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Treatment Refractory Psychosis: What ’ s new and what ’ s not…

Treatment Refractory Psychosis: What ’ s new and what ’ s not… Dr Fiona Gaughran, Lead Consultant, National Psychosis Service, South London and Maudsley Trust. F Gaughran: Declaration of Interests. Last 3 years: Honoraria /Advisor: BMS, Roche . Family professional links; GSK, Lilly

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Treatment Refractory Psychosis: What ’ s new and what ’ s not…

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  1. Treatment Refractory Psychosis: What’s new and what’s not… Dr Fiona Gaughran, Lead Consultant, National Psychosis Service, South London and Maudsley Trust Declaration of Interests: Honoraria/Grants/Advisor: BMS, Roche. Family professional links; GSK, Lilly

  2. F Gaughran: Declaration of Interests Last 3 years: Honoraria/Advisor: BMS, Roche. Family professional links; GSK, Lilly Previously funds for conferences / unrestricted research grants / advisory bodies: Astra-Zeneca, Janssen, BMS, Lilly

  3. National Psychosis Service

  4. National Psychosis Service: Why are people referred?

  5. Team

  6. Van Os and Kapur, 2010 Assessment

  7. Assessment of Past Treatments

  8. Psychological Therapies

  9. Kane J, Honigfeld G, Singer J et al. Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry. 1988; 45: 789-796

  10. Quetiapine Clozapine Risperidone Olanzapine Any Cause Lack of Efficacy CATIE – 2E 1.0 0.8 0.6 0.4 0.2 0.0 Proportion of Patients Continuing Treatment Patient’s Decision Intolerability 1.0 0.8 0.6 0.4 0.2 0.0 0 3 6 9 12 15 18 0 3 6 9 12 15 18 Time to Phase 2 discontinuation (months) McEvoy, et al. Am J Psychiatry 2006;163:600-610

  11. Other evidence echoes this • Early rather than late (CATIE) • Offer it after only 1 AP? • Cost effectiveness – (Cutlass) • Clozapine given to 33% in NZ; • Low discontinuation. • Longer treatment associated with • Independent living, • more OT, • less compulsory Rx • less hospitalisation • Wheeler et al 2008

  12. Clozapine Optimisation

  13. Optimising clozapine essential, including psychosocial aspect

  14. Re-Challenge after neutropaenia Was it all down to the Clozapine? • Do you challenge the CNRD? • Benign Ethnic Neutropaenia/ other meds at fault? • Does Lithium help? • When is GCSF useful and how is it best used?

  15. Other Problems • Post Cardiac Side effects • Post-pericarditis • Post-hepatitis • Close collaboration with Medical Specialists (with an interest in psychotropic side effects) is essential

  16. Waddington et al, 1998 Barbui et al, 2009; Attard and Gaughran, 2009 Zink et al 2010; Augmenting clozapine with another anti-psychotic • “Marginal therapeutic benefit – but effect size small - Taylor & Smith 2009 • “Modest therapeutic benefit – but effect size small” – Taylor et al 2012 • increases mortality risk • High dose guidelines • Interactions can result in higher blood levels and longer QTc • Sulpiride • Amisulpride • Risperidone • Aripiprazole 5-15mg - Lower Clozapine dose / fewer s/e.

  17. Augmenting Clozapine with non AP • Lamotrigine (Cochrane & Tiihonen et al 2005) • Meta-analysis shows effect • Also useful in bipolar depression and seizure prophylaxis • Topiramate (Kane 2011) • help or hinder? Weight??? • Fish Oils – modest • Antidepressant for –ve symptoms (Cochrane)

  18. Taylor et al, 2009, Leucht et al 2007, Schwarz et al 2008

  19. Alternatives to Clozapine • High Dose Olanzapine • Equivalent effect on psychopathology, but Clozapine better on GAF • Weight gain worse on Olanzapine • Combinations of anti-psychotics • NICE: “Do not initiate regular combined antipsychotic medication” • More work needed • FGA plus Mirtazepine • ECT plus anti-psychotics? • Melperone Meltzer at el, 2008; Correll et al, 2008; Matheson et al, 2010; Tharyan et al, 2005

  20. Many novel treatments, eg; • Anti-inflammatories; • Minocycline, ?aspirin! • Hormone Receptor Modulators • Tamoxifen; Oestradiol, etc • Memantine/ Donepezil/ Rivastigmine • Allopurinol • But none reliably useful

  21. Why do RCTs promise so much and deliver so little? • Inclusion of treatment-intolerant patients • Compared to un-optimised clozapine • Impossibility of blind trials with clozapine • Placebo effect • Interest of sponsor

  22. Summary • Full MDT assessment • Optimise clozapine wherever possible • Manage adverse effects proactively • Augment in partial responders • Collaboration with medical specialties if rechallenge • Limited data for alternatives; consider high dose olanzapine, antipsychotic combinations, ECT? …. • All combined with psychological therapies (CBT, CRT, Family work) and OT

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