This post is another public service announcement to the criticism psychiatric medications in perspective. It is an essential part of the continuous production of antipsychiatry rhetoric because it must be. If you are arguing that there are no such thing as psychiatric disorders – you do not need any treatment for them. On that basis overprescribing easily occurs because any prescribing is overprescribing. There are mixed agendas on claims that antidepressants in general cause increased number of suicides and aggressive behavior. But the most significant rhetoric has always been that there are massive conflicts of interest in psychiatry due to payments or relationships with the pharmaceutical industry. In a rare piece of special interest politics, a US Senator made these claims. Now that we have a database, it is easy to show that psychiatrists in general are not even close to the top when it comes to physician payments from the pharmaceutical and medical devices industries and in fact that most physicians have no significant conflict of interest. This post specifically is about the top 15 selling drugs in the period 1990-2021, and where drugs typically prescribed by psychiatrists end up on that list.
I will qualify this by saying as I have many times in the
past, that the only medication that psychiatrists prescribe more of than any
other medical specialty is lithium.
Practically all other classes of psychiatric drugs are prescribed in
greater amounts by primary care physicians, pediatricians, and an
ever-increasing number of non-physician prescribers primarily nurse
practitioners and physicians assistants-certified.
The methodology for this post is subject to several
limitations. First it depends on word
and term frequencies counts from search engines that look at the popular,
press, academic journals, newspapers, websites, and books. By comparison the Google NGRAM search looks
only at frequencies in their book collection. Algorithms are used to determine
relevance and importance – but the weighting of the algorithm is not available
so the actual search is a black box – but consistently applied. It does not count word frequencies in the
non-print media and in the US that would include direct to consumer advertising
for many of these drugs. A second limitation is that all the counts obtained
here were for the years 1990-2021 in aggregate. No curves were generated by
year like the ones available in NGRAM. Sometimes a verbal estimate was
available like “most of these references occurred in the past 10 years”. A third limitation occurred when searching
for terms like “antidepressant overprescribing” the search engine went from
Google Scholar to Lexis-Nexis even though I had no direct access to
Lexi-Nexis. I have a request pending for
that access to see if I can confirm the results listed here, especially because
much of this search required an artificial intelligence search engine (Google
Bard). If I cannot get direct access to
Lexis-Nexis I will attempt to check the results with a second AI search engine.
My goals were to compare the general publicity with the
negative publicity of the top 15 selling medications of all time. When I looked at that list – only one of the
15 medications was a psychiatric medication and that was olanzapine (Zyprexa).
For that reason, I decided to extend the comparison to all antidepressants that
were discovered during the same years (1990-2021). During that time there was continuous
criticism of psychiatrists that was primarily antidepressant based. The
suggestion was that all psychiatrists were in lock step with Key Opinion
Leaders (KOLs) and prescribing whatever Big Pharma wanted them to irrespective
of patient need or diagnosis. This is obviously an absurd criticism but it was
taken very seriously for the better part of two decades. An associated
criticism was that clinical trials of psychiatric medication were permanently
tainted by the same conflict of interest.
Psychiatrists were mere puppet prescribers for the pharmaceutical
industry. Like most dichotomous
arguments there were vehement supporters of both poles but very little
discussion of the reality that psychiatrists are the treatment
providers of last resort dealing with difficult problems and they
just happened to have the most expertise in prescribing these medications.
These arguments also ignored the fact that psychiatrists are taught to critique
literature and apply it to practice and that this life-long skill makes it
doubtful that anyone prescribes a medication just based on the word of a
salesman. All the attacks on monolithic psychiatry ignored what was potentially
the most significant cause of antidepressant prescribing – checklist-based
diagnoses popularized by managed care and electronic health record systems. No comprehensive
psychiatric evaluation – just a cutoff number on a checklist. And yet no
criticism of managed care companies doing this?
I have also not heard the same level of criticism for telepsychiatry
services that are currently advertising their antidepressant prescription services.
Table 1. Top 15 gross selling medications of
all time:
|
Medication |
Sales (Kiplinger 2017) |
Sales (Bard 2023) |
Word Frequency References 1990-2021(1) |
Overprescribing by drug references1990-2021
(1) |
|
Lipitor
(atorvastatin) 2001 |
$150
B |
$130B |
38M |
20,000 |
|
Humira
(adalimumab) 2008 |
$109
B |
$240B |
17M |
1,000 |
|
Advair
(fluticasone/salmeterol) 2000 |
$95.7
B |
$350B |
12M |
1,000 |
|
Remicade
(infliximab) 1998 |
$90.3
B |
$100B |
2.5M |
100 |
|
Plavix
(clopidogrel) 1997 |
$83.7
B |
$55B |
13M |
10,000 |
|
Rituxan
(rituximab) 1997 |
$81.6
B |
$60B |
1.3M |
100 |
|
Enbrel
(etanercept) 1998 |
$81.2
B |
$100B |
5.7M |
300 |
|
Herceptin
(trastuzumab) 1998 |
$70.5
B |
$140B |
1.2M |
100 |
|
Avastin
(bevacizumab) 2004 |
$67.4
B |
$100B |
1.5M |
100 |
|
Nexium
(esomeprazole) 2001 |
$61.8
B |
$150B |
7M |
20,000 |
|
Lantus
(insulin glargine) 2000 |
$61.6
B |
$100B |
1M |
1,000 |
|
Diovan
(valsartan) 2005 |
$60.8
B |
$100B |
2M |
200 |
|
Zyprexa
(olanzapine) 1996 |
$60.6
B |
$55B |
3.5M |
1,000 10,000
for APs |
|
Crestor
(rosuvastatin) 2003 |
$56.9
B |
$125B |
1.5M |
20,000 |
|
Singulair
(montelukast) 1998 |
$47.9
B |
$50B |
200K |
100 |
Table 2. Antidepressants approved 1989-2021
|
Antidepressant |
Total Sales |
Literature references (1) |
Overprescribing by class 1990-2021 (1) |
|
Wellbutrin
(bupropion) 1985 |
$40B |
2.5M |
100,000 |
|
Prozac (fluoxetine)
1987 |
$32B |
22M |
|
|
Zoloft (sertraline)
1991 |
$50B |
16M |
|
|
Paxil (paroxetine)
1992 |
$40B |
13M |
|
|
Effexor (venlafaxine)
1993 |
$70B |
10M |
|
|
Celexa (citalopram)
1998 |
$50B |
12M |
|
|
Lexapro
(escitalopram) 2002 |
$40B |
8M |
|
|
Cymbalta (duloxetine)
2004 |
$35B |
14M |
|
|
Viibryd (vilazodone)
2011 |
$1.5B |
3M |
|
|
Trintellix
(vortioxetine) 2013 |
$2B |
1M |
1. Lexis-Nexis
search via Bard.
Table 3.
Approximate Number of Prescriptions
|
Drug Class |
Estimated Number of Prescriptions |
|
Statins
(atorvastatin, rosuvastatin) |
200M worldwide |
|
Antidepressants
(table 2 plus earlier ADs) |
150M worldwide |
|
Monoclonal Antibodies
|
Millions |
|
PPIs (esomeprazole) |
17.9M in 2008 |
|
Clopidogrel |
18M in 2016 |
|
Valsartan |
18M in 2016 |
|
Advair |
2.5M worldwide |
|
Etanercept |
2.5M worldwide |
A couple of qualifiers before comments. First there is no organized registry or pharmacosurveillance
system for basic monitoring of any prescriptions in the United
States and in most countries. Total prescriptions and sales in the US have
always been proprietary data. It
typically involves sampling local pharmacies and then extrapolating those sales
to the larger population. Practically none of that data is available to the
public but it occasionally shows up in articles in both the popular and
professional press. Second, the proxies chosen here for comparing drug classes
including the number of times a particular drug or term is mentioned in the
popular and professional literature is also approximate because these words can
be used frequently in the same paragraph and the context is not apparent – the
words could be used in both positive and critical contexts. The
“overprescribing” term closely paired to the drug name was chosen as a proxy
for critical articles – but even then, the level of criticism and whether it
was appropriate or not is an open question.
Looking at the general number of people exposed to each drug class it is
reasonable to assume that 5 of the drug classes – statins, antidepressants,
PPIs, clopidogrel, and valsartan have probably all been prescribed to about
200M people. The immunological drugs including the monoclonal antibodies and
etanercept have been prescribed to many less probably somewhat less than 10M
people. The Advair number seems very low to me since it has been around for 23
years and was able to continue patent protection beyond the expiration date not
for the medication but the unique dispenser.
I have the following observations based on what is available:
1. Despite an overall increase in antidepressant prescriptions – new antidepressant prescribing and revenue is low. This is probably due to the abundance of generic antidepressants and associated rationing of access to newer antidepressants by managed care companies (MCO) and pharmacy benefit managers (PBMs). My only interest in revenue is as a proxy for total number of prescriptions. Looking at the total revenue over years of availability in table 2 – antidepressants generated about $1-2B per year.
This is the downside to the antidepressant prescribing
conspiracy theory. If the business model
was as simple as influencing mindless doctors there would not be such a drop in
revenue. There would be a never-ending
revenue stream available just from that manipulation. The conspiracy theory
fails to account for the regulatory model that rewards innovation with time
limited patent protection but even then there are limits, in this case an abundance
of generic drugs due to expired patent protection.
The conspiracy theory also fails to account for the fact
that these patterns are well known and have happened in the past. When I was an
intern one of my attendings commented that it was ironic that pharmaceutical
companies were making billions off of indigestion with H-2 blockers while there
was hardly any research being done on malaria - a disease that was killing a million people a year at that time. When the H-2 blockers
(cimetidine, ranitidine, famotidine) became generics, proton pump inhibitors
took their place in the billion-dollar profit cycle. With the current regulatory landscape this
cycle will continue to repeat. At any
given peak in the cycle it may appear there is a conspiracy to increase Pharm
profits – but it appears those suggestions only happen when psychiatric
medications are involved.
2. The current top
selling drugs take the approach of selling to very large populations or selling
very expensive agents to smaller populations. Atorvastatin as an example
generates about 3 times a much revenue per year as an antidepressant targeting
about the same population size. I have
some insider information about atorvastatin and its manufacturing. I was told by a chemist that at the time of
its original manufacturing it was the most expensive tablet every produced and
that cost was $1.00 per pill. Today it
is possible to get a 90 day supply of 10 mg tablets for $3.44 to $6.44 and the
generic manufacturers are still making money.
3. One of the rationales
for regulatory protection of patent protection is the high cost of research. Is there any evidence this applies to the
current landscape of psychiatric medications? At least one industry analysis expects slower
than expected growth in “mental health therapies” but much greater growth in immunological
therapies, cancer therapies and obesity therapy. All would appear to be driven by current
profits in these areas. The current down
cycle in psychiatric research may also explain the attempts to resuscitate
hallucinogens and psychedelics for this application. There has long been the
outcry that the only reason these drugs have not been adequately researched was
their classification as Schedule I compounds – but the research so far has not
been impressive.
4. Given the
limitations, the most striking number in the tables are the number of
“antidepressant overprescribing” articles in the popular and professional
literature. That number (100K) exceeds
the total number of overprescribing references in Table 1. by 25%. There is not much granularity there but when
taken in combination with statements seen in both the popular press and
research literature it may confirm what has been known for a long time –
psychiatry is by far
the most criticized specialty whether that criticism is rational or not.
The cycles of feast and famine in the pharmaceutical industry
are always the product of innovation, marketing, and politics just like any
other capitalistic enterprise in the US. There is an opportunity to do immense
good and we have just seen that happen with the vaccines and medications
invented to stop a pandemic. Even the best possible treatments have side
effects and sometimes very bad side effects. That is the expected cost of
treating any diverse biological population. Psychiatrists and the medications they use are not better than that biological constraint –
but they certainly are not worse.
George Dawson, MD, DFAPA
References:
1: Brumely J. The 15
All-Time Best-Selling Prescription Drugs.
Kiplinger. December 17, 2017
2: Urquhart L. Top
drugs and companies by sales in 2018. Nature Reviews Drug Discovery. 2019 Mar
12:NA-.
3: Urquhart L. Top
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1;19(4):228-9.
4: Arrowsmith J. A
decade of change. Nature Reviews Drug Discovery. 2012 Jan 1;11(1):17.
5: Moorkens E,
Godman B, Huys I, Hoxha I, et al. The Expiry of Humira® Market Exclusivity and
the Entry of Adalimumab Biosimilars in Europe: An Overview of Pricing and
National Policy Measures. Front Pharmacol. 2021 Jan 8;11:591134. doi:
10.3389/fphar.2020.591134. PMID: 33519450; PMCID: PMC7839249.
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