The world's number one anti-acne drug has been accused of causing depression, even of leading people to attempt suicide. MARTIN JOHNSTON reports.
John Wilkinson's worries about his mentally troubled teenage son Hugo went up another notch when his daughter arrived home in the early hours of a Saturday morning.
He thought Hugo, aged 19, was asleep in his bedroom after playing an evening rugby match and that his daughter was out in the car he had just bought for them.
But when his daughter returned to their Remuera home at 1am, she told her father Hugo had taken the car.
"I went to Hugo's room," Mr Wilkinson told a coroner's inquest into Hugo's death. "He was not there. I noticed his rugby boots were still in his room.
"I drove to the [Auckland] University Rugby Club to see if he was there. I came back and found a suicide note in his room."
Mr Wilkinson called the police and took them the note and a photograph of Hugo. He and Hugo's mother, Henrietta Wilkinson, then drove to Bastion Pt, a special place for the family. They had flown kites there when their children were younger and Hugo had liked to walk the family dog there.
Mr Wilkinson walked past the reserve's locked gate and found Hugo at about 4am on Saturday, June 17, 2000. He had committed suicide.
For three months before his death Hugo had been taking a powerful acne drug, Roaccutane, which causes side-effects ranging from dry skin to birth defects and, allegedly, depression and suicide.
Hugo's parents believe it contributed to his rapidly deteriorating mental state.
About 5000 New Zealanders take either Roaccutane, developed and made by Hoffman-La Roche, or its Government-funded equivalent, Oratane, made by Douglas Pharmaceuticals.
Since the Herald reported the inquest by Auckland coroner Sarn Herdson last week, other patients have contacted the newspaper with similar concerns about the drug.
An 18-year-old Auckland University student said that when he took Roaccutane capsules in his mid-teens he became lethargic and irritable - symptoms of depression - when the dose was increased to 40mg a day.
He had no history of depression and the symptoms disappeared when the dose was reduced.
An Auckland nurse said her 24-year-old daughter started suffering panic attacks when she went on Roaccutane aged 13 and had been troubled by them since. "It has fundamentally upset her life."
The Ireland-based lobby group Accutane Action says the US Food and Drug Administration (FDA) received 54 reports of Accutane-associated suicides between January 1998 and September 2000.
In the United States, the family of Charles Bishop, who crashed a stolen plane into an office tower, are suing Roche for US$70 million ($156 million). They allege the drug, sold in the US as Accutane, caused the Florida teenager to commit suicide.
Elsewhere, Roche says a jury has rejected an Oklahoma woman's claims that Accutane caused her to suffer depression.
New Zealand's Centre for Adverse Reactions Monitoring, at Otago University, has received 14 reports of depression, three of attempted suicide, and one of suicide. (Hugo's case will not be recorded as suicide until the Auckland Coroner rules that it is.)
The centre's medical assessor, Dr Michael Tatley, said the link between the drug and the one recorded suicide was tenuous: "The event occurred quite some time after medication discontinued. The patient became depressed and whether it was underlying depression or the drug that caused it we can't say."
His comments highlight the international scientific community's uncertainty about the drug's links to psychotic illness.
But the US has taken a tougher overall line than New Zealand. The FDA has forced Roche to state in patient literature that some patients taking Accutane have suffered mental problems and some have killed themselves.
The information for health workers is stronger: "Accutane may cause depression, psychosis and, rarely, suicidal ideation [thoughts], suicide attempts and suicide", although it contains the caveat about the lack of a proven causal link.
It says that simply ceasing to take the drug may be insufficient and that further monitoring of patients may be necessary.
These warnings appeared in 1998. In New Zealand, a Health Ministry review that year of early studies on the drug concluded that about 10 per cent of patients using it suffered mild depression, but severe depression affected less than 1 per cent of patients.
Warnings mentioning suicide appeared in patient leaflets in New Zealand only last year.
These warnings still fall well short of those given in America, where patients are required to sign a four-page informed-consent document that highlights the association with suicide. Females are required to sign a second document confirming their understanding that they must not take Accutane if pregnant.
A senior medical adviser to the New Zealand ministry, Dr Stewart Jessamine, said such documents were unnecessary in New Zealand, mainly because they were designed to limit doctors' liability in a legal environment where they could be sued for medical misadventure.
In New Zealand, medical misadventure was covered by the accident compensation system.
Also, the US had experienced major problems with birth defects in women who had used Accutane. In New Zealand there had been only one case of a pregnant woman using the drug (although he was unaware of the outcome).
Dr Jessamine believed this problem was linked to looser controls on the drug in the US, where it could be prescribed by family doctors. In New Zealand, it could generally be prescribed only by specialist dermatologists.
Roche says no causal link has been established between its drug and psychiatric symptoms, emphasising that the reported cases are only associations.
The company did not comment on the number of psychiatric events reported among Roaccutane users because they were not evidence of a causal link, said Roche Products NZ's pharma business manager, Stuart Knight.
"Roche is committed globally to ensuring Roaccutane is used safely and appropriately, and continues to work with all health authorities to provide educational information," he said.
He referred the Herald to research suggesting acne itself could be the source of depression.
One article in the British Journal of Dermatology said: "Our findings ... indicate that in some instances even clinically mild to moderate disease ... can be associated with significant depression and suicidal ideation."
Other experts disagree.
Dr Ian Goodwin, an Auckland Hospital psychiatrist called as an expert witness by the Auckland coroner, said the studies Roche relied on to show an acne-depression link lacked rigour.
He sees about 1000 patients a year at the hospital emergency department, which handles patients aged over 15, after they have attempted suicide.
"I can't recall any that were over acne. They're about relationship break-ups or being depressed and other life events. They're not about having acne."
Doctors prescribing Roaccutane should tell their patients about the risk of psychiatric side-effects, he said. They should also say that they are rare.
There was no need to emphasise or even mention suicide, because if they did, to the exclusion of more common potential side-effects such as depression, patients might miss out on hearing about something more likely to affect them.
In follow-up sessions, doctors should probe patients for any symptoms of depression.
Dr Goodwin was surprised to learn from the Herald that the Dermatological Society has no written guidelines for members on prescribing Roaccutane.
"It's such a commonly prescribed drug," he said. "If you find something out of the ordinary happening I think it would be wise to look at written guidelines."
The society's president, Christchurch dermatologist Dr Ken Macdonald, said it had not written guidelines because a causal link between the drug and psychiatric effects had not been proven.
Even if it was proven, the drug should remain available.
"I think even if there is a causal link, and there might be, it would be very rare and it would be important to have this very effective treatment remain available to the majority of people who won't be affected."
It was probably prudent to mention to patients the rare association with suicide, but it depended on the patient. He mentioned it to some and not others.
While taking a patient's medical history he asked about psychiatric problems, as well as checking on whether they were socially isolated or had family support.
But there was a risk that by mentioning suicide a patient could be scared off the drug, Dr Macdonald said.
"It is very important, but you don't want to stop someone getting a medication which prevents scarring, because that can be an awful thing with respect to loss of self-esteem."
"It would be very sad to lose this medication. Acne undoubtedly causes depression, reactive depression, loss of self-esteem ... They just don't get out. They fail to socialise in critical areas of their life. It can be an absolutely devastating disease."
Roaccutane is registered for use only against severe forms of the disease, and only after the failure of other treatments.
But Dr Macdonald said it was sometimes used in milder cases as a last line of therapy if the patient was particularly troubled by the acne.
The drug's opponents, especially groups of former patients now established in several countries, complain that this is one of the problems - it is used far too widely.
The Wilkinsons note how quickly Hugo's symptoms developed after he started taking Roaccutane in March 2000.
They say he went from being a normal teenager to a paranoid, introverted, slow-talking young man.
"[He became] haunted," said Mrs Wilkinson.
"He walked around the house like a ghost."
She and her husband want the ministry to ban the drug, or at least to strengthen patient warnings about possible side-effects.
But for now they will have to wait. The ministry says changes, if there are any, will be considered only after the coroner publishes her findings, which may be weeks away.
Roaccutane (in New Zealand), Accutane (in the United States), Oratane.
Isotretinoin, a chemical derived from Vitamin A.
10mg or 20mg pill, taken once or twice daily with food.
5000, mainly teenagers.
13 million since the drug was launched in 1982.
Roaccutane decreases the amount of oil produced by the skin's sebaceous (oil) glands. It also stops the clogging of hair follicles, slows the growth of acne-causing bacteria and reduces inflammation and the chance for scarring.
Roaccutane is considered the biggest breakthrough in acne drug treatment in the past 20 years. Eighty-five per cent of patients find their acne clears completely after a five-month course.
Dry lips and skin, rashes, nosebleeds, tiredness, headaches.
Severe birth defects and miscarriage in babies of female patients. The United States Food and Drug Administration also warns that Roaccutane may cause serious psychiatric problems, including depression and suicide.
37 patient suicides in the US between 1982 and 2000 (24 while on the drug and 13 after stopping), plus 110 patients admitted to hospital for depression, attempted suicide and suicidal thoughts.
The Food and Drug Administration says patients may have been depressed before taking the drug but advises doctors to treat Roaccutane as if it could have psychiatric effects.
- Additional reporting by Elizabeth Binning