PhD Project Available- Risk Factors High Risk Pscyhosis

Risk factors and outcomes of persistent primary negative symptoms in those at high risk of psychosis

Supervisors: Alison Yung, Barnaby Nelson, Hok Pan Yuen

Negative symptoms of schizophrenia, such as lack of facial expressions (blunted affect), anhedonia, and avolition, have long been described 1. Primary negative symptoms, that is those that are not caused by medication side effects or positive or depressive symptoms, are considered fundamental to the illness 2-4. Their neurobiological basis remains unknown 5. Underlying pathology may depend on their nature, as there is now evidence that there are two distinct negative symptom sub-groups: diminished expression and amotivation 6, 7, which may have different underlying causes.

Negative symptoms occur early in the illness, including in the first episode of psychosis 8, 9. They are associated with poor functional outcome, especially if they are persistent 4, 6, 10. They are recognised as an area of unmet therapeutic need 11. However, no effective treatments have been found 4, 12. Indeed, while Early Intervention Services for psychosis have shown benefits in improving symptoms and functioning, those least likely to recover are those with high negative symptoms at baseline 13.

A different approach to understanding and treating negative symptoms may be to focus even earlier in the course of illness than the first psychotic episode, by targeting individuals at Ultra High Risk (UHR) for psychosis (also known as Clinical High Risk and At Risk Mental State)14. UHR individuals are at high risk of developing a psychotic disorder. Negative symptoms are common in this group 14-20 and are associated with increased risk of development of psychotic disorder 17, 18, 21, low functioning and quality of life 16, 22.

The aim of this PhD project is to identify risk factors and outcomes for PPNS in the UHR group. This will be done through analysis of existing data. We have data on over 1000 participants who participated in UHR studies and had a baseline assessment between 1993 and 2018. PPNS can be identified in this cohort and risk factors, such as history of trauma and neurocognitive impairment and outcomes, such as development of psychotic disorder and social disability, examined.

This PhD project will give the student the opportunity to work with a rich and unique data set –the largest and longest running UHR group in the world. The research will create new knowledge and potentially lead to hypothesis driven interventions in the future.

References

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2. Veerman S, Schulte PF, de Haan L. Treatment for negative symptoms in schizophrenia: A comprehensive review. Drugs 2017;13:1423-1459.

3. Kirkpatrick B, Mucci A, Galderisi S. Primary, enduring negative symptoms: an update on research Schizophrenia Bulletin 2017;43:730–736.

4. Bucci P, Galderisi S. Categorizing and assessing negative symptoms. Current Opinion in Psychiatry 2017;30:201–208.

5. Galderisi S, Merlotti E, Mucci A. Neurobiological background of negative symptoms. European Archives of Psychiatry and Clinical Neuroscience 2015;265:543–558.

6. Marder S, Galderisi S. The current conceptualization of negative symptoms in schizophrenia. World Psychiatry 2017;16:14–24.

7. Strauss G, Horan W, Kirkpatrick B, et al. Deconstructing negative symptoms of schizophrenia: Avolition–apathy and diminished expression clusters predict clinical presentation and functional outcome. Journal of Psychiatric Research 2013;47:783–790.

8. Galderisi S, Mucci A, Bitter B, Libiger J, Bucci P, Fleischhacker W, Kahn RS. Persistent negative symptoms in first episode patients with schizophrenia: Results from the European First Episode Schizophrenia Trial. European Neuropsychopharmacology 2013;23:196–204.

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10. Fervaha G, Foussias G, Agid O, Remington G. Motivational deficits in early schizophrenia: Prevalent, persistent, and key determinants of functional outcome. Schizophrenia Research 2015;166:9-16.

11. Kirkpatrick B, Fenton WS, Carpenter WT, Marder SR. The NIMH-MATRICS consensus statement on negative symptoms. Schizophrenia Bulletin 2006;32(2):214-219.

12. Fusar-Poli P, Papanastasiou E, Stahl D, Rocchetti M, Carpenter W, Shergill S, McGuire P. Treatments of negative symptoms in schizophrenia: Meta-analysis of 168 randomized placebo-controlled trials. Schizophrenia Bulletin 2015;41:892–899.

13. Hegelstad WV, Larsen TK, Auestad B, et al. Long-Term Follow-Up of the TIPS Early Detection in Psychosis Study: Effects on 10-Year Outcome American Journal of Psychiatry 2012;169:374-380.

14. Yung AR, Phillips LJ, Yuen HP, Francey SM, McFarlane CA, Hallgren M, McGorry PD. Psychosis prediction: 12-month follow up of a high-risk ("prodromal") group. Schizophrenia Research 2003;60(1):21-32.

15. Piskulic D, Addington J, Cadenhead K, et al. Negative symptoms in individuals at clinical high risk of psychosis. Psychiatry Research 2012;196:220-224.

16. Wood S, Lin A, Nelson B, McGorry P. Negative symptoms in the at-risk mental state—association with transition to psychosis and functional outcome. Early Intervention in Psychiatry 2014:8:23.

17. Demjaha A, Valmaggia L, Stahl D, Byrne M, McGuire P. Disorganization/cognitive and negative symptom dimensions in the at-risk mental state predict subsequent transition to psychosis. Schizophr Bull 2012;38:351-359.

18. Devoe D, Cadenhead K, Cannon T, et al. Negative symptoms in youth at Clinical High Risk of Psychosis Schizophrenia Bulletin 2017;43:S207–S208.

19. Goldsmith D, Haroun E, Miller A, et al. Association of baseline inflammatory markers and the development of negative symptoms in individuals at clinical high risk for psychosis. Brain, Behavior, and Immunity 2019;76:268-274.

20. Azar M, Pruessner M, Baer LH, Iyer S, Malla AK, Lepage M. A study on negative and depressive symptom prevalence in individuals at ultra-high risk for psychosis. Early Intervention in Psychiatry 2018;12:900-906.

21. Nelson B, Yuen HP, Wood SJ, et al. Long term follow up of a group at ultra high risk ("prodromal") for psychosis: the PACE 400 study. . JAMA Psychiatry 2013;70:793-802.

22. Yung AR, Cotter J, Wood SJ, McGorry P, Thompson AD, Nelson B, Lin A. Childhood maltreatment and transition to psychotic disorder independently predict long term functioning in young people at Ultra High Risk for psychosis. Psychological Medicine 2015;45(16):3453-3465.