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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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slide1

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

f gaughran declaration of interests
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

slide9

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

catie 2e

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

other evidence echoes this
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
re challenge after neutropaenia
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?
other problems
Other Problems
  • Post Cardiac Side effects
  • Post-pericarditis
  • Post-hepatitis
  • Close collaboration with Medical Specialists (with an interest in psychotropic side effects) is essential
augmenting clozapine with another anti psychotic
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.
augmenting clozapine with non ap
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)
alternatives to clozapine
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

many novel treatments eg
Many novel treatments, eg;
  • Anti-inflammatories;
    • Minocycline, ?aspirin!
  • Hormone Receptor Modulators
    • Tamoxifen; Oestradiol, etc
  • Memantine/ Donepezil/ Rivastigmine
  • Allopurinol
  • But none reliably useful
why do rcts promise so much and deliver so little
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
summary
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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