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pharmacological alternatives to antipsychotics and the evidence ...

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pharmacological alternatives to antipsychotics and the evidence ...

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    1. PHARMACOLOGICAL ALTERNATIVES TO ANTIPSYCHOTICS AND THE EVIDENCE BEHIND DIFFERENT OPTIONS Serge Gauthier, MD, FRCPC McGill Centre for Studies in Aging Douglas Mental Health University Institute, Montréal, Canada

    4. CASE -1 Woman aged 82 with progressive cognitive decline over 2 years: misplacing things, needing reminders for appointments, forgetting birthdays False beliefs of “people stealing things from her” MMSE 19/30 Good general health, not depressed “Normal for age” head CT scan First line treatment?

    5. CASE -2 On a ChEI she improved clinically; MMSE 21/30 after 3 months of treatment. A year later spouse reports agitation at the end of the day. Additional treatments ?

    6. CASE - 3 With more light in the house, less noise from TV and reassurance, the agitation has improved. 6 months later she gets up at night, wanting to go “home”. More recently she did not recognize her spouse and asked him to leave the room. Additional treatments ?

    7. CASE - 4 Options beyond caregiver education: (1) quetiapine 25 mg HS (2) risperidone 0.25 mg HS (3) olanzapine 5 mg HS (4) change the ChEI (5) add memantine (6) trazodone 50 mg HS

    8. OUTLINE Illustration of BPSD with typical case of AD Natural history of BPSD and measurement issues Management issues Back to our case…

    9. Peak Frequency of Behavioural Symptoms as Alzheimer’s Disease Progresses

    10. Behavioural Clusters in Dementia

    11. Frequency of BPSD across the stages of Alzheimer’s disease using items from the NPI - 10

    12. MEASUREMENT OF BPSD USING THE NPI Ask lead question for each item Score frequency over past 4 weeks Score severity Multiply F X S and add up the items ->total NPI score

    13. GALANTAMINE EFFECTS ON NPI-10 IN MILD AD

    14. ADDITIONAL 2 ITEMS TO THE NPI-10 -> NPI-12 Nighttime behaviour Appetite changes

    15. DONEPEZIL EFFECTS ON NPI-12 IN MODERATE TO SEVERE AD

    16. ADDITIONAL 2 ITEMS TO THE NPI-12 -> NPI-14 or NPI-C Inappropriate sexual behaviour Inappropriate vocalizations Clinician score Under validation, led by Kate de Medeiros

    17. Meta-analysis on 6 memantine studies NPI-12 total scores, OC analysis (MMSE <20) The OC results for the behavioural domain (NPI), in the meta-analysis of six studies in moderate to severe AD (MMSE <20), favoured memantine treatment (0.12; p=0.03). The LOCF results also favoured memantine treatment (p=0.01). H. Lundbeck A/S. Data on file. Ebixa® EPAR. The OC results for the behavioural domain (NPI), in the meta-analysis of six studies in moderate to severe AD (MMSE <20), favoured memantine treatment (0.12; p=0.03). The LOCF results also favoured memantine treatment (p=0.01). H. Lundbeck A/S. Data on file. Ebixa® EPAR.

    18. Effects of memantine on behaviour, pooled data from six studies (MMSE <20), NPI single items (Week 24/28, LOCF)

    19. NPI domains: improvement in baseline symptomsPooled data from six studies (MMSE <20), % of patients showing improvement, NPI single items (LOCF)

    20. NPI domains: reduced emergence of symptoms Pooled data from six studies (MMSE <20), % of patients remaining asymptomatic, NPI single items (LOCF)

    21. Natural history of BPSD BPSD often co-exists There are patterns or “clusters” of BPSD BPSD often precede the diagnosis of dementia and can be used as markers for risk of progression from MCI to AD Some BPSD have specific diagnostic criteria which need further refinement (ex. depression, psychosis, apathy)

    22. New criteria for apathy A. Loss/reduction in motivation in comparison to previous level B. One in at least two of the following for = 4 weeks and present most of the time B1. Loss/reduction in goal directed behavior B2. Loss/reduction in goal directed cognitive ability B3. Loss/reduction in emotion C. A + B cause clinically significant impairment D. Not exclusively explained by physical disabilities or the effects of a substance

    23. OUTLINE Illustration of BPSD with typical case of AD Natural history of BPSD and measurement issues Management issues Back to our case…

    24. Management of BPSD Define target symptoms Establish or reconsider medical diagnoses Establish or reconsider psychiatric diagnoses Assess and reverse aggravating factors Modify environment

    25. Management of BPSD Non-pharmacological Behavioural Environmental Psychotropics* Antidepressants (SSRIs, SNRIs) Atypical antipsychotics, conventional neuroleptics Mood stabilising anticonvulsants (valproate, gabapentin, carbamazepine) Anti-dementia agents Cholinesterase inhibitors Memantine

    26. ANTIDEPRESSANTS & ANTICONVULSIVANTSFOR BPSD - 1 Antidepressants vs neuroleptics have comparable efficacy against agitation More difficult to show benefit for depression vs placebo in severe stages of dementia Some scales may be more sensitive to others (CSDD vs HAM-D) Mostly short term (= 12 weeks) studies

    27. ANTIDEPRESSANTS & ANTICONVULSIVANTSFOR BPSD - 2 Carbamazepine vs placebo showed efficacy on agitation in severe dementia -> needs further studies Negative results with sodium valproate and divalproex sodium Trazodone vs placebo showed some benefit in FTD, but not in AD with agitation

    28. Management of BPSD Non-pharmacological Behavioural Environmental Psychotropics* Antidepressants (SSRIs, SNRIs) Atypical antipsychotics, conventional neuroleptics Mood stabilising anticonvulsants (valproate, gabapentin, carbamazepine) Anti-dementia agents Cholinesterase inhibitors Memantine

    29. ChEIs and BPSD Variable results on total NPI scores, particularly in nursing home settings Efficacy on NPI items apathy, depression aberrant motor behaviours Visual hallucinations predict a better response overall to ChEIs

    30. Management of BPSD Non-pharmacological Behavioural Environmental Psychotropics* Antidepressants (SSRIs, SNRIs) Atypical antipsychotics, conventional neuroleptics Mood stabilising anticonvulsants (valproate, gabapentin, carbamazepine) Anti-dementia agents Cholinesterase inhibitors Memantine

    31. MEMANTINE AND BPSD - 1 Variable differences in NPI total scores In a meta-analysis of six studies, patients receiving memantine improved on the NPI total score and in some individual items, particularly agitation/aggression * The effect on agitation is seen in those without the symptom at baseline (delayed emergence) and in those with the symptom (symptomatic improvement) In the meta-analysis of six clinical studies (MRZ-9605, MD-01, MD-02, 99679, MD-10, MD-12), memantine showed a significant effect on behaviour (NPI score; p=0.01 vs placebo, LOCF analysis) in patients with moderate to severe AD (MMSE <20). This effect on the behavioural domain was supported by an analysis of pooled data from the same six studies. Memantine-treated patients (MMSE <20) had significantly less deterioration from baseline in NPI scores, vs placebo-treated patients from week 12 onwards (see next slide). H. Lundbeck A/S. Data on file. Gauthier S, Cooper J, Loft H. Memantine improves behavioural symptoms in patients with moderate to severe Alzheimer’s disease. Poster presented at the 10th International Conference on Alzheimer’s Disease and Related Disorders (ICAD), Madrid, Spain, 15–20 July 2006. In the meta-analysis of six clinical studies (MRZ-9605, MD-01, MD-02, 99679, MD-10, MD-12), memantine showed a significant effect on behaviour (NPI score; p=0.01 vs placebo, LOCF analysis) in patients with moderate to severe AD (MMSE <20). This effect on the behavioural domain was supported by an analysis of pooled data from the same six studies. Memantine-treated patients (MMSE <20) had significantly less deterioration from baseline in NPI scores, vs placebo-treated patients from week 12 onwards (see next slide). H. Lundbeck A/S. Data on file. Gauthier S, Cooper J, Loft H. Memantine improves behavioural symptoms in patients with moderate to severe Alzheimer’s disease. Poster presented at the 10th International Conference on Alzheimer’s Disease and Related Disorders (ICAD), Madrid, Spain, 15–20 July 2006.

    32. MEMANTINE AND BPSD - 2 The effect on agitation is being tested prospectively in a memantine with ChEIs placebo-controlled study with the Cohen –Mansfield Agitation Index as a co-variable for behaviour A reduction of use of psychotropic drugs is suggested by the French national healthcare system (CNAM-TS) database after the introduction of memantine In the meta-analysis of six clinical studies (MRZ-9605, MD-01, MD-02, 99679, MD-10, MD-12), memantine showed a significant effect on behaviour (NPI score; p=0.01 vs placebo, LOCF analysis) in patients with moderate to severe AD (MMSE <20). This effect on the behavioural domain was supported by an analysis of pooled data from the same six studies. Memantine-treated patients (MMSE <20) had significantly less deterioration from baseline in NPI scores, vs placebo-treated patients from week 12 onwards (see next slide). H. Lundbeck A/S. Data on file. Gauthier S, Cooper J, Loft H. Memantine improves behavioural symptoms in patients with moderate to severe Alzheimer’s disease. Poster presented at the 10th International Conference on Alzheimer’s Disease and Related Disorders (ICAD), Madrid, Spain, 15–20 July 2006. In the meta-analysis of six clinical studies (MRZ-9605, MD-01, MD-02, 99679, MD-10, MD-12), memantine showed a significant effect on behaviour (NPI score; p=0.01 vs placebo, LOCF analysis) in patients with moderate to severe AD (MMSE <20). This effect on the behavioural domain was supported by an analysis of pooled data from the same six studies. Memantine-treated patients (MMSE <20) had significantly less deterioration from baseline in NPI scores, vs placebo-treated patients from week 12 onwards (see next slide). H. Lundbeck A/S. Data on file. Gauthier S, Cooper J, Loft H. Memantine improves behavioural symptoms in patients with moderate to severe Alzheimer’s disease. Poster presented at the 10th International Conference on Alzheimer’s Disease and Related Disorders (ICAD), Madrid, Spain, 15–20 July 2006.

    33. Summary of evidence on the treatment of BPSD Some BPSD can be treated only by non-pharmacological means (ex wandering, elation/elation) Relative lack of level I evidence for some non-pharmacologic therapies Negative results in many placebo-controlled drug studies using the NPI total score Safety concern for certain classes of drugs (typical and atypical antipsychotics) Evidence that ChEIs may have an effect of apathy Evidence that memantine has an effect on agitation/aggression

    34. OUTLINE Illustration of BPSD with typical case of AD Natural history of BPSD and measurement issues Management issues Back to our case…

    35. CASE - 3 With more light in the house, less noise from TV and reassurance, the agitation is improved. 6 months later she gets up at night, wanting to go “home”. More recently she did not recognize her spouse and asked him to leave the room. Additional treatments ?

    36. CASE - 4 Options beyond caregiver education: (1) quetiapine 25 mg HS (2) risperidone 0.25 mg HS (3) olanzapine 5 mg HS (4) change the ChEI (5) add memantine (6) trazodone 50 mg HS

    37. Thank you

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