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
Donepezil
(Aricept)
Rivastigmine
(Exelon)
Galantamine
(Razadyne)
BuChE Small Yes Small
Nicotinic
modulation
No No Yes*
Half-life 50-70 hrs ½-2 hrs 5-7 hrs
Starting Dose 5 mg/day 1.5 mg bid 4 mg bid
Ending Dose 5-10 mg/day 3-6 mg bid 8-12 mg bid
*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

13. 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)

14. 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

15. 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)

16. 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

17. 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

18. 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

19. 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)

20. 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

21. 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)

22. 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

23. Commonly Prescribed Non-Psychiatric Drugs with Significant
Anticholinergic Activity
ocimetidine & ranitidine
oprednisolone
otheophylline
odigoxin/Lanoxin
ofurosemide
onifedipine
odiphenhydramine (OTC)
•To a lesser extent: codeine, warfarin, dipyradimole, isosorbide
dinitrate

24. 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

25. 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)

26. 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

27. 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

28. Memantine
• Can 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

29. 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”

30. 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

31. 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

32. 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.

33. 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

34. 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

35. 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

36. 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

37. 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

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

39. 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

40. 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

41. 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

42. 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.

43. 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

44. ?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

45.  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

46. 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

47. 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

48. 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

49. 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

50. 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

51. 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

52. 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

53. 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 (glycosaminoglycans) –Alzhemed – interferes with formation of insoluble
amyloid protein fragments

54. 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

55. 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)

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

57. 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

58. 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!

59. THANK YOU