1. No category

AN UNBIASED MONTHLY COVERING ALL THINGS PSYCHIATRIC
VOLUME 5, NUMBER 5
Medications for Dementia: An Update
I
t has been ten years since the first of
the second-generation cholinesterase
inhibitors (CIs), Aricept (donepezil)
was approved for Alzheimer’s dementia.
(The original CI, tacrine, is rarely prescribed these days because of the risk of
bradycardia and hepatotoxicity.) Soon
after Aricept’s approval, other companies
got busy producing their own me-too drugs,
including Exelon (rivastigmine) in 2000,
and Razadyne (IR and ER) (galantamine)
in 2001. Namenda (memantine) came
along in 2003 and is an NMDA receptor
antagonist rather than a CI.
Unfortunately, the initial burst of
enthusiasm for these drugs diminished in
response to an influential study questioning the magnitude of their clinical
MAY 2007
WWW.THECARLATREPORT.COM
effectiveness. The British AD2000 study
randomized 486 patients with AD to
two different doses of Aricept (5 mg
and 10 mg) or placebo and followed
them for three years. At the end of the
study, there were no differences in rates
of institutionalization or progression to
severe disability among the groups,
although Aricept patients averaged a 1
point higher score on their MMSEs
(Lancet 2004;363:2105-2115).
Nonetheless, the latest systematic
reviews published by the Cochrane
database endorse all three CIs as being
modestly effective for AD. They all lead to
about a 2 point improvement in the ADASCog (the standard research instrument
Continued on Page 2
IN THIS ISSUE
Focus of the Month:
Topics in
Geriatric Psychiatry
• Medications for Dementia:
An Update
• Normal Forgetfulness vs. PreDementia: How to Distinguish
Them
• Research Updates
• Expert Q & A:
James Ellison, M.D.,
on Treating Agitation and/or
Depression in Older Patients
Normal Forgetfulness vs. Pre-Dementia: How to Distinguish Them
A
70-year old man comes into
your office and asks: “Doctor, I
keep misplacing my keys-am I
getting Alzheimer’s?” You detect the note
of anxiety in his voice, and you want to
give an answer, and soon.
Here is a reasonable approach, based
on the latest research data.
First, rule out dementia.
If you haven’t reviewed them lately, the
DSM-4 criteria for dementia are actually
more stringent than you might recall.
Your patient must meet the following
three criteria:
1. Significant memory impairment.
This is most easily tested by asking them
to recall the date, and to perform a simple
delayed recall task, such as repeating
and then remembering three unrelated
words after two minutes of delay. If family
is present, ask them whether they’ve
noticed a significant decline in the patient’s
memory over the last few years; it’s probably as reliable as any office-based testing
you can do, according to at least one
study (Harwood et al., Age and Ageing
1997;26:31-35). Ask specifically if they
have noticed the patient asking the
same question or telling the same story
repeatedly.
2. At least one of the following:
• Apraxia. Ask: “Have you had problems
doing simple everyday tasks, like getting
dressed, balancing a checkbook, driving,
and preparing meals?” Asking whether
there have been problems using the TV
or DVD remotes is even more sensitive
but may well lead to false positives!
• Agnosia. Ask: “Have you had problems
recognizing people whom you really
know?”
• Executive functioning impairment. Ask:
“Have you had problems planning things
and getting them done, like cooking a meal
or a gardening project?” You can also
have patients do the clock-drawing task:
“Draw a clock on this page and draw in the
hands to show ‘ten after eleven.’”
• Aphasia. Ask: “Have you been having real
problems remembering the right word for
things?” “Have you had trouble understanding what people are saying to you?”
3. The symptoms must significantly
impair everyday functioning. The best
way to ascertain this is by asking if the
patient has been requiring someone else’s
help in performing a basic activity of daily
living. Ask: “Have your memory problems
Continued on Page 3
Learning objectives for this issue: 1. Cite the advantages and disadvantages of different medications for dementia. 2. Outline a practical approach for
assessing mild cognitive impairment. 3. Describe the latest data regarding the treatment of agitation and depression in the elderly.
This CME activity is intended for psychiatrists, psychiatric nurses, and other health care professionals with an interest in the diagnosis and treatment
of psychiatric disorders.
May 2007
PA G E 1
Medications for Dementia: An Update
used in the field), and they produce small
benefits in activities of daily living. There
are no detectable efficacy differences
among them (Birks J, Cochrane Database
of Systematic Reviews, updated 8/2006).
While they may be equivalently effective, each has its own character, so let’s
go through all of the currently available
AD meds, in turn (see table, “Current
Medications for Dementia”).
But first, some general notes. Every so
often, CIs will lead to rapid and noticeable
improvement in cognition and behavior
(“my mother is herself again!”). Usually,
however, they act by slowing the rate
of cognitive decline. Patients and family
understandably become impatient if
all they have to look forward to is a
more gradual worsening. It sometimes
helps to compare CIs to blood pressure
medications – “you take them everyday and
you don’t feel any different, but having a
lower blood pressure will eventually prevent you from having a stroke.” In the
same way, taking a CI will cause imperceptible neurotransmitter changes that
may prevent a dementia catastrophe, like
getting lost, or causing a fire in the
kitchen.
All CIs commonly cause nausea,
vomiting, and dizziness, and this is why
the recommended dosing schedule is
excruciatingly slow, generally no faster
than one increment every 4 weeks. (For
more detailed side effect information,
see our medication fact sheets on
www.TheCarlatReport.com, free to subscribers.)
Aricept (donepezil). Mnemonic to
remember generic name: the first letter
of the trade and generic names juxtaposed
Continued from Page 1
are “AD” for Alzheimer’s Disease. The
first to be approved, it is also the most
prescribed of the three CIs. It recently
got a boost from the FDA when it was
approved for use in severe dementia (in
addition to its current mild-to-moderate
dementia approval). Start at 5 mg QAM,
and go up to 10 mg QAM after 4 weeks.
The company recommends PM dosing,
but giving it in the morning may prevent
the insomnia and vivid dreams that
All CIs commonly cause
nausea, vomiting, and dizziness, and this is why the
recommended dosing
schedule is excruciatingly
slow, generally no faster than
one increment every
four weeks.
some patients report with Aricept. Key
advantages: Once a day dosing, easy
titration.
Exelon (rivastigmine). Mnemonic:
“Excellent river!” Exelon recently won a
second FDA indication for dementia
associated with Parkinson’s Disease (PD) on
the strength of a single placebo-controlled
trial of 541 patients with PD and dementia. Clinically meaningful improvement
occurred in 5% of PD patients on
Exelon, whereas 10% of patients on
placebo worsened. Unfortunately,
Exelon is a pain to use, both because it
requires BID dosing (start at 1.5 mg BID,
go to 3 mg BID after one month and
finally to 6 mg BID) and because it leads
to unacceptably high rates of nausea
Current Medications for Dementia
Trade name
Generic name
Supplied as…
Starting dose
Target dose
Aricept
Exelon
Namenda
Razadyne
donepezil
rivastigmine
memantine
galantamine
5, 10
1.5, 3, 4.5, 6
5, 10
4, 8, 12
5 Q PM
1.5 BID
5 QD
4 BID
10 Q PM
3 - 6 BID
5 - 10 BID
8 - 12 BID
Note: Dosing information from Physician’s Desk Reference; all doses are in milligrams.
(47%) and vomiting (31%). Titrating it very
slowly may reduce nausea. Word on the
street has it that an Exelon patch will
soon receive FDA approval, which will be
more convenient for patients and possible
easier on the GI tract. Key advantage:
No cytochrome p450 interactions,
unlike other CIs.
Razadyne (galantamine) and
Razadyne ER. Mnemonic: “Lots of
Razzamatazz at a gala!” The relative
newcomer, Razadyne was approved in
2001. Its original name was “Reminyl”
but the company changed it because
pharmacists were sometimes confusing
written scripts with Amaryl, a diabetes
medication. Razadyne’s claim to fame is
that it has a “dual” mechanism of action,
modulating cholinergic nicotinic receptors
in addition to inhibiting acetylcholinesterase. Drug reps from Ortho
McNeil will use this factoid to argue that
Razadyne is more effective than the other
CIs and will even trot out a companysponsored study or two to back it up. But
when all studies from all companies are
analyzed, there is no significant outcome
difference. Razadyne recently released its
ER (extended release) version, which is
what most clinicians prescribe. Start at 8
mg QD, increase to 16 mg QD after one
month and then to 24.
Razadyne got burned recently when
the company’s own clinical data showed
a 1.5% mortality rate in patients taking the
medication for mild cognitive impairment
(MCI) versus a 0.5% mortality rate in the
placebo arm. According to the FDA, the
two treatments did not differ in the main
outcome variable, which was percent
progressing to dementia (see
http://www.fda.gov/cder/drug/InfoSheets/
HCP/galantaminelHCP.pdf.). The significance of the mortality findings has been
questioned, because the placebo mortality
rate was abnormally low. Key advantage:
Once a day dosing with ER form.
Namenda (memantine). Namenda
is stuck with a bum indication (moderate
to severe dementia only) but it does boast
a unique mechanism of action (NMDA
Continued on Page 8
May 2007
PA G E 2
EDITORIAL INFORMATION
Publisher and Editor-in-Chief: Daniel J. Carlat, M.D., is assistant clinical professor of psychiatry at Tufts University School of Medicine and
maintains a private practice in Newburyport, Massachusetts. He graduated from the psychiatric residency at Massachusetts General Hospital in
1995 and is founding editor of The Practical Guide Series in Psychiatry, published by Lippincott Williams & Wilkins.
Associate Editor: Marcia L. Zuckerman, M.D., practices psychiatry at HRI/Arbour in Brookline, Massachusetts.
Editorial Board:
Dan Egli, Ph.D., private practice, Williamsport, Pennsylvania
Ivan Goldberg, M.D., creator, Depression Central Web Site, psychopharmacologist in private practice, New York City
Alan D. Lyman, M.D., child and adolescent psychiatrist in private practice, New York City
Robert L. Mick, M.D., medical director, DePaul Addiction Services, Rochester, New York
Michael Posternak, M.D., staff psychiatrist, Massachusetts General Hospital, Boston
Dr. Carlat, with editorial assistance by Dr. Zuckerman, is the author (unless other authorship is specified) of all articles and interviews for
The Carlat Psychiatry Report. All editorial content is peer reviewed by the editorial board. Dr. Carlat, Dr. Egli, Dr. Goldberg, Dr. Lyman, Dr. Mick,
Dr. Posternak, and Dr. Zuckerman have disclosed that they have no significant relationships with or financial interests in any commercial
companies pertaining to this educational activity.
Normal Forgetfulness vs. Pre-Dementia: How to Distinguish Them
made it necessary for you to get help with
anything, like shopping, balancing your
checkbook, cooking, or driving?”
Second, rule out mild cognitive
impairment.
Let’s assume that your quick dementia
screen was negative. Most elderly patients
with subjective memory complaints who
do not have dementia generally fit into
one of the following two diagnostic
categories: Age Associated Memory
Impairment (AAMI) or Mild Cognitive
Impairment (MCI). (I am assuming, of
course, that you have already considered
other common causes of memory
impairment, such as depression, anxiety,
medication side effects, substance abuse,
and medical illness.)
You and your patient both hope that
the problem is AAMI, otherwise known
as “benign senescent forgetfulness,” and
defined as the normal memory decline
of aging. The key citerion is memory
decline that is quite mild, not even close
to causing functional impairment. Formal
memory tests would show a memory
below normal for a 25 year old, rather
than below normal for your patient’s
age. Clinically, AAMI presents with minor
memory lapses, such as briefly forgetting
someone’s name, or misplacing the car
keys more often than in the past. Patients
with AAMI probably do not progress to
dementia any faster than the baseline rate
(see the following good recent review of
memory impairment for a discussion of
AAMI: Feldman HH et al, Am J Geriatr
Psychiatry 2005;13:645-655).
Mild Cognitive Impairment (MCI), on
the other hand, is not so benign. Patients
with MCI progress to dementia at a rate
May 2007
Continued from Page 1
of 10-15% per
Diagnostic Choices for Memory Impairment
year, vs. a 1-2%
AAMI
MCI-amnestic
Dementia
per year rate
Functional
among normal
No
No
Yes
elderly. How do impairment?
you diagnose
Degree of
1 SD below norm
1.5 SDs below
More severe
it? While there
memory loss
for a young person
norm for age
than MCI
are different
subcategories
AAMI = Age-Associated Memory Impairment
of MCI, the
MCI-amnestic = Mild Cognitive Impairment, amnestic type
most common
Study (ADCS) randomized MCI patients to
subtype is amnestic MCI, for which the
Aricept (10 mg QD), vitamin E (2000
Mayo Clinic recommends the following
IU/day) or placebo. Aricept slowed progresdiagnostic criteria: (1) a subjective memory
sion only during the first 12 months of
complaint, (2) normal activities of daily
the three year study--by the end of the
living, (3) normal general cognitive funcstudy, all three groups had the same rate
tion, (4) abnormal memory for age, and
of progression to AD. Vitamin E showed
(5) not demented (see Petersen RC, Arch
no beneficial effect at any point in the study
Neurol 1999;56:303-308). As you can
(Petersen RC et al., NEJM 2005; 352:2379see, the key criterion differentiating MCI
2388). Other cholinesterase inhibitors
from AAMI is #4: abnormal memory for
have shown similarly lackluster results,
age, usually defined as 1.5 standard deviaand as mentioned elsewhere in this issue,
tions below average for age on elaborate
galantamine led to a higher mortality
research-based memory tests.
rate than placebo in industry trials.
Practically speaking, a patient with
In the absence of good medication
MCI will describe memory problems that
treatments, many geriatric psychiatrists
are “pretty” severe (a judgment call for
will focus on lifestyle changes. Recent
you), but that don’t quite lead to the
studies have suggested that physical
impaired functional status of a patient
exercise (Podewils LJ et al., Am J Epidemiol
with dementia. In contrast, the patient
2005;161:639-651) and mental stimulation
with AAMI has a degree of absent-mind(Ball K et al., JAMA 2002;288:2271-2281)
edness that is annoying but not even
can both enhance memory. And don’t
close to causing functional decline (see
forget to encourage your patients to pay
a recent article in Rosenberg PB et al.,
frequent visits to their primary care
Am J Psychiatry 163(11):1884-1890 for
physicians for management of hypertenmore diagnostic tips).
sion and high cholesterol, both of which
Can MCI be treated?
Unfortunately, trials of various strategies
to slow the progression of MCI to dementia
have been disappointing. For example,
the Alzheimer’s Disease Cooperative
can lead to vascular dementia.
TCPR
VERDICT:
AAMI: benign memory lapses;
MCI: pre-dementia
PA G E 3
This Month’s Expert:
James Ellison, M.D., MPH
Agitation and Depression in Older Patients
With
the Expert
Clinical Director, Geriatric Psychiatry Program, McLean Hospital
Associate Professor of Psychiatry, Harvard Medical School
Dr. Ellison has disclosed that he is on the speaker’s bureaus of Pfizer, Inc., Wyeth, Inc., and Forest Laboratories,
and has spoken about Aricept, Effexor XR, Lexapro, and Namenda. He has received between $5,000 and $20,000
over the last 12 months for these activities. He has also received research grant support, via McLean hospital, from
GlaxoSmithKline for research on Avandia (rosiglitazone). Dr. Carlat has reviewed and edited the content of this
interview to ensure a balanced and unbiased presentation.
TCPR: Why don’t we start with the issue of agitation? The question in many psychiatrists’ minds is how seriously we
should take the FDA advisory about the dangers of atypical antipsychotics?
Dr. Ellison: Seriously but not definitively. The concern about antipsychotics in the elderly began several years ago with an
Australian study of demented patients with psychotic symptoms (Brodaty H et al., J Clin Psychiatry 2003;64(2):134-43). In that
study, risperidone was more effective than placebo for the treatment of agitation, but it was associated with an increased rate of
cerebrovascular adverse events; Janssen disclosed this information to the FDA, resulting in a 2003 warning about cerebrovascular
adverse event risk in psychotic demented patients. Then in 2005, further analysis of adverse event data led the FDA to assign a class
warning to the atypicals regarding an “increased risk of death compared to placebo” in the treatment of “elderly patients with
dementia-related psychosis.” In October 2006, the results of the CATIE-AD study didn’t reassure clinicians about the atypicals’ effectiveness
in treating agitation in demented patients. The atypicals outperformed placebo but were associated with significant adverse effects
for a relatively modest benefit (Schneider LS et al., N Engl J Med 2006;355:1525-1538). Many clinicians have since been looking for
alternatives such as citalopram, anticonvulsants, anxiolytics, or typical antipsychotics, though it’s not clear that any alternative
choice is associated with both better efficacy and greater safety.
TCPR: And what is your take on the risks of antipsychotics?
Dr. Ellison: We don’t have good alternatives yet – but these days I’ll consider using a cholinesterase inhibitor or memantine
(Namenda), an SSRI such as citalopram, or an anticonvulsant if the agitation is mild. For psychosis, a typical neuroleptic is probably
no less dangerous than an atypical. Any psychotropic (but especially the atypical antipsychotics) should be used at lowest effective dose for the shortest necessary time in this
fragile population.
Instead of complaining about
TCPR: Is there any other new information about antipsychotics in the elderly that
"depression"
or "sadness," you
we should be aware of?
may
hear
depressed
elders talk
Dr. Ellison: An interesting point that we sometimes fail to consider is that cognitive
about "weariness" or "nerves."
performance can be negatively affected by the atypical antipsychotics. Schneider comments on
this in his outstanding review (Schneider LS et al., Am J Geriatr Psychiatry 2006;14:191–James Ellison, M.D.
210). The mean decrease he notes in MMSE scores with atypicals is of a similar magnitude to
the gain we see with the cholinesterase inhibitors, so it is probably of clinical significance.
TCPR: What are the medications that have the best data to support this risk of a cognitive decline?
Dr. Ellison: Less data are available about ziprasidone (Geodon) and aripiprazole (Abilify) than about olanzapine (Zyprexa), risperidone
(Risperdal), and quetiapine (Seroquel).
TCPR: Let’s move on to the issue of late-life depression. Does depression present differently in older patients?
Dr. Ellison: It can. Instead of complaining about “depression” or “sadness,” you may hear depressed elders talk about “weariness”
or “nerves.” In addition, you might notice more of a behavioral presentation: these patients might be withdrawn or irritable; they
are no longer as interested in hobbies or social activities; they might talk about having “lived long enough” and feeling “ready for
death.” There are often prominent somatic symptoms, and a number of patients are afraid that they are “losing their mind” and
that they are developing dementia. We have to avoid taking that worry at face value, since depressed patients can be erroneously
diagnosed as demented and then inappropriately institutionalized in a nursing home.
TCPR: What is “pseudo-dementia?”
Dr. Ellison: Pseudo-dementia is a very interesting term because it is not exactly dementia, and it is also not exactly “pseudo;” it was
Continued on Page 5
May 2007
PA G E 4
Q & A With the Expert
Continued from Page 4
considered a reversible cognitive impairment attributable to depression but is often only partially reversible through treatment of
depression. Typically, pseudo-demented patients are depressed and also complain of profound difficulties with memory and
concentration. If you follow these patients, they have a greater risk of eventually converting to dementia. So that raises the question
of whether depression is a prodrome of dementia. Or, and this is a possibility that would heighten the importance of treating
depression aggressively, does depression in some way hasten the onset or increase the risk of dementia?
TCPR: Are there particular kinds of questions that we should be asking elderly patients to diagnose depression?
Dr. Ellison: Yes, and many of these questions are on the Geriatric Depression Scale, which is an excellent 15 item scale that is in
the public domain [Ed. Note: This scale is easily accessed by doing a Google search; one site allowing you to score it online is
http://www.stanford.edu/~yesavage/Testing.htm]. It asks questions like: “Have you dropped many of your activities and interests?
Do you feel like your life is empty? Do you feel worthless? Do you feel that most people are better off than you are?” So you can see
that the approach is somewhat different than the DSM-IV where you are asking about such neurovegetative symptoms as sleep and
appetite, both of which are frequently disturbed in the elderly for reasons other than depression.
TCPR: What is there to say about specific treatment for late-life depression?
Dr. Ellison: The first thing to clarify is that antidepressants do, indeed, work in the elderly. There are over 70 randomized controlled
trials of the pharmacotherapy of geriatric depression, and the average response rate to medication is 50-65% compared to a 25-30%
placebo response. Remission rates are 30-40% for drug vs. 15% for placebo. So, in terms of a number-needed-to-treat, that would be 4-7.
TCPR: So medications do work. Which ones should we choose?
Dr. Ellison: I’ll tell you my opinion about this. Let’s go through the potential differences between antidepressants and how these
apply to treating elders. All the antidepressants have been shown to be efficacious, so if we try to decide on the basis of efficacy we
wouldn’t be able to make a choice. Likewise, if we go on the basis of FDA indication, this doesn’t help us because the only drug that is
FDA-approved for late-life depression is Prozac (fluoxetine), which hasn’t been convincingly shown superior to other antidepressants in
this role. The next factor to consider is cost, because even though there is prescription coverage under Medicare Part D, nonetheless
as costs go up the patient is pushed into the expensive so-called “donut hole.”
TCPR: Can you explain what the Part D donut hole is, exactly?
Dr. Ellison: With Medicare Part D there is an upfront deductible after which most of the cost of the medication is covered by
Medicare up to a limit. Beyond that limit, the patient becomes fully responsible for the cost, until the cost reaches a certain point,
and then catastrophic coverage kicks in. The more costly medications push the patient up more quickly to that donut hole where
they become fully financially responsible. The point is, we should always go with less expensive generic medications initially, and
there are excellent generics available. The only ones that are not generic would be Lexapro, Paxil CR, Effexor XR, Cymbalta, and
Emsam, and there are generics for everything else.
TCPR: What other factors should we consider?
Dr. Ellison: Then the next factor is side effects. And a meta-analysis comparing the tricyclics to the newer antidepressants came up
with the conclusion – no big surprise – that the newer drugs are a little bit more tolerable, but actually not as much more tolerable
as you might have thought. To some extent, there is a different domain of side effects. With the tricyclics you experience cardiac
complications, dry mouth, constipation, drowsiness, dizziness, lethargy, but with the new drugs there is sexual dysfunction,
gastrointestinal symptoms and sleep disturbance. And the elderly can have sleep disturbances anyway, so sometimes that is an issue.
TCPR: What about issues of pharmacokinetics?
Dr. Ellison: That’s crucial, especially drug-drug interactions. The average patient at age 65 is on five prescribed medications and
the average patient at age 75 is on eight prescribed medications.
TCPR: So what’s the bottom line?
Dr. Ellison: The bottom line is that if you look at all of the available antidepressants you could say that sertraline (Zoloft) and
citalopram (Celexa) are available generically, have an appropriate amount of evidence of tolerability and efficacy in the elderly; their
half-life is right for once-a-day dosing; they are not likely to produce discontinuation symptoms; their drug-drug interactions are
minimal; and they don’t produce anticholinergic effects or postural hypotension.
TCPR: So your favorites are sertraline and citalopram. Are there any others that you consider in this population?
Dr. Ellison: There are four others that I often use. I use nortriptyline because with monitoring of the blood level it can be dosed in
such a way that it is very tolerable and effective. Venlafaxine (Effexor) is an alternative that has dual neurotransmitter effects.
Bupropion (Wellbutrin), a more stimulating drug, may be helpful with some patients who present with apathy. Finally, mirtazapine
(Remeron) may be useful in patients with significant anxiety, insomnia and anorexia.
May 2007
PA G E 5
Research Updates
IN PSYCHIATRY
BIPOLAR DISORDER
Antidepressants shown ineffective for
bipolar depression.
The largest and most rigorous study
to date on the treatment of bipolar
depression was just published in the New
England Journal of Medicine. The study,
conducted as part of the NIMH-funded
Systematic Treatment Enhancement
Program for Bipolar Disorder (STEP-BD),
enrolled a total of 366 subjects with
either bipolar I or II disorder during a
major depressive episode. These patients,
all of whom were already taking a mood
stabilizer, were randomly assigned to two
groups: 179 received their current mood
stabilizer plus an antidepressant (paroxetine or bupropion), and 187 received
their mood stabilizer plus placebo. The
investigators found that the addition of
either paroxetine or bupropion did not
improve either response or remission
rates compared to a placebo control
group. On a somewhat reassuring note,
antidepressants did not increase rates of
either suicidal ideation or switches to
mania (Sachs GS et al., NEJM 2007;356:1-12).
TCPR’s Take: These disappointing
results argue against the standard practice of
adding antidepressants to mood stabilizers
in bipolar depression. These findings will
likely cause a boost in prescriptions of
atypical antipsychotics in bipolar depression,
particularly in light of Seroquel’s (quetiapine) recent FDA approval for this indication (see TCPR Feb 2007 for details).
ADHD
FDA orders consumer medication
guides for stimulants.
On February 21, the FDA directed all
manufacturers of stimulants to develop
Medication Guides for patients, spelling
out, in non-technical language, the dangers of taking these medications. Last
year, the FDA required an additional
black box warning for stimulants warning
of the risk of sudden death due to cardiac
complications. This new directive responds
May 2007
to concerns that the black box information
wasn’t filtering down to consumers. You
can view the drafts of these medication
guides at http://www.fda.gov/cder/
drug/infopage/ADHD/default.htm. Don’t
worry, you won't have to keep a stack of
these in your office; the pharmacist who
fills the script will hand them to your
patients.
TCPR’s Take: This will certainly lead
to many questions from patients and family
members, as well as fewer stimulant
prescriptions overall – which is either a
good or a bad thing depending on your
pharmaco-politics. Some psychiatrists
believe that ADHD is severely under-treated,
while others believe that the current wave of
stimulant enthusiasm has gone overboard.
You can find research data to support either
position if you look hard enough!
ATYPICAL ANTIPSCHOTICS
The molecular mechanism of antipsychotic-induced weight gain is found.
We’ve known for some time now that
clozapine and Zyprexa (olanzapine) cause
the most weight gain of any antipsychotic,
but we didn’t know the actual mechanism
– until now. Researchers from Johns
Hopkins and the University of Vermont
found that both clozapine and Zyprexa
increase levels of a specific enzyme in the
hypothalamus that boosts the appetite.
The enzyme, AMPK (AMP-protein kinase),
is one of the brain's major fuel-sensors,
and leads to various biochemical reactions
that eventually cause weight gain and
metabolic abnormalities. Atypical antipsychotics that cause little weight gain, such
as Risperdal, Abilify, and Geodon, increase
AMPK levels only minimally. Interestingly,
the way clozapine and Zyprexa stimulate
AMPK appears to be via histamine-1 receptor
antagonism, a neurotransmitter pathway
that has long been a prime suspect as a
mediator of weight gain (Kim SF et al., Proc
Nat Acad Sci 2007:104(9): 3456-3459).
TCPR’s Take: It’s rare to find a clear
molecular explanation for anything in
psychiatry, so this finding is intriguing for
that reason alone. Are there any clinical
implications? Not really, since we already
knew which antipsychotics caused the most
weight gain. But researchers will use these
findings to develop more targeted medications, both to prevent and to treat obesity
in our psychotic patients.
TRANSCRANIAL
MAGNETIC STIMULATION
TMS for the treatment of auditory
hallucinations.
In the February issue of TCPR, we
reported a recent FDA panel’s opinion
that rTMS (repetitive transcranial magnetic
stimulation) was relatively ineffective for
treatment-resistant depression. The type
of rTMS that has been tested for depression
generally involves 10 Hz (ten pulses per
second). But when the pulse of magnetic
coils is slowed down to only 1 Hz, this
reduces neuronal excitability, temporarily
“stunning” those neurons subjected to
the magnetic field. Researchers have been
using this property to try to turn off the
parts of the brain responsible for auditory
hallucinations in schizophrenic patients.
In a recent meta-analysis of such studies,
the authors reviewed 10 TMS controlled
trials (with sham-TMS as the control), and
reported a robust average effect size of
0.88 (Aleman A et al., J Clin Psychiatry
2007;68:416-421). In the largest of the
studies they reviewed, the anti-hallucination
effect lasted about five months.
TCPR’s Take: This is potentially exciting
stuff, but as is always the case with research,
the devil is in the details. Most of these
studies use specially created auditory
hallucination scales to demonstrate a benefit
of rTMS. These scales yield “hallucination
scores” that decrease significantly with
treatment, and are great for statistical
testing, but not so helpful for clinicians
trying to divine the applicability of the
results to their patients. In fact, this
meta-analysis found that while slow rTMS
appears to decrease AH, it does not improve
overall ratings of positive symptoms,
making it debatable how useful this
expensive treatment is likely to be for
our patients.
PA G E 6
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Please identify your answer by placing a check mark or an X in the box accompanying the appropriate letter.
1. A true statement about cholinesterase inhibitors is:
[ ] a. Clinical trials have shown that Aricept is the most effective.
[ ] b. Exelon is the best-tolerated of the three.
[ ] c. Razadyne is approved for dementia in Parkinson’s Disease.
[ ] d. All three require very gradual titration to minimize side effects.
2. Age-associated memory impairment (AAMI) is distinguished from mild cognitive impairment (MCI) by
[ ] a. AAMI is more likely to convert to dementia.
[ ] b. Patients with MCI have clear functional impairment.
[ ] c. Patients with AAMI have only minor memory lapses.
[ ] d. MCI shows a more robust response to cholinesterase inhibitors.
3. Both Aricept and Razadyne ER are commonly dosed twice a day.
[ ] a. True
[ ] b. False
4. The data on atypical antipsychotics indicate that
[ ] a. They pose a mortality risk in the elderly.
[ ] b. They lead to a one-point increase in the MMSE score.
[ ] c. They rarely cause metabolic problems in the elderly.
[ ] d. They are effective for depression in the elderly.
5. According to Dr. Ellison, generic citalopram and sertraline are first-line choices for late-life depression.
[ ] a. True
[ ] b. False
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May 2007
PA G E 7
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Normal Forgetfulness vs. Pre-Dementia Continued from Page 2
receptor antagonist) and it has some data to support its usefulness as an augmenter of Aricept (JAMA, 2004; 291:317-324).
Thus, many specialists will put the majority of their demented
patients on the combination of one of the CIs and Namenda,
starting at 5 mg QAM and titrating up by 5 mg each week, up to
a maximum of 10 mg BID. Side effects of Namenda? Look for
dizziness, sedation, transient confusion, headache, and
constipation. However, it tends to be well-tolerated over the
long term. Key advantage: Augments actions of CIs.
Coming soon? Alzhemed and Flurizan.
Neurochem Pharmaceutical has just completed a large
Phase III trial of the new drug Alzhemed (tramiprosate),
which works by binding to the peptide Amyloid-Beta, thereby
slowing the formation of amyloid plaques. According to
business publications, the company will release the results
sometime soon (http://www.pharmaceutical-business-review.com).
Flurizan (tarenflurbil), manufactured by Myriad Pharmaceuticals,
is an SALA, or Selective Amyloid-Beta Lowering Agent. Currently
in Phase III clinical trials for the treatment of mild AD, it is
reportedly ineffective for moderate AD. See the company’s
web site, http://www.myriad.com, for an entertaining video
clip about how Flurizan works.
TCPR
VERDICT:
CIs: Gains are modest, but probably real.
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May 2007
This Month’s Focus:
Topics in
Geriatric Psychiatry
Next Month in The Carlat Psychiatry Report: Treating PTSD, including a review of the recent
controversy about its diagnostic validity and a discussion of evidence-based medication strategies
with Harvard’s David Osser, M.D.
PA G E 8