Adventures in Accutane

Jezebel has a post up discussing the link between Accutane and suicide.  I link to the Jezebel post and not the new article because I find the comments interesting.

First, some background.  Accutane (generic name: Izotretinoin) is mostly an anti-acne medication, although it’s occasionally used for other skin disorders and cancers.  Depending on who you ask, it’s either a form of vitamin A or a close relative of vitamin A.  Vitamin A is fat soluble, which means if you take too much it will kill you (the livers of many arctic mammals are toxic for this reason).  One to two courses of Accutane (generally lasting 8-10 months) is usually enough to permanently cure severe acne.

Izotretinoin is a notorious teratogen, meaning it can cause serious birth defects if taken during pregnancy.  The cause appears to be that izotretinoin serves as a signalling molecule in a certain stage of pregnancy, but this is not definite.  In America, the relevant legal authority has responded with the iPLEDGE system.  Only prescribers registered with iPLEDGE can prescribe accutane. They must register recipients (with a detailed sexual and menstrual history) in the system and certify that they’ve been  warned about the risk of birth defects, and promised to take two forms of birth control.  Prescriptions must be picked up in a seven day window, lost prescriptions cannot be replaced, a prescription must be for exactly 30 days.  Recipients must take a blood (not urine) test for pregnancy every month before getting their prescription.  They recently relaxed the latter requirement for men and women of non-child-bearing age to pledge to take birth control, but still require a blood test.

This program represents some of the worst government interventions in health to me.  It imposes huge burdens of time, money, and privacy.  It infantilizes women by requiring a pregnancy test even if they report no sexual activity, yet takes their word on the whole birth control thing.  It very nearly requires hormonal birth control, and while I recognize hormonal birth control as a life changing intervention for many people, I think the dangers are understudied and under reported and dislike anything that dismisses its costs.  The timing restrictions seem to be designed to force users to adhere to pregnancy tests, which are predicated on the idea that you can’t trust women to notice they’re pregnant.  And of course, you have to do all this for people without working uteruses.  It’s also considerably more work than you need to do to take thalidomide, an even more notorious teratogen, which means the decision to impose iPLEDGE is being made based on something other than strict rational consideration of costs and benefits.

No one is quite sure how izotretinoin works.  It may induce cell death in the sebaceous glands.  It may act as an anti-microbial.  It may affect the expression of hundreds of genes.  It has shown promise as a cancer treatment, which means it probably inhibits cell growth.

Some people report that Accutane has psychological side effects, including suicide.  This is really tricky.

A lot of Accutane users are teenagers, who are already an emotionally chaotic group.  You can compensate for differing risk with a control group, but a higher variance is still more likely to lead to a false report of differing means.

Second, suicidality and depression are not as linked as you would think.  People at the absolute pit of depression are often too overwhelmed and apathetic to kill themselves. Suicide risk actually increases when treatment starts working (which may be why anti-depressants are linked to suicide in teenagers, and is definitely why mixed states are so dangerous).  Severe acne is socially isolating, which can lead to depression.  It’s entirely possible that getting better frees up enough emotional energy to feel bad, or that the first set back after an improvement feels unmanageable, and so while the drug has no direct psychoactive effects, it looks like it does through its effects on the skin.

On the other hand, it’s a known biohazard with no accepted explanation for why it works, and almost any disruption in physical systems can manifest as depression and anxiety.  The weird thing would be if it didn’t.  The Jezebel comment thread is full of people saying it induced terrifying psychosis in them.  It’s also full of people saying it saved their lives by clearing up their acne.  A 24 mouse study showed some increase in depression-like behavior in mice following injection.   An even smaller study showed that Accutane reduced cell growth in certain regions of the brain, which is terrifying for a drug we give to teenagers but hard to draw concrete conclusions from.

So what do you do, as a potential patient or parent of same, in the absence of good evidence?  Clearly you need to watch new patients closely for behavioral changes and discontinue if they occur, but what about the risk of subtle long term damage?    I don’t know how to weigh that.