The Ultra High Risk for psychosis concept: progress, pitfalls and plans for the future Professor Alison Yung Institute of Brain Behaviour and Mental

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1 The Ultra High Risk for psychosis concept: progress, pitfalls and plans for the future Professor Alison Yung Institute of Brain Behaviour and Mental Health University of Manchester Den Haag, May 2013

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3 Our land abounds in nature s gifts Of beauty rich and rare

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8 Not to scale

9 Overview History of the concept Recent research Controversies Future Directions

10 Idea of the UHR state Can we detect the prodrome of schizophrenia prospectively?

11 sys treatment psychosis prodrome DUP time

12 If possible to identify the prodromal phase, can we intervene to ameliorate the onset of schizophrenia, delay onset or even prevent it?

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14 Prodromal symptoms Non -specific symptoms eg depressed mood, anxiety, sleep disturbance Subthreshold or attenuated psychotic symptoms Behavioural changes eg social withdrawal, deterioration in role functioning

15 sys treatment psychosis prodrome DUP time

16 sys Threshold for diagnosis of psychosis? time

17 True Positive sys Threshold for diagnosis of psychosis psychosis prodrome time

18 sys False positive Threshold for diagnosis of psychosis resolving symptoms time

19 False false positive sys Threshold for diagnosis of psychosis symptoms resolved with intervention time

20 sys treatment psychosis prodrome DUP time

21 sys treatment psychosis At Risk Mental State DUP time

22 At Risk Mental State (ARMS) A cluster of symptoms and signs that is associated with a high risk of onset of psychotic disorder in the near future Ultra High Risk (UHR) criteria are the operationalised criteria used to detect ARMS

23 Ultra High Risk criteria Age: adolescence to young adulthood: age range at highest risk for onset of a psychotic disorder Attenuated psychotic features, and/or BLIPS: Brief Limited Intermittent Psychotic Symptoms and/or Family history of psychotic disorder in a first degree relative PLUS evidence of deterioration - significant decline in functioning

24 Arbitrary line Psychosis threshold

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26 Psychosis threshold Arbitrary line Full threshold positive psychotic symptoms For at least one week Several times per day Empirically defined

27 Can we predict outcome?

28 Setting PACE Clinic established Youth friendly and easily accessible health service Personal Assessment and Crisis Evaluation Individuals seen are help-seeking Help-seeking therefore an implicit UHR criterion

29 Proof of Concept 2003 PACE Clinic study found rate of onset of psychotic disorder transition rate of 40.8% in 12 months (20 of 49) Many other clinical UHR services around the world Meta-analysis (Fusar-Poli 2012): 22% in I year, 29% in 2 years and 36% after 3 years Recent PACE study: 35% in 10 years

30 Proof of Concept Although transition rates not as high as initial study, still several hundred fold above rates of onset of psychotic disorder in the general population. UHR state identifies individuals at increased risk of psychotic disorder Highest risk is within the first 1-2 years of helpseeking About 73% of those developing a psychotic disorder fulfill criteria for schizophrenia.

31 Controversies 1 1. Unethical to treat these people Help seeking, symptomatic Referred to PACE (or similar service) from another service eg GP, counseling service High rates of mood disorder, problems with living

32 Treatment of UHR state In RCTs: Antipsychotic medication, cognitive therapy and fish oil all seem to be of benefit in reducing current symptoms and preventing or delaying transition to psychosis

33 Treatment of UHR state Given the effectiveness of benign interventions, such as cognitive therapy and fish oil, antipsychotic medication is not recommended These benign treatments likely to be effective for mood disorder, general distress anyway ie treating false positives

34 Controversies 2 2. Unethical to label these people How to communicate increased risk Important to address issues such as potential for decreasing risk, stigma Risk is not disorder

35 Controversies 3 Proposal to make a subgroup of UHR criteria a diagnosis in DSM 5

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37 Ultra High Risk criteria Attenuated psychotic features, BLIPS: Brief Limited Intermittent Psychotic Symptoms and/or Family history of psychotic disorder in a first degree relative PLUS evidence of deterioration - significant decline in functioning

38 Ultra High Risk criteria Attenuated psychotic features, BLIPS: Brief Limited Intermittent Psychotic Symptoms and/or Family history of psychotic disorder in a first degree relative PLUS evidence of deterioration - significant decline in functioning

39 Should the Attenuated Psychosis Syndrome be included in DSM5? We need to consider the following 1. Is it a valid mental disorder? 2. Can it be reliably detected? 3. If there are doubts about either of these issues, are there still reasons to include it? 4. Are there reasons to not include it?

40 Is APS a real clinical entity? How is a disease/disorder validated? 1. Clinical description 2. Course and outcome 3. Delimitation from other disorders 4. Response to treatment 5. Laboratory studies 6. Family studies (based on Robins & Guze)

41 Is APS a real clinical entity? Clinical description People presenting with the syndrome are probably a heterogenous group - different types of psychotic like experiences (PLEs) PLEs may have different underlying aetiologies

42 In a given individual, PLE might be: a. An expression of an underlying, more fundamental disturbance suggesting vulnerability to a psychotic disorder such as schizophrenia. b. Clinical noise around a non-psychotic syndrome ( incidental PLE). c. Present in non-clinical normal individuals, and not associated with distress or disability or increased vulnerability to psychotic disorder.

43 Is APS a real clinical entity? Course and outcome of UHR group varies considerably

44 Delimitation from other disorders Comorbidity with other Axis I disorders is common Depressive disorders and anxiety disorders often have psychotic symptoms Likely that psychotic symptoms in the context of major depression ( incidental PLEs ) have different aetiology than those without depression

45 Delimitation from other disorders Also issue of distinguishing psychotic like experiences (PLEs) that represent a risk state for disorder and PLEs that are found commonly in the general population

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47 More information needed on 3. Response to treatment 4. Aggregation in families 5. Distinctive findings on laboratory tests

48 Are there social reasons why it should be included? Enables people with the diagnosis to access health care (within US system) Possibility of more research funding

49 Are there social reasons why it should NOT be included? May result in labeling that could be lifelong stigma discrimination (life insurance, access to adoption, entry into US!) self-stigmatization discrediting of opinions, evidence

50 Unintended consequences People being labelled as at risk, the majority of whom will not be at risk of psychosis. Involuntary, unwanted or unnecessary treatment How long will the label apply? Increased pharma funding may result in increased use of antipsychotics, that will not be indicated in the majority of patients

51 Other social effects of diagnosis May enable people - to avoid military service - claim diminished responsibility for actions, including crimes May also result in changes to the way mental health professionals view patients Diagnostic creep - people on the boundaries now given diagnoses

52 Although intentions are good, there could be unintended negative social effects

53 Should it be a diagnosis NO! No doubt that distressed people with attenuated psychotic symptoms seeking help need treatment But should they attract a specific DSM diagnosis that implies progression to more severe illness? Although intentions are good, there could be unintended negative social effects More research needed on validators to enhance prediction and decrease false positives, and to increase reliability

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55 Proposals from DSM5 working group Attenuated Psychosis Syndrome NOT to be included as a diagnosis Proposed for Section III, a section of DSM- 5 for conditions that require further study

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59 Controversies 4 Is the transition point meaningful?

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61 Are all transitions meaningful? Transition is an arbitrary line

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64 Investigation of the relationship between transition and functional outcome

65 Functional outcome research questions Does the group that transitioned have lower long-term functional outcome compared to the group that did not transition? How valid is transition status as a determinant of poor long-term functional outcome?

66 Method Poor functional outcome was defined by low scores on the Quality of Life Scale (QLS; Heinrichs, Hanlon and Carpenter, 1984) and the Social and Occupational Functioning Assessment Scale (SOFAS; Goldman et al., 1992) at follow-up assessment.

67 Method Cluster analysis analysis was used to identify 3 groups: good, average and poor functional outcome. The good and average group were combined (n = 214) and compared to those with the worst outcome (n = 54).

68 Results Transition at follow up Poor functioning at follow up Yes No Yes No

69 Results Note: 45 individuals transitioned but had good functioning at follow up 26 individuals did not transition but had poor functioning at follow up

70 Results We can treat transition like a test and poor long term functional outcome as the gold standard definition of the disorder we are interested in. The question becomes, How well does transition identify people with poor longterm functioning? The usual methods of evaluating a test can be applied:

71 Results Odds Ratio of Transition predicting poor outcome = 4.04 (2.2, 7.6). Chi square p< Sensitivity (0.380, 0.654) Specificity (0.728, 0.841) PPV (0.274, 0.505) NPV (0.809, 0.909)

72 Results Thus the likelihood of having poor outcome if a UHR individual transitions is less than 40%. Most people who transition do not develop poor long-term outcome. (PPV)

73 Results Just over 50% of those with poor outcome are identified through their transition status. Nearly half of those with poor longterm outcome have not experienced transition. (sensitivity)

74 Baseline predictors of poor functioning Cognitive impairment Low functioning Negative symptoms

75 Discussion Not all transitions have poor outcome Poor outcome can occur in the absence of transition

76 Discussion Not all transitions have poor outcome Poor outcome can occur in the absence of transition

77 Controversies 5 How specific are the UHR criteria for psychosis? Examination of presence of non-psychotic disorders at 2 14 years follow up

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80 UHR research what we have learned?

81 UHR research what we have learned? Attenuated (subthreshold) psychotic sys are nonspecific. Many people presenting with UHR criteria have non-psychotic disorders, particularly depression. In many of these cases depression persists over the long term. A smaller number have new onset of incident depression. This is coupled by the finding that depressive and anxiety disorders often have psychotic sys

82 UHR research what we have learned? Many people meeting UHR criteria develop psychotic disorders, including schizophrenia. Predictors of transition include low psychosocial functioning at intake, negative sys, long duration of sys. The criteria are relatively specific for psychosis compared to depression & anxiety disorders, when baseline prevalence is taken into account.

83 UHR research what we have learned? Some people who transition function well. Maybe because their transition is not really a transition, but a temporary worsening of preexisting psychotic sys, : trivial transition. Not indicative of onset of a psychotic disorder like schizophrenia.

84 UHR research what we have learned? Some who transition may function well because of early intervention - negligible DUP, good relationship with treating team, optimal treatment. Some may do well because they are the type of person that sought help early, do not use substances, good social support (all reasons why they sought help early in first place). Ie they have good prognostic indicators

85 Future directions Examine outcomes other than psychosis Examine resilience factors Link outcomes with biological markers eg brain structure and function (eg connectivity)

86 Future directions Examine effect of being told of at risk status Stigma associated with receiving intervention and attending service versus stigma of having symptoms and feeling unable to cope

87 Future directions Develop new interventions - ongoing multisite trial of fish oil - vitamin D

88 Acknowledgements Barnaby Nelson Ashleigh Lin Andy Thompson Cathy Greenwood-Smith Rachel Koelmeyer Magenta Simmons Christos Pantelis Elizabeth Cosgrave Danny Kelly Lisa Phillips Steven Leicester Lisa O Dwyer Stephen Wood Daniela Spiliotacopoulos Christina Brossard Annie Bruxner Patrick McGorry Paul Amminger Shona Francey Kathryn Baker Margaret Ross Hok Pan Yuen Gregor Berger John Koutsogiannis Dennis Velakoulis Helen Krstev Carrie Stanford Susanne Jones Natalie Kobilek Henry Jackson Any many more

89 The end - thanks!

90 Discussion