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Antipsychotic drug treatment 2006 Shôn Lewis

Antipsychotic drug treatment 2006 Shôn Lewis. The dopaminergic pathways of the brain. Basal ganglia. Nigrostriatal dopamine pathway. Mesolimbic dopamine pathway. Substantia nigra. Mesocortical dopamine pathway. Hypothalamus. Tegmentum. Tuberoinfundibular dopamine pathway.

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Antipsychotic drug treatment 2006 Shôn Lewis

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  1. Antipsychotic drug treatment 2006Shôn Lewis

  2. The dopaminergic pathways of the brain Basal ganglia Nigrostriatal dopamine pathway Mesolimbicdopamine pathway Substantia nigra Mesocortical dopamine pathway Hypothalamus Tegmentum Tuberoinfundibulardopamine pathway

  3. The Dopamine Hypothesis Schizophrenia is the result of increased dopaminergic function in certain brain areas : EITHER from disruption at predominantly post-synaptic sites; e.g. increased post-synaptic receptor numbers (supersensitivity) OR from disruption at predominantly pre-synaptic sites; e.g. increased absolute levels/ turnover (?mesolimbic system) (?mesolimbic system)

  4. Antipsychotics : Association between Clinical Potency and Dopamine D2 receptor Affinity .promazine .chlorpromazine sulpiride. trazodone. .clozapine .thioridazine .prochlorperazine .trifluoperazine IC50 (moles/litre) 10-10 10-9 10-8 10-7 .haloperidol .fluphenazine .pimozide .benperidol .spiroperidol 0.1 1 10 100 1000 mean effective clinical dose (mg/day) after Seeman, 1986

  5. Early versus delayed acute drug action Agid, Kapur et al 2003

  6. What is ‘atypicality’? • Relatively low affinity for dopamine D2 receptors • Unique ‘balance’ of interaction with dopamine receptor subtypes • Relatively high affinity for 5HT2a receptors • High 5HT2a : D2 ratios • Relative limbic selectivity • Efficacy on ‘negative’ symptomatology • Enhanced efficacy in ‘treatment resistance’ • Reduced liability of extrapyramidal side effects

  7. Are all SGA’s equal? Efficacy compared to FGA’s Davis JM et al Arch Gen Psychiat 2003 Metaanalysis with n=124 rct’s Results closely similar to metaanalysis with n=171 rcts (zotepine also > FGAs) Bagnall AM et al Health Technology Assessment 2003

  8. Greater Manchester atypical antipsychotic expenditure 1996-2002

  9. Greater Manchester atypical antipsychotic expenditure 1996-2002

  10. Greater Manchester clozapine use 1996-2005 Population-Adjusted Data

  11. What’s wrong with the current evidence? • Question asked in UK NHS first in 1996 • Most of the trial data from outside routine settings • Samples often unrepresentative • no substance use • Follow up is short term, with high dropout • Outcomes focus on symptoms • No economic outcomes • Most trials are sponsored by industry

  12. Shôn Lewis Manchester Peter Jones Cambridge Thomas Barnes Imperial Robin Murray Inst Psychiatry Linda Davies Karen Hayhurst Alison Markwick Graham Dunn Helen Lloyd First generation versus second generation (non-clozapine) antipsychotic drugs versus clozapine in schizophrenia:The CUtLASS trials Jenny Massie, Fiona Hynes, Candice Blackwell, Ahmed Mahmoud, Emma Sowden, Natasha Newberry, Fionnbar Lennihan, Eleanor Page, Maria Clark, Paul Monks, Rhona Howitt, X Jin, Maurice Gervin

  13. UK NHS response 2 pragmatic RCTs of effectiveness & cost utility: • CUtLASS 1 • FGA versus non-clozapine SGA • CUtLASS 2 • SGA versus clozapine Funded by NHS R&D Health Technology Assessment Programme (non-industry): international peer review

  14. CUtLASS 1 and 2 Trial Design Two trials in parallel with shared catchment areas and clinicians • Five centre, randomised controlled trial in UK • Blinded outcome assessments 4 times over 52 weeks • Clinician & patient open • Participant randomised to class of medication • FGA or SGA (CUtLASS 1) • SGA or clozapine (CUtLASS 2)

  15. CUtLASS 1 and 2 Trial Design • Individual FGA or SGA selected in advance by clinician • “If your patient is randomised to an FGA, which one do you want it to be?” • All patients changed medication at randomisation • Randomisation was concealed • Randomisation via a remote telephone service. • Stratified by treatment centre • Clinicians encouraged to keep patients on the randomised treatment for a minimum of 12 weeks, if compatible with good practice; other clinical management as usual • Patients were recruited from August 1999 to April 2002.

  16. CUtLASS 1 Primary Hypothesis Second generation (atypical) drugs will outperform first generation (conventional) drugs in improving quality of life and symptoms in people with schizophrenia responding poorly to, or having side effects from current drug treatment This will equate to a 5 points difference on QLS

  17. Participants • 275 patients referred from 73 clinicians • 227 patients randomised : FGA 118; SGA 109 • 75% power to detect difference of 5 points on QLS, although 40% of planned sample recruited • Mean age 41 yrs, 68% male • First episode 11% • 45% inpatients at baseline • 70% on FGA at baseline • Follow up interview at 52 weeks in 81%

  18. Medication assignment

  19. Mean end of study dose: SGAs

  20. CUtLASS 1 Values for occasional missing items were imputed using the median of observed responses within other sub-scales for that subject.

  21. CUtLASS 1

  22. CUtLASS 1 Quality of Life Hypothesis of 5 point advantage for SGA Favors FGA Favors SGA

  23. CUtLASS 1 Quality of Life Hypothesis of 5 point advantage for SGA excluded Favors FGA Favors SGA

  24. CUtLASS 1: other outcomes • No differences in total extrapyramidal side effects FGA vs SGA • Patients expressed no preference for either class of drug

  25. CUtLASS 1: Costs over 1 year • Wide variation in net costs of care - mean of $34 750 (£18 800) in FGA group - mean of $37 185 (£20 100) in SGA group • 2.1% and 3.8% of these costs are drugs

  26. CUtLASS 2 Primary Hypothesis Clozapine will outperform the class of non-clozapine second generation drugs in improving quality of life and symptoms in people with schizophrenia responding poorly to trials of at least two antipsychotic drugs This will equate to a 10 points difference on QLS

  27. Participants • 161 patients eligible • 136 patients randomised (98% of planned sample): clozapine 67; SGA 69 • Mean age 38 yrs, 68% male • 56% inpatients at baseline • Follow up interview at 52 weeks in 87% of sample

  28. CLOZAPINE (n=67) Clozapine 67 SGA (n=69) Olanzapine 30 Quetiapine 20 Amisulpride 9 Risperidone 7 Medication assignment Median time from randomisation to first dose: 7 days

  29. CUtLASS 2: mean end of study dose

  30. Medication at follow up 12 weeks • 70% of those randomised to clozapine and 71% of those randomised to an SGA remained in the randomised class 1 year • Follow-up assessments on 87% at 1 year • 36 participants (54%) were still receiving clozapine as randomised • 39 participants (57%) were still in the SGA randomised arm (51% on original drug)

  31. CUtLASS 2 results: estimates of treatment effect for QLS and PANSS Estimate* SE 95% CI P value QLS 3.63 2.08 -0.46 to 7.71 p=0.082 PANSS -4.93 1.98 -8.82 to -1.05 p=0.013 *QLS score difference: positive favours clozapine PANSS score difference: negative favours clozapine

  32. CUtLASS 2 Quality of Life Hypothesis of 10 point advantage for clozapine excluded Favors SGA Favors clozapine

  33. CUtLASS 2: other outcomes • Clozapine showed a trend towards having less total extrapyramidal side effects (p=0.1) • Patients reported at 12 weeks that their mental health was significantly better with clozapine than with new atypicals (p<0.05)

  34. CUtLASS 2: costs over 1 year • Wide variation in net costs of care - mean of $62 523 (£33 726) in clozapine group - mean of $52 555 (£28 408) in SGA group • 4.0% and 3.3% of these costs are drugs

  35. Conclusions In patients with schizophrenia whose medication is being changed due to failure to respond to two or more antipsychotic drugs, there is a statistically significant advantage in terms of symptoms (but not QoL) over 1yr in commencing clozapine rather than one of the non-clozapine class of SGA drugs Funding NHS R&D Health Technology Assessment

  36. Effectiveness of Antipsychotic Drugs in Patients with Chronic Schizophrenia: Efficacy, Safety and Cost Outcomesof the CATIE Trial Jeffrey Lieberman, MD Columbia University College of Physicians and Surgeons New York State Psychiatric Institute For the CATIE Investigators

  37. Beliefs About SGAs • Increased efficacy • Lower side effects • Better outcomes • Cost effective

  38. Primary Questions Addressed by CATIE Schizophrenia Trial • How do the second generation antipsychotics compare with a representative first generation antipsychotic? • What is the comparative effectiveness of the second generation antipsychotic drugs? • Are the second generation antipsychotics cost-effective? Stroup TS et al. Schizophr Bull. 2003;29:15-31.

  39. CATIE: Broad Inclusion & Minimal Exclusion Criteria • DSM-IV schizophrenia, 18-65 years old • Not first-episode or treatment resistant • Concomitant medications, medical illnesses, substance use disorders allowed • No adjunctive antipsychotic after randomization Stroup TS et al. Schizophr Bull. 2003;29:15-31.

  40. Primary Outcome Measure:All-Cause Treatment Discontinuation Efficacy Tolerability All-Cause Discontinuation Patient Input Clinician Input

  41. Hypotheses for Primary Outcomes: • There are overall differences in discontinuation rates between antipsychotic medications(olanzapine, quetiapine, risperidone, ziprasidone and perphenazine). 2a. The SGAs(olanzapine, quetiapine, risperidone and ziprasidone) are more effective than FGAs(perphenazine) as measured by discontinuation rates 2b. There are differences between SGAs in measures of efficacy and safety(olanzapine, quetiapine, and risperidone)

  42. 1460 Patients with Schizophrenia Randomized CATIE Phase 1: Double-Blinded and Randomized Olanzapine 7.5–30 mg/day Perphenazine 8–32 mg/day Quetiapine 200–800 mg/day Risperidone 1.5–6 mg/day Ziprasidone 40–160 mg/day * Persons with TD not assigned to perphenazine * Ziprasidone added after 40% sample enrolled Stroup TS et al. Schizophr Bull. 2003;29:15-31.

  43. Time to Discontinuation for Any Reason Overall p-value = 0.004* P<0.001 for olanzapine vs quetiapine P=0.002 for olanzapine vs risperidone

  44. Highlights of Phase I • High rate of discontinuation (switching) • Hypothesized 60% • Consistent with practice and clinical trials • OLZ most effective • Best efficacy, worst side effects • PER comparably effective to SGAs • Slightly higher EPS • No differential effects of SGAs on Sxs including negative Sxs • Cognition, substance abuse, violence • Differences in types and severity of side effects • Consistent results across multiple measures within domains • Full dose range not explored before switching

  45. CATIE Phase 2: Preference Pathways (for people who discontinue Phase 1) Clozapine—open-label Efficacy Pathway Randomized Olanzapine, Quetiapine, or Risperidone—one of these not taken in Phase 1 Randomized Tolerability Pathway Ziprasidone Randomization within chosen pathways Stroup TS et al. Schizophr Bull. 2003;29:15-31.

  46. Time to Discontinuation for Any Cause Overall p-value= 0.028*

  47. Prescribing in the first episode

  48. Drug treatment in the first episode: 12 week outcomes haloperidol vs olanzapine Lieberman et al, 2002

  49. How long to treat after the first episode? • Guidelines vary: 1-2 years minimum. No definitive trial data • But antipsychotics remain protective indefinitely • Take initial DUP and severity into account • Treat refractory symptoms early (clozapine) • Discuss with patient and carers • statistical risks • other risk factors eg street drugs • compliance

  50. MESIFOS STUDY • Epidemiologically-derived sample • 157 first-episode psychosis patients • 131 remitted within 6 months and stable 6 months • Randomised to targeted or maintenance treatment for 18 months • Twice as many relapses in targeted (n=29, 43%) as maintenance (n=13, 21%) treatment group • No difference in symptoms, social function or QoL • Twice as many holding regular job in targeted (n=18, 27%) than maintenance (n=9, 14%) treatment group Wunderink et al 2005

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