What Big Pharma

doesnt want you

to know
Part one:
Dangerous drugs
Over-the-counter drugs
2 OTC drugs: medicines dark side
7 Death by aspirin

Drugs for depression

11 The great depression myth
15 The great Prozac conspiracy
19 SSRIs: bad prescribing habits
21 SSRIs: discontinuation syndrome

Drugs for children

23 Kiddie killers
28 Puffers get blown out
29 The kiddie upper takes tumble

Antibiotics
31 Life after antibiotics
35 Antibiotics: definitely not kids stuff
A Drug-induced disease

WDDTY
publication
36
40
46
47
Medicine and the elderly
The damaged brain: how drugs cause dementia
Anticholinergic drugs: the stupid pills
Diabetes: epidemic by prescription
51 HRT: the latest cancer risk
52 The big cure-all unmasked

WWW.WDDTY.COM
Over-the-counter drugs
OTC drugs: medicines dark side
Over-the-counter
remedies are thought
to be safe because they
can be easily purchased
from pharmacies and
stores, but its an
unregulatedand
boomingmarket of
medications that can be
every bit as dangerous
as prescription drugs
TC, or over-the-counter,
O drugsremedies that you
can buy in pharmacies
and stores without a
prescriptionare the dark side of
medicine. Many of the active agents in
the OTC drugs that are sold every day
have never passed any safety trials, so
no one knows what happens to
consumers once they walk out of
the store with their medications.
There are more than 100,000
different OTC remedies available for
us to self-medicate a range of common
ailmentsincluding migraine head-
aches, insomnia, stomach pain and
indigestion problems, arthritis, general
aches and pains, and coughs and
coldsas well as products to help us
lose weight and stop smoking.
Because we can walk into any high-
street pharmacy or chemist and buy
them with a minimum of fuss and
questions asked, we believe they are
safe for us to take. And because we
think they are safe, we are much more
likely to take several OTC drugs in
combination, even though they may
well share some of the same active
agents, thereby increasing the amount
of each agent we are taking every time.
Indeed, the US Centers for Disease
Control and Prevention (CDC) has also
reckoned that around half of all child-
ren under the age of three years are
regularly given an OTC preparation,
such as Tylenol or Calpol.
Their potential dangers appear to
become the subject of public concern
only when they affect a celebrity, such
as Hollywood film actor Heath Ledger,
who died in 2008 after overdosing on
2 WDDTY Dangerous drugs
OTC sleeping pills, to which he had
become addicted.
Tragically, many hundreds of
thousands of people suffer the same
fate as Heath Ledger every year as a
direct result of an OTC drugbut their
deaths are never recorded as such
because there is no monitoring system
in place.
Researchers at the Eastern Virginia
Medical School reckon that OTC pain-
killers that contain aspirin are, on their
own, responsible for 20,000 deaths and
100,000 hospitalizations every year in
the US. Yet, not only are these drugs
never suspected of being the cause, but
most patients who need hospital care
dont even bother to mention that they
were taking such drugs as aspirinso
harmless are OTC drugs thought to be.
As the lead researcher and gastro-
enterologist of the above report, Dr
David Johnson, has said: This reflects
a common misperception that these
medications are insignificant or benign
when actually their chronic use,
particularly among the elderly and in
those with conditions such as arthritis,
is linked to serious and potentially
fatal GI [gastrointestinal] injury and
bleeding (Proceedings of the Annual Scien-
tific Meeting of the American College of Gastro-
enterology, October 15, 2007, Philadelphia, PA).
In fact, millions of people may well
be addicted to OTC drugs, especially
those that contain codeine, which is a
controlled substance derived from
opium. However, its a major social
problem that remains invisible, as the
UK governments All-Party Parliamen-
tary Group on Drug Misuse is
discovering. Dr Brian Iddon, the cross-
party group chairman, said: Our
inquiry has only scratched the surface
of this problem. Yet, it isnt clear how
his enquiry can ever go deeper, as there
are no records of who is buying these
drugs and how often, although one
place that the enquiry could start is
with a self-help group of 4000 people
registered on a website because of
their addiction to Solpadeine, an OTC
concoction of codeine and parace-
tamol (BMJ, 2007; 334: 9178).
Very few people who are regularly
self-medicating realize that the drugs
they are taking invariably contain
active ingredients, such as codeine,
that have never been subjected to any
rigorous safety tests. In the UK, a
regulatory framework for OTC drugs
came into existence only in 1971
and, in the US, in 1962so any active
compound that was introduced before
those dates has never been tested. This
means that agents such as aspirin,
codeine, dextromethorphan (DXM),
paracetamol (acetaminophen in the
US) and diphenhydramine have never
passed any proper safety trials, and yet
they are found in many popular
household OTC brands such as Alka-
Seltzer, Calpol, Tylenol and Vicks.
Double trouble
The OTC market has been earmarked
as the next major happy-hunting
ground of pharmaceutical companies.
Over the next few years, we are likely
to see many more powerful drugs
that up to now, have only been available
from the doctor and only with a
prescriptionput on the shelves for
everyone to buy.
Thousands of prescription-only
drugs have already made the transition
to OTCa process known as Rx to
OTC in the US and as OTC switching
in the UKand many more are
expected to follow suit as patents
expire on a host of blockbuster
prescription drugs. One example from
last year was the switching of Novartis
Prevacid 24HR, a heartburn remedy
and the first proton-pump inhibitor to
obtain OTC approval in America since
2003. As a prescription drug, it was
among the top five best-sellers in the
 US, with annual sales of $3.37bn in
Think twice about these OTC drugs 2008and yet, it has now become an
OTC remedy that is being marketed
Theyre household names and they may well be in your medicine cabinet right directly to the approximately 50
now. Yet, despite their popularity, you may want to think twice before you start million Americans who suffer from
popping any of these products. frequent heartburn (www.reuters.com/
u Advil or Motrin (ibuprofen): These are painkillers that can also reduce fever, article/idUSLE40551720090514).
but they can also cause stomach pain and dizziness. Their prolonged use As a result of this refocusing, the
can lead to ulcers, raised blood pressure, kidney and liver damage, and even OTC marketalready worth around
stroke and heart attack. $7.8bn in the US this year, and consis-
u Aleve (naproxen): A painkiller that also reduces inflammation, this can tently growing by 8 per cent annually
cause stomach pain, and its prolonged use can bring about the same since the early 1990sis set to double
adverse effects as Advil (see above). by 2023, according to the World OTC
u Aspirin (acetylsalicylic acid): One of the first non-steroidal anti- Pharmaceutical Market Analysis &
inflammatory drug (NSAID) painkillers, its preeminent position has been Forecasts, 20082023 (www.piribo.com/
challenged by newer, and supposedly safer, agents such as ibuprofen and publications/otc/world_otc_pharmaceutical_
paracetamol (acetaminophen in the US). However, it is still considered a first- market_analysis_forecasts_20082023.html).
choice remedy for migraine and as a preventative for heart disease. Yet, it Although the prescription drugs
causes gastrointestinal bleeding, Reyes syndrome in children and can be a market is far more lucrative, the
major cause of stroke in the elderly (see box, page 4). pharmaceutical industry is being
u Benadryl, Tylenol (diphenhydramine): These drugs are primarily intended forced to change its strategy. The
to ease gastrointestinal problems, although older patients also use them industry is reaching a significant
as sleep aids. They are increasingly being linked with cognitive impairment, watershed as scores of big-selling
causing confusion, agitation, memory loss and incoherent speech. proprietary drugs are soon to lose their
u Contac (pseudoephedrine): This decongestant causes dizziness, patents, which would allow a wash of
nervousness and sleeping problems. It should be avoided if you have high cheaper me-too generic drugs from
blood pressure, diabetes, prostate problems, thyroid disease or a heart competitors onto the market. To
condition. counter such an event, a drug company
u Nurofen (codeine, methylmorphine): This painkiller contains codeine, a often adopts a double-pincer move by,
controlled substance that can become addictive in chronic users. Codeine is on the one hand, supercharging the
found in many OTC remedies and, depending on the formula, can cause prescription drugsuch as by
nausea, euphoria and rash. Codeine is an opiod, a family of agents that can increasing its potency or making a
lead to fatal respiratory depression. Codeine metabolizes into morphine, and minor change to the formulation
this can be passed through a mothers breast milk in lethal amounts. which would then allow it to extend
u Nytol (diphenhydramine): This is a sleep aid and, like most OTC remedies its protective patent while, on the
for insomnia, its an antihistamine, which promotes drowsiness. Common other hand, making the original drug
side-effects, which especially affect older patients, include dizziness and available in the OTC marketplace.
forgetfulness, constipation and blurred vision. However, these remedies can The types of drugs that are expected
be fatal if you become a chronic user and you regularly overdose, as to make the switch include gastro-
happened to Hollywood film actor Heath Ledger. Overdosing is common intestinal remedies, cholesterol-
as the body becomes adjusted to the recommended dose. lowering agents, osteoporosis treat-
u Solpadeine (paracetamol, codeine): This is one of the most popular OTC ments and contraceptives. Also, the
painkillers in the UK. Although it is supposed to be taken for no more than pharmaceutical industry is fiercely
three days, many people become addicted to it. The combination can cause lobbying drugs regulators such as the
drowsiness, and serious liver and kidney damage, especially if taken US Food and Drug Administration
together with another OTC remedy that contains paracetamol. Other side- (FDA) to extend the categories of
effects include constipation, rash and nausea. agents that can be sold as OTC. Its a
u Sudafed (phenylephrine): See Contac (above). battle theyre expecting to win, and
u Tylenol (acetaminophen): This was promoted as a safer alternative to new categories are likely to be
aspirin, but it can cause kidney failure, and several prescription drugs that included in the OTC arena, says
contain this agent are now being closely monitored. Tylenol also contains industry analyst group Kalorama
codeine, a controlled substance in most countries. Its reckoned that ( www.fiercehealthcare.com/story/study-
acetaminophen is responsible for 100 deaths and 56,000 emergency-ward recession-could-pump-mkt-over-counter-
visits every year in the US alone. drugs/2009-04-20).
u Vicks, Robitussin (dextromethorphan): These cough-and-cold remedies However, the battle is already all
contain DXM, a chemical that is similar to morphine; indeed, some teenagers but over in the UK, which is known to
deliberately overdose on them to get a high. The US Drug Enforcement operate one of the most liberal drug-
Administration (DEA) has classified DXM as a drug of concern, but has licensing regimes in the world, where
done nothing to restrict its sales in stores. cholesterol-lowering statin drugs were
allowed to be sold without a pres-
cription as early as 2004.

WDDTY Dangerous drugs 3

Over-the-counter drugs

Whos at risk?
As with most drugs, the young, the elderly and those who are
pregnant are most at risk from the side-effects of
OTC remedies, although any userespecially any chronic
usercan suffer an adverse reaction.
Around 71,000 preteenagers are rushed to an emergency
ward in the US every year after being poisoned by an OTC
drug, such as cough syrup (Am J Prev Med, 2009; 37: 1817), while
many teenagers are deliberately overdosing with DXM, which
is found in cough medicines, to experience a high. From
1999 to 2004, there was a 15-fold increase in cases of DXM
poisoning and over-doses among young Americans aged
nine to 17 years (Arch Pediatr Adolesc Med, 2006; 160: 121722).
The under-12s who take aspirin are also at greater risk of
developing Reyes syndrome, a rare and often fatal multiorgan
disorder (BMJ, 2002; 325: 988). Yet, ironically, acetaminophen is
promoted as safe for children. However, the drugs regulators
are now beginning to realize that its even more dangerous
than aspirin, and can cause life-threatening liver problems
(JAMA, 2009; 301: 23156).
Pregnant women who take an NSAID (non-steroidal anti-
inflammatory drug) like aspirin increase their risk of
miscarriage by 80 per cent. The risk is even higher when the
drug is taken at around the time of conception or
for more than one week. These drugs are thought to suppress
the production of prostaglandins, fatty acids that help to
ensure that an embryo is successfully implanted in the womb
(BMJ, 2003; 327: 368).
Women who take any drug that lowers their folic-acid
levelsincluding OTC preparations such as NSAIDsrun a
far greater risk of giving birth to a child with a birth defect. Also,
the risk of cardiovascular defects increases
by 240 per cent and that of oral clefts, by 160 per cent
(N Engl J Med, 2000; 343: 160814).
OTC cough remedies that contain DXM are another cause
of birth defects. One studyalbeit in animals, so it may not
apply to humansfound that DXM is so powerful that just one
dose can result in a birth defect, and can affect the embryo
even before the pregnancy is known. So, all women who are
pregnant, or who are planning to become so, are advised not
to take any OTC cough medicine that contains DXM (Pediatr
Res, 1998; 43: 17).
Women in general who use an OTC slimming aid that
contains phenylpropanolamine will dramatically increase their
risk of stroke. In one study of 702 women who had suffered a
stroke and who were compared with 1376 healthy controls, an
OTC appetite suppressant was found to increase stroke risk
by more than 16 times, while women who had taken an OTC
cough or cold remedy that contained phenylpropanolamine
were more than three times more likely to suffer a stroke (N
Engl J Med, 2000; 343: 182632).
Nursing mothers should also avoid any OTC remedy that
contains codeine. As this agent metabolizes into morphine, it
can pass from the breast milk to the babyat levels that can
be fatal to the infant.
However, the elderly are perhaps at the greatest risk of
suffering an adverse reaction to an OTC drug, partly because
they are generally taking more of them and their immune
systems are less able to cope, but also because it is usually
part of a drugs cocktail that includes prescription medications,
too. Also, aspirin is often part of the health regimen in the
elderly, who take it is a preventative against heart disease and
stroke.
But a study from Oxford University suggests that the drug
has a paradoxical effect among the over-75sand
is, in fact, a cause of stroke resulting in either disability or
death.
The researchers have discovered that aspirin had caused
a sevenfold increase in stroke in the elderly patients who
participated in their study. As research team leader Professor
Peter Rothwell said: There are elderly people who take
aspirin as a lifestyle choice, and, in that situation, the trials
have shown theres no benefit. And what our study suggests
is that, particularly in the very elderly, the risks of aspirin
outweigh the benefits (Lancet Neurology, 2007; 6: 48793).
In addition, OTC sleep aids are a significant cause of falls
in elderly people. Falls and complications after falls are the fifth
most common cause of death in the developed world.
Researchers from the University of British Columbia in
Canada reviewed 22 studies, involving more than 79,000
elderly participants who had falls, and found that prescription
and OTC sedatives and anti-depressants were mainly
responsible for the accidents (Arch Intern Med, 2009; 169:
195260).
However, both the elderly and the young are at special risk
from OTC sleep aids that contain antihistaminesand
diphenhydramine in particular. While the drugs can cause
abnormal muscle spasms and blurred vision in the general
population, they also cause nervousness and, paradoxically,
insomnia in the very young and in older adults
(Pharmacotherapy, 1994; 12: 4926).

The British drugs regulators were
undeterred by the dubious safety
record of statins, which lists heart
failure, liver and kidney damage, and a
potentially fatal muscle-wasting dis-
order known as rhabdomyolysis
among their side-effects. In 2001, one
statin, Baycol, was withdrawn from the
market after 31 people died because
of rhabdomyolysis in the US and after
being linked to around 100 deaths
worldwide (http://news.bbc.co.uk/2/hi/europe/
1481178.stm;http://news.bbc.co.uk/2/hi/busines
s/2916979.stm).
As a spokesman for the pharma-
ceutical market research company
Piribo states: The worldwide OTC
market will see a remarkable period of
dynamic change. Ageing populations
and rising incidence of lifestyle
diseases, as well as the need to reduce
healthcare costs, will open up new
therapeutic areas for OTC switching.
This explosion in OTC sales is also
fuelled by consumer demand. More
and more people are looking to self-
medicate, which they consider to be
inexpensive, convenient and safe,
compared with a visit to the doctor,
which might involve a more careful
review of the problem. Consumer
demand for the heartburn remedy
Prilosec became so great in 2004 that

4 WDDTY Dangerous drugs

pharmacies were out of stock for most
of the year. Although manufacturer
Proctor & Gamble increased its
production, it wasnt until 2005 that
shelves were replenished (Berenson A.
Where Has All the Prilosec Gone? The New York
Times, March 3, 2005).
To make the switch from pres-
cription to OTC, the drug manufac-
turer will often reduce the dose level
or change the formulation to produce
a weakened version for the mass
market. Nevertheless, these smaller
dosages can still be lethal, and is
certainly addictive, as the few statistics
that are available demonstrate.
Indeed, our drugs watchdogs are at
pains to point out that there is no such
thing as a safe drug, and they urge
consumers to read the label before
taking any medication. But as OTC
regulations are far less rigorous than
they are for prescription remedies, the
demands and guidelines for the
manufacturer regarding the inclusion
of patients information are hardly
onerous. For example, the safety sheet
that comes with the prescription-only
version of Motrin, a painkiller that
contains ibuprofen, includes possible
side-effects such as oedema, blurred
vision, nausea, heartburn, diarrhoea,
gastric ulcer with bleeding and/or
perforation, dizziness, nervousness,
rash and tinnitus. In contrast, the label
on the OTC version of Motrin merely
mentions that ibuprofen may cause
stomach bleeding, and the list of side-
effects has been omitted.
Hidden interactions
The OTC drug manufacturer also
doesnt have to make any mention of
the fact that the remedy can interact
with other drugs or remedies,
including vitamins. Paracetamol
(acetaminophen) is a common pain-
killing agent found in hundreds of
OTC remedies and, yet, none of them
mentions that it can increase bleeding,
possibly to a dangerous level, if taken
in conjunction with the blood-thinning
drug Coumadin (warfarin).
The FDA is also becoming increas-
ingly concerned about prescription
drugs that contain acetaminophen,
and one of their advisory committees
last year went so far as to recommend
that all drugs that combined this agent
with narcotics should be immediately
removed from the market.
The history of OTC drugs
Regulators on both sides of the Atlantic have been slow to regulate OTC
drugs, as well as the active agents they contain. In the US, alcohol, cocaine,
marijuana and opium were regularly included in therapeutic concoctions
without the need for any special licence, and that only changed with the
passing of the US Federal Food, Drug, and Cosmetic Act (FFDCA) of 1938.
Yet, even then, this piece of legislation failed to distinguish between
drugs that were available only by prescription and those that were sold in
stores. The situation was clarified only slightly in 1951 with an amendment
to the act that defined prescription drugs as those that were habit-forming,
toxic, unsafe or used only under a doctors supervision. In other words, a
drug could be sold over the counter if it was none of the above although,
even today, many OTC drugs are, in fact, habit-forming and toxic, and
possibly unsafe.
The laws only began to tighten up in 1962 with the thalidomide scandal
in the UK and yet another amendment to the FFDCA of 1938 in the US. The
latter then required that OTC drugs should be both effective and safe, an
amendment that has been little more than window dressing, as no reporting
system was created to confirm either of these qualifiers.
In the UK, the College of General Practitioners set up a Register of
Unexpected Toxicity in the wake of the thalidomide scandal, which caused
5000 appalling deformities in newborn babies in the UK, and around 10,000
cases worldwide. One year later, the British did what the British do best:
they set up a committee which, in 1963, suggested that the problem of
drugs monitoring and regulating could best be served by the creation of a
new committeethe Committee on Safety of Drugs (CSD)which, in turn,
comprised four subcommittees.
However, despite all these committees, the OTC market was still not
covered and was not regulated until 1971, when the Medicines
Commissionthe main statutory advisory body set up under the UK
Medicines Act of 1968began its work to monitor all drugs.
The committee argued that the non-autistic controls, the children who
chances of overdose and severe liver were given an aceta-minophen-
injury were high, and that the risks far containing remedy were six times more
outweighed any benefits that such likely to develop autism after the
drugswhich include Vicodin and vaccine, and nearly four times more
Percocetoffered. likely to suffer regression in
Also, the report stated that aceta- their development, compared with the
minophen, which is commonly used to controls. The children who had been
reduce fever, had been linked to 56,000 given ibuprofen to treat fever after the
emergency room visits, 26,000 hos- MMR vaccine had no autism (Autism,
pitalizations and 458 deaths during 2009; 13: 1234).
the 1990s in the US. Yet, no one Most cough medicines include
recommended that any OTC drug dextromethorphan (DXM) and, yet, the
containing acetaminophen be taken off warningif there is one at allis
the market (http:// news.health.com/ woefully inadequate. Although one
2009/06/30/fda-panel-urges-ban-vicodin- OTC preparation, Robitussin, men-
percocet/). tions that it shouldnt be taken with
Acetaminophen is even suspected any prescription antidepressant known
of being a cause of autism. Its found in as an MAOI (monoamine-oxidase
the childrens OTC remedy Calpol, inhibitor), it doesnt state that the
which is regularly used by parents to interaction is, in fact, life-threatening.
reduce fever, which also commonly DXM also interacts with other anti-
occurs after receiving the MMR depressants such as Prozac, Paxil and
(measlesmumpsrubella) vac-cine. In Zoloft (all of which are SSRIs, or
one study of 83 children with autism selective serotonin-reuptake inhibi-
who were compared with 80 healthy, tors), to produce a serious condition
WDDTY Dangerous drugs 5
Over-the-counter drugs
known as serotonin syndrome, which
can trigger symptoms such as muscle
twitches, fever, nausea, dizziness,
confusion, shock and coma. DXM side-
effects, even when not mixed with
another drug, include impaired
judgement, loss of coordination,
dizziness, nausea, hot flashes, hallucin-
ations, brain damage, seizure and
death. Again, virtually no OTC drug
that contains DXM mentions these
possible adverse effects.
Drug manufacturer Merck, which
also publishes The Merck Manual of
Medical Information, says: Often, the
labels of OTC drugs do not list the full
range of possible side effects. As a
result, many people assume that these
drugs have few, if any, side effects. For
example, the package insert for one
analgesic (not named) cautions people
not to take the drug for more than
10 days for pain. However, the possible
serious side effects that can occur with
long-term use (such as life-threatening
bleeding from the digestive tract) are
not mentionednot on the box,
bottle, or package insert (www.merck.
com/mmhe/print/sec02/ch018/ch018a.html).
Americas Generic Pharmaceutical
6 WDDTY Dangerous drugs
Association (GPhA) recognizes the
double standards that now apply to
prescription and OTC drugs, and is
calling for the same approval
process for all drugs, irrespective of
the way in which they reach the
marketplace and consumers.
While FDA-approved prescrip-
tion drugs are subjected to a rigid
application-based approval process
. . . other products are marketed
either under a minimally regulated
system or no regulatory system at
all. Specifically, numerous OTC
drugs have been on the market for
years and some predate the laws
that require proof of safety and
effectiveness before marketing . . .
[so] the unregulated OTC drug
market continues to fall between
the cracks, an association
spokesman says (www.gphaonline.org/
media/press-releases/2009/02/12/fda-
standards-and-foreign-inspections).
Double blind
With the OTC market becoming the
new focus of Big Pharma, it is
imperative that it is protected by the
same regulatory framework that
controls prescription drugs. While it
is forgivable that the consumer might
believe OTC drugs are safer, its not
acceptable that our drugs regulators
should also share the same view.
In fact, the regulators know that
OTC drugs are every bit as dangerous
as their prescription counterparts,
even though they may be acting
otherwise. Why else do OTC drugs
not have to list all of their possible
adverse effects, or any of their
possible interactions with other drugs
and medications.
But worse than that is the fact
that the OTC market is completely
invisible. Nobody knows who is buying
these drugs or what happens to them
afterwards. This is because theres
little incentiveand almost no
fundingto investigate the dangers
of OTC drugs. However, the little that
has been done uncovers a worrying
picture, with aspirin alone causing
around 100,000 deaths worldwide
every year.
The OTC market is truly
medicines dark side, but its time
that light be shed upon it.
Bryan Hubbard
Death by aspirin
Aspirin may be a major killer, and one that none of us even suspects
spirin is the ultimate lifestyle may soon overtake hypertension (high

A drug, and is seen as one of

our great allies in warding off
heart disease. With the
encouragement of health guardians
around the world, we pop 100 billion
blood pressure) as the major cause of
stroke.

What studies now tell us

In the first of the new studies,
pills of this just-in-case drug every researchers reckoned that the drug is
year, and 37 per cent of them are taken killing 20,000 Americansand
by healthy people as part of their daily sending another 100,000 to hospital
health regime. every year just because
Its the inexpensive and readily of GI problems. Astonishingly, each of
available magic bullet that can protect these deaths and reactions is slipping
us against cardiovascular disease, under the radar, and is not being
mankinds greatest killer. The humble associated with aspirin at all.
aspirin can, according to its
proponents, reduce blood pressure and
help thin the blood, so lowering the The story of aspirin
risk of stroke and heart attacktwo
functions that today dwarf its original
Aspirin holds an unusual place in trademark law. As Aspirin with a
purpose as a painkiller, an anti-
capital A, it is a protected brand, owned by Bayer, the German
inflammatory and antipyretic (fever-
pharmaceutical giant.
reducer).
As aspirin, it is a generic drug that can be used in countries where
Best of all, it appears to be a
Aspirin is not trademark-protected. Around 50 other over-the-counter
relatively benign drug. The American
preparations contain aspirin, using either the name or ASA, an
Association of Poison Control Centers
abbreviation that stands for Aspirins generic name, acetylsalicylic acid.
receives reports of just 59 aspirin
Aspirin was the very first drug in the family of NSAIDs (non-steroidal,
deaths in the US each year, while
anti-inflammatory drugs) when Bayer began marketing it in 1899, along
researchers put the mortal-
with another of the companys discoveries, heroin. Its principal
ity rate for all painkilling, non-
ingredient is salicylic acid, derived from the bark of the willow tree and
steroidal, anti-inflammatory drugs
from the herb meadowsweet. It was recognized by Hippocrates as a
(NSAIDs) such as aspirin, ibuprofen
pain-reliever and an antipyretic (fever-reducer) as long ago as in the 5th
and naproxen at around 7600 deaths a
century BC .
year (Scand J Rheum Suppl, 1992; 92: 214).
Chemists at Bayer were successful in synthesizing salicylic acid with
Either way, doctors argue that these
the common chemical acetic anhydride, so giving Aspirin its generic
figures represent an entirely
name.
acceptable risk compared with the
Despite its widespread use and popularity, no one understood how
many thousands more who might
the drug worked until 1971, when the British pharmacologist John Vane
otherwise have died because of heart
found that aspirin suppresses the production of prostaglandins and
disease.
thromboxanes, hormones that regulate many physiological functions.
But scientists are now discovering
Today, we globally consume around 35,000 tons of aspirin every
that we have all been dramatically
yearamounting to around 100 billion tabletsa figure that is increasing
and catastrophically misled by the
annually by 15 per cent. Aspirin continues to be viewed as a benign
assurances of the medical community.
painkiller, which has helped to fuel its growing use at
Far from being benign, aspirin may be
a time when bad news and scares have hounded some of the other
a major killer in our society, and one
NSAIDs and COX-2 drugs.
that is never suspected.
Most recently, the COX-2 painkiller Vioxx was withdrawn from the
The new claim centres on the drugs
market after it was found to cause heart problemssome fatal. It was the
well-documented side-effect of causing
subject of the largest civil lawsuit in history until its manufacturer Merck
seriousand, in some cases, fatal
settled with a $4.85bn payout.
gastrointestinal (GI) bleeding. But
Aspirin has been dogged by its own fair share of side-effects. The most
researchers in a separate study have
common are stomach bleeding and other GI problems, but added to that
discovered a new, and worrying, side-
are stroke, anaemia, ulcers, liver damage, hives, wheezing, tinnitus,
effect of aspirinit may be a major
chronic catarrh, headache, confusion and hypotension (low blood
cause of stroke among the elderly.
pressure) followed by collapse. Asthmatics have also died from a severe
Because of its widespread use,
attack after having taken aspirin.
researchers warn that these little pills

WDDTY Dangerous drugs 7

Over-the-counter drugs
Researchers at the Eastern Virginia
Medical School made their alarming
discovery when they interviewed
patients at a clinic that specializes in
GI problems. They found that one in
five patients was taking aspirin or some
other painkilling NSAID, but the fact
wasnt being reported to the medical
staff because it wasnt regarded as
significant.
This reflects a common mis-
perception that these medications are
insignificant or benign when actually
their chronic use, particularly among
the elderly and those with conditions
such as arthritis, is linked to serious
and potentially fatal GI injury and
bleeding, said Dr David Johnson, one
of the Virginia researchers.
If the researchers death and injury
rates for the US is correct, this could
mean that the worldwide aspirin and
other NSAID death toll is 100,000
individuals every year. Whats more, a
further 500,000 of us will need hospital
care to treat a serious reaction to the
drug, such as the result of a GI reaction
(Proceedings of the Annual Scientific Meeting of
the American College of Gastroenterology, 15
October 2007).Currently, none of these
deaths is even recorded as an aspirin
fatality.
Equally worrying is the drugs effect
among the over-75s. Far from
protecting them against stroke, it
appears to be causing just such an
attack that is either fatal or results in
disability. Researchers at Oxford
University have discovered that
the drug has caused a sevenfold
increase in intracerebral haemor-
rhagic strokebleeding within the
brainduring the past 25 years among
groups of elderly patients who
participated in their trial.
Research-team leader Professor
Peter Rothwell says that aspirin may
soon replace high blood pressure as the
leading cause of intracerebral
haemorrhagic stroke, especially among
the over-75s.
There are elderly people who take
aspirin as a lifestyle choice, he says,
and, in that situation, the trials have
shown theres no benefit. And what our
study suggests is that, particularly in
the very elderly, the risks of aspirin out-
weigh the benefits.
In Rothwells study, researchers
assessed the records of stroke victims
between 1981 and 1985, and again
8 WDDTY Dangerous drugs
Is it truly a heart helper?
Aspirins popularity today is more to do with its ability to protect us from
cardiovascular disease (CVD) than as a painkiller, for which it has been
superseded by newer kids on the block such as ibuprofen.
Around 37 per cent of the 100 billion aspirin pills swallowed every year are
taken as a preventative against heart disease and stroke, while 23 per cent of
users are arthritis sufferers who take it for its anti-inflammatory qualities. Only 14
per cent of users take it to relieve
a headache.
Its principal role as an anti-inflammatory and antipyretic began to change
when Dr L.L. Craven, a GP working in California, discovered that it was providing
benefit to his heart patients (Mississippi Valley Med J, 1953; 75: 3844).
More recent trials have confirmed its role as a preventative agent, and
particularly for heart patients. In 1998, the US drugs regulator, the Food and Drug
Administration (FDA), widened the scope of aspirin to encompass its
new role, especially among those who had had a heart attack, stroke, angina, or
bypass surgery or angioplasty.
Since then, two meta-analyses have concluded that aspirin can reduce the
risk of cardiovascular disease by 13 per cent (Arch Intern Med, 2000; 160: 31237),
and heart attack by as much as 32 per cent (Heart, 2001; 85: 26571).
Despite these glowing recommendations, however, many groups remain
cautious and recommend that healthy people not use aspirin as a prophylactic
just-in-case. The US Preventive Service Task Force is still not convinced and,
despite the meta-analyses, says the data are insufficient to make any categorical
pronouncement (Ann Intern Med, 2002; 136: 15760). The European Society of
Cardiology suggests that those at high risk of heart disease should take aspirin
only at a low daily dose of 75 mg.
Similar cautious voices have been raised concerning aspirins ability to
prevent stroke, despite the seemingly impressive research. The Antiplatelet
Trialists Collaboration (ATC) prepared a series of landmark trials that appeared
to establish aspirin as an important agent for treating stroke.
Yet, within a year, its findings were being questioned. The Thrombosis
Research Institute analyzed the third arm of the ATC trial, which focused on the
efficacy of aspirin in reducing venous thrombosis and pulmonary embolism after
surgery. The Institute declared that some of the ATCs conclusions were not
justified, and that several of the studies included in the meta-analyses werent of
a high-enough standard (BMJ, 1994; 308: 12137).
Worse, the ATC researchers had also played down the issue of side-effects
such as internal bleeding. Without them, said the Institute, the true riskbenefit
ratios couldnt be worked out.
In the face of these criticisms, the ATC researchers moved away from their
earlier effusive position and instead suggested that aspirin was not the complete
solution, but should be seen as part of a range of measures.
The ATC studies were an interesting object lesson in how the myth of the
healing powers of aspirin always manages to outpace the actual studies on
which it has been founded. Nevertheless, despite the legend, there is only a
handful of research to support the theory that aspirin can prevent heart disease
and stroke. Even used as a preventative by heart patients, the evidence is thin on
the ground.
The editorial team of a prestigious peer-reviewed journal once stated that
aspirin seems as effective as any other single agent or combination of agents
(BMJ, 1994; 308: 712), which is saying far less than aspirins advocates believe
between 2002 and 2006. While the same, mainly because there had been
overall rate of stroke caused by high an increase in the number of strokes
blood pressure had dropped by 65 per among patients taking blood-thinners
cent between those two periods, the such as aspirin.
rate among the over-75s remained the The team discovered that the
use of these drugs had increased
dramatically and especially among
healthy people who were taking
the drugs as a preventative. From 1981
to 1985, only 4 per cent of patients
were taking a blood-thinner, but this
had risen to 40 per cent between 2002
and 2006 (Lancet Neurology, 2007; 6:
48793).
In fact, the true dangers of aspirin
have been known for some time,
although no one has been prepared to
do anything about it. Scientists from
the West Midlands Regional Health
Authority in Birmingham were among
the first to raise the warning flag 12
years ago, when they did an
investigation into the reasons why
people were in hospital for treatment
of bleeding peptic ulcer.
At that time, they discovered that
12.8 per cent of the 1121 patients
being investigated were regular users
of aspirin, which they defined as five
days a week for at least a month. When
they compared these patients against
other patients with the same prob-lem,
but who were not regularly taking
aspirin, it was evident that taking the
NSAID had increased the risk of
hospitalization for bleeding peptic
ulcer by 2.3 times at a low dose of just
75 mg, and by up to 3.9 times at the
more standard dose of 300 mg (BMJ,
1995; 310: 82730). The 300-mg dose is
the recommended level for just-in-case,
or prophylactic, use against heart
disease.
These researchers didnt track the
progress of patients after identifying
their cause of hospitalization, but one
group of scientists didand came up
with a horrifying picture. Of those who
were being treated in hospital for
serious upper gastrointestinal bleeding
or perforation, 10 per cent had died.
Who are most at risk?
This alarming scenario was derived
from an analysis of 12 studies
published between 1980 and 2000.
Those who were especially at risk were
older individuals, and there were
around twice as many men as women
who ended up in hospital
(J Clin Epidemiol, 2002; 55: 105763).
So, as well as age and gender, people
who take several NSAIDs in
combination also increase their risk of
having a serious GI reaction. In a
separate study, researchers who
examined patients records from
databases in the UK and Spain found
that 60 per cent of those
who suffered a GI reaction from an
NSAID were aged over 60, 13 per cent
were using several NSAIDs in
combination, and 6 per cent had a
recent history of peptic ulcers, even
though patients with pre-existing GI
problems should not be taking any sort
of NSAID in the first place (BMC
Medicine, 2006; 4: 22).
But perhaps the most lethal drug
combination is an NSAID with
an SSRI (selective serotonin reuptake
inhibitor) type of antidepressant such
as Prozac, Zoloft or Paxil. In fact, this is
a common drug cocktail, especially
among arthritis sufferers, who are
often given an NSAID to ease their joint
pain and inflammation, and an SSRI to
ease their mild depression.
When these two drugs are taken
concomitantly, the risk of upper
GI haemorrhage increases by 6.3
times. Translated into everyday usage,
a patient has to take the combination
just 82 times before suffering a serious
gastrointestinal adverse reaction. Such
an event would occur less than three
months into the treatment, assuming
the combination is taken daily.
Researchers from the University of
East Anglia made this discovery when
they carried out a meta-analysis of four
trials involving a total of 153,000
patients who were taking either an
SSRI or an NSAID, or a combination of
the two types of drug. Patients who
took just the SSRI increased their risk
of a GI reaction 2.4 times, and those
taking just an NSAID had a 3.2-times
greater risk (Aliment Pharmacol Ther, 5
October 2007; doi: 10.1111/j.1365-
2036.2007.03541).
Lead researcher Dr Yoon K. Loke
commented: Before I did this study, I
didnt worry at all when I saw patients
who were on combinations of SSRIs
and NSAIDs. Now that I have seen the
fairly substantial excess risk, physicians
should review the patients chartsdo
they need to be on these drugs at all, or
are there safer alternatives?
Gastrointestinal problems with
aspirin have been known for a long
timeeven if the actual severity and
extent have only recently been
revealedand manufacturers have
tried to reduce the risks by either
producing a version that is enteric-
coated, which allows the tablet to
transit through the stomach to the
small intestine before releasing the
medicine, or buffered, where the
standard pill is coated with a sub-
stance that neutralizes stomach acid.
But again, far from reducing the GI
risk, these coatings appear to increase
it. Researchers from the Boston
University School of Medicine
interviewed 550 hospital patients who
had major upper gastrointestinal
bleeding about their aspirin use. To
their surprise, they found that those
who had regularly taken buffered
aspirin were at a slightly greater risk of
developing GI problems than were
those taking regular aspirin tablets. At
doses greater than 325 mg, patients
taking the buffered tablets were seven
times more likely to develop GI
problems whereas the risk was
increased nearly sixfold with the
standard pills (Lancet, 1996; 348: 14136).
Aspirin: still a wonder drug?
Extraordinarily, the popular use of
aspirin seems to be immune to
any bad news. This may be because
aspirin is still perceived as being a
wonder drug. Every year, its
estimated that around 3500 studies
are carried out on the drug, and
researchers seem to consistently come
up with new health problems that they
believe it can solve. Its been claimed to
fight cataracts (Arch Ophthalmol, 1992; 110:
33942), and cancers of the prostate,
colon, pancreas, upper GI tract, and
lungclaims that usually no one
is able to replicate and so are,
eventually, forgotten.
This is, of course, in addition to its
more traditional, and accepted, uses as
an antipyretic to reduce fever in cases
of rheumatic fever, as an anti-
inflammatory in cases of rheumatoid
arthritis and osteoarthritis, and as a
painkiller for minor aches and pains
such as headache.
But if the risks of regularly taking
aspirin outweigh its benefits among
healthy over-75s, as suggested by
Oxfords Professor Rothwell, then
should healthy individuals of any age be
taking it?
Not according to Charles H.
Hennekens, former chief of preventive
medicine at Brigham and Womens
Hospital in Boston, and one of aspirins
main advocates. Yet, even he believes it
WDDTY Dangerous drugs 9
Over-the-counter drugs
is wrong for any healthy individual to
take aspirin as a preventative as the
risks are simply too high.
A 30-year-old womans risk of a
heart attack is typically very small, and
remains so even over the next 30 years.
Aspirin would give her no benefit and it
could cause gastro-intestinal effects or
dangerous bleeding, he says in a Food
and Drug Administration (FDA) report.
Children aged under 12 should also
no longer be given aspirin because of
the very real danger of Reyes
syndrome, a rare, often fatal, disorder
primarily seen in children recovering
from a viral illness and associated with
aspirin use (BMJ, 2002; 325: 988).
If the healthy should not be taking
aspirin, this suggests that nearly 40 per
cent of daily aspirin use is
inappropriate, and may even be
endangering thousands of lives without
any realistic benefits.
Nevertheless, it should be part
of the daily health regime of anyone
who has a heart problem, says the
American Heart Foundation. It
estimates that between 5000 to 10,000
of the 900,000 lives lost each year to
cardiovascular disease in the US alone
could have been prevented had the
10 WDDTY Dangerous drugs
patient taken a daily aspirin. It points
to research that suggests that aspirin
can help to prolong the lives of people
who have suffered a stroke or heart
attack, or recurring blockages
following heart bypass surgery or
angioplasty to clear obstructed
arteries.
But these positive claims have to be
countered with the more recent
findings that the drug could be killing
20,000 Americans every year because
of GI complications alone, a figure that
may well increase if stroke victims are
also included.
But no drug is a substitute for
a sensible lifestyle. A healthy diet that
is rich in vegetables and fruit,
moderate exercise, and stress- and
cigarette-free living can do more for He says: If you are healthy and have a
the healthy individual and the low risk of heart disease or stroke, the
recovering patient alike. increased risk from side-effects of
As the FDAs Debra Bowen says: aspirin are likely to outweigh the
Physicians really need to look at benefits of preventing stroke.
aspirin in the context of complete care, Aspirin is as close as medicine has
as part of a whole treatment plan for ever come to producing a magic
people at risk of heart attack or bulletand one that appears to be
stroke. Teflon-coated, too. Neverthe-less, given
Its a view shared by Dr Peter these latest discoveries, its an ideal
Coleman, deputy director of res-earch that is apparently as far away as ever.
for the Stroke Association in the UK. Bryan Hubbard
Drugs for depression

The great depression myth

SSRI drugs sell on the basis of the false chemical imbalance theory
very year around the world,

E we take $13bn (6.6bn)-

worth of antidepressants,
and more than 80 per cent
of those is an SSRI (serotonin
selective reuptake inhibitors) such as
Prozac, Paxil and Zoloft.
SSRIs are among the best-selling
drugs in medicine, and their enor-
mous success is based on the
chemical imbalance theory, which
proposes that people are depressed
because they are low in serotonin, a
brain chemical and neurotransmitter
that acts on the nervous system.
An SSRI redresses such a chemical
imbalance by helping to promote
serotonin, and can treat not only
depression, the manufacturers claim,
but also other psychiatric problems
such as social anxiety disorder and
obsessivecompulsive disorder.
The SSRI signalled a revolution in
mental care. Suddenly, clinical and
severe depression wasnt something
that the sufferer just had to endure
or learn to get over. Instead, heres a
simple remedy to hand: a chemical
to treat a chemical. As a result, weve
become a Prozac Nation, as Eliza-
beth Wurtzels best-selling book says.
The pharmaceutical industry has
been the major promoter of the
depressionserotonin theoryfor
obvious reasons. Yet, astonishingly,
the concept has never been actually
proven since it was first postulated in
1967and not because there havent
been many attempts to do so.
Given that the theory remains
unproven, its not surprising that the
SSRI antidepressant is far less
effective than the drug companies
are claiming. In a meta-analysis of
both published and unpublished
trials so far, researchers found that
the trials, usually funded by the drug
manufacturer itself, either put an
unwarranted positive spin on the
results or were suppressed if the
results were not positive (N Engl J Med,
2008; 358: 25260).
Whats the idea?
Its generally accepted by doctors
as well as the general publicthat
severe depression is the result of a
chemical imbalance nd, especially,
low levels of the neurotransmitter
serotonin in particular. Joseph
Schildkraut was one of the pioneers
of the general theory that chemical
imbalances cause depression and, in
1965, he postulated that depression
was associated with low levels of a
neurotransmitter. These imbalances
caused mood swings, and the prob-
lem could be corrected by drugs, he
believed. Two years later, researchers
zoned in on serotonin as the neuro-
transmitter responsible (Br J Psychiatry,
1967; 13: 123764).
But this acceptance has far more
to do with aggressive marketing by
the drug companies, who sell their
SSRIs on the basis of the theory, than
research from neuroscientists, who
have triedunsuccessfullyfor 40
years to come up with conclusive evi-
dence to support the theory.
Researchers who analyzed the
cerebrospinal fluid of clinically
depressed and suicidal patients
couldnt find any differences in their
serotonin levels compared with
healthy controls. Even participants
in medical trials whose levels of
serotonin were deliberately lowered
failed to become depressed (Pharmaco-
psychiatry, 1996; 29: 211). Similarly,
depressed people who were given
huge increases of serotonin failed to
witness any improvements in their
condition (Arch Gen Psychiatry, 1975; 32:
2230).
Not only has neuroscience been
unable to prove the theory in
independent studies, it has found
plenty of evidence to suggest that
depression and other mental
disorders are the result of far more
complex factors than a simple
neurotransmitter deficiency.
The lack of substantiating evi-
dence isnt helped by the fact that
no one knows what an ideal serotonin
level is supposed to look like, let
alone the profile of a pathological
imbalance.
There is not a single peer-
reviewed article that can be
accurately cited to directly support
claims of serotonin deficiency in any
mental disorder, says Jeffrey
Lacasse, a PhD candidate from
Florida State University and co-
author (with neuroanatomy professor
Dr Jonathan Leo of Lake Erie College
of Osteopathic Medicine) of the essay
Serotonin and Depression: A
Disconnect Between the Advertise-
ments and the Scientific Literature

WDDTY Dangerous drugs 11

Drugs for depression
(PLoS Med, 2005; 12: 12116).
The psychiatric bible, The Diag-
nostic and Statistical Manual of
Mental Disorders (DSM-IV; published
by the American Psychiatric Associa-
tion), lists the definitions of all psy-
chiatric diagnoses, and does not list
serotonin as a cause of any mental
disorder. However, the Textbook of
Clinical Psychiatry, 4th edn (Hales
RE, Yudofsky SC, eds. Washington,
DC: American Psychiatric Publish-
ing, 2003) does describe serotonin
deficiency as an unconfirmed
hypothesis, adding: Additional
experience has not confirmed the
monoamine depletion hypothesis.
The SSRI explosion
Nevertheless, and despite the lack of
evidence, SSRI drug sales increased
by 353 per cent between 1981 and
2000 (Ann Pharmacother, 2002; 36: 1375
9). Indeed, its even anticipated that
SSRI sales will peak in 2010 with
global revenues of $14.6bn, and
Japan is expected to be a major
market for growth over the next
couple of years, with sales there
anticipated to increase by 52 per
cent (Datamonitor; at www.marketresearch.
com/search/results.asp?sid=92042647-
406931770-490552493&query=ssri+future+
use+Japan&vendorid=72&publisher=Datam
onitor&cmdSubmitLt=Go).
The first blockbuster SSRI, Prozac
(fluoxetine hydrochloride), was
launched in 1986, and is the most
widely prescribed antidepressant
medication in history, according to
its manufacturer, Eli Lilly. Another
SSRI, Pfizers Zoloft (sertraline), was
the 10th best-selling drug in the
world in 2003, with sales of $3.4bn.
Before the SSRIs were developed,
only 100 people per one million
population were diagnosed as being
depressed; today, this figure now
stands at 100,000 people per million
population (Healy D. Let Them Eat Prozac.
New York: NYU Press, 2006).
The depressionserotonin hypoth-
esis has been actively promoted by
drug companies in advertisements
to both doctors and the general
public, and in seminars to health
professionalsand so successfully
that it has been widely accepted as
a physiological fact. In the US, where
drug companies are permitted to
market directly to consumers,
12 WDDTY Dangerous drugs
What can cause depression?
Depression is a chronic and debilitating condition that goes far beyond feeling
down or having the blues. While doctors recognize that it can take various
formssuch as moderate or severe, or clinicalthey dont know precisely
why some people become depressed, other than accepting that it can be
due to a complex mix of causes. However, the one thing that is known with
certainty is that the oft-repeated theory of a chemical imbalance is simplistic and
not supported by any scientific evidence.
While patients help groups often point to obvious causes of depression such
as death in the family, job loss or chronic illness, WDDTYs scouring through the
literature has uncovered many other, often unsuspected, causes.
u Hypothyroidism. Around one in five cases of chronic depression are
believed to be due to the body producing too little thyroid hormone. One
study found that women with even just mildly decreased thyroid function had
three times the rate of depression compared with the average (Ann Rev Med,
1995; 30: 3746). To check if your thyroid gland is underperforming, place a
thermometer under your armpit for 10 minutes immediately upon waking in
the morning. Any temperature below the normal range of 97.898.2 degrees
F (36.637 degrees C) may be indicative of an underactive thyroid.
u Low blood sugar. This conditionwhich has the medical name of reactive
hypoglycaemiais a recognized cause of depression. It can occur after
compulsive snacking on sweet or starchy foods and, once these foods and
carbohydrates are removed from your diet, the depression may well lift.
u Irritable bowel disease. Gastrointestinal problems are a major cause of
irritability and depression. One-third of all sufferers of Crohns disease
complain of headache, eye problems and depression (South Med J, 1997; 90:
60610).
u Coeliac disease. Depression is associated with this gastrointestinal
condition, where the inner lining of the small intestine is damaged by eating
wheat, rye, oats and barley.
u Allergies. One study found that a third of all depressed people also suffer
from some sort of allergy such as to certain foods, or hayfever or bronchial
asthma (J Affect Disord, 1981; 3: 2916).
Pfizers TV advertising for Zoloft has since 1997. In fact, the Irish Medical
claimed that depression may be due Board has banned GlaxoSmithKline
to a chemical imbalance, and that from claiming in its patient
Zoloft works to correct this information that Paxil corrects a
imbalance. In the support literature chemical imbalance. Nevertheless,
for its SSRI, Pfizer states that the company continues to make the
scientists believe that it (depress- claim on its website and in other
ion) could be linked with an im- countries.
balance of a chemical in the brain However, despite these occasional
called serotonin. slaps across the wrist, manufacturers
SmithKline Beecham, the manu- are generally allowed to continue
facturer in the US of the SSRI Paxil promoting the hypothesis.
(paroxetine), has this to say on its
website: Scientific evidence sug- The SSRIs dont work
gests that depression and certain Not surprisingly for drugs based on a
anxiety disorders may be caused by false hypothesis, they arent effective.
a chemical imbalance in the brain. In a recent meta-analysis of 74 trials
Paxil helps balance your brains involving 12 antidepressants that
chemistry. had been logged with the FDA,
The idea is repeated constantly by researchers from the Oregon Health
SSRI manufacturers, even though the and Science University discovered
US drugs regulatory body, the Food that the manufacturers either tried
and Drug Administration (FDA), has to hide the fact or put a positive spin
sent out 10 warning letters to them on any results that suggested that
their drug was not helpful.
As for 22 studies that had negative
results, the researchers found that
none of them had been published,
while a further 11 reported positive
conclusions that were not backed
up by the research findings. Of the
published trials, 94 per cent were
positive, suggesting that the drug
was considerably better than a
placebo in treating depression. Yet,
the FDAs analyses of the same trials
concluded that only 51 per cent
presented positive findings (N Engl J
Med, 2008; 358: 25260).
In a separate analysis of clinical
trials involving SSRIs submitted to
the FDA, researchers discovered that
a placebo, or sugar pill, replicated up
to 80 per cent of the benefits of the
so-called active agent, and that 57
per cent of all trials, published and
unpublished, failed to demonstrate
any statistically significant
differences between the drug and a
placebo (Prev Treat, 2002; 5: article 23;
online at http://content.apa.org/journals/
pre/5/1/23).
Other drugs and remedies for
depression appear to work just as
well asif not better thanan SSRI
drug, which serves to further
challenge the depressionserotonin
hypothesis. A Cochrane review of
various antidepressants found that
there was no major difference in
effectiveness between SSRIs and
tricyclics, an older class of anti-
depressants that was developed in
the 1950s (Cochrane Database Syst Rev,
2000; 3: CD002791).
In randomized trials, bupropion
(Wellbutrin; Zyban), an antidep-
ressant that is more commonly used
today as a stop-smoking drug, and
reboxetine (Edronax; Norebox) were
found to be equally as effective as
SSRIs for treating depression and,
yet, neither interferes with serotonin
levels (J Clin Psychiatry, 1997; 58: 5327; J
Clin Psychiatry, 2000; 61 [Suppl 10]: 318).
The herbal remedy St Johns wort
(Hypericum perforatum) was more
effective than an SSRI in one trial
involving patients with moderate-to-
severe depression (BMJ, 2005; 330: 503),
and the SSRI sertraline was even
bested by a placebo in another trial
involving patients who were severely
depressed (JAMA, 2002; 287: 180714).
Indeed, exercise was just as
Treating depression without drugs
There is a range of strategies that can be adopted to help to overcome
depression, depending on its severity, and they dont involve the use of
toxicor dubiousdrugs such as the SSRIs.
u St Johns wort (Hypericum perforatum). This herb, dubbed Natures
Prozac, is a proven remedy for mild-to-moderate depression, although it
has also proved effective in more severe cases. In Germany, it has become
the standard treatment for depression, and is even preferred over
antidepressant drugs. Numerous studies have shown that the herb works.
One found that 300 mg three times a day cured 75 per cent of depressed
people (J Geriat Psychol Neurol, 1994; 71: 124). Doctors in the UK and Ireland
have been opposed to the herb only because it can interfere with
prescription drugs.
u Diet. Oily fish can ease depression. Tryptophan-rich foods, such as turkey,
salmon and dairy, may also help, as may foods rich in vitamin B6, including
soy-beans, lentils, meat, poultry, fish, fruit and brown rice. Make sure that
you consume plenty of mono- or poly-unsaturated fats, and cut out caffeine
and refined sugar, and eat only dark chocolate.
u Nutrition. The B-complex vitamins, including B12 and folic acid, can help
with depression, as can calcium, zinc and the omega-3 essential fatty
acids.
u Thought Field Therapy. The TFT technique involves finger tapping on
specific acupuncture points around the body at the same time that the
patient is generating a negative thought or emotion. The tapping is
supposed to release the trapped emotion. However dubious it may sound,
the therapy has been tested in several trials, and the early results are
promising.
u Cognitive behavioural therapy. This form of talking therapy, which is
based on the idea that how we think, act and feel all interact with each
other, is one of the most successful ways to treat mild-to-moderate
depression. Its as effective as SSRI drugs, but without the dangerous side-
effects (BMJ, 2006; 332: 10302).
u Exercise. Exercise can be surprisingly effective in combating depression.
Even moderate exercise, which involves just walking briskly or jogging for
40 minutes, three or four times a week, can help. Those who already
exercise regularly are less likely to become depressed. One study found
that moderate exercise was as effective as the powerful SSRI sertraline
(Zoloft) (Arch Intern Med,
effective a remedy against depression The risk was thought to be
when pitted against Zoloft in a greatest among adolescents and
randomized trial of older patients teenagers, but the FDA has admitted
with severe depression (Arch Intern Med, that anyone who takes an SSRI is at
1999; 159: 234956). greater risk of committing suicide.
At an FDA drugs advisory com-
SSRI dangers mittee meeting held in December,
The FDA has issued more public 2006, psychiatrist Dr David Healy
warnings and black-box notices told the members: The idea that you
prominent announcements in the would have a risk in one age group
drugs literature and patient infor- but not in another is just wrong.
mation sheetsregarding the Another psychiatrist, Dr Peter
dangers of SSRIs than for almost Breggin, also testified, and said:
any other family of drugs. Although Americas drug watchdog needs to
the drugs come with a vast array of come clean because its been approv-
adverse reactions, drugs regulators ing depressants as antidepressants.
are especially concerned over the The primary data on suicidality has
SSRI potential to increase the risk been generated in short-term
of suicide. controlled clinical trials planned by
WDDTY Dangerous drugs 13
Drugs for depression
drug companies, carried out by drug
company hacks, and evaluated by
drug company employees at cor-
porate headquarters. If that kind of
carefully cultivated evaluation bears
such bad fruit, imagine what the real
data must show.
Despite these very real dangers,
doctors continue to prescribe SSRIs
to children. In one study, researchers
discovered that children as young as
six years of age were being prescribed
an SSRI, and they were 52 per cent
more likely to commit suicide within
the following two months. Overall, a
child on an SSRI was 15 times more
likely to kill himself than one not
taking such a drug (Arch Gen Psychiatry,
2006; 63: 86572).
In addition to the suicide risk,
SSRIs have been linked to a wide
range of other adverse reactions.
Prozac alone has 242 different side-
effects listed, including 34 problems
of the genitourinary tract. In one
review of drug reactions, it was found
that during a 10-year period, Prozac
was associated with more hospital-
izations, deaths or other serious
adverse effects reported to the FDA
than any other drug in America
(Moore T. Prescription for Disaster. New York:
Dell Publishing, 1998).
The most common problems seen
with SSRIs are neurological (22 per
cent), psychiatric (19.5 per cent),
gastrointestinal (18 per cent) and
dermatological (11.4 per cent) (Drug
Safety, 1999; 20: 27787).
14 WDDTY Dangerous drugs
Every SSRI manufacturer has
active lawsuits pending. Forest Lab-
oratories, which makes Lexapro
(escitalopram oxalate) and Celexa
(citalopram), has been involved in at
least 25 lawsuits recently, says US law
firm Pogust & Braslow, and most of
these involve cases of unexplained
suicide or attempted suicide.
Off-label prescribing
One major cause of the enormous
success of the SSRIs has been off-
label prescribing by doctorswhere
they prescribe drugs either to people,
such as the very young or very old,
for whom no safety trials have ever
been undertaken, or for problems for
which the drug has never been
intended.
Although the SSRIs are labelled as
antidepressants, the FDA has allowed
their use as remedies for eight other
psychiatric disorders, including
social anxiety disorder, obsessive
compulsive disorder (OCD) and pre-
menstrual dysphoric disorder (a
severe form of PMS).
Despite such a loose definition of
an antidepressant, one study found
that 75 per cent of all prescriptions
for SSRIs were off-label, as treat-
ments for conditions for which the
drugs have not been approved
(J Clin Psychiatry, 2006; 67: 97282). Lead
author Dr Hua Chen, from the
University of Houston, said that the
findings reveal a significant gap in
the US drugs-safety system.
Over the years, SSRIs have been
prescribed for pain, insomnia,
shyness, menstrual discomfort,
dementia and restless leg syndrome,
and to every age group, including
young children, and even to preg-
nant women, despite evidence that
these drugs are harmful to an
expectant mother as well as to her
fetus (N Engl J Med, 1996; 335: 10105).
While its not illegal for a doctor
to prescribe a drug off-label, it is not
allowed for drug companies to
promote a drug for such unapproved
uses, although it is known to be a
widespread practice and one that has
been the subject of a US House
Committee hearing.
Mind over matter
The SSRIs are some of the most
dangerous drugs ever developed and,
yet, they are probably the least
effective. Based on an hypothesis
that stubbornly remains unproven,
these agents usually fare little better
than placebo, which suggests that
any benefit while taking them is very
likely being generated by the patient
himself.
Depression can be debilitating,
but it can be resolved without the use
of these powerful, yet ineffect-ive,
drugs. It may be that the most
important contribution of SSRIs has
been to our understanding of the
power and importance of our own
minds in bringing about health.
Bryan Hubbard
The great Prozac conspiracy
After 20 years of these so-called miracle antidepressants,
psychiatrists are shocked to discover that drug
companies withheld information about the risks of this
class of drugsand with the tacit approval of the drug
regulators.
t all started so promisingly, when
I drugs like Prozac first came on
the market in the 1980s. Here at
last, we were told, was a new class
of antidepressants that would
transform the world of psychiatry.
Out would go the old dirty
psychiatric drugs of the 1950s, and in
would come a set of drugs honed by
science to target the biochemical core
of depression in the brain.
These new drugs had a very
scientific-sounding nameselective
serotonin reuptake inhibitorswhich
neatly morphed into the catchy
acronym SSRIs. They are among the
most successfully marketed drugs in
history, so much so that the brand
leader Prozac is almost a synonym for
antidepressants, just like Hoover is for
vacuum cleaners.
But now, some two decades later,
the world of psychiatry has finally
discovered it has been largely taken for
a ride with SSRIs, by both drug
companies and lax regulators.
Miracle science
In the brain, messages are passed
between brain cells (neurones) across
a tiny gap called a synapse. This gap
is filled with chemicals, which have
the job of controlling the communica-
tion between brain cells, transmitting
information from one neurone to the
other. Hence, these chemicals are
called neurotransmitters. When one
neurone communicates with its
neighbour, it floods the synapse with
a cocktail of neurotransmitters, one
of which is serotonin.
By the 1970s, it had been dis-
covered that some prescription drugs
can cause depression as a side-effect, a
problem traced to low brain levels of
serotonin. It was then argued that, if a
way could be found to increase
serotonin in the brain, it would reduce
depression.
Its already known that the brain
naturally conserves neurotransmitters
by allowing the transmitting cell to
reabsorb them from the synapse (a
process that is called reuptake). So, if
a way can be found to stop (or inhibit)
this reuptake, the synapse would
remain constantly bathed in neuro-
transmitters. But only one neurotrans-
mitterserotoninis involved in
depression, which means that only
serotonin needs to be selectively
isolated from the rest of the neuro-
transmitter cocktail.
So, in the mid-1970s, the pharma-
ceutical companies set themselves the
task of finding a drug that would select
out serotonin, and inhibit its
reabsorption by the transmitting
neurones. Ten years later, the family of
SSRIs was created.
The first SSRI appeared in the mid-
1980s from the Swedish pharma
company Astra. The drugs chemical
name was zimelidine, but it was
Safety and side-effects
In addition to suicide risk, SSRI side-
effects include:
Insomnia (up to 35 per cent of patients
need sleeping pills)
Sexual dysfunction (anorgasmia in up
to 83 per cent of men; this may
be permanent, even after the drug
is withdrawn. In bizarre contrast,
SSRIs can also cause yawning-
excitement syndrome, where pa-
tients experience sexual arousal
Other effects
Nausea Weight gain
Vomiting Lethargy
Diarrhoea Fatigue
Gastrointestinal bleeding Sweating
Headache Anorexia
Agitation Forgetfulness
Nervousness Seizures
Rash Anxiety
quickly withdrawn from the market
when patients developed Guillain
Barr syndrome (a serious auto-
immune condition involving damage
to the peripheral nerves). Soon after-
wards, a second SSRI, a French drug
called indalpine, was also stopped after
it was found to damage blood cells.
These straws in the wind didnt
deter other drug companies, however
although the SSRIs hoped-for lack
of side-effects had been intended to
be a major part of their sales pitch.
when they yawn, often progressing
to orgasm)
Akathisia, described by an SSRI
spokesman as overwhelming dis-
tress and unbearable discomfort,
making patients feel like death is
a welcome result. It can some-
times be mistaken for worsening
depression, prompting some doc-
tors to increase the dosage (J
Psychopharmacol, 1998; 12: 192214).
Mania
Dizziness
Problems in
urinating
Trembling or shaking
Dry mouth
Hostility
Aggression
WDDTY Dangerous drugs 15
Drugs for depression
The first SSRI to come to market
was fluvoxamine (see box, right),
but its manufacturer Solvay Pharma-
ceutical, based in Georgia, lacked
marketing clout, making its launch a
bit of a damp squib.
It took the marketing power
wielded by the giant US (and
international) drug company Eli Lilly
to collar most of the SSRI public
relations when it launched fluoxetine
in 1987, under the memorable trade-
name Prozac. Newspapers were quick
to swallow the companys sales pitch,
with headlines describing Prozac as a
happiness pill. Even normally cynical
journalists described Prozac as a
valuable, quick, emotional fix, and a
panacea for the stresses of the 20th
century.
But the marketing dream soon
turned into a PR nightmare as patients
began to complain of unpleasant side-
effects such as nausea, sexual dys-
function, insomnia and gastrointes-
tinal bleeding. Worse, Prozac some-
times caused violent, irrational
behaviour. In one infamous case, a
middle-aged factory worker became
homicidal while taking Prozac, killing
five people and wounding 12 others at
his workplace.
In another example of horrific
behaviour as a result of taking this
drug, a female patient attacked her
mother by biting her so viciously that
she managed to rip away 20 chunks of
her mothers flesh. Eli Lilly was
ordered to pay substantial damages.
After SmithKline Beecham (now
GlaxoSmithKline or GSK) weighed in
with their own SSRI, Seroxat (parox-
etine), similar side-effects were seen
with their drug, too. Even doctors
began to express some concerns.
Physicians are seeing long-term side-
effects from SSRIs far in excess of
what was expected from the clinical
trial data, Dr Norman Sussman, a
psychiatrist at New York University
Medical Hospital, told the press in
1998 (Clin Psychiatr News, 1998; 26: 1).
Within a few years, Seroxat was
following Prozac into the courts. In
June 2001, GSK was ordered to pay
$6.4m to the family of Donald Schell,
who, after just two days on Seroxat,
killed his wife, daughter, grand-
daughter, and finally himself. Although
GSK tried to claim that the drug
wasnt to blame, the British expert
16 WDDTY Dangerous drugs
Patently profitable
Generic (trade) names Manufacturer Patent expiry date
citalopram Lundbeck 2002
(Celexa, Cipramil, Emocal,
Sepram)
fluoxetine Eli Lilly 2000
(Prozac, Fontex, Seromex,
Seronil, Sarafem, Fluctin)
fluvoxamine maleate Solvay 1996
(Luvox, Faverin)
paroxetine GlaxoSmithKline 2006
(Paxil, Seroxat, Aropax,
Deroxat)
sertraline Pfizer 2005
(Zoloft, Lustral, Serlain)
witness Dr David Healy, of Bangor every antidepressant licensed since
University in North Wales, told the 1987 [showed] an excess of suicides.
court he had uncovered early Smith- The companies, he said, had
Kline Beecham documents which obscured the suicide evidence by
acknowledged that serious symptoms fudging the data, a practice
of agitation could occur after taking euphemistically referred to as
the drug for just a few days. recoding.
When Healy challenged Pfizer
Whistleblower (which makes sertraline, marketed as
Dr Healy, now a professor of psychia- Zoloft) and GSK with his bombshell
try at the North Wales Department of discovery, they didnt deny that
Psychological Medicine, has recently recoding had occurred, but noted that
been in the news again, after the FDA [Food and Drug Adminis-
publishing an article in the scientific tration, the US watchdog regulatory
literature accusing drug companies body] has neither criticised these data
and their official regulators of dirty or the report as inappropriate, nor
tricks (BMJ, 2006; 333: 925). required additional analyses.
The target of his concern was the However, documents obtained
fact that the drugs cause some people under the Freedom of Information Act
to commit suicide: indeed, these reveal that FDA regulators were fully
highly sophisticated drugs apparently aware of the recoding but, says Healy,
can precipitate the fatal behaviour told the pharma industry that they did
that psychiatrists spend their lives not see the SSRIsuicide connection
trying to prevent. as a real issue, but rather as a public
The first warnings of this effect relations problem.
were sounded as early as 1991, when And yet, no fewer than four clinical
researchers looked at the placebo- studies published between 1990 and
controlled clinical evidence for 2000 have shown SSRIs to cause an
fluoxetine, and discovered a spike of increased risk of suicidality,
suicides (BMJ, 1991; 303: 68592). culminating in a British report
Drug companies glossed over such entitled Deliberate Self-Harm and
findings, and even complained that Antidepressant Drugs. This was a
placebo-controlled trials were survey of the Accident & Emergency
unethical, as SSRIs were self-evidently case notes from one UK hospital area
both effective and safe. However, as that revealed a five-and-a-half times
Professor Healy revealed in his British extra risk of suicides among people
Medical Journal article, he obtained taking SSRIs (Br J Psychiatry, 2000; 177:
access to some of the original drug- 5516).
company data, which gave the lie to
their official PR line. He was able to Slow-acting regulator
confirm that, in the evidence Healy showed that there has been
presented to the licensing authorities, collusion between the authorities and
the drug companies in putting as good the suicide problem. His own analysis aged two to 19 tripled in just the 10
a gloss on the data as possible. shows that the latest data for years from 1988 to 1998from 40
For example, the FDA had a back- paroxetine indicates as much as a million prescriptions to 120 million
door agreement with Pfizer that the fivefold increase in suicide risk, a after the introduction of fluoxetine
sertraline suicide data should be statistic consistent with previous (Pediatrics, 2002; 109: 7217).
analysed as if it were a constant findings. Equally surprisingly, very few SSRIs
hazard, even though they knew the Another area of concern is children. have actually been formally licensed
evidence clearly shows that suicides Astonishingly, SSRIs have been given for use by children, so all of this
peak in the first few weeks of use. to kids as young as two years old, and prescribing to them has been off-
This averaging-out is outright the figure is rising exponentially for label. This term is used to describe
manipulation of data, says Healy, older children, too. For example, when doctors prescribe drugs that
because it disguises the true extent of sertraline prescriptions for youngsters have been officially approved for one
purpose to treat other, unauthorized
conditions.
In fact, few drugs are ever tested
What to do instead on children. The reasoning behind this
practice is that children are simply
Allergies, food intolerance and nutritional deficiency all cause depression. So, first little adults, so the hazard profile of
ensure that you are receiving the nutrients you need by taking the following a drug may safely be applied to them
nutritional supplements: so long as the appropriate reductions
u good vitamin B-complex, one which contains 50 mcg of B12 and biotin, 400 in dosage have been made to
mcg of folic acid and 50 mg of all other B vitamins accomodate their smaller size.
u Vitamin C, 500 mg twice a day But this is not necessarily true. For
u Calcium, 500 mg/day and magnesium, 200 mg/day (both necessary for nerve example, Ritalinthe infamous hyper-
function). One recent study showed rapid recovery (less than seven days) activity drugappears to act as a
from major depression with magnesium supplements (Med Hypotheses, 2006; 67: depressant in children, but is a
36270) stimulant when taken by adults.
u 5-HTP (plant-based tryptophan), 200 mg/day. When compared with So we know that children can react
fluvoxamine, for example, 5-HTP is at least 10 per cent better at reducing totally differently from adults, partic-
depression, anxiety, insomnia and physical symptomsand works faster, too ularly when mood-altering drugs are
(Psychopathology, 1991; 24: 5381) concerned.
u Zinc, 15 mg/day Indeed, in the case of SSRIs, it was
u Omega-3 essential fatty acids (EFAs; for example, cod liver oil)) 2 g/day, or largely childrens violently self-
EPA (eicosapentaenoic acid) 1 g/day. In one study, taking EFAs for just 12 harming reactions to the drugs that
weeks reduced depression by half in patients for whom all conventional drugs alerted psychiatrists to the suicide
had failed (Arch Gen Psychiatry, 2002; 59: 9139) problem in the first place.
u St Johns wort, 300 mg three times a day. A meta-analysis of 23 studies In 1991, Yale University doctors
showed this herb to work in mild-to-moderate depression, and to be just as reported the case notes of six children,
effective as the standard drug treatments, but with fewer adverse side-effects aged 10 to 17, who developed intense
(BMJ, 1996; 313: 2538). Check that the tablets contain a standardized content self-injurious ideation or behaviour
of 0.3 per cent hypericin (the major active ingredient in St Johns wort), as well while taking Prozac. For example, after
as 5 per cent hyperforin, recently discovered to be another key natural three weeks on the drug, one 14-year-
ingredient (Pharmacopsychiatry, 1998; 31 Suppl 1: 549). Choose solid tablets as old girl, who had never been suicidal
they have a much longer shelf-life than capsules. before, began cutting and otherwise
Other alternative treatments include: injuring herself. She told hospital staff,
u Exercise. Get your body moving. A German study showed that 30 minutes Im just waiting for the opportunity
of treadmill exercise a day helped reduce major depressive episodes in to kill myself, and chanted, Kill, kill,
100 per cent of patients, of whom more than half experienced substantial kill; die, die die; pain, pain, pain (J Am
improvement. The benefit was particularly marked in people for whom Acad Child Adolesc Psychiatry, 1991; 30:
antidepressant drugs had failed (Br J Sports Med, 2001; 35: 1147) 17986).
u Acupuncture. A recent Chinese study compared acupuncture head-to-head Another study carried out 10 years
with Prozac. Acupuncture was found to be superior as it worked much faster, later again found that SSRIs increased
and the only side-effect was mild fatigue (J Tradit Chin Med, 2005; 25: 2436) suicidal behaviour in children (J Am Acad
u Thought Field Therapy (fingertapping on acupuncture points). TFT has been Child Adolesc Psychiatry, 2001; 40: 13645).
found to cut symptoms of emotional distress by 50 per cent (Traumatology, 1999; And yet, it wasnt until 2003 that
5: 1, article 4) the British Medicines and Healthcare
u Light therapy. Choose a light box with an output of at least 10,000 lux, and use Products Regulatory Agency (MHRA)
it for 30 minutes between 7am and 9am. A recent clinical trial pitted light finally recommended that SSRIs not
therapy against Prozac, and found that the drug worked no better be given to childrenand this only
(Am J Psychiatry, 2006; 163: 80512). after being shamed into action by
media reports of teen suicides caused

WDDTY Dangerous drugs 17

Drugs for depression
by Seroxat.
Why did they take so long?
According to Healy, there were two
main reasons: a lack of statistical
expertise on the part of the MHRA
(and the FDA, too); and a mindset
which overstates the benefits and
underestimates the risk of drugs.
As a result, both the British and
the American regulatory bodies, he
says, insist on such cast-iron statistical
proof of harmful effects that they
demand an all but unreachable
threshold.
The crowning irony of this official
intransigence came in May of this year,
when GlaxoSmithKline themselves
sent a letter to doctors, warning them
that paroxetine could cause a sixfold
increase in the risk of suicidesa
figure that neither the FDA nor the
MHRA has so far acknowledged.
Many people expect drug com-
panies to be slow to concede that a
drug causes hazards, commented
Healy dryly, but we do not expect
our regulators to be even slower.
Major side-effects
Excess suicides are just the beginning.
There are also major issues of side-
effects and efficacy. After 20 years of
experience with SSRIs, it now turns
out that these super-sophisticated
drugs that were once hoped to be
relatively free of side-effects are, in
fact, potentially more dangerous than
the crude tricyclic antidepressants
(TCAs) of the 1950s they were meant
to surpass (see box, page 15).
But the SSRI scandal stretches even
beyond that. The only reason SSRIs
were allowed onto the market in the
first place was that the drug com-
panies claimed they were far superior
to the existing TCAs. In the heady days
of the 1980s, figures of 80 per cent
effectiveness were confidently bandied
aboutthis was three times better
than with TCAs, said SSRI manu-
18 WDDTY Dangerous drugs
facturers.
But those claims have since turned
out to be highly optimistic. Study after
study has shown that SSRIs are
actually little better than the TCAs.
Recently, researchers have pulled
together 15 to 20 years worth of
statistics, including previously sup-
pressed data amassed by the drug
companies themselves, as a sort of
final overall verdict on the SSRI
experience.
These huge clinical meta-analyses
have looked at SSRI use by a variety of
patient groups. Here, for example, are
direct quotes from what researchers
have found in three different types of
patients:
u people with mild depression: . . .
no differences between TCAs and
SSRIs (Cochrane Database Syst Rev,
2000; 4: CD001130)
u depression in general: There are
no clinically significant differences
in effectiveness between SSRIs and
TCAs (Cochrane Database Syst Rev,
2000; 2: CD001851)
u The elderly: . . . SSRIs and TCAs
are of the same efficacy (Cochrane
Database Syst Rev, 2006; 1: CD003491).
So the truth is finally revealed: SSRIs
have never worked any better than the
drugs they were intended to replace.
The anger in response to this
revelation among the psychiatric
profession is now palpable. Even
normally conservative medical jour-
nals have spoken out against the
drugs. An article in a major psychiatric
journal recently concluded that drug-
company-sponsored research is no
longer reliable: Caution is needed in
interpreting drug company sponsored
trials given the evidence of selective
reporting and publication bias (Curr
Opin Psychiatry, 2005; 18: 215).
Similarly, another peer-reviewed
journal revealed that, if the true data
for these drugs had not been
suppressed, it would have served as
evidence that they dont work:
We learned that pharmaceutical
companies selectively released data
that reflected positively on their
products, and that combining sup-
pressed and published data suggested
that most of these medications had
questionable efficacy (J Clin Psychol,
2006; 62: 23541).
Any residual confidence in the
SSRIs is now likely to be permanently
eroded. However, most of the large
pharmaceutical companies that
produced the SSRIs will not receive
any negative fallout on their share
prices. After all, most of the SSRI
patents have now expired (see box,
page 16). So, it would seem that the
drug giants have already made
whatever money they can and can now
do a runnera kind of smash-and-
grab raid on the world of psychiatry.
Nevertheless, their future share in
this lucrative market may be
damaged. Pharma-industry analysts
warn that the world antidepressants
market is in serious trouble, with
revenues of only $7 billion a year
50 per cent down from their peak (The
World Market for Antidepressants, 2006).
They also predict that the world
market will crash, mainly because
there are not enough new anti-
depressants in the pipeline.
That may indeed be so, but the
market may also crash for at least
three other reasons, too. The trust
that may have existed between
psychiatrists and their patients and
the pharmaceutical companies is
likely to be permanently tarnished.
With this whole sorry episode, the
biochemical model of depression
and biochemical manipulation as a
solutionis now in question. The
result is that patients may be more
willing to turn to the many safe,
natural antidepressants that are
available to them.
Tony Edwards
SSRIs: bad prescribing habits
ust when it seemed as if it
J
couldnt get any worse for
manufacturers of antidep-
ressants like Prozac, new
evidence reveals that they havent been
correctly prescribed since their release
on the market.
Thousands of patients are being put
at risk of life-threatening side-effects,
including an increased risk of acts of
self-harm such as suicide, because they
are being given the drug beyond the
point where it will do any good.
New evidence shows that, if the
drugs are going to have any benefit
at all, it will happen within the first
two weeks of taking the drug. Conse-
quently, many patients are being put
at risk of lethal side-effects because
the drug companies and doctors are
recommending that the drugs be taken
for at least six weeks, if not longer.
The conventional wisdom about the
new antidepressants holds that it takes
a little time for them to work.
According to recent guidelines issued
by Britains National Institute for
Health and Clinical Excellence (NICE),
. . . patients started on antidepress-
ants should be informed about the
delay in onset of effect.
This was certainly the clinical and
laboratory experience with the older
tricyclic antidepressants. The drug
companies and scientists believed that
this early generation of drugs worked
quickly until the research proved
otherwise. Animal models showed that
the drugs only worked once the ani-
mals (and, it was assumed, human
patients) had developed an insensitivity
in certain brain receptors.
A review of all of the studies in the
scientific literature also confirmed a
delay in the time it took the drugs to
start kicking in (Arch Gen Psychiatry, 1984;
41: 7826). In addition, many of the
sophisticated theories concerning how
selective serotonin reuptake inhibitors
(SSRIs) worked all stressed this delay
in onset.
Then, when the SSRIs were first
launched, psychiatrists and researchers
simply assumed the same delay would
occur. The assumption of a lengthy
time between the start of treatment
and any actual effect underpinned the
prescribing habits of doctors for all
the years the SSRIs have been on the
market.
However, after many years, the
science has begun to challenge this
basic assumption. A 2005 review of
76 double-blind, placebo-controlled
studies of antidepressants discovered
that nearly two-thirds of the improve-
ment seen in patients took place within
the first two weeks. Half of all patients
who responded to the drug within a
six-week period did so during the first
fortnight (Am J Psychiatry, 2000; 157:1423-
8).
Then, a review of the major placebo-
controlled studies of SSRIs cast even
more light on the timing of therapeu-
tic benefit. This meta-analysis showed
that the greatest period of therapeutic
response occurs within the first week
and that benefit declines with every
week thereafter. In fact, one-third of
the full effect of treatment is apparent
Signs of SSRI-induced suicidal impulses
The following symptoms have all been reported by both adult and paediatric
patients taking antidepressants. Although a causal link between these side-
effects and suicidal impulses has not yet been established, the FDA is
concerned that they may be precursors to a drug-induced desire to kill
oneself.
v Anxiety
v Agitation
v Panic attacks
v Insomnia
v Irritability
v Hostility
in that first week (Arch
Gen Psychiatry,
2006; 63: 121723).
This result jibes with the new
neuroscience about the brain, which
has found that the longer depressive
thoughts remain unchanged in the
brain, the more likely they are to
become hardwired in and the less
likely is the person to respond to
conventional treatment.
So worrying is this new finding that
the US drugs watchdog, the Food and
Drug Administration (FDA), has now
issued a blanket mandate, instructing
all manufacturers of SSRIs to update
their black-box warnings. The new
labelling must now include the warn-
ing that young adults aged from 18
to 24 taking these drugs may increase
their risk of suicidal thinking and
behaviour, even during initial treat-
mentthe first month or two. Manu-
facturers of all SSRIs are being given
just 30 days to submit revised product
labels and medication guides to the
FDA for review.
The new labelling follows quickly
on the heels of the 2005 black-box
warnings issued by the FDA, which
warned of the increased risk of suicide
among children and adolescents. At
that point, the FDA asked that
manufacturers include in the warning
that all children and teenagers be
closely observed and monitored while
taking the drugs. Furthermore, SSRI
drug companies were asked to develop
medication guidesFDA-approved in-
formation packs for patients and their
families to be handed out with each
new prescription or refill. These guides
were designed to be user-friendly and
v Aggressiveness
v Impulsivity
v Akathisia
(psychomotor restlessness)
v Hypomania
v Mania.
WDDTY Dangerous drugs 19
Drugs for depression
easily comprehensible by non-medical
people, and to improve monitoring of
symptoms.
However, after this latest bombshell,
the FDA itself decided to examine
whether adults also faced any similar
risks. The agency began its own review
of nearly 3000 antidepressant studies,
which included more than 77,000
adults taking SSRIs. At the end of last
year, the evidence was in. The studies
showed that there were five additional
suicides or suicidal impulses for every
1000 young adults studied. An earlier
study showed that the drug causes
20 WDDTY Dangerous drugs
14 additional cases of suicidal impulses
per 1000 in those under 18. The
FDAs Psychopharmacologic Drugs
Advisory Committee concluded that
new labelling changes were necessary
to inform healthcare professionals that
young adults, as well as teenagers and
children, also face suicide risk with
these antidepressants.
This new information about SSRIs
calls for a drastic revision of the use
of SSRIs. Patients should only be given
these drugs for, at most, two weeks.
Thereafter, doctors are needlessly
exposing their patients to an increased
risk of drug-induced self-inflicted
death.
The FDA is quick to add that the
scientific data to date does not show
an increased risk of suicide among
those aged over 24. Indeed, it appears
that adults over 65 taking antidepress-
ants decrease their risk of suicidea
benefit that will be highlighted in the
new black-box warnings.
One can only guess whether this last
bit of received wisdom will also be
undermined by evidence unearthed at
a later date.
Lynne McTaggart
SSRIs: Its not addiction,
its discontinuation syndrome
Call it what you will, but these drugs can still lead to
dependence and withdrawal symptoms
ollywood celeb Lindsay
H Lohans admission to
a Los Angeles court
last month that shes
addicted to antidepressants reopens
a controversy that the drugs industry
has tried to keep under wraps for 30
years.
After the hearing, Lohans father
Michael told journalists: These
drugs are killing my daughter and
killing millions of kids in America,
and someone has to stop it.
But, so far, no one has succeeded.
Not even a US Senate hearing in
2007 could force an admission from
SSRI makers that their drugs are
addictive.
The drugs industry has played a
damage-limitation game ever since
Eli Lillys first SSRI, Prozac
(fluoxetine), was approved in 1977. It
heralded a new family of drugs based
on the idea that depressed people are
low in sero-tonin, a brain chemical
that acts on the nervous systema
theory that has never been proven
(see box, page 22).
Whats in a name?
The first indications that SSRIs were
addictive appeared in 1992 for
fluvox-amine (Br J Psychiatry, 1992; 160:
2834), and opened the floodgates to
similar reports for paroxetine a year
later and, for sertraline, in 1994.
In a move to deflect concerns
about the SRRIs addictive qualities,
Eli Lilly coined the term
discontinuation syndrome in 1996,
a euphemism that started appearing
on packaged inserts in 2001.
The World Health Organization
(WHO) was not impressed. SSRIs
are an example of how a conceptual
confusion over terminology can
affect proper reporting, inter-
pretation and communication of
adverse drug reactions related to
dependence (www.who.int/medicine-
docs/en/d/Js4896e/ 9.html). In other
words, give the problem a different
name, and it will throw everyone off
the scent.
The depressing reality
Call it what you like, the reality
remains the same: SSRIs are highly
addictive. The independent Uppsala
Monitoring Centre database lists three
SSRIsfluoxetine, paroxetine and
sertralineamong the 30 highest-
ranking drugs for dependency (www.
who.int/medicinedocs/en/d/Js4896e/9.html). Of
these, paroxetine is cited as the most
addictive of them all (http://news.bbc.co.
uk/2/hi/health/1382551.stm).
Claims of paroxetines addictive
qualities have dogged its manufacturer
GlaxoSmithKline (GSK) from the time
of its launch in 1992. GSK has always
maintained that its SSRI is not habit-
forming and that, at worst, around 2
per cent of patients might suffer from
discontinuation syndrome. However,
secret company papers from 1997
showed that 62 per cent of patients
were addicted to the drug (Ann Neurol,
2008; 64: A79).
The US drugs monitoring agency,
the Food and Drug Administration
(FDA), issued a warning about the
drug in 2002 and, that same year, the
International Federation of Pharma-
ceutical Manufacturers Association
accused GSK of misleading the public
and of breaching two codes of practice.
Since 1992, around 5000 Americans
have sued GSK for downplaying the
drugs serious side-effects, while law-
suits citing similar issues have been
issued in the UK. In 2004, GSK settled
charges of consumer fraud by paying
out $2.5 million. Legal discovery
uncovered a deliberate and systematic
suppression of unfavourable studies
(Angell M. The Truth About the Drug Companies.
Random House: London, 2005).
Although drug companies maintain
that discontinuation syndrome is mild
and short-lived, the packaged inserts
admit that withdrawal reactions can be
intolerable, with symptoms such as
dizziness, electric-shock effects, sweat-
ing, nausea, insomnia, tremor, confu-
sion, nightmares and vertigo (BMJ, 2005;
331: 824). Sexual dysfunction, such as
loss of libido and impotence, is also
common (J Sex Med, 2008; 5: 22733).
But all this downplaying, aided and
abetted by psychiatrists, keeps drug
sales high, with global revenues in
2008 of $11 billion. Wyeths Effexor
(venlaxafine) leads the field with a 36-
per-cent share of the total market and
annual sales worth $3.93 billion (www.
wikinvest.com/concept/Antidepressant_Drug_
Market).
A major driver of salesat least in
the USis direct-to-consumer (DTC)
advertising. There, drug companies can
advertise prescription drugs directly to
the public. Also, as depression is often
subjective, many people can be con-
vinced that they have it. As a result,
$120 million of the $900 million spend
on DTC in 2005 was dedicated to anti-
depressants. In 2001 in the month
after the 9/11 attack on the World
Trade Center, GSK doubled its DTC
advertising spend on paroxetine (CNS
Drugs, 2009; 23: 10320).
Depression was once a serious
clinical condition suffered by a small
WDDTY Dangerous drugs 21
Drugs for depression
minority, but its now a lifestyle disease
that many of us have from time to
time, and SSRIs such as Prozac have
become our chemical friends.
Behind this is the assumption that
the drugs are safe and non-addictive.
Not so, says Dr David Healy, a leading
expert on antidepressants. He believes
that more than half of paroxetine users
are physically dependent on the drug
( http://news.bbc.co.uk/2/hi/health/1382551.
stm).
Safety is also an issue. GSK paid out
$6.4 million after a man murdered
three members of his family before
killing himself after taking paroxetine
for just two days. In Australia, a judge
ruled that sertraline had caused a man
to murder his wife and then attempt
his own suicide. Healy believes that one
in 1000 people taking paroxetine could
suffer from such suicidal thoughts.
Bryan Hubbard
22 WDDTY Dangerous drugs
The drugs dont work
If the theory of chemical imbalance is false, it follows that SSRIs wont ease
depression, at least not beyond the placebo effect.
In fact, an analysis of 74 SSRI studies bears this out. Researchers found
that one-third of such studies were never published because the results
were so poor. Around 94 per cent of the papers that were published had a
positive result. Yet, when researchers from the US Food and Drug
Administration (FDA) re-analyzed the findings, they found that the SSRI was
effective in only half of the studies. These studies had been paid for by the
manufacturer of the drug being tested (N Engl J Med, 2008; 358: 25260).
Drug companies have an overly simplistic view of depression, which
explains the overall ineffectiveness of SSRIs, say researchers from the
Northwestern University Feinberg School of Medicine. Eva Redei, a
professor of psychiatry at Northwestern, says that antidepressants are
based on two false claims: that a stressful life causes depression; and that
depression is caused by a chemical imbalance.
Redei believes that depression is in some way associated with the
development and functioning of neurons, and only when this is properly
understood can an effective antidepressant be developed (Presentation at the
39th Annual Society For Neuroscience Conference, October 1721, 2009, Chicago, IL).
Drugs for children
Kiddie killers
Many of the mainstays of modern medicine can damage children
n 12 October 2007, three of
O the worlds leading drug
companies voluntarily
withdrew a clutch of cold
and cough remedies for infants. This
announcement was made immediately
after a bombshell US Food and Drug
Administration (FDA) report showed
that everyday childrens medications
had caused over 120 deaths over the
last 37 years in the US alone. Most of
the victims were infants under the age
of two. In its defence, the drug industry
partly blamed parents for not reading
labels, thus inadvertently overdosing
their children.
At another extreme, parents have
not only been blamed, but sent to jail
because of drug side-effects (see box).
These two extremes are merely the
twin peaks of a huge iceberg. Doctors
have been warning us for years that
there are major problems concerning
childrens medications in general, a
situation that both the drugs industry
and regulators have largely ignored.
ADRs in children
In the last few years, a slew of medical
reports has revealed the damaging
effects of prescription drugs on
children. Paediatricians across the
globe have become aware that children
are at particularly high risk of so-called
adverse drug reactions (ADRs) from
relatively common medications.
Among the first whistleblowers were
British researchers from Nottingham
University who, six years ago, complet-
ed a major audit of the reasons given
for childrens hospital admissions. They
found that a staggering one in 50 hos-
pital admissions was because of ADRs,
and nearly 40 per cent of these were
life-threatening reactions. As ADRs
are often worse in children than in
adults, they constitute a significant
public health issue (Br J Clin Pharmacol,
2001; 52: 7783).
Its a similar story in other countries,
too. Three years ago, doctors did a six-
year audit of paediatric admissions in
Ohio hospitals. Again, a significant
percentage was found to be due to
ADRs, with antibiotics, anticonvulsants
and narcotics being the main offenders.
Ironically, to combat the ADRs, 73 per
cent of cases were treated with even
more drugs, according to the hospital
records (Drug Saf, 2004; 27: 81929).
Earlier this year, pharmaceutical
chemists at the University of British
Columbia, in Canada, audited toxic
reactions to drugs among their nations
children. Their four-year survey revealed
that 61 per cent of ADRs in children
were serious, with as many as 41
(out of 1193) children actually dying
as a result of drug side-effects. The
main culprits were isotretinoin (an
anti-acne preparation), paroxetine (an
antidepressant), methylphenidate (Rit-
alin, the hyperactivity drug), amoxy-
cillin (an antibiotic) and valproic acid
(an anticonvulsant used in epilepsy)
Whos the criminal?
u In November 1997, two-month-old Alan Yurko, born in a weakened state
after a difficult pregnancy, suddenly stopped breathing. His father rushed
the infant to a Florida hospital, where he died two days later. The hospital
accused the father of causing shaken baby syndrome (SBS); he was
subsequently convicted and sentenced to life imprisonment.
Appeals court lawyers asked Dr Al-Bayati to investigate, who says, The
hospital was at fault on two main counts: it failed to review the childs
medical notes, which showed a history of infections, and to take account of
the side-effects of the vaccines the baby had already received from the
family physician. Furthermore, the child was given high doses of sodium
bicarbonate and heparin by the hospital itself, and it was those drugs which
caused the cardiac arrest and internal bleeding. I was able to establish that
these symptoms, which are similar to those of SBS, did not develop until
after the baby was admitted to hospital (Medical Veritas, 2004; 1: 20131).
u In August 2005, two-month-old Averial was rushed to hospital by her
mother, and diagnosed as suffering from acute bronchopneumonia and
respiratory distress syndrome. Blood analysis suggested major infection.
Chest x-ray showed pneumonitis, and physical examination and body
scans revealed no evidence of physical injury. The hospital gave her
epinephrine (adrenaline), sodium bicarbonate, antibiotics and other drugs.
It was only then that skull and rib fractures were seen on the scans. The
baby died 11 days after admission. The post mortem found evidence of
bleeding both inside and outside the skull which, taken with the rib
fractures, was consistent with physical trauma. The girls 27-year-old father
was accused of shaking his daughter to death and is currently awaiting trial.
Dr Al-Bayati was called in. My investigation reveals that the infants
bleeding, brain oedema and necrosis, and skull and rib fractures occurred
after she had been brought to A&E. These injuries were caused by the
original infection and the medications she received in hospital (Medical
Veritas, 2007; 4: 145269).
WDDTY Dangerous drugs 23
Drugs for children
(Can J Clin Pharmacol, 2007; 14: e45e57).
A considerably longer, 15-year sur-
vey found that, in Swedish children,
the most frequent causes of adverse
reactions were vaccines and antibiotics.
Again, children died808 out of
5771as a direct result of medication
(Pharmacoepidemiol Drug Saf, 2005; 14: 4939).
This survey came hard on the heels
of a more intensive Swedish study that
tried to measure the reliability of drug-
reaction reporting in general. The
researchers found that both doctors
and the reporting system were
particularly lax in recording serious
drug side-effects. An intensive analysis
of 1349 patient records from five
Swedish hospitals revealed an under-
reporting rate of as much as 86 per
cent. Of 107 patients whose symptoms
had probably been caused by drugs,
only 15 had ever been recorded as an
ADR; the other 92 cases of drug toxic-
ity had been totally ignoredand this
in spite of the efficient, state-run
Swedish medical system (Pharmacoepi-
demiol Drug Saf, 2004; 13: 4837).
This suggests that the already
substantial official rate of annual child-
hood ADRs is very likely far below
the true figures. Indeed, last year,
researchers from the Drug Safety Unit
at Southampton University completed
a huge survey of ADRs across 12
countries, and found that ADRs were
underreported by an average of an
incredible 94 per cent (Drug Saf, 2006;
29: 38596).
This means that, to get a real picture
of the situation, any official ADR
statistics should be multiplied by 20.
Yet, behind all these figures lies a
stark and rather disturbing fact: most
prescription drugs have never been
tested to see if they are safe for children
or, indeed, if they actually work for
them. Less than 25 per cent of drugs
can be advertised as safe and effective
[for children], say the British Colum-
bia pharmacologists.
How can the authoritiesor doc-
tors, for that matterallow children
to be given drugs that lack safety or
efficacy data for such patients? It
appears that as long as a drug has been
approved by the regulatory authorities
for at least one medical condition, it
can be used for any other medical
purpose. Doctors have carte blanche
to prescribe any approved drug for
conditions for which it hasnt been
24 WDDTY Dangerous drugs
The main culprits
u Decongestants
v Anything with codeine, dextromethorphan, carbinoxamine, ephedrine,
pseudoephedrine, phenylephrine or brompheniramine (CDC MMWR Surveill
Summ, 2007; 56: 14)
v Cough suppressants containing hydrocodone can lead to serious illness,
injury, or death, says the FDA, which has issued a formal ban on most
(over 200) of these products (www.fda.gov/bbs/topics/
NEWS/2007/NEW01713.html)
v Withdrawn drugs: Dimetapp Decongestant Infant Drops, Robitussin Infant
Cough DM Drops, Little Colds Decongestant Plus Cough, Pediacare Infant
Drops Decongestant, Tylenol Concentrated Infant Drops Plus Cold and
Cough, Triaminic Infant & Toddler Thin Strips Decongestant.
u Antihistamines
v Anything with diphenhydramine, brompheniramine or chlorpheniramine
(Nonprescription Drug Advisory Committee Meeting, 2007-4323b1-02-FDA 10-01-2007).
u Asthma drugs
v Inhaled corticosteroids can stunt growth, and may cause osteoporosis
(J Allergy Clin Immunol, 2003; 112 [3 Suppl]: S140).
u NSAIDs
v Ibuprofen, aspirin and paracetamol (acetaminophen) are a significant
cause of morbidity in children (Br J Clin Pharmacol, 2005; 59: 71823).
u Antibiotics
v More than half of all antibiotics cause ADRs (Biomedica, 2007; 27: 6675)
v These drugs are one of the leading causes of fatal ADRs in children (Arch
Dis Child, 2002; 87: 4626)
v Amoxycillin is one of the most common causes of ADRs (Can J Clin
Pharmacol, 2007; 14: e4557).
u Behavioural drugs
v Ritalin causes headache, insomnia, anorexia and tachycardia (Curr Opin
Pediatr, 2002; 14: 21923).
u Vaccines
v The most recent CDC report records 11.4 ADRs per 100,000 doses,
primarily in children under six, and 14.2 per cent of all reports were
seriousincluding life-threatening illness, hospitalization, permanent
disability and death (MMWR Surveill Summ, 2003; 52: 124).
tested and for patients in whom it doctors of potential off-label uses.
hasnt been studied. Not surprisingly, some doctors are
The drug industry uses two relatively feeling increasingly uneasy about the
innocuous terms to describe this impact this is having on children.
situation: off-label and unlicensed. There have been numerous studies to
The former refers to the use of drugs show that many of the medicines used
for conditions not indicated in the in children are used off-label or are
products license, including dosage, unlicensed for use in children, says
type of medical condition and age of Professor Ian Wong, of the School of
patient. Unlicensed refers to prescrib- Pharmacy, University of London. Some
ing a drug for types of patients, such people may see these children as
as children or the elderly, for whom it unknowing participants in informal and
has not been authorized. uncontrolled experiments (Drug Saf,
Astonishingly, both uses are legal. In 2003; 26: 52937).
the UK and rest of Europe, they are For decades, the pharmaceutical
permitted under the Medicines Act of industry has argued that children
1968 and EU Pharmaceutical Directive should be excluded from experimental
89/341/EEC. In the US, the Food and premarketing clinical trials to protect
Drug Modernization Act of 1997 them from possible harm. However,
confirms the longstanding practice, another motive may well be financial.
even allowing drug makers to inform Clinical trials involving children are
both expensive and difficult to carry
out and, yet, the market for childrens
drugs is much smaller than that for
adults. The end result is that children
given even ordinary drugs like pain-
killers are likely to be exposed to
substances with no objective evidence
of safety or efficacy, or riskbenefit
analysis.
One Swedish survey of its doctors
prescribing habits found that, on
average, more than 40 per cent of the
drugs prescribed to children were off-
label and that these were more likely
to cause serious ADRs than approved
drugs. In this case, anti-asthmatics
were the most frequent category of
problem drug, causing almost one in
every three ADRs (Pharmacoepidemiol Drug
Saf, 2004; 13: 14752).
The fact that GPs use drugs off-label
is somewhat understandable, given that
they are generally not in the vanguard
of research. However, Italian research-
ers found that hospitals, rather than
GPs, are the chief offenders. After a
worldwide data search going back to
1985, they found that up to 80 per
cent of hospital drug prescriptions
for children were either off-label or
unlicensed. The drugs most commonly
used were paracetamol (acetamino-
phen), cisapride, chloral hydrate and
salbutamol (Eur J Pediatr, 2005; 164: 5528).
Small wonder, therefore, that
children have been shown to be most
vulnerable to ADRs in hospital. In fact,
according to the Nottingham University
researchers, as many as one in 10
children suffers ADRs as a direct result
of drug treatment received at the hands
of hospital doctors (Br J Clin Pharmacol,
2001; 52: 7783).
Voices in the wilderness
None of this will come as a surprise to
Dr Mohammed Al-Bayati, a toxicologist
and pathologist, who fled Saddam
Husseins Iraq 30 years ago and settled
in California. When he arrived in the
US, he was shocked to find an almost
equally repressive regime in the guise of
Western medicine. He was confronted
with case after case of parents being

Non-drug treatments for childhood problems

Many children suffer adverse reactions when given drugs for
problems that can be treated with safer alternatives. But, do
consult a qualified practitioner before taking this route.
INFECTIONS
u Bacterial and fungal
v Colloidal silver. Take care not to overdose: 100
mcg/day is safe for a child weighing 20 kg (Curr Probl
Dermatol, 2006; 33: 1734)
v Tea tree oil. As effective as standard antibiotics for skin
infections, including MRSA (J Antimicrob Chemother, 2003;
51: 2416), although it may cause skin reactions.
u Colds
v Echinacea (Lancet Infect Dis, 2007; 7: 47380) and vitamin C
(Cochrane Database Syst Rev, 2007; 3: CD000980)
v Saltwater nose drops
v Inhaling steam from water containing Friars Balsam, a
600-year-old herbal remedy.
u Coughs
v EPs 7630, a herbal medicine from geranium (Pelar-
gonium sidoides) roots (Phytomedicine, 2007; 14 [Suppl 6]:
6973), made by Schwabe Pharmaceuticals, Karlsruhe,
Germany; www.schwabepharma.com
v CORSHE-E, an Ayurvedic herbal linctus (J Herb
Pharmacother, 2004; 4: 112). A similar product is Olbas
Cough Syrup.
u Urinary and bladder
v Cranberry or blueberry juice (N Engl J Med, 1991; 324:
1599).
u Diarrhoea
v Individualized homeopathic medicine (Pediatr Infect Dis J,
2003; 22: 22934).
u Inner ear
v Naturopathic herbal ear drops containing tea tree oil,
garlic and other herbs (Cochrane Database Syst Rev, 2006;
3: CD005657)
v Individualized homeopathic medicine (Pediatr Infect Dis J,
2001; 20: 17783)
v Homeopathic Pulsatilla (J Am Inst Homeop, 1986; 79: 34).
u Sore throat
v Throat spray containing 15-per-cent sage (Salvia
officinalis) extract (Eur J Med Res, 2006; 11: 206); a similar
product is Echinacea Throat Spray, made by A. Vogel,
Switzerland
v Slippery elm, as a pre-drug therapy
v Do nothing, rather than use drugs like penicillin (BMJ,
2003; 327: 13247).
PAIN
u Headache
v Peppermint oil applied to the forehead and temples
(Nervenarzt, 1996; 67: 67281)
v Acupressure (Digital Dissertation Abstracts, 1990; DAI-B 50/
12: 5890)
v Self-hypnosis (Pediatrics, 1987; 79: 5937)
v Check for food allergy (J Pediatr, 1989; 114: 518)
v Feverfew may work (Lancet, 1988: ii: 18992), although a
recent survey casts some doubt (Curr Opin Neurol, 2005;
18: 28992)
v Homeopathy (although there are no clinical trials).
u Toothache
v Oil of cloves
v Activated charcoal compress
v Tincture of Plantago major (plantain)
v Purple passion flower (Passiflora incarnata) for hyper-
sensitive teeth
v Prickly ash (Zanthoxylum americanum) bark tincture
to numb teeth and gums.
u Colic
v See Q&A, page 19, for treatment alternatives.
BAD BEHAVIOUR
v Remove additives from the childs diet (Lancet, 2007;
epub ahead of print; DOI:10.1016/S0140-6736(07)61306-3)
v Check for food allergy in general (J Pediatr, 1989; 114: 518)
v Pycnogenol, the extract from the bark of the French
maritime pine tree (Eur Child Adolesc Psychiatry, 2006; 15:
32935)
v Omega-3 and -6 supplements (Pediatrics, 2005; 115:
13606).

WDDTY Dangerous drugs 25

Drugs for children
prosecuted for killing their children,
with some parents in jail and others
even facing the death penalty. Looking
at these cases, one thing stood out
clearly to Al-Bayati: doctors, hospitals,
prescription drugs and vaccinations
were almost always involved in the
childrens deaths. He soon found
himself defending parents as an expert
witness in the courts, sometimes the
appeals courts (see box, page 23).
To date, Dr Al-Bayati has successfully
defended over 20 cases in the US and
Canada. His success has relied on
exhaustive detective work, forensically
drilling down into fine medical detail.
One of his latest cases was that of
Patrick, a three-month-old baby boy. In
November 2005, he became severely
ill, and his parents took him to hos-
pital. The hospital ran a battery of tests,
and reported that the child had sub-
dural and subretinal bleeding, seven rib
fractures in various stages of healing,
severe anaemia, thrombocytosis, low
blood creatinine levels, hyperglycaemia,
and elevated neutrophils and monocyte
counts. The hospital doctors decided
the child was suffering from shaken
baby syndrome, and accused the
parents of having violently abused their
child.
The parents lawyers called in Dr Al-
Bayati, who soon saw the gaping holes
in the indictment. The underlying
problem was that Patrick had always
been a sick childborn prematurely,
and prone to vomiting and feeding
problems, leaving him malnourished.
Two weeks before the hospital emer-
gency, the child had developed a severe
cough, for which he was prescribed
Tylenol. Five days later, the boy had
gastrointestinal reflux, for which he
was given Zantac, the antiulcer drug.
The underlying culprit
For Al-Bayati, that was the root of the
problem. Patrick was treated with
Tylenol, he says, which contains
acetaminophen, at a dose of 200 mg
a daya high dose for such a young
childand one that could cause liver
toxicity. The child was then treated with
Zantac (ranitidine), despite the fact
that ranitidine is known to potentiate
the toxic effects of acetaminophen.
Thus, liver poisoning partly explains
the subdural and subretinal bleeding,
which was exacerbated by the childs
inherent vitamin K deficiency and
26 WDDTY Dangerous drugs
anaemia.
But what about the rib factures?
How could they be explained? The
child had a chronic cough, says Al-
Bayati. The child was already deficient
in protein and vitamin K, which would
cause weakening of the bones, and so
the childs ribs would be vulnerable to
any violent coughing (Medical Veritas,
2006; 3: 101940).
Twenty years ago, Dr Al-Bayati was a
lone voice in the wilderness but, today,
theres now a huge groundswell of
concern within the medical profession
itself. Its begun to realize that few
drugs have ever been tested for
use in childrenmainly because the
official drug-approval process only
requires evidence of safety and efficacy
in adults. Many doctors are now
clamouring for major reforms.
The current situation regarding
the licensing of medicines for children
is a profoundly unsatisfactory state of
affairs both for children and their
doctors, says Professor Peter Hill, of
the Great Ormond Street Hospital for
Children (Arch Dis Child, 2005; 90: i178).
The practice of giving children drugs
meant for adults is being roundly
condemned as unscientific guesswork.
Says Professor Andrew Bush, of
Londons National Heart and Lung
Institute: . . . the differences between
adults and children, and at different
stages of childhood development,
mandate strategies to improve this
situation rather than continually
relying on extrapolation from adult
studies . . . Disease phenotypes may be
completely different in children . . .
wheeze in infants is not miniature adult
asthma(Paediatr Drugs, 2006; 8: 2717).
According to Professor Laura
Cuzzolin, of the University of Verona,
Italy, there is a need to take immediate
action for a more rational use of drugs
in paediatrics, to avoid exposing child-
ren and infants to unnecessary risks
(Fundam Clin Pharmacol, 2003; 17: 12531).
Regulatory authorities have finally
begun to act. In 2001, the US Food and
Drug Administration (FDA) asked the
drug industry to provide specific
paediatric safety and efficacy data for
any drugs prescribed to children, in
return for which the FDA offered six
extra months of drug-patent exclusivity.
Although the industry appeared to
have embraced this enthusiastically,
so far, virtually all the applications
for extended patents have been for
cardiovascular and other drugs that
are rarely prescribed in the paediatric
population, but for which an extra six
months of exclusivity is very lucrative
in adults, wryly observe Dutch paedia-
tricians at the Erasmus University
Medical Centre in Rotterdam (Eur Respir
J, 2004; 23: 3103).
Changes: too little too late
Another major problem is that ADRs
occur not just with prescription drugs,
but with everyday over-the-counter
(OTC) medicines, too, most marketed
for relatively trivial conditions.
On 1 October, the FDA issued a
356-page report on OTC decongestants
(cough and cold medicines) which
included the revelation that, between
1969 and 2006, 54 children died after
taking these medicines, and 69 died
after taking antihistamines. The report
admits that, since ADRs are under-
reported, those figures are likely to be
significant underestimates (Nonprescrip-
tion Drug Advisory Committee Meeting, 2007-
4323b1-02-FDA 10-01-2007).
As we go to press, the FDA is
reviewing whether the roughly 800
decongestants on the market are either
safe or effective for children. It has
already banned one group of cough
medicines. Running for cover, manu-
facturers have now voluntarily with-
drawn another set marketed to infants
(see box, page 24). In September, the
Consumer Healthcare Products Asso-
ciation (CHPA), the OTC trade associa-
tion in the US, relabelled childrens
decongestants, advising against their
use in the under-twosalmost certainly
in response to a damning report seven
months earlier from the US Centers
for Disease Control and Prevention
(CDC), which warned: Caregivers and
clinicians should be aware of the risk
for serious illness or fatal overdose from
administration of cough and cold
medications to children aged under
2 years (CDC MMWR Surveill Summ, 2007;
56: 14).
But all this activity masks the
underlying problem. With no safety or
efficacy data, childrens medications
as a whole are in chaos, and yet,
authorities appear to be paralyzed. In
Europe in 2002, the EU published
Better Medicines for Children as a
prelude to new regulations for
childrens medications, but has gone
no further. In the US, the FDA is only
shutting the proverbial stable door,
and then only to address a tiny part
of the problem.
This climate of regulatory dithering
is deeply frustrating to many paedia-
tricians. WDDTY has collated a dossier
of over 30 medical reports about
childrens drugs written over the past
decade. The pleas from doctors for
the authorities to act are almost
anguishedundesirable situation,
requires action and irrational are
just a few of the comments. Doctors
have rarely been so united against an
industry they so often perceive as their
lifes blood.
Meanwhile, thousands of children
are being injured by side-effects and,
in some of them, fatally.
Tony Edwards
WDDTY Dangerous drugs 27
Drugs for children
Puffers get blown out
The onetwo punch of steroids plus puffers for childhood asthma has
just been knocked out by new findings
ong-acting beta-agonists (or
L LABAs), the standard-bearer
of treatment for childhood
asthma, have been found to be
not only useless as a chaser drug, but
also responsible for increasing the
incidence of serious asthma attacks in
children.
So weighty is the evidence against
the drugs in this categoryincluding
Glaxos Advair and Serevent, Astra-
Zenecas Symbicort and Novartis
Foradilthat the US Food and Drug
Administration (FDA) had an advisory
meeting in mid-December during
which FDA staff members recom-
mended withdrawing approval for all of
these drugs for children, and for
Serevent and Foradil for adults, too. The
last two contain only LABAs, while
Advair and Symbicort combine them
with an inhaled steroid.
The FDAs move is a huge blow to
drug makers, as LABAs with steroids
have been the mainstay of asthma
treatment for children with persistent
or severe asthma that fails to respond
to low- or medium-dose steroids.
Indeed, some products such as Advair
are fixed combinations of a LABA
(salmeterol) and inhaled steroid
(fluticasone). LABAs are also used
against exercise-induced asthma and
chronic obstructive pulmonary disease
(COPD).
The FDAs sudden interest in this
class of drugs represents a particular
blow to Glaxo, for which Advair is its
number-one bestseller.
LABAs are bronchodilators that
relax the muscles around the airways in
the lungs that, when tightened up,
cause wheezing or bronchospasm.
LABAs are said to relax constricted
airways for 12 hours or longer, and so
are often used for moderate-to-severe
asthma and particularly to prevent
nighttime episodes.
Nevertheless, regulatory bodies have
begun to realize that, although LABAs
reduce the frequency of asthmatic
episodes, they also have a rebound
effect in that, when episodes do occur,
they are more severe.
A recent Cochrane Library overview
28 WDDTY Dangerous drugs
of seven reviews of LABAs as the
primary or add-on therapyincluding
four reviews of the therapy in
childrenfound that inhaled ster-oids
plus LABAs led to a significantly higher
risk of adverse events vs steroids plus a
Salmeterol Multicenter
Research Trial (SMART), which
examined the safety of adding
Asthma
placebo. Although the two-stage salmeterol to a patients usual steroid-
therapy improved the need for rescue based asthma regime. Those taking the
medicine, nighttime awakenings and salmeterol suffered a significant
pulmonary function (as measured by increase in asthma-related deathfour
the blow test), the researchers times that of those taking a placebo.
concluded, There is no clear benefit to This works out to one additional death
LABA in preventing asthma for every thousand patients. However,
exacerbations in children (Evidence- the study did not include any patients
Based Child Health, 2008: 3: 90919; online: 10 under age 12.
December 2008). In its advisory, the FDA warned that
The FDAs own meta-analysis of LABAs should not be used as a first-line
110 trials, involving nearly 61,000 treatment, or to relieve sudden
patients, found that, for every 1000 wheezing or wheezing that is growing
patients treated with LABAs, 2.8 had a worse.
more serious asthma attack. Those at One reason why it took so long for
greatest risk appeared to be children problems with LABAs to surface is that
aged 411 years, with blacks and conventional meta-analyses focus on
women also at higher risk than other single comparisons between drugs
users. rather than on a number of analyses
The FDA has been tracking beta- of different drug regimens to rank their
agonist problems since earlier this year, effectiveness.
when the agency called for drug giants Indeed, a study using a networking
Glaxo, Novartis, AstraZeneca, Mylan meta-analytical technique attempted to
and Sepracor to provide clinical-trial do just that for the most commonly
data demonstrating the safety of this used inhaled drug regimens for
class of drugs. reducing COPD attacks (BMC Med, 2009;
The agency was first alerted in 2007 7: 2; doi:10.1186/1741-7015-7-2). It found
during a routine yearly review of that beta-agonists performed worse
adverse/safety data for drugs approv-ed than all other regimes (long-acting
for children. For Serevent alone, the anticholinergics, inhaled steroids and
agency uncovered nine adverse-event combination treatments) in patients
reports in children and five deaths over with more serious forms of COPD, with
a 13-month period. the steroid/LABA combination only
The FDA had already set a black-box reducing exacerbations in those with
warning in 2006 for salmeterol and milder disease.
Advair on the basis of findings from the Lynne McTaggart
Beware of these long-acting puffers
u Serevent Diskus, a disk-shaped inhaler that pumps out salmeterol
u Advair Diskus, which combines salmeterol with the inhaled steroid
fluticasone, also delivered via a disk-shaped device
u Foradil Aerolizer, a puffer containing the LABA formoterol
u Symbicort, AstraZenecas combo drug, mixes formoterol and the
inhaled steroid budesonide.
To find alternatives to puffers that can help respiratory problems, consult
The Asthma Manual, now available as an e-book (www.wddty.com) or at
www.wddtyhealthshop.com/products.asp?recid=220.
The kiddie upper takes a tumble
f Ritalin is the Miss America
I of the ADHD drugs, then
Dexedrine is the runner-up. When
Ritalin doesnt work, doctors
usually prescribe one of several
amphetamines such as Dexedrine,
Adderall or Dextrostat.
Dexadrine used to be the
recreational upper of choice for
everyonefrom students cramming
for an exam to overworked Hollywood
starletsuntil it was vastly misused
and discredited as a largely
recreational drug that was known on
the street as speed, another one of
mothers little helpers.
Then ADHD (attention-deficit/
hyperactivity syndrome) gave Dexe-
drine a new lease on life. ADHD is
listed as its number-one indication for
children between ages three and 16;
the drug is routinely prescribed by
family doctors if Ritalin (methyl-
phenidate) doesnt do the trick.
This cozy position is set to change
with a recent requirement by the US
Food and Drug Administration (FDA)
that Ritalin and the Dexedrine-type
drugs must now issue a warning on
their labels, explaining that the drug
can cause sudden death and serious
cardiovascular adverse events. There
have been reports of children with
heart trouble dying suddenly while
taking the drug.
Dexedrine (dextroamphetamine
sulphate) is an amphetamine that
works by mimicking the effects of the
hormone adrenaline (epinephrine),
which triggers the bodys classic fight-
or-flight responses.
The medical profession maintains
that ADHD results from a genetically
based abnormality in glucose levels and
neurotransmitters in the brain. The
prevailing view is that drugs like the
amphetamines, which speed up bodily
processes in adults, have a paradoxical
effect on children, calming them down
and somehow sorting out the
biochemical imbalance.
But this latest warning suggests
that the two drugs act as stimulants in
children as well as in adults, raising
blood pressure which, in turn, leads to
heart problems.
The FDA still hasnt decided
whether the problems merit a black-
box warningthe agencys strongest
classification of warning.
The new boxed warning also points
out that amphetamines have a high
potential for abuse, that prolonged
prescription may lead to drug depend-
ence and must be avoided and that
the drugs should be prescribed or
dispensed sparingly.
The FDAs decision, following the
recommendations of two independent
review panels, has shocked American
doctors who, up until now, have handed taking stimulant drugs at the regular
out these drugs to all comers. The FDA prescribed dosage for ADHD. Although
estimates that one million adults and the FDA and medicine itself readily
two million children refill a prescrip- admits it doesnt understand how great
tion for an ADHD drug every month. a role is played by these drugs in
A national study among American causing these effects, it warns that any
children by New York Universitys Child adult suffering from heart problems of
Study Center discovered that about any variety should not be taking
one in seven of the parents of school- stimulants.
age children reported giving their According to GlaxoSmithKline
children this type of daily psychoactive (GSK), stimulant drugs cause an
medication. increase in blood pressure of 24
The new label warnings alert parents mmHg and an increase in heart rate
that sudden death has resulted from of three to six beats per minute. All
this type of central-nervous-system patients taking stimulant medication
stimulant treatment at ordinary are now to be monitored, according to
dosages in both children and the new warnings. Anyone suffering
adolescents with structural cardiac from hypertension, heart failure, a
abnormalities or other serious heart recent heart attack or ventricular
problems. These include cardio- arrhythmias is now being advised to
myopathy (weakening of the heart avoid this class of drugs.
muscle), abnormalities in heart As for children, the new warnings
rhythms and any other problems that suggest that, before a patient of any
predispose them to be vulnerable to age is given a stimulant-type drug, he
stimulation of the central nervous should undergo a thorough physical
system. exam to determine if they have cardiac
Sudden death, stroke and heart disease. The same advice should apply
attack have all been reported in adults to anyone developing chest pain or
Psycho-cocktails
When children dont immediately respond with one of the old standbys,
todays doctors tend to prescribe a cocktail of psychoactive drugs.
These back-up drugs can even include antidepressants such as
desipramine (a tricyclic drug) or, inexplicably, high-blood-pressure drugs such
as clonidine (an antiadrenergic).
One American girl was given Ritalin for her ADHD, and Prozac to help
manage her anxiety, hypersensitivity and fear of bugs. When her teacher
complained that she was still disruptive in class, her doctor then handed her
Dexedrine. Her mother then noticed that her daughter was pulling out her
eyebrows and eyelashes and, at that point, said Enough is enough and
discontinued the Dexedrine.
WDDTY Dangerous drugs 29
Drugs for children
other problems suggestive of heart
problems while taking the drugs.
But that isnt the only area of
concern. The warning now states that
new psychotic or manic symptoms,
including hallucinations, delusional
thinking or mania in children and
adolescents, can also be caused by
stimulants at the prescribed dosages.
A meta-analysis of a number of
short-term studies discovered that
these kinds of symptoms occurred in
one child out of 1000 (GSK prescribing
information, 2006). As many children are
having to take the drugs for years, the
statistics could be far higher.
Other worrisome side-effects listed
in the new warnings include aggressive
behaviour and hostility, and long-term
suppression of growth. Studies of
children aged between seven and 10,
randomized to receive Ritalin or a
30 WDDTY Dangerous drugs
Not so calming:
other side-effects
u Restlessness
u Insomnia
u Dyskinesis(involuntary
movements such as spasm)
u Tourette syndrome
u Exacerbation of muscle and
phonic tics (any possible sound
or noise)
u Dysphoria (exaggerated feelings
of depression and discontent)
u Euphoria (feelings of wellbeing
and elation)
u Tremor
u Diarrhoea or constipation
u Anorexia/weight loss
u Impotence and changes in libido
placebo over three years, found that
the treated children suffered a slowing
of growth (2 cm less in height and
2.7 kg less in weight) over three years.
Although this effect was temporary
in the short-term, its not known if it
becomes permanent in chronic users.
Increasing susceptibility to seizures
and blurred vision are other reported
side-effects in the new warnings. GSK
also notes: Long-term effects of
amphetamines in paediatric patients
have not been well established.
Lynne McTaggart
Antibiotics

Life after antibiotics

A new superbug could signal the end of antibioticsthe
drugs that ended research on phage therapy, an
approach that harnesses the power of viruses to kill
deadly bacteria
he test results from the getting that the bugs had finally won. bug into a superbug that is resistant

T hospitals laboratory were

worse than the doctors had
even dared to fear. They
signalled the end-days of a war that had
raged for more than 60 years between
antibioticsarguably the most
successful group of drugs ever
developed, and which have made much
of modern medicine possibleand the
bugs.
Specialists at the hospital in London
knew from the results they were
They were looking at a doomsday
scenario of a world without
antibiotics, said Professor John Conly,
a specialist in infectious diseases,
months later. We are essentially back
to an era with no antibiotics (Bull World
Health Organ, 2010; 88: 8056).
The tests revealed that a gene
already known to doctors in Indiahad
made its way to the West. NDM-1 (New
Delhi metallo-beta-lactamase) is the
ultimate superbug. It transforms any
to every antibiotic, including the last-
resort carbapenems. In August of last
year (2010), when the discovery was
made, 50 patients in hospitals in
London and Nottingham had been
infected with NDM-1, most of whom
were health tourists who had gone to
India for cosmetic surgery.
Since then, NDM has been
discovered in New Delhis public water.
Researchers have found 11 new species
of bacteria carrying the NDM-1 gene,

Alternatives to antibiotics
Phage therapy is not the only alternative to antibiotics. Many
others have been used for centuries in traditional medicine,
although proof of their efficacy often rests on anecdotal
stories and case studies. Good research is limited because
funding usually comes from drug companies, which have no
commercial interest in discovering non-drug approaches.
u Echinacea. Up until the late 1930s and the advent of
antibiotics, Echinacea, a North American herbaceous
flowering plant of the daisy family, was a popular herbal
remedy for treating infections. In recent years, its primary
use has been side-tracked by interest in its supposed
abilities to fight the common cold, although some
researchers are still interested in Echinaceas antibacterial
qualities.
Using the commercially available product Echinaforce,
researchers at the University of British Columbia in
Vancouver discovered that it could combat upper
respiratory infections, often the result of a viral
complication. Echinacea purpurea also has an anti-
inflammatory effect, they discovered (Phytomedicine, 2010; 17:
5638).
Echinacea works in a similar way to antibiotics by
attacking the bugs cell wall, researchers at Carleton
University in Ottawa have found (Med Mycol, 2010; 48:
94958).
u Essential oils. Used as aromatherapy, essential oils have
successfully combatted a host of bacteria, such as
staphylococci, streptococci and Proteus species. Within
three hours, 90 per cent of the bugs were killed in one test
that used clove, lavender, lemon, marjoram, mint, niaouli,
pine, rosemary and thyme oils (Chir Dent Fr, 1976; 46: 53).
u Goldenseal. This herb is a broad-spectrum natural
antibiotic that is especially effective when used together
with Echinacea. On its own, it has proved to be a
successful antidote against some of the more familiar
bugs, such as Chlamydia, E. coli, Salmonella and
Helicobactor pylori (Antibiotics, 1976; 3: 57788; Phytother Res,
2003; 17: 21721).
u Honey. Manuka honey can clean chronically infected
wounds and might help to reverse bacterial resistance to
antibiotics. Honey interferes with the growth of three types
of bacteria: Pseudomonas aeruginosa, streptococci and
MRSA, researchers from the University of Wales have
discovered (Presented at the Society for General Microbiology
Spring Conference, held in Harrogate, England, April 13, 2011).
u Garlic. Crushed garlic has been a recognized natural
antibiotic for many centuries, and was recommended by
Hippocrates as a disinfectant. Even garlic juice can slow
the growth of up to 20 types of bacteria. Yet, despite its
age-old use, good research to prove its effectiveness is
virtually non-existent.
u Tea tree oil. This essential oil, made from the leaves of
Melaleuca alternifolia, has been used topically on the skin
to fight MRSA and other skin infections, such as acne,
athletes foot, nail fungus, wounds and infections. In
laboratory tests, the oil killed the deadly MRSA bacteria,
although funds have never allowed a full clinical study to
be undertaken (Am J Infect Control, 2004; 32: 4028).
u Cranberry. These berriestaken as a juice, an extract,
capsule or tabletare most often used against urinary
tract infections (UTIs). They have also been tested against
H. pylori infection, which can cause peptic ulcers.
Although they are a proven UTI preventative, the evidence
that they can also fight the infection is still inconclusive
(Cochrane Database Syst Rev, 2008; 1: CD001321).
u Others. Other natural antibiotics that have plenty of
anecdotal evidence, but precious little scientific support,
include St Johns wort, colostrum, selasih, liver herbs, wild
oregano, grapefruit seed extract, colloidal silver and
liquorice root.

WDDTY Dangerous drugs 31

Antibiotics
some of which can cause cholera and
dysentery, in the citys water supply.
Professor Tim Walsh, the lead
researcher from Cardiff Universitys
School of Medicine, fears that public
water throughout India, Pakistan
and Bangladesh could be
contaminated with the super-bug.
Westerners who had not been in Indian
hospitals have already been infected,
he added (Lancet Infect Dis, 2011; 11:
35562).
Ironically, the NDM superbug may
be the creation of the pharmaceutical
industry. Researchers have discovered
that Indias waterways are polluted by
pharmaceuticals, including antibiotics.
Many pharmaceuticals are processed in
India, where manufacturers can take
advantage of lax environmental
controls to deposit their waste into the
nearest river.
Researchers from the University of
Gothenburg in Sweden, who made the
discovery, fear that the manufacture of
pharmaceuticals could paradoxically
spark a global epidemic of infectious
diseases (PLoS ONE, 2011; 6: e17038)
NDM is the inevitable end-point of
an injudicious use of antibiotics that,
since the mid-1940s, have been
inappropriately prescribed, used on
crops, fed to live-stock, and washed
away into our water-ways and back into
the public systems.
The phage is set
The discovery of antibiotics was
accidental. While he was studying
influenza at Londons St Marys
Hospital Medical School in 1928,
biologist Alexander Fleming noticed on
his return from a holiday that mould
had grown on a set of culture dishes
being used to develop the
staphylococci germ. The mould had
created a bacteria-free circle around
itself. Fleming experimented further
and named the active substance
penicillin. However, it took another
17 years before penicillin went into
mass production.
Despite its slow progress, Flemings
accidental discovery halted research
into an equally promising antibacterial
approach that was happening at the
same time. Phage therapy harnesses
the natural power of a type of virus
called bacteriophages (which literally
translates to bacteria-eaters) to kill
bacteria.
32 WDDTY Dangerous drugs
Probiotics and the good bacteria
The human gut contains hundreds of different types of bacteria. Most of them
are good probiotics; they maintain the ecological balance that keeps us
healthy and wards off the bad bacteria. However, when the bad bacteria gain
the upper hand, we take a broad-spectrum antibiotic that kills the good along
with the bad.
When that happens, the guts natural eco-system is disturbed, the defence
system is impaired, and we are more likely to become a host for bad bacteria
and especially Clostridium difficile.
Probiotics are the best way to restore our natural barriers after a course of
antibiotics, researchers at the University of Paris-Sud in France have found. In
one study of 53 infants, 26 tested positive for C. difficile bacteria. Those who did
not have the bug had high levels of Bifidobacterium longum, a species of the
good probiotic bacteria (J Clin Microbiol, 2010; 49: 85865).
Just as with Fleming and successfully countered dysentery and
antibiotics, bacteriophages were gangrene.
discovered by accident. In fact, two Even after the war, Russian
meneach working independently scientists persisted with the therapy,
discovered them at around the same although the restrictions of the Cold
time. War prevented any research findings
One of them, George Eliava, head of from reaching the West.
the Central Bacteriology Laboratory in
the Georgian capital of Tbilisi, Phage one
collected specimens of water from the Bacteriophages have many advantages
citys Mtkvari river to study cholera over antibiotics. They are in limitless
bacteria. He left the slide under a supply, they attack only a specific
microscope for three days and, when he bacterial species and do not have the
next looked, the bacteria had gone. same debilitating effects on the overall
There had been something else in the immune system that antibiotics can
water that was choleras natural enemy, have.
he surmised, and that something was The one major disadvantage of the
bacterio-phages, as they had been therapy is that there is only one
dubbed earlier by French-Canadian bacteriophage for each bug, so there
scientist Flix dHerelle. has to be one Escherichia coli
The two men collaborated and, from bacteriophage to nullify the E. coli bug.
1923, worked together at a new This presents two problems for the
institute in Tbilisi, which was later doctor: he may not be able to treat the
renamed in Eliavas honour. patient immediately, as he first has to
Within a few years, the scientists at be sure of what is causing the infection
the institute had created an and, second, there is no such
armamentarium of more than a dozen thing as a broad-spectrum
phages that could treat a range of bacteriophageone that will kill a
bacterial infections. wide range of bugsas there is in
Bacteriophages became part of antibiotics.
conventional medicine in the new However, the greatest advan-tage of
USSR. In the US, drugs giant Eli Lilly bacteriophages is their natural ability
took a keen interest in the therapy, to adapt as quickly as their preythe
and started its commercial bacteriawhereas an antibiotic
development. However, the early represents a frozen moment of millions
results were not convincing, and of years of evolution while the bacteria
research and production stopped once continue to adapt, eventually creating
the first antibiotics were produced. an antibiotic-resistant superbug. As a
However, in the USSR, phage result, there is no such thing as a
therapy continued, and bacterio- superbug that can beat its
phages were regularly used to treat the bacteriophageor, at least, not for
wounds of Russian soldiers fighting in longas the phage will adapt in order
the Second World War. The therapy to continue having the upper hand.
The age of the superbug
Superbugs began to appear within a
few years of the start of penicillins
mass production. By 1947, four years
after penicillin was launched,
researchers discovered the existence of
a form of Staphylococcus aureus that
was resistant to methicillin, then the
most popular antibiotic in use. Today,
these bacteria are better known by the
initials MRSA (methicillin-resistant
Staphylococcus aureus), and they join
a host of other antibiotic-resistant
superbugs that have become familiar
names, including E. coli, Clostridium
difficile and Salmonella.
Each year, antibiotic-resistant bugs,
such as MRSA, kill around 100,000
patients in hospitals in America alone
(Clin Infect Dis, 2011; 52 [suppl 5]; doi:
10.1093/cid/cirl154). MRAB (multidrug-
resistant Acinetobacter baumannii) is
another common cause of infection in
hospitals. In one study of 164 infected
patients, 37 died, and 72 per cent of
the MRAB samples were resistant to
multiple drugs (BMC Infect Dis, 2010; 10:
196).
In Sweden, the staphylococcal skin
bacteria S. epidermidis are widespread
in hospitals. They have the capacity to
adapt to hospital environments,
accord-ing to a doctoral research paper
by Micael Widerstrm at Umea
University, Sweden (submitted in
September, 2010).
Another superbug, known as KPC
(Klebsiella pneumoniae carba-
penemase), has been making its way
across the US since its discovery on the
East Coast in 1999, and there have also
been outbreaks in Israel. According to
a report from the Rush University
Medical Center in Chicago, IL, in
October 2010, KPC causes pneumonia
and urinary tract infections.
The rise of the superbug has been
caused by the widespread misuse of
antibiotics. Today, there are more than
150 different antimicrobial comp-
ounds, and most of them are being
prescribed inappro-priately. One study
estimates that 80 per cent of antibiotic
prescriptions are written for ailments
that the drugs cannot treat, such as
viral infections (J Antimicrob Chemother,
2007; 60 [suppl 1]: i3i90).
Finlands health authority
was one of the first to act when, 20
years ago, it issued new guidelines to
Antibiotics down on the farm
Even if we dont take antibiotics, we are still exposed to them whenever we eat
meatespecially poultry.
But theres an alternative for poultry breeders that American scientists have
been testing. A dietary yeast extract appears to be every bit as good as an
antibiotic for decreasing pathogens in organic turkey production, say
researchers working for the US Department of Agricultures Agricultural
Research Service (ARS).
The yeast extract works by boosting the immune system and so providing a
natural defence against the bacteria that cause illness in the birds (Poult Sci, 2010;
89: 44756).
In a separate study, researchers from the University of Delaware say there is
growing evidence for several alternatives to antibiotics that poultry breeders
could use. These include bacteriocinsnatural agents that
are lethal to bacteriaas well as antimicrobial peptidesa natural defence
against some pathogensand bacteriophages (see main story) (Poult Sci, 2003;
82: 6407).
stop indiscriminate antibiotic use. It discovered that mincemeat sold in
had discovered that group A German shops was contaminated with
streptococci, a virulent infection, was vancomycin-resistant enterococci
becoming resistant to erythromycin, (Lancet, 1996; 347: 1047).
which is used as an alternative for Our waterways have also become a
people who are allergic to penicillin. breeding ground for superbugs, and
After the policy change, the level of they may already have entered our
strepto-coccal bugs fell from 16.5 per drinking water, one research team
cent in 1992 to 8.6 per cent in 1996 (N fears.
Engl J Med, 1997; 337: 4416). The UKs They took water samples from
National Institute for Health and rivers, lakes and wells throughout
Clinical Excellence (NICE) issued its North America, Europe and East Asia,
own edict in 2008 in an attempt to and discovered significant traces of
reduce the 38 million prescriptions pharmaceutical drugs, including
written for antibiotics every year in antibiotics. Industrial plants wash the
Great Britain. waste from the manufacture of
pharmaceuticals into waterways, and
Eating and drinking antibiotics patients often flush prescription drugs
In fact, even when we arent taking down the toilet. They are also used on
antibiotic drugs, were absorbing them farms for crop-growing to control
through the environment and the food disease and these, too, can be washed
we eat. Researchers have discovered into the nearest river. The researchers
that nearly half of the meat and poultry found three classes of antibiotics in the
sold in stores is contaminated by water they analyzed that can create
antibiotic-resistant staph infections. superbugs. Once in the waterways, they
The bugs, which can cause life- can make their way into the public
threatening diseases such as supply and the water we drink, wash
pneumonia and sepsis, are the result of and cook with, says lead researcher
intensive-farming methods. The Sbastien Sauv, from the University of
research team bought 136 meat Montreal (Environ Health Perspect, 2009; 117:
samples from 26 stores in five US 67584).
cities; of these samples, 47 per cent
were contaminated with S. aureus Turning the phage
bacteria. Although the bacteria are Despite the rise of the superbug,
usually killed in the cooking process, research into phage therapy began to
the researchers fear that some of the dwindle in the USSR and, by the mid-
bugs may be left on kitchen surfaces 1970s, the Eliava Institute had virtually
during preparation (Clin Infect Dis, 2011; closed its doors. Without electricity,
52: 122730). This is not a even the phage samples being stored in
new development. In 1996, researchers the refrigerators would have been lost
WDDTY Dangerous drugs 33
Antibiotics
had the researchers not taken them
home. In 1993, the electricity was
switched off for good, and the Institute
was closed.
Today, phage therapy is active only
in Georgia and, to a lesser extent, in
Poland.
However, in the West, it was
beginning to dawn on the researchers
who were studying the rise of
superbugs that antibiotics carry the
signature of their own eventual
ineffectiveness. They started to take a
fresh look at phage therapy. In 1994,
researchers used phages to help
improve the success of skin grafts in
laboratory mice by reducing
the underlying Pseudomonas
aeruginosa infection (Burns, 1994; 20:
20911).
Phages for killing Listeria, the food-
poisoning bacteria, have started to be
used tentatively in the West (Lancet,
2000; 356: 1418).
A clinical trial of phage therapy for
otitis, a bacteria-caused middle-ear
infection, has been underway at
Londons Royal National Throat, Nose
and Ear Hospital (Clin Otolaryngol, 2009; 34:
34957), while a research team at the
University of Minnesota in Minneapolis
tested a cocktail of phages against
various antibiotic-resistant bugs such
as MRSA and E. coli in venous leg
ulcers (J Wound Care, 2009; 18: 2378,
2403).
Animals first
Acceptance of phage therapy
may be slow in the West, but it appears
to be happening faster for agricultural
and livestock purposes. In 2006, the
European Union banned the use of
antibiotics for non-medical purposes in
animals and livestock, while several
manufacturers have been phasing out
growth-promoting antibiotics.
A number of companies are
currently working on the commercial
mass production of phages for
livestock. One, Intralytix, has been
granted a US license to develop
a phage to combat Listeria
monocytogenes in poultry. The licence,
granted in 2006, is for a product called
ListShield (www.intralytix.com/Intral_
34 WDDTY Dangerous drugs
Diseases caused by antibiotics
Antibiotics dont only help to create the superbugs. They can also cause
asthma, leave us open to serious bacterial attack, cause birth defects and send
us to the hospital emergency room with hypotension (abnormally low blood
pressure).
u Asthma. Babies who are given antibiotics are 50 per cent more likely to
develop asthma when they are small children. In a study of around 1400
children with asthma, around one-third had been given antibiotics by the
time they were six years old. The antibiotics interfere with the good bacteria
in the gut, which prevents the immune system from maturing, say
researchers from the Norwegian University of Science and Technology (Am J
Epidemiol, 2010; 173: 3108).
u Birth defects. Antibioticsand the sulphonamides and nitrofurantoins in
particularcan cause birth defects if taken when a woman is pregnant.
Although defects were also seen in women who had taken penicillin, the risk
was less evident (Arch Pediatr Adolesc Med, 2009; 163: 97885).
u Immunity. Our natural immunity can be impaired for up to two years after
taking antibiotics, leaving us more open to serious infection. A study by the
Swedish Institute for Infectious Disease Control revealed that the impact of
antibiotics is far greater
than the common belief that impairment lasts for only a month or so
(Microbiology, 2010; 156: 321623).
u Hypotension. Antibiotics can cause life-threatening shock and hypotension
(too-low blood pressure) if they are taken with common blood-pressure
medications. The macrolide antibioticswhich include erythromycin,
clarithromycin and azithromycincan increase the risk of sudden
hypotension sixfold if taken with a calcium-channel blocker drug (CMAJ, 2011;
doi: 10.1503/cmaj.100702).
News_PR062308.htm). has adapted in order to outwit the
Intralytixwhich recruited several antibiotic.
researchers from the old Eliava Understanding this, antibiotics
Instituteis hoping that the use of should have been treated as a precious
ListShield will demonstrate the safety resource and used sparingly. Instead,
of phage therapy and will eventually we have killed the goose that laid the
herald in a way of combatting killer golden egg.
bugs in the way that Nature intended. Fortunately, there is another goose
that can come to our rescueMother
The new age of the phage Nature herself.
Antibiotics have been medicines Bacteriophages are Natures own
greatest success story, and have answer to bugs, and there
doubtlessly saved millions of lives. They is one bacteriophage for every bug.
have been the doctors most powerful They are found in limitless supplyjust
ally, and have granted him miraculous put a bucket into any river and you will
healing powersand, as a result, have fish out trillions of themand they
been absurdly overprescribed over adapt along with the bug.
the years. Whats needed is just for the West to
While the antibiotic has been a realize that the end-days of antibiotics
moment of millions of years of are with us now, and to work with the
evolution frozen into a chemical Russians on the research they carried
formula, its preythe bughas out right up until the 1970s, and begin
continued to adapt in order to survive. funding the age of the bacteriophage.
The superbug is just thata bug that Bryan Hubbard
Antibiotics: definitely not kids stuff
Routinely given as preventative drugs to mothers-to-be
and infants, antibiotics are far more dangerous than we
could have previously imagined, as new research
suggests.
ntibiotics are routinely given
A to pregnant women and
young children. In the US,
30 million prescriptions are
written each year for childhood ear
infections alone, and there are more
than 60 different antibiotics that can
now be given to infants.
However, while these drugs have
saved lives, they are also known to be
among the most dangerous groups of
drugs around.
One study found that antibiotics
can cause long-term health problems
in children whose mothers took these
drugs during pregnancy. Antibiotics
are regularly given in pregnancy to
reduce the possibility of premature
labour and to guard against infection.
Yet, this routine procedure has
genuine health risks for the unborn
child. Researchers at the University of
Leicester in the UK found that the
antibiotic erythromycin dramatically
increased the risk of having a child
who would develop visual or hearing
impairment, or even cerebral palsy, by
the age of seven.
The team tracked 4221 women who
had taken either erythromycin or
amoxicillintwo commonly used
antibioticsor a placebo while preg-
nant. Of these, 658 children whose
mothers had taken an antibiotic had
some kind of functional impairment.
Their health problems included
seizures, ADHD (attention-deficit/
hyperactivity disorder), respiratory
conditions such as asthma, diabetes
and bowel disorders.
In general, the children of mothers
who had taken the drugs were nearly
twice as likely to develop cerebral
palsy vs those whose mothers took a
placebo. These children were also
much more likely to have problems
in learning to walk, other learning
difficulties and poor eyesight by the
age of seven compared with those
whose mothers had taken a placebo.
Worst of all, the researchers found
that the drugs had not been any more
effective than a placebo in preventing
infection, not even in cases of a
ruptured membrane.
This suggests, say the researchers,
that only those women who are very
likely to develop infection due to
membrane rupture or to suffer other
injuries that could lead to infection
should be given antibiotics in future.
Certainly, their routine use should
be stopped (Lancet, 2008; Sep 18; Epub
ahead of print).
Nevertheless, and despite these
findings, the Royal College of Obstet-
ricians and Gynaecologists, which sets
the best practice guidelines in the
UK, says it will not be altering its
current recommendations. In 2001,
the RCOG changed its guidelines
for the management of preterm
membrane rupture to exclude co-
amoxiclav (amoxicillin and clavulanic
acid) from the treatment protocol.
Drugs for newborns
Antibiotics are just as dangerous for
newborns. One study has established
that children who are given an
antibiotic in their first 12 months of
life are twice as likely to develop
asthma by the time they are seven.
The risk is highest among children
who have undergone four courses of
antibiotics and have taken broad-
spectrum drugs for general just-in-
case healthcare.
Researchers in Canada made the
discovery when they reviewed the
medical histories of 13,116 children.
Those who were prescribed anti-
biotics for anything other than a
respiratory problem, thereby exclud-
ing those who had a preexisting
condition that might have led to
asthma, were twice as likely to develop
asthma as those given a placebo
(Chest, 2007; 131: 17539).
But the dangers of antibiotic use in
children have been known for years. A
study published as far back as 12 years
ago found that children
in Nigeria were losing their hearing
because of indiscriminate antibiotic
use. It was reckoned that two-thirds of
cases of deafness in children were
being caused by the overprescribing of
antibiotics such as streptomycin and
gentamicin (BMJ, 1996; 313: 648).
The lessons to be learned seem
clear, says Alison Russell, of Warwick
Medical School in the UK. Contrary
to the popular opinion that anti-
biotics dont do any harm so we might
as well give them, antibiotics are not
risk-free.
Adverse events are common
Dr Russells opinion has been
supported by the fact that antibiotics
are responsible for 20 per cent of
all drug-related visits to Accident &
Emergency departments. It appears
that, over a two-year period, 142,000
Americans reacted so badly to an
antibiotic that they had to be admit-
ted to hospital. Indeed, antibiotics
were as dangerous as drugs such as
warfarin, insulin and digoxin, all of
which have a known track record for
causing serious adverse reactions.
Nearly 80 per cent of the antibiotic
patients who received hospital care
did so because of allergic reactions,
whereas the rest of the patients
suffered from severe diarrhoea, head-
ache or dizziness. Also, around 6 per
cent had to stay in hospital for at least
one night (Clin Infect Dis, 2008; 47: 73543).
Yet, despite these dangers, doctors
continue to give so many antibiotics
to children that there are now
considerable rates of antibiotic
resistance, researchers at Oxford
University have found. In 119 children
with acute respiratory tract infection,
71 were given amoxicillin,
a moderate-spectrum penicillin. After
just two weeks, the number of these
treated children carrying antibiotic-
resistant bacteria had doubled
compared with those only taking a
placebo (BMJ, 2007; 335: 429).
Bryan Hubbard
WDDTY Dangerous drugs 35
Drug-induced disease

Medicine and the elderly:

age shall not weary
thembut drugs might
For the elderly, the cure is
very likely worse than the
disease

oets may exhort us not to

P grow old, but they could have

added the rider that, when we
do, stay away from the doctor
for as long as possible. Growing
evidence suggests that aggressive
interventions by doctors are
accelerating the decline in the general
health and mental capacities of the
elderly, and may even be a direct
contributor to their death.
The over-65s take one-third of all
pharmaceuticals that are prescribed
by doctors every year, despite the fact
that they represent just 13 per cent of
the total population. On average, an
elderly person is taking around six
drugs at any given time (Johnston CB.
UCSF Division of Geriatrics Primary Care Lecture
Series May 2001. Geriatric Assessment in a Time
Dependent Practice: Practical Approaches for
Primary Care Practitioners).
Polypharmacywhen more than
one drug is prescribed at a timeis an
even bigger problem in hospitals and
care homes, where the average patient
is given at least seven different drugs
every day. In addition, powerful
dementia drugs are being prescribed
for most patients as a chemical cosh
to keep them quiet, evidently mainly
for the convenience of the medical
staff. An official UK government
review has revealed that the drugs are
being inappropriately prescribed in
around 80 per cent of cases. In the UK
alone, this works out to around
150,000 people who are being given
anti-psychotic drugs just to keep them
pacified. Worse, the drugs are directly
responsible for about 1800 deaths
every year (http://news.bbc.co.uk/2/
hi/8356423.stm).
This may perhaps explain why 11
per cent of elderly patients, admitted
to hospital for other medical
conditions, will suffer a heart attack
while they are there. In addition, they
are also twice as likely as a younger
patient to die within 30 days from
such an attack. Researchers made the
discovery when they examined the
health records of 7054 patients who
were admitted to hospital as part of
the US Veterans Health
Administration between 2003 and
2004. Of those patients, 792or 11.2
per centsuffered a heart attack
while under hospital care (Arch Intern
Med, 2006; 166: 14106).
Tick-box medicine
Most patients are over 65 and, yet,
they rarely see a doctor who
specializes in geriatric medicine. This
might be because, in almost every
country except the UK, there is a
serious shortage of geriatricians. In
Canada, for example, there are fewer
than 200 qualified geriatricians
serving the entire country. In an
attempt to attract more medical
graduates into geriatric medicine, Dr
Laura Diachum, at the University of
Western Ontario, has gone as far as to
describe the speciality as totally
sexy (J Am Geriatr Soc, 2006; 54: 145362).
As a result of the lack of geriatric
specialists, an elderly patient is
invariably seen by a general practi-
tioner, whose almost instinctive
tendency will be to start reaching for
the prescription pad. Sadly, as discover-
ed by a doctoral thesis defended by
Sandra Pennbrant, at the Sahlgrenska
Academy in Sweden, elderly patients
tend to become passive when faced by
the doctor and feel intimidated by the
practitioners power and, so, fail to
participate in the consultation by
almost never challenging the decision
to start taking a drug or even asking
any questions (http://gupea.ub.gu.se/dspace/
handle/2077/21198).
Doctors routinely hand out
prescription drugs simply because the
patient is old, not because he or she
needs them, says Michael Oliver, an
emeritus professor of cardiology at
Edinburgh University. This tick-box
medicine, as he calls it, means that
elderly people are not only taking
drugs they dont need, but they are also
being exposed to side-effects that can
seriously endanger their health.
Nowadays, few elderly people are
allowed to enjoy being healthy, he says
(BMJ, 2009; 338: b873).
One example of this so-called tick-
box medicine is bringing down levels
of blood cholesterol, especially in the

36 WDDTY Dangerous drugs

elderly. But this is, in fact, a failure to
understand the changing metabolism
of older patients, who appear to need
higher levels of cholesterol for their
general wellbeing and, especially, to
support mental acuity. One study that
involved 3572 men, aged 7193 years,
discovered that those who had the
lowest cholesterol levelsfrom 2.09
to 4.32 mmol/L (80.0 to 167.0
mg/dL)were up to 40 per cent
more likely to die than those whose
cholesterol levels were higher. Indeed,
this study, which monitored the
health of the partici-pants for 20
years, questioned whether there was
any scientific justification for
lowering cholesterol to very low
concentrations (below 4.65 mmol/L
[179.8 mg/dL]) in elderly people
(Lancet, 2001; 358: 3515).
Not only may higher cholesterol
levels be health-giving in the elderly,
but the cholesterol-lowering drugs
themselves may also be doing more
harm than good, according to a study
from the Yale University School of
Medicine. There, the researchers found
that, while there was a marginal benefit
from the drugs in reducing heart
fatalities, they also found that the
patients were dying of other causes as
a result of taking the drugs (JAMA, 1994;
272: 133540).
Worse, most general practitioners
are unaware of the dangers of the
drugs they are prescribing to their
elderly patients, despite the frequent
drug alerts and warnings they are sent
by drug-monitoring agencies.
In fact, researchers have discovered
that around one in five elderly patients
is being given drugs that are dangerous,
and could be the cause of debilitating
side-effects. In a study of 760,000
elderly people taking a prescription
drug, it was revealed that 21 per cent
were taking one or more drugs that
were on the Beers list, a compilation of
all the prescription drugs that geriatric
patients, in particular, should avoid
(Arch Intern Med, 2004; 164: 16215).
In another study, researchers found
that 20 drugs had been identified as
being too dangerous for use by the
elderly and, yet, most of these patients
(79.6 per cent) were being prescribed
one of these drugs and 20.4 per cent
were taking two or more, including the
beta-blocker propranolol, the anti-
hypertensive agents methyldopa and
reserpine, the painkiller dextropropoxy-
phene and the anticoagulant dipyrid-
amole (JAMA, 1994; 272: 2926).
Many elderly people regularly take a
common NSAID (non-steroidal anti-
inflammatory drug) such as aspirin and
ibuprofen to help ease their aches and
pains. Yet, according to a survey of 4099
people aged 70 years and over, these
drugs increase the risk of kidney
dysfunction. Those who took an NSAID
at least once a day had the highest
levels of blood urea nitrogen and serum
creatinine, both of which are markers of
kidney problems (J Am Geriatr Soc, 1999; 47:
50711).
Prescribed drugs may also be

Living a long and healthy life

Aside from avoiding drugs and medicine, there are three
keys to a healthy life into old age: diet; exercise; and an
active social life.
u Diet. Vitamin Efound in nuts, seeds, and corn and olive
oilis arguably the single most important nutrient in
determining whether or not we will live a long and healthy
life. In a study of 698 men and women, aged over 65 and
living in Tuscany, Italy, those who had low levels of the
vitamin in their circulation suffered a decline in their
physical capacity over a three-year period compared with
those who had higher levels of the vitamin. This was also
the only vitamin that had a direct impact on the physical
wellbeing of the study participants. Their levels of folate,
vitamin D, iron and B vitamins apparently made no
difference to the physical decline. The researchers believe
that vitamin E, which is an antioxidant, prevents damage
to DNA, muscles and neurons (JAMA, 2008; 299: 30815).
The Mediterranean diet, primarily consisting of fresh
fruit, vegetables and olive oil, has been proven in
countless studies to help maintain health into older age.
One study, involving 1393 participants, discovered that
the diet protects against cognitive decline as we age.
Those who stayed close to the diet nearly halved their
chances of developing mild cognitive impairment
compared with those who ate low amounts of fruits and
vegetables (Arch Neurol, 2009; 65: 21625).
u Exercise. Even moderate exercise, such as a brisk walk
every day, can help to keep you healthy into older age,
and even elderly patients who already have conditions
such as heart disease and arthritis can see improvement.
In heart patients aged 50 years and over, moderate
exercise that leaves you a little out of breath increased life
expectancy by 3.7 years in men and 3.5 years in women
(Arch Intern Med, 2005; 165: 235560). Older people with
osteoarthritis of the knee also noticed improvements in
their knee pain and mobility after 18 months of brisk
walking for 40 minutes, three times a week (JAMA, 1997;
277: 2531). Overall, older people who take regular exercise
have stronger hearts, better circulation, stronger bones,
better balance, less pain, better sleep quality, sharper
minds and a lower risk of developing most cancers (Am
Fam Physician, 2002; 65: 41926).
u Social networks. An active social life, including volunteer
work, attending sports and social events, and visiting
friends and relatives, is as important as exercise for
helping older people to maintain good health. In a US
study of 906 retired people, it was found that physical
decline was up to a third more rapid in those who were
socially inactive, even when they took regular exercise
(Arch Intern Med, 2009; 169: 113946). Curiosity and
maintaining an interest in the world also play important
roles in determining how longand how wellwe live.
One study of 1118 men, with an average age of 70 years,
found that having this attitude in life was the single most
important factor in determining longevity.
In ancillary analyses in 1035 older women (mean age:
69 years), curiosity appeared to be equally important in
women as well (Psychol Aging, 1996; 11: 44953).

WDDTY Dangerous drugs 37

Drug-induced disease

therapy (Age Ageing, 1996; 25: 2738).

Staying sharp In a separate small US study a
year later, the geriatric researchers
Mental decline isnt an unavoidable consequence of ageing. Theres lots we in Durham, NC, found that benzo-
can do to stay sharp right up to the end. diazepines acted directly on the
People who exercise at least once a week, dont smoke and maintain an central nervous system, and affect
active social life are more likely to retain their cognitive abilities throughout their neuromuscular processing and
70s and 80s, according to a study of 2500 participants aged 7079. However, balance control, thereby causing
an eight-year follow-up showed major cognitive decline in 16 per cent of this falls, disorientation and slower
population, whereas 53 per cent displayed normal, age-related decline. Yet, the responses in the elderly (J Am Geriatr
research team saw a unique profile of activity and social engagement that Soc, 1997; 45: 43540).
appeared to have protective effects in around 30 per cent of participants who Powerful antidepressants of the
displayed no cognitive decline whatsoever. A good education, not smoking class known as SSRIs (selective
and a good level of literacy were found to be important factors, and those who serotonin-reuptake inhibitors) as
carried out volunteer work and were not living on their own also appeared to well as the older tricyclic drugs, can
be less likely to suffer from cognitive decline (Neurology, 2009; 72: 202935). also significantly increase the risk of
Maintaining an interest in intellectual pursuits, such as reading and doing falls in the elderly (N Engl J Med, 1998;
crossword puzzles, can also help to ward off dementiaand the more you do, 339: 87582). As a consequence,
the better. The study participants who engaged in 11 intellectual activities a elderly people taking an SSRI are 2.4
week, such as reading every day and doing the crosswords four times a week, times more likely to suffer hip
delayed the onset of dementia by 1.29 years compared with those who read or fractures compared with those not
did the crosswords taking these drugs, researchers from
the University of Toronto, Ontario,
responsible for dry eyes and dry mouth, and Cassell, 1965). Every health concern have found. However, the earlier
assumed to be a natural consequence in the elderly could be traced back to types of antidepressant are not much
of growing old. However, common pain- one of those four conditions, he said. safer for elderly patients. In this
killers such as aspirin could be respon- However, neither Isaacs nor the other study, which involved 8239 patients,
sible, according to a study of 2481 pioneers of geriatric medicine could aged 66 years and over, who had
patients aged 6584 years. Antidepress- have foreseen that, in many older been treated in hospital for hip
ants and antipsychotics may also be the patients, these giants would be caused fractures, it was found that those
cause of similar side-effects (Arch Intern by the very medicines that were taking a tricyclic antidepressant
Med, 1999; 159: 135963). supposed to help them, and not by the such as desipramine or nortriptyline
Whats more, doctors are more than ageing process itself. were 2.2 times more likely to suffer
ready to prescribe off-labelhanding u Immobility and instability. Around from hip fractures as a result of falls
out drugs for health problems for which 30 per cent of all over-65s fall each (Lancet, 1998; 351: 13037).
they have been neither tested nor year, and this proportion rises to half Insulin can also cause falls, and is
licensed to treat. The problem has of all those in hospital or in nursing among the three drugs that are also
become so prevalent, and dangerous, care, where multiple drugs are an most likely to cause an adverse
that Americas drugs watchdog, the essential part of their daily regimen. reaction in the elderly; the other two
Food and Drug Administration (FDA), Also, 25 per cent of these patients are warfarin, a blood thinner, and
has warned doctors to stop using die within six months of falling. digoxin, a heart drug. The three
atypical antipsychotic drugs to treat While there may be a number of drugs alone accounted for 59,108 of
general behavioural problems in elderly reasons why an elderly person falls, the 177,504 cases of adverse drug
patients. Indeed, agents such as olanza- prescription drugs are among the reactions reported by US emergency
pine, aripiprazole, risperidone and biggest causes, responsible for services in 20042005. Insulin can
quetiapine are so dangerous that they around 18 per cent of all cases cause sudden hypoglycaemia (low
double the risk of deathand they are (Johnston CB. UCSF Division of Geriatrics blood sugar), which may result in a
supposed to be prescribed only to those Primary Care Lecture Series May 2001. seizures or unconsciousness (Ann
with schizophrenia (www.fda.gov/cder/drug/ Geriatric Assessment in a Time Dependent Intern Med, 2007; 147: 75565).
advisory/antipsychotics.htm). Practice: Practical Approaches for Primary In fact, most prescription and
Care Practitioners). over-the-counter drugs appear to
The four giants Tranquillizers and sedatives, such increase the risk of falling. In a meta-
In 1965, when geriatric medicine was as benzodiazepine, can increase the analysis of studies published from
still in its infancy, Bernard Isaacs, a risk of a fall in an elderly patient by 1996 to 2007, involving more than
professor of geriatric medicine at nearly threefold. Flurazepam and 79,000 participants, aged over 60,
Birmingham University in the UK, said triazolam (both of which are benzo- who were taking some sort of
the elderly were faced with four giants diazepines) are the most dangerous, pharmaceutical, it was found that
that would determine their health: according to Canadian researchers, many drugs significantly raised
immobility; instability; incontinence; and the elderly patient was most the risk of falls. The biggest culprits
and impaired intellect (Isaacs B. An likely to suffer a fall within the first included sedatives, SSRIs, antihyper-
Introduction to Geriatrics. London: Ballire, Tindall two weeks of starting such drug tensives, diuretics, beta-blockers,

38 WDDTY Dangerous drugs

 and even NSAID painkillers such as
aspirin and ibuprofen.
Elderly people may be more
sensitive to drugs effects and less
effective at metabolizing medica-
tions, leading to adverse events
which, in turn, lead to falls, said
researcher Carlo Marra, at the
University of British Columbia in
Vancouver, Canada (Arch Intern Med,
2009; 169: 195260).
u Incontinence. This is often viewed as
an unfortunate consequence of
ageing, but this is not so. The US
Agency for Health Care Policy and
Research reports that eight out of 10
cases of incontinence can b either
resolved or greatly improved by
medical interventions (Agency for
Health Care Policy and Research. Overview:
Urinary Incontinence in Adults, Clinical
Practice Guideline Update. Rockville, MD.
March 1996; www.ahrq.gov/clinic/uiovervw.
htm). The one exception is age-
related prostate enlargement, which
can cause urinary incontinence.
In fact, incontinence can arise
for many reasons and in people of
all ages, although one in 10 of those
aged over 65, and three in 10 aged
over 80, have some loss of bladder
control, and half of all elderly
patients in nursing homes have
incontinence. Many prescription
drugs cause temporary incontin-
ence and, as the elderly take one-
third of all drugs prescribed, its not
unreasonable to conclude that they
are a primary cause of the condi-
tion in the over-65s. Anticholinergic
agents, which block the passage of
neural impulses, include drugs such
as antihistamines, antidepressants,
opiates, antispasmodics and Parkin-
sons drugs, and can all lead to
incontinence (Cochrane Database Syst
Rev, 2006; 4: CD003781), as can heart
drugs such as the calcium-channel
blockers.
Diuretics, or water pills, increase
the bodys loss of fluid by promoting
the production of urine and, as a
result, can frequently cause acute
incontinence. They are among the
most regularly prescribed drugs
among the elderlyand often
unnecessarily so, as one study has
identified (BMJ, 1994; 308: 5113).
Alpha-adrenergic blockers, which
include drugs for hypertension (high
blood pressure) such as doxazosin
(Cardura), prazosin (Minipress) and
terazosin (Hytrin), can also cause
incontinence (Drug Saf, 1994; 11: 1220),
as can the angiotensin-converting
enzyme (ACE) inhibitors such as
benazepril (Merck Manuals; www.merck.
com/mmhe/sec11/ch147/ch147a.html).
u Impaired intellect. Around 22 per
cent of those aged 71 years and over
have some degree of cognitive
impairment, which is often seen as
a forerunner of dementia and
Alzheimers disease (Ann Intern Med,
2008; 148: 42734). However, research-
ers at the Mayo Clinic reckon that
this figure could be lower, with only
12 per cent of individuals aged
between 70 and 89 years displaying
such symptoms, according to a study
funded by the National Institute on
Aging (www.mayoclinic.org/news2006-rst/
3306.html).
The Mayo researchers define
cognitive impairment as having
problems with remembering words,
or placing things in time and space,
or finding it more difficult to make
decisions, or suffering from short-
term memory loss. The problem
doubles in those aged between 80
and 89, and it also appears to affect
more people who have received only
basic levels of education.
However, although ageing is a
genuine factor in cognitive decline,
pharmaceuticals also play a role in
accelerating the problem. Scientists
from the University of Florida have
demonstrated that any drug that has
anticholinergic (nerve-blocking)
qualities can speed cognitive decline
in the elderly patient. Although this
includes drugs known to have
anticholinergic actions, such as
those used to treat an overactive
bladder, many other drugs have
similar effects, but have not been
listed as such in the literature
(Presentation at the American Academy of
Neurology 60th Annual Meeting, Chicago, IL,
Abstract S51.001, 17 April 2008).
Indeed, it appears that almost
every commonly prescribed or over-
the-counter drug can produce
symptoms that resemble dementia
in the elderly. A pair of researchers
from the Medical University of South
Carolina have reported that many
drugs cause side-effects that include
confusion and memory loss, two
signs of cognitive impairment. In
addition, the problem can be
magnified when the patient is taking
more than one drug at the same
time (J R Soc Med, 2000; 93: 45762).
Polypharmacy
Its evident that the dangers to the
elderly of taking any one drug are bad
enough, but its almost impossible to
measure the negative impact of taking
many drugs at the same time, as most
elderly patients are doing.
Even young Hollywood celebrities,
such as Heath Ledger and Brittany
Murphy, may have died as a result of
taking several pharmaceuticals at the
same time.
As Dr Bruce Goldberger, a professor
of toxicology at the University of
Floridas College of Medicine, said of
the latters death, Mixing a number of
these drugs could have resulted in her
death.
Every drug is tested for its safety and
efficacy on its own, but no one is testing
the lethal cocktails that can result from
taking several powerful chemical
compounds in combination.
Nevertheless, what is clear, as
pharmacologists at the University of
Wales College of Medicine, Cardiff, have
pointed out, is that drugsand
especially polypharmacymay be
responsible for many of the common
health problems seen among the
elderly, such as confusion, weakness,
incontinence, depression and falls, all
of which have been blamed on growing
old (Drugs Aging, 1998; 12: 48594).
Without drugs and medicine,
perhaps getting older wouldnt be such
an unhealthy rite of passage.
Bryan Hubbard
WDDTY Dangerous drugs 39
Drug-induced disease
The damaged brain: how drugs
cause dementia
New evidence shows that all forms of dementia
may largely be caused by most of the drugs we
take as we get older
e may be living longer
W and better than ever but,
by the time we reach our
golden years,
chances of us having any awareness
of it are rapidly fading. Dementia of
the
all varieties, including Alzheimers
disease, is now epidemic,
approaching an incidence similar to
that of the major killers: for instance,
seven million Americans aged over
65 are currently diagnosed with
dementia compared with 10 million
of all ages with cancer.
Furthermore, the incidence rates
of dementia are sharply on the
increase. Predictions suggest that
the disorder will increase fourfold
among the elderly within the next 40
years, and escalate across all age
groups.
Nevertheless, the raw statistics fail
to reveal the most insidious aspect of
the diseasenamely, that the
chances that any one of us will suffer
from dementia sharply increases with
every decade. According to one team
of researchers, who tracked the
incidence of the disorder over time,
after the age of 60, your risk of
developing dementia doubles every
five years. This means that, by the
time you reach your mid-80s, you
face a one-in-four risk of having
dementia and, by the time you reach
90, the odds increase to one chance
in three (Alzheimer Dis Assoc Dis, 2003; 17:
637).
One reason for the prevalence is
simply due to the ambiguous nature
of the term. Virtually every form of
cognitive decline is now classified as
dementia, including memory loss,
and impairment in planning, judg-
ment, reasoning and ordinary
thought processes.
However, modern medicine must
take the greatest blame for the
mental decline seen among the
40 WDDTY Dangerous drugs
elderly. Even though they represent
only one-seventh of the population,
the over-65s take one-third of all
prescription drugsand usually a
cocktail of them. The average senior
is taking six drugs at a time, many of
which affect the brain.
Evidence is emerging that a large
coterie of drugs given for other
conditions, such as high cholesterol,
depression, inflammation, insomnia,
anxiety, heart disease and arthritis
in short, most of the drugs given to
us as we grow oldercan all bring on
dementia.
Many of these drugs cause actual
damage to the structure of the brain,
including shrinking brain volume and
destroying the crucial fatty struct-
ures of brain cells, thus leading to
the abnormal accumulation of tissue
in vital brain structures.
Given the fact that some 90 per
cent of Americans from their mid-50s
onwards are taking at least one drug
regularly and nearly one-third are
taking five or more drugs, it may well
beas American psychiatrist Grace
E. Jackson claims in her brilliant and
damning self-published studythat
dementia is, in many cases, a drug-
induced disease (Jackson GE. Drug-
Induced Dementia. AuthorHouse, 2009). Of
the 36 million Americans who now
take statins, for instance, an
estimated 162,000 people could be
severely cognitively impaired because
of these drugs in the US alone.
The chicken or egg dilemma
Although used as an all-purpose
catch phrase, dementia could be
defined as any condition in which
there is an observable abnormality
involving neurons or glial cells. On
the basis of such a description, it
could be said that there are four
types of true dementia:
u Lewy body dementia, in which
patients have movement disorders
much like those seen in Parkin-
sons disease, with abnormal
deposits of Lewy body proteins,
named after the German neurol-
ogist who first observed them,
throughout the neurons of the
brain;
u vascular dementia, where the
brains blood supply has become
cut off or interrupted, usually as a
result of large or small strokes,
causing the death of neurons;
u frontotemporal dementia, usually
diagnosed in patients aged under
65, where the frontal or temporal
lobes (including the hippocam-
pus) of the brain shrink; and
u Alzheimers disease.
According to Jackson, Alzheimers
victims all share three specific
abnormalities:
u senile plaques, abnormal clumps
of amyloid and other sorts of
proteins that form outside of cells
in the gray matter of the brain;
u neurofibrillary tangles, abnormal,
twisted bundles of fibres within
brain neurons mostly made up of
tau proteins that impair the
formation of tubulin, a protein
necessary for healthy connective
nerve tissue, the result of which is
that messages in the brain arent
transmitted properly; and
u granulovacuolar degeneration
(GVD), where neurons in the brain
have abnormal holes (vacuoles),
 each of which contains a small,
dense protein.
The problem is that researchers
cannot agree on whether these
characteristic findings are the cause
or the effect of an abnormal process
in the body. The evidence from
studies of the effects of aluminium
and mercury on the brain suggest
that they are the result of toxicity
rather than being a true cause of
dementia. In test-tube studies using
human brain cells, for instance,
minute doses of mercury produced
changes identical to those seen in
Alzheimers disease (J Neurochem, 2000;
74: 2316).
In other, animal studies, professor
of medical biochemistry Boyd Haley
and colleagues at the University of
Kentucky fed rats aluminium, but
observed no changes in tubulin
levels, whereas mercury-fed rats
displayed diminished tubulin levels
similar to those seen in typical
Alzheimers patients. Furthermore,
some researchers suggest that the
vacuoles seen in GVD are filled with
toxic materials, such as aluminium,
which the neuron has fenced in to
keep the rest of the brain safe (Am J
Pathol, 1999; 155: 116372).
Research at the University of
Pittsburgh has discovered that a fat-
binding agent known as apolipo-
protein D (or apoD in medico-speak)
is present in the brain plaques seen
in patients with Alzheimers disease.
However, apoD is also found in
other kinds of pathology, and many
animal and human studies have
shown that antipsychotic drugs
induce the production of apoD.
Furthermore, scientists have found
this type of lipoprotein in fat and
brain cells following injury, which
suggests that it plays a role in cell
renewal and repair.
Nevertheless, the evidence in
general suggests that toxicitya
form of insult to the brainrather
than natural cellular degeneration is
the cause of dementia.
Antidepressants
There is no doubt that certain drugs
cause damage to the structure of the
brain, thereby impairing its function.
Among the chief offenders are
antidepressants, which appear to
target the white matter of the brain.
Why the brain needs fats
Although medicine used to believe that the master conductor of brain
activity was the neurons, or nerve cells, that create and release
neurotransmitters and electrical signals, this view has been revised by a
more holistic view of the brain. This concept appreciates that the brain
works in its entirety through a web of activity between neurons and four
varieties of glial cells. Glial cells, which surround the neurons, keep them
in place, provide them with nutrients, and destroy and mop up pathogens.
They also insulate one neuron from another and modulate the transmission
of signals. One major function of glial cells is to form myelinthe insulating
sheath that covers every tentacle of a nerve cellwhich is largely made up
of lipid (fatty) tissue.
Yeon-Kyun Shin, a professor of biophysics at Iowa State University,
recently went on record to say that high cholesterol is vital for good brain
function, and a lack of cholesterol impairs the brains thinking ability and
memory.
If you deprive the brain of cholesterol, then you directly affect the
machinery that triggers the release of neurotransmitters. Neurotransmitters
affect the data-processing and memory functions; in other words, how
smart you are and how well you remember things, he said (Proc Natl Acad
Sci USA, 2009; 106: 51416).
The white matter is the part of the with those for patients who were not
brain that contains bundles of nerve using any such drugs.
fibres covered with myelin, a white They found similar incidences
fatty substance that forms an insu- between the two groups of virtually
lating sheath around each fibre. It is every condition looked atdiabetes,
through these neural bundles that stroke, heart attacks, hypertension
messages are passed between save one. Those taking the anti-
different areas of gray matter, which depressant drugs experienced more
is made up of unmyelinated nerve bright spots in the white matter on
cells, within the nervous system. MRI. This sort of appearance on a
This means that the white matter scan is thought to indicate damage
is rather like a telephone network, to blood vessels, impaired blood flow,
responsible for the rapid transmis- demyelination (degeneration of the
sion of nerve impulses and cell-to-cell myelin sheath of nerve cells),
communication. disintegration of the bloodbrain
One natural aspect of ageing is barrier and even damage to the nerve
losing neural connections. Each of us cells in the gray matter of the brain
begins adulthood with some 176,000 (Stroke, 2008; 39: 85762).
km of white matter, but we all should Indeed, those taking the drugs
expect to lose around 10 per cent of suffered a 36-per-cent incidence of
these connections with every decade white-matter damage compared with
of life. 27 per cent in those who had been
However, antidepressants clearly drug-free over the decade. In
hasten this process. In 2008, a US addition, all types of antidepressants
study carried out by Duke University be they old or newhastened the
Medical Center in Durham, NC, decline. Whats more, although the
published the results of the 10-year worst offenders were the old-style
study, which examined the magnetic tricyclic antidepressants, adverse
resonance imaging (MRI) scans of effects were observed with all of the
more than 1800 patients performed newer types of drugs that inhibit the
over two periods of timefirst, from uptake of serotonin. Overall, 60 per
1991 to 1994, and then, from 1997 cent of the patients who used either
to 1999. The authors compared the type of antidepressants showed
findings for the 163 patients who increased damage to white matter
had begun taking antidepressants that was above the norm.
between the first and second scans Antidepressants also appear to
WDDTY Dangerous drugs 41
Drug-induced disease
shrink the hippocampus, part of the
limbic system of the brain that is
involved in long-term memory,
spatial navigation, learning and
mood. There is solid scientific
evidence that patients who are
chronic users of antidepressants,
particularly SSRIs (selective seroto-
nin reuptake inhibitors) such as
Prozac (fluoxetine), have smaller
hippocampal structures compared
with controls.
In one fascinating study, the
hippocampi of long-time depressed
patients who were taking long-term
medication were compared with
those of two other patient groups:
those whod just been diagnosed
with the illness and had not yet
begun taking any drugs; and a group
of non-depressed controls. There
was no difference in brain size
between the just-diagnosed depress-
ed patients and the controls, whereas
the long-time medicated showed a
hippocampus that was 12 per cent
smaller, on average, than those of
the others (Proc Natl Acad Sci USA, 2003;
100: 138792).
The importance of this study is
that it demonstrates that its the
drugs themselves, and not the
depression on its own, that causes
the brain to shrink.
Autopsies of cavaders have also
revealed brain damage in those
whod been long-term users of anti-
depressants. In one Dutch study, of
patients whod been taking anti-
depressants, 73 per cent showed
evidence of brain cell death
(apoptosis) compared with 33 per
cent in patients using long-term
steroids and 6 per cent of their
matched controls (Am J Pathol, 2001;
158: 45368).
In addition, epidemiological
studies have also shown a greater
incidence of dementia among
populations using antidepressants.
Researchers in Copenhagen carried
out a sweeping study, involving nearly
a third of the entire Danish popu-
lation, focused on patients aged over
40 whod taken antidepressants, even
if just one single time. The risk of
developing dementia was two to five
times higher in those whod used
antidepressants compared with non-
users (J Affect Disord, 2009: 117: 249).
However, Jackson believes that
42 WDDTY Dangerous drugs
The role of coenzyme Q10
It is well known that patients taking statins lose coenzyme Q10 (CoQ10) in
a dose-related manner. The drugs block production of both cholesterol
and CoQ10 by inhibiting the enzyme precursor of not only cholesterol, but
also that of CoQ10.
CoQ10 participates in chemical reactions, particularly those that involve
cellular energy production, and helps to make cell membranes more resis-
tant to oxygen damage. It is found abundantly in the heart mostly because
of the huge energy requirements of cardiac cells.
In fact, studies have shown that a deficiency of CoQ10 is linked with
heart failure and impaired heart function. Of 15 published studies in the
literature, nine have confirmed that statins can significantly lower CoQ10
levels (Arzneim Forsch, 1999; 49: 3249).
Critics of statins believe that the widespread use of these drugs has
caused an increase in statin cardiomyopathy, where the heart loses its
ability to pump blood or heart rhythm is disturbed, leading to irregular
heartbeats. Drug manufacturers tacitly acknowledge this effect by offering
several drug formulations that combine a statin with CoQ10.
But a less well-known problem with blocking CoQ10 is that it interferes
with cognitive performance, resulting in memory loss and muddled
thinking. In an elderly person, this sort of side-effect is almost invariably
passed off as age-related dementia, requiring yet another coterie of
wonder drugs.
Other researchers have been discovering that statins also inhibit and
cause mutations in mitrochondria cells, the energy power packs of the
body. Scientists now suspect that an array of neurodegenerative diseases
are due to mutated or altered mitochondria.
this population study may have biosynthesis. Nevertheless, although
underestimated the risk, as one-fifth the drugs lowered cholesterol in the
of those using antidepressants died brain, this had no alleviating effects
during the study follow-up period. on Alzheimers disease whatsoever
(Alzheimer Dis Assoc Disord, 2010 May 13
Statins doi: 10.1097/WAD.0b013e3181d61fea).
Statins, those miracle cholesterol- In fact, the lack of effectiveness
lowering drugs, also appear to lead to of statins as a treatment for
progressive cognitive decline. This is Alzheimers disease was finally estab-
particularly ironic, as medicine has lished last year, when two reviewers
been under the illusion that cutting independently analyzed two large-
down on cholesterol in the elderly is scale randomized controlled trials,
desirable particularly for the brain involving a total of 26,340 patients as
(see box, page 41) and, consequently, part of the HPS 2002 and PROSPER
that statins can keep Alzheimers at 2002 studies, and reached an agree-
bay. ment after discussing their results.
It is true that statins can cross Their conclusion was that statins
the bloodbrain barrier and alter given late in life to individuals at risk
cholesterol metabolism in the brain, of vascular disease have no effect in
but this has no bearing on preventing either Alzheimers
Alzheimers disease. Earlier this year, disease or dementia (Cochrane Database
Harvard University researchers, in Syst Rev, 2009; 2: CD003160).
conjunction with a number of other Indeed, far from helping memory
centres in the US, Germany and and cognitive function, statins can
Spain, gave statins for 12 weeks to cause sudden and complete memory
patients with mild Alzheimers loss.
disease or mild memory loss. This evidence emerged when flight
During the course of this study, surgeon Duane Graveline suffered
they found a modest but signifi- global amnesia when taking atorva-
cant inhibition of brain cholesterol statin (Lipitor) for the first time.
When his family doctor Jay S. Cohen
took up his case with Pfizer, the
drugs manufacturer, he was sent
clinical evidence gathered before the
drugs release showing that there
were 4.5 cases of severe cognitive
disturbance out of every 100 patients
given the drug.
This included cases of impaired,
worsening or general lapses of
memory, general forgetfulness and
short-term memory loss. Pfizers own
studies had also discovered instances
in which patients had difficulty
concentrating, or suffered
abnormally slow or difficulty in
thinking, slowed or decreased mental
activity, impaired intellect or
judgment and even irrational
thinking.
Graveline and Cohen then con-
ducted an online literature search of
MedWatch, the US Food and Drug
Association (FDA) database of
reported drug side-effects, for
reports of severe cognitive
impairment or serious amnesia
associated with Lipitor. They found
662 such reports, including 399
cases of amnesia and 236 cases of
memory impairment. The
investigating pair also found that,
over time, the complaints had
become more frequent (Townsend Lett
Docs, 2009; 311: 6470).
MedWatch, which is thought to be
notified of only 2.5 to 5 per cent of
all drug side-effects, therefore suffers
from vast underreporting, so the true
incidence of memory problems from
statins is probably closer to 66,000
or more. In fact, Graveline and
Cohen believe that virtually every
patient taking the drug suffers from
cognitive damage in one form or
another that may be too mild to be
initially detected. This is perhaps
because all statins lower levels of
coenzyme Q10, known to be vital for
brain function (see box, page 42).
Graveline and Cohens detective
work has also been vindicated by a
meta-analysis carried out by Duke
University in Durham, NC, which
uncovered 60 patients with memory
loss attributable to statins. Half the
patients had noticed cognitive
decline within just two months of
starting the drugs; of these, more
than half found that their memory
improved as soon as they stopped
Other drugs to avoid
Besides the agents already mentioned (see main story), there is mounting
evidence that you should also avoid the following types of drugs.
u Stimulants, such as methylphenidate (Ritalin). A vast number of animal
studies show that all amphetamines cause parts of the brain to shrink,
trigger degeneration of dopamine cells in the brain and reduce the
survival of neurons in the hippocampus, among many other effects
(Jackson GE. Drug-Induced Dementia. AuthorHouse, 2009).
u Beta-blockers, calcium-channel blockers and ACE inhibitors, and
other drugs that aggressively lower blood pressure. These antihyper-
tensives can lower blood flow to the brain and produce all the hallmarks
of Alzheimers disease (Drugs Aging, 1999; 15: 1528).
u Antiarrhythmic drugs, given to correct abnormal heart rhythms, can
also cause dementia.
u Anticholinergic drugs, a giant category that includes drugs for gastro-
intestinal problems such as diverticulitis and ulcerative colitis,
respiratory ailments such as asthma and genitourinary disorders such
as cystitis or prostatitis, are associated with cognitive decline in the
elderly (Presentation at the American Academy of Neurology 60th Anniversary
Annual Meeting in Chicago, IL, 17 April 2008).
u Opioids, many of which can cause delirium (Drugs Aging, 1993; 3: 34957;
Postgrad Med J, 2004; 80: 38893).
u Non-steroidal anti-inflammatory drugs (NSAIDs). Initially thought to
offer protection against Alzheimers, different types of these common
painkillers can cause a variety of cognitive changes, ranging from
delirium (indomethacin and sulindac) to disturbances in memory and
concentration (naproxen and ibuprofen) (Drugs Aging, 1999; 15: 1528).
u Levodopa. This antiparkinsonian medication causes cognitive
symptoms in up to 60 per cent of users (Clin Geriatr Med, 1998; 14: 10127).
taking the drugs. Furthermore, all of introduced the next generation of
the four patients who started taking neurolepticswhich also includes
the drugs again suffered a recurrence olanzapine (Zyprexa), quetiapine
of their memory problems. (Seroquel) and risperidone (Risper-
As a further nail in the coffin, not dal)that were dubbed atypical
one single experimental study could antipsychotics to distinguish them
find any evidence to support any from their older and supposedly more
benefit with statins in delaying dangerous cousins. These drugs are
cognitive decline (Pharmacotherapy, supposed to suppress the psychotic
2003; 23: 87180). and antisocial aspects of schizo-
phrenia without all the antipyramidal
Antipsychotic agents effects (World J Biol Psychiatry, 2000; 1:
Another major culprit causing 20414).
dementia is that broad class of drugs However, this newer generation of
called antipsychotics. The first so- drugs comes with its own laundry list
called neuroleptic medications were of dangerous, even life-threatening,
developed in the 1950s to relieve side-effects, including serious mental
patients suffering from hallucina- deterioration.
tions, paranoid schizophrenia and There is no doubt that the so-
other psychoses. Unfortunately, called antipsychotic drugs can
these drugs brought with them cause or speed up the development of
unwanted extrapyramidal (brain dementia (J Neurol Neurosurg Psychiatry,
motor system) side-effects such as 2007; 78: 2339). This is ironic because
tardive dyskinesia, characterized by these drugs are often given to sedate
muscle stiffness, tics, tremors and or calm patients with dementia,
other awkward movements. whereas it appears that they are also
The arrival of clozapine (Clozaril) speeding up and worsening the
WDDTY Dangerous drugs 43
Drug-induced disease
process of cognitive decline.
Nevertheless, the most compelling
evidence comes from autopsy studies
that have compared patients using
antipsychotic drugs with those who
did not.
In one study by the Wolfson Centre
for Age-Related Diseases at Kings
College London, those whod been
given neuroleptics had a 30-per-cent
greater density of amyloid plaques
and 65- to 367-per-cent more
neurofibrillary tangles than those
who were free of neuroleptic drugs
(Int J Geriatr Psychiatry, 2005; 20: 8725).
Moreover, in a similar US study,
102 patients with schizophrenia
showed evidence on autopsy of brain
deterioration that was suggestive of
Alzheimers or some other form of
dementia. The signs were present in
74 per cent of those whod been
given antipsychotic drugs, but in only
36 per cent of those whod died prior
to the advent of these drugs (Alzheimer
Dis Assoc Disord, 1994; 8: 21127).
In other words, taking anti-
psychotics more than doubled the
patients chances of developing
dementia.
The worst combination of all is
taking an antipsychotic together
with an antidepressant, which
appears to quadruple the speed at
which the disease develops (J Neurol
Neurosurg Psychiatry, 2007; 78: 2339).
Whats more, Alzheimers patients
who are given an antipsychotica
common practice, usually to sedate
themhave double the usual risk of
death. In a major study involving
various centres across the UKthe
first independent study of its kind
not paid for by a drug companyless
than half the patients (46 per cent)
taking an antipsychotic were still
alive at the two-year follow-up. After
three years, only 30 per cent of those
taking antipsychotics were alive
compared with 59 per cent taking a
placebo (Lancet Neurol, 2009; 8: 1517; doi:
10.1016/S1474-4422(08)70295-3).
In another UK study that was
focused on care facilities in the
North East of England, the London-
based researchers compared the
efficacy of the antipsychotic quetia-
pine, the cholinesterase inhibitor
rivastigmine and a placebo in
calming institutionalized patients
with dementia. Neither of the
44 WDDTY Dangerous drugs
patients in the active-treatment
groups were any calmer than those
who were simply taking sugar pills,
although there was one significant
difference with quetiapineit was
associated with significantly greater
cognitive decline (BMJ, 2005; 330: 874).
Antipsychotics also appear to
shrink the volume of the frontal lobes
of the brain by 0.2 per cent per year,
according to a University of Iowa
study (Arch Gen Psychiatry, 2003; 60:
58594). Other studies have shown
size reductions in a variety of areas of
the brain with both older (halo-
peridol) and newer (olanzapine)
antipsychotic medications (Arch Gen
Psychiatry, 2003; 60: 58594).
What is coming to light is a clear
association between antipsychotic
drugs and cognitive decline. In a
painstaking English survey, every
case of dementia recorded on a
dementia register during 19931994
was examined. Researchers studied
the patients diagnoses and treat-
ments from their various medical
carers and interviewed their next of
kin, then matched these patients to a
similar group of elderly people living
in Southeast London.
Of the patients on the register, 13
per cent had a past history of
psychiatric treatment, and the use of
psychiatric drugs was three to four
times higher among those whod
gone on to develop dementia (Age
Ageing, 1998; 27: 1818).
Benzodiazepines
In addition to the major anti-
psychotic drugs, benzodiazepine
tranquillizers and sleeping pills are
also responsible for cognitive
decline. One Argentinian study noted
evidence that sleeping pills, which
are often handed out without a
prescription in that country, led to
severe memory and cognitive
impairment, and delirium (Vertex,
2001; 12: 2725).
Newer studies now show that this
effect has to do with an effect on
gangliosides in the brain. These
molecules, which contain fat and
sugar, are present to a large extent in
brain lipids and on the surface of
every neuron. They are essential for
regulating cell growth, maintaining
the integrity of the material con-
tained within cells, and responding
to foreign invasion by toxins and
bacteria. Without these gangliosides,
we lose myelin and entire neurons,
and may even die.
A series of studies by the Institute
for Medical Research in Belgrade,
Yugoslavia, has demonstrated that, at
least in ratsso it may not apply to
humanschronic doses of Valium
(diazepam) led to the loss of 46 per
cent of gangliosides in the cere-
bellum within six months. After a
short period of total drug withdrawal,
the rat brain still had not fully
recovered (Physiol Res, 1999; 48: 1438).
When the researchers repeated
the study in 2002, focusing especially
on the effects of the drug on various
regions of the brain, they found
significant reductions of gangliosides
in the hippocampus, cerebral cortex
and cerebellum, as well as increases
of simple gangliosides in other areas
(Neurol Sci, 2002; 23: 6974). These
findings are consistent with those of
many human neurological diseases,
including Alzheimers.
Indeed, in a 1993 British study,
researchers took computed tomog-
raphy (CT) brain scans of long-term
benzodiazepine users and compared
them with those of drug-free
controls. The scans revealed that the
drug users had a reduction of brain
tissue in their frontal and occipital
lobes, as well as in the left caudate
nucleusareas that are crucial for
cognitive function (Psychiatry Res, 1993;
48: 13544).
At present, in the US alone, six
million patients are being treated for
dementia at a cost of $90 billion, or
one-third of all Medicare bills. This
means that 1 per cent of the entire
gross domestic product of the US is
being spent on a mostly iatrogenic
(doctor-induced) condition.
Medicine has reached the point
where it is chasing its own tail,
attempting to mop up with yet more
drugs and treatments a vast and
costly problem that it has itself
caused in the first place.
Evidence is mounting that one of
the major toxic insults to the brain is
the mercury from amalgam fillings,
but this effect may be eclipsed by
the dangers we face from the modern
medical response to ageing.
Keeping bright and alert in old age
requires a few simple practices:
regular exercise; eating an anti-
oxidant-rich wholefood diet along
with good fats; minimizing toxic
exposure to heavy metals; engaging in
regular brain workouts (crossword
puzzles or reading); and staying
connected through a social network.
However, now there is one more
simple homily to add to the list: avoid
as many prescription drugs as you
can.
Lynne McTaggart
WDDTY Dangerous drugs 45
Drug-induced disease
Anticholinergic drugs: the
stupid pills
A giant class of drugs has
been implicated in the
development of dementia
and loss of physical
functionality
nticholinergic drugs, widely
A
prescribed to the elderly for
everything from incon-
tinence to ulcers, can hasten
an older persons decline.
Recent studies carried out in the US
found that nursing-home patients
taking dementia and incontinence
drugs at the same time had a 50-per-
cent faster rate of physical decline
compared with those taking only
dementia drugs.
Anticholinergics work by blocking
impulses in the parasympathetic
nervous system, responsible for the
involuntary actions of smooth muscle
in many parts of the body. They also
prevent the neurotransmitter acetyl-
choline from binding with its receptors
in nerve cells.
Three types of these drugs are used
for problems such as ulcers, bladder
spasm, heart arrhythmias, motion
sickness, Parkinsons and control of
blood pressure, and as muscle relax-
ants or pre-anaesthetics. Perhaps the
best-known examples of this drug
family are Zantac (ranitidine) and
nifedipine (Adalat, Procardia).
In this latest study, researchers
examined 3536 nursing-home resi-
dents, aged 65 and older, who were
taking a bladder anticholinergic (oxy-
butynin or tolterodine) for incon-
tinence. They then carried out
repeated analyses to assess the effects
of the two drugs on cognitive function,
and also examined any changes in daily
activities. Around 10 per cent of the
residents were taking both drugs.
They found that the combination
of drugs most affected those whod
started out with higher levels of
functioning in activities such as
personal hygiene, dressing, bed
mobility, eating and toileting. Among
these residents, those given both drugs
46 WDDTY Dangerous drugs
suffered a 50-per-cent greater decline
in functionality compared with those
given only cholinesterase inhibitors
[for Alzheimers (AD)].
Those given both drugs dropped
1.62 points per quarter on the scale for
daily living function, while those given
the single drug for AD declined 1.08
points. Those starting out with lower
functionality had no further decline
with both drugs compared with single
therapy (J Am Geriatric Soc, 2008; 56:
84753). However, the research-ers
concluded that the tests they
used were not sensitive enough to
determine whether taking both drugs
together increased mental decline.
Nevertheless, according to the
studys lead author, Kaycee Sink, the
decline was analogous to a nursing-
home resident who initially required
only limited assistance suddenly
becoming completely dependent on
others to help him perform his daily
routine.
The researchers believe that the
results may be due to an oppositional
effect between the two sorts of drugs.
Dementia drugs such as donepezil
(Aricept) and galantamine (Raza-dyne)
increase acetylcholine, whereas the
anticholinergics do just the opposite.
The team concluded that such
pharmacological opposites would
cancel out the effectiveness of either
or both drugs.
However, even on their own, anti-
cholinergics may lead to functional
decline. Older adults taking these
Dementia or side-effects?
u Loss of coordination
u Disorientation
u Agitation
u Confusion
u Short-term memory loss
u Inability to concentrate or maintain a train of thought
u Illogical thinking
u Incoherent speech
u Muscle jerks
u Visual and auditory hallucinations.
drugs on their own for incontinence,
high blood pressure or allergies are
likely to suffer from impaired physical
function.
This was shown in a study of 3000
seniors, 40 per cent of whom were
taking anticholinergics. Patients whod
started out needing only limited
assistance in a physical activity were
entirely dependent on assistance one
year later. These findings were pre-
sented at the American Geriatrics
Society meeting in Washington, DC, in
May of this year. According to the
researchers, these effects were seen
even in older adults who had normal
memory and cognitive abilities.
The effect is essentially that of a
three- to four-year increase in age,
said Sink. So someone who is 75 in
our study and taking at least one mod-
erately anticholinergic medication is
at a similar functional level to a 78 to
79 year old.
Earlier studies suggested that drugs
for incontinence may be associated
with cognitive decline.
The most worrying aspect of these
studies is the sheer number of elderly
people whose decline is being hasten-
ed by polypharmacy. Dementia and
incontinence represent two of the
most common conditions for which
drugs are dispensed in nursing homes.
According to Sink, nearly a third of all
patients taking anticholinergics also
take a drug for incontinence.
In this instance, Alzheimers may
not be all in the patients head. With
this class of drugs, a patient may be
trading incontinence for incapacity.
Lynne McTaggart
Diabetes: epidemic by prescription
Dr Lisa Landymore-Lim, a British chemist specializing in
immunology and biomedical chemistry, became curious
about the explosion of childhood illnesses such as
asthma and diabetes, and carried out a pilot study of
drug-prescribing among juvenile diabetics. In 1994,
WDDTY published her initial findings. Here is her
evidence for suggesting a link between the excessive use
of antibiotics and diabetes.

ases of chemicals and drugs destructive agents that have been

C causing temporary and per-

manent insulin-dependent
dia-betes (IDD) are well
documented in the medical lit-erature
(Pharmacol Rev, 1970; 2: 485518; J Rheumatol,
implicated in the onset of cancer.
Other chemicals known to be
capable of producing diabetes in
humans include the drugs dapsone,
used in the treatment of leprosy, and
1987; 14: 7325). Unfortunately, such pentamidine isethionate, an anti-
cases dont usually come to the protozoal agent used to treat pneu-
attention of physicians, and most monia in AIDS patients.
patients are completely unaware of However, dapsone and pentamidine
these potential hazards. bear little structural resemblance to one and pentamidine with the drugs
Two of the best-known chemicals streptozocin and alloxan, except that frusemide and chlorthiazide, diuretics
capable of damaging pancreatic beta dapsone does contain electronegatively reportedly associated with the onset
cellsresponsible for the production charged oxygen atoms that are double- of diabetes, also reveals structural
of insulinare the antibiotic strep- bonded to sulphur (instead of carbon). similarities. In frusemide, once again
tozocin (Zanosar, also used in Both drugs also have electronegative we see the electronegative sulphonyl
chemotherapy) and the chemical terminal amino (NH2) groups attached (S=O) group and a terminal amino
alloxan. These drugs are routinely used to, or in close proximity of, a benzene (NH2) group, whereas chlorthiazide
in animal experiments to study ring. has two SO2 groups and a terminal
diabetes. Vacor, a rat poison, has also Nevertheless, comparison of daps- NH2.
been reported to cause the disease.
There is a structural similarity
between the chemicals streptozocin, Dispensing habits in the UK
alloxan and Vacor: in each, there is at
least one oxygen atom joined by two
Region Rates per 100,000 of incidencea
bonds to a carbon atom (C=O),
forming a carbonyl group, which is
East Anglia 17.7b
flanked on each side by a nitrogen (N)
Wessex 17.1c
atom.
Northern 15.8c
This is of interest because carbonyl
Mersey 15.8c
groups and nitrogen atoms can be
Oxford 15.2c
considered reactive species due to
Yorkshire 14.9c
their excess of negative charge. This
North Western 14.6c
means that they are electron-rich and,
Trent 13.5c
thus, have an affinity for positively
South Western 13.4c
charged species such as zinc ions
West Midlands 13.3c
(Zn2+). Thus, they behave like mag-
SE Thames 13.1d
nets, attracting oppositely charged
SW Thames 12.4d
species.
NE Thames 11.8d
Insulin is stored in the pancreas
NW Thames 8.0d
together with zinc. In fact, the pan-
creas has the highest concentration of aof diabetes in children under 15 years of age; bhigh; dmedium; dlow
zinc in the body, making it potentially
NB: This shows more than a twofold variation in incidence between the North
a major target for chemical attack.
West Thames region and East Anglia. What could account for such variation
In addition, double-bonded oxygen
between area health authorities that are situated in close proximity? Could it be
groups are also potential sources for
that dispensing practices are a factor in the onset of diabetes?
the formation of free radicals, those

WDDTY Dangerous drugs 47

Drug-induced disease
Indian J Exp Biol, 1982; 20: 934).
It has also
NIDD: low-grade poisoning? been reported that penicillin interacts
with zinc (J Pharm Pharmacol, 1966; 18:
Non-insulin-dependent diabetes (NIDD), where the diabetic symptoms are not 72938).
severe enough to warrant the use of insulin, is, in the present authors opinion, So, it is conceivable that a chemical
simply subclinical insulin-dependent diabetes. Many patients who are not such as penicillin circulating in the
treated with insulin have abnormally high blood-glucose levels and often bloodstream could be attracted to the
eventually require insulin. beta cells of the pancreas, which
One reason why insulin-dependent diabetes (IDD) and NIDD have been contain zinc. This could result in the
considered two separate and distinct disorders is that NIDD is most commonly displacement of insulin bound to zinc
detected in mature adults and islet-cell antibodies are not found in such and chelation of penicillin to zinc,
patients. However, if chemicals are capable of causing diabetes and with thereby changing the acidity within
exposure taking place over many years, antibody levels in NIDD may be low the cells as new, different bonds are
as the onset of the disease is likely to be much more gradual. formed. This, in turn, could cause the
The idea that IDD and NIDD are essentially the same disorder (apart from insulinzinc aggregates to dissolve,
differences in the degree of insulin-producing impairment) is supported by the leading to a marked increase in
following findings: osmotic pressure and cellular rupture.
u Some 50 per cent of newly diagnosed IDD children do not have detectable It is then possible that such
islet-cell antibodies chemical changes within the pan-
u Some 8 per cent of non-diabetics have been found to have islet-cell creatic beta cells might activate the
antibodies bodys immune-defence system, result-
u Many NIDD patients eventually require insulin therapy ing in the formation of antibodies
u NIDD has been found to be as common as IDD in a study of school children directed against the beta cells in an
in Japan. attempt to bind and destroy them, as
they are now seen as being foreign to
the body.
Such groups are not commonly similarity with chemicals known to This may account, at least in part,
found in drugs. In the American cause diabetes. for the presence of islet-cell antibodies
Hospital Formulary Service Drug To summarize, the chemicals and in the blood of many newly diagnosed
Information database, which lists some drugs currently known or suspected to diabetics. And if this is so, the agent
1000 drugs, less than 5 per cent have be associated with a risk of diabetes that caused the diabetes would be the
either an amino group or a carbon appear to have a primary amine (NH2), chemical that led to rupture of the
atom bound to a benzene ring. a carbonyl (C=O) group close to a pancreas cells, but not to the pro-
Sulphonyl groups, however, are nitrogen or an oxygen atom, and S02 or duction of antibodies, as the cells
commonly found in thiazide diuretics NO2 groups. Primary amines and of the pancreas have already been
and sulphonamide drugs. Alarmingly, oxygen atoms bound to carbon, damaged.
in Australia, diuretics like hydro- sulphur or nitrogenall considered This is an important distinction as,
chlorthiazide (identical to chlorthia- reactive species due to their negatively after the discovery of islet-cell anti-
zide except for an additional hydrogen charged centreswill bind to zinc bodies, the current scientific thinking
atom) are given to young women to under the right conditions by a process as to the origin of diabetes has centred
treat premenstrual water retention. known as chelation, a form of tight on its being an autoimmune disorder,
Indeed, diuretics are among the top chemical attachment. causing the body, for some unknown
most frequently prescribed drugs in The pancreas, being a rich source reason, to manufacture antibodies
the West. If drugs such as thiazides of zinc, could therefore be a potential directed against pancreatic beta cells,
are causing diabetes, then it comes target for attack by zinc-seeking damaging their ability to produce
as no surprise that the incidence of chemicals. Indeed, it has been sug- insulin. This scenario implies that it is
diabetes is increasing in adults. gested that chemicals that can cause the patients constitution (immune
There have also been reports that diabetes may do so by interacting with function) that is at fault.
some antihypertensives (drugs pres- zinc in the insulin-secreting beta cells However, if chemicals and drugs
cribed to control high blood pressure) of the pancreas (Mol Pharmacol, 1985; 27: can cause diabetes, there is every
may also cause diabetes. One of these 36674). likelihood that both IDD and NIDD
is the calcium channel-blocker This suggestion is supported by which in many Western countries
nifedipine. Again, although the overall the fact that diabetes arising from today has reached epidemic propor-
structure of this drug is not like any of chemical exposure is accompanied by tionsare predominantly the result
the other drugs previously mentioned, a loss of detectable zinc from the of chemical exposure by way of pres-
it does contain several electronega- pancreatic beta cells (Arch Exp Pathol cription drugs.
tive double-bonded oxygen groups, Pharmakol, 1952; 216: 45772), and that zinc
including an NO2 group bound to a injected into animals before exposure Possible zincdrug interaction
benzene ring such as is found in Vacor to a diabetes-causing chemical will If its true that drugs, or the chemical
rat poison. So, indeed, it is evident that protect the animals against developing byproducts formed in the body fol-
nifedipine shares some structural the disease (Anat Record, 1951; 109: 377; lowing their ingestion, have an affinity

48 WDDTY Dangerous drugs

for zinc, then when they enter the
bloodstream and pass through the
pancreas, they will bind to the zinc
in the islet cells of the pancreas. This
could displace someif not allof
the six insulin molecules that are
temporarily bound to zinc in the
pancreas.
Such an interaction could change
the acidity of the cells, causing them
to burst as the osmotic pressure within
them becomes too great. The result
would be irreversible damage to the
cells that, in turn, could result in
activation of the immune system as it
detects a deformed cell, which it
would regard as foreign (abnormal
in form).
This would trigger the formation of
antibodies, proteins that are directed
against such foreign (non-self) agents
within the body, and explain why many
newly diagnosed diabetics have islet-
cell antibodies in their blood.
However, if this were the case, these
islet-cell antibodies would simply be
formed as a result of preexisting
damage to the pancreas, but would
not be the agents responsible for the
destruction of the insulin-producing
capacity of the pancreasas is cur-
rently thought.
If chemicals such as drugs or their
byproducts are not responsible for
eliciting an immune response that
results in the formation of antibodies,
the unanswered question then
remains: what is it that triggers the
immune system to produce these
antibodies?
On the other hand, if some
chemicals are indeed capable of
destroying the ability of pancreatic
beta cells to secrete insulin, as is
known to occur in those who have
ingested the rat poison Vacor, then it
is conceivable that the damage may
be gradual, with just a portion of the
pancreas being destroyed with each
chemical attack.
Also, it would appear to be logical to
suppose that children who are exposed
as fetuses and newborns to such an
agent might become diabetic at a
younger age than those exposed to the
same agent as babies or children, and
may require only one exposure to cause
damage if it occurred in utero or soon
after birth.
For example, if a fetus of 25 weeks
has half of its insulin-producing cells
Drugs causing diabetes
One drug that appears to have the potential to cause diabetes is the barbiturate
phenobarbitone, due to its similarity in structure to the chemical alloxan.
Phenobarbitone and other barbiturates used in human medicine also bear some
resemblance to alloxan.
Chemical modifications of alloxan have also been shown to cause diabetes
in some animal models. So, all of these chemicals, which share structural
similarities, can cause diabetes in animals. Nevertheless, Lisa Landymore-Lim
is unaware of any investigations into their potential diabetogenic effects in
humans.
The following drugs could be considered the major potential culprits in
causing diabetes:
u Antibiotics
Penicillins (such as amoxycillin)
Cephalosporins (structurally similar to penicillin)
Erythromycin
u Tranquillizers
Barbiturates (structurally similar to alloxan)
Benzodiazepines
u Other drugs
Syntocinon (synthetic hormone, used to induce labour, containing
ergometrine)
Ergometrine (used to stop postpartum bleeding)
Paracetamol (analgesic).
already destroyed during its devel- personal communication).
opment, it would be unlikely to present The probability of binding (chela-
any of the clinical symptoms currently tion) between zinc and organic
associated with diabetes. However, compoundsthat is, compounds
after birth, the child may be expected containing carbon, nitrogen and
to run out of its insulin-producing oxygenis high. Such binding usually
capability at an earlier age than a baby occurs between the negative-ion-
that is exposed to the same amount rich centres of either the oxygen or
of toxic chemical, but after birth. In nitrogen groups of the chemical and
the latter child, a smaller proportion of the positively charged zinc (Zn2+) ion.
the pancreas would be affected as its In the case of insulinzinc complexes
exposure was later in its development. found naturally in the pancreas, the
Damaged pancreatic cells, unlike liver binding is reversible, as it enables
cells, are not replaced as they lack any insulin to be stored until required.
significant capacity for regrowth. Whatever the route of destruction of
So, as the body weight of both these the pancreas ability to secrete insulin,
infants increases after birth, the one it is worthwhile noting that some of
with the lower level of insulin- the drugs that diabetic children are
producing capability would be exposed to during fetal development
expected to exhibit signs of diabetes are structurally similar to each other.
sooner, at an earlier age. For example, in the survey of diabetic
The drug penicillaminewhich is children that I carried out, one child
also one of the breakdown products of was exposed to Asacol (mesalamine)
penicillinis an effective chelator of and another to paracetamol. The
metal ions, including zinc, and is used structure of Asacol is similar to para-
in medicine as chelation therapy for aminophenol, a highly toxic chemical
the reduction of toxic levels of zinc formed in the body in tiny quantities
salts. Also, although erythromycin was following paracetamol (acetamino-
reported some 25 years ago as not phen) breakdown.
binding to zinc, it is now known that Whats more, Asacol and penicilla-
it can be made to react in vitro [in mine both have an amine (NH2) and a
the lab] in a one-to-one ratio (Brocades carboxyl (COOH) group.
Pharma [now known as Yamanouchi Europe], a A drug connection would also
WDDTY Dangerous drugs 49
Drug-induced disease
account for another mysterious feature
of diabetes: that only the beta cells of
the pancreas are destroyed. The alpha
and delta cells of the pancreas, also
located in the islets of Langerhans
where the beta cells are, are not
damaged in diabetes. It is only the
zinc-containing beta cells that are
damaged. This selective destruction
may well be caused by chemicals with
an affinity for zinc.
UK dispensing practices
When considering diabetic children in
the same family, rather than heredity,
the cause may be the family doctor.
If the familys physician commonly
prescribes antibiotics to babies and
children, and if one accepts that
antibiotics may be implicated in the
onset of diabetes, then it would not be
surprising to find more than one
diabetic child in the same family.
The table shown in the box on page
47 shows the geographical variation in
the incidence of diabetes in England
among the under-15-year-old age
group. East Anglia, a predominantly
rural area, has the highest incidence,
whereas the four Thames regions,
areas of higher population density
and pollution, have the lowest. The
incidence in East Anglia is more than
double that of the North West Thames
region.
This pattern of a rural area having
a higher incidence of diabetes than an
urban region is also seen in Scotland.
In the UK, doctors are allowed to
dispense their own drugs for patients
who are living more than a mile away
from the closest pharmacy. Conse-
quently, although few GPs in builtup
areas dispense their own drugs, in rural
areas, the proportion of dispensing
practices can be rather high.
In one study comparing children
living in the Cambridgeshire and
Wessex Areas, the health authorities
data showed that a high proportion
of diabetic children lived in the
countryside and not in the towns,
50 WDDTY Dangerous drugs
despite the presumably higher
population density of children in the
latter.
In other words, if all children were
at equal risk of diabetes irrespective
of where they lived, the expectation
would be to find more diabetic chil-
dren in the urban areas.
Furthermore, it appears that some
of the dispensing practices in the
countryside were considerably more
affluentdespite being supported by
fewer GPscompared with those in
the outer-London areas. Indeed, some
surgeries had recently been purpose-
built, and at considerable cost. It was
also noticeable that in some of these
practices, antibiotics were apparently
being liberally prescribed to babies
and children. The small areas looked
at were located in area health
authorities with a high incidence of
diabetes.
This raises the question of whether
the proportion of dispensing doctors
might be related to the incidence of
diabetes in children. If drugs such as
antibiotics were implicated in any
way with the onset of diabetes, and if
dispensing doctors prescribed them
more liberally perhaps as a result of
financial incentives, then it might be
reasonable to expect to find a higher
incidence of diabetes in country vs
city children.
The North Western and Mersey
regions, which both have a medium
incidence of diabetes and yet a low
number of dispensing doctors, are
both, incidentally, regions with the
highest number of prescriptions
(excluding those dispensed by pres-
cribing doctors) per person in England
for 1981 and for 1990. They are also
the regions with the greatest increase
in the number of prescriptions per
person in England between 1981 and
1990an average increase of 25 per
centcompared with around 8.7 per
cent for the four Thames regions over
the same time period.
In addition, the NW Thames area
[the Thames region with the lowest
incidence of diabetes in under-15s
during 1988] was also the region with
the lowest number of prescriptions per
person in 1981 and in 19905.6 and
5.9, respectively.
By way of comparison, the SE
Thames area (the Thames region with
the highest incidence of diabetes) was
the Thames region with the highest
number of prescriptions per person for
1981 and 1990 (6.3 and 7.0,
respectively).
Although these data do not include
prescriptions issued by dispensing
doctors, the percentage of dispensing
doctors in both of these Thames
regions is approximately the same.
However, the SW Thames region,
which has a low percentage of dis-
pensing doctors (6 per cent), but
ranked second highest for incidence
of diabetes of the four Thames regions
(see box, page 47), was reported in
1985 to have the highest rate of
induced births in England (23.9 per
cent), compared with an average of
17.2 per cent for the other Thames
regions (Francome C. Changing Childbirth:
Interventions in Labour in England and Wales.
London: Maternity Alliance, 1989).
Since dispensing doctors are more
liberal in handing out drugs, then it
might be expected that an area with a
high proportion of dispensing doctors
would also have a high incidence of
diseasewhich is indeed the case
here.
Furthermore, regions with a higher
number of prescriptions per person
also had a higher incidence of
diabetes.
The idea that drugs can cause
diabetes is not new. What is novel is
the suggestion that there are drugs
in common use that may be partly
responsible for the epidemics
currently seen in many industrialized
countries today.
Lisa Landymore-Lim
Dr Landymore-Lim is a chemist who
specializes in immunology.
 HRT: the latest cancer risk
Just when it looks as if it couldnt get any worse for
HRT, a new study shows that it causes lung cancer
nyone with shares in hor-
A mone replacement therapy
(HRT) is in the doldrums.
HRT was touted as the
modern-day equivalent of the fountain
of youthuntil 2002, when the US
Womens Health Initiative (WHI) study,
one of the largest-ever studies of these
drugs, discovered that women taking
HRT were more likely to have breast
cancer, ovarian cancer, stroke and heart
disease.
And now, new evidence from the
WHI data shows that the use of HRT
during the menopause increases lung
cancer by 60 per cent after five years.
Dr Rowan Chlebowski, a medical
oncologist at Harbor-UCLA Medical
Center in Los Angeles, CA, analyzed
the WHI statistics, and found a link
between prolonged HRT use and non-
small cell (NSC) lung cancer.
Although most of the adverse
publicity after the WHI study focused
on the breast cancer risk, this is the
first time that a link between HRT and
lung cancer has been identified. It also
happens that NSC lung cancer is the
leading cause of death in women.
The most vulnerable women were
smokers using HRT, who accounted for
slightly more than half of all cases of
NSC lung cancer. In the WHI study, the
researchers found one extra
death from this for every 100 women
using Prempro, Wyeths combination
oestrogenprogestin HRT drug.
Ovarian cancer risk
This announcement, made at the
annual meeting of the American
Society of Clinical Oncology in May,
coincided with the release of the
findings from a large-scale, long-term
Danish study showing that women who
take HRT increase their risk of ovarian
cancer by 38 per cent (JAMA, 2009; 302:
298305).
The study, which included more than
900,000 women aged 5079, found
that the current use of hor-mones
accounted for a 38-per-cent greater
chance of ovarian cancer. This
translates to one extra case every year
for every 8300 women using HRT, or
140 extra cases during the eight-year
follow-up, accounting for 5 per cent of
all cases of the cancer.
The risk of having the disease were
the same regardless of how long the
drug was taken, which formulation was
by HRT (Epidemiology, 2009; 15 May: doi:
10.1097/EDE. 0b013e3181a71279).
used, how much oestrogen was Fewer cases after the facts
included in the mix and what sort of Following the disclosures of the WHI
delivery method was chosen. trial, breast cancer rates fell by 13 per
As ovarian cancer is difficult to cent among more affluent women in
detect and is often fatal, such a risk California, but only by 7 per cent in
should not be brushed aside, the rural areas. When researchers from the
Copenhagen researchers noted. Northern California Cancer Center
investigated the discrepancy, they
HRT to blame found that women in the more rural
Up to now, medicine has tended to areas had not heard about the link
blame a familial predispositionthat between HRT and cancer, and so had
is, a family history of breast cancer and continued taking the drugswhich
the presence of certain predisposing would again tend to point the finger at
geneson many inci-dences of breast HRT (BMC Med, 2009; in press).
cancer, particularly in women using After the WHI results were reported,
HRT. Nevertheless, the latest trawl Wyeths products took a hammering,
through the WHI data shows that HRT and their use declined
shoulders much of the blame. by 50 per cent. Nevertheless, sales of
Epidemiologists from the Univer-sity the oestrogen-only drug Premarin and
of Rochester Medical Center, in New various cream formulations still
York, followed-up the more than 16,000 constitute a business totalling up to
postmenopausal women given either one billion dollars per year.
HRT or a placebo during the five-year Last month, the US Food and Drug
WHI study, which was abruptly Administration added a final nail in the
abandoned when the health risks HRT coffin with a boxed warning for
emerged. When they evaluated the 349 Prometrium, a progesterone drug,
women whod developed breast cancer, warning of the WHIs results showing
they could find no link with a family increased risks of heart attack, stroke,
history. invasive breast cancer, blood clots and
The researchers concluded that a deep vein thrombosis, and a greater risk
family history and hormones have of dementia, among those taking
independent and non-interacting combined oestrogens and progesto-
effectsin other words, the cases of gens of any variety.
cancer were most likely entirely caused Lynne McTaggart
The current risks of HRT
According to the US Womens Health Initiative study, hormone therapy
increases your chances of developing the following diseases by these
percentages:
u Coronary heart disease-related events, 29 per cent
u Stroke, 41 per cent
u Deep vein thrombosis, 200 per cent
u Blood clot in lungs, more than 200 per cent
u Invasive breast cancer, 24 per cent
u All cancers among previous users, 86 per cent
u Ovarian cancer, 38 per cent
u Lung cancer, 60 per cent.
WDDTY Dangerous drugs 51
Drug-induced disease
The big cure-all unmasked
The great all-purpose preventative for cholesterol has
been found to cause prostate cancer
tatins, the gold standard of
S cholesterol treatment,
have become the liver
tonic of the modern age.
Doctors hand them out for
everything from osteoporosis to
senile dementia, as early studies
suggest that they may have
preventative effects.
When early laboratory evidence
showed that statins induce
apoptosis (cell death) and reduce
prostate cancer cell growth and
spreading (Cancer Epidemiol Biomarkers
Prev, 2008; 17: 8894 ), medicine
concluded that statins were a
potent cancer preven-tative (J Natl
Cancer Inst, 2006; 98: 181925) . Early
studies bolstered this view, offering
preliminar y evidence that long-
term statin use could prevent
cancers of the breast, prostate,
blood and colon.
Studies of populations with
prostate cancer found links
between statins and the prevention
of more advanced forms of the
disease ( Curr Opin Urol, 2008; 18:
3339). Doctors were particularly
enthusiastic when a case-control
study found a cancer risk
reduction of 20 per cent with
statins (J Clin Oncol, 2004; 22: 238894).
Now, that reputationthat
statins are a powerful cancer
preventativehas been sullied
with the latest findings that statins
may actually cause prostate cancer
in overweight men. Researchers at
the Fred Hutch-inson Cancer
Research Center in Seattle, WA,
discovered the link while studying
more than 1000 cases of prostate
cancer, diagnosed between
20022005, compared with a
similar number of age-matched
controls.
Although there was no risk of
developing the disease in normal-
weight statin users, including
those who had taken the drugs for
more than 10 years, overweight
men those with a body mass
52 WDDTY Dangerous drugs
index of more than 30 kg/m2
increased their risk by 1.5 times
over overweight non-users. Also,
the risk increased to 1.8 times with
statin use for five or more years
(Am J Epidemiol, 2008; 168: 25060).
But the Seattle evidence is only
the latest to challenge the myth of
cancer prevention. A University of
Athens review of 19 epide- evidence of statin use and cancer
miological studies found no incidence. Their review of 14
evidence of a protective effect with studies found no evidence to
statins and even suggested that the support claims that statin use can
earlier evidence of lowered risk was protect against malignancies of
just coincidental (Int J Cancer, 2008; the blood, such as leukaemia (Br J
123: 899904). Clin Pharmacol, 2007; 64: 25562 ).
More detailed analyses found a They also found no evidence that
lower incidence of advanced statins can significantly reduce the
cancer, but no reduction in the risk of colorectal cancer, although
risk of overall prostate cancer ( Curr they concluded that there might
Opin Urol, 2008; 18: 3339 ). An even be some effect with higher doses (J
larger meta-analysis of 35 Clin Oncol, 2007; 25: 34628 ). The same
randomized controlled trials methodology also found no
showed a link between the drug evidence that statins can reduce
and developing cancer, depending the risk of either pancreatic or
on the patients age: the older the breast cancers (Am J Gastroenterol,
man, the more likely he was to 2008; 103: 264651; J Clin Oncol, 2005; 23:
develop cancer (J Clin Oncol, 2006; 24: 860612).
480817). Yet another research team, from
Another meta-analysis of prava- the Department of Epidemiology
statin in elderly patients confirmed and Survellance Research at the
an association between the drug Ameri-can Cancer Society, found
and an increased risk of cancer that neither short- or long-term
with increasing age (CMAJ, 2007; 176: (five years or more) use of the drug
64954). prevented colorectal cancer (J Natl
As for other forms of cancer, the Cancer Inst, 2006; 98: 6972 ).
Department of Pharmacology team Similarly, a Boston University
at the University of Athens School study of more than 3600 patients
of Medicine has systematically in Massachusetts could also find no
examined and combined all the protective effect other than a lower
Take as little as possible
If you must take a statin drug, take the smallest dose possible. New
evidence shows that even the minimum daily dose of 20 mg/day causes
potentially fatal muscle pain and weaknessand may even lead to
complete breakdown of muscle tissue (N Engl J Med, 2008; 359: 78999).
Higher doses or taking the drug with other drugs had a magnifying effect,
causing a far higher incidence of myopathy than the official figures claim.
The latest evidence shows that as much as 1.6 per cent of patients develop
muscle weaknessthats 128,000 patients in the US alone.
risk of stage IV (advanced, metas-
tasizing) cancer among statin
users, an association that the
authors believe requires
confirmation (J Natl Cancer Inst, 2007;
99: 3240).
The final blow was dealt by a
University of Connecticut School of
Pharmacy meta-analyses of nearly
90,000 participants involved in all
studies claiming a protective effect
against all cancers. Again, the data
indicate that no type of cancer is
affected by statin use (JAMA, 2006;
295: 7480).
Aside from the damning evidence
against its role as a cancer
preventative, the latest evidence
also shows that statins dont
prevent fractures or type 2 diabetes
either ( Pharmacoepidemiol Drug Saf,
2007; 16: 62740 ; Curr Med Res Opin, 2008;
24: 135962). This kicks away several
platforms on which the drugs
reputation as a preventative
treatment has been based.
Lynne McTaggart
WDDTY Dangerous drugs 53