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  1. 1. Cognitive Enhancers Role of memantine
  2. 2. Background <ul><li>Dementia </li></ul><ul><li>Drug therapy of dementia </li></ul><ul><li>Alzheimer’s disease </li></ul><ul><li>Memantine </li></ul>
  3. 3. Dementia The basics
  4. 4. Mild cognitive impairment (MCI) <ul><li>MCI is a relatively recent term, used to describe people who have some problems with their memory but do not actually have dementia. </li></ul><ul><li>It is estimated that 15% of the population may be experiencing MCI. </li></ul><ul><ul><li>Some people (80%?) will be in the early stages of Alzheimer’s disease or another dementia. </li></ul></ul><ul><ul><li>Others, however, will have MCI as a result of stress, anxiety, depression, physical illness or just an ‘off day’. </li></ul></ul>
  5. 5. Dementia - background <ul><li>Mainly affects older people, with 2% - 10% of all cases starting before the age of 65. </li></ul><ul><li>After this, prevalence doubles with every 5 year increment in age </li></ul><ul><li>Consequence of diffuse disease of the brain hemispheres, maximally affecting the cerebral cortex and hippocampus </li></ul>
  6. 6. Dementia - incidence <ul><li>In general the order in which symptoms become apparent, and their severity depends on the aetiology of the dementia but incidence is rising globally. </li></ul>
  7. 7. Dementia - definition <ul><li>Dementia is a symptom of disease rather than a single disease entity. </li></ul><ul><li>A syndrome due to brain disease characterised by progressive, global deterioration in intellect, behavior and personality including: </li></ul><ul><ul><li>Memory </li></ul></ul><ul><ul><li>Learning </li></ul></ul><ul><ul><li>Orientation </li></ul></ul><ul><ul><li>Language </li></ul></ul><ul><ul><li>Comprehension </li></ul></ul><ul><ul><li>Judgement </li></ul></ul>
  8. 8. Dementia - subtypes <ul><li>Dementia is of various types and due to various causes. </li></ul>
  9. 9. Dementia - Causes <ul><li>Alzheimers Disease </li></ul><ul><li>Vascular Dementia </li></ul><ul><li>“ Mixed” Dementia (Alzheimers Disease and Vascular Dementia) </li></ul><ul><li>Dementia with Lewy Bodies </li></ul><ul><li>Frontotemporal Dementia </li></ul><ul><li>Parkinsons Disease with Dementia </li></ul><ul><li>Others </li></ul>
  10. 10. Dementia – site classification
  11. 11. Dementia – clinical course <ul><li>Rate of progression depends upon the underlying cause. </li></ul><ul><li>Duration of history helps establish cause of dementia: </li></ul><ul><ul><li>Alzheimer‘s disease is slowly progressive over years, whereas encephalitis may be rapid over weeks. </li></ul></ul><ul><ul><li>Dementia due to cerebrovascular disease appears to occur ’stroke by stroke‘. </li></ul></ul>
  12. 12. Dementia - sequence <ul><li>Memory must be impaired to make the diagnosis of dementia. </li></ul><ul><li>Loss of memory for recent events is the earliest feature of dementia. </li></ul><ul><li>Subsequent symptoms include: </li></ul><ul><ul><li>abnormal behavior, </li></ul></ul><ul><ul><li>loss of intellect, </li></ul></ul><ul><ul><li>mood changes, and </li></ul></ul><ul><ul><li>difficulty coping with ordinary routes. </li></ul></ul><ul><ul><li>Insight may be retained initially, but is then usually lost. </li></ul></ul><ul><ul><li>Ultimately, there is loss of incontinence, wandering, self-care and often paranoia . </li></ul></ul>
  13. 13. Dementia - management
  14. 14. Dementia - medications <ul><li>Cure disease </li></ul><ul><li>Prevent disease or delay onset </li></ul><ul><li>Slow progression of disease </li></ul><ul><li>Treat primary symptoms eg memory </li></ul><ul><li>Treat secondary symptoms eg. depression, hallucinations </li></ul>Treat primary symptoms eg memory
  15. 15. Medications to treat primary symptoms <ul><li>Cholinesterase inhibitors: </li></ul><ul><li>Memantine </li></ul><ul><li>Ginkgo biloba </li></ul>
  16. 16. Cholinesterase inhibitors The types & MOA
  17. 17. Neurotransmitters in memory <ul><li>Acetylcholine has a role of in cognition and memory formation but in early stages of dementia, acetylcholine levels are reduced. </li></ul><ul><li>Acetylcholine in the synaptic cleft is broken down by enzyme - Acetylcholinesterase </li></ul><ul><li>Cholinesterase inhibitors inhibit the action of the enyzme acetylcholinesterase and stop the breakdown of acetylcholine </li></ul><ul><ul><li>This boosts acetylcholine levels in the brain. </li></ul></ul>
  18. 18. Cholinesterase inhibitors <ul><li>These drugs do not prevent progression of underlying disease </li></ul><ul><ul><li>Patients on these drugs show modest improvement in cognition and function, and behavioural symptoms. </li></ul></ul><ul><li>Response to therapy: </li></ul><ul><ul><li>1/3 improve, </li></ul></ul><ul><ul><li>1/3 stabilise, </li></ul></ul><ul><ul><li>1/3 have no response </li></ul></ul>
  19. 19. Cholinesterase inhibitors <ul><li>Donepezil (Aricept) </li></ul><ul><ul><li>given once daily, dosage of 5mg to 10mg </li></ul></ul><ul><li>Galantamine (Reminyl) </li></ul><ul><ul><li>given once daily, dosages of 8mg to 24mg </li></ul></ul><ul><ul><li>(can also be given twice daily) </li></ul></ul><ul><li>Rivastigmine (Exelon) </li></ul><ul><ul><li>given twice daily, dosages of 3mg to 12mg </li></ul></ul>
  20. 20. Cholinesterase inhibitors <ul><li>Donepezil, galantamine and rivastigmine are </li></ul><ul><ul><li>used in the treatment of mild to moderate dementia due to Alzheimer's disease and </li></ul></ul><ul><ul><li>may be helpful in the treatment of dementia with Lewy bodies. </li></ul></ul><ul><li>Comparative trials of anticholinesterases are few </li></ul><ul><li>Donepezil, galantamine and rivastigmine seem to have similar efficacy, but at full dose oral rivastigmine may have more GI adverse effects. </li></ul>
  21. 21. Cholinesterase inhibitors <ul><li>Deterioration of cognition is delayed in patients with mild-to-moderate Alzheimer’s disease: </li></ul><ul><ul><li>by 6 months in 25–50% of patients, and </li></ul></ul><ul><ul><li>by 1 year in 12–20%. </li></ul></ul><ul><li>As there are no reliable predictors of response, carefully assess benefit after 3 months of treatment at full or highest tolerated dose. </li></ul><ul><ul><li>Patients unresponsive to one anti-cholinesterase show improvement when switched to another. </li></ul></ul><ul><ul><li>Stop therapy if there are significant adverse effects, poor compliance or lack of symptom improvement. </li></ul></ul>
  22. 22. Cholinesterase inhibitors Cognition <ul><li>Improvement (memory, thinking, and language) in about two thirds of people with Alzheimer’s disease </li></ul><ul><li>May slow cognitive decline in some </li></ul><ul><li>If a patient does improve, the amount of improvement over one year is roughly equal to the amount of decline typically observed in untreated people with Alzheimer’s disease over 8 - 12 months. </li></ul>Daily function & behavior <ul><li>Cholinesterase inhibitors & Memantine can also help with deficits in daily functioning and behaviour that are prevalent in people with Alzheimer’s disease. </li></ul><ul><li>Even small improvements in daily functioning and behaviour are important because these problems are major reasons. </li></ul>
  23. 23. Cholinesterase inhibitors <ul><li>Side effects </li></ul><ul><ul><li>Common </li></ul></ul><ul><ul><ul><li>nausea, vomiting, diarrhoea, anorexia, abdominal pain, dyspepsia, headache, insomnia, vivid dreams, depression, fatigue, drowsiness, dizziness, tremor, weight loss, muscle cramps, urinary incontinence, increased sweating, hypertension, syncope </li></ul></ul></ul><ul><ul><li>Infrequent or rare </li></ul></ul><ul><ul><ul><li>bradycardia, heart block, seizure, agitation, hallucination, confusion, GI haemorrhage </li></ul></ul></ul><ul><li>Contraindications </li></ul><ul><ul><li>Liver disease, Peptic ulcer, Hypersensitivity, Pregnancy </li></ul></ul><ul><li>Problematic for </li></ul><ul><ul><li>Asthma, seizures, bradycardia, cardiac conduction disorders </li></ul></ul>
  24. 24. Alzheimer’s disease The basics
  25. 25. Alzheimer's disease <ul><li>C ommonest cause of dementia and rarely occurs < 45 years ; with incidence increas ing by age. </li></ul><ul><li>C ause of AD is not known (neurodegenerative) & d iagnosis of AD is established during life by : </li></ul><ul><ul><li>E arly memory failure, </li></ul></ul><ul><ul><li>S low progression , and </li></ul></ul><ul><ul><li>E xclusion of other causes. </li></ul></ul><ul><li>Up to 30% of cases are familial (the loci were found on chromosome 21 and 19). </li></ul><ul><ul><li>Pathology – presence of neurofibrillary tangles & senile plaques in the brain. </li></ul></ul>
  26. 26. Alzheimer's disease
  27. 27. Alzheimer's disease <ul><li>CT scanning aids diagnosis by excluding multiple infarction or a mass lesion. </li></ul><ul><li>MRI shows bilateral temporal lobe atrophy. </li></ul><ul><li>SPECT usually shows temporoparietal hypoperfusion. </li></ul>
  28. 28. Alzheimer's disease
  29. 29. Alzheimer's disease <ul><li>Mangement of AD requires careful advice and counseling of the patient and family and shared care involving the family, caregivers, GPs, hospital specialist, and community psychiatric services. </li></ul><ul><li>Treat concurrent depression, anxiety and sleep disorders. </li></ul><ul><li>Neuroleptic use may be required for behavioral disturbance. </li></ul>
  30. 30. Alzheimers Disease - Management <ul><li>Medication is just one of many strategies in the management of this disease and one can use multiple medications with different modes of action together or separately across the various stages of the disease </li></ul><ul><li>As we cannot currently prevent or cure Alzheimers Disease, the main aim of treatment is </li></ul><ul><ul><li>to reduce symptoms, and </li></ul></ul><ul><ul><li>to improve quality of life </li></ul></ul>
  31. 31. Memantine Understanding in depth
  32. 32. Glutamate [glutamic acid] <ul><li>Glutamate or glutamic acid = most abundant excitatory neurotransmitter in the nervous system and is affected by AD . </li></ul><ul><li>At normal levels, glutamate aids in memory and learning. But in an ischemic cascade, levels are high and over-stimulation of the glutamate receptors occurs as part of the process called excitotoxicity </li></ul><ul><ul><li>Nerve cells get overstimulated, Glutamate allows Ca+ to enter cell, exciting the neuron. Excessive excitatory activity leads to neuronal damage & eventual cell death </li></ul></ul>
  33. 33. The role of Neurotransmitters in memory <ul><li>Memantine is a glutamate receptor antagonist which addresses the excitotoxic effects of glutamate by occupying NMDA receptor sites. </li></ul><ul><li>Memantine displaces Mg ++ from N-Methyl-D-Aspartate (NMDA) receptors, thus moderating the excitatory effect of glutamate </li></ul><ul><ul><li>Memantine is a major breakthrough in AD, as it does not affect the normal function of glutamate signalling, but only the excessive actions leading to cell death. </li></ul></ul><ul><ul><li>Memantine blocks the pathological effects of abnormal glutamate release, and allows better function of the impaired brain. </li></ul></ul>
  34. 34. Memantine - uniqueness in A D <ul><li>As Glutamate receptors are required for normal brain function, learning and memory in particular, attempts to develop drugs other than memantine that block action of glutamate were not useful for AD. </li></ul>
  35. 35. Memantine - MOA
  36. 36. Memantine - MOA
  37. 37. Memantine - MOA <ul><li>Based on the fact that cerebrospinal fluid (CSF) levels of memantine after therapeutic doses in man are between 0.5 and 1 µM, potentially 4 targets (as of current knowledge) could play a role in therapeutic activity by antagonism at </li></ul><ul><ul><li>NMDA receptors, </li></ul></ul><ul><ul><li>cholinergic nicotinic alpha7 receptors, </li></ul></ul><ul><ul><li>nicotinic alpha 9/10 receptors, and </li></ul></ul><ul><ul><li>5-HT 3 receptors. </li></ul></ul>
  38. 38. Memantine - MOA <ul><li>Memantine is a low-affinity uncompetitive antagonist at glutamatergic NMDA receptors. </li></ul><ul><ul><li>By binding to the NMDA receptor with a higher affinity than Mg2+ ions, memantine is able to inhibit the prolonged influx of Ca2+ ions, which forms the basis of neuronal excitotoxicity. </li></ul></ul><ul><ul><li>The low affinity and rapid off-rate kinetics of memantine at the NMDA receptor-channel, however, preserves the physiological function of the receptor, as it can still be activated by the relatively high concentrations of glutamate released following depolarization of the presynaptic neuron. </li></ul></ul>
  39. 39. Memantine - MOA <ul><li>The interaction of memantine with g;utamatergic NMDA receptors plays a major role in the symptomatic improvement that the drug produces in Alzheimer's disease. </li></ul><ul><li>However, there is no evidence as yet that the ability of memantine to protect against NMDA receptor-mediated excitotoxicity has a disease-modifying effect in Alzheimer's, although this has been suggested in animal models. </li></ul>
  40. 40. Memantine - pharmacology <ul><li>Memantine is well absorbed (100%) after oral administration, showing plasma protein binding of approx. 45 %. </li></ul><ul><li>ER Cmax is approximately 9–12 h postdose, as compared to conventional of approx. 3–7 h. </li></ul><ul><li>Unaffected by food, but Tmax shortened. </li></ul><ul><li>Memantine ER at 28 mg once daily reaches a maximum concentration that is 48% higher and a 24-h area under the curve that is approximately 33% higher than 10 mg twice daily memantine. </li></ul>
  41. 41. Memantine - pharmacology <ul><li>The elimination half-life of memantine is about 60–80 h. </li></ul><ul><li>Approximately 48% of memantine is excreted as unmetabolized memantine </li></ul><ul><li>It can be used with other AD medications </li></ul><ul><li>It is metabolised to a minor extent, is mainly eliminated through the kidney </li></ul><ul><li>Memantine benefit and good tolerability has been confirmed by a meta analysis study (Winblad et al., 2007). </li></ul>
  42. 42. Memantine use in A D <ul><li>Need specialist diagnosis of Alzheimers Disease + MMSE [ Mini-Mental State Examination ] score of 10 to 24. </li></ul><ul><li>Warn against unrealistic expectations and watch for return of insight leading to depression or anxiety. </li></ul><ul><li>Need to show an improvement on MMSE of 2 points to continue medication. </li></ul><ul><ul><li>Side effects - nausea, vomiting, diarrhoea, dizziness, headache, muscle cramps </li></ul></ul><ul><ul><li>Use carefully if gastric ulcer, heart disease, chronic lung disease present. </li></ul></ul>
  43. 43. Memantine – scope in AD <ul><li>Improves cognition and daily living skills of demented patients </li></ul><ul><li>Positive effects upon activities of daily living and behavioural disturbances in the Alzheimer’s patients (Doody et al., 2004; Gauthier et al., 2005; Cummings et al., 2006). </li></ul>
  44. 44. Memantine - indications <ul><li>Indicated for treatment of moderate to severe Alzheimer's disease </li></ul><ul><li>As of April 2011 new research has emerged that shows this drug is not effective for treatment in stopping the progression of mild to moderate Alzheimer’s disease. </li></ul><ul><li>In a review of 3 studies covering 431 patients with mild AD and 697 with moderate AD - there was no difference in the effectiveness of the drug Memantine. </li></ul>
  45. 45. Memantine - indications <ul><li>In mild to moderate AD, </li></ul><ul><ul><li>memantine significantly attenuated symptomatic decline as a monotherapy following 24 weeks of treatment as evaluated by CIBIC-plus (cognition, behaviour, daily living skills) and ADAScog (cognition). </li></ul></ul><ul><li>In moderate to severe stages, </li></ul><ul><ul><li>A slower decline was observed in patients treated with memantine for 28 weeks as measured by ADCS-ADL scales (Reisberg et al., 2003). </li></ul></ul><ul><ul><li>These results were subsequently confirmed by 24 weeks extension trial (Ferris et al., 2003). </li></ul></ul>
  46. 46. Memantine - combination <ul><li>Combination of memantine with Donepezil produced an additional, significant benefit on functional and cognitive decline over 24 weeks period both in (ADCS-ADL19 and cognitive (SIB) scales (Tariot et al., 2004). </li></ul><ul><li>In another study, combination therapy of memantine + Donepezil produces better effects than Donepezil alone e.g. </li></ul><ul><ul><li>on decline in higher level functions, autonomy (ADCS-ADL19 subscales.) (Feldman et al., 2006) </li></ul></ul><ul><ul><li>aggression agitation, irritability, appetite loss (Robinson and Keating, 2006). </li></ul></ul>
  47. 47. Memantine -dosage <ul><li>Dosage: start with 5mg daily and increase to10mg twice daily. </li></ul><ul><li>Stopping of medication: </li></ul><ul><ul><li>unacceptable side effects </li></ul></ul><ul><ul><li>lack of response to medication </li></ul></ul><ul><ul><li>late stages of the disease </li></ul></ul><ul><li>Side effects - headaches, dizziness. </li></ul><ul><li>Do not use in kidney disease / seizure disorders </li></ul><ul><li>Trials show slowing in cognitive and functional decline and decrease in agitation in treated group compared to placebo. </li></ul>
  48. 48. Memantine - dosage <ul><li>For immediate release, the initial dosage is one 5mg oral tablet per day. </li></ul><ul><li>A dosage increase may be made after at least one week upto 20mg Memantine per day. </li></ul><ul><li>Any dosage greater than 5mg per day must be given in 2 doses. </li></ul><ul><li>In patients with severe renal impairment (creatinine clearance of 5–29 ml/min) limit dose to 5 mg twice daily. </li></ul>
  49. 49. Memantine - dosage <ul><li>For extended release, the initial dosage is one 7 mg oral tablet per day. </li></ul><ul><li>A dosage increase may be made after at least one week to 28mg Memantine per day. </li></ul><ul><li>Note: When switching from the intermediate release product to the extended release product, begin taking the extended release product the day after the last dose of the nprmal product. </li></ul><ul><ul><li>For Vascular Dementia, the dosage is initially one 5mg tablet once daily, increasable to 10mg twice daily. </li></ul></ul>
  50. 50. Memantine Studies
  51. 51. Memantine - studies
  52. 52. Memantine - studies
  53. 53. Memantine in severe AD
  54. 54. Memantine + donezepil in severe AD
  55. 55. Memantine in Severe Dementia: Results of the M-Best Study Benefit and Efficacy in Severely Demented Patients During Treatment With Memantine
  56. 56. Study Design No. of patients N = 166 (nursing home) Design Double-blind, randomized, placebo- controlled, multicenter study Diagnosis Primary dementia (AD, VaD, mixed types) Age 60 – 80 years (mean 68.4) Severity MMSE < 10 (mean 6.3), GDS 5 – 7 Dose; duration 10 mg memantine/day; 12 weeks Primary efficacy Global: CGI-C parameters Care Dependence: BGP subscore Secondary efficacy Function/Behavior: D-Scale, BGP parameter Winblad and Poritis., Int J Geriat Psychiatr 1999
  57. 57. Memantine Improves Global Impression (CGI-C) Responders [%] in CGI-C ITT analysis, N = 166 Response = improvement * p = 0.006, ** p = 0.001 versus placebo Winblad and Poritis., Int J Geriat Psychiatr 1999 Week 4 Week 12 * ** 80 70 60 50 40 30 20 10 0 59% 40% 73% 45% Memantine Memantine Placebo Placebo
  58. 58. Summary <ul><li>Memantine is efficacious in severely demented patients suffering from probable Alzheimer’s disease or probable vascular dementia </li></ul><ul><li>Functional improvement was significant in memantine- treated patients </li></ul><ul><li>Tolerability of memantine was good </li></ul>Winblad and Poritis., Int J Geriat Psychiatr 1999
  59. 59. PMS 1 <ul><li>Time to nursing home placement was significantly reduced in patients who were given cholinesterase inhibitors compared with patients who received no treatment, </li></ul><ul><li>This delay was even greater among patients who were treated with both cholinesterase inhibitor and memantine. Time to death was not associated with either of the medication regimens </li></ul>
  60. 60. PMS 2 <ul><li>The second study followed patients from a memory disorders clinic at Massachusetts General Hospital (MA, USA) to compare cognitive and functional outcomes between </li></ul><ul><ul><li>patients who received no pharmacological treatment, </li></ul></ul><ul><ul><li>patients who were treated with cholinesterase inhibitor only, and </li></ul></ul><ul><ul><li>patients who were given memantine in addition to a cholinesterase inhibitor. </li></ul></ul>
  61. 61. PMS 2 <ul><li>Patients were followed in the study for an average of 30 months. </li></ul><ul><ul><li>Treatment with memantine and cholinesterase inhibitor was associated with a slower rate of decline in cognitive and functional impairment compared with both the cholinesterase inhibitor-only group and the no treatment group. </li></ul></ul>
  62. 62. AD ahead