[Epistemic status: I am still in training. I am not an expert on drugs. This is poorly-informed speculation about drugs and it should not be taken seriously without further research. Nothing in this post is medical advice.]

I.

Which is worse – ruining ten million people’s sex lives for one year, or making one hundred people’s livers explode?

I admit I sometimes use this blog to speculate about silly moral dilemmas for no reason, but that’s not what’s happening here. This is a real question that I deal with on a daily basis.

SSRIs, the class which includes most currently used antidepressants, are very safe in the traditional sense of “unlikely to kill you”. Suicidal people take massive overdoses of SSRIs all the time, and usually end up with little more than a stomachache for their troubles. On the other hand, there’s increasing awareness of very common side effects which, while not disabling, can be pretty unpleasant. About 50% of users report decreased sexual abilities, sometimes to the point of total loss of libido or anorgasmia. And something like 25% of users experience “emotional blunting” and the loss of ability to feel feelings normally.

Nefazodone (brand name Serzone®, which would also be a good brand name for a BDSM nightclub) is an equally good (and maybe better) antidepressant that does not have these side effects. On the other hand, every year, one in every 300,000 people using nefazodone will go into “fulminant hepatic failure”, which means their liver suddenly and spectacularly stops working and they need a liver transplant or else they die.

There are a lot of drug rating sites, but the biggest is Drugs.com. 467 Drugs.com users have given Celexa, a very typical SSRI, an average rating of 7.8/10. 14 users have given nefazodone an average rating of 9.1/10.

CrazyMeds might not be as dignified as Drugs.com, but they have a big and well-educated user base and they’re psych-specific. Their numbers are 3.3/5 (n = 253) for Celexa and 4.1/5 (n = 47) for nefazodone.

So both sites’ users seem to agree that nefazodone is notably better than Celexa, in terms of a combined measure of effectiveness and side effects.

But nefazodone is practically never used. It’s actually illegal in most countries. In the United States, parent company Bristol-Myers Squibb (which differs from normal Bristol-Myers in that it was born without innate magical ability) withdrew it from the market, and the only way you can find it nowadays is to get it is from an Israeli company that grabbed the molecule after it went off-patent. In several years working in psychiatry, I have never seen a patient on nefazodone, although I’m sure they exist somewhere. I would estimate its prescription numbers are about 1% of Celexa’s, if that.

The problem is the hepatic side effects. Nobody wants to have their liver explode.

But. There are something like thirty million people in the US on antidepressants. If we put them all on nefazodone, that’s about a hundred cooked livers per year. If we put them all on SSRIs, at least ten million of them will get sexual side effects, plus some emotional blunting.

My life vastly improved when I learned there was a searchable database of QALYs for different conditions. It doesn’t have SSRI-induced sexual dysfunction, but it does have sexual dysfunction due to prostate cancer treatment, and I assume that sexual dysfunction is about equally bad regardless of what causes it. Their sexual dysfunction has some QALY weights averaging about 0.85. Hm.

Assume everyone with fulminant liver failure dies. That’s not true; some get liver transplants, maybe some even get a miracle and recover. But assume everyone dies – and further, they die at age 30, cutting their lives short by fifty years.

In that case, putting all depressed people on nefazodone for a year costs 5,000 QALYs, but putting all depressed people on SSRIs for a year costs 1,500,000 QALYs. The liver failures may be flashier, but the 3^^^3 dust specks worth of poor sex lives add up to more disutility in the end.

I don’t want to overemphasize this particular calculation for a couple of reasons. First, SSRIs and nefazodone both have other side effects besides the major ones I’ve focused on here. Second, I don’t know if the level of SSRI-induced sexual dysfunction is as bad as the prostate-surgery-induced sexual dysfunction on the database. Third, there are a whole bunch of antidepressants that are neither SSRIs nor nefazodone and which might be safer than either.

But I do want to emphasize this pattern, because it recurs again and again.

II.

In that spirit, which would you rather have – something like a million people addicted to amphetamines, or something like ten people have their skin eat itself from the inside?

I can’t get good numbers on how many adults abuse Adderall, but a quick glance at the roster for my hospital’s rehab unit suggests “a lot”. Huffington Post calls it the most abused prescription drug in America, which sounds about right to me. Honestly there are worse things to be addicted to than Adderall, but it’s not completely without side effects. The obvious ones are anxiety, irritability, occasionally frank psychosis, and sometimes heart problems – but a lot of the doctors I work with go beyond what the research can really prove and suggest it can produce lasting negative personality change and predispose people to other forms of addictive and impulsive behavior.

If you’ve got to give adults a stimulant, I would much prefer modafinil. It’s not addictive, it lacks most of Adderall’s side effects, and it works pretty well. I’ve known many people on modafinil and they give it pretty universally positive reviews.

On the other hand, modafinil may or may not cause a skin reaction called Stevens Johnson Syndrome/Toxic Epidermal Necrolysis, which like most things with both “toxic” and “necro” in the name is really really bad. The original data suggesting a connection came from kids, who get all sorts of weird drug effects that adults don’t, but since then some people have claimed to have found a connection with adults. Some people get SJS anyway just by bad luck, or because they’re taking other drugs, so it’s really hard to attribute cases specifically to modafinil.

Gwern’s Modafinil FAQ mentions an FDA publication which argues that the background rate of SJS/TEN is 1-2 per million people per year, but the modafinil rate is about 6 per million people per year. However, there are only three known cases of a person above age 18 on modafinil getting SJS/TEN, and this might not be different from background rates after all. Overall the evidence that modafinil increases the rate of SJS/TEN in adults at all is pretty thin, and if it does, it’s as rare as hen’s teeth (in fact, very close to the same rate as liver failure from nefazodone).

(also: consider that like half of Silicon Valley is on modafinil, yet San Francisco Bay is not yet running red with blood.)

(also: ibuprofen is linked to SJS/TEN, with about the same odds ratio as modafinil, but nobody cares, and they are correct not to care.)

I said I’ve never seen a doctor prescribe nefazodone in real life; I can’t say that about modafinil. I have seen one doctor prescribe modafinil. It happened like this: a doctor I was working with was very upset, because she had an elderly patient with very low energy for some reason, I can’t remember, maybe a stroke, and wanted to give him Adderall, but he had a heart arrythmia and Adderall probably wouldn’t be safe for him.

I asked “What about modafinil?”

She said, “Modafinil? Really? But doesn’t that sometimes cause Stevens Johnson Syndrome?”

And then I glared at her until she gave in and prescribed it.

But this is very, very typical. Doctors who give out Adderall like candy have no associations with modafinil except “that thing that sometimes causes Stevens-Johnson Syndrome” and are afraid to give it to people.

III.

Nefazodone and modafinil are far from the only examples of this pattern. MAOIs are like this too. So is clozapine. If I knew more about things other than psychiatry, I bet I could think of examples from other fields of medicine.

And partially this is natural and understandable. Doctors swear an oath to “first do no harm”, and toxic epidermal necrolysis is pretty much the epitome of harm. Thought experiments like torture vs dust specks suggest that most people’s moral intuitions say that no amount of aggregated lesser harms like sexual side effects and amphetamine addictions can equal the importance of avoiding even a tiny chance of some great harm like liver failure or SJS/TEN. Maybe your doctor, if you asked her directly, would endorse a principled stance of “I am happy to give any number of people anxiety and irritability in order to avoid even the smallest chance of one case of toxic epidermal necrolysis.”

And yet.

The same doctors who would never dare give nefazodone, consider Seroquel a perfectly acceptable second-line treatment for depression. Along with other atypical antipsychotics, Seroquel raises the risk of sudden cardiac death by about 50%. The normal risk of cardiac sudden death in young people is about 10 in 100,000 per year, so if my calculations are right, low-dose Seroquel causes an extra cardiac death once per every 20,000 patient-years. That’s ten times as often as nefazodone causes an extra liver death.

Yet nefazodone was taken off of the market by its creators and consigned to the dustbin of pharmacological history, and Seroquel is the sixth-best-selling drug in the United States, commonly given for depression, simple anxiety, and sometimes even to help people sleep.

Why the disconnect? Here’s a theory: sudden cardiac death happens all the time; sometimes God just has it in for you and your heart stops working and you die. Antipsychotics can increase the chances of that happening, but it’s a purely statistical increase, such that we can detect it aggregated over large groups but never be sure that it played a role in any particular case. The average person who dies of Seroquel never knows they died of Seroquel, but the average person who dies from nefazodone is easily identified as a nefazodone-related death. So nefazodone gets these big stories in the media about this young person who died by taking this exotic psychiatric drug, and it becomes a big deal and scares the heck out of everybody. When someone dies of Seroquel, it’s just an “oh, so sad, I guess his time has come.”

But the end result is this. When treatment with an SSRI fails, nefazodone and Seroquel naively seem to be equally good alternatives. Except nefazodone has a death rate of 1/300,000 patient years, and Seroquel 1/20,000 patient years. And yet everyone stays the hell away from the nefazodone because it’s known to be unsafe, and chooses the Seroquel.

I conclude either doctors are terrible at thinking about risk, or else maybe a little too good at thinking about risk.

I bring up the latter option because there’s a principal-agent problem going on here. Doctors want to do what’s best for their patients. But they also want to do what’s best for themselves, which means not getting sued. No one has ever sued their doctor because they got a sexual side effect from SSRIs, but if somebody dies because they’re the lucky 1/300,000 who gets liver failure from nefazodone, you can bet their family’s going to sue. Suddenly it’s not a matter of comparing QALYs, it’s a matter of comparing zero percent chance of lawsuit with non-zero percent chance of lawsuit.

(Fermi calculation: if a doctor has 100 patients at a time on antidepressants, and works for 30 years, then if she uses Serzone as her go-to antidepressant, she’s risking a 1% chance of getting the liver failure side effect once in her career. That’s small, but since a single bad lawsuit can bankrupt a doctor, it’s worth taking seriously.)

And that would be a tough lawsuit to fight. “Yes, Your Honor, I knew when I prescribed this drug that it sometimes makes people’s livers explode, but the alternative often gives people a bad sex life, and according to the theory of utilitarianism as propounded by 18th century philosopher Jeremy Bentham – ” … “Bailiff, club this man”.

And the same facet of nefazodone that makes it exciting for the media makes it exciting for lawsuits. When someone dies of nefazodone toxicity, everyone knows. When someone dies of Seroquel, “oh, so sad, I guess his time has come”.

That makes Seroquel a lot safer than nefazodone. Safer for the doctor, I mean. The important kind of safer.

This is why, as I mentioned before, I hate lawsuits as a de facto regulatory mechanism. Our de jure regulatory mechanism, the FDA, is pretty terrible, but to its credit it hasn’t banned nefazodone. One time it banned clozapine because of a flashy rare side effect, but everyone yelled at them and they apologized and changed their mind. With lawsuits there’s nobody to yell at, so we just end up with people very quietly adjusting their decisions in the shadows and nobody else being any the wiser.

I don’t want to overemphasize this, because I think it’s only one small part of the problem. After all, a lot of countries withdrew nefazodone entirely and didn’t even give lawsuits a chance to enter the picture.

But whatever the cause, the end result is that drugs with rare but spectacular side effects get consistently underprescribed relative to drugs with common but merely annoying side effects, or drugs that have more side effects but manage to hide them better.