Are Antipsychotics Overprescribed?

Larry Culpepper, MD, MPH; Nassir Ghaemi, MD, MPH

Posted: 02/18/2011
Editor's note: Antipsychotics are now the top-selling class of medications in the United States, with
prescription sales of $14.6 billion in 2009.[1] Many clinicians worry these agents are being overprescribed
and used inappropriately. Medscape recently hosted an email discussion between Dr. Nassir Ghaemi, a
psychiatrist, and Dr. Larry Culpepper, a primary care physician with expertise in psychiatry, exploring the
question of whether antipsychotics are being used appropriately by prescribing clinicians.

Are Antipsychotics Overprescribed? Introduction

Nassir Ghaemi, MD, MPH: I think antipsychotics are overprescribed. Let's first think about the most
legitimate uses, and then we can identify how and why they're overprescribed. These agents are most
legitimately used, obviously, for schizophrenia in both the short term and long term.[2] They are also
legitimately used in the short term (meaning a few months) for acute mania.[3] That's about it, in my view.

Now, some antipsychotics are US Food and Drug Administration (FDA) indicated for maintenance
treatment of bipolar disorder. But for various scientific reasons, I believe the studies on which these
approvals are based are deeply flawed.[4,5] So despite the president's stamp of approval, I don't think we
can give a scientific stamp of approval. I think [antipsychotics] are scientifically proven for only a few
months of mania, and then they should be stopped in general, both due to lack of proven efficacy (despite
what the FDA says) and for safety concerns associated with some of the drugs.[4,5]

Antipsychotics are also used for bipolar depression, and some have FDA indications for the condition. Here
too I am skeptical about the related studies. But even if accepted, the evidence only supports short-term
use (8 weeks), not long-term use for prevention; hardly any data exist with any antipsychotics by
themselves in the prevention of bipolar depression, and what little data does exist are subject to many
scientific problems.[4,5]

Then there is so-called major depressive disorder, or plain old depression. Certain antipsychotics have an
FDA indication here, but again only for short-term use. Hence, short-term use might be justifiable, but
scientifically long-term use is not.[6]

Are Anxiety and Sleep to Blame?

Now let's look at anxiety and sleep: these are major sources of overuse. [Antipsychotics] may have some
symptomatic benefit [in these conditions]; they can be sedating and some, like quetiapine, which is a many-
fold more potent antihistaminic than diphenhydramine, have anxiolytic effects. But then again, so does
diphenhydramine, without risk of [cardiovascular disease].[7]

These scenarios are where antipsychotics are most overused among general practitioners. The long-term
treatment of bipolar disorder is where they are most overused by psychiatrists. In the former case, an
unthinking reliance on symptom-oriented treatment is a major factor in overuse (as opposed to a disease-
oriented approach, as advocated in the Hippocratic tradition). In the latter, I believe spinning of the science,
along with misinterpretations of FDA labeling, leads to overuse.

Of these causes, I believe the most important is the non-Hippocratic symptom-oriented approach to
medical practice, which has bedeviled our professions for 2 millennia. This is the long twilight struggle we
need to keep waging, I believe: to teach our colleagues and our patients that if every symptom is met with a
drug, we do more harm than good, and that the best doctor is he who recognizes diseases and knows how
to treat them, and he who recognizes symptoms that are not based in disease and knows how to avoid
treating them.
A (Slight) Difference of Opinion

Larry Culpepper, MD, MPH: First, I agree that the data we have available to guide the use of
antipsychotics, and particularly the newer atypical antipsychotics, are limited. We have strong evidence for
effectiveness in schizophrenia and bipolar mania.[1,2] Beyond those conditions, we have limited evidence for
use acutely in bipolar depression and as augmentation for treatment resistant depression, but for only
some of the atypicals, and for only a relatively short (weeks) interval.[4-6]

But the world primary care physicians (PCPs) live in is significant here. For many chronically ill patients,
including those with resistant depression and bipolar depression, the PCPs are also the "quaternary" care
physician. By this I mean the PCP is also the professional the patient returns to for long-term care, after
they have gone through the often limited specialty care options available. We are the "physicians of last
resort" to whom such multiproblem and treatment-resistant patients return after exhausting other sources of
care. Most of us in primary care have a fairly small number of such patients compared with psychiatric
practices. These are the patients for whom the question about a treatment is not "what does the evidence
say?" rather it's "will it help in Mary Jones?"

For such patients, the clinician's "N-of-One" trials are what is left after standard (evidence-based) treatment
has been exhausted. They are marked by desperation on the patient's part because of their suffering, and
on the physician's part because of limited treatment options. For these patients with resistant depression
and bipolar depression, if a clinical trial indicates efficacy, then continued use is reasonable. However, it is
reasonable within the framework of careful monitoring of continued efficacy, and of side effects, with
potential trials of tapering.

Other uses like for run-of the-mill depression, anxiety, and sleep, are where Dr. Ghaemi and I agree. Use
[of antipsychotics] for these conditions should be discouraged. In part, the real issue for the clinician and
patient here is the same as the above one of risk-benefits in comparison to other treatment options. Quite
simply, there are well-established medications (and nonpharmacologic therapies) that are at least as
effective but with much less risk and costs that should be the mainstay of treatment. While the atypical
might be considered novel or cutting edge for some of these conditions, the role of the physician here
should be to minimize the potential for harm, rather than uncontrolled experimentation with new options.

Dr. Ghaemi: I think it is important to emphasize that the benefit shown for some of the atypical neuroleptics
for both bipolar and unipolar depression is only short term, as Dr. Culpepper noted. The studies were
mostly around 2 months (often 6 weeks) long.[4-6] This means that these drugs work for up to 2 months,
period -- not 2 months and 1 day, nor 2 years, nor 20 years. We cannot assume they have long-term
benefits just because they have short-term benefits. There are many examples in medicine where this is
not the case: antibiotics come to mind. One might call this the "happily ever after" fallacy. Once a patient
gets better, that's no reason to leave all the drugs alone until the Day of Judgment.

For the desperation cases, as Dr. Culpepper mentions, if they are few in number, one might make
exceptions and give long-term treatments even though the evidence isn't there, as long as one is constantly
monitoring side effects and thinking about stopping the medication if possible, as he notes. But we should
be honest: this is faith, not science; if it is medicine, it is the medicine of the believer, not the knower.

We agree, as he says, on garden-variety depression, anxiety, and sleep issues. These expensive drugs
are being marketed for use while cheaper therapies are probably just as good and certainly have never
been shown to be worse. For instance, at the low doses in which it is used for sleep and anxiety, ie, below
150 mg/d, quetiapine basically has very little dopamine blockade, but it has major antihistamine effects,
over 20-fold more potent than Benadryl in animal studies.[7] So low-dose quetiapine is basically like giving
10-20 over-the-counter Benadryl pills (25-mg tablets). Some people might improve with a prescription for
100 mg/d of Benadryl rather than 25 mg/d of quetiapine.
A Return to Hippocratic Tradition

I would go farther still: it is little appreciated that if we reduce medicine to nothing but risk/benefit analysis,
we will practice non-Hippocratically. In the Hippocratic tradition, the main role of the doctor is to identify
diseases that cause symptoms, and then to treat those diseases that can be treated; the Hippocratic view
strongly argued against using drugs to treat symptoms directly. Not that this should never be done;
obviously it is part and parcel of daily medical practice. But the Hippocratic view is that we should de-
emphasize symptom-oriented treatment, even when the risks seem low and there appear to be benefits. In
the long run, this approach causes more harm than good. This is the thinking behind the maxim incorrectly
translated as "First do no harm." It really was: "As to diseases, try to help, or at least not harm."

So I would take this a step farther and say that the use of atypical neuroleptics (or any drugs) for symptoms
rather than diseases, frequently and long term, will produce more harm than good. We should avoid using
drugs to treat sleep or anxiety or depressive symptoms as much as possible; or if we use drugs in those
settings, it should be at low doses and for short durations. In contrast, we should vigorously look to identify
and treat the diseases that commonly cause those symptoms, like unipolar depression or bipolar disorder,
and then use those drugs that really work for those diseases, even if they have many risks and side effects,
like lithium.

I think it is true that bipolar disorder is commonly misdiagnosed and underdiagnosed, not only in primary
care, but unfortunately also in the specialty psychiatric setting. I agree, though, that one should not
diagnose by prescription; there is not a good scientific or ethical rationale for using atypical neuroleptics in
case the patient might have bipolar disorder. One should find out. A good start is to use a self-report
screening tool that the patient can fill out in the waiting room: the Mood Disorder Questionnaire [8] is the
most commonly used; my unbiased view is that the Bipolar Spectrum Diagnostic Scale[9] (a scale I helped
develop and which is available freely online) is better. They can both be used, and each take 5 minutes.
The physician can quickly review the scales and then discuss them with the patient in the course of getting
more history.

It is important to emphasize that patient self-report is not sufficient to rule out bipolar disorder (though self-
report usually suffices to rule it in). If a patient denies having had manic symptoms, it is key to confirm this
with third parties. PCPs have the major advantage of usually knowing family, often in the waiting room; they
should be invited into the exam room and interviewed along with the patient. Confidentiality is not an issue:
the family is talking to the doctor; the doctor is not revealing any information to the family. Such interviewing
will identify bipolar disorder in most cases, along with the help of the screening forms.

Even then, when bipolar disorder is diagnosed, I wouldn't recommend starting with atypical neuroleptic
medication prescriptions, but rather with true mood stabilizers: lithium, lamotrigine, carbamazepine, or
divalproex. Atypical neuroleptics can later be useful as adjuncts for acute mood episodes of mania, mixed,
or depressive states that is, added to standard mood stabilizers. But the biggest mistake I see is that
atypical neuroleptics are given in place of standard mood stabilizers like lithium; I believe this is an error. In
my view, we should be clear that atypical neuroleptics are not themselves mood stabilizers, but that's a
topic for a future discussion.

In some patients, concern on the part of the physician regarding diagnosis "I don't want to miss a bipolar
patient atypicals are safe for them" has been suggested as a reason for reaching for the atypical in
routine depression care. However, here, improved diagnostic assessment, either taking the time in the
primary care setting or through referral to a mental health professional, is the necessary response. To do
otherwise is a disservice both to the patient and in the long-run to the physician.

But in Primary Care, It's Not That Simple

Dr. Culpepper: Dr. Ghaemi and I agree on most aspects of these discussions. Use of the atypicals on a
symptom basis is not good medicine. Recognition, and then diagnosis is critical. And for bipolar disorder,
seeking corollary input from those close to the patient can provide critical information. We also agree that
for many patients mood stabilizers are a preferred treatment option.

However, I do not agree that since our studies on the atypicals are for the most part only of 2-months (or 6-
weeks) duration, that that means these drugs only work for 2 months, and not 2 months and a day or
longer. The reality is that in primary care (as well as many other areas of medicine) a large majority
(perhaps 80%) of what we do for patients is not evidence based, simply because the evidence, pro or con,
is not available. We do agree that a key value for the profession is "do no harm." However, harm can
accrue from withdrawal of a medication that is working when the evidence-based warrantee on its
effectiveness runs out just as it can from the uncritical use in individual patients of medications based on
group data of effectiveness.

In primary care, a common saying is that many situations require the physician to "know the patient's
name" to be able to be of benefit. By this we mean that our role is to get to know the individual deeply, and
use this knowledge in creating a treatment recipe that is truly individualized. The role of the physician is to
blend an understanding of best evidence from group (eg, RCT [randomized controlled trial]) data with this
deep understanding of the patient.

Another fundamental in primary care relates to the use of time in the doctor-patient relationship. The
primary care relationship is one that is ongoing; we continue to monitor, fine tune, educate, and encourage
our patients. A third fundamental is that we come to know and treat our patients in context that is within
their family, social, and work environment and build on their resources and minimize the liabilities
inherent. Within this framework, if a patient has benefited from short-term use of an atypical, I do try to
reduce or withdraw it periodically. However, if the medication does continue to provide benefit, I will
continue its use again with close monitoring, education, and work translating the symptom and possibly
disease control gained into improvements in the patient's relationships and resources. I believe this
approach has more potential to "do no harm" than one based on the time limits explored in studies.

So How Long Is Too Long?

Dr. Ghaemi: Dr. Culpepper and I agree in general, but in the interests of advancing a discussion, I will just
focus on our partial disagreement on the issue of whether one should use a drug for 2 months and 1 day,
when it is only proven effective for 2 months.

Obviously, stated thus, the claim is silly, but it makes a point. If 2 months and 1 day is okay, how is 2
months and 2 days? Three months? Six months? One year? Two years? Twenty years?

Where do you draw the line? And when? And why?

I believe the scientific evidence suggests that atypical neuroleptics do not have the long-term efficacy often
claimed for them.[5,10] These studies demonstrate that neuroleptics do not prevent depressive episodes, by
themselves, in the long-term in bipolar disorder; and since the next episode in those studies, which began
with acute mania, is typically depressive, the lack of benefit for depression benefit throws into doubt
whether there is any monotherapy preventive benefit at all for these agents in bipolar disorder in general. I
base these statements on my own analysis of those randomized studies, some of which I have previously
published,[4,5,11] and some of which is in press in a more detailed analysis along with my colleague Frederick
Goodwin, of the maintenance studies of these drugs in bipolar disorder.
But for the purposes of the present discussion, let's just presume that there is not sufficient scientific
evidence to make reasonable judgments about long-term efficacy with atypical neuroleptics in mood
conditions. In that case, what should the average clinician do?

There are many scenarios in medicine like this one; one cannot expect the taxpayers to fund an RCT for
every medical question. Thus, it will always be the case that it will be false to claim that "evidence" or
"evidence-based medicine" (EBM) is the answer. Of course we don't have enough "evidence" to answer, in
the case of neuroleptics for acute depression, 2 months and a day, or 2 days, or 3 days, or 4 days -- but
that is a straw man argument. It is not really informative to make an extreme claim, and then "refute" it.

So, though I fully agree with Dr. Culpepper's explanation about how, in primary care, one has to
individualize treatment and pay attention to social context (believe me, psychiatry has prayed this mantra
for decades), I worry that "science" is underappreciated in this context.

"Evidence" and EBM are just synonyms for science. So, if I may translate and simplify, I believe medicine is
not just a science, pure and simple. Again, this is a straw man: of course, this is the case. Humans are not
rats; doctors are not laboratory scientists; we can't create genomes, and control environments like we do in
laboratory rat experiments.

This, too, goes back to the Hippocratics, who said that medicine involves 3 factors: the doctor, the patient,
and the disease. Osler always emphasized that medicine is, first and foremost, an art, but it is an art based
on science. Osler defined the "art" of medicine as the art of balancing probabilities. That art is most
effective when we don't have to guess on the probabilities; the role of science is to provide us as much real
knowledge as possible about the probabilities.

Now in the case of 2 months of treatment vs 2 months and 1 day, I fully agree that we need to make
decisions that go beyond the knowledge provided by our science. My only claim is this: we should not
sanguine about it. Let's be honest, in these cases, we are guessing.

The wisdom of the Hippocratic tradition is just in guiding us about what to do when we do not know, when
the evidence is not there. Most of the time in medicine, what we should do is nothing. Nothing is a very
hard thing to do, and nothing is not nothing. Nothing is a very powerful intervention, because we let nature
heal, we get out of the way, instead of adding to the harm by guessing at treatments when we really don't
know if they work.

Dr. Culpepper makes a rational case for long-term treatment with neuroleptics when they seem helpful.
But, the same case was made for 40 years for hormone replacement therapy (HRT), and after a decade-
long randomized trial of over 16,000 women, it turned out that HRT increased breast cancer rates by 26%
(which is not much, and was not detectable in daily clinical practice based on the observations of
clinicians). This translates, in my calculations, to about 5000 excess deaths per year for women in the
United States. (I know this example generates many passions among PCPs; I know that HRT is effective
for some things, such as fracture prevention and menopausal psychological symptoms, but this does not
refute the proven increase in breast and uterine cancer mortality, not to mention the randomized trial result
of increased cardiovascular mortality).

It turns out that atypical neuroleptics are carcinogenic in animal studies, so are many of our other drugs. [11,12]
I am not claiming that these agents are carcinogenic in humans also; I am stating that, like HRT, there's a
chance that they could be. This is exactly the reason why the Hippocratic tradition urges us to err on the
side of not treating, rather than treating, when our scientific knowledge does not prove that the benefits
outweigh any harms.

Where Does This Leave Us?

This takes us far beyond the initial topic of this discussion: we both agree that atypical neuroleptics are
overused in the primary care setting and I would say they are also overused in the psychiatric specialty
setting because they are given for symptoms, rather than diseases, and they are given outside of the
areas where they are scientifically proven. It seems we differ somewhat on their long-term use when given
for syndromes where they are mainly proven to only have short-term benefit, as in acute mania and acute
severe depression.

Dr. Culpepper: I can see Dr. Ghaemi's points, and do agree with most of them our patients are best
served when treatment is informed by science. However, we as clinicians must translate the evidence
available to us through RCTs and other studies about groups of patients into decisions for individual
patients. The reality is that most medicines, especially in the psychiatric realm, are effective in only a
minority of patients treated, thus even for treatments deemed effective by RCTs, one of our tasks is to
remove those not beneficial to a particular patient. So our job is to work with our patients over time using
our knowledge of them, their past histories both with the disease process and other medications, and our
knowledge of their resources and liabilities as well as our understanding of available "science" to identify,
monitor, and refine the treatment plan that is of greatest benefit to them. Within such a framework of active
management of individualized treatment over time, if a patient's response demonstrates continued benefit
greater than adverse effects in the judgment of the clinician, and there are no less deleterious treatments
available for the particular patient, then the physician is doing his best for the patient, including honoring
the Hippocratic mandate: "I will prescribe regimens for the good of my patients according to my ability and
my judgment and never do harm to anyone."

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