The only FDA approved treatment for mild to moderate Alzheimer's disease are the cholinesterase inhibitors.  However, research has shown that the benefits are very minimal and definitely not worth the high costs.  The most popular of these is donepezil (Aricept).  The government wastes huge amounts of money keeping the giant drug companies happy.  The drug companies keep cranking out studies, most showing minimal benefits, but spin the results and advertise and lobby to increase sales.

Galantamine Helped Korean Alzheimer’s: In a 16-week DB PC study, 300 Koreans suffering from Alzheimer’s disease were given galantamine 8, 16, or 24 mg/d; The ADAS cognitive subscale improved from 3.7 to 5.6 points in the galantamine groups, vs. a 4.7 point deterioration with placebo (P < 0.001). Improvements in all 3 treatment groups were observed in mean DAD-K, BEHAVE-AD-K, and CIBIC-plus-K scores (P < 0.001, P < 0.005, and P < 0.001). A prospective, double-blind, community-controlled comparison of three doses of galantamine in the treatment of mild to moderate Alzheimer's disease in a Korean population. Suh GH, Yeon Jung H, et al. Hallym University College of Medicine, Seoul, Korea. Clin Ther. 2004 Oct;26(10):1608-18. Ed: This study looks a little too good to be true, which probably means it is.  Cholinergic inhibitors, at their current high prices, are just not worth the small benefits they give.  

Vitamin E, Donepezil (Aricept) Fail to Help Mild Cognitive Impairment: In a 3-year DB PC study of 769 patients with mild cognitive impairment, vitamin E had no effect on 769 patients with mild cognitive impairment. The expensive anti-dementia drug donepezil (Aricept) showed no slowing of the rate of progression of the disease after three years compared with placebo, although it had a limited benefit during the first year. Donepezil will no longer be prescribed by the National Health Service in England for new dementia patients. The overall rate of progression from mild cognitive impairment to early Alzheimer▓s disease was 16% a year. Probability of progression for vitamin E was increased by 2% and for donepezil decreased by 20%, both of which were far from significant. Petersen RE, et al. N Engl J Med. 2005 Jun 9;352(23):2379-88

Donepezil Modest Benefit for Alzheimer: In a 24-week DB PC study of 153 adults with mild Alzheimer disease, donepezil 5 mg/d for 6 weeks, then 10 mg/d made a treatment differences of 2.3 (P = .001) points in the ADAS-cognitive scores. MMSE changes favored donezezil by 1.8 (P = .002) points. Efficacy of donepezil in early-stage Alzheimer disease: a randomized placebo-controlled trial. Seltzer B, Zolnouni P, et al. Tulane University . Arch Neurol. 2004 Dec;61(12):1852-6. Ed: While these changes are significant, they are modest in size and only slightly slow down the progression of the disease. For more, see Alzheimer disease.

Donepezil (Aricept) Not Cost-Effective for Mild Cognitive Impairment; Only Mild Benefit: In a 24-week, 270-patient DB PC study of mild cognitive impairment (MCI), those receiving donepezil ( 5 mg/day for 42 days, then 10 mg/day) or placebo (n = 137) did not show benefit on the primary efficacy measures of the NYU Paragraph Recall test and the ADCS CGIC-MCI. More did show improvements in ADAS-cog total scores, in tests of attention and psychomotor speed, and in PGA scores. Efficacy of donepezil in mild cognitive impairment: a randomized placebo-controlled trial. Salloway S, Ferris S, Kluger A, Goldman R, Griesing T, Kumar D, Richardson S; Donepezil 401 Study Group. Brown University. Neurology. 2004 Aug 24;63(4):651-7. Ed: At the high cost of donepezil, the small amount of improvement is just not worth the public's money.

Donepezil Not Cost-Effective for Alzheimers: In a 3-year DB PC study of 565 community-resident patients with mild to moderate Alzheimer's disease using donepezil (Aricept) (5 or 10 mg/day) or placebo, cognition averaged 0.8 MMSE (mini-mental state examination) points better (p<0.0001) and functionality 1.0 BADLS points better (p<0.0001) with donepezil over the first 2 years. No significant benefits were seen with donepezil in preventing institutionalization (42% vs. 44% at 3 years) or progression of disability (58% vs. 59% at 3 years). No significant differences were seen between donepezil and placebo in behavioral and psychological symptoms, carer psychopathology, other formal care costs, unpaid caregiver time, adverse events or deaths, or between 5 mg and 10 mg donepezil. The authors conclude that donepezil is not cost effective, with benefits below minimally relevant thresholds. Long-term donepezil treatment. Long-term donepezil treatment in 565 patients with Alzheimer's disease (AD2000): randomised double-blind trial. Courtney C, Farrell D, Gray R, Hills R, Lynch L, Sellwood E, Edwards S, Hardyman W, Raftery J, Crome P, Lendon C, Shaw H, Bentham P; AD2000 Collaborative Group. University of Birmingham, UK. Lancet. 2004 Jun 26;363(9427):2105-15. Ed: Memantine is even less useful.  However, I have seen many demented nursing home patients on both at a cost of over $7,000 per year.  While huge amounts of money are wasted on such treatments, government is cutting the amount of money in actual dollars paid to physicians every year.  I see many patients failing to receive much less expensive but cost-effect treatments simply due to lack of physician time to provide good care.  Indeed, I am the only psychiatrist out of 25 in Champaign-Urbana willing to go to nursing homes since the pay is so poor. 

Donepezil Slight Benefit Slowing Progression from Mild Cognitive Impairment to Dementia: In a DB PC study comparing vitamin E 2000 IU, donepezil 10 mg/day, and placebo, 769 patients with mild cognitive impairment were treated for 3 years. Vitamin E slowed progression 2 months, not a statistically significant benefit. However, over the first half, or 18 months, of the three-year trial, mild cognitive impairment patients treated with donepezil had a reduced risk of progressing to Alzheimer's disease; the average delay in disease progression was about six months in those subjects who progressed to Alzheimer's disease. Although the patients treated with donepezil initially progressed to Alzheimer's disease at a slower rate than patients treated with vitamin E or placebo, this risk-reduction effect was short term. By the end of the study, the risk of progression to Alzheimer's disease was the same among all three treatment groups. Without treatment, 12-15% of individuals with mild cognitive impairment progress to Alzheimer's disease each year, although some never do. Among those who progressed to Alzheimer's disease, patients treated with donepezil averaged 661 days until diagnosed with Alzheimer's disease, vitamin E averaged 540 days, and placebo averaged 484 days. Patients who have mild cognitive impairment have memory impairment that is out of proportion to that expected for their age, yet they do not meet commonly accepted criteria for Alzheimer's disease or other types of dementia. Difficulties in performing more challenging cognitive tasks, such as managing one's finances and medications, preparing meals and traveling independently, can be early warning signs that indicate the presence of mild cognitive impairment. Researchers have also found that those who have mild cognitive impairment show brain volume loss in the hippocampus, the area of the brain that controls the sorting, storage and recall of information. Ronald Petersen, Mayo, 9th International Conference on Alzheimer's Disease and Related Disorders 7/18/04. Industry-funded. Ed: The high cost of donepezil suggests that treatments like vitamin E, fish oil, and other healthy vitamins and minerals are more cost-effective.

Cholinesterase Inhibitors Help a Little: Studies with tacrine, donepezil, galantamine, revastigmine, metrifonate, and physostigmine show mild improvement in cognitive and used as palliative. Arch Neurol 11/98 55:1396. Donepezil at 10 mg/day had lower adverse effects although 16% stopped the medicine in 24 week study due to side-effects.

Meta-Analysis: Donepezil (Aricept) Fewest Side-Effects, Galantamine Lower Efficacy, All Modest: Donepezil inhibits acetylcholinesterase but not butyrylcholinesterase; the latter is thought to be a component of neuritic plaques and tangles, the pathological hallmarks of AD. Rivastigmine has central selectivity and inhibits both acetylcholinesterase and butyrylcholinesterase. Galantamine is unique in that it provides allosteric modulation of nicotinic receptors, a characteristic postulated to confer disease-modifying benefits. Meta-analysis found nine DB PC 12 week studies on AD. Number Needed to Treat (NNT) = 12 to benefit 1 patient, i.e., modest and some decreasing trend with time. NNTs are 3 for antipsychotics in schizophrenia, 4 for antidepressants for depression in medical illness and 29 to 86 (5-year NNT) for antihypertensives to prevent 1 major event (myocardial infarction, stroke or death). U Toronto. Efficacy and safety of cholinesterase inhibitors in Alzheimer's disease: a meta-analysis. Krista Lanctot, Nathan Hermann, CMAJ • September 16, 2003; 169

Cholinesterase Inhibitor Did Slow Decline in Severe Alzheimer's at a High Cost: In a 12 month study of 44 severe Alzheimer's disease patients, rivastigmine was slowly increased during the year up to an average of 11 mg/day at the end. For placebo, 45% declined by at least 4 points on the ADAS-cog. vs. 18% with rivastigmine. Patients benefited from high-dose rivastigmine treatment on all outcome measures, including the Mini-Mental State Examination, Progressive Deterioration Scale, as well as the Global Deterioration Scale (p < 0.001). By 52 weeks, rivastigmine was still favored. A 12-Month Study of the Efficacy of Rivastigmine in Patients with Advanced Moderate Alzheimer's Disease. Karaman Y, Erdogan F, Koseoglu E, Turan T, Ersoy AO. Erciyes University, Kayseri, Turkey.   Dement Geriatr Cogn Disord. 2004 Sep 21;19(1):51-56. Ed: Like many physicians, I don't think the small benefit is worth the high cost. Donepezil can be obtained from India much more cheaply and might be worth it.  Quite a number of alternative remedies appear to be of benefit at a much lower cost: fish oil, sage, lemon balm, etc.

Anticholinergics May Worsen Alzheimer’s: 69 patients on donepezil for over 2 years found that the 16 on concomitant medications with anticholinergic properties (16) lost 7 MMSE points vs. 3 for those not taking any anticholinergic meds (53). The anticholinergics may have been interfering with donepezil’s cholinesterase inhibitor effect or might act directly on Alzheimer’s. Emory Univ. Lu C, Tune L: Chronic exposure to anticholinergic medications adversely affects the course of Alzheimer disease. Am J Geriatric Psychiatry 2003;11:458-461. Some meds with anticholinergic effects include diphenhydramine, warfarin, ranitidine, some antibiotics, anxiolytics, corticosteroids, diuretics, and pain killers according to Psychiatry Drug Alerts 9/2003.

Donepezil Behavioral Disturbances: Within 13 weeks starting for AD, 7 elderly patients had recurrence of previous behavioral problems: 5 agitation, 1 depression, 1 anxiety with somatic preoccupation. Wengel, AJP 98;155:1632

Donepezil Helps Behavioral in Dementia a Little: DB PC 24 week 140 pt moderate to severe. Depression, anxiety, and apathy helps p<.05 out of 12 measures. Efficacy of donepezil on behavioral symptoms in patients with moderate to severe Alzheimer's disease. Gauthier S, Feldman H, Hecker J, Vellas B, Ames D, Subbiah P, Whalen E, Emir B; Donepezil MSAD Study Investigators Group. McGill, Int Psychogeriatr. 2002 Dec;14(4):389-404

Donepezil Helps Lewy Body Dementia Hallucinations: In an open study of 9 patients treated with 5-10 mg/day for 8-24 weeks, it was found that hallucinations were markedly reduced in 8 of 9 while on donepezil, cognition improved in 6, but 3 experienced a worsening of parkinsonism. Internatl Psychogeriatrics 98;10:229

Donepezil Helps Vascular Dementia: In a DB PC study of 603 patients treated with 5 mg/day and 5-10 mg/day after 1 month, researchers found no increase in side-effect dropouts with 5 mg (11%) but 22% with 10 mg. There was some decrease in ADAS-cognitive symptom scores (-1.9 for 5mg and -2.3 for 10mg). Efficacy and Tolerability of Donepezil in Vascular Dementia. Positive Results of a 24-Week, Multicenter, International, Randomized, Placebo-Controlled Clinical Trial. Black S, Roman GC, Geldmacher DS, Salloway S, Hecker J, Burns A, Perdomo C, Kumar D, Pratt R. Stroke. 2003 Sep 11; Similar results from another site in a study of 616 patients. UK. Neurology. 2003 Aug 26;61(4):479-86.

Donepezil Urinary Incontinence Self-Resolving: 7 of 94 on Aricept had incontinence, 6 with increase to 5mg/d. 5 of 6 continuing donepezil resolved in 2-14 days. Hashimoto, Lancet 00;356:568

Donepezil Helps Normal Pilots: Jerome Yesavage, Stanford, 18 pilots aged 30 to 70 had 75-minute practice flights on a simulator, including complex sets of maneuvers, new air traffic control commands every three minutes and a variety of emergency situations. For the next 30 days the volunteers took either donepezil or a placebo. Then two more test flights. The pilots taking donepezil performed just as well - evidence that they had retained what they had learned - the placebo pilots did significantly worse. Yesavage says older pilots tended to get more benefit, though that the finding was not statistically significant. New Scientist 7/8/02.

Donepezil Helped Somewhat: DB PC 24 week, 9 country study 818 pt found both 5mg and 10mg helped with 41% and 81% decrease in annual rate of deterioration and increased the number judged to be improved. Well-tolerated. Gauthier, McGill, APA 5/30/98; Side-effects highest after 1 week (nausea 19%, diarrhea 15%, insomnia 14%, fatigue 8%, vomiting 8%, cramps 8%, but decrease to near placebo levels by 6 weeks. Reichman, APA 5/30/98

Donepezil Helps Hippocampus: A Duke University study of 67 patients using MRI scans of patients treated with donepezil found N-acetylaspartate increased and the hippocampus deteriorated more slowly than among the patients who received a placebo. Hippocampal volume decreased by 8.2 percent in the placebo group compared with a 0.4 percent decrease in those taking donepezil. Ranga Krishnan, American J Psychiatry 11/03.

Galantamine Benefit Lasts Three Years: 194 elderly in DB PC trials were later followed in open format for three years and compared to dropouts and to a mathematical progression of placebo patients. Univ. Washington. The Cognitive Benefits of Galantamine Are Sustained for at Least 36 Months: A Long-term Extension Trial. Raskind MA, Peskind ER, Truyen L, Kershaw P, Damaraju CV. Arch Neurol. 2004 Feb;61(2):252-6

Galantamine (Reminyl) Helps Some: Galantamine reportedly more specific than other acetylcholinesterase inhibitors. Increases release of glutamate and monoamines. Might reduce formation of amyloid. 2500 outpatients probable AD and mild-mod dementia. 4 studies up to 6 months in duration. One with 353 pt DB PC24-32mg/d 6 months. May be better as slowing deterioration than reversing it. Colye, Harvard, Janssen, Biol Psychiatry 01;49:289;

Galantamine Helps: DB 653 mild-mod AD pt 24-32mg/d for 12 weeks found benefit. Reversible inhibition of acetylcholinesterase. BMJ 12/9/01 Wilcock

Galantamine for AD or Prob Vasc Dementia: Galantamine amplifies the acetylcholine response by inhibiting acetylcholinesterase and modulating nicotinic receptors. It has shown broad, sustained benefits in patients with AD. In patients with a diagnosis of probable vascular dementia or Alzheimer's disease combined with cerebrovascular disease randomly assigned galantamine 24 mg/day (n=396) or placebo (n=196) in a multicentre, DB 6-month trial. Primary endpoints were cognition (Alzheimer's disease assessment scale, cognitive subscale [ADAS-cog]) and global functioning (clinician's interview-based impression of change plus caregiver input [CIBIC-plus]). Secondary endpoints included assessments of activities of daily living and behavioural symptoms. Galantamine showed greater efficacy than placebo on ADAS-cog (galantamine change -1.7 [SE 0.4] vs placebo 1.0 [0.5]; treatment effect 2.7 points; p<0.0001) and CIBIC-plus (213 [74%] vs 95 [59%] patients remained stable or improved, p=0.0001). Activities of daily living and behavioural symptoms were also significantly improved compared with placebo (p=0.002 and p=0.016, respectively). Galantamine was well tolerated. Lancet 2002 Apr 13;359(9314):1283-90

Rivastigmine ( Exelon) Helps a Little: Exelon, a third cholinesterase inhibitor, is approved by FDA for AD along with tacrine (Cognex) and donepezel (Aricept). No drug interactions for rivastigmine. In 2 DB studies of 1424 pt for 26 wk at 6-12mg/d found modest improvement in 25-30% at higher dose. Scores declined after 40 weeks in the open phase. Med Letter 10/2/00

Rivastigmine Seems to Help Moderate-to-Severe Alzheimer's: Extracting data on 117 patients with MMSE scores of 10-12 from three 6-month DB PC rivastigmine studies of 2126, these more demented patients did appear to benefit with a 6.3 point deterioration on placebo vs. a 0.2 point gain on the medication 6-12 mg/day. Efficacy of rivastigmine in subjects with moderately severe Alzheimer's disease. Burns A, Spiegel R, Quarg P. Int J Geriatr Psychiatry. 2004 Mar;19(3):243-9

Thomas E. Radecki, M.D., J.D.

modern-psychiatry.com

Email: [email protected]