Acne destroys teenagers' lives and affects millions. But the wonder
drug that cures it may also lead to psychosis and suicide
The American explorer Elisha Kent Kane is commemorated by a bay
in the Arctic, a crater on the moon and a place in medical history.
In the mid-1880s he ensured lasting fame when, after surviving two
winters in an iced-up ship in the Arctic, he led his crew on a desperate
900-mile trek across the ice to Greenland. Aided by Eskimos, they
stayed alive by eating polar bears.
On January 5 this year, a 15-year-old student, Charles Bishop,
took a Cessna light aircraft from a flight school in Florida and
flew it into the 28th floor of the Bank of America Plaza in Tampa.
A note in his pocket expressed sympathy for the September 11 hijackers,
whose example he had intended to follow.
Other, more private, deaths have been no less tragic. In December
1997, Seumas Todd, the 20-year-old son of the actor Richard, killed
himself with a shotgun. In 1998 an 18-year-old sixth-former, David
Bebby, jumped from a multistorey car park in Newport, Gwent, and
a 20-year-old Dublin student, Liam Grant, hanged himself from a
In 2000 a young married woman, Susan Johnson, stood in the path
of a high-speed train on the London-Plymouth railway line.
In New Zealand, a 19-year-old student, Hugo Wilkinson, cheerfully
waved from a window as his father went out to a rugby match, then
returned to his room and killed himself.
In the United States, the 18-year-old son of Congressman Bart Stupak
of Michigan, a popular college football player, shot himself after
a prom-night party. Later the same year, a congressional committee
heard how two other normal, healthy teenagers, Daniel Baumann, 15,
of Illinois, and Clay Jackson, 17, of Texas, had suddenly decided
to end their own lives, and how another, 14-year-old Amanda Callais,
had taken an overdose but had been saved by her mother. On his website,
Congressman Stupak drew attention to a total of 54 suicides in the
US between 1998 and 2000.
The thread that binds all these people together could hardly seem
We all depend on vitamin A for the health of our skin, hair and
mucous membranes. It helps night vision and our reproductive systems.
We need it to develop our bones and teeth. Yellow fruit and dark
green vegetables are the best sources, though we also get it from
meat, fish, milk and eggs. It is the basis of all the anti-wrinkle
creams with 'retinol' or 'retinoids' in their formulae. Pro-health
and anti-ageing, it's exactly the kind of thing we can't get too
The trouble is that anything taken in excess stops being food or
medicine and becomes instead a poison. Overdose, after all, is what
transforms innocent headache remedies into killers. And so it is
with vitamin A. Overdose causes a condition known as hypervitaminosis
A, the symptoms of which have disturbing effects on mind and body
alike. This is the discovery we owe to Elisha Kane.
Why was it, he wondered, that instead of feeling elation after
their life-preserving feasts of polar bear, he and his crew had
become irritable and depressed? The answer, it transpired, was that
the animals' livers contained so much vitamin A that it caused a
psychotic reaction - classic symptoms of hypervitaminosis A.
There is a further, more precise, connection between Charles Bishop,
Bart Stupak and the other young suicide victims of the late 20th
and early 21st centuries. They all suffered from acne, and all had
been prescribed a powerful drug called isotretinoin, a vitamin-A
derivative made by the Swiss giant Hoffman-La Roche and sold in
100 countries worldwide. Its brand names are Roaccutane (UK) and
Accutane (US). On both sides of the Atlantic it has made the kind
of headlines normally reserved for mass murderers or airline disasters:
Suicide is linked to acne pill (The Sun, May 8, 1998). My face cleared
and my life went dark (The Independent, June 30, 1998). Acne drug
maker faces lawsuit over pill's 'suicide link' (The Guardian, November
19, 1998). Every day I wanted to die. I have lost years (the Daily
Mail, January 2, 1999). Suicide of woman depressed by acne drug
(the Daily Mail, July 19, 2000). Could an acne drug have driven
this boy to fly a plane into a tower? (The Independent, January
The 54 American suicides recorded by Stupak were all linked by
isotretinoin and are mirroredby other reports from across the world
- in the UK since 1983 there have been 15.
Since 1997 in France, and 1998 in the US and the UK, isotretinoin
has come with a warning that it may cause depression and suicide.
Yet depression is not the only - and perhaps not even the worst
- side effect.
Women now are prescribed it only on condition that they are not
pregnant, and do not become pregnant while taking it. In the US,
where the hot breath of the litigation lawyer is seldom far from
practitioners' necks, female patients must agree to use two methods
of contraception for as long as the drug remains in their bodies.
Roche itself describes the risk of birth deformity as 'extremely
high', and abortion is recommended for women who become pregnant
during treatment. Before the pregnancy ban, babies were born with
deformed, misplaced or absent ears, abnormally wide-set eyes, enlarged
heads and small chins. There were also cases of mental retardation
and physical defects of the heart, brain and nervous system.
Almost all isotretinoin users can expect some side effects. Normal
reactions include chapped lips, itching and peeling of the skin
and dryness of the mucous membranes that may cause nosebleeds. Hair
may thin. Eyes may become dry and night vision may be impaired.
'Other less common, unwanted effects,' says the leaflet given
to patients, 'include headaches, feeling sick, tiredness, sweating,
menstrual changes, slight loss of hearing, changes in vision (including
colour vision disturbances), jaundice, liver disease, anaemia, seizures,
inflammatory bowel disease, inflammation of the pancreas, systemic
infections, local bacterial infections such as infection of the
tissue around the base of the nail, changes in the nails, increased
facial pigmentation, swellings discharging pus, swollen glands,
inflammation of blood vessels (sometimes with bruising and red patches),
blood in the urine, diabetes, changes in blood glucose levels...
Such effects are usually temporary but the risks are enough for
isotretinoin to be classified as a treatment of last resort - ie,
it should not be prescribed for mild outbreaks of adolescent spots
but only for severe cases of potentially scarring cystic acne that
have not responded to antibiotics or other treatments. In the UK
it may be prescribed only by a dermatologist, not by a GP.
In reality, however, not even lip service has been paid to the
idea of restricting isotretinoin to a minority of worst cases. Worldwide
it is Roche's second-highest earner, with annual sales of one billion
Swiss francs (£434m). This hardly suggests that doctors have been
holding back on the prescriptions.
Indeed, it is central to Roche's case that so much of it has been
prescribed with so few lasting side effects. As early as 1992, the
influential Leeds Foundation for Dermatological Research calculated
that just 40% of isotretinoin prescriptions were for severe acne;
the majority were moderate cases prescribed 'off-label'.
In 1995, doctors calculated that only 16% of prescriptions were
for severe disease; the rest were for moderate or mild cases. Thus,
it is argued, thousands more young people are exposed to the risks
of liver damage, diabetes, depression, suicide and all the rest.
Inevitably it is the suicides that dominate the headlines, but
some of the survivors' tales are scarcely less harrowing. The chairman
of the UK branch of the Roaccutane Action Group, 25-year-old David
Chow, was prescribed isotretinoin for mild acne in 1994. Not unexpectedly,
he suffered the common side effects of dry eyes, dry lips and nosebleeds.
Less predictably, the damage to his lips not only persisted after
he finished taking the drug but went on getting worse.
'After the course,' he says, 'I continued to experience extremely
dry lips. They would not only crack and bleed but the skin got to
the stage where it was so thin, it turned into a white mush when
touched by water.' The result has been persistent infections and
years of pain, severe enough to make eating and speaking a test
of willpower. Though he has studied successfully for a business
degree, he is unable to work and has had to give up sport.
'Often I have had to stop speaking for days,' he says. As a direct
result of the evidence he gave to the UK Medicines Control Agency
(MCA) last year, the condition from which he suffers - known as
persistent exfoliative cheilitis - has been added to the list of
side effects against which UK patients are warned. He is now campaigning
for the further addition of blepharitis (chronic inflammation of
the eyelids, already covered by official warnings in Australia),
plus impotence and loss of libido, which between them account for
up to a half of all the e-mails the action group receives from worried
More frightening still is the case of Luke Hassett, now 22, who
was prescribed isotretinoin for mild acne while studying at Leeds
Metropolitan University. His mother, Muriel, tells the story. 'He
was a nice, popular lad,' she says, 'happy, kind-hearted and well
liked.' His first year at university went well, but then early in
his second year, saying nothing to his parents, he consulted his
GP about acne and was referred to Leeds General Infirmary. 'He only
had about five spots. His friends didn't think he had acne at all.'
His decline was precipitous. 'We became aware that he was behaving
a bit oddly. He was a bit paranoid, very suspicious of the people
he was sharing with and thought his computer was bugged.'
One day Luke phoned his mother at work and she knew at once that
something had gone very badly wrong. 'He was paranoid,' she says
simply. Without delay she drove from Manchester to Leeds to bring
him home and was shocked by what she found. 'He was crashing around,
bumping into things, having so much trouble with his balance that
I thought he might have CJD. I couldn't persuade him to eat or drink.
One of his eyes had dropped and he looked physically awful.' He
had stomach pains and his skin was yellow, 'so I knew he had liver
problems'. On the way back to Manchester he tried to jump out of
the car on the M62.
For a while, there was hope. 'I thought that when the drug was
out of his system he would get better. He slept for months. There
was no pattern or rhythm to his life but he slowly got better.'
So much better, in fact, that he was able to catch up with his coursework,
and in the following September he returned to university. 'He was
quiet and calm and we thought he was better.'
Within two weeks it had become clear that the optimism was misplaced,
and Muriel Hassett drove once again to fetch her son from Leeds.
This time his physical condition was worse. 'His lips were all fissured.
The lining of his nose was coming away. His eyes drooped. He looked
as if he'd had a stroke.' Luke accompanied her voluntarily to Leeds
General Infirmary but withdrew his co-operation after a night-long
wait in the hospital's casualty department.
In the morning he was sectioned under the Mental Health Act and
transferred to a psychiatric unit. Bad turned to worse. Allergic
reaction to drug therapy put Luke into a coma that brought him close
to death. 'When he recovered from this, all the doctors rejected
the idea that the problem was caused by Roaccutane. They tried all
sorts of stuff on him. He used to crawl on all fours, banging his
head on the floor and howling like a wolf.'
Miraculously, however, he recovered a second time and, once again,
went back to university. 'He settled down nicely. We thought he
was doing so well.' And this, ironically, was his undoing. He was
doing so very well that he thought he could stop taking his medication.
This time Muriel had to intercept him at Liverpool airport, where
he was on his way to join his tutor and other students on a field
trip to Amsterdam. '
I had to get his bags off the plane,' she says. He was sectioned
again, and detained in the psychiatric unit at Manchester's Trafford
General Hospital, where he still remains.
There is hope. 'He is great at the moment. He comes home for four
hours every day on home leave, and seems to be okay.' But there
is also anger. 'I cannot believe the MCA allows people to dispense
this drug off-licence all the time.' With the support of the Roaccutane
Action Group, Muriel Hassett is now planning legal action against
Leeds General Infirmary.
Stories like this are common. In the US, more than a hundred lawsuits
are taking shape, including Charles Bishop's, though none so far
has come to court. In the UK, previous attempts to sue have foundered
largely on economic grounds. Pauline Roberts, of the law firm Smith
Llewellyn in Swansea, at one time had 80 cases on file. 'In some
cases,' she says, 'the link between Roaccutane and the psychiatric
injury was very clear-cut.
Nevertheless, some of the claims were complicated by the fact that
the complainants were teenagers already suffering from depression.
Counsel's advice was that, because the psychiatric injuries were
short-lived, the claims were not economically viable - the costs
would exceed the likely benefit in damages.' Even in cases of suicide
there is no guarantee that any award of damages would justify the
cost of an action - the value placed on a teenager's life is limited
because nobody relies on them financially.
Yet even where the damage is short-term, the effects may be traumatic.
To understand this, you have only to reflect on the words of the
14-year-old survivor Amanda Callais, in evidence to the US congressional
committee. 'My downfall started the moment I took the first pill.
I found myself feeling sad and I often cried for no reason. I hated
myself more and more each day and I began to cut myself with razor
blades.' To find a worse ethical outrage you'd have to look all
the way back to Dr Josef Mengele. Except...
Here is another mother. Her 39-year-old son, William (not his real
name), who still lives with her, developed the first signs of acne
at the age of 11. By his mid-teens his face, chest and back were
horribly disfigured by weeping boils. Antibiotics were prescribed
in ever stronger doses but nothing worked. Huge cysts had to be
surgically removed from his cheeks. 'He had the stuffing knocked
out of him,' his mother says. 'He didn't look at people when he
spoke to them, and he still doesn't. He was bullied throughout his
school years, had no teenage social life and I'm absolutely certain
it's why he hasn't married.' Once while mother and son were out
walking, he summoned the courage to speak to two girls he knew from
college. 'Next day they went up to him in class and told him never
to speak to them again in public.'
Then the family's GP heard about a new miracle drug that had a
near-100% success rate. He sent William back to his dermatologist,
who agreed to prescribe Roaccutane. 'It was a saviour,' says his
mother. 'It dried everything up. The acne went, but he was left
with awful scarring.' Scarring so bad that, even with the acne itself
long disappeared, it still affects him.
The experience has left his mother feeling sad that isotretinoin
was not available soon enough to protect him from disfigurement,
and angry - really, blazingly angry - that people complain to newspapers,
and appear on radio and television programmes to attack a drug which,
to her, is a life-saver. 'Acne ruined William's life,' she says,
'and the only thing that helped him was Roaccutane.'
Contradictions abound. The Roaccutane Action Group lists more than
40 studies that it says have established a connection between isotretinoin
and psychosis. In particular it quotes the work of Tzarina Middelkoop,
a researcher at University College, Dublin, who concluded that isotretinoin
users were 900 times more likely to suffer depressive symptoms than
patients on antibiotics.
For its part, Roche favours Susan Jick, of the Boston University
School of Medicine, and other consultants in the US, who argue that
isotretinoin users are no more likely to commit suicide than anyone
else. 'We have done six studies, involving 33,000 patients, and
have found no association,' says Daniel Kenny, international medical
manager of Roche in Basel.
There are things he wants people to understand; things that, to
his regret, have escaped the attention of the newspapers - the fact,
for example, that there is 'no plausible biological link' between
isotretinoin and the biochemistry of the brain. But then you remember
that very similar things were said by the tobacco industry about
lung cancer. You remember Elisha Kane. You remember, too, that Roche
is not famous for its candour.
The company was reprimanded by the FDA for withholding evidence
of adverse reactions to isotretinoin, failing to disclose in 1997
that the French government had ordered suicide risk to be added
to the list of possible side effects, and for falsely advertising
the drug as a treatment for depression.
None of this proves anything, but it is hardly calculated to pour
oil on the troubled waters of suspicion. Support groups for families
and patients have now sprung up in 40 countries, including Ireland,
Norway, Sweden, South Africa, New Zealand and France as well as
America and the UK. All insist, with mounting certainty after each
new case, that there is a direct link between isotretinoin, depression
Yet, despite all the claim and counterclaim, patients are supposed
to give 'informed consent' before the drug can be prescribed. What
is 'informed consent' when there is no consensus on the degree,
or even existence, of danger? 'Signing a consent form,' says one
senior British dermatologist, 'simply indicates that a discussion
has taken place. It doesn't prove that the patient has understood
anything.' There is, rather, a juggling of responsibility. The dermatologist
cannot quantify the risk, so the patient (who may already be depressed,
and is under the duress of a disfiguring disease) has to decide.
Risk of scarring versus risk of suicide. What happens in the consulting
room may be confidential, but there are shadows on the wall. Behind
the doctor stands the drug company, and behind the drug company
stands the lawyer. You can't take isotretinoin these days and say
you haven't been warned.
Between the licensing of isotretinoin in 1982 and August 31 last
year, 12m people worldwide had been treated with it - a startling
total of 4.1m patient-years of exposure. This we know with reasonable
certainty (the figures are Roche's own). Knowing exactly how many
suffered severe or long-term damage, however, is impossible. A bad
reaction becomes a statistic only if it is reported to an official
body such as the FDA or Britain's Medicines Control Agency (MCA),
which logs it as an Adverse Drug Report (ADR). It is accepted that
the vast majority of mishaps are not recorded in this way, though
there is little agreement on the amount of under-reporting. The
FDA has put it as high as 99%; a more common estimate is 85-90%,
while the MCA offers no figure at all.The Roaccutane Action Group
says that there have been more than 500 formally reported ADRs involving
suicide, attempted suicide or suicidal intent ('suicide ideation'
in the jargon). In the US, the FDA recorded 54 suicides, 51 attempted
suicides and 111 cases of suicide ideation between January 1998
and September 2000. In the UK, in 18 years the MCA has recorded
2,039 adverse reactions shared between 1,208 afflicted patients.
Of these, 247 were psychiatric disorders, including 82 cases of
depression, 14 of depression made worse, 14 of suicide ideation,
10 unsuccessful suicide attempts and 15 suicides. Nine more died
of other related causes.
Trying to draw conclusions from this is like tap-dancing in treacle.
Allowing for under-reporting, the 15 suicides could multiply to
a hidden total of anything between 150 and 1,500. Or they might
not... As the MCA points out, these are only 'suspected' associations
with isotretinoin. There are many reasons why young people might
become depressed or attempt suicide, and there can be no proof that
isotretinoin was the cause. Roche's Daniel Kenny puts it bluntly:
'There is no direct causality,' he says. 'The patients just happened
to be on the drug at the time the events occurred. All the evidence
is that the suicides were caused by other factors.'
This has been Roche's line throughout all the years of argument,
and it doesn't impress bereaved parents. If all the evidence pointed
one way, there would be no controversy. There is evidence, and plenty
of it, that isotretinoin may cause depression severe enough to lead
to suicide. What is lacking is not evidence - dead children are
evidence - but proof.
Roche is unarguably right, however, when it asserts that acne
itself causes depression. Alison Dudley, the chief executive of
the Acne Support Group, says that 75% of her 15,500 members report
symptoms of depression and 15% have felt suicidal. In Boston, Susan
Jick makes the link work almost to isotretinoin's advantage. She
suggests that acne sufferers often blame their appearance for lack
of personal success, then become depressed if their lives are not
transformed after isotretinoin has done its work. By this account,
the drug's only fault is that it works.
Daniel Kenny argues that young people in general are more likely
to feel depressed or suicidal. Any group of adolescents, he says,
will contain a higher than average number of suicides, irrespective
of any treatment that they may be receiving. Young people, too,
are more likely to suffer mood swings caused by alcohol or recreational
drugs. The problem with this argument, in the UK at least, is that
it rests on a false premise. Young people in the crucial age range
of 15 to 24 are less, not more, likely than average to commit suicide.
There is no statistically validated predisposition among British
teenagers to kill themselves, and it is not safe to presume that
the deaths of young isotretinoin patients can be marked down to
problems of adolescence.
For opponents of the drug, the smoking guns are the patients whose
depression lifted when they stopped taking isotretinoin, only to
reappear when they started again. When this happens it is difficult
to deny the possibility of a link. Difficult, but not impossible.
Depression, say Roche's experts, is episodic - patients get better;
then they relapse. Given the number of patients worldwide, the laws
of chance dictate that a number of 'psychotic events' will indeed
stop and start at the same time as isotretinoin. It is pure coincidence.
This is the kind of number-juggling that most infuriates parents,
who cannot accept that their personal experiences can be denied
by a computer. They have seen happy, healthy teenagers fall suddenly
into fatal depression. Despite what the statisticians say, this
cannot be explained in terms of 'normal' suicidal behaviour.
Professor Keith Hawton, the director of the Centre for Suicide
Research at Oxford university, confirms that teenagers who kill
themselves do not act spontaneously with no previous sign of depression.
But still the statisticians won't let go. Even if a teenager does
suddenly commit suicide, they say, it does not mean that isotretinoin
is to blame, or that the victim was not already depressed. The likelier
explanation is that parents and friends simply, tragically, did
not recognise depression when they saw it. With teenagers, how can
you tell? Mood swings are the norm and it takes a trained eye to
spot the difference.
One of the saddest aspects of the story is the extent to which
the debate has been poisoned by rancour. Action groups accuse Roche-funded
researchers of falsifying their results - in effect, of putting
profit before life. They are scandalised by money-making, and by
the funding of hospital dermatology units, including the one at
Leeds, by Roche.
The company's apologists in return accuse their critics of naivety
and hysteria. At the FDA hearing in September 2000, a company lawyer
implicitly suggested that the densely argued testimony of Liam Grant,
the Irish founder of the Roaccutane Action Group, be discounted
precisely because he had a personal interest and was currently involved
in litigation (his son killed himself in 1997). 'I think it was
important that you be aware of that,' he said, as if it changed
Despite all the negative publicity, the deaths and the doubts,
British dermatologists last year issued 3,000 prescriptions for
isotretinoin. The man nominated by the British Association of Dermatologists
(BAD) to explain the reasons for this is Richard Motley, consultant
dermatologist at the University Hospital of Wales in Cardiff.
Is he aware that many prescriptions are 'off-label', for mild or
moderate rather than severe acne? Does he approve? Yes, of course
he is aware, and yes, he does approve. The point is not to ignore
the patient's mental state but to be ruled by it. If a patient is
suicidal because of a minute amount of acne, he says, then the correct
prescription is the one that is going to work fastest - Roaccutane.
The same applies to patients whose mild or moderate acne has not
responded to other treatments. 'But,' he says, 'I wouldn't prescribe
for a moderate case if the patient was unconcerned.'
Overall, BAD's message is simple. There may be a risk of psychotic
damage in isotretinoin users, but it is much less than the risk
of untreated acne. 'Several small, vocal pressure groups have formed
around the tragic suicides of three or four patients taking the
drug. Unfortunately, there are no similar representatives for the
many more untreated or inadequately treated patients - including
those who killed themselves because of depression caused by the
appearance of their acne.'
This is a point to which dermatologists return time and again.
On the balance sheet of tragedy, isotretinoin produces the least
awful bottom line - it saves more lives than it costs. And, they
insist, the best way to prevent severe acne is to treat moderate
acne. Through its Retinoid Working Party, BAD is currently conducting
yet another review of the evidence on mood change.
The working party's chairman is Mark Goodfield, a consultant dermatologist
at Leeds, who acknowledges that important questions do remain to
be answered. His own replies are buffered with professional tact
- yes, there are some reports that suggest isotretinoin may cause
depression, and, yes, others that suggest its physical side effects
may sometimes be prolonged - but he is ready to accept that more
and better research is needed. The problem with all the studies
so far, he agrees, is that the numbers of patients surveyed were
too small and, because of the under-reporting of ADRs, the figures
cannot be relied upon.
It is at this point that the professional view finally converges
with the protesters'. Last month, representatives of the Roaccutane
Action Group met the MCA to press the case for a large-scale independent
clinical trial, paid for by Roche, that would settle once and for
all the question of isotretinoin's safety.
As it happens, Roche itself is discussing just such a trial with
the FDA - a trial which, says Daniel Kenny, 'would be done by international
collaborative effort and would involve tens of thousands of patients'.
End of story? Alas, no. The trial would require volunteer acne patients
worldwide to be separated into two matched groups. One would be
given isotretinoin; the other would receive either a placebo or
an antibiotic. Scientists would then monitor and compare their psychological
It would answer the question all right, but at what cost? Normally,
isotretinoin is prescribed only when other treatments fail. The
consequence of such a trial, therefore, would be to withhold effective
treatment from half the patients involved in it. Not only would
they face lifelong scarring but they would risk the depression that
acne itself can cause. 'There are some ethical problems here,' Daniel
There are other problems, too. Increasing the rate of depression
among the 'control group' could erode any differences between the
two groups and make the entire study meaningless. Kenny insists
the statisticians could 'adjust for this', but would any doctor
allow his patients to take the risk? 'It's certainly a tricky one,'
says Mark Goodfield. 'I would be anxious at withholding the drug.
There would be problems recruiting patients for such a trial.
' So: if there is a way forward, what is it? How can patients who
need this 'very important, almost uniformly effective drug', as
Goodfield describes it, both be persuaded to take it and be protected
from side effects?
It is common sense, not science, that supplies the answers: careful
prescribing, good advice and close monitoring of patients not only
by their doctors but also by their friends and families. Any change
in mood or behaviour should result in the immediate withdrawal of
the drug. It is sensible, unexceptionable advice, but for many,
for certain, it simply will not be enough.