Drugs: Accutane, the acne drug

Accutane works by preventing acne from developing, while most other treatments (such as antibiotics and Retin-A) attempt to control acne once it has appeared. And there’s no doubt that it’s effective. Approximately 85 per cent of patients treated with a single course of Accutane have a positive response in terms of acne reduction (Adv Dermatol, 2003; 19: 1-10).

However, because it’s a high-risk treatment, with side-effects ranging from impaired hearing to fatal haemorrhagic pancreatitis, Accutane is supposed to be the last-chance saloon of acne medicines, reserved for cases where all other treatments have failed.

But like many drugs, the drug is overprescribed for all forms of acne, despite major concerns that it is teratogenic (able to damage the fetus when used in pregnancy). But now, there’s an even more immediate concern – the possibility that Accutane causes depression and even suicide in its users (Am J Ther, 2004; 11: 507-16).

According to American congressman Bart Stupak, whose son committed suicide while taking Accutane, French health authorities required Roche to add “suicide attempt” to the drug’s list of side-effects in 1997. Roche, however, neglected to inform the US Food and Drug Administration (FDA) of this side-effect. The FDA only became aware of these side-effects when its MedWatch received reports of people taking Accutane who either committed suicide or were hospitalised for suicide attempts or severe depression (see below). These made isotretinoin the third highest on the MedWatch list of the most frequently reported drugs.

In February 1998, the FDA insisted that Roche add a bold-face warning to its physician package insert regarding depression and suicidal thoughts (with the UK and Ireland following suit a month later). By 2000, the full psychiatric warnings – in bold, and covering depression and suicide as well as intracranial hypertension – were included on the package label itself. The FDA stated that “patients treated with Accutane should be observed closely for symptoms of depression or suicidal thoughts”. Patients and their caregivers are warned to discontinue treatment and seek further evaluation if symptoms of depression – such as irritability, acting on dangerous impulses, weight changes and aggression – develop.

The depression connection
Among the voluntary FDA reports received, 37 were suicides, 110 were cases where patients had been hospitalised for depression or suicidal tendencies, and 284 were cases of general depression. In all of these cases, there was a time link between use of the drug and onset of depression (J Am Acad Dermatol, 2001; 45: 515-9).

Individual case reports have also drawn attention to the link between Accutane and suicidal depression. In one instance, five men developed manic psychosis following exposure to the drug. In three of them, the psychosis lasted for more than six months. Three of the men also attempted suicide (Int Clin Psychopharmacol, 2005; 20: 39-41).

In another case, a young man developed symptoms of acute depression just two weeks into the therapy. His symptoms improved as the dosage was reduced, and worsened as it was increased. He eventually attempted suicide. When he finally stoppped the medication, his suicidal depression resolved (World J Biol Psychiatry, 2001; 2: 159-61).

Although Accutane is now among the FDA’s top-10 list of drugs associated with suicide – and Britain’s Medicines and Healthcare Products Regulatory Agency (MHRSA) is currently assessing reports of suicide or suicidal attempts associated with the medication – a link between Accutane and suicidal depression has yet to be clinically proven (Int Clin Psychopharmacol, 2005; 20: 39-41).

Nevertheless, studies have found that the drug decreases brain metabolism in a part of the brain that regulates mood. Furthermore, depression and suicide can occur in patients using Accutane who don’t have a personal or family history of either (Am J Psychiatry, 2005; 162: 983-91; Am J Ther, 2004; 11: 507-16).

It has long been known that Accutane can damage fetuses, but this hasn’t stopped it being handed out to women of childbearing age. Indeed, a number of cases of fetal abnormalities and miscarriages have been linked to the drug (J Clin Pharmacol, 1989; 29: 463-5).

To Dr David J. Graham, mph (Masters in Public Health), Associate Director for Science in the FDA’s Office of Drug Safety, the solution is clear-cut. In testimony to the US Senate Committee on Finance last November, the veteran scientist stated that, of 12 drugs for which he has recommended market withdrawal during his career, Accutane is one of the two that remain available.

Last month, the FDA approved a strengthened risk-management programme called ‘iPLEDGE’ to reduce possible Accutane exposure during pregnancy. The programme will ensure that US prescribers and patients agree to specific responsibilities so that women do not fall pregnant while taking Accutane (and aren’t given prescriptions if they are already pregnant). For example, women of childbearing age must have with a negative pregnancy test to receive the drug, and prescribers must assume responsibility for their pregnancy counselling. As of 31 December 2005, all potential prescribers and patients must be registered on the iPLEDGE system.

The UK and France have led a recent European initiative, the Pregnancy Prevention Programme (PPP), with prescriptions limited to only 30 days and only valid for a week.

In the UK, only specialists in dermatology – and not GPs – are currently allowed to prescribe oral isotretinoin.

Kim Wallace