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Antipsychotic drug treatment 2006 Shôn Lewis. The dopaminergic pathways of the brain Mesocortical dopamine pathway Basal ganglia Tuberoinfundibular dopamine.

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Presentation on theme: "Antipsychotic drug treatment 2006 Shôn Lewis. The dopaminergic pathways of the brain Mesocortical dopamine pathway Basal ganglia Tuberoinfundibular dopamine."— Presentation transcript:

1 Antipsychotic drug treatment 2006 Shôn Lewis

2 The dopaminergic pathways of the brain Mesocortical dopamine pathway Basal ganglia Tuberoinfundibular dopamine pathway Tegmentum Substantia nigra Mesolimbic dopamine pathway Nigrostriatal dopamine pathway Hypothalamus

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)

4 Antipsychotics : Association between Clinical Potency and Dopamine D2 receptor Affinity 0.1 1 10100 1000 mean effective clinical dose (mg/day) IC50 (moles/litre) 10-10 10-9 10-8 10-7. spiroperidol. benperidol. pimozide. fluphenazine. haloperidol. trifluoperazine. prochlorperazine. thioridazine. clozapine trazodone. sulpiride.. chlorpromazine. promazine after Seeman, 1986

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

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

7 Are all SGA’s equal? Efficacy compared to FGA’s Effect size compared to FGA Clozapine0.49 Amisulpride0.29 Risperidone0.25 Olanzapine0.21 All other SGAsNS 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

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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 First generation versus second generation (non-clozapine) antipsychotic drugs versus clozapine in schizophrenia: The CUtLASS trials Shôn Lewis Manchester Peter Jones Cambridge Thomas Barnes Imperial Robin Murray Inst Psychiatry Linda Davies Karen Hayhurst Alison Markwick Graham Dunn Helen Lloyd 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 FGA Armn=118SGA Arm* n=109 chlorpromazine8amisulpride13 droperidol1olanzapine50 flupenthixol1quetiapine23 flupenthixol dec.2risperidone22 fluphenazine dec.3* Two data points are missing haloperidol7 haloperidol dec.2 loxapine3 pipothiazine palm.2 sulpiride58 thioridazine1 trifluoperazine21 zuclopenthixol5 zuclopenthixol Dec.3 Medication assignment

19 Mean end of study dose: SGAs olanzapine15.0mg quetiapine450mg risperidone5.0 mg amisupride610mg

20 CUtLASS 1 QLSFGASGA nMeanSDnMeanSD Baseline11843.321.710843.520.3 1210049.219.98746.619.0 269349.220.58750.418.8 52 weeks 10053.221.28551.319.6 Values for occasional missing items were imputed using the median of observed responses within other sub-scales for that subject.

21 CUtLASS 1 PANSS FGASGA nMeanSDnMeanSD Baseline11872.917.210871.316.5 52 weeks 9964.615.18566.217.5

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

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

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 Medication assignment CLOZAPINE (n=67) Clozapine67 SGA (n=69) Olanzapine30 Quetiapine20 Amisulpride 9 Risperidone 7 Median time from randomisation to first dose: 7 days

29 CUtLASS 2: mean end of study dose clozapine333mg olanzapine19.0mg quetiapine520mg risperidone6.0 mg amisupride680mg

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 Estimate*SE95% CI P value QLS 3.632.08-0.46 to 7.71 p=0.082 PANSS-4.931.98-8.82 to -1.05 p=0.013 CUtLASS 2 results: estimates of treatment effect for QLS and PANSS *QLS score difference: positive favours clozapine PANSS score difference: negative favours clozapine

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

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 Outcomes of 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 All-Cause Discontinuation EfficacyTolerability Clinician Input Patient Input

41 Hypotheses for Primary Outcomes: 1.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 CATIE Phase 1: Double-Blinded and Randomized Persons with TD not assigned to perphenazine Stroup TS et al. Schizophr Bull. 2003;29:15-31. 1460 Patients with Schizophrenia 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 * * Ziprasidone added after 40% sample enrolled

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

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) Randomization within chosen pathways Efficacy Pathway Tolerability Pathway Clozapine—open-label Olanzapine, Quetiapine, or Risperidone—one of these not taken in Phase 1 Ziprasidone Randomized 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

51 MESIFOS STUDY

52 Total grey matter volume change over one year after first episode psychosis and antipsychotic drug load Total Gray Matter This correlation was evident even when controlling for poor clinical outcomes. Cahn et al 2002

53 Do antipsychotic drugs damage your brain? Dorph-Petersen et al (2005) 18 macaque monkeys assigned to 2 year course of placebo, haloperidol or olanzapine at doses equivalent to therapeutic human doses Brain volume change at 2 years:  Placebo0%  Haloperidol-8.8%  Olanzapine-10.5% p<0.05 for both drugs

54 NICE in schizophrenia: two separate documents Technology appraisal for use of newer (atypical) drugs in schizophrenia. –Released June 2002 –10 points of guidance, plus background and suggested audit. 20 pages Clinical practice guideline for schizophrenia –commissioned by NICE, done by NCCCG –released December 2002

55 NICE Rapid Tranquillisation Feb 23 2005 Psychotic context –Oral: lorazapam plus antipsychotic –IM: lorazepam im plus haloperidol im OR olanzapine im if moderate disturbance (no lorazepam within one hour) –IV: benzodiazepine OR haloperidol Zuclopenthixol acetate not recommended for RT due to long onset and duration

56 NICE technology appraisal guidance: newer (atypical) drugs for schizophrenia Choice based on discussion with patient New atypicals to be “considered in the choice” of first line treatments Atypicals indicated if intolerance to typicals Stay on typical if effective and tolerated Use clozapine early in TRS, defined by non- response to 2 antipsychotics for 6-8 weeks, at least one of which is atypical

57 NICE technology appraisal guidance: newer (atypical) drugs for schizophrenia Risk assessment for non-concordance, with appropriate use of depots Use cheapest drug if more than one considered appropriate Atypicals preferred if full patient discussion not possible Clinician and key worker monitor therapeutic progress and tolerability No concurrent use of typicals and atypicals

58 NICE Rapid Tranquillisation Feb 23 2005 Psychotic context –Oral: lorazapam plus antipsychotic –IM: lorazepam im plus haloperidol im OR olanzapine im if moderate disturbance (no lorazepam within one hour) –IV: benzodiazepine OR haloperidol Zuclopenthixol acetate not recommended for RT due to long onset and duration

59 National Clinical Practice Guideline for Schizophrenia The treatment and management of schizophrenia in primary and secondary care National Collaborating Centre for Guideline Development NICE 2002

60 National Clinical Practice Guideline for Schizophrenia: For All Phases Be happy Build treatment alliance Give good quality information Assess and treat promptly Use and record advance directives Speak clearly NICE 2002

61 National Clinical Practice Guideline for Schizophrenia: Drug treatment Reiterates NICE atypicals guidance Principles, risks and techniques of rapid tranquillisation, including drug and non-drug methods and CPR Atypicals probably better than haloperidol at relapse prevention Depot if patient prefers or if covert non-compliance an issue Can add a 2nd antipsychotic to clozapine 4 th line NICE 2002

62 Antipsychotic polypharmacy No known increased efficacy More side effects More cost Increased risk of “high dose” prescribing There’s always another way! –clozapine, add lithium, high dose SGA, second opinion etc

63 Antipsychotic Prescribing in the treatment of Schizophrenia Karen Hayhurst ERC, Wythenshawe Hospital

64 CAPRI: Study Outline 1.Baseline antipsychotic prescribing audit 2.Measurement of attitudes toward antipsychotic prescribing in schizophrenia 3.Prescribing talk – Professor Shôn Lewis Manchester University & MMHSCT 4.Individual clinician visits – Karen Hayhurst Researcher Manchester University 5.Reminder system 6.Re-audit of antipsychotic prescribing 7.Re-measurement of attitudes toward antipsychotic prescribing


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