Anti-Dementia drugs

An overview of drug treatment of Dementia

1. ANTI-DEMENTIA DRUGS PRESENTER – Dr. Sriram.R , PG MD Psychiatry CHAIRPERSON – Dr. Sivabalan.E , Assistant Prof of Psychiatry

2. Objectives Understand the use of cholinesterase inhibitors in the treatment of alzheimer type, vascular and mixed dementias Review the current literature regarding the use of Memantine for severe dementia Review the appropriate use of antipsychotics for psychosis and behavioral symptoms in dementia Discuss possible means of preventing dementia

3. The role of medications in the management of dementia Cure disease Prevent disease or delay onset Slow progression of disease Treat primary symptoms eg memory Treat secondary symptoms eg depression , hallucinations

4. Overview Cholinesterase inhibitors in the treatment of AD, vascular and overlap dementias Memantine Treatment of behavioral symptoms Prevention Future Directions

5. The Cholinergic Hypothesis Depletion of acetylcholine and nicotinic receptors thought to occur early and relate to memory impairment with AD Focus on AD treatment with Acetylcholinesterase inhibitors: Recommended as first line treatment for patients with mild to moderate AD

6. Reduce Serum anticholinergic load Precursor strategies (e.g. lecithin and choline) Receptor/synaptic strategies Metabolic strategies (anticholinesterases) CHOLINERGIC SYSTEM STRATEGIES

7. Cholinesterase Inhibitors Trials in patients with mild to moderate disease (10-24 on MMSE ) On average these drugs seem to stabilize cognitive function and activities of daily living and may have benefits with QOL and behavioral disturbances for at least one year Side Effects: GI

8. Current AChE Inhibitors *promotes binding of acetylcholine

9. Tacrine Trials demonstrating delay of cognitive decline by 6 months Delayed time to nursing home placement: At 800 days, 45% in low dose or no tacrine underwent placement vs 21% in high dose tacrine group Evidence for long term cost effectiveness Reversible hepatotoxicity in 50%

10. Donepezil (Aricept) Three large RCT demonstrate modest effectiveness in stabilizing cognitive function Well tolerated (no difference in adverse events compared to placebo) Not hepatoxic , no significant drug-drug interactions Single bedtime dose: start 5 mg, increase to 10 mg after 4-6 weeks Most common side effects: sleep disturbance, GI

11. Rivastigmine May have increased selectivity for hippocampus and neocortex (areas affected by AD) Modestly effective in treatment of mild to moderate AD (but only at high doses of 6-12 mg/day) Recommended starting dose: 1.5 mg BID with breakfast and dinner Minimize GI side effects with 4-6 week titration, increasing to 3 mg BID, 4.5 mg BID, 6 mg BID More GI side effects, weight loss (dose dependent)

12. Galantamine Potential second mechanism: modulator at nicotinic cholinergic receptor Three large RCTs indicate effectiveness in mild to moderate AD (same degree as other agents) at doses of 16, 24, 32 mg/day Open label 6 month extension of US trial: Possible disease modifying effect Starting dose: 4mg BID with meals, increase by 4mg BID every 4-6 weeks

13. Anticholinesterase Side Effects (i.e. procholinergic ) GI – nausea, vomiting, diarrhea, increased gastric acid secretion Muscle cramps Fatigue Insomnia Syncope (2% vs 1% for placebo) (?bradycardia)

14. Cholinesterase inhibitors in moderate to severe AD RCT of donepezil vs placebo: 24 week international trial of 290 patients (MMSE 5-18) 63 % of donepezil treated patients were stable/better vs 42% in placebo group

15. Comparison of Cholinesterase Inhibitors… Cochrane Dementia Group: 3 systematic reviews on efficacy of donepezil, rivastigmine, and galantamine Each drug seems to have similar treatment effect at 6 months on global and cognitive rating scales No double blind head to head trial

16. Cholinesterase Inhibitors and AD: Summary Approved for treatment of mild to moderate AD Probably effective in treatment of more severe AD Goal: stabilization (not miracle drugs) Delay in nursing home placement, decline in ADLS Probably benefits behavioral and functional status as well Data suggest no big difference in efficacy among the 3 agents, although donepezil is easier to titrate and better tolerated

17. Cholinesterase Inhibitors and Other Dementias… Vascular dementia and Dementia with Lewy Bodies each account for 10-15% cases Prominence of mixed pathology (especially vascular and AD in older population)

18. Galantamine: Vascular and AD/Vascular Dementia Placebo controlled trial, 6 months, 592 patients 50% in study had AD plus radiological evidence of CVD, 41% had probable vascular dementia, 9% indeterminant Results for the whole group were similar to previous trials in typical AD : 74% galantamine groupwere improved/stable vs 59% in placebo group AD-CVD subgroup similar effects to prior trials with AD patients

19. Summary of Galantamine and Vascular dementia Patients with typical features of AD mixed with features of CVD or evidence of CVD on radiological tests seem to respond similarly to patients with AD alone Subgroup with CVD alone does better over long term (even with placebo) Surprise: patients with what appears to be only CVD also seem to have some benefit (these patients not traditionally felt to have specific degeneration of cortical cholinergic pathways)

20. Cholinesterase Inhibitors and Other dementias Lewy Body Dementia: may respond even more than AD patients Frontal Lobe Dementia: often respond adversely to cholinesterase inhibitors with increased agitation and insomnia

21. Commonly Prescribed Non-Psychiatric Drugs with Significant Anticholinergic Activity cimetidine & ranitidine prednisolone theophylline digoxin/ Lanoxin furosemide nifedipine diphenhydramine (OTC) To a lesser extent : codeine, warfarin, dipyradimole , isosorbide dinitrate

22. Memantine Glutamate is the principal excitatory neurotransmitter in brain regions associated with cognition and memory (i.e. it stimulates cholinergic neurons ) Glutamate hypothesis of dementia suggests that overactivation of these neurons leads to excitotoxic damage to these brain areas (by allowing calcium to continuously ‘leak in’ to cells). It is post-synaptic receptor sensitivity rather than excess release of glutamate that is the problem . Memantine is a weak antagonist of glutamate-gated NMDA receptor channels which prevents overactivation during memory formation but allows normal function

23. Memantine NMDA (glutamate) receptor activation thought to be involved in neurodegeneration Memantine: NMDA antagonist aimed at protecting neurons from glutamate mediated excitotoxicity Approved in Europe in 2002 for treatment of severe AD (MMSE 3-14)

24. Memantine Randomized, double blind, placebo controlled study: 166 patients with severe dementia (AD and vascular, MMSE <10) Cognitive and Behavioral Rating Scale significantly better with treatment, regardless of dementia type Other European studies have looked at treatment for moderate-severe Vascular Dementia, demonstrating similar efficacy

25. Memantine 28 week RCT of 252 patients with severe AD (MMSE 3-14) in NEJM: memantine associated with less deterioration in cognitive and functional measures than placebo Problem: small numbers, high drop out rate Preliminary study: 400 patients with severe AD, 6 months RCT of memantine plus donepezil vs placebo plus donepezil: memantine group had significant benefit in comparison

26. Memantine C an use with other AD medications side effects - headaches, dizziness do not use in kidney disease or seizure disorders dosage: start with 5mg daily and increase to 10mg twice daily

27. Memantine: Summary Approved for treatment of moderate-severe AD Likely of benefit also in severe vascular and mixed dementias as well Likely will be used in combination with donepezil or other cholinesterase inhibitors Cochrane Dementia Group: “ memantine is a safe drug and may be useful for treating AD, vascular and mixed dementia, although most of the trials so far reported have been small and not long enough to detect clinically important benefit”

28. Depression and Alzheimer’s Common early in the course of the illness Incidence 40-50% Use SSRIs first; avoid anticholinergic antidepressants ECT can be helpful but may temporarily worsen cognitive symptoms

29. Treatment of Depression Recognize that irritability and/or apathy /withdrawal may be indicative of depression Allow patient choices and control Identify pleasurable activities (such as singing old songs, pet therapy, etc.) Cognitive enhancers (e.g. Aricept) may help Consider Ritalin for apathy, poor appetite

30. Medications for Agitation Buspirone – Takes a while to work Antidepressants (SSRIs, Trazodone) Anticonvulsants (esp. valproate) Atypical Antipsychotics (stroke risk concerning) Low dose narcotics? Marinol ? Estrogen? Benzos – ataxia, worsening memory and disinhibition are problematic .

31. Sexually Disinhibited Behavior Includes: sexual talk, sexual acts, implied sex acts, false reporting Treatment or sexual aggression and/or disinhibition Psychosocial : reminders, move to private room, clothing modification, staff education Pharmacological: SSRIs, antiandrogens (medroxyprogesterone acetate, cyproterone acetate), estrogen patches

32. Use of Atypical Antipsychotics Older, “typical” agents such as haloperidol and thioridazine (mellaril) associated with significant extrapyramidal symptoms Theoretically combination of dopamine and serotonin effects of atypical agents allow treatment of positive and negative psychotic symptoms with less EPS

33. Risperidone Evidence demonstrates efficacy in treatment of psychotic and behavior symptoms in patients with dementia Exacerbates movement disorder in patients with Parkinson’s Start .25/day, average daily dose 1-1.5mg/day EPS in dose dependent manner (6mg/day) Insomnia, hypotension, weight gain Elevation of prolactin levels

34. Olanzapine Evidence that it is effective in AD patients Increases motor symptoms in PD patients Recommended not to use with PD Start: 1.25-2.5/day, increase to 5/day (dosages of 10-15/day are not more effective!) More sedating than others (more anticholinergic effects) Sedation, weight gain, orthostatic hypotension, seizures, glucose intolerance

35. Quetiapine (Seroquel) Showing promise in patients with AD and PD Does not exacerbate movement disorder of PD May be first line for PD patients with psychosis 12.5 QHS, titrate every 3-5 days Sedation, HA, orthostatic hypotension ?Cataract formation

36. Ziprasidone (Geodon) New, clinical data lacking Non dose-dependent QT prolongation

37. Clozapine Very effective in treating psychosis in PD patients The most effective agent in treatment of drug induced psychosis in PD Some efficacy with AD patients Start: 6.5mg/day Agranulocytosis, frequent monitoring limits use

38. Atypical Antipsychotics & Risk of Serious Adverse Events Retrospective review revealed a small (2-3%) but ~2 fold increase in risk of stroke in demented patients receiving these agents compared to placebo. # FDA required ‘Black Box’ warning due to 1.6 to 1.7-fold increase in mortality in pooled sample of >5000 persons with dementia exposed to these agents (in particular this was found in studies of olanzapine, risperidone and aripiprazole) # Hermann N, et al. CNS Drugs 2005;19(2):91-103

39. Atypical Antipsychotics & Risk of Serious Adverse Events The risk with traditional antipsychotics may be even higher. $ Recent meta-analysis of 15 trials (some unpublished) by Schneider in JAMA & confirmed a small increase in death with these agents compared with placebo. This was significant for the pooled data but not the individual drug data. The OR was 1.54 $ Gill S, et al. BMJ 2005;330(7489):445 & Schneider LS, et al. JAMA 2005;294(15):1934-1943

40. Recommendations on Use of Antipsychotic Agents in Dementia Have a justifiable use -> severe, distressing psychotic symptoms e.g. Do not use first-line for non-psychotic behavioral disturbances. Use lowest amounts for shortest possible times Caution patients and family about risk but remember that older agents may be worse, and there is little data on other psychotropics to suggest that they are safe.

41. Antipsychotics in Dementia: Summary Start very low, monitor for hypotension, P450 effects, sedation, EPS Monitor and avoid use as “chemical restraint” Avoid if at all possible in Dementia with Lewy Bodies

42. ?Prevention of Dementia HTN and Hyperlipidemia Observational studies show less risk of AD in patients on statin agents (RCTs do not show effect) Original HTN in Elderly studies: patients initially on placebo with systolic HTN had persistent elevation in risk of dementia Vascular risk factors seem to play role even for AD! Evidence lacking for Vit E, Estrogen, NSAIDS

43. Calcium channel modulation and excitatotoxic systems attenuation (such as memantine ) Anti-inflammatory/immunosuppressive strategies(e.g. NSAIDs) Gene therapy for defective protein regulation Toxin removal ( Desferroxamine , clioquinol ) / Ventriculoperitoneal shunting ( COGNIShunt ) Amyloid Protein strategies Other Neuroprotective strategies STRATEGIES TO SLOW OR HALT PROGESSION

44. Neuroprotective Strategies Nerve Growth Factor Acetyl-l( levo ) carnitine ( ALCAR ) Estrogen Homocysteine reduction( folate, B6, B12) Antioxidants ( Vit E, Gingko, deprenyl ) ‘Statins’ (Lipitor, Pravachol ) (may lower abnormal amyloid levels) Rosiglitazone (Avandia) -anti-inflammatory, amyloid processing modulation activities Nutraceuticals

45. Nutraceutical Strategies Vitamin E (antioxidant) Homocysteine Reduction (folate, B6, B12) Beta-carotene – Physician’s Health Study II found a cognitive protective effect of 50 mg every other day over two decades of use Gingko (antioxidant) Resveratrol

46. Vitamin E Potent antioxidant properties Has been shown to slow progression at least as much as Deprenyl in one head-to-head study Recent study showed no difference from placebo in preventing progression from MCI to AD over 3 yrs Few side effects even in high doses, though recent studies in Europe suggest a higher death rate in those on hi-dose Vitamin E Doses used in recent studies: up to 1000 IU bid Consider 400-800 IU per day for prevention May work better if combined with Vitamin C

47. Estrogen At this point the summary of many studies suggests that Hormone replacement therapy (HRT) is questionably effective in slowing the onset of AD in some women The earlier started, the better. Limited exposure may be best. Progesterone may be detrimental Tacrine response can be enhanced by Estrogen WHY? neurotrophic effects, incr. ChAT , high serum E2 suppresses Apo E

48. Ginkgo biloba Extract from the ginkgo tree (EGb761) taken in doses of 120mg to 240 mg daily anti-inflammatory, anti-oxidant properties trials show modest improvements in some measures of function and memory reasonably safe and well tolerated, but watch for bleeding current trial for prevention of Alzheimer’s disease underway with 3000 participants

49. Statins Lovastatin( Mevacor ), pravastatin( Pravachol ), simvastatin(Zocor), atorvastatin(Lipitor) May prevent aggregation of B-amyloid* in the brain by preventing cholesterol build up. May activate alpha-secretase . Conflicting evidence – recent U of Wash study did not find a benefit, but looked at older individuals on statins only a short while. Earlier studies were more positive Not sure if all these drugs are equal… Ability to enhance tissue plaminogen activator ( tPA ) and thus production of plasmin may be important. Plasmin may activate alpha-secretase and can also increase production of BDNF. *AKA amyloid-beta peptide or ABeta

50. NSAID Use & AD in Elderly Patients 2708 patients enrolled Examined NSAID use and prevalence of Alzheimer’s Disease NSAID users had ~50% lower risk of being affected by AD Aspirin trended this way but was not significant Treatment studies have not shown any consistent benefits yet however. Landi , et al, Am J Geriatric Psychiatry, March-April, 2003

51. Abnormal Amyloid Protein Strategies Most genetic mutations associated with AD affect amyloid processing Senile plaques contain abnormal amyloid B fragments (that precipitate out of solution easily) Attack enzymatic pathways that lead to production of abnormal type and amount of amyloid ( beta or gamma- secretase inhibitors ) Enhance alpha-secretase system to promote normal amyloid Prevent aggregation (NSAIDS may do this!) Alter the abnormal gene expression GAG mimetics ( g lycos a mino g lycans ) – Alzhemed – interferes with formation of insoluble amyloid protein fragments

52. Reversal Strategies Destroy the current plaques/amyloid Vaccination Strategy : AN-1792 vaccine is in testing. This is an amyloid B protein fragment which can induce antibodies that bind to plaques and activate microglial destruction processes. Trial halted b/o menigoencephalopathies ‘ Plaque busters ’ Alzhemed prevents Amyloid B fragments from forming fibrils Clioquinol - A metal-protein-attenuating compound (MPAC) that inhibits zinc and copper ions from binding to beta-amyloid, thereby helping to dissolve it and prevent it from accumulating. Transthyretin shows promise at interfering with toxic effects Generate new tissue - neuroregeneration strategies (STEM cells) neurotransplantation strategies

53. Other Drugs in the Pipeline Tau protein modulators (to prevent abnormal phosphorylated ‘tau’ protein Beta and gamma-secretase inhibitors Alpha secretase stimulators Bryostatin – CA drug that stimulates brain protein production. Reduces B-amyloid levels in mice, enhances memory and learning. New generation NSAIDS (flubiprofen) – testing in humans looks promising Immune enhancers (immunoglobulin) New vaccines and new anticholinesterases (huperzine)

54. Future Directions Amyloid B peptide (plaque component) vaccination Amyloid modulators ?Anti-inflammatory drugs Treatment with statins ?Low flow VP shunting

55. Take Home Points Cholinesterase Inhibitors are MODESTLY effective in treatment of mild to moderate AD Cholinesterase Inhibitors are probably effective in more severe AD No large difference in efficacy between agents, but Donepezil more easily titrated and tolerated Evidence to support use of cholinesterase inhibitors for vascular and vascular/AD dementia Memantine looks to be effective for more severe AD and vascular dementia, will likely be used in combination with cholinesterase inhibitors

56. Take Home Points Behavioral symptoms common, first line of treatment is nonpharmacologic Atypical antipsychotics can be effective, but use in low doses and watch carefully for problems (especially EPS, hypotension) For PD, quetiapine (seroquel) may be first line for psychotic symptoms Avoid antipsychotics with Lewy Body Disease!

57. THANK YOU