Most Promising Agents in Treatment of Dementias Dr. Vikas Dhikav, Department of Neurology, Dr. RML Hospital & PGIMER, GGS IP University, New Delhi-110001 vikasadhikav@hotmail.com Most Promising Agents in Treatment of Dementias

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.

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.

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):1531-2. 

BPSD… Contribute to: Caregiver burden Predict hospitalization Caregiver stress Dhikav V, Anand KS, Int Psychogeriatr. 2012;24(9):1531-2. 

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):20140150.

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

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

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; 1154-1166.

Donepezil Effective in trials of 3-6 months Continued efficacy in open-label extension studies. Doody et al., Neurology 2001; 1154-1166.

ChIs..whats on offer? Sudden improvement in small percentage of patients. Slowing decline. Stabilization. Doody et al., Neurology 2001; 1154-1166.

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; 1154-1166.

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

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

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

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.

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; 295-301.

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

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

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

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

Individual Anticholinesterases

Tacrine Tacrine Aminoacridine Short acting Low bioavailability Hepatotoxicty

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

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

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.

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

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.  http://www.cochrane.org/CD005593/DEMENTIA_cholinesterase-inhibitors

Comparison

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

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

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)

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):618-23.

Limitations… Existing drugs have adverse effects

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

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

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):20140150.

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

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

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

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

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

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:10.1136/jnnp-2014-308883.11 .

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. 

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):170-177. 

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.

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):357-66. 

Mifepristone Antiprogestin Used as an abortifacient (emergency contraceptive)

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

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.

Issues Will it work?

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.

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

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

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.

Thank you