Interplay between genes and environment? In: Häfner H (ed) Risk and protective factors in schizophrenia. Steinkopff-Verlag,Darmstadt, pp 29–38 </li></ul><ul><li>38. Warner D (2001) The prevention of schizophrenia: what interventions are safe and effective? Schizophr Bull 27:551–562 </li></ul><ul><li>39. The epidemiology of schizophrenia By Robin Murray (MD, M Phil, MRCP, MRC Psych.), </li></ul><ul><li>40. Morrison AP, Stewart SL, French P, Bentall RP, Birchwood M, Byrne R, Davies LM, Fowler D, Gumley AI, Jones PB, Lewis SW, Murray GK, Patterson P, Dunn G. Early detection and intervention evaluation for people at high-risk of psychosis-2 (EDIE-2): trial rationale, design and baseline characteristics. Early Interv Psychiatry. 2011 Feb;5(1):24-32. </li></ul><ul><li>41.Haynes RB,Sackett DL,Guyatt GH et al 2006: Clinical Epidemiology, Lippincott Williams and Williams. </li></ul>
    53. 53. References <ul><li>42. BCU Mental Health Evaluation &Community Consultation Early Psychosis Guide </li></ul><ul><li>43. Tandon R, Nasrallah HA, Keshavan MS Schizophrenia, &quot;just the facts&quot; 5. Treatment and prevention. Past, present, and future. Schizophr Res. 2010 Sep;122(1-3):1-23 </li></ul><ul><li>44. Woods SW, Walsh BC, Saksa JR, McGlashan TH; The case for including Attenuated Psychotic Symptoms Syndrome in DSM-5 as a psychosis risk syndrome..Schizophr Res. 2010 Nov;123(2-3):199-207 </li></ul><ul><li>45. Amminger GP, Schäfer MR, Papageorgiou K, Klier CM, Cotton SM, Harrigan SM, Mackinnon A, McGorry PD, Berger GE. Long-chain omega-3 fatty acids for indicated prevention of psychotic disorders: a randomized, placebo-controlled trial. Arch Gen Psychiatry. 2010 Feb;67(2):146-54. </li></ul><ul><li>46. Ruhrmann S, Schultze-Lutter F, Salokangas RK, Heinimaa M, Linszen D, Dingemans P, Birchwood M, Patterson P, Juckel G, Heinz A, Morrison A, Lewis S, von Reventlow HG, Klosterkötter J. Prediction of psychosis in adolescents and young adults at high risk: results from the prospective European prediction of psychosis study. Arch Gen Psychiatry. 2010 Mar;67(3):241-51 </li></ul>

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