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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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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



National psychosis service why are people referred
National Psychosis Service: Why are people referred?




Assessment of p ast treatments
Assessment of Past Treatments



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 aspectneutropaenia

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 aspect

  • 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 aspect

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 aspect

  • 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)


Taylor et al, 2009, aspectLeucht et al 2007, Schwarz et al 2008


Alternatives to clozapine
Alternatives to Clozapine aspect

  • 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; aspect

    • 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? aspect

    • Inclusion of treatment-intolerant patients

    • Compared to un-optimised clozapine

    • Impossibility of blind trials with clozapine

    • Placebo effect

    • Interest of sponsor


    Summary
    Summary aspect

    • 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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