1. Most Promising Agents in Treatment of Dementias
Dr. Vikas Dhikav,
Department of Neurology,
Dr. RML Hospital & PGIMER,
GGS IP University, New Delhi
Most Promising Agents in Treatment of Dementias

2. Dementia Global Loss of Cognitive Abilities Memory impairment
& at least one of the following:
Aphasia
Apraxia
Agnosia
Disturbances in executive functioning
Am J Geriatr Psychiatry. 2011; 19(3): 205–210.

3. What is MCI? (1) Memory problems (2) Objective memory disorder
(3) Absence of other cognitive disorders or repercussions on daily life
(4) Normal general cognitive function and
(5) Absence of dementia.
MCI Working Group. J Neurol Neurosurg Psychiatry. 2006; 77(6): 714–718.

4. BPSD Behavioral & Psychological Symptoms of Dementias.
 ”A wide spectrum of non-cognitive manifestations of dementia, including verbal and physical aggression, agitation, psychotic symptoms (hallucinations and delusions), sleep disturbances, oppositional behavior, and wandering”
International Psychogeriatric Association
Dhikav V, Anand KS, Int Psychogeriatr. 2012;24(9):  

5. BPSD… Contribute to: Caregiver burden Predict hospitalization
Caregiver stress
Dhikav V, Anand KS, Int Psychogeriatr. 2012;24(9):  

6. BPSD…pathophysiology
Genetic mutations (presanlin-I)
Receptor polymorphism
Higher load of NFT
Medial temporal lobe1 & hippocampal volume reduction
Dhikav V, Sethi M, Anand KS. Br J Radiol. 2014;87(1042):

7. Existing drugs Disease modifying NMDA receptor antagonist
Vitamin E
NMDA receptor antagonist
Memantine
Cholinesterase inhibitors
Donepezil
Rivastigmine
Galantamine

8. Classification… Drugs for BPSD Benzodiazepines SSRIs Antipsychotics
Lorazepam
SSRIs
Ecitalopram
Sertraline
Antipsychotics
Older
Haloperidol
Newer
Amisulpiride
Risperidone
Quetiapine
Beta-blockers
Propranolol

9. Cholinesterase inhibitors (ChIs)
Primary pharmacological treatment.
Included in AAN guidelines.
Donepezil
Rivastigmine
Galantamine
Effective in double blind placebo controlled trials.
Doody et al., Neurology 2001;

10. Donepezil Effective in trials of 3-6 months
Continued efficacy in open-label extension studies.
Doody et al., Neurology 2001;

11. ChIs..whats on offer?
Sudden improvement in small percentage of patients.
Slowing decline.
Stabilization.
Doody et al., Neurology 2001;

12. Benefits on non-cognitive symptoms
Neurobehavioral symptoms
Apathy
Visual hallucinations
Betterment of ADL
Or slowing decline in worsening of ADL
Doody et al., Neurology 2001;

13. ChIs…dose titratrion
“Dose is increased progressive till beneficial effects noted or side effects appear”.
Bradley et al., Neurology in Clinical Practice, 5th Ed, 2008, pp-1871

14. ChIs..adverse effects GI side effects Others Give after meals
Slow dose escalation
Others
Hallucinations
Vivid dreams
Sleep disturbances
Acute muscular dystonia (Rivastigmine)
Bradley et al., Neurology in Clinical Practice, 5th Ed, 2008, pp-1871

15. When to change?
“If one agent appears ineffective or intolerable, another agent should be tried”
Bradley et al., Neurology in Clinical Practice, 5th Ed, 2008, pp-1871

16. Glutamate receptor antagonist
Memantine
Improvement in cognition & functioning reported in two pivotal trials for moderate to severe AD.
Dose: 5 mg twice daily  10mg twice daily.
No specific side effects noted in clinical trials.

17. Disease modifying… Estrogens Ginkgo Biloba NSAIDs/Prednisolone
Two trials failed to stop AD progression
Ginkgo Biloba
Mixed results
NSAIDs/Prednisolone
No effect on symptomatic AD
1000 IU recommended twice daily
Cardiotoxicity
Failure to slow down conversion of MCIAD
Handerson et al., Neurology 2000;

18. Management of BPSD (non-pharmacological)
Illumination at night
Signboards to reduce confusion
Evaluate UTI
Clear communication
Caregiver training

19. Management of BPSD (pharmacological)
Antipsychotic
Quetiapine, risperidone, olanzapine
Low dose
Careful titration
Depression
SSRIs
Reduce anxiety
Irritability
Agitation
Bradley et al., Neurology in Clinical Practice, 5th Ed, 2008, pp-1872

20. BPSD…
“Traditional anitpsychotics are more likely to produce extrapyramidal side effects, leading to cognitive worsening”
Bradley et al., Neurology in Clinical Practice, 5th Ed, 2008, pp-1871

21. BPSD…antipsychotics
“Antipsychotics carry a high risk of mortality in elderly if used indiscriminately”.
Bradley et al., Neurology in Clinical Practice, 5th Ed, 2008, pp-1871

22. Individual Anticholinesterases

23. Tacrine Tacrine Aminoacridine Short acting Low bioavailability
Hepatotoxicty

24. Donepezil Reversible anticholinesterase Specific to brain
Peak plasma levels after approximately 4 hours & . plasma steady state 14 and 21 days
Long half-life of over 70 hours
Excretion is slow and occurs via renal and the cytochrome P450 system

25. Rivastigmine Selective carbamate ‘pseudo-irreversible’ inhibitor
CNS selectivity (Cortex, hippocampus)
Poor protein binding
No hepatic metabolism
Available as a patch, capsules
5-15 mg/cm2

26. Matrifonate Prodrug, used in schistosomiasis
Short half-life in plasma (2h), but has long activity in the CNS due to its irreversible activity.
Poor protein binding.
Lacks brain specificity.

27. Safety of anticholinesterases
Well tolerated
Side effectsmild to moderate
Fatigue
Nausea, Vomiting, Diarrhoea
Muscle cramps
Sleep disturbances
Hallucinations
Allergic rashes (Rivastigmine)

28. Comparative efficacy
Despite the slight variations in the mode of action of the three cholinesterase inhibitors there is no evidence of any differences between them with respect to efficacy. 

29. Comparison

30. Combination therapy Anti-cholinesetrase+memantine (n>2000)
Beneficial for the treatment of moderate-to- severe Alzheimer's disease
Well tolerated.
Cognition
Behavioral disturbances
Activities of daily living
Global assessment

31. Current status…
Donepezil, favoured compared to rivastigmine due to longer duration of action.
DonepezilLongest, most selective & most potent.
Tacrine had the shortest half-life, requiring dosage 4 times dailyhetotoxic

32. Current status… Donepezil
Better tolerability smoother AChe inhibition achieved with longer duration of action.
This avoids the fluctuations in enzyme inhibition, and lessening cholinergic side effects.
Int J Neuropsychopharmacol. 2014;18(5)

33. Limitations Though the symptoms of dementia go on for years
Phase III trials of the cholinesterase inhibitors , were typically of only 3- to 6- months' duration.
Limited long term data available
Decision to carry individualized
Can J Psychiatry. 2014 Dec;59(12):

34. Limitations…
Existing drugs have adverse effects

35. Alzheimer’s disease Most common cause of dementia.
Occurs after 65 years of age.
Advancing age, low educationrisk factors.

36. Alzheimer’s disease … Risk factors… Diabetes Hypertension Seizures
Depression

41. Depression & hippocampal atrophy
“Medial temporal Lobe Atrophy in Patients with Alzheimer's disease and Mild Cognitive Impairment”
Dhikav et al., Br J Radiol. 2014;87(1042):

42. High perceived stress in AD/MCI
Dhikav V et al., Annals of Ind Acad Neurol 2015

43. Normal Vs Abnormal Hippocamapal Volumes
Dhikav V et al., Annals of Ind Acad Neurol 2015

44. Putative risk factors ..for AD
Alterations of:
B12
Homocysteine
Cortisol
Vitamin D3

45. Mifepristone Anti-progestin Anti-glucorticoid Approved for:
Cushing’s disease

46. Glucocorticoids and Alzheimer’s disease
Hypothesis (2007)
“Glucucorticoids could initiate Alzheimer’s disease”

47. Why need a new drug in Alzheimer's disease?
Not curable
Existing drugs have modest usefulness
Recent article questioned their usefulness1
1J Neurol Neurosurg Psychiatry 2014;85:e3 doi: /jnnp .

51. Hippocampus and glucocorticoids
Hippocampus helps us remember things.
Glucocorticoids are toxic to hippocampus and involved in its shrinkage.
Metabolism. 2005;54(5 Suppl 1):20-3. 

55. Donepazil, the winner?
Currently, no drug affects hippocampal atrophy or medial temporal lobe atrophy.
Donepazil has shown some favourable effects
Dement Geriatr Cogn Disord. 2014;38(3-4):  

56. Glucocorticoids in Alzheimer’s disease
Alzheimer's disease has abnormalities of the hypothalamic pituitary adrenal axis.
Elevated cortisol levels associated with rapid progression of the illness.
Elevated cortisol levels may directly contribute to cognitive deficits in Alzheimer's disease
Curr Alzheimer Res. 2005 Apr;2(2):125-9.

57. What does mifeprostone do in Alzheimer’s disease?
Glucocorticoids may be intiating agents.
Interferes with beta-amyloid processing.
Blocks tau pathology.
Mifepristone may be potential agent.
What does mifeprostone do in Alzheimer’s disease?
Biol Psychiatry. 2013 Sep 1;74(5):  

58. Mifepristone Antiprogestin
Used as an abortifacient (emergency contraceptive)

59. Mifepristrone…Clinical trials
Also in
Cushing’s disease
Endometriosis
Fibroid
Glaucoma
Meningioma
Depression
PTSD

60. Mifepristone: Old wine in a new bottle?
There is a proposal to slow down Alzheimer’s disease using mifepristone
J Mol Neurosci. 2002;19(1-2):201-6.

61. Issues
Will it work?

62. Potential of mifepristone
Neuroprorective in hippocampus
Reduces oxidative stress
Decreases amyloid beta deposition
Reduces excitotoxicity
Mifepristone could be potentially useful in Alzheimer’s disease.
Curr Opin Investig Drugs. 2007;8(7):563-9.

63. Concerns 200mg-1200mg daily used in clinical trials
Side effects significant
? What side effects in elderly population

64. Concerns Useful in Cushing’s psychosisuseful in Alzheimer’s disease
Adrenal insufficiency
Endometrial hyperplasia.
Eur J Endocrinol. 2007;157(5):561-9.

65. Monitoring
Adrenal insufficiency can be assessed only by careful clinical evaluation
Hormonal parameters not reliable during receptor block
Eur J Endocrinol. 2007;157(5):561-9.

66. Thank you