I.

It all started when I made that phone call.

I was really bad. All the tenure-track positions I’d applied to had politely declined, and I saw my future in academia gradually slipping away from me. Then the night before, my boyfriend had said he thought maybe we should start seeing other people. I didn’t even know if we were broken up or not, and at that point I couldn’t bring myself to care. I sat on my bed, thinking about things for a while, and finally I called the suicide hotline.

“Hello?” a woman’s voice answered on the other side. Somehow, just hearing someone else made me feel about five times better.

“Hello,” I said, a little more confidently. “I’ve been thinking of committing suicide. I need help.”

“Okay,” she said. “Is there a gun in your house?”

“No.”

“All right. The first thing you need to do is get one. Overdosing on pills is common, but it almost never works. You can get a firearm at almost any large sporting goods store, but if there aren’t any near you, we can start talking about maybe jumping from a high…”

“What the HELL?” I interrupted, suddenly way more angry than depressed. “You’re supposed to @#!$ing tell me not to do it!”

“This is the suicide hotline,” the woman said, now sounding confused. Then, “Are you sure you weren’t thinking of the suicide prevention hotline?”

“Give me a break! I took a psychology class in undergrad, I know what a suicide hotline is!”

“I’m sorry you seem to be upset. But this is the suicide hotline. It’s like how there’s the Walk For Breast Cancer, but also the Walk Against Breast Cancer.”

“There’s the what? But…I was in the Walk For Breast Cancer! I thought…”

“It sounds like you have some issues,” said the woman, politely.

“Ugh,” I said. “Yeah.”

“Do you feel like you need professional help?”

“Yeah.”

“I do have a free clinic with an opening available tomorrow at three PM, would you like me to slot you in for an appointment?”

So you’re probably wondering why in the world I would take an appointment arranged by the suicide hotline that wasn’t a suicide prevention hotline. The answer is – were you even listening? A free clinic? With an appointment available the next day? Normally I was lucky if I found a place with an opening in less than two months and a co-pay that wasn’t completely ruinious. You bet I was taking that appointment before someone else snatched it up.

Dr. Trauer’s office looked gratifyingly normal. There was a houseplant, a diagram of the cranial nerves, some Abilify® merchandise, and on the wall one of those Magic Eye stereographic images that resolved into a 3D picture of the human brain. Dr. Trauer himself looked like your average doctor – a little past middle age, a little overweight, a short greying beard. He motioned me to sit down and took the paperwork I’d been filling out.

“Hmmmm,” he said, reading it over. “29 years old, postdoc in biochem, recent relationship trouble…mmmm…you did the right thing.”

“In coming here?”

“No, in considering suicide. After getting rejected from a tenure-track position, your life is pretty much over.”

“WHAT?”

“I mean, here you are, hundreds of thousands of dollars in debt, with only one area of expertise, and now you’ve been rejected from it. I can totally see why you might think it’s worth ending it all.”

“But…there are lots of other things I can do! I can get a job in industry! I can work in something else! Even if I can’t find a job right away, I have parents who can help support me.”

“Industry!” Dr. Trauer was having none of it. “A bunch of bloodsuckers. Do you realize how bad work in the private sector is these days? They’ll abuse you and then spit you out, and once you’ve been out of university too long nobody else will want you.”

“Lots of people want biochemists! If I work for a company for a few years, I’ll have more experience and maybe that will make me more attractive to employers! What…what kind of a psychiatrist are you, anyway?”

“Cindy didn’t tell you?”

“Cindy?”

“The woman on the phone.”

“She didn’t really tell me anything!”

“Well,” said Dr. Trauer. “To answer your question, we’re dark side psychiatrists. This is the state’s only dark side psychiatry clinic.”

“Dark side psychiatry? Really?”

“We’re a…well, some people say sect, but I like to think of it as more of a guild…dedicated to improving negative mental health. Think of it this way. When you’re a hijacked murder-monkey hurtling toward your inevitable death, sanity is a completely ridiculous thing to have. And when the universe is fifteen billion light-years across and almost entirely freezing void, the idea that people should have ‘coping skills’ boggles the imagination. An emotionally healthy person is a person who isn’t paying attention, and our job is to cure them.”

“There’s more than one of you?”

“Oh, yes. There’s a thriving dark side psychiatric community. There are dark side psychopharmacologists – you’d be amazed what a few doses of datura can do to a person. There are dark side psychotherapists who analyze and break down people’s positive cognitions. There are dark side child psychiatrists who catch people when they’re young, before sanity has had a chance to take root and worsen. And there are dark side geriatric psychiatrists, who go from nursing home to nursing home, making sure that the elderly are not warehoused and neglected at exactly the time it is most important to ensure that stroke or dementia does not protect them from acute awareness of the nearness of death.”

“That’s awful!” I said.

“Is it? Look where sanity’s gotten you. You want to kill yourself, but you don’t have the courage. Work with me for ten sessions, and I promise you we can help you get that courage.”

“You’re a @#!$ing quack,” I said. “And if you think killing yourself is so great, how come you haven’t done it yourself yet?”

“Who says I haven’t?” asked Dr. Trauer.

His hand went to his face, and he plucked out his right eye, revealing an empty void surrounded by the bleached whiteness of bone. I screamed and ran out of the clinic and didn’t stop running until I was in my house and had locked the door beside me.

II.

“…and that’s pretty much the whole story, doctor,” she told me. “And then I looked to see if there were any real psychiatrists in the area and someone referred me to you.”

“Well,” I said, my face unreadable. “I can certainly see why you’re complaining of, how did you put it, ‘depression and acute stress disorder’.”

“Not so acute anymore. It took me two months to get an appointment at your clinic.”

“Oh,” I said. Then, “Sorry, we’re sort of backed up.” Then, “Okay. We’ve got a lot we have to work on here. Let me tell you how we’re going to do it. We’re going to use a form of therapy that challenges your negative cognitions. We’re going to take the things that are bothering you, examine the evidence for them, and see if there are alternative explanations.”

“What do you mean?” she asked.

“Well,” I said. “It seems to be this Dr. Trauer incident that’s traumatized you a lot. I can see why you would be stressed out. The way you tell it, it sounds absolutely terrifying.”

“You don’t believe me,” she said, not accusatory, just stating a fact.

“I think it would be helpful to examine alternate explanations,” I said. “I’m willing to assume it happened exactly as you tell it. I can see why you would think Dr. Trauer wanted you to commit suicide. But are there any alternative explanations for the same event?”

“I don’t see how there can be,” she said. “He outright said that he thought I should kill myself.”

“Right. But from what you know of psychiatrists and therapy – and you did say you took some classes in undergrad – are there any other reasons he might have said something like that?”

She thought for a second. “Wait,” she told me. “There’s a technique in therapy called paradoxical intention. Where you take a patient’s irrational thought, and then defend and amplify it. And then when the patient hears it from someone else, she realizes how silly it sounds and starts arguing against it, and then it’s really hard to keep believing it after you’ve shot it down yourself.”

I nodded. “That’s definitely a therapeutic method, and sometimes a very effective one. Do you have any evidence that this is what Dr. Trauer was doing?”

“Yes! As soon as he said I should commit suicide, I started arguing against him. He told me that if I couldn’t get a tenure track position there would be no other jobs available, and I told him there would be! Then he told me that the jobs would be terrible and I’d never be able to make a happy life for myself with them, and I argued that I would! That must have been what he was going for!”

She suddenly looked really excited. Then, just as suddenly, the worry returned to her face.

“But then what happened with his eye? I swear I saw him take it right out of the socket.”

I nodded. “Can you think of any alternate explanations for that?”

Thinking about it that way, it only took her like five seconds. She slapped her head like she’d been an idiot. “A glass eye. He probably had some kind of injury, had to put in a glass eye, and could take it out any time he wanted. He must have thought it would be a funny gag and didn’t realize how traumatized I’d be. Or he wanted to scare me into realizing how much I wanted to live. Or something.”

I nodded. “That does sound like a reasonable explanation.”

“But…don’t people with glass eyes usually have like scar tissue and normal skin behind them? This guy, I swear it was just the bone and this empty socket, like you were seeing straight to his skull.”

“You’re asking the right questions,” I said. “Now think a little more.”

“Hmmmm,” she said. “I guess I was really, really stressed out at the time. And I only saw it for, like, a fraction of a second. Maybe my brain was playing tricks on me.”

“That can definitely happen,” I agreed.

She looked a lot better now. “I owe you a lot of thanks,” she said. “I’ve only been here for, like, fifteen minutes, and already I think a lot of my stress has gone away. All of this really makes sense. That paradoxical intention thing is actually kind of brilliant. And I can’t deny that it worked – I haven’t been suicidal since I talked to the guy. In fact…okay, this is going to sound really strange, but…maybe I should go back to Dr. Trauer.”

I wrinkled my forehead.

“It’s not that I don’t like you,” she said. “But he had this amazing free clinic, and what he did for me that day…now that I realize what was going on, that was actually pretty incredible.”

“Hold on a second,” I said.

I left the room, marched up to the front desk, took the directory of medical providers in the area off the shelf, marched back to the room. I started flipping through the pages. It was in alphabetical order…Tang…Thompson…Tophet…there we go. Trauer. My gaze lingered there maybe just a second too long, and she asked if I was okay.

“Um, yeah,” I said. “It’s just that he doesn’t – he doesn’t take your insurance. That’s the problem.”

“It’s okay,” she told me. “He said it was a free clinic. So that shouldn’t a problem.”

“Well, uh…the thing is…when you see out-of-network providers, your insurance actually charges, charges an extra fee. Even if the visit itself is free.”

She looked skeptical. “I’ve never heard of that.”

“It’s new. With Obamacare.”

“Really? How high a fee is it?”

“It’s…um…ten thousand dollars. Yeah, I know, right? Thanks, Obama.”

“Wow,” she said. “I definitely can’t afford that. I guess I’ll keep coming here. Not that there’s anything wrong with that. You’ve been very nice. It’s just that…with Dr. Trauer…well…sorry, I’ll stop talking now. Thanks a lot, doctor.” She stood up and shook my hand before heading for the door. “Seriously, I can’t believe how much you’ve helped me.”

No, I thought, as she departed you can’t. I told her she was asking the right questions, and she was, but not all of them.

For example, why would a man with only one working eye have a stereographic Magic Eye image in his office?

I picked up my provider directory again, stared a second time at the entry for Dr. Trauer. There was a neat line through it in red pen, and above, in my secretary’s careful handwriting, “DECEASED”.

Before returning the directory to the front desk, I took my own pen and added “DO NOT REFER” in big letters underneath.

Here’s a vignette from cognitive-behavioral therapy book When Panic Attacks, heavily edited for length:

A chronically anxious medical school professor named Nate suffered from low-self-esteem and feelings of inadequacy. One day, Nate brought me a copy of his CV. I was blown away. He’d listed over sixty pages of research publications, prestigious awards, and keynote addresses he’d given at major conferences around the world. I asked Nate how he reconciled his low self-esteem with all of his accomplishments. He said that every time he looked at his CV, he felt discouraged and told himself that his colleagues’ research studies were far more rigorous and important than his own. He said his paper seemed “soft” and consisted primarily of theoretical work, rather than hard-core laboratory research with real tissue. He said “Dr. Burns, no matter how much I accomplish, it never seems good enough.”

Perfectionism was clearly one of Nate’s self-defeating beliefs. I suggested that Nate use the Pleasure/Perfection Balance Worksheet to test this belief. I told him to write “If I can’t do something perfectly, it’s not worth doing at all” on the top of the sheet, and asked him to list several activities in the left-hand column. I told him to predict how satisfying and rewarding each activity would be, to record how satisfying and rewarding it was afterwards, and to rate how perfectly he did each activity. That way he could find out of it was true that he only enjoyed the things he did perfectly.

The next week, Nate had some interesting results to share with me. One of his activities was giving the welcoming lecture ot the incoming class of medical students. Nate gave this lecture every year because he was considered to be the most charismatic speaker at the medical school. Nate predicted this lecture would be 70% satisfying, but his actual satisfaction as only 20%. This was surprising, since he’d received a thirty-second standing obation, and he’d rated his perfection level for the talk at 90%.

I asked Nate why his satisfaction rating was so low. He explained that he always got standing ovations, so he routinely timed them. The previous year, the medical students had stood and cheered for more than a minute at the end of his talk. This year, the only stood and cheered for half a minute. Nate felt disappointed and started worrying that he was over the hill.

The second entry on Nate’s Pleasure/Perfection Balance Worksheet was that [he fixed a broken pipe in his bathroom]. He had to make several trips to the hardware story to buy tools and parts and to get tips on how to do it, so he didn’t get the pipe fixed until 10 PM. How explained that any plumber could have fixed the pipe in five minutes, so he rated his perfection as 5%. But his satisfaction level for this activity was 100%. In fact, he felt exhilarated. Nate said it was the most satisfying thing he’d done in years.

The result of Nate’s experiment was not consistent with his belief that things weren’t worth doing unless he did them perfectly. It dawned on him that there were many sources of satisfaction in his life that he’d overlooked, such as taking a walk through the woods with his wife, even though neither of them were world-class hikers, playing squash with his son, even though neither of them were champions, or just going out with his family for ice cream cones on a warm summer evening.

This experiment had a significant impact on Nate’s feelings of self-esteem and on his career. He told me that his feelings of anxiety and inferiority decreased, and his productivity actually increased because he was no longer so worried about having to do everything so perfectly.

At first I assumed this story was made up, but the book claims these are based on real patients, and even mentions how the writer showed videos of some of these therapy sessions to his classes. Interesting. How about another?

Several years ago, I did a three-day intensive workshop for a small group of psychotherapists in Florida. A marriage and family therapist named Walter explained that he’d been struggling with anxiety and depression for several months because Paul, the man he’d lived with for eight years, had found a new lover and left him. He put his hand on his chest and said: “It feels real heavy, right here. There’s just a sense of loneliness and emptiness about the whole experience. It feels so universal and final. I feel like this pain is going to go on forever, until the end of time.”

I asked Walter how he was thinking and feeling about the breakup with Paul. What was he telling himself? He saidL “I feel incredibly guilty and ashamed, and it seems like it must have been my fault. Maybe I wasn’t skillful enough, attractive enough, or dynamic enough. Maybe I wasn’t there for him emotionally. I feel like I must have screwed up. Sometimes I feel like a total fraud. Here I am, a marriage and family therapist, and my own relationship didn’t even work out. I feel like a loser. A really, really big loser.”

Walter recorded these five negative thoughts on his daily mood log:

1. I’ll never be in a loving relationship again
2. I must be impossible to live with and impossible to be in a relationship with
3. There must be something wrong with me
4. I totally screwed up and flushed my life down the toilet
5. I’ll end up as an old, fat, gray-haired, lonely gay man

He believed all of these thoughts very strongly.

You can see that most of Walter’s suffering results from the illogical way he’s thinking about the rejection. You could even say that Walter is treating himself far more harshly than Paul did. I thought the Double Standard Technique might help because Walter seemed to be a warm and compassionate individual. I asked wehat he’d say to a dear friend who’d been rejected by someone he’d been living with for eight years. I said “Would you tell him that there’s something wrong with him, that he screwed up his life and flushed it down the toilet for good?”

Walter looked shocked and said he’d never say something like that to a friend. I suggested we try a role-playing exercise so that he could tell me what he would say to a friend who was in the same predicament […]

Therapist (role-playing patient’s friend): Walter, there’s another angle I haven’t told you about. What you don’t understand is that I’m impossible to live with and be in a relationship with. That’s the real reason I feel so bad, and that’s why I’ll be alone for the rest of my life.

Patient (role-playing as if therapist is his friend who just had a bad breakup): Gosh, I’m surprised to hear you say that, because I’ve known you for a long time and never felt that way about you. In fact, you’ve always been warm and open, and a loyal friend. How in the world did you come to the conclusion that you were impossible to be in a relationship with?

Therapist (continuing role-play): Well, my relationship with [my boyfriend] fell apart. Doesn’t that prove I’m impossible to be in a relationship with?

Patient (continuing role-play): In all honesty, what your’e saying doesn’t make a lot of sense. In the first place, your boyfriend was also involved in the relationship. It takes two to tango. And in the second place, you were involved in a reasonably successful relationship with him for eight years. So how can you claim that you’re impossible to live with?

Therapist (continuing role-play:) Let me make sure I’ve got this right. You’re saying that I was in a reasonably successful relationship for eight years, so it doesn’t make much sense to say that I’m impossible to live with or impossible to be in a relationship with?

Patient (continuing-role-play:) You’ve got it. Crystal clear.

At that point, Walter’s face lit up, as if a lightbulb had suddenly turned on in his brain, and we both started laughing. His negative thoughts suddenly seemed absurd to him, and there was an immediate shift in his mood…after Walter put the lie to his negative thoughts, I asked him to rate how he was feeling again. His feeling of sadness fell all the way fromj 80% to 20%. His felings of guilt, shame, and anxiety fell all the way to 10%, and his feelings of hopelessness dropped to 5%. The feelings of loneliness, embarassment, frustration, and anger disappeared completely.

The book is quite long, and it’s full of stories like this. The author, who’s one of the top cognitive-behavioral psychiatrists in the world, describes his experience with the therapy as:

[When I first learned about this therapy, I thought] depression and anxiety seemed far too serious and severe for such a simplistic approach. But when I tried these methods with some of my more difficult patients, my perceptions changed. Patients who’d felt hopeless, worthless, and desperate began to recover. At first, it was hard to believe that the techniques were working, but I could not deny the fact that when my patients learned to put the lie to their negative thoughts, they began to improve. Sometimes they recovered right before my eyes during sessions. Patients who’d felt demoralized and hopeless for years suddenly turned the corner on their problems. I can still recall an elderly French woman who’d been bitterly depressed for more than fifty years, with three nearly-successful suicide attempts, who started shouting “Joie de vivre! Joie de vivre!” (“joy of living”) one day in my office. These experiences made such a strong impact on me that I decided my calling was in clinical work rather than brain research. After considerable soul-searching, I decided to give up my research career and become a full-time clinician. Over the years, I’ve had more than 35,000 psychotherapy sessions with depressed and anxious patients, and I’m every bit as enthusiastic about CBT as when I first began learning about it.

Okay. I am not one of the top cognitive-behavioral therapists in the world. I’ve been studying formal cognitive-behavioral therapy for about a week now, and been doing untrained ad hoc therapy on inpatients for a couple years. But I’ve also gotten to observe a lot of other people doing therapy, and talked to people who have had therapy, and treated patients who were simultaneously undergoing therapy, and the impression I got was very different.

Dr. Burns asks patients to question whether their anxiety and their negative thoughts are rational, and their faces light up and all of their psychiatric problems suddenly melt away.

The therapists I’ve seen ask patients to question whether their anxiety and their negative thoughts are rational, ever so tactfully, and the patients say “No shit, Sherlock, of course they aren’t, but just knowing that doesn’t help or make them go away, and I’ve been through this same spiel with like thirty people already. Now shut up and give me my Xanax.”

In my last post, someone asked what to do if they found cognitive-behavioral therapy hokey and patronizing. I said, only half joking, that “if you don’t like hokey patronizing things, CBT may not be for you.” I know it’s mean, and pessimistic, but everyone I’ve talked to has had pretty much the same experience. I used to attribute this to my friends being pretty smart, and maybe CBT was aimed as less intelligent people, but Nate The Genius Medical School Professor seems pretty smart. So does Walter The Therapist. Burns’ book includes a bunch of other vignettes about high-powered lawyers, graduate students, et cetera. They all find his suggestions of “Well, have you considered that your irrational negative thoughts might not be rational?” super life-changing.

You might have read the study this graph comes from: The Effects of Cognitive-Behavioral Therapy As An Anti-Depressive Treatment Is Falling: A Meta-Analysis. As you can see, the Hedges’ g declined from about 2.5 in 1980 to around 1 today. The latest embarrassing set of results now show CBT doing no better than its old nemesis psychoanalysis. Why?

There are a lot of possible explanations. The smart money is always on “it never worked very well, but we’re finally doing studies that aren’t hopelessly biased”, but the analysis doesn’t find a clear difference in study quality. Other suggestions are that therapists have gotten less committed over time, or that the patient populations has changed. All of these sound reasonable. But let me mention one more possibility.

Every so often, psychiatrists joke about how so many people are depressed we might as well put Prozac in the water supply. Sometimes we say the same thing about lithium, although in that case we’re not joking.

Nobody’s ever talked about putting cognitive-behavioral therapy in the water supply, but insofar as that’s meaningful at all I would say we’ve kind of done it. Cognitive-behavioral ideas, like perfectionism, excessive self-blame, conditional versus unconditional self-respect, deep breathing, goal-setting, et cetera have become basic parts of popular culture. The whole self-esteem movement isn’t exactly cognitive-behavioral, but it’s certainly allied, and it certainly represents a shift to a style of thinking about the self and about psychology in a way that’s much more fertile for cognitive-behavioral ideas. Inside Out was kind of “Cognitive Behavioral Therapy: The Movie”.

Although the particular book I’m reading is from 2006, Burns himself was one of Aaron Beck’s original students and one of the first cognitive-behavioral therapists ever. I wonder how many of these patients who seem absolutely shocked to realize that maybe their anxiety isn’t rational come from that very early period.

It’s very hard to track changes in people’s basic beliefs about psychology. I was flabbergasted to learn that until Dr. Benjamin Spock’s landmark 1940s book on child care, parents were told not to hug, kiss, or show affection to babies, because that would coddle them and make them weak, pampered adults. Before that, parents interacted with their kids much less, and it was assumed that siblings and nannies and friends would raise them, or they would raise themselves. It’s easy to read books about ancient Greece and not notice that they have a completely different view of the role of the self/individual than we do. So it wouldn’t surprise me if a lot of the psychology we consider “obvious” is CBT that has seeped out into the water supply over the past thirty years.

If that were true, it would explain why CBT is no longer as effective – it’s just telling people things they already know.

It could be fairly asked: then why isn’t everybody already better? Depression seems to be increasing, though there’s a lot of argument about exactly how much; that doesn’t sound like what would happen if everyone were automatically getting a background level of therapy.

Here’s a theory, though it’s on even shakier ground than the other one. The meta-analysis proposes that CBT may have lost some placebo effect over time because patients no longer think of it as The Exciting New Thing. I’m not sure I can go along with that – my own analysis of psychotropic medications suggests patients very much prefer the old ones for some reason. But a big part of psychotherapy is placebo effect, so they might be on to something.

What part of psychotherapy provides the placebo? Is it going to the clinic? Talking to the therapist? Hearing fancy words like “self-estimation”? Doing worksheets?

One thing a lot of therapies have in common is that they provide the feeling of insights. For example, psychoanalysts are very good at coming up with surprising-but-plausible ways that your current problems are linked to things that happened to you as a child; the usual result is a patient feeling enlightened, like “You’re right, the leg pain that’s been bothering me is in the same part of my leg that accidentally brushed up against my mother’s breast one time when I was seven, that’s pretty interesting.”

Suppose that in the old days, CBT was an insight a minute and you were constantly hearing surprising things you’d never thought about before. And nowadays, you’re kind of absorbing a lot of those things by osmosis without it seeming too insightful, and then the therapy itself is anticlimactic. Could that lessen the placebo effect enough to account for the data?

I don’t know. Maybe after I’ve been training in formal CBT for more than a week, I’ll have more data and can report back to you.

[EDIT: Sarah writes: “In a way, seeing CBT stuff in pop culture inoculates people, I think. People will get as far as noticing “this negative thought is an anxiety symptom”, but not as far as *actually reversing it*. When people hadn’t heard of CBT, they first got the “this negative thought is irrational” message in a context when they were actively working on their problems, so they followed through with the ‘hard’ step of actually reversing the thought. Now, people run into the revelation that the ‘inner critic’ is wrong just by browsing facebook, when they’re *not* actively trying to fight their anxiety problems, so the revelation loses its force.”]

[EDIT 2: Paul Crowley points out a very similar theory in The Guardian]

But it’s hard to describe how disabling anxiety can be. A lot of people with nominally much worse conditions – depression, bipolar, even psychosis – will insist that they want their anxiety treated before anything else, because they can live with the rest. On the other hand, while a lot of people with psychosis have enough other problems that treating the psychosis barely puts a dent in their issues, a lot of people with anxiety would be happy and productive if they could just do something about it.

Since I’ve gotten some positive comments on my discussion of depression treatments I thought I’d go through some of the things I’ve seen used to treat anxiety. I’ll include the same disclaimer:

This will be inferior to reading official suggestions, but you will probably not read official suggestions, and you may read this. All opinions here are my own, they are not endorsed by the hospital I work at, they do not constitute medical advice, I have a known habit of being too intrigued by extremely weird experimental ideas for my own good, and you read this at your own risk. I am still a resident (new doctor) and my knowledge is still very slim compared to more experienced professionals. Overall this is more of a starting point for your own research rather than something I would expect people to have good results following exactly as written.

I’ll mostly be talking about what’s called generalized anxiety disorder, with some applicability to panic disorder. Social anxiety, specific phobias, et cetera are their own thing, as is anxiety secondary to other illnesses – but some of the advice may cross over. I’m not going to get too into diagnosis, because generalized anxiety disorder is pretty much exactly what you think it is and a lot (though not all) of this will be applicable for subclinical anxiety as well.

I. Diet And Lifestyle

You didn’t think you were going to get out of this part, did you?

Pretty much every study – epidemiological or experimental, short-term or long-term, has shown that exercise decreases anxiety. The effect seems limited to aerobic exercise like walking, running or swimming, preferably for longer than twenty minutes. Various mechanisms have been postulated including norepinephrine, endogenous opioids, and decreased inflammation.

There’s less agreement on diet. The people who hate fat says high-fat diets cause anxiety. The people who hate carbs say high-carb diets cause anxiety. The people who hate processed food say processed foods cause anxiety. The people who recommend fish oil for everything say insufficient fish oil causes anxiety. None of it seems super credible, but Mayo Clinic has some suitably bland advice.

The one very important connection – if you drink too much coffee, or any other source of caffeine, that will make you anxious. I once had a patient come to me with severe recurrent anxiety. I asked her how much coffee she drank, and she said about twenty cups per day. Suffice it to say this was not a Dr. House-caliber medical mystery.

Also needless to say: get enough sleep. Seriously. Get enough sleep.

Many people find that various breathing exercises or other sorts of mindfulness activities can be helpful in the short term and sometimes build skills useful for the long term. My hospital gives people these handouts on breathing techniques and progressive muscle relaxation. I’ve made fun of HeartMath in the past, but I only learned about them because many people find some success, probably placebo-ish, with their quick coherence technique. If you’re an overachiever and want to get really into this sort of stuff, people always say good things about yoga and especially pranayama breathing. Studies seem to back this up (1, 2, 3) though you’ve got to be careful to weed out the studies by very religious Hindus trying to prove they’ve been right all along.

Meditation has similarly positive results. Here’s a study showing that an intervention to teach patients meditation resulted in decreased anxiety with p < 0.001 even three years later. Here's a meta-analysis of 39 studies finding an effect size of about 0.6 (medium) in the general population, and an effect size of about 1.0 (large) in people with anxiety disorders. But here’s an equal and opposite review that found only “equivocal” results. As far as I can tell, most people investigating meditation think it works pretty well. The meditation techniques that seem to work best are mindfulness meditation and transcendental meditation. You can learn a little about mindfulness meditation here. In order to learn about Transcendental Meditation, send a check made out for $5000 to Maharishi Mahesh Yogi, PO Box….

II. Therapy

Cognitive-behavioral therapy works okay for anxiety just like it works okay for everything else. The Big Graph O’ Effect Sizes says that psychotherapy on average has an effect size of 0.51 in generalized anxiety, compared to medication’s 0.31. This shouldn’t be taken too seriously – the confidence intervals overlap and there’s a wide range of efficacy for different medications – but you won’t be doing any worse by going for the therapy first. Even the Cochrane Review, famous for never drawing any conclusion other than “more research is needed”, is tentatively willing to say that psychotherapy works for anxiety disorders. Their study trends towards finding that cognitive behavioral therapy works better than supportive therapy, but is unable to prove significance – apparently more research is needed.

Exposure therapy can also be useful for panic attacks or specific phobias. This is where they expose you to the thing you’re scared of (or deliberately initiate a panic attack) and keep doing it until you stop being scared and start being bored. According to a bunch of studies it works neither better nor worse than cognitive-behvioral therapy for most things, but my unsupported impression has always been that it’s better at least for panic disorder. Cognitive-behavioral therapy seems clearly superior for social phobia.

You can get psychotherapy from any qualified psychotherapist, a category including counselors, social workers, psychologists, and sometimes psychiatrists. Ones who use “a school” (for example, describe themselves as practicing cognitive behavioral therapy) are usually considered better than those who don’t (“Oh, I do a little of everything with every patient”). If you can’t find (or don’t want to find) a good therapist, there is preliminary evidence that a good self-help therapy workbook (“bibliotherapy”) is about as good as real therapy – including for anxiety (study, other study, yet another study).

I have no special insight into which self-help workbooks are any good, but The Cognitive Behavioral Workbook for Anxiety: A Step-By-Step Program seems to get pretty good ratings.

III. Medications

To be tried after diet and lifestyle interventions when possible.

Medication can work either instead of or in addition to therapy. There are at least seven categories of commonly used conventional anxiety medications: SSRIs, SNRIs, antihistamines, antipsychotics, anticonvulsants, benzodiazepines, and azapirones. These can be divided into mostly-acute (antihistamines and benzos) and mostly-long-term (SSRIs, SNRIs, anticonvulsants, azathioprines), with antipsychotics kind of being a tossup. Depending on whether you just need to get through the occasional panic attack or whether you’re in a chronic unremitting anxiety state, you might want one, the other, or both.

You probably know antihistamines (example: Benadryl) from the many common over-the-counter members of this class. They have some mild short-term anti-anxiety effects. Benadryl will work in a pinch if you need something without a prescription, but the most commonly used anxiolytic antihistamine is hydroxyzine (“Vistaril”, “Atarax”), which is a bit more powerful and less likely to make you fall asleep. As far as anxiolytics go it’s pretty safe as long as it doesn’t make you too sleepy. If you just need something to take the edge off the occasional anxiety attack, this works fine.

Benzodiazepines (examples: Xanax, Ativan, Valium, Klonopin) are very effective in the short-term but also very controversial. In some people they are very habit-forming and can produce a picture very similar to addiction to alcohol (which they chemically resemble). Keep in mind how bad an idea it might be to become extremely addicted to prescription pills that you may suddenly lose access to depending on how your doctor is feeling (you might expect doctors would take the difficulty of coming off these drugs into account, but you might expect a lot of things from doctors that don’t always happen). Studies suggest benzodiazepines can sometimes build tolerance, and that after a month or two of frequent use, they lose their positive effect and you need them just to feel normal. That having been said, a subset of patients – and I can’t tell at this point if it’s a majority or a minority – go on benzodiazepines, do very well, stay on them for long periods without getting dependent, and never have anxiety again. It’s kind of a crapshoot. The most generally recognized “safe” use of benzos is the occasional Xanax to deal with rare but very stressful situations (for example, flying on an airplane if you’re scared of heights). Other people say Klonopin is safer than some of the others and that it’s worth a shot as long as you realize that “Klonopin dose gradually creeping upwards” is a sign that you’re getting into a bad place and need to react immediately. Most people recommend trying other things first before you come here, but once you’ve exhausted other options these can be a powerful last resort.

SSRIs (examples: Prozac, Celexa, Lexapro, Zoloft) are the mainstay of chronic anxiety treatment just like they’re the mainstay of chronic everything-else treatment. As usual, they have real but modest effects after about a month or so, more in some people and less in others. As usual, if one SSRI doesn’t work for you, you might want to try another. These are pretty safe aside from the sexual side effects. Some people get mild withdrawals if they go off these too quickly, so don’t do that. A lot of people use both an SSRI for chronic treatment, plus either an antihistamine or benzo for “break-through” anxiety.

SNRIs (examples: Effexor, Cymbalta) are like SSRIs, but for two neurotransmitters instead of one. This is supposed to make them a little bit more effective. Maybe they are, maybe they aren’t. Fewer sexual problems than SSRIs, but worse discontinuation syndrome. They’re a good second-line chronic medication if SSRIs don’t work. Effexor is probably the best.

Azapirones (example: BuSpar) is, unusually, a rare drug which is specifically targeted at anxiety, rather than a being a repurposed antidepressant or something. BuSpar is very safe, not at all addictive, and rarely works. Every so often somebody comes out with a very cheerful study saying something like “Buspar just as effective as benzodiazepines if given correctly!” and everybody laughs hysterically and goes back to never thinking about it.

Anticonvulsants (examples: Depakote, Neurontin, Tegretol, Lyrica) are seizure medications that sometimes sort of work for anxiety. Most of them have strong side effects and limited utility. The exception is Lyrica (pregabalin), which is pretty new but has shown excellent safety and efficacy in studies. It doesn’t have an FDA indication for anxiety and it’s pretty expensive, so you might have a hard time getting it, but it is at least a well-kept secret.

Atypical antipsychotics (examples: Seroquel, Zyprexa, Abilify, Geodon) are, as always, overused. Most of them either make you gain lots of weight, put you at increased risk for heart rhythm problems, make you feel terrible, put you at risk of permanent movement disorders, or all of the above. They do often treat anxiety, sometimes very well, and psychiatrists like them because they’re good all-purpose no-nonsense drugs with big advertising budgets, but unless you’re also psychotic consider trying some other things first before you try these.

An article in Journal of Psychopharmacology tries to compare the efficacy of all of these classes of drugs and gets the following effect sizes (bigger number = bigger effect):

Pregabalin: 0.5
Antihistamine: 0.45
SNRI: 0.42
Benzo: 0.38
SSRI: 0.36
Azapirone: 0.17
Alternative medicine: -0.31

(remember, other studies suggest psychotherapy is around 0.5)

I heavily challenge the claim that antihistamines are more effect than (or anywhere near as effective as) benzos. I don’t know the confidence intervals on these numbers, so I would suggest reading it as “Everything is about equally effective, except azapirones which aren’t as good”. Their “alternative medicine” category was mostly kava and homeopathy, and I have no idea why it came out negative (kava’s pretty good, and homeopathy shouldn’t separate from 0).

There are also some less commonly used drugs that might help people who don’t respond to any of these.

As usual, MAOIs are very effective, moderately dangerous, and super hard to get. They seem to work especially well for panic disorder and social anxiety.

Clonidine is a medication usually used to control blood pressure. It’s somewhat effective against anxiety and some people think it should be used more. But it can cause you to become too sedated (abnormally low heart rate) and in some people it makes anxiety worse for some reason.

Beta-blockers (example: propranalol) are another blood pressure medication. It is especially effective against somatic symptoms of anxiety – racing heartbeat, shaking, et cetera – and sometimes getting rid of those can make the anxiety go away entirely. It’s most famous for its use against performance anxiety: about a third of musicians use them in concerts, and I’ve heard similar rumors about public speakers, actors, et cetera. I used to think this was a little-known piece of trivia, but whenever I bring it up to doctors (“Hey, did you know some people use beta-blockers for performance anxiety”) the usual response is “Oh, yeah, I prescribe myself some of that when I have to give a presentation at grand rounds.” They don’t seem quite as good for longer-term anxiety disorders, though some people have had good results with them.

I once saw an excellent psychiatrist whom I deeply respect try everything on a patient with severe treatment-resistant anxiety with no results whatsoever until finally he came to Thorazine. This treated the patient’s anxiety pretty well, at the cost of provoking quite a bit of anxiety in the doctor.

Without meaning to give medical advice, and with the caveat that you should ask your doctor for their opinion – one good pharmacological treatment algorithm for anxiety disorders is:

If you just have occasional outbursts that bother you, take occasional doses of hydroxyzine.

If you have a longer-term problem, start with an SSRI. If that doesn’t work, either try more SSRIs and SNRIs, or go to Lyrica. You might as well be on BuSpar somewhere in the process too. If none of that works, choose your poison (or have it chosen for you) among MAOIs, benzos, clonidine, or antipsychotics.

IV. Alternative Treatments

To be used out of curiosity or desperation only – you have other options and these are not guaranteed safe or effective.

Massage therapy, acupuncture, aromatherapy, and everything else in the category of “unnecessarily medicalized relaxing thing” all perform very well as long as you don’t look too hard for a suitable control group. Yes, these are probably placebo, but they’re very effective placebos and if they both work I would rather take a placebo than an antipsychotic.

Inositol and l-theanine are both found in small quantities in the diet (inositol in some vegetables, theanine in tea) and supplementing them has been inconsistently found to help with anxiety. Inositol had some preliminary evidence for effectiveness in panic disorder, but a more recent meta-analysis was unimpressive. I can only say that I have some anecdotal evidence of extremely positive reactions to inositol, but we all know what they say about anecdotal evidence. Keep in mind that the dose used in studies is way larger than the dose anyone will give you – usually corresponding to about 20 of those 500 mg inositol pills a day. This makes it expensive and inconvenient, and most people just compromise by taking so little inositol it shouldn’t possibly be able to have any effect. L-theanine also has a lot of small studies in support, although there’s some question on whether it works on its own or whether it just has useful synergistic effects with caffeine. Sun-theanine is generally considered the most effective form, and recommended dose is about 100 – 400 mg. Both these supplements are afaik very safe and a good option for people who want to test things that might or might not work but have minimal risk. Magnesium should also be in here somewhere.

GABA is the main inhibitory neurotransmitter in the nervous system, and a lot of these other interventions are attempts to convince the brain to release more GABA or potentiate the GABA that’s already released. Can we just cut out the middleman and ingest GABA pills directly? The supplement industry would like you to think so, and you can certainly buy them anywhere supplements are sold, but it’s generally believed that orally ingested GABA can’t cross the blood-brain barrier. The Russians have developed a modified version of GABA that doesn’t have this problem; called picamilon, it seems to be a pretty popular anxiety treatment on the other side of the Pharmacological Iron Curtain. It’s pretty easy to get as a non-prescription supplement here in the West. There are very few studies on it, the ones that exist are in Russian, and I have nothing to go on but a couple of anecdotal reports, most of which are positive (though I personally noticed no effects). But the mechanism of action is plausible, and the long history of successful Russian use at least suggests it probably won’t kill you immediately. Most common dosage seems to be about 100 – 300 mg.

The nootropics/supplement/nutraceutical community also suggest ashwagandha and bacopa for anxiety; various low-quality studies support the use of both (ashwagandha meta-analysis, bacopa study 1, bacopa study 2, bacopa study 3). Bacopa may take several months of frequent use before it starts working; I tried it briefly and had to stop because of gastrointestinal side effects, which are pretty common. There’s also some worry around heavy metal contamination. Swanson’s and Nootropic Depot’s are two that have third-party testing showing they’re uncontaminated.

Kava is a traditional drink from various Pacific islands with anxiolytic properties. Multiple meta-analyses including a Cochrane review find it to be an effective anxiety treatment, but its safety is in question after reports of several cases of liver failure caused by the plant. This may be yet another case of people exaggerating freakishly rare side effects; the risk has been estimated at less than one in a million doses (though remember that if you take it daily for ten years, that number bcomes 1/300). Others suggest a rate as low as one in a hundred million but this assumes zero underreporting; others challenge this assumption. Possibly it is only poorly prepared kava causes liver problems; for traditionally prepared kava, look for preparations that specify they are made from root/rhizome material only. The American Academy of Family Physicians recommends that:

Physicians who supervise patients taking kava for the treatment of GAD should take care to avoid the following: (1) high dosages (more than 300 mg per day); (2) combining kava with hepatoactive agents; (3) using non-root preparations; and (4) exposure for longer than 24 weeks. Use of WS1490 standardized kava extract is also recommended. If these safety precautions are followed, kava can be appropriate therapy for selected patients diagnosed with GAD

Don’t take kava if you have any liver problems, if you’re on any medications that might interact with it, or if you plan on drinking alcohol at the same time. Consider talking about it with your doctor first and getting plans to check liver enzymes regularly.

Selank is an experimental Russian anti-anxiety medication going through their version of clinical trials. It’s a bit high-maintenance – you have to keep it refrigerated or else it decays, and the only two functional means of administration are injection or nasal spray – but anecdotal evidence is extraordinarily positive. No side effects have been found thus far, but needless to say by the time you get to “injecting experimental Russian medications into yourself” we have left the point where we can entirely guarantee this is a good idea. Ceretropic sells a nasal spray version, which is probably more convenient than having to inject it.

Phenibut is another Russian anti-anxiety medication, but it’s very addictive and dangerous. Even the fearless people of r/nootropics stay away from this one. Highly un-recommended.

Overall, the best evidence seems to be for l-theanine (especially if you drink coffee) and bacopa (especially if you’re willing to wait months for any effect), with picamilon also worth your time to try and Selank as an option for the very adventurous.

V. Conclusions

No treatment stands out as extremely effective, and the best route to dealing with anxiety probably depends on many factors like your amount of free time, your motivation, your access to medical care, and your willingness to put up with side effects. After you’ve fixed lifestyle issues, I think any of “self-help workbook”, “start SSRIs”, or “try l-theanine” are good first options. On the other hand, benzodiazepines, antipsychotics, and kava are all options I would hold off on until you’ve tried a couple of other things.

Like with the depression post, the most important conclusion you can take from this is that you have lots of options. Please don’t let people give you an SSRI and then give up. Work with your doctor. Anxiety actually has a pretty good prognosis if people work on it, but it can be a difficult and frustrating process. Just remember: there are lots of options.

PS: Relevant Onion

Old news, but I only just heard about it: Long Island woman says psych ward doctors believed she was delusional for insisting Obama follows her on Twitter.

The story: a woman was brought in for psychiatric evaluation. During the evaluation, she said President Obama followed her on Twitter. The psychiatrists decided she was psychotic and forced medication on her. But in fact, President Obama does follow her on Twitter, just as he does six hundred thousand other people. So they committed a perfectly sane person for telling the truth, leading to what the article calls a “frightening eight-day ‘One Flew Over the Cuckoo’s Nest’ ordeal”.

I don’t know anything about this case or this person, and I definitely don’t want this to sound like I have anything to say one way or the other about this person I have never met. But I’ve been involved in enough similar cases to have a different perspective, and wonder whether it was quite as much of an outrage as the article makes it out to be.

Consider: the comment occurred when she was in a hospital for psychiatric evaluation; that is, she was brought in before the Obama comment. According to the article:

The bizarre experience began Sept. 12, when the NYPD seized her prized 2003 BMW 325Ci in Harlem because they suspected she was high on weed, her attorney, Michael Lamonsoff, said. Cops found no marijuana but confiscated her ride anyway, he said. The NYPD declined to comment.

The following day, Brock walked into the NYPD’s Public Service Area 6 stationhouse in Harlem to retrieve her car, her suit charges. Brock — an eccentric 32-year-old born in Jamaica with dreams of making it big in the entertainment business — admitted in an interview she was “emotional,” but insisted she in no way is an “emotionally disturbed person.” Nevertheless, cops cuffed her and put her in an ambulance bound for the hospital, her suit charges.

This sort of elides over everything in between “went into police station to ask for car back” and “cops put her in an ambulance bound for the hospital.”

I’ve had patients sent by ambulance from the police station. It’s almost always because they started screaming and yelling threats at the police. Now, screaming and yelling threats at the police, although not a very good idea, is not always evidence of psychiatric disorder. But it often is. If you’re manic or on drugs, you’re a lot more likely to have the particular type of bad judgment that makes screaming threats at the police a seem like a good idea.

I don’t know what happened with Ms. Brock, and the article doesn’t say. I did take a look at her Twitter account, which is mostly angry tweets about Trayvon Martin, Mike Brown, and police brutality. A typical example is “Police should NOT be allowed to Murder the Citizens of this Country!!! We are not Animals!!! @BarackObama fix it NOW!!! #BanGuns”. Other Tweets seem maybe a little threatening, like the ominous “@NRA you people deserve the wrath that will come on you in the very near future” and “#KillRacists”.

So – cops have just done something very unfair to a person who likes making threats and doesn’t like cops, and who herself admits to being “eccentric” and “emotional”. Again without knowing what went on, my guess was that her “discussion” with the police was sufficiently exciting that they thought calling an ambulance for a psych evaluation was in order.

So imagine you’re the psychiatrist, you’re receiving a patient from the police for evaluation after she got in some kind of screaming match with them. And now she tells you Barack Obama follows her on Twitter. The article says:

“I told (the doctor) Obama follows me on Twitter to show her the type of person I am. I’m a good person, a positive person. Obama follows positive people!”

This is weird. At best, it displays a surprising ignorance of how Twitter and/or the world works. Yes, Obama follows 600,000 people on Twitter, but this does not prove that each of them is “a positive person”. I would assume he has some program that auto-follows anyone who mentions him. When you think this is a good thing to bring up during, of all times, a psychiatric evaluation, then I start to wonder.

(I should also add here that, in my limited experience, social media is God’s gift to grandiose psychiatric patients. None of them are “a guy with a Facebook page”. They’re all “social media celebrities with hundreds of followers”. It’s always “YOU CAN’T DO THIS TO ME! DO YOU KNOW WHO I AM? I HAVE HUNDREDS OF FOLLOWERS ON TWITTER! EVEN [NAME OF TWITTER PERSON I HAVE NEVER HEARD OF] FOLLOWS ME! THIS IS GOING TO GO VIRAL!” One patient even told me, in a threatening manner, that his blog had over a thousand hits. “You mean a day?” I asked. “No, total,” he answered. Then he wondered why I was so utterly failing to look impressed.)

So I’ll be honest – if someone had just been brought in for a shouting match with police, and the first thing they told me was that President Obama follows them on Twitter, well – among the most common symptoms of mania are irritability, grandiosity, poor decision-making, and flamboyant dress/behavior. Getting in a fight with the police sounds like irritability and poor decision making, thinking the Obama follow is relevant sounds like grandiosity, and this woman’s Facebook photo certainly suggests a flair for the dramatic. I’m not saying I would commit her on these factors alone, and a lot would depend on the rest of the history. But she already would have started digging quite a hole for herself.

Remember, psychiatrists have to err on the side of admitting people. Even if this lady didn’t have bipolar disorder, admitting her for further evaluation seems like the sort of thing that could be an honest mistake.

(and remember, all we have here is her side of the story. Goodness only knows what other things she might have said or done that she didn’t leak to the news for their sympathetic article based entirely on her testimony.)

But then there’s the hospital’s subsequent conduct. They said that she was unemployed. She said she was employed and could prove it through her Internet presence. The hospital apparently didn’t check and continued to say she was psychotic for thinking she was employed. How could the hospital possibly be so incompetent as to not check the link to her employment documents that she was personally giving them?

II.

Let me tell you about Professor T.

(this would be a good time to reiterate that every patient story I tell here is a composite of multiple different people with all of the details changed around to protect anonymity. The gist of the story points out a true thing, but the specifics are all twisted around so thoroughly that even the people involved couldn’t recognize themselves.)

Professor T came to me in handcuffs. The police had picked him up in response to a call at the local university, where he was trying to give a lecture to a class that wasn’t expecting him and didn’t want him. The class’s actual professor had asked what the heck he was doing, and he had explained that he was Professor T, world-famous physicist, and that the head of the college had invited him to give a lecture on his theories that day, and it was too bad she hadn’t communicated this with the rank-and-file teachers, but he was a very busy man and they should all be honored by his presence and stop what they were doing and listen to him. A quick call to the administration confirmed none of them had any idea who he was either, and when he refused to go away or stop trying to lecture, the police were called to remove him. He started yelling and screaming at the police and telling them they were fools who were too small-minded to recognize a great scientist when they saw one, and they’d get what was coming to them. The cops decided this was a job for a psychiatrist and brought him to me.

Professor T said he’d just been really angry that the bureaucracy had screwed up badly enough to make him miss his lecture and that no one was willing to accommodate him. He was, after all, a very important leading scientist with a busy schedule. He moved in elite circles! Famous people like Edward Witten knew him well, and I was welcome to call to confirm that! He was used to being shown more respect!

I got a weird vibe from Professor T during our discussion. I know that distinguishing between professors and hobos is a famously difficult problem, but he just struck me as a little too much towards the hobo end for comfort. So I asked him if I could see any proof that he was who he said that he was.

He was happy to comply, and once we got to a computer he showed me some scientific papers with his name on top, suitably peppered with complicated words like “tachyon” and “chromodynamics”. He showed me a picture of him winning some prestigious physics prize, dressed in a lab coat with a medal around his neck. He even showed me what looked like a press release: “Professor T comes up with new Theory Of Everything that may explain Higgs Boson”. It was pretty convincing.

But.

First, a bunch of patients had cancelled on me that day, so I had way too much free time.

Second, I used to be in a really complicated geopolitical simulation. One of my roles was the local investigative reporter. I researched and published stories about all of the weird conspiracies and manipulations going on. I was pretty good at it. One day, a trusted source sent me links to what turned out to be the biggest story I’d ever stumbled upon. A bunch of forwarded emails and a password protected forum (which my source helpfully provided the password to) proved that the people nobody trusted were in fact involved in a large and highly illegal plot against everyone else. Delighted, I published the story, only to be met with total denial from everyone involved. Not the sort of denial I usually got in situations like this. The kind of denial you get when someone actually didn’t do something. Further investigation eventually revealed that my “trusted” source had made it all up. He’d laboriously faked both sides of all the email conversations he sent me, then made the entire secret forum by himself, posting daily under five or ten different aliases for weeks in order to create the illusion of a large community. Some famous magician – I can’t find the quote right now – once said that the secret of magic was to spend more effort preparing than any sane person would think possible. That was how my trusted source got me, and it was a lesson that really, really stuck.

So since I had the time, I started looking into Professor T’s credentials a little more. His papers were hosted on a private site and didn’t show up on Google Scholar and didn’t seem to be affiliated with any journal. The press release was on the same website, and seemed suspiciously badly written. There was nobody else in his photograph, and it was impossible to see what was written on the medal. Was it possible that a crazy hobo had just written some things that looked like papers, written something that looked like a press release, and then bought a lab coat and medal and taken a picture with them? Do real theoretical physicists even wear lab coats?

So I asked him if I could talk to Dr. Witten, whom he said he knew well. Professor T agreed. I Googled his phone number and called him up.

(It wasn’t actually Dr. Witten whom I called, but the case I’m adapting this story from involved someone else about as famous)

His secretary answered the phone, and I said I was a psychiatrist, and I asked if I could speak to Dr. Witten. The secretary was reluctant, but when I said it was about Professor T, she immediately asked me to hold, and I got Dr. Witten himself. I asked him if he knew Professor T.

“Absolutely,” said Dr. Witten. “He’s a crazy guy who keeps calling me up and telling me he’s solved physics. I don’t think he’s actually a professor of anything. I read one of his papers once, just for kicks, and it’s just a bunch of science terms like ‘tachyon’ and ‘chromodynamics’ strung together without rhyme or reason. It might fool a layman, but trust me, it makes no sense. I told him to stop calling me, and he wouldn’t, and finally I had to block him on my phone, and now he’s sending me letters in the mail, and it’s always same ranting about tachyon chromodynamics, which isn’t even a real thing. Did you say you’re a psychiatrist? Perfect, I’m so glad he’s finally getting treatment.”

I told Professor T about this, and he nodded his head. “Yes,” he said “I told you that Dr. Witten knows me well. I didn’t say he liked me. He still doesn’t fully understand my theories. But I am sure he’ll come around.”

I kept Professor T in hospital for about a week, and I can’t count how many times he yelled at me and complained that I was being unfair to him by not doing whatever the heck he wanted me to do that day. Read another one of his papers that would convince me his theories were sound. Call up yet another famous physicist he “knew”. Look at yet another of his fake websites devoted to himself. Every day, he threatened to sue me and my boss and the entire hospital for keeping him there even though he’d “proven” to us he was who he said.

Remember, delusions are fixed false beliefs. People are quite sure they’re true, quite sure they have evidence for them, and nothing (except occasionally really good psychiatric treatment) will convince them otherwise. They’ll keep demanding you take time to investigate more and more bizarre “arguments” and “evidence”, and if you ever stop, even after days and days of everything they say being one hundred percent refuted, they’ll accuse you of acting in bad faith.

(it’s like Internet arguments, only more so)

In everyday life, we get by on an assumption of trust. If I tell my boss I’m sick, he probably believes me. If he doesn’t believe me, and I send him a doctor’s note, he probably believes that the doctor’s note isn’t forged. If he doesn’t believe that, and he asks me for a number to call the doctor at, he probably believes it’s a real doctor and not my brother pretending to be a doctor to help me out. Yes, there are a couple of people who abuse that trust, but few enough that the rest of us are usually able to get by.

In psychiatry, there are a bunch of delusional people, paranoid people, narcissists, compulsive liars, and others who deliberately or unknowingly stretch the truth past the breaking point. Worse, a lot of the cues we use to detect liars, like “Are they shifty-looking?” don’t work, either because the person involved really believes what they’re saying or because they’re too far from the neurotypical norm for our usual intuitions to apply. A lot of the assumptions of trust we usually use crash and burn. If the person sitting next to me on the train says he’s a physics professor, I believe him. If the person brought in by police for a psychiatric evaluation says he’s a physics professor, maybe I don’t, and “how much time do I spent assessing the evidence and how much do I believe?” is a really tough question.

I am not trained as a police officer, detective, or judge. I’m also not paid to do their jobs. I’m also stuck in a system where the primary incentive is that if I ever fail to commit someone, then if they do anything bad after that I can be sued for everything I own. So I am stuck drawing partial conclusions, from incomplete evidence, in time I don’t have, from people I can’t necessarily trust, without even the ability to err on the side of caution.

I don’t think the hospital in the article followed great practices – in particular I’m unclear on how they came to believe the person was unemployed. And sending her the bill for her own involuntary commitment is an obvious injustice (albeit a universally practiced one). But the mistakes in the admission process are all ones I can imagine any psychiatrist making. Including me.

And that means something. You can trust me. After all, four different Dalai Lama accounts follow me on Twitter.

A while back one of my patients was having a foot problem, so I consulted the hospital podiatrist. He met me in my workroom, and I explained exactly what I needed from him, but over the course of the explanation he started looking more and more uncomfortable and distracted, so finally I stopped and was just like “Okay, out with it, what’s your problem?”

And he said: “That guy with the wild hair pounding on the window and shouting threats and obscenities at us.”

And I said: “Oh, him? That’s just Bob. Don’t worry about him, he always does that.”

The podiatrist seemed inadequately reassured.

I thought about this because as of today I am halfway done with my four-year psychiatry residency.

One of my teachers told me that you go to medical school to learn things, and then you go to residency to get used to them. It’s not quite that simple – you certainly learn a lot in residency – but there’s a lot of truth to it. I remember that my first week on call, somebody had a seizure and I totally freaked out – AAAAH SEIZURE WHAT DO I DO WHAT DO I DO? – even though I had previously been able to pass tests on that exact situation. But my last time on call, somebody also had a seizure, and I sort of strolled in half-asleep, ordered the necessary tests and consultations and supportive care, then strolled out and went back to bed.

And then there are the little things, like learning to tune out a psychotic guy banging on the window and yelling threats at you.

II.

It’s interesting that psychiatric hospitals are used as a cliche for “a situation of total chaos” – I think I’ve already mentioned the time when the director of a psych hospital I worked at told us, apparently without conscious awareness or irony, that if Obamacare passed our hospital would have too many patients and “the place would turn into a madhouse”. There’s a similar idiom around “Bedlam”, which comes from London’s old Bethlehem psychiatric hospital.

In fact, psych hospitals are much more orderly than you would think. Maybe 80% of the patients are pretty ‘with it’ – depressed people, very anxious people, people with anger issues who aren’t angry at the moment, people coming off of heroin or something. The remaining 20% of people who are very psychotic mostly just stay in their rooms or pace back and forth talking to themselves and not bothering anyone else. The only people you really have to worry about most of the time are the manic ones and occasionally severe autistics, and even they’re usually okay.

For a place where two dozen not-very-stable people are locked up in a small area against their will, violence is impressively rare. The nurses have to deal with some of it, since they’re the front-line people who have to forcibly inject patients with medication, and they have gotten burned a couple of times. And we doctors are certainly trained to assess for it, defuse it, and if worst comes to worst hold our own until someone can get help.

Yet in the two years I’ve worked at Our Lady Of An Undisclosed Location, years when each doctor has talked to each of their patients at least once a day, usually alone in an office, usually telling them things they really don’t want to hear like “No, you can’t go home today” – during all that time, not one doctor has been attacked. Not so much as a slap or a poke.

I am constantly impressed with how deeply the civilizing instinct has penetrated. When I go out of the workroom and tell Bob, “I’m sorry, but you’re disturbing people, you’re going to have to stop banging on the window and shouting threats, let’s go back to your room,” then as long as I use a calm, quiet, and authoritative voice, that is what he does. With very few exceptions, there is nobody so mentally ill that calmness + authority + the implied threat of burly security guards won’t get them to grumble under their breath but generally comply with your requests, reasonable or otherwise.

III.

I’d like to say I’ve taken advantage of this to go mad with power. But it’s actually a really crappy situation for everyone involved.

The most common reason for admission to a psychiatric hospital is “person is a danger to themselves or others”. The average length of stay in a psychiatric hospital is about one week.

Some clever person might ask: “Hey, don’t most psychiatric medicines require more than a week to take effect?” Good question! The answer is “yes”. Antidepressants classically take four weeks. Lithium and antipsychotics are more complicated, but the textbooks will still tell you a couple of weeks in both cases. And yet people are constantly being brought to psychiatric hospitals for dangerousness, treated with medications for one week, and then sent off. What gives?

As far as I can tell, a lot of it is the medical equivalent of security theater.

The most common type of case I see is “person who was really angry, said ‘I’ll kill myself’ in a fit of rage, and then their partner called the cops and they were brought to hospital.” These people stop being angry after a day or two and then no longer make these comments, even assuming they meant it in the first place which most of them don’t.

The second most common type of case I see is “person who was really angry, did try to kill themselves, and it didn’t work.” Again, these people have stopped being angry. Failed suicide attempts also have their own interesting way of clearing the mind for a little while, so they’re in a sort of grace period. Sending these people to a psychiatric hospital makes the public feel good because they’re Doing Something About Suicide, and makes psychiatrists feel good because after a few days they’ve stopped being suicidal so it looks like we’re Making A Difference. There is no way we could leave this equilibrium now even if we wanted to, because if we didn’t keep these people for a week and they ever attempted suicide again, we would get sued to oblivion.

The third most common type of case I see is “severely mentally ill person who’s been living at a care home for twenty years, but then they got in a fight and so their care home sent them to the hospital.” We shuffle their medications around and send them back to the care home where they’d been living happily for twenty years until some random trigger set them off.

We don’t call this “security theater”. We do sometimes call it a “holding environment”. Psych hospitals are kind of boring. There’s no boyfriend to get in a screaming match with, no boss pushing you to work harder, and no drug dealers to get heroin from. On the other hand, there’s lots of structure – art therapy at 10, meeting with your doctor at 11, recreation group at 12, and so on. It’s like a terrible vacation in the world’s least attractive hotel. People get a chance to cool off and forget about whatever set them off. Then they go back to their life. If they’re lucky, our social workers have managed to connect them to a better outpatient psychiatrist, care home, or support group, and maybe that will improve their lives sometime down the line. But I don’t think anyone imagines there was some fundamental Quality Of Dangerousness in them which is now gone.

To the degree that it is all security theater, it’s really hard to give an honest answer to a patient asking why they have to stay in hospital.

When I first started this work, my reaction to these people was “Come on, it’s only a week, it’s not like you’re stuck here forever, just deal with it.” This lasted until I remembered that when some stupid policy forces me to come into hospital on a day I would otherwise have off, I freak out, because I value my free time too much to be okay with having it taken away from me for bad reasons. Heck, my power was out the past couple of days, and I couldn’t use the Internet, and I was calling the power company and being like “COME ON YOU NEED TO FIX THIS ALREADY I AM LOSING DAYS OF MY LIFE THAT I COULD OTHERWISE BE SPENDING IN IMPORTANT STUFF.” So now I try to avoid throwing stones.

(there’s another aspect of this, which is that people constantly protest that horrible things will happen to them based on that week. For example: “My boss said if I miss one more day of work, I’ll lose my job, and then I’ll have no way to support my family.” Or: “My rent payment is due tomorrow, if I miss it I’ll be evicted and all of my stuff will go to the landfill, and there’s no way I can handle this through Internet or telephone or asking a friend to help.” I assume 90% of these stories are false, but the 10% that are true are still bad enough to more than outbalance any good we can do.)

After that, my reaction to these people was “Yes, you may be angry now, but you will thank us later.” This is true of many people, including some of the most histrionically upset. But I’ve since learned that it’s probably not true of the majority. The Shrink Rap blog surveyed former psychiatric inpatients and found that 62% said their experience was not helpful and they were “the same or worse at discharge”. I’d like to dismiss this as people just carrying a grudge for having to be there at all, but the same survey finds that a very similar 56% of voluntarily admitted patients said the same thing (although not all “voluntary” admissions are as voluntary as the name expects). Now, I don’t know for sure what to think about that survey – a lot of people describe their hospitals as doing things which are super illegal and which I wouldn’t expect a hospital to be able to get away with and stay open for more than twenty-four hours, and the population of psych patients who read psychiatric blogs is probably a nonrandom sample – but I no longer feel like I can confidently say that our patients will thank us later.

(none of this is to say that you shouldn’t check yourself into a hospital if you’re feeling suicidal – you’ll get the holding environment that makes sure you don’t kill yourself for the immediate future, you’ll get connected to a system that can give you useful referrals and medications much faster, and 38% will also end up being directly helped.)

So now what I tell people is the Cliffs’ Notes version of the above – “I’m sorry you have to be here, but we are going to keep you for a few more days to evaluate you, your estimated day of discharge is X but that’s not a promise, if there’s anything specifically making you uncomfortable please let me or the nurses know and we’ll see what we can do.”

I can’t figure out a good way to say the spiel without the last sentence, which is too bad because then they do let me and the nurses know things. Most of them are things that I, as a low-ranking doctor who cannot totally rearrange the unit according to my will, have no ability to change. Some of them are things nobody can change.

Like! It turns out when you lock constitutionally anxious people in a new environment full of psychotic people, they become really really anxious. They tend to request antianxiety drugs. I am happy to give them reasonable doses of the non-addictive anti-anxiety drugs, which then totally fail to do anything, because their idiot outpatient psychiatrist was giving them heroin mixed with horse tranquilizers every day or something. They demand whatever they were getting on the outside, but twice as much, and I can’t give it to them even if I want to because of our safety policies. And now I’m the bad guy.

Or! Some people don’t like noise. I sympathize with this as I am just about the most misophonic person in the world. On the other hand, there’s always one screamer in a psychiatric hospital. Sometimes this screamer chooses to do their thing at four in the morning. The law gives us limited ability to lock them in a soundproof room, and definitely not all the time. So if you are startled by loud noise, you are kind of out of luck. Even if we can put you on the other side of the ward, you’re still going to be bothered by staff coming in your room every fifteen minutes to make sure you haven’t killed yourself, which they are legally required to do. You can complain that the lack of sleep is hurting your recovery, and I believe you, but aside from showing you where we keep the earplugs there’s not much I can do. Once again, now I’m the bad guy.

Add to this people with picky tastes that our kitchen can’t satisfy, people who get bored in the absence of some kind of entertainment we can’t provide, smokers who are unsatisfied by nicotine patches, and the occasional very honest drug addict who just wants some drugs, and I spend about 30% of my day patiently explaining to people why their preferences are totally reasonable and I realize they’re in pain but there’s nothing I can do for them at this moment.

And I know it sounds really selfish of me to say so, but this is really exhausting.

Sometimes I wonder if the concentration camp guards in Auschwitz ever had this problem. Like, the ones who weren’t especially sadistic, but who took it because it was a 9-5 job, and word around the water cooler was that it was an easy way to make Scharführer after a few years. And every night they would come home to their wives and be like “Gott in Himmel, Helga, you have no idea what I have to put up with every day, all of these prisoners won’t stop asking me for food and water and stuff, and I try to give them a couple of extra scraps when the regulations allow, but even after I do that they just want more food and they never stop, don’t they realize it makes me feel really guilty and there’s nothing I can do, and every day is more miserable and draining than the last, and I mean, seriously Helga, how entitled can people get?”

I know that’s a horrible metaphor, and our hospital is really good and run by some of the best staff and nurses and doctors I have ever met and tries 100% to help patients whenever it can. It’s just how I feel sometimes.

As you may have guessed, I do not very much like inpatient work. You can adjust to having to treat someone having a seizure. You can adjust to somebody banging on the window and screaming. But it’s really hard to adjust to constant moral self-questioning.

IV.

Now I am halfway done with my residency. I will be switching to outpatient work. Everyone who sees me will be there because they want to see me, or at worst because their parents/spouses/children/friends/voices are pressuring them into it. I will be able to continue seeing people for an amount of time long enough that the medications might, in principle, work. It sounds a lot more pleasant.

I have two equal and opposite concerns about outpatient psychiatry. The first is that I might be useless. Like, if someone comes in complaining of depression, then to a first approximation, after a few basic tests and questions to rule out some rarer causes, you give them an SSRI. I have a lot of libertarian friends who think psychiatrists are just a made-up guild who survive because it’s legally impossible for depressed people to give themselves SSRIs without paying them money. There’s some truth to that and I’ve previously joked that some doctors could profitably be replaced by SSRI vending machines.

The second concern is that everybody still screws it up. There’s an old saying: “Doctors bury their mistakes, architects cover theirs with vines, teachers send theirs into politics.” Well, outpatient psychiatrists send their mistakes to inpatient psychiatrists, so as an inpatient psychiatrist I’ve gotten to see a lot of them. Yes, to a first approximation when a person comes in saying they’re depressed you can just do a few basic tests and questions and then give them an SSRI. But the number of cases I’ve seen that end in disaster because their outpatient psychiatrist forgot to do the basic tests and questions, or decided that Adderall was the first-line medication of choice for depression – continues to boggle my mind. So either it’s harder than I think, or I’m surrounded by idiots, or I’m an idiot and don’t know it yet. In which case I’m about to learn.

Still, if it’s a disaster, it will be a different type of disaster.

And the thing I love about psychiatry – other than, I am contractually obligated to say, The People You Meet and The Chance To Make A Difference – is the lore. If all science is either physics or stamp collecting, psychiatry is stamp collecting par excellence with the world’s most interesting postal system, hunting through this incredibly confused and unsystematic mass of work done by thousands of brilliant people and trying to drag some kind of meaning out of it. Sometimes that involves dredging up weird drugs that no one else thinks about or remembers but which are perfectly suited for the precise situation at hand. Sometimes it’s disentagling complicated claims about what does and doesn’t work so you can be sure to give your patients the former. Other times it’s something totally out of left field, like reading this study and massively increasing the amount my consult patients liked me pretty much overnight with zero work.

I think outpatient will be good for this. There’s more freedom, more focus on treatment rather than warehousing, and a little bit more of an academic bent to it.

In the meantime, I am now a third year resident. There are people beneath me, and sometimes they do what I say! I get enough of a raise that I can say, for the first time in my life, that I am making the US median household income! I mostly get weekends off, except when I don’t!

And in two years, I’ll be done in Michigan and maybe I can move somewhere else and hang out with some of you people full-time.

I.

I’ve been playing around with data from Internet databases that aggregate patient reviews of medications.

Are these any good? I looked at four of the largest such databases – Drugs.com, WebMD, AskAPatient, and DrugLib – as well as psychiatry-specific site CrazyMeds – and took their data on twenty-three major antidepressants. Then I correlated them with one another to see if the five sites mostly agreed.

Correlations between Drugs.com, AskAPatient, and WebMD were generally large and positive (around 0.7). Correlations between CrazyMeds and DrugLib were generally small or negative. In retrospect this makes sense, because these two sites didn’t allow separation of ratings by condition, so for example Seroquel-for-depression was being mixed with Seroquel-for-schizophrenia.

So I threw out the two offending sites and kept Drugs.com, AskAPatient, and WebMD. I normalized all the data, then took the weighted average of all three sites. From this huge sample (the least-reviewed drug had 35 ratings, the most-reviewed drug 4,797) I obtained a unified opinion of patients’ favorite and least favorite antidepressants.

This doesn’t surprise me at all. Everyone secretly knows Nardil and Parnate (the two commonly-used drugs in the MAOI class) are excellent antidepressants¹. Oh, nobody will prescribe them, because of the dynamic discussed here, but in their hearts they know it’s true.

Likewise, I feel pretty good to see that Serzone, which I recently defended, is number five. I’ve had terrible luck with Viibryd, and it just seems to make people taking it more annoying, which is not a listed side effect but which I swear has happened.

The table also matches the evidence from chemistry – drugs with similar molecular structure get similar ratings, as do drugs with similar function. This is, I think, a good list.

Which is too bad, because it makes the next part that much more terrifying.

II.

There is a sixth major Internet database of drug ratings. It is called RateRx, and it differs from the other five in an important way: it solicits ratings from doctors, not patients. It’s a great idea – if you trust your doctor to tell you which drug is best, why not take advantage of wisdom-of-crowds and trust all the doctors?

The RateRX logo. Spoiler: this is going to seem really ironic in about thirty seconds.

RateRx has a modest but respectable sample size – the drugs on my list got between 32 and 70 doctor reviews. There’s only one problem.

You remember patient reviews on the big three sites correlated about +0.7 with each other, right? So patients pretty much agree on which drugs are good and which are bad?

Doctor reviews on RateRx correlated at -0.21 with patient reviews. The negative relationship is nonsignificant, but that just means that at best, doctor reviews are totally uncorrelated with patient consensus.

This has an obvious but very disturbing corollary. I couldn’t get good numbers on how times each of the antidepressants on my list were prescribed, because the information I’ve seen only gives prescription numbers for a few top-selling drugs, plus we’ve got the same problem of not being able to distinguish depression prescriptions from anxiety prescriptions from psychosis prescriptions. But total number of online reviews makes a pretty good proxy. After all, the more patients are using a drug, the more are likely to review it.

Quick sanity check: the most reviewed drug on my list was Cymbalta. Cymbalta was also the best selling antidepressant of 2014. Although my list doesn’t exactly track the best-sellers, that seems to be a function of how long a drug has been out – a best-seller that came out last year might have only 1/10th the number of reviews as a best-seller that came out ten years ago. So number of reviews seems to be a decent correlate for amount a drug is used.

In that case, amount a drug is used correlates highly (+0.67, p = 0.005) with doctors’ opinion of the drug, which makes perfect sense since doctors are the ones prescribing it. But amount the drug gets used correlates negatively with patient rating of the drug (-0.34, p = ns), which of course is to be expected given the negative correlation between doctor opinion and patient opinion.

So the more patients like a drug, the less likely it is to be prescribed².

III.

There’s one more act in this horror show.

Anyone familiar with these medications reading the table above has probably already noticed this one, but I figured I might as well make it official.

I correlated the average rating of each drug with the year it came on the market. The correlation was -0.71 (p < .001). That is, the newer a drug was, the less patients liked it³.

This pattern absolutely jumps out of the data. First- and second- place winners Nardil and Parnate came out in 1960 and 1961, respectively; I can’t find the exact year third-place winner Anafranil came out, but the first reference to its trade name I can find in the literature is from 1967, so I used that. In contrast, last-place winner Viibryd came out in 2011, second-to-last place winner Abilify got its depression indication in 2007, and third-to-last place winner Brintellix is as recent as 2013.

This result is robust to various different methods of analysis, including declaring MAOIs to be an unfair advantage for Team Old and removing all of them, changing which minor tricylics I do and don’t include in the data, and altering whether Deprenyl, a drug that technically came out in 1970 but received a gritty reboot under the name Emsam in 2006, is counted as older or newer.

So if you want to know what medication will make you happiest, at least according to this analysis your best bet isn’t to ask your doctor, check what’s most popular, or even check any individual online rating database. It’s to look at the approval date on the label and choose the one that came out first.

IV.

What the hell is going on with these data?

I would like to dismiss this as confounded, but I have to admit that any reasonable person would expect the confounders to go the opposite way.

That is: older, less popular drugs are usually brought out only when newer, more popular drugs have failed. MAOIs, the clear winner of this analysis, are very clearly reserved in the guidelines for “treatment-resistant depression”, ie depression you’ve already thrown everything you’ve got at. But these are precisely the depressions that are hardest to treat.

Imagine you are testing the fighting ability of three people via ten boxing matches. You ask Alice to fight a Chihuahua, Bob to fight a Doberman, and Carol to fight Cthulhu. You would expect this test to be biased in favor of Alice and against Carol. But MAOIs and all these other older rarer drugs are practically never brought out except against Cthulhu. Yet they still have the best win-loss record.

Here are the only things I can think of that might be confounding these results.

Perhaps because these drugs are so rare and unpopular, psychiatrists only use them when they have really really good reason. That is, the most popular drug of the year they pretty much cluster-bomb everybody with. But every so often, they see some patient who seems absolutely 100% perfect for clomipramine, a patient who practically screams “clomipramine!” at them, and then they give this patient clomipramine, and she does really well on it.

(but psychiatrists aren’t actually that good at personalizing antidepressant treatments. The only thing even sort of like that is that MAOIs are extra-good for a subtype called atypical depression. But that’s like a third of the depressed population, which doesn’t leave much room for this super-precise-targeting hypothesis.)

Or perhaps once drugs have been on the market longer, patients figure out what they like. Brintellix is so new that the Brintellix patients are the ones whose doctors said “Hey, let’s try you on Brintellix” and they said “Whatever”. MAOIs have been on the market so long that presumably MAOI patients are ones who tried a dozen antidepressants before and stayed on MAOIs because they were the only ones that worked.

(but Prozac has been on the market 25 years now. This should only apply to a couple of very new drugs, not the whole list.)

Or perhaps the older drugs have so many side effects that no one would stay on them unless they’re absolutely perfect, whereas people are happy to stay on the newer drugs even if they’re not doing much because whatever, it’s not like they’re causing any trouble.

(but Seroquel and Abilify, two very new drugs, have awful side effects, yet are down at the bottom along with all the other new drugs)

Or perhaps patients on very rare weird drugs get a special placebo effect, because they feel that their psychiatrist cares enough about them to personalize treatment. Perhaps they identify with the drug – “I am special, I’m one of the only people in the world who’s on nefazodone!” and they become attached to it and want to preach its greatness to the world.

(but drugs that are rare because they are especially new don’t get that benefit. I would expect people to also get excited about being given the latest, flashiest thing. But only drugs that are rare because they are old get the benefit, not drugs that are rare because they are new.)

Or perhaps psychiatrists tend to prescribe the drugs they “imprinted on” in medical school and residency, so older psychiatrists prescribe older drugs and the newest psychiatrists prescribe the newest drugs. But older psychiatrists are probably much more experienced and better at what they do, which could affect patients in other ways – the placebo effect of being with a doctor who radiates competence, or maybe the more experienced psychiatrists are really good at psychotherapy, and that makes the patient better, and they attribute it to the drug.

(but read on…)

V.

Or perhaps we should take this data at face value and assume our antidepressants have been getting worse and worse over the past fifty years.

This is not entirely as outlandish as it sounds. The history of the past fifty years has been a history of moving from drugs with more side effects to drugs with fewer side effects, with what I consider somewhat less than due diligence in making sure the drugs were quite as effective in the applicable population. This is a very complicated and controversial statement which I will be happy to defend in the comments if someone asks.

The big problem is: drugs go off-patent after twenty years. Drug companies want to push new, on-patent medications, and most research is funded by drug companies. So lots and lots of research is aimed at proving that newer medications invented in the past twenty years (which make drug companies money) are better than older medications (which don’t).

I’ll give one example. There is only a single study in the entire literature directly comparing the MAOIs – the very old antidepressants that did best on the patient ratings – to SSRIs, the antidepressants of the modern day⁴. This study found that phenelzine, a typical MAOI, was no better than Prozac, a typical SSRI. Since Prozac had fewer side effects, that made the choice in favor of Prozac easy.

Did you know you can look up the authors of scientific studies on LinkedIn and sometimes get very relevant information? For example, the lead author of this study has a resume that clearly lists him as working for Eli Lilly at the time the study was conducted (spoiler: Eli Lilly is the company that makes Prozac). The second author’s LinkedIn profile shows he is also an operations manager for Eli Lilly. Googling the fifth author’s name links to a news article about Eli Lilly making a $750,000 donation to his clinic. Also there’s a little blurb at the bottom of the paper saying “Supported by a research grant by Eli Lilly and company”, then thanking several Eli Lilly executives by name for their assistance.

This is the sort of study which I kind of wish had gotten replicated before we decided to throw away an entire generation of antidepressants based on the result.

But who will come to phenelzine’s defense? Not Parke-Davis , the company that made it: their patent expired sometime in the seventies, and then they were bought out by Pfizer⁵. And not Pfizer – without a patent they can’t make any money off Nardil, and besides, Nardil is competing with their own on-patent SSRI drug Zoloft, so Pfizer has as much incentive as everyone else to push the “SSRIs are best, better than all the rest” line.

Every twenty years, pharmaceutical companies have an incentive to suddenly declare that all their old antidepressants were awful and you should never use them, but whatever new antidepressant they managed to dredge up is super awesome and you should use it all the time. This sort of does seem like the sort of situation that might lead to older medications being better than newer ones. A couple of people have been pushing this line for years – I was introduced to it by Dr. Ken Gillman from Psychotropical Research, whose recommendation of MAOIs and Anafranil as most effective match the patient data very well, and whose essay Why Most New Antidepressants Are Ineffective is worth a read.

I’m not sure I go as far as he does – even if new antidepressants aren’t worse outright, they might still trade less efficacy for better safety. Even if they handled the tradeoff well, it would look like a net loss on patient rating data. After all, assume Drug A is 10% more effective than Drug B, but also kills 1% of its users per year, while Drug B kills nobody. Here there’s a good case that Drug B is much better and a true advance. But Drug A’s ratings would look better, since dead men tell no tales and don’t get to put their objections into online drug rating sites. Even if victims’ families did give the drug the lowest possible rating, 1% of people giving a very low rating might still not counteract 99% of people giving it a higher rating.

And once again, I’m not sure the tradeoff is handled very well at all.⁶.

VI.

In order to distinguish between all these hypotheses, I decided to get a lot more data.

I grabbed all the popular antipsychotics, antihypertensives, antidiabetics, and anticonvulsants from the three databases, for a total of 55,498 ratings of 74 different drugs. I ran the same analysis on the whole set.

The three databases still correlate with each other at respectable levels of +0.46, +0.54, and +0.53. All of these correlations are highly significant, p < 0.01. The negative correlation between patient rating and doctor rating remains and is now a highly significant -0.344, p < 0.01. This is robust even if antidepressants are removed from the analysis, and is notable in both psychiatric and nonpsychiatric drugs.

The correlation between patient rating and year of release is a no-longer-significant -0.191. This is heterogenous; antidepressants and antipsychotics show a strong bias in favor of older medications, and antidiabetics, antihypertensives, and anticonvulsants show a slight nonsignificant bias in favor of newer medications. So it would seem like the older-is-better effect is purely psychiatric.

I conclude that for some reason, there really is a highly significant effect across all classes of drugs that makes doctors love the drugs patients hate, and vice versa.

I also conclude that older psychiatric drugs seem to be liked much better by patients, and that this is not some kind of simple artifact or bias, since if such an artifact or bias existed we would expect it to repeat in other kinds of drugs, which it doesn’t.

VII.

Please feel free to check my results. Here is a spreadsheet (.xls) containing all of the data I used for this analysis. Drugs are marked by class: 1 is antidepressants, 2 is antidiabetics, 3 is antipsychotics, 4 is antihypertensives, and 5 is anticonvulsants. You should be able to navigate the rest of it pretty easily.

One analysis that needs doing is to separate out drug effectiveness versus side effects. The numbers I used were combined satisfaction ratings, but a few databases – most notably WebMD – give you both separately. Looking more closely at those numbers might help confirm or disconfirm some of the theories above.

If anyone with the necessary credentials is interested in doing the hard work to publish this as a scientific paper, drop me an email and we can talk.

Footnotes

1. Technically, MAOI superiority has only been proven for atypical depression, the type of depression where you can still have changing moods but you are unhappy on net. But I’d speculate that right now most patients diagnosed with depression have atypical depression, far more than the studies would indicate, simply because we’re diagnosing less and less severe cases these days, and less severe cases seem more atypical.

6. Consider: Seminars In General Psychiatry estimates that MAOIs kill one person per 100,000 patient years. A third of all depressions are atypical. MAOIs are 25 percentage points more likely to treat atypical depression than other antidepressants. So for every 100,000 patients you give a MAOI instead of a normal antidepressant, you kill one and cure 8,250 who wouldn’t otherwise be cured. The QALY database says that a year of moderate depression is worth about 0.6 QALYs. So for every 100,000 patients you give MAOIs, you’re losing about 30 QALYs and gaining about 3,300.

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.

Mad In America apparently doesn’t like being called an anti-psychiatry blog, so let’s call it a blog…that discusses psychiatry…and doesn’t usually like what it sees. They were heavily involved in popularizing the idea that psychiatry erred grieviously in overselling “chemical imbalance”, and they didn’t much like my post on the same topic:

Alexander argues that the notion that psychiatrists once promoted the idea of low serotonin as a cause of depression and Selective Serotonin Reuptake Inhibitors (SSRIs) as proper treatment for that deficiency is all simply a false “narrative” invented by “antipsychiatry” activists. These activists then “frame it as ‘proof’ that psychiatrists are drug company shills who were deceiving the public.” Alexander points to quotes of American Psychiatric Association officials in a post by MIA Blogger Philip Hickey, and notes that none of the quotes specifically describe a low-serotonin explanation for depression. The Hickey post cited is not actually about that topic, but about the promotion of the phrase “chemical imbalance”; nevertheless, Alexander broadly refers to Hickey and all of Mad in America as “antipsychiatry”, and he then writes, “If the antipsychiatry community had quotes of APA officials saying it’s all serotonin deficiency, don’t you think they would have used them?” Alexander argues, “The idea that depression is a drop-dead simple serotonin deficiency was never taken seriously by mainstream psychiatry.” There seems to be a lot of evidence to the contrary still today readily available even on the web, though.

This is exactly the sort of fight I probably shouldn’t get involved in continuing. But I’m going to do so anyway, because I think Mad In America’s counterargument is actually going to end up supporting my point and maybe shed more light on the situation.

Up there, when they say “Alexander points to quotes of American Psychiatric Association officials in a post by MIA Blogger Philip Hickey, and notes that none of the quotes specifically describe a low-serotonin explanation for depression [but] the Hickey post cited is not actually about that topic, but about the promotion of the phrase ‘chemical imbalance'” – that’s where I get pretty confident they’ve missed my point.

Remember, the thesis of my last post was that the “chemical imbalance” argument hides a sort of bait-and-switch going on between the following two statements:

(A): Depression is complicated, but it seems to involve disruptions to the levels of brain chemicals in some important way

(B): We understand depression perfectly now, it’s just a deficiency of serotonin.

If you equivocate between them, you can prove that psychiatrists were saying (A), and you can prove that (B) is false and stupid, and then it’s sort of like psychiatrists were saying something false and stupid.

Given that this is my thesis, it’s exactly right for me to debate a post on “chemical imbalance” by showing that none of the quotes involved reduce the problem to just a basic serotonin deficiency!

And when Rob Wipond from MIA says he’s found “a lot of evidence to the contrary still readily available even on the web”, well, spoiler, he’s found more people saying A.

II.

Let’s go through his examples:

For example, a 2004 Washington University in St. Louis press release, about a study published in Biological Psychiatry, states that the “brain’s serotonin receptors” are “at abnormally low levels in depressed people” and that antidepressants “work by increasing serotonin levels in the brain.”

I assume he’s talking about this press release about a study that shows abnormally low levels of serotonin receptors in depressed people. First of all, the study actually did show this. I don’t think it’s irresponsible to mention that a study shows low levels of serotonin receptors in depressed people when a study actually shows this. Second of all, the press release makes it extremely clear that they don’t know exactly what’s going on: “Little is understood about how depression makes people feel sad, but neuroscientists do know that the brain chemical serotonin is involved.” They mention that SSRIs appear to work for depression, but admit that “The bad news is that beyond that first step of increasing serotonin, we understand very little about how these drugs relieve symptoms of depression”. Finally, this study actually found something much more complicated than the prevailing narrative – a serotonin deficiency model of depression would have predicted high levels of serotonin receptors in related brain structures (more chemicals = fewer receptors) but in fact it found the opposite. This fits with the emerging theory that depression may be related to increased serotonin levels in certain parts of the brain, which SSRIs provoke a compensatory response against.

This press release is actually as good as the harshest critic could have wished for. It admits we don’t really know how depression works, it admits we don’t really know how SSRIs treat it, and then it presents the result of a study that shows that serotonin is implicated but not in the way the “serotonin deficiency” theory would expect.

The only way Mad In America turned this into a poster child for psychiatry deceiving people about serotonin was to quote from it extremely out of context.

Let’s go to their next example:

And there is prominent psychiatrist Richard Friedman writing in the New York Times in 2007 that psychiatrists were soon going to be able to conduct “a simple blood test” to determine “what biological type of depression” a person had and then treat them with the right drug. “For example,” writes Friedman, “some depressed patients who have abnormally low levels of serotonin respond to S.S.R.I.’s, which relieve depression, in part, by flooding the brain with serotonin.”

Okay, but Friedman starts with a story about how SSRIs often don’t work for patients, then says that this is because some people have depression that doesn’t seem to be serotonergic: “Some depressed patients who have abnormally low levels of serotonin respond to SSRIs, which relieve depression, in part, by flooding the brain with serotonin. Other depressed patients may have an abnormality in other neurotransmitters that regulate mood, like norepinephrine or dopamine, and may not respond to SSRIs”. He says (correctly!) that “in everyday clinical practice, we have little ability to predict what specific treatment will work for you”.

These are not the words of a drug company shill who says that depression is 100% serotonin in order to put everyone on SSRIs! These are the words of someone who agrees with me that depression is somehow related to neurotransmitters, but it’s still very uncertain which ones and how. His only sin seems to be an overly optimistic view of the speed at which we would come out with genetic tests.

Next example:

There’s also a lot of evidence that the low-serotonin theory of depression is still today being taken seriously by mainstream psychiatry and is still being promoted to the public. A current University of Bristol public education website on depression explains that, “Low serotonin levels are believed to be the cause of many cases of mild to severe depression.”

That appears to be this University of Bristol public education website. The site says it’s by “Claire Rosling”, so I searched her name and I get this roster of people’s sophomore chemistry projects. Ms. Rosling’s is…the website Mad In America cited. Apparently this was part of some college chemistry assignment where people write about molecules to compete for a £50 prize. Ms. Rosling’s was serotonin.

So Mad In America argues that the entire psychiatric establishment is pushing the “depression = serotonin” argument, but the best example they can come up with is some poor woman’s undergraduate chemistry homework?

(in case you’re wondering, she didn’t win. Some girl named Anna won for her webpage on Recycling Plastic.)

Next example!

A current Harvard Medical School special health report, “Understanding Depression”, explains that, “Research supports the idea that some depressed people have reduced serotonin transmission. Low levels of a serotonin byproduct have been linked to a higher risk for suicide.”

Once again, holy !@#$, they’re reporting the results of actual studies. It’s dishonest to do studies on serotonin and find that it is linked to depression? Anyway, when I look up the actual report it starts with the following paragraph: “It’s often said that depression results from a chemical imbalance, but that figure of speech doesn’t capture how complex the disease is. Research suggests that depression doesn’t spring from simply having too much or too little of certain brain chemicals. Rather, depression has many possible causes, including faulty mood regulation by the brain, genetic vulnerability, stressful life events, medications, and medical problems. It’s believed that several of these forces interact to bring on depression.”

Once again, this is the best you can do to find psychiatrists pushing an oversimplified version of the chemical imbalance theory??!

Next example:

WebMD’s “Depression Center” states that, “There are many researchers who believe that an imbalance in serotonin levels may influence mood in a way that leads to depression. Possible problems include low brain cell production of serotonin, a lack of receptor sites able to receive the serotonin that is made… According to Princeton neuroscientist Barry Jacobs… common antidepressant medications known as SSRIs, which are designed to boost serotonin levels, help kick off the production of new brain cells, which in turn allows the depression to lift.”

First of all, this page does not use the classic “serotonin deficiency” theory of depression. This is the hippocampal neurogenesis theory, which in my last post I specifically contrasted with the classic serotonin deficiency theory. Yes, it involves serotonin in some way, but since one of the most important facts about depression is that SSRIs treat it, every theory is going to involve serotonin in some way.

Further, right after this paragraph, WebMD continues: “Although it is widely believed that a serotonin deficiency plays a role in depression, there is no way to measure its levels in the living brain. Therefore, there have not been any studies proving that brain levels of this or any neurotransmitter are in short supply when depression or any mental illness develops. Blood levels of serotonin are measurable — and have been shown to be lower in people who suffer from depression – but researchers don’t know if blood levels reflect the brain’s level of serotonin. Also, researchers don’t know whether the dip in serotonin causes the depression, or the depression causes serotonin levels to drop.”

Once again, I see nothing here to indicate that they are covering up flaws in this theory, pushing it to unsuspecting consumers, or claiming that exploratory research is settled science. They’re presenting the best theories we’ve got, then noting how tentative they are and what the flaws are.

(on the other hand, the article does say that there are “40 million” brain cells, when in fact there are about 90 billion. I’m not saying you should trust WebMD, just that they don’t bungle depression in that particular way)

Next example:

And if the theory was never taken seriously and isn’t being taken seriously, no one has apparently told the National Academy of Sciences or two news media outlets with expert psychiatric editorial boards yet. Psychiatry Advisor’s February 12, 2015 headline for a report about a Duke University study is, “Serotonin Deficiency May Up Depression Risk.” Psychiatry Advisor explains that, “(m)ice with normal serotonin levels, the control group, did not demonstrate depression symptoms a week after the social stress, while the serotonin-deficient rodents did(.)” The study, appearing in the Proceedings of the National Academy of Sciences, states that, serotonin deficiency has been “implicated in the etiology of depression” though a cause-effect relationship has not yet been “formally established.” The researchers write that their results, “provide additional insight into the serotonin deficiency hypothesis of depression.” Medical News Today headline their report on it even more strongly: “Mouse study finds that serotonin deficiency does increase depression risk.” (Medical News Today notes in passing that an earlier, somewhat similar study by a different team came to the exact opposite findings.)

At this point Mad in America’s examples are self-refuting. I am getting the impression they will never be happy unless no news media ever covers the dozens of studies that come out each year linking depression to serotonin. I know this sounds mean, but what other conclusion am I supposed to come to? Here we have a study that provides some evidence for serotonin’s involvement, says very specifically that “a cause-effect relationship has not been formally established”, mentions that other studies have shown the opposite – and yet Mad In America still wants me to accept this as an example of irresponsibly pushing the serotonin theory!

Look. Hundreds of studies have shown some sort of relationship between serotonin and depression. At this point that’s not controversial. What’s controversial is the importance of the relationship, whether it’s causal, whether other things matter more, et cetera. Every single one of Mad In America’s examples has been pretty exemplary in saying that all of these things are still uncertain and need to be investigated further. What more could they do to be more responsible? A total blackout on all news coverage of the new evidence for serotonin’s involvement that keeps coming in?

Ironically, if people had done that, we would have far less evidence that depression was not just a simple serotonin deficiency. The most important nail in that theory’s coffin was that tianeptine, a medication that lowers serotonin levels, effectively treats depression. But that’s a study about serotonin of exactly the same sort as the University of Washington study Mad In America complains about! One of the most convincing alternatives to a purely serotonergic picture is the BDNF-neurogenesis theory. But that’s exactly the theory being pushed in the WebMD article Mad In America complains about!

III.

I raised some of these issues in a comment on the Mad in America blog, and author Rob Wipond kindly responded to me:

Let me address some of these objections piece by piece:

Yes, you’re right, many psychiatrists, media, pharmaceutical companies and others promoting the serotonin deficiency theory of depression have often included generalized, softening “qualifiers” and “equivocations” such as the ones you quoted, even as they have also made those very bold, unequivocal claims explicitly intended to persuade that I quoted. Taken in full context, then how are such qualifiers different than brash infomercials on television with legal disclaimers like, “not all results will be the same for all people”?

The very bold, unequivocal claims explicitly intended to persuade that you quoted WERE A SOPHOMORE CHEMISTRY PROJECT, PLUS A BUNCH OF PEOPLE SPECIFICALLY SAYING THAT THESE SHOULD NOT BE TAKEN AS VERY BOLD UNEQUIVOCAL CLAIMS, BUT THEN YOU QUOTED OUT OF CONTEXT TO TAKE THAT PART OUT. AND THE SOPHOMORE CHEMISTRY PROJECT DIDN’T EVEN WIN THE £50 PRIZE.

Okay. Sorry. I shouldn’t have yelled like that. More seriously: there are a lot of things we don’t totally understand, but which scientific research suggests some weak preliminary theories about. For example, we don’t understand fibromyalgia, but if I were writing a textbook on fibromyalgia, or if a patient asked me what it was, then after some appropriate caveats and equivocations, I would say it has something to do with some sort of inflammation in the fascia which causes central sensitization to pain stimuli. Could I end up being totally wrong? Yeah. But at this point I think there’s enough evidence in this direction that, insofar as it’s important to satisfy patients’ curiosity about what’s going on with them, that it’s proper to mention the current best guess. Likewise, if I am a researcher or a scientific publication, I don’t think I have some duty to carefully hide my results. A big part of scientific progress is people saying “I just got some small amount of evidence which makes me think it’s this” and then other people trying to confirm or refute that with more evidence, until eventually it comes together into a strong theory.

I think researchers and psychiatrists were pretty responsible in coming up with the serotonin deficiency theory. It was inspired by the effectiveness of serotonergic drugs. Then a bunch of studies – Wipond agrees there were hundreds – provided results that seemed to confirm it. Given all of this information, I don’t think it was negligent to say that there was quite a bit of evidence pointing to serotonin, as long as you followed this with caveats that the evidence was still preliminary and lots of other things seemed to be involved too. As I’ve been arguing all along, that’s exactly what most people did.

I know of no one (certainly not me) who has ever said that there were never any studies making tenuous, feeble attempts to draw links between serotonin levels and depression in different ways — there were hundreds, I believe (I haven’t counted) as the psychiatric community and pharmaceutical industry made enormous efforts to try to prove the theory or buttress its apparent validity in the public eye. And as I note, those are still being produced today. What critics have often correctly pointed out, however, is that the main, strongest argument that psychiatrists have often used in support of the low-serotonin theory has always been that SSRIs allegedly boost serotonin levels. Of course, most of the public has never known that SSRIs have barely beaten placebos in clinical trials, so they’ve not been able to understand the true spuriousness of even that argument.

I don’t really understand this objection. There was a strong piece of evidence in favor of serotonin in the form of SSRI-effectiveness, scientists pursued that lead by doing hundreds of studies implicating serotonin using different methodologies, most were in favor and so scientists thought the theory had some merit…what exactly is wrong here? This sounds like every scientific theory – Wegener noted that continents looked like they fit together in a way that implied continental drift, geologists did hundreds of other studies that all pointed to continental drift, therefore they started believing in continental drift.

While Wipond may not know of the people saying there was no evidence for serotonin besides SSRI effectiveness, these people certainly exist and provide one of his side’s major arguments. Indeed, many of the articles I linked to on my original post made exactly that argument. The BBC said that: “although ideas like the serotonin theory of depression have been widely publicised, scientific research has not detected any reliable abnormalities of the serotonin system in people who are depressed.” New York Review Of Books says: “Instead of developing a drug to treat an abnormality, an abnormality was postulated to fit a drug…But the main problem with the theory is that after decades of trying to prove it, researchers have still come up empty-handed”.

To learn more about the claim that SSRIs barely beat placebo, see my article on this.

I notice that your argument has now changed to “far fewer people” and “less important” psychiatrists made such claims, rather than none at all made such claims. Very well; apparently we would now only potentially disagree on subjective notions such as how many is “fewer” and how unimportant is “less important”, rather than disagreeing on the main issue at hand. And then Leo and Lacasse’s question becomes all the more significant: Where is the evidence that the “important” psychiatrists were vigorously trying to correct the public record and clarifying that these were only weak hypotheses with no compelling evidence to support them instead of weighty theories with ever mounting evidence to support them?

In retrospect, “no one has ever said” is a stupid thing for me to have said. I do not deny that a sophomore at University of Bristol once said low serotonin caused depression. And you can find individual psychiatrists who believe a lot of stupid stuff. Some psychiatrists believe in homeopathy. Some psychiatrists believe in reincarnation (the guy in that article conducted my job interview at the University of Virginia. I tried to be very polite.) Some psychiatrists believe that after losing hundreds of thousands of dollars to online Nigerian scammers, it makes perfect sense to give hundreds of thousands more dollars to other Nigerian scammers, because “these were different Nigerians”. But I will venture to say none of these are consensus positions in the psychiatric community.

And this is why I wanted to continue this discussion here on this blog. If I had selected a set of statements from eminent psychiatrists that had lots of caveats and were extremely responsible, I could be justifiably accused of cherry-picking. Instead, Mad In America selected some statements, probably intending to cherry-pick the other way, but when looked at more closely, they’re all pretty responsible and say exactly what I would have said at the time – SSRIs seem to work, there’s some evidence pointing to serotonin being involved, but the whole thing is terribly complicated. To me, this establishes the consensus position in a way much more clearly than I could have done on my own.

And yes, this consensus position got simplified and distorted. I have no doubt that drug companies drew from it to do exactly the sort of infomercials that Mr. Wipond describes. I have no doubt that individual psychiatrists, when faced with low-functioning patients who are bad at understanding complicated systems but who really wanted to know what was going on, said “serotonin” and left it at that. And I have no doubt that to a public who still largely think evolution means “once upon a time a chimp gave birth to a human baby”, complicated caveats about how serotonin levels are linked to depression but might not cause depression largely went over their heads except for the single word “serotonin”.

(“That’s the happiness molecule! Right?”)

But in general I think my point stands. “Chemical imbalance” as generally used points to a sophisticated model of interacting metabolic pathways which goes far beyond serotonin, and which as far as I know is still very much on the table. While serotonin was justifiably pointed to as a promising candidate early on, it was generally done with appropriate caveats that turned out to be warranted, and the research community has now retreated from some of that earlier language while still considering serotonin a promising lead. And SSRIs continue to be moderately effective antidepressants in the people for whom they are indicated.

(ie somewhere less than half of the people for whom they are prescribed).

I.

IO9’s new article The Most Popular Antidepressants Are Based On An Outdated Theory jumps on a popular bandwagon of criticizing psychiatry for botching the “chemical imbalance” theory. See for example The New Yorker, BBC, The New York Times, and various books.

(…and also The Myth Of Chemical Imbalance, Debunking The Chemical Imbalance Myth, The Chemical Imbalance Fraud, and Depression Delusion, The Myth Of The Chemical Imbalance, etc)

According to all these sources psychiatry sold the public on antidepressants by claiming depression was just a chemical imbalance (usually fleshed out as “a simple deficiency of serotonin”) and so it was perfectly natural to take extra chemicals to correct it. However, they had no real evidence for this theory except that serotonergic drugs effectively treat depression, which is not very much evidence at all (antibiotics effectively treat pneumonia, but pneumonia isn’t “an antibiotic deficiency”). And now the research is unequivocal that serotonin deficiency is not the cause of depression, and psychiatry has ended up with lots of egg on its face.

This narrative is getting pushed especially hard by the antipsychiatry movement, who frame it as “proof” that psychiatrists are drug company shills who were deceiving the public. The conversation has required a host of rebuttals and counter-rebuttals.

For example here antipsychiatry blog Mad In America attemps to rebut psychiatrist Dr. Ronald Pies, who argues that psychiatrists never pushed the chemical imbalance theory. Pies says that “The ‘chemical imbalance theory’ was never a real theory, nor was it widely propounded by responsible practitioners in the field of psychiatry,” and cites the American Psychiatric Association’s 2005 statement on the causes of depression:

The exact causes of mental disorders are unknown, but an explosive growth of research has brought us closer to the answers. We can say that certain inherited dispositions interact with triggering environmental factors. Poverty and stress are well-known to be bad for your health—this is true for mental health and physical health. In fact, the distinction between “mental” illness and “physical” illness can be misleading. Like physical illnesses, mental disorders can have a biological nature. Many physical illnesses can also have a strong emotional component

Mad In America doesn’t accept his claim, and counter-cites two speeches by American Psychiatric Association presidents to prove that they did push the chemical imbalance theory:

In the last decade, neuroscience and psychiatric research has begun to unlock the brain’s secrets. We now know that mental illnesses – such as depression or schizophrenia – are not “moral weaknesses” or “imagined” but real diseases caused by abnormalities of brain structure and imbalances of chemicals in the brain.” – Richard Harding, 2001 APA president

And:

The way nerves talk to each other, and communicate, is through the secretion of a chemical called a neurotransmitter, which stimulates the circuit to be activated. And when this regulation of chemical neurotransmission is disturbed, you have the alterations in the functions that those brain areas are supposed to, to mediate. So in a condition like depression, or mania, which occurs in bipolar disorder, you have a disturbance in the neurochemistry in the part of the brain that regulates emotion. – Jeffrey Lieberman, 2012 APA President

I have no personal skin in this game. I’ve only been a psychiatrist for two years, which means I started well after the term “chemical imbalance” fell out of fashion. I get to use the excuse favored by young children everywhere: “It was like this when I got here”. But I still feel like the accusations in this case are unfair, and I would like to defend my profession.

I propose that the term “chemical imbalance” hides a sort of bait-and-switch going on between the following two statements:

(A): Depression is complicated, but it seems to involve disruptions to the levels of brain chemicals in some important way

(B): We understand depression perfectly now, it’s just a deficiency of serotonin.

If you equivocate between them, you can prove that psychiatrists were saying (A), and you can prove that (B) is false and stupid, and then it’s sort of like psychiatrists were saying something false and stupid!

But it isn’t too hard to prove that psychiatrists, when they talked about “chemical imbalance”, meant something more like (A). I mean, look at the quotes above by which Mad In America tries to prove psychiatrists guilty of pushing chemical imbalance. Both sound more like (A) than (B). Neither mentions serotonin by name. Both talk about the chemical aspect as part of a larger picture: Harding in the context of abnormalities in brain structure, Lieberman in the context of some external force disrupting neurotransmission. Neither uses the word “serotonin” or “deficiency”. If the antipsychiatry community had quotes of APA officials saying it’s all serotonin deficiency, don’t you think they would have used them?

Further, anyone who said that depression was caused solely by serotonin deficiency wouldn’t just be failing as a scientist, but also failing as a drug company shill. Pfizer spent billions of dollars on Effexor, which hits norepinephrine as well as serotonin, and they’re just going to dismiss all of that as useless? GlaxoSmithKline has Wellbutrin, which hits dopamine and norepinephrine and maybe acetylcholine but doesn’t get serotonin at all. So everyone, including the shills, especially the shills, has been very careful to say that depression was a “chemical imbalance” rather than a serotonin deficiency per se.

So if you want to prove that psychiatrists were deluded or deceitful, you’re going to have to disprove not just statement (B) – which never represented a good scientific or clinical consensus – but statement (A). And that’s going to be hard, because as far as I can tell statement (A) still looks pretty plausible.

II.

If you listen to these articles, psychiatrists decided that neurotransmitters (or just serotonin?) were implicated in depression solely on the evidence that SSRIs were effective antidepressants, even though every study trying to measure serotonin levels directly came back with negative results. For example, The Myth Of The Chemical Imbalance Theory writes:

There is no question that the chemical imbalance theory has spurred chemists to invent new anti-depressants, or that these anti-depressants have been shown to work; but proof that low serotonin is to blame for depression – and that boosting serotonin levels is the key to its treatment – has eluded researchers.

For starters, it is impossible to directly measure brain serotonin levels in humans. You can’t sample human brain tissue without also destroying it. A crude work-around involves measuring levels of a serotonin metabolite, 5-HIAA, in cerebrospinal fluid (CSF), which can only be obtained with a spinal tap. A handful of studies from the 1980s found slightly decreased 5-HIAA in the CSF of depressed and suicidal patients, while later studies have produced conflicting results on whether SSRIs lower or raise CSF levels of 5-HIAA. These studies are all circumstantial with regards to actual serotonin levels, though, and the fact remains there is no direct evidence of a chemical imbalance underlying depression.

The corollary to the chemical imbalance theory, which implies that raising brain serotonin levels alleviates depression, has also been hard to prove. As mentioned previously, the serotonin-depleting drug reserpine was itself shown to be an effective anti-depressant in the 1950s, the same decade in which other studies claimed that reserpine caused depression-like symptoms. At the time, few psychiatrists acknowledged these conflicting reports, as the studies muddled a beautiful, though incorrect, theory. Tianeptine is another drug that decreases serotonin levels while also serving as a bona-fide anti-depressant. Tianeptine does just the opposite of SSRIs – it enhances serotonin reuptake. Wellbutrin is a third anti-depressant that doesn’t increase serotonin levels. You get the picture.

If you prefer your data to be derived more accurately, but less relevantly, from rodents, you might consider a recent meta-analysis carried out by researchers led by McMaster University psychologist Paul Andrews. Their investigation revealed that, in rodents, depression was usually associated with elevated serotonin levels. Andrews argues that depression is therefore a disorder of too much serotonin, but the ambiguous truth is that different experiments have shown “activation or blockage of certain serotonin receptors [to improve] or worsen depression symptoms in an unpredictable manner.”

Other problems with the chemical imbalance model of depression have been well documented elsewhere. For instance, if low serotonin levels were responsible for symptoms of depression, it stands to reason that boosting levels of serotonin should alleviate symptoms more or less immediately. In fact, antidepressants can take more than a month to take effect. Clearly, something here just doesn’t add up.

Clearly!

GABA is a neurotransmitter that promotes inhibition and relaxation. Suppose I were to tell you that alcohol is a drug that mimics the effects of GABA. Which it is.

You might say: something is wrong with this theory! After all, people who drink alcohol don’t always get relaxed and inhibited. A lot of the time they get uninhibited and angry and violent! And then if they drink too much of it, they get super-inhibited to the point where they’re in a total blackout. Also, alcoholics who have been drinking for many years have higher levels of anxiety than non-alcoholics, but anxiety is also the opposite of relaxation! Clearly, something here just doesn’t add up. Maybe the neuroscientists are all shills for Budweiser!

Or else maybe the brain is kind of complicated. In the case of alcohol we pretty much know what’s going on. Alcohol does inhibit and relax you, but in some people and at some doses, it preferentially inhibits and relaxes the parts of the brain involved in inhibiting and relaxing the rest of the brain, meaning that the person as a whole because more uninhibited and violent. At higher doses, it inhibits and relaxes the entire brain, leading to confusion and eventually blackout. And once you’ve been taking alcohol for many years, your brain adjusts to the higher level of GABA-like chemicals by producing fewer GABA receptors, making you more anxious.in general. It’s a whole bunch of contradictory effects, but when you look at the neuroscience it makes sense.

We know less about the serotonin picture, but what we know suggests something similar is going on. Serotonin has different effects in lots of different parts of the brain. There are fourteen different types of serotonin receptor, all of which do subtly different things. Some serotonergic neurons have autoreceptors that cause decreased release of serotonin in response to serotonin. The brain responds to different levels of serotonin by slowly altering endogenous serotonin production as well as the expression of the different serotonin receptors. Etc, etc, etc.

Lest it sound like I’m making excuses rather than presenting evidence: A study on a monkey model – generally preferred to humans when you want to kill your patients and take apart their brains when you’re done – showed that depressed macaques had elevated levels of serotonin in the dorsal raphe nuclei and decreased levels of serotonin in the hippocampus, resulting in average levels of serotonin in the cerebrospinal fluid where the experiments mentioned above took their serotonin measurements. A study with a more sophisticated measurement process, Elevated Brain Serotonin Turnover in Patients With Depression, found that depressed subjects had serotonin turnover as measured in the jugular vein about twice as high as healthy controls (p = 0.003), and successful treatment with SSRI therapy corrected this imbalance (though others dispute the methodology).

All of this sort of fits. If depression involves a distorted pattern of serotonin across the brain, then both certain drugs that increase serotonin levels and certain drugs that decrease it might be helpful. And SSRIs might take a month to work if their mechanism of action isn’t the direct serotonin increase, but a contrary response they provoke from the brain. I think I heard from someone in the field that a month is about how long it takes for them to change the levels of expressed 5HT receptors by altering genetic transcription. Or something. I’m not a neuroscientist (though you can read some more complicated work from people who are) and I don’t know. The point is that you can get a heck of a lot more complex than just “Too little serotonin!” versus “Too much serotonin!”

So does this mean depression “was really serotonin after all”?

No. It means we have good evidence serotonin is involved somewhere. Among the other things that we have good evidence are involved somewhere are: dopamine, norepinephrine, acetylcholine, cytokines, BDNF, thyroid hormones, and whether the kids at school picked on you in first grade.

Suppose you ask me what caused you to become blind. I happen to have your medical records and know that the answer is proliferative retinopathy secondary to Type 2 diabetes, but you’ve been living in a cave your entire life and never even heard of diabetes. Which is the correct answer to your question?

1. Your blindness is caused by tiny little blood vessels growing all over your eyes
2. Your blindness is caused by imbalance in a chemical called protein kinase C-delta and the resulting signaling cascade
3. Your blindness is caused by too much sugar in your blood
4. Your blindness is caused by your cells becoming less sensitive to insulin
5. Your blindness is caused by you drinking too much Coca-Cola

All of these are true. You drink too much Coca-Cola, it causes your cells to lose insulin sensitivity, that causes too much sugar in the blood, that increases the activity of PKC-delta, and that causes little blood vessels to grow all over your eyes. Sometimes the chain is different. Maybe you drank too much lemonade instead of too much Coca-Cola. Maybe you drank too much Coca-Cola, but actually instead of causing diabetes it caused hypertension and then you got hypertensive retinopathy which made you blind. Maybe it was diabetic retinopathy, but actually you haven’t gotten to the proliferative stage yet, and you just had a lot of your blood vessels get damaged and start leaking and causing macular oedema. Maybe it was diabetic retinopathy, but you had a perfect diet and lost the genetic lottery. I don’t know.

If someone told you “We think it involves an imbalance in protein kinase” it would be woefully incomplete. But if someone said “That doctor there said your blindness was caused by an imbalance in protein kinase, that proves he’s a fraud!”, well, no, it wouldn’t.

Except the situation is even more complicated than this, because at least I specified this guy had diabetic retinopathy. What if somebody just asked “What causes blindness?” “High protein kinase” or “high blood sugar” would be two answers, and you could find tests supporting both. But “cataracts” would be another good answer. So would “people getting acid thrown in their eyes”.

All I’m saying is that depression is complicated. Discovering its relationship to the serotonin system is a lot like saying “blindness quite often has something to do with the retina”. It’s a big step forward, and don’t believe anyone who says it isn’t, but it’s not anywhere near the whole picture.

III.

And this starts to get into the next important point I want to bring up, which is chemical imbalance is a really broad idea.

Like, some of these articles seem to want to contrast the “discredited” chemical imbalance theory with up-and-coming “more sophisticated” theories based on hippocampal neurogenesis and neuroinflammation. Well, I have bad news for you. Hippocampal neurogenesis is heavily regulated by brain-derived neutrophic factor, a chemical. Neuroinflammation is mediated by cytokines. Which are also chemicals. Do you think depression is caused by stress? The stress hormone cortisol is…a chemical. Do you think it’s entirely genetic? Genes code for proteins – chemicals again. Do you think it’s caused by poor diet? What exactly do you think food is made of?

Diabetes is caused by a chemical imbalance: too much sugar (or too little insulin) in the blood. Parkinson’s is caused by a chemical imbalance: too little dopamine in the basal ganglia. Heart attacks are caused by a chemical imbalance: too many of the wrong kinds of lipids and lipid-related plaques in the coronary arteries.

I can get even more nitpicky if you want. The Donner Party died of chemical imbalance – too few fatty acids, proteins, and carbohydrates. The passengers of the Titanic died of a chemical imbalance – H2O in the lungs instead of O2. And it was a chemical imbalance that got Hiroshima in the end: excess uranium-235. Anything that’s not caused by ghosts is going to be “a chemical imbalance” in some sense of the word.

This is why I’m being so insistent that psychiatrists referred to “a chemical imbalance” rather than “a serotonin deficiency”. They were hedging the heck out of their bets. It might be BDNF, or cytokines, or whatever. But if something happens in the body and doesn’t show up as a gross anatomical defect on MRI, it’s a pretty good bet it’s chemical in some sense of the word.

So is this a giant cop-out? Psychiatrists said “it’s a chemical imbalance” to make it sound like they knew what they were talking about, when in fact all they meant was “it’s a thing that exists”?

Sort of.

Anything that isn’t caused by ghosts is going to be “a chemical imbalance” in some sense of the word. But in the latter half of the twentieth century, “depression is not caused by ghosts” was a revolutionary statement, and one that desperately needed to be said.

I still see this. People come in with depression, and they think it means they’re lazy, or they don’t have enough willpower, or they’re bad people. Or else they don’t think it, but their families do: why can’t she just pull herself up with her own bootstraps, make a bit of an effort? Or: we were good parents, we did everything right, why is he still doing this? Doesn’t he love us?

And I could say: “Well, it’s complicated, but basically in people who are genetically predisposed, some sort of precipitating factor, which can be anything from a disruption in circadian rhythm to a stressful event that increases levels of cortisol to anything that activates the immune system into a pro-inflammatory mode, is going to trigger a bunch of different changes along metabolic pathways that shifts all of them into a different attractor state. This can involve the release of cytokines which cause neuroinflammation which shifts the balance between kynurinins and serotonin in the tryptophan pathway, or a decrease in secretion of brain-derived neutrotrophic factor which inhibits hippocampal neurogenesis, and for some reason all of this also seems to elevate serotonin in the raphe nuclei but decrease it in the hippocampus, and probably other monoamines like dopamine and norepinephrine are involved as well, and of course we can’t forget the hypothalamopituitaryadrenocortical axis, although for all I know this is all total bunk and the real culprit is some other system that has downstream effects on all of these or just…”

Or I could say: “Fuck you, it’s a chemical imbalance.”

Last time I talked about the definition of disease I said that people want diseases to “be caused by the sorts of thing you study in biology: proteins, bacteria, ions, viruses, genes.”

I don’t think I could actually get away with telling a patient’s family “it’s caused by, you know, biology stuff” without them asking if I really went to medical school. I don’t think I’d use the term “chemical imbalance” precisely; too likely to trigger a knee-jerk reaction from people reading exactly these articles I’m responding to. But I think I would say something alone those lines. “We don’t know exactly, but it probably involves problems with brain structure and brain chemicals,” maybe. That covers about the same ground as “biology stuff” while also sounding like I’m at least trying to answer their question.

So if what I’m actually saying with that is “depression is caused by complicated biology stuff you don’t understand, and not by things like your son not really loving you, or being lazy,” am I sure that’s right?

I won’t say all depression is 100% caused by internal failures of biology in the same way that for example cystic fibrosis is caused 100% by internal failures of biology. I am happy to admit that some depressions can be caused by being in a crappy social situation, being abused as a child, being stuck in an unhappy marriage, being worried about problems at work, stuff like that.

But it’s far from obvious that being stuck in an unhappy marriage should drain your energy, drain your concentration, make you stop enjoying your hobbies, and finally drive you to suicide. We can imagine another person, or another way of designing a person, where someone says “I hate my husband, so I try to stay away from him as much as I can by working extra hard and spending my free time playing frisbee with my dog in the park.” But instead, someone hates their husband, and it drives all the joy out of their life to the point where they can’t go to work, they can’t play with their dog, they just sit around wishing they were dead.

And is that the fault of “biology stuff”? That’s a harder question than it sounds. What would it mean to say ‘no’? If we are strict materialists who don’t believe in some kind of division of labor between the brain and the soul, then yes, if it’s a feeling you’re having, it’s based in biology.

I’ve previously said we use talk of disease and biology to distinguish between things we can expect to respond to rational choice and social incentives and things that don’t. If I’m lying in bed because I’m sleepy, then yelling at me to get up will solve the problem, so we call sleepiness a natural state. If I’m lying in bed because I’m paralyzed, then yelling at me to get up won’t change anything, so we call paralysis a disease state. Talk of biology tells people to shut off their normal intuitive ways of modeling the world. Intuitively, if my son is refusing to go to work, it means I didn’t raise him very well and he doesn’t love me enough to help support the family. If I say “depression is a chemical imbalance”, well, that means that the problem is some sort of complicated science thing and I should stop using my “mirror neurons” and my social skills module to figure out where I went wrong or where he went wrong.

In other words, everything we do is caused by brain chemicals, but usually we think about them on the human terms, like “He went to the diner because he was hungry” and not “He went to the diner because the level of dopamine in the appetite center of his hypothalamus reached a critical level which caused it to fire messages at the complex planning center which told his motor cortex to move his legs to…” – even though both are correct. Very occasionally, some things happen that we can’t think about on the human terms, like a seizure – we can’t explain in terms of desires or emotions or goals an epileptic person is flailing their limbs, so we have to go down to the lower-level brain chemical explanation.

What “chemical imbalance” does for depression is try to force it down to this lower level, tell people to stop trying to use rational and emotional explanations for why their friend or family member is acting this way. It’s not a claim that nothing caused the chemical imbalance – maybe a recent breakup did – but if you try to use your normal social intuitions to determine why your friend or family member is behaving the way they are after the breakup, you’re going to get screwy results.

(in much the same way, if I just saw you take a giant handful of amphetamines, I pretty much know why you’re having a seizure, but I still can’t rationally / intuitively model the experience of why you’re “choosing” to move your limbs the way that you are.)

(though it’s important for me to temper this by mentioning that many people diagnosed with depression don’t have it)

There’s still one more question, which is: are you sure that depression patients’ experience is so incommensurable with healthy people’s experiences that it’s better to model their behavior as based on mysterious brain chemicals rather than on rational choice?

And part of what I’m going on is the stated experience of depressed people themselves. As for the rest, I can only plead consistency. I think people’s political opinions are highly genetically loaded and appear to be related to the structure of the insula and amygdala. I think large-scale variations in crime rate are mostly attributable to environmental levels of lead and probably other chemicals. It would be really weird if depression were the one area where we could always count on the inside view not to lead us astray.

So this is my answer to the accusation that psychiatry erred in promoting the idea of a “chemical imbalance”. The idea that depression is a drop-dead simple serotonin deficiency was never taken seriously by mainstream psychiatry. The idea that depression was a complicated pattern of derangement in several different brain chemicals that may well be interacting with or downstream from other causes has always been taken seriously, and continues to be pretty plausible. Whatever depression is, it’s very likely it will involve chemicals in some way, and it’s useful to emphasize that fact in order to convince people to take depression seriously as something that is beyond the intuitively-modeled “free will” of the people suffering it. “Chemical imbalance” is probably no longer the best phrase for that because of the baggage it’s taken on, but the best phrase will probably be one that captures a lot of the same idea.

This conference consisted of a series of talks about all the most important issues of the day, like ‘The Menace Of Psychologists Being Allowed To Prescribe Medication’, ‘How To Be An Advocate For Important Issues Affecting Your Patients Such As The Possibility That Psychologists Might Be Allowed To Prescribe Them Medication’, and ‘Protecting Members Of Disadvantaged Communities From Psychologists Prescribing Them Medication’.

As somebody who’s noticed that the average waiting list for a desperately ill person to see a psychiatrist is approaching the twelve month mark in some places, I was pretty okay with psychologists prescribing medication. The scare stories about how psychologists might prescribe medications unsafely didn’t have much effect on me, since I continue to believe that putting antidepressants in a vending machine would be a more safety-conscious system than what we have now (a vending machine would at least limit antidepressants to people who have $1.25 in change; the average primary care doctor is nowhere near that selective). Annnnnyway, this made me kind of uncomfortable at the conference and I Struck A Courageous Blow Against The Cartelization Of Medicine by sneaking out without putting my name on their mailing list.

But before I did, I managed to take some notes about what’s going on in the wider psychiatric world, including:

– The newest breakthrough in ensuring schizophrenic people take their medication (a hard problem!) is bundling the pills with an ingestable computer chip that transmits data from the patient’s stomach. It’s a bold plan, somewhat complicated by the fact that one of the most common symptoms of schizophrenia is the paranoid fear that somebody has implanted a chip in your body to monitor you. Can you imagine being a schizophrenic guy who has to explain to your new doctor that your old doctor put computer chips in your pills to monitor you? Yikes. If they go through with this, I hope they publish the results in the form of a sequel to The Three Christs of Ypsilanti.

– The same team is working on a smartphone app to detect schizophrenic relapses. The system uses GPS to monitor location, accelerometer to detect movements, and microphone to check tone of voice and speaking pattern, then throws it into a machine learning system that tries to differentiate psychotic from normal behavior (for example, psychotic people might speak faster, or rock back and forth a lot). Again, interesting idea. But again, one of the most common paranoid schizophrenic delusions is that their electronic devices are monitoring everything they do. If you make every one of a psychotic person’s delusions come true, such that they no longer have any beliefs that do not correspond to reality, does that technically mean you’ve cured them? I don’t know, but I’m glad we have people investigating this important issue.

– I’ll come out and say it: cluster randomization is really sketchy. Today I got to hear about a multi-center trial which randomized by location – half of their hospitals were the control group, the other half were the experimental group. Problem is, the patients in each hospital were given group-appropriate consent forms – either “We will be treating you as usual, but monitoring you more closely for a study” or “We will be giving you extra experimental treatment”. Not only does that break blinding, but it implies a different population of patients in each group – the ones willing to consent to monitoring versus the ones willing to consent to treatment? Might sicker people be more willing to sign the treatment consent, since they don’t want to deal with monitoring but treatment offers the chance for personal gain? Might paranoid people be more willing to sign the control consent, since they’re not being used as guinea pigs? I don’t know. But I checked those pre-intervention inter-group comparisons they have to show, and there were big differences between the two groups (for example, I think one – I can’t remember which – had like twice as many black people). Either randomize peopple properly or at least keep people blind to condition.

– On the other hand, I’m quickly losing my prejudice that RCTs always beat naturalistic studies. I’ll write more about this later, but today’s showcase was long-acting injectable versus oral antipsychotics. Conventional wisdom is that long-acting antipsychotics, in the right patient population, decrease relapse because they remove the option of not taking the medication. The best randomized controlled trials don’t find that. The best naturalistic epidemiological studies do. The expert who spoke today theorized – and I agree – that the naturalistic studies are right. He argued that one feature of RCTs is very close monitoring, which means the patients in them comply with their medication at an unnaturally high rate – thus removing the long-acting drugs’ one advantage. The studies conducted in the real world of patients not taking their medications regularly are more relevant.

– They say psychotic people don’t take their meds because they hate the side effects, or because they’re too crazy to know better, or because they just can’t be bothered. But one of the doctors today raised a novel hypothesis: are antipsychotics anti-addictive? After all, some of the most addictive drugs are those that raise dopamine levels – cocaine, meth, and MDMA are all either dopamine releasing agents or dopamine reuptake inhibitors. Antipsychotics have pretty much the opposite effect as those, lowering dopamine in the brain. Suspicious. But I have a feeling this isn’t true. Dopamine is more complicated than that. Levodopa-carbidopa, which is one step short of pure dopamine and is given to dopamine-deficient Parksinson’s patients, is as far as I know not addictive at all. It’s also very clearly antagonistic to antipsychotics. Probably antipsychotics are the opposite of non-addictive levodopa, not the opposite of cocaine or anything. I don’t know how to phrase it more rigorously than that. Still, I like the way that person thinks.

– Ever since Indiana’s legislature debated a bill that implied pi = 4, Midwestern states have had a reputation for trying to legislate science. Maybe this had something to do with the claim by one psychiatry lobbyist that Kansas’ legislature is trying to ban the DSM. I can’t find anything on it online and it sounds like an urban legend to me. Tangentially related silly clickbait: Arizona lawmakers say horses aren’t animals.

– Unintentional puns are some of my favorite puns. I still remember fondly when the head of a psychiatric hospital where I used to work said that if Obamacare passed there would be too many patients and the place would “turn into a madhouse”. I collected another good one today when an activist was talking about gun rights for psychiatric patients: “Taking guns from psychiatric patients isn’t going to be a panacea for violence – would anyone like to take a stab at why?”

– Clozapine really is the best antipsychotic, hands down, and the evidence isn’t even subtle. It’s also the most dangerous, and the rules say that you should only prescribe it to a patient after you’ve tried and failed with two other antipsychotics. One of the speakers was a researcher who’s trying to get a grant to prove that it’s actually more effective to try clozapine after only one failed antipsychotic, but the NIMH rejected his proposal because “even if you proved that, no one would listen”. They’re probably right. A lot of psychiatrists hate clozapine because it’s messy, scary, and requires a lot of paperwork and monitoring. The speaker presented survey after survey of psychiatrists making lame excuses like “My patients wouldn’t want it”, and then survey after survey of those psychiatrists’ patients saying they do so want it but nobody asked them. Clozapine is messy and scary and requires lots of paperwork, but if you’re a good doctor you’ll give your patient the drug that will help them anyway.

– The APA representative says that 95% of candidates supported by the APA’s PAC get elected. I think it was supposed to be a boast, like “look how effective we are”, but that’s a bit much. Either the APA single-handedly controls all American politics, or else they’re very careful to always back the winning side. Properly understood, that number should probably be taken as a measure of exactly how cynical they are.

– Not that they didn’t admit their cynicism straight out. Our Political Activism Consultant explained that state legislators are all sorta new and confused and inexperienced all the time because of term limits. And if you put on a nice suit and a tie and tell them “Hey, I’m a doctor from your district, here’s how you need to do health care policy…” you have a pretty good chance of getting them to nod along and assume you know what you’re doing. I didn’t realize how easy this was, and I hope I never use this power for evil.

– This is basically how the Eternal War Against Psychologists Being Allowed To Prescribe Medications is being fought, but the psychologists have caught on and now they have nice suits and ties too. Also, it turns out senators have a hard time differentiating the APA (American Psychiatric Association, fighting tooth and claw against psychologist prescribers) from the APA (American Psychological Association, fighting tooth and claw for psychologist prescribers) and they end up freaking out and trying to figure out why the same people are lobbying for both sides and whether this is some kind of weird shrink mind game thing.

– Drug companies were giving out stress brains! Like stress balls, only they’re shaped like brains and have little sulci and gyri on them! If in ten years I’m one of those people who never prescribes clozapine, it’ll because I’m prescribing the drug by the company that gave me a stress brain instead.