UPDATES ON ANTIPSYCHOTICS AND ALZHEIMER'S DISEASE
From Limitless Learning from Lively Laudable Luminaries, presented by the University of Wisconsin School of
Medicine and Public Health and the Madison Institute of Medicine, Inc.
| UPDATE ON THE METABOLIC EFFECTS OF ANTIPSYCHOTICS —Jonathan M. Meyer, MD, Assistant
Professor of Psychiatry, University of California, San Diego, School of Medicine
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| Introduction: obesity rampant in United States and incidence of type 2 diabetes mellitus increasing; most atypical
antipsychotics cause weight gain; “biggest offenders” in 2003 consensus paper were clozapine and olanzapine;
aripiprazole and ziprasidone metabolically neutral; quetiapine and risperidone in middle (data discrepant)
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| Obesity in mental health population: for number of reasons, people with major mental illness live on average
25 to 30 yr less than general population; cardiovascular disease, to which obesity and diabetes contribute significantly,
important cause of mortality among people with schizophrenia; people with major mental disease have 2-
fold increase in risk for death from cardiovascular disease, compared to those in general population
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| Cardiovascular risk among people with mental illness: 65% smoke (20% in general population); 50% are
obese (33% in general population); 14% have diabetes (7% in general population); in Western world, patient with
diabetes considered to have same risk for heart attack as person who already has had heart attack
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| Type 2 diabetes: risk for diabetes increases as body mass index (BMI) increases; development of diabetes long-
term process; peripheral insulin resistance initial phase of development of diabetes; some people can maintain this
low level throughout their lives, perhaps by pancreas overproducing insulin; genetic risk—usually determined by
family history and ethnicity; anyone not of Northern European ethnicity living in United States and consuming US
diet seems to be at increased genetic risk of developing diabetes; in those with genetic vulnerability, eventually
pancreatic β-cells cannot keep up with excess output of insulin, and insulin levels drop off (again, over long period);
increased glucose on oral glucose tolerance test earliest sign that person developing diabetes (fasting glucose
test last sign); goal to identify patient in prediabetic state and try to prevent progression to diabetes
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| Metabolic syndrome: also known as dysmetabolic syndrome and syndrome X; includes problems with glucose
metabolism, insulin resistance, high triglycerides, low high-density lipoprotein (HDL), increased inflammatory
markers, and clotting abnormalities (all of which probably contribute to development of cardiovascular disease)
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 | Criteria: abdominal obesity; high triglycerides; low HDL; high blood pressure (BP; or taking antihypertensive
medication to control); impaired glucose control; National Cholesterol Education Program (NCEP) requires that
patient have any 3 of these criteria; International Diabetes Federation (IDF) requires that patient have abdominal
obesity and any 2 of remaining 4 criteria; using either set of criteria, general prevalence of metabolic syndrome
in United States ≈27%; having metabolic syndrome not only increases risk of developing diabetes, but increases
risk of developing cardiovascular disease as well
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| Schizophrenia and metabolic syndrome (data also applicable to people with bipolar disorder): in general
population, smoking considered “modifiable risk factor,” but difficult to get patients with mental illness to stop
smoking; evidence that some antipsychotic medications may cause problems with glucose metabolism, independent
of their causing weight gain; lifestyle affects cardiovascular risk; negative symptoms of schizophrenia cause
patients to be inactive, contributing to weight gain; unknown whether having schizophrenia itself predisposes patient
to developing diabetes; some studies suggest yes, others no; studies ongoing
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| Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study: prevalence of metabolic syndrome
36% among men with schizophrenia, 20% among men in general population; 52% among women with
schizophrenia, 25% among women in general population; speaker concludes there is more metabolic syndrome
among people with schizophrenia than in general population, and magnitude of problem greater in women; also,
people with schizophrenia develop metabolic syndrome at younger age than those in general population; in CATIE
study, patients on olanzapine gained most weight (average of 2 lb/mo); those on quetiapine and risperidone gained
≈0.5 lb/mo; perphenazine, 0.2 lb/mo; and ziprasidone “neutral”; people taking olanzapine also had higher blood
glucose, glycosylated hemoglobin (HbA1C ), cholesterol, and triglycerides than those taking other agents; ziprasidone
most neutral metabolically
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| How do atypical antipsychotics increase risk for diabetes? in animal studies, single doses of olanzapine and
clozapine directly decreased hepatic insulin sensitivity, independent of their effects on weight; resulted in immediate
changes in whole-body insulin sensitivity and hepatic glucose production; effects reversed when drugs discontinued;
results not yet replicated in humans
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| Leptin: regulates appetite and adiposity; central feedback mechanism decreases appetite and peripheral actions to
increase metabolism; in studies of patients with schizophrenia who took antipsychotics, leptin levels identical to
those in people who did not take antipsychotics; speaker concludes that increase in leptin due to weight gain, not to
drugs themselves
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| Monitoring guidelines: baseline—family history; weight and BMI; waist circumference; BP; fasting lipids and
fasting glucose, if patient can cooperate with fasting; if not, obtain HDL and total cholesterol levels; HbA1c not
used to diagnose diabetes due to 2-mo lag in documenting glycemic changes and to fact that some patients with diabetes
have normal HbA1C values; monthly—weight and BMI; BP; quarterly—fasting lipids and fasting glucose;
annually—waist circumference; abnormal values—refer patient to colleague with experience in treating metabolic
syndrome and diabetes
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| Conclusions: metabolic syndrome highly prevalent in patients with schizophrenia, especially among women; drug-
related mechanisms becoming better understood, but questions remain; unclear whether patients with schizophrenia
have biologic vulnerability to metabolic dysfunction, independent of treatment effects
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| UPDATE ON ALZHEIMER’S DISEASE —Rachelle Smith Doody, MD, PhD, Effie Marie Cain Chair in
Alzheimer’s Disease Research, Alzheimer’s Disease Center, Baylor College of Medicine, Houston, TX
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| Normal aging: “we don’t study normal people longitudinally very often or very well”; in addition, study of groups
produces averages but does not determine what happens in individual; average speed of mental processing goes
down, but does specific individual’s speed go down? psychomotor slowing occurs, along with trouble recalling
names (primarily proper nouns) or finding specific words and “what did I come in here for?” phenomenon; “too often,
truly concerning symptoms are dismissed by physicians”
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| Troublesome signs: being repetitive, not just for emphasis or due to psychiatric disorder; not recalling names or
words later on; not recalling that conversations or events took place; not realizing that memory problem exists;
trouble remembering low-frequency common nouns (eg, watch face, buckle); Alzheimer’s disease (AD)—
develops across lifespan; data suggest that in person who develops dementia in 70s, amyloid deposition began in
30s or 40s, followed by microglial changes, neurofibrillary tangles, loss of neurons, neurochemical transmitter abnormalities,
and, ultimately, dementia; average age of dementia in sporadic AD 74 yr
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| Mild cognitive impairment (MCI): set of disorders; speaker focuses on amnestic MCI, likely transitional phase
between normalcy and AD; ≈15% of patients who have delayed verbal memory that puts them 1.5 standard deviations
below mean for their age and education level develop AD; neuroimaging—shows some loss of hippocampal
volume in MCI and more in AD; the smaller the hippocampus in asymptomatic person with mild memory loss, the
greater the likelihood he or she will develop AD; normal person has little amyloid in cortex and a few neurofibrillary
tangles in hippocampus; in MCI, more prevalent and larger deposits of amyloid seen, maybe more neurofibrillary
tangles in hippocampus; AD characterized by many amyloid deposits and diffuse neurofibrillary tangles in
hippocampus
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| Alzheimer’s disease: syndrome of cognitive and usually functional decline, treated primarily with medications and
support; variable noncognitive or behavioral manifestations treated with medications and nonpharmacologic
strategies; AD underdiagnosed, and when diagnosed, undertreated
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| Standard treatment: cholinesterase inhibitors and memantine; cholinesterase inhibitors—now approved for treating
mild, moderate, and severe AD; affect cognition, function, and behavior; may produce small improvements,
but more commonly used to stabilize abilities; if treatments discontinued, AD reverts to natural history of progression;
effects of treatments may be long lasting; speaker looks for stability at every patient visit; if downward
trend seen, dose of medication may be increased or second drug added
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| Controversies: how should high-dose vitamin E be used? AD studies show that 1000 U bid of vitamin E slows loss
of abilities, but cardiology studies show 5% increased mortality in people taking >400 U/day; should research be
aimed at treating symptoms or at modifying disease process? which patients should be treated pharmacologically
for behavioral and psychologic symptoms of dementia?
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| AD risk factors: speaker’s research suggests intelligence quotient (IQ) better marker for cognitive reserve than education
level; dietary factors (eg, high cholesterol, low antioxidants) may modify risk (fish seems to have somewhat
protective role); elevated homocysteine, glucose, and/or BP; menopause; aging; inflammatory processes
(“chronic inflammation is probably a predisposing factor”)
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| AD risk factors and therapy: epidemiologic studies cannot prove mechanisms or causality; effective preventions
may or may not be beneficial as treatments for established disease; therapies that delay (rather than prevent) AD
also would be useful (by delaying onset for 5 yr in all cases, prevalence could be reduced by 50% in one generation)
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| Search for new AD therapies: drugs and nutraceuticals based on epidemiologic observations available, but not
being used as primary prevention (being tested as treatments); neurotransmitter-based therapies (other than cholines
terase inhibitors and memantine) under development; glial- , amyloid- , and tau-modulating drugs under study
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| Alzheimer’s Disease Cooperative Study (ADCS) group: several trials under way to study use of docosahexaenoic
acid (DHA; principal component of fish oil), lowering of homocysteine, and use of simvastatin as treatments;
industry-sponsored studies include trials of atorvastatin plus donepezil and of peroxisome proliferator-
activated receptors (PPAR), PPAR-gamma (PPAR-γ) agonists rosiglitazone and pioglitazone
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| Transmitter-based therapies: may offer additional mechanisms of neuroprotection; under study are xaliproden,
rasagiline (monoamine oxidase B [MAO-B] inhibitor), dimebon (cholinesterase inhibitor, NMDA-receptor antagonist
and some neuroprotection), neramexane (follow-up compound on memantine), α-amino-3-hydroxy-5-methylisoxazole-4-propionic
acid receptor (AMPAR) agonists, and muscarinic and nicotinic agonists
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| Glial-modulating therapies: under study are nitroflurbiprofen (PPAR-γ agonist), astrocytic modulators, and receptors
for advanced glycation end products (RAGE) agonists
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| Conclusions: primary prevention of AD not seriously under study; once preclinical disease can be identified, agents
with more risk can be studied; once patients develop symptoms, multiple synergistic treatments necessary; even if
AD cannot be cured or prevented, it will be able to be managed effectively
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Suggested Reading
Doody RS et al: Practice parameter: management of dementia (an evidence-based review). Report of the Quality
Standards Subcommittee of the American Academy of Neurology. Neurology 56:1154, 2001; Gauthier S et al: International
Psychogeriatric Association Expert Conference on mild cognitive impairment. Mild cognitive impairment.
Lancet 367:1262, 2006; Gilman S et al: AN1792(QS-21)-201 Study Team. Clinical effects of Abeta
immunization (AN1792) in patients with AD in an interrupted trial. Neurology 64:1553, 2005; Goff DC et al: A
comparison of ten-year cardiac risk estimates in schizophrenia patients from the CATIE study and matched controls.
Schizophr Res 80:45, 2005; Houseknecht KL et al: Acute effects of atypical antipsychotics on whole-body insulin
resistance in rats: implications for adverse metabolic effects. Neuropsychopharmacology 32:289, 2007; Jin H et al:
Atypical antipsychotics and glucose dysregulation: a systematic review. Schizophr Res 71:195, 2004; Klunk WE et
al: Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound-B. Ann Neurol 55:306, 2004; Koro
CE, Meyer JM: Atypical antipsychotic therapy and hyperlipidemia: a review. Essent Psychopharmacol 6:148,
2005; Markesbery WR et al: Neuropathologic substrate of mild cognitive impairment. Arch Neurol 63:38, 2006;
Masliah E et al: Abeta vaccination effects on plaque pathology in the absence of encephalitis in Alzheimer disease.
Neurology 64:129, 2005; McEvoy JP et al: Prevalence of the metabolic syndrome in patients with schizophrenia:
baseline results from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial and
comparison with national estimates from NHANES III. Schizophr Res 80:19, 2005; Meyer JM et al: Effects of
switching from olanzapine to risperidone on the prevalence of the metabolic syndrome in overweight or obese patients
with schizophrenia or schizoaffective disorder: analysis of a multicenter, rater-blinded, open-label study. Clin
Ther 27:1930, 2005; Meyer JM et al: The Clinical Antipsychotic Trials Of Intervention Effectiveness (CATIE)
Schizophrenia Trial: clinical comparison of subgroups with and without the metabolic syndrome. Schizophr Res 80:9,
2005; Meyer JM, Koro CE: The effects of antipsychotic therapy on serum lipids: a comprehensive review.
Schizophr Res 70:1, 2004; Meyer JM: Treating the mind and body in schizophrenia: risks and prevention. CNS
Spectr 9(10 Suppl 11):25, 2004; Nicoll JA et al: Neuropathology of human Alzheimer disease after immunization
with amyloid-beta peptide: a case report. Nat Med 9:448, 2003; Orgogozo JM et al: Subacute meningoencephalitis
in a subset of patients with AD after Abeta42 immunization. Neurology 61:46, 2003; Petersen RC et al: Neuropathologic
features of amnestic mild cognitive impairment. Arch Neurol 63:665, 2006; Reisberg B et al: Memantine
Study Group. Memantine in moderate-to-severe Alzheimer’s disease. N Engl J Med 348:1333, 2003; Schneider
LS et al: CATIE-AD Study Group. Effectiveness of atypical antipsychotic drugs in patients with Alzheimer’s disease.
N Engl J Med 355:1525, 2006; Smith Doody R: Update on Alzheimer drugs (donepezil). Neurologist 9:225,
2003; Stroup TS et al: CATIE Investigators. Effectiveness of olanzapine, quetiapine, risperidone, and ziprasidone
in patients with chronic schizophrenia following discontinuation of a previous atypical antipsychotic. Am J Psychiatry
163:611, 2006; Winblad B et al: Severe Alzheimer’s Disease Study Group. Donepezil in patients with severe
Alzheimer’s disease: double-blind, parallel-group, placebo-controlled study. Lancet 367:1057, 2006.
Educational Objectives
| The goal of this program is to improve management of metabolic syndrome in patients who take atypical antipsychotic
medications and to improve treatment of Alzheimer’s disease. After hearing and assimilating this program, the
clinician will be better able to:
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| 1. Discuss the relationship between obesity, metabolic syndrome, and type 2 diabetes, and explain why all are
more prevalent in people with mental illness than in the general population.
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| 2. Determine the risk for obesity, metabolic syndrome, and type 2 diabetes associated with various atypical antipsychotics
medications.
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| 3. Monitor mentally ill patients for obesity, metabolic syndrome, and diabetes, and develop an appropriate course
of treatment should these disorders occur.
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| 4. Describe cognitive changes that occur with normal aging and with Alzheimer’s disease.
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| 5. Discuss current controversies in the treatment of Alzheimer’s disease.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, the Audio-Digest Foundation requires all faculty members
to disclose relevant financial relationships within the past 12 months that might create any personal conflict of
interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care
education and not a proprietary business or commercial interest. For this program, Dr. Meyer disclosed that he has received
grant support from the National Institute of Mental Health, National Institutes of Health-University of California,
San Diego, General Clinical Research Center, Bristol-Myers Squibb, and Pfizer; he is a speaker or consultant for
Bristol-Myers Squibb, Pfizer, and Janssen Pharmaceuticals; and he is a consultant for Wyeth. Dr. Doody is a consultant
for Eisai/Pfizer, Forest Laboratories, and Novartis, and a speaker for Eisai/Pfizer.
Acknowledgements
Drs. Meyer and Doody were recorded at Limitless Learning from Lively Laudable Luminaries, held March 2-3, 2007,
in Madison, WI, and sponsored by the University of Wisconsin School of Medicine and Public Health and the Madison
Institute of Medicine, Inc. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation
in the production of this program.
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