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Could also add to the nutritional section something about how probiotics are suggested to help depression: https://newsroom.ucla.edu/releases/changing-gut-bacteria-through-245617

It's preliminary, but also a very benign intervention if you just tell someone to try and eat more probiotics. Very limited risk there, unless you're lactose intolerant I suppose...

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"except by drilling a hole in your skull and injecting it directly – something which cures depression reliably when scientists do it to rats"

This was funny, but the imagery made me feel squeemish

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No mention of post-natal depression. Is that deliberate?

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I've been really impressed by the effectiveness of SAM-e. I take it pretty regularly when I'm feeling depressed, and it works wonders.

It's also worth mentioning that SAM-e is prescription only in Europe, at least according to Wikipedia.

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My main initial reaction is: who is the target audience for this? As a nerdy SSC/ACT fan I love it as a ‘much more then you ever wanted to know’ post, but I’m not sure how, say, a person wondering if they might be suffering from depression would read this?

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Regimen 3A/3B imply "Person with/without access to a doctor, high time/energy budget" but might be worth calling that out explicitly as with 1 and 2.

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Typo: adapting -> adopting. (I still have to triple check those words in my head every time I try to use one of them.)

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How nerdy/STEM-educated/comfortable with technical vocabulary do you expect the audience for this page to be? I enjoyed the discussion of depression as an attractor state in a dynamical system, for example, and enjoyed your longer post on that too; but for someone less mathematically inclined, I worry it might seem so jargon-y or academic as to make them less likely to read on. I unfortunately don't have good enough theory of mind about non-mathematically-inclined people to tell whether this is a justified worry. But I do recommend that if you want this to be attractive, engaging reading for people less nerdy than the typical SSC reader, you should seek out some such people to give you feedback.

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Trying to bring up neuroendocrinology objectively in the modern era is unfortunately frequently academic self-immolation- but I think it might be worth it. Eg NDRIs and testosterone, PMDD and temporal SSRI scrips

Just as a first pass-mainly cause my startup just got a deal with Sage/Biogen and they have some of the first endocrine based treatments

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My PubPeer plugin tells me you're quoting an article which has a worrying comment on PubPeer (the comment is from a bot which outputs warnings when the summary statistics seem weird, and should probably be checked). Weirdly, I can't find the relevant link in your article right now, but here is the comment if you want to check: Updating positive and negative stimuli in working memory in depression (https://pubpeer.com/publications/0DD5CCD0457CAF07AAB1E74607D109)

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One thing that's helped my wife is consumption of a sugar called inositol, which is about half as sweet as glucose, IIRC. It helps with rather specific types of depression. An issue with inositol is intestinal absorption which limits the amounts used in some studies or dietary compliance. But alpha-lactalbumin assists with asborption to some extent. Alpha-lactalbumin is a component of whey.

One of the effects of lithium in people with bipolar disorder is to reduce inositol concentration in parts of the brain.

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In one spot you list SAM-e but the rest of the time you drop the hyphen (I don't know which is correct)

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You seem to hint at the idea that depression that comes from anxiety is different. How would you approach it differently? And is it not common for depression to not be tied with anxiety? ( thought they were frequently comorbid.

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Depression is sometimes the result of a vicious cycle of failure causing low self-esteem causing failure. Methylphenidate works surprisingly well for escaping the cycle.

Foods high in carbs reliably give me brain fog, anxiety, and short-term depression for hours after eating, so the mediterranean diet recommendation would make my depression worse. Fruits and meats don't have these issues for me. If anyone can diagnose my dietary condition based on this description, please do.

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Vitamin C powder; cutting out refined sugar, most meats, coffee, dairy, and soda; yoga; and skateboarding work for me

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Re. "You can address the social causes by changing your life circumstances (and research suggests people underestimate the potential benefits of making major life changes)."

This is more true if by "people" you mean psychologists. I had severe depression in the years around 2000, and it recurs when bad things happen in my life. I wrote psychologists off forever after several attempts, because whenever I talked about what I saw as my life-circumstance problems, they would try to get me to think or feel about them differently. They tried to talk me out of my attempts to remove what I saw as the causes of my depression. They said that the belief that improvements in your circumstances would make you happier was a trap, like thinking that earning more money could make you happier.

In related news, earning more money can make you happier.

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I seem unable to be depressed for more than one day. This might happen once, maybe twice in a year. My strategy for that day is basically to stay in bed and eat potato chips. Next day I'm back to normal. Is there something wrong with me?

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Boring edit: refrigerator spelled wrong

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Thank you! Have you done anything like this but for anxiety/depersonalization ?

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I think the “what is depression” section to be pretty jargon heavy. I’m a medical student, and if I ever heard someone say “psychomotor” in one of our exam practice sessions I’d call them out on it because patients don’t know a lot of the words that we get taught, or at least aren’t able to figure out on the fly. For instance, I recently saw some paediatric cardiologists tell a parent that their kid’s aortic valve was prolapsing into hole in their heart. I appreciate they said “hole” rather than “ventral septal defect”, but I’ve never heard the word “prolapsing” outside a medical context, and lots of people don’t remember their high school biology cardiac anatomy enough to know what an aorta is or how valves work.

I could just be underestimating my patients, but I’d try to use more accessible language in that section at least

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I’d saw some links on how anti-inflammatory drugs can be used to treat depression. Twitter search: @degenrolf depression or @degenrolf anti-inflammatory is where I found it

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Depression in men is one of the symptoms of low testosterone and testosterone levels have been falling 1% every year for a long time now, so it's possible that a lot of male depression is due to low testosterone.

The problem is made much worse, because most labs (at least here in Europe) don't have age-adjusted ranges for "normal values", so a 20 year old guy would have to have the testosterone level of a 90 year old suffering from erectile dysfunction before a diagnosis of low testosterone is made and supplementation is offered.

I talked to a medical doctor about this. He is recognized as a leading authority on these issues here in Estonia and is often in the news. He said that falling male testosterone levels are good for society and therefore he and his colleagues have decided to only treat cases, where low testosterone directly and clearly affects reproductive health. Depression and other less important symptoms he leaves to other doctors.

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It may be worthwhile to add a section on ways to help prevent depression from occurring in the first place. That's one of my concerns as a fairly neurotypical person; I really would like to not become depressed, since the condition works against you seeking out ways to improve yourself.

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cutting out soda might result in caffeine withdrawal (some people who drink a lot of soda all day), which could make depression or anxious symptoms worse in the short term.

maybe worth warning about this and suggesting green tea or something?

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Whoa, now you're playing hard mode. Nice read! Some comments mostly on the non-medical parts:

I'm not quite sure why you are treating hypomania as a bad thing in 1.2.1 (at least the sort that contents itself with messing with one's emotions rather than encroaching on one's perception). I'm aware of the specific problem with suicidal people getting more likely to try it out when out of depression, but should the rest of us worry? If I am to name what's wrong with the world, overconfidence isn't what comes to mind. But I guess there are some things that become hard to say once one calls oneself a doctor (thank goodness a PhD does not count).

I wasn't aware of the Levitt study you referenced in 2.1.1. That might be useful not just for the depressed? At a quick glance ( https://www.nber.org/system/files/working_papers/w22487/w22487.pdf ), there does appear to be a selection bias issue here: a study on Freakonomics and MR readers will necessarily have a certain kind of slant that may make its conclusions -- such as the incredibly high happiness returns on starting a business -- somewhat less generalizable than one might hope for. Still, if there is an effect here, yolotherapy might be the next big thing. (Though oracles and fortunetellers might have been living off the same land for millenia; this study should be lauded for observing the same effect in some of the groups least likely to use the services of the former.)

Mediterranean diet. Someone is going to retweet the hell out of this.

2.1.3: In my experience with something-like-depression (I think there should be an IANAL-like disclaimer for discussions of undiagnosed psychological symptoms, particularly when one doesn't even believe one has the real thing), I found hiking helpful... for the duration of the hike. The effect dissipated on return, probably because of the transient nature of the whole thing. On the other hand, far-from-wholesome nerd work (think coding until 5AM) worked like a charm if there was something tangible to show at the end. Neither to generalize nor to pollute the data, but I feel that there is some kind of internal accounting of accomplishment and progress involved that is not easily tricked. Maybe serious gamification (Pokemon Go?) could help, but unless you manage to forget the artificiality and sideshow-ness of the attained achievements, it's likely to be a hard sell to the "you suck" mob inside your mind. (Preemptive "don't worry about me" to the commenters here; I am doing fine and my symptoms have always been subclinical.)

2.3: "If neither of them work, and you’re feeling optimistic" hehe.

I'd have wished for some discussion of tolerance in 2.3 and 2.4. Is it less of a thing than I expect it to be, or is less about it known?

Typos: "pasTTimes" (did the proximity to "hoBBies" lead you astray here?), "refriDgerator" (wouldn't have spotted this one if the "d" didn't stand out so awkwardly in a Latin root), missing period after "hardest to do it anyway", "only proportional" (should probably be "proportionally"), "enough enough".

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>German studies tend to do the best and American studies the worst, which might either reveal something about those countries’ cultural biases, or about the different strains and extracts of the plant used in the two countries.

I heard on a podcast that the difference is likely that St. Johns Wort supplements are regulated in Germany, and not so much in America. Which would mean German St. Johns Wort supplements are much less likely to be adulterated.

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This is generally excellent.

However, on first reading the beginning section - "The short version" - read really oddly to me. It seemed peremptory, confusing, and almost flippant. I may not have any idea if I'm depressed or not, and suddenly I'm being told to consider a Mediterranean diet, methylfolate AND electroconvulsive therapy! However, once I had read the whole text, I reread this section, and this time it seemed fine. So IDK... but maybe consider expanding it a little and clarifying to the reader what the section is.

The "What is Depression" segment perhaps assumes a bit too much knowledge in the reader. I was trying to put myself in the shoes of someone who feels depressed but doesn't know much about depression, and I wondered if such a person would necessarily follow the use of quotation marks as a compressed way of referencing a whole complex area of what constitutes a real symptom, what psychosomatic means etc. I would consider laying out the issue briefly but explicitly rather than in this more coded form.

With your use of humour, I felt that at moments you were a shade too close to your blog style. In particular "being a moron", and "because the researchers were cowards", plus maybe the hole in the skull bit. I found these funny, as usual, but I wondered whether someone in a vulnerable state might find their trust in your otherwise very steady and reassuring voice undermined a touch.

The writing is refreshingly free of jargon. Exceptions were "modality" and "high withdrawal potential", the second of which I took to mean that it had danger of withdrawal symptoms, but I wasn't certain.

This sentence -

Some people act like the episode “continues under the surface” even when a medication is treating it, and if you restart earlier than this, it will show up again.

- for some reason I found it hard to follow and had to read it three times. I can't find any syntactic or stylistic reason why this should be so, so it's probably me. Maybe I'm depressed?

In the passage about the mathematical explanation, maybe you should link to your attractor posts? For someone without much maths it would be hard to get a sense of what the passage means.

Finally - and this is something you know approximately a million times more than me about, so apologies for the presumption... but I wondered if there should be more in the way of caveats? Particularly when it comes to medication, you say "You should consult with your doctor" but don't really stress that they shouldn't start necking escitalopram-ketamine-and-St-John's-Wort cocktails without seeking more advice first. I worried that someone like my cousin, who is not always depressed, but is always a total maniac, might just immediately get on the dark web and buy the whole list.

Typo in 2.1 - "enough enough"

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> Along with the neurological, biochemical, and cognitive levels mentioned above, there’s a fourth level on which you can try to understand depression – a mathematical level. On the mathematical level, depression is an attractor state in a dynamical system. It looks like that dynamical system takes both life events and biochemical factors as inputs, and based on the different weights of the edges of the graph in different people (probably at least partly genetically determined), either or both of those can shift it into the new depressed attractor state.

This entire paragraph is very hard to parse for the non-mathematically inclined. I'd suggest either toning down the jargon or linking the hell out of it so that readers who don't understand the technical terms can go read a writeup of how that math works.

Additionally, the diet stuff looks *awesome* but there's enough to that section that you may want to make it its own page. Note how you went into a 4th level of numbering--typically that's a good sign that you've gotten technical enough that it should be its own page that you link to on the main page.

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Really like the doc! It's really valuable putting all your expertise into these articles & think it will eventually be the Paul's Notes of Psychiatry.

I don't think this paragraph adds anything for the vast majority of people reading it and it just kind of hangs there without being connected to anything else:

> Along with the neurological, biochemical, and cognitive levels mentioned above, there’s a fourth level on which you can try to understand depression – a mathematical level. On the mathematical level, depression is an attractor state in a dynamical system. It looks like that dynamical system takes both life events and biochemical factors as inputs, and based on the different weights of the edges of the graph in different people (probably at least partly genetically determined), either or both of those can shift it into the new depressed attractor state.

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Get a dog. :P

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Other material I've read makes a hard distinction between mild-to-moderate depression and severe depression, with the later being more amenable to treatment. No?

I think rhodiola extract helps. Worth researching?

I've found that the best thing for self-hatred, though not a complete solution, is to identify with the self being attacked rather than the attacking voice. Saying to myself that the attacking voice is factually wrong wasn't especially helpful. It's more feasible now that I'm less identified with the attacking voice, but it wasn't a place I could start.

One of the nasty things about diet is that the taste of sugar cuts through the depressive haze better than most things. I don't know whether there's a general solution for that. Fortunately, I'm able to take it seriously that too much simple carbs makes me feel bad.

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Loved it and more helpful than anything I've read since coming to understand this was a trait in my wife's family... nit: 'pasttimes' not a word, s/b 'pastimes'.

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You briefly mention wake therapy, but you do not mention the symptoms that suggest it might work, as described in your post https://astralcodexten.substack.com/p/sleep-is-the-mate-of-death . Is the omission deliberate? I'm one of those people who feel terrible in the morning, better as the day progresses, and good enough in the evening that I try to delay going to sleep. That post made me seriously consider the possibility that I might be depressed.

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Good overview. Though I'd say my major depression comes from hopelessness, feeling disconnected. So there's a lot of existential pieces to it. Also, dunno about saying therapy from a book is just as effective. Sort of discounting the role of interpersonal psychotherapy in untangling and adjusting core beliefs through a real relationship, which can then translate to real world. Thanks for the read.

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I liked this a lot! I would increase the emphasis on the fact that major depressive episodes tend to ease up on their own after 6 months. You note this in passing at the end in the context of medication but I found this knowledge super helpful when a doctor mentioned it while I was depressed (and, anecdotally, other depressed people I've known seemed surprised when I mentioned this to them). It helped me reframe depression from something I was failing to fix and made me see it more as something washing over me I just had to survive.

As you say, it feels terrible to be depressed and keep getting advice on how to be less depressed that you know you won't have the willpower to execute. (And if you think you'll feel this way forever unless you miraculously get your act together, suicidal ideations feel much more tempting.) In my case, just telling myself that waiting out the clock was also an option and I probably wouldn't feel this way forever even if I never managed to get on the right meds helped me about as much as anything else I did in terms of breaking the depression spiral.

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Broad note: this feels less approachable than your average article, which seems unfortunate in something that depressed people are presumably going to be trying to read. I wonder if there's some way to organize each FAQ item so that it starts with an engaging claim or anecdote, continues with concrete recommendations, and only then goes into the justifications?

> Realistically, most people know if they’re depressed or not and don’t need to go through a checklist to figure it out.

This is not my experience at *all.* IME depression is a lot like being abused -- no matter how bad yours is, you probably don't think you're *really* depressed.

> The most common are depressing jobs, depressing relationships, and (surprisingly often) depressing grad school programs.

Presumably massive sampling bias, but the two I see most often are "depressed from living with abusive family" (but convinced that their family is lovely; depression fixed when they move out) and "depressed from dysphoria" (but convinced they're cis; depression fixed when they transition).

> What’s the role of sunlight in treating depression?

I'm perpetually confused about what tradeoffs I should be making on this, as someone depressive who's also very pale with a family history of skin cancer. Should I be covering up on sunny days or taking my shirt off? Do I still get the depression-related benefits if I'm slathered in sunscreen?

> They come from normal healthy eating. Less processed food, junk food, and soda; more whole foods, nutritious foods, vegetables, and water.

I've always figured there's a Maslow's Hierarchy sort of thing going on here, where the base of the pyramid is *actually eating food.* I know a lot of depressed people who struggle to reliably eat *at all*; I wonder if it's worth actively recommending processed junk food in the cases where that might make it easier to get calories in your body while depressed.

Finally, some questions I hear a lot from depressed people which aren't addressed here (I'm sure you've already thought about many of these and decided against including them, but just in case):

- But what if antidepressants turn me into a drugged-up artificially happy zombie who can't feel sad about genuinely sad things?

- If I talk to a therapist about my depression, won't I get committed to a mental institution?

- What if I'm just a genuinely evil person who really should feel bad, and treatment makes me stop feeling bad?

- How can I tell if I'm depressed, or just right that the world is a terrible place hurtling towards destruction and ruled by people who torture babies?

- I've been on medication for my depression for ten years, and as long as I'm on it I'm good, and every time I go off it I become suicidal. But I'm good right now, so probably I was never depressed and this medication isn't doing anything, so it's a great idea to stop taking it, right?

(Okay, no one actually asks that last one. But it sure does come up a lot.)

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I really enjoyed the dynamical systems post, but I think without the massive amount of context that it provides, its inclusion in the short version is confusing.

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Which (if any) of these supplements would you recommend for a non-depressed person?

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> Realistically, most people know if they’re depressed or not and don’t need to go through a checklist to figure it out. On the other hand, if you really like going through checklists to figure out if you’re depressed, you can take the HAM-D, a very official depression test used in studies, and it will tell you exactly how depressed you are.

In my experience, chronically depressed people often assume that they feel the way everyone else feels and are just less virtuous and able to deal with normal life stressors. I've encouraged people I know to take the Beck Depression Inventory and they've found it very helpful with realizing that their situation is abnormal.

It might be worth mentioning eating disorders in the section on the Mediterranean diet, because lots of depressed people have EDs. Anecdotally, a lot of depressed people I know undereat, and getting enough calories tends to improve their mood.

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I live with someone with hereditary treatment-resistant depression that requires a continually evolving cocktail of pharmacologic therapies. She even went as far as ECT during a particularly acute phase of her depression before we found a new cocktail that has put her depression back in remission (for now).

Given this experience, I am likely biased in how I think about depression. And, with this bias, I found the Short Version a bit...glib? It certainly would turn her off if she were reading the short version. The long version I feel gets the balance far more right, but she might never get to the long version due to the short version's feel. Just something to think about if you're looking to attract and educate people who *are* depressed.

Other thoughts:

Before she did her first ECT treatment, I read up on what it does and how it works intensely, because I was scared of this procedure too. What I picked up was that ECT actually shuts down hyper-active neuron activity, and this made sense to me (but flies in the face of what you state in your long description).

It does appear to me that, when depressed, the patient is unable to turn off the "bad news feed" - and this appears to resemble over-processing, not under-processing, of information.

Further, it seems like a depressed person resembles an incredibly self-centered person as well - a negative narcissist, if you will. The pain they are in makes their entire existence about *them* at all times, which is probably not normal or healthy. Further, I completely agree with the intersectionality of depression and anxiety, but I would like to suggest that sensitivity be added in here as well.

When she is depressed, I witness someone who is hyper-sensitive to stimuli, hyper-aware of self (in a negative context), and constantly swirling in a heated stew of brain pain. It's a vicious cycle. An analogy I use to describe what I witness is that while I go through life in a car with shock absorbers, she's going through life dragging her knees on the pavement. She's just so much close to the ground, with no ability to modulate or buffer the inputs.

And it's this inability to modulate or buffer the incoming data that leads me to the hypothesis that depression is actually about hyper-active neuron activity vs. too little.

Hope this helps.

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Regarding psilocybin for depression: when I've looked this up, all the writeups I find are on this one study from November 2020:


"In this randomized clinical trial of 24 participants with major depressive disorder, participants who received immediate psilocybin-assisted therapy compared with delayed treatment showed improvement in blinded clinician rater–assessed depression severity and in self-reported secondary outcomes through the 1-month follow-up."

It does sound promising, but the facts that 1) it's one very recent study, with 2) a sample size of 24, and 3) only *one month* follow up give me some pause. Is anyone aware of other research on psilocybin for depression? Is there any reason to believe that this apparent ameliorative effect for one month would continue (or not)?

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The paragraph beginning “In a study in India” has a duplicated comma and what feels like too long of a link to me? It’s hard to distinguish that link with the subsequent link to an iron supplement - I would make the link attach only to the word “study” at the beginning.

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This paragraph was the first paragraph I could not easily understand.

Along with the neurological, biochemical, and cognitive levels mentioned above, there’s a fourth level on which you can try to understand depression – a mathematical level. On the mathematical level, depression is an attractor state in a dynamical system. It looks like that dynamical system takes both life events and biochemical factors as inputs, and based on the different weights of the edges of the graph in different people (probably at least partly genetically determined), either or both of those can shift it into the new depressed attractor state.

I don’t know what an attractor state is, and how it relates to “weights of the edges of the graph.” You may want to translate this paragraph into layman’s terms.

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PS. Spooky retraction at a distance: your Lorien link on light therapy cites https://osf.io/8ev4u/ , which has been retracted for a painfully stupid reason. The up to date link seems to be http://sci-hub.se/https://doi.org/10.1177%2F1745691620950690 . Here's hoping the conclusions didn't change in peer review...

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Some random comments below. Overall, shorter paragraphs would be good. Walls of text are hard for someone who is depressed. Seems like this may be trying to do too many things at once -- I wonder if a more spare structure with links to side subjects might be better. The level of generality varies a lot which makes it a bit unclear to me who you see the main target audience to be. It's clearly more than just potential patients, but for people beyond potential patients, it seems maybe too specific about dosages and supplements/meds in a way that strikes me as risky.

Some of the details are lovely -- like the Levitt study.

Okay, some specific points, take or leave, for what they're worth:

* Section 2, para 2 "so nobody should feel obligated to try any modality that doesn’t feel like a good fit for them" -- I think reluctance to try things is a big barrier to treatment. People are terrified that something new will make them feel worse and that they can't risk that. So I think people ought to be encouraged to TRY things and that only by trying things will they learn what might be a good fit. There are so many people out there who say "Oh I hate antidepressants" who have never taken them or "I know therapy won't work for me" who have never tried. We are incredibly wrong sometimes about what we think we know and are so good at making excuses when we're afraid. We want to encourage people to take some risks in order to get treatment while their depression is likely to make them extremely, paralytically risk-averse.

* Stress isn't mentioned anywhere in here that I saw. Stress is sometimes a really big factor in depression. You mention situational things like bad jobs or relationships. It might be good to mention that long stretches of elevated stress can produce depression as a result, and that stress-reduction may be an important part of treating depression for some people.

* Women and hormones. I had two cases just this week of women who were on different forms of hormonal birth control who upon discontinuing (or changing) saw all their depressive symptoms resolve after years of suffering needlessly -- these stories are widespread. Hormones mediate mood for women a great deal. I know for men as well, though differently. Worth a shout-out somewhere. You could include where you mention thyroid and anemia or separate para. Research I saw said HRT is more effective for depression in perimenopausal women than any kind of antidepressant -- and yet doctors are still not acting like that's the case. Women are perimenopausal for like a decade of their lives and are routinely put on SSRIs during that time for mood issues. And side note: I still meet psychiatrists who don't realize that you can treat PMDD by doing SSRIs for last part of cycle only.

* Lots of depressed people I've known/worked with were surprised how much their physical pain turned out to be part of their depression. Some mention of that might be helpful. You mention in passing re: Duloxetine, but might be good to say somewhere up top related to symptoms of depression itself.

* I know a number of psychiatrists and psychotherapists using psilocybin-assisted psychotherapy. Is it right to just say that psilocybin is illegal?

* I've recommended L-methylfolate to a ton of people and many people have reported benefit well below 7-15 mg. It seems a bit definite to me to recommend the max dose if you're going to be mentioning specific dosages in here at all. I encourage people to find min. effective dose in everything because people metabolize all these somewhat differently. You could cut part about MTHFR because people who don't know about it won't care and people who do won't gain anything from your mentioning it (I would edit out mention of more things like this in there, not central to what you need to convey). I agree it doesn't need to be factored in.

* Do you think it's worth mentioning neurofeedback? Defer to your research. Have seen some good results for depression (and trauma and anxiety and insomnia).

* Surprised you recommend Wellbutrin as the first-line since anxiety is so often also an issue and people may respond badly. OTOH, I like that you do because it's under-recommended. But then this raises for me why you want to lay out these specific regimens anyway -- if readers are going to be your patients, they're going to get your best judgment for their situation. If they're going somewhere else for a prescription, they're not going to get Wellbutrin because they read about it on your website. I think you could make the regimens more general and thus simpler.

* None of the regimens say "see a therapist." Which seems inconsistent after pointing out that combo meds AND therapy are the most effective.

* There seems to be some equivocation between 5-HTP and SAM-e and then you end up recommending 5-HTP mainly. Not sure the logic there. I've had equally mixed and good experience from people with both. 5-HTP game changer for some, totally ineffective for others, and made some people VERY anxious. SAM-e seems to produce less love/hate reactions in my experience. Don't see a reason to recommend one over another, but your experience may say different. All the supplements are a bit of a black hole unless you want to address in a separate article. The only one I feel like is a no-brainer for people to try is L-methylfolate.

* I guess I take issue with recommending behavioral activation above all other forms of psychotherapy. Many psychiatrists say to their patients, "if you're going to go see a therapist, at least make sure they do CBT." That one doesn't offend me quite as much as a narrow focus on behavioral activation. It's also going to be harder for people to find a therapist by saying "I want someone who will do behavioral activation." There's decent research that the outcomes for intensive short-term dynamic psychotherapy were more durable and just as effective as CBT. People with long-standing, recurring depression are going to need something more comprehensive than behavioral activation. In any case, I don't see a reason to single that modality out from the point of view of the person seeking therapy particularly when we don't know what's going on with that reader's particular depression.

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I'm surprised by the advice not to listen to "sad music" when depressed. Does the psychiatric community not view catharsis as legitimate or useful? When I'm down I'm going to be more in the mood for Leonard Cohen or the blues or Schoenberg. It seems to make me feel better. A sign that I'm really down is when I'm not in the mood for music at all. That's more like staying in the dark bedroom. Good, "sad" music seems to work a lot like hearing a good cynical joke. Perhaps it's a "misery loves company" effect. Music that fits your mood can be good company.

Or perhaps it is analogous to what you say about exercise: perhaps it would be better to listen to more energetic, "happy" music if you can stand it, but that's more like a vigorous workout, whereas listening to "sad" music can be more like a walk that at least gets you outside.

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Disclaimer: Pro: I'm a Psychiatry resident. Con: I'm a psychiatry Resident

I feel this guide (and modern psychiatry for that matter) does a major disservice by grouping all of depression into 1 category. In the beginning, you mention it has biological, psychological, and social causes... but you don't mention that there's biological depression, psychological depression, etc... and that these are completely different entities with completely different treatment modalities. I think you can still leave everything grouped, but consider giving more credence in the beginning to the fact that a 50-year-old man with catatonic depression has a categorically different disease from the "really depressed" 16-year-old girl who "just can't" while sipping on her mocha latte.

Also... I would consider removing from "The short version" recommending reading David Burns' book (or any book for that matter, especially one you haven't read). I personally think it severely minimizes how complicated the psychological cause is for psychiatry. I'm one of those weirdos who likes psychoanalytics, and think Depressive personality disorder should be more widely recognized. The thought of someone with a personality disorder reading a book with the intention of fixing their "psychological depression" makes me hurt inside.

There's a now-defunct blog, The Fugitive Psychiatrist. He wrote a long post on anti-depressants and it's essentially a guide to depression. I think he did a really sublime job, I would consider checking it out: https://web.archive.org/web/20190803223834/https://fugitivepsychiatrist.com/antidepressant-guide/

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In section 2.1, you might consider that "getting away from the depressing thing" is only useful advice if a person is depressed by outside circumstances. (Or has the financial wherewithal to change their current work/life situation.) People suffering from depression brought on by internal things like PTSD, body dysmorphia, or internalized self-worth issues are more likely to see themselves as the problem. And if you are the problem then the fastest, most effective, and permanent route to "get away" is suicide.

Obviously, that's not what you're suggesting, but it is the worst possible way that section could be read. And your target audience is primed to read things in the worst possible way.

This is a good rough draft, but the people you want to help are going to have a lot of heavy triggers and you should consider having someone read it through for those.

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With apologies, an objection on your diet advice:

As an anxious person who cooks a lot, I have always found injunctions against "processed food" deeply panic-inducing because I have no idea which of the things I do in my kitchen are "processing" and the underlying studies tend to be based on unhelpful or weirdly demanding (eg, Siga says that flour is an "unprocessed" food, baked bread is "processed", and sliced bread is "ultraprocessed"; who knew my hands and knife were so powerful!) or inconsistent (NOVA says "extrusion" is ultraprocessing, but pasta "unprocessed" despite being made by extrusion?) and seem to assume that nobody ever prepares their own food.

And that's without even starting on fermentation.

So if you are going to ask an anxious person to avoid processed food, please do them the service of telling them what "processing" is in the context that you intend, or check that the studies you are relying on use the same definition of process and of UPF. There is after all no need to drive us any crazier than we already are.

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I would not mention ECT in the first paragraph. It makes the topic seem scary, and ECT is rarely used anyways.

I think one of the main contributors to depression that is possible to solve but hard to solve, is an unhealthy living situation. Living with an abusive household member, working a dead-end job or a job you hate, living in an expensive area with no hope of upward mobility, living in a gloomy place if you have SAD. All of these contributors have a solution, but the solution requires a big change in the patient's life. Often treating the symptoms is all that can be done, but sometimes the cure is removing the big problem in your life. These solutions are more social work than psychiatry. Even if you are not equipped to help apply them you could assemble a roster of helpful resources for your patients.

Maybe your patient profile is more in line with the person who has a great life yet thinks they are a failure because of a biological condition. But many people are depressed because they have bad life situations. It would be a great thing to help even a few.

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>On the cognitive level, depression is a global prior on negative stimuli.

Unless your entire patient body is Bayesian thinkers, I would recommend finding a different way to state this.

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> Most studies that found supplementation helped got effects only from very high doses (around 2 g daily), more than you could realistically get from capsules – so if you are supplementing for this purpose you should consider liquid oil.

I have 2000mg fish oil capsules right here (though admittedly they are quite big). Looking at the ingredients just now, I see, however, that it's only 700mg Omega-3 fatty acids and the rest is, I guess, other kinds of oils, so maybe I should buy other capsules.

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I loved this article and very much wish it had existed when I was a depressed 19 year old so I could have read it then (I'm 34).

I don't have a critique of what is written, but I think there's a very very very important section you need to add. You talk in 2.6 (and mention earlier) that before treating depression one needs to figure out if he is bipolar, or if the depression is caused by insomnia, etc. This is all great and true, but would be VERY USEFUL which is not provided here or by any other depression resource I've seen is ***how to tell if you're depressed or ___________***. A thing that could go a long way here is some simple scripts for how to talk to a healthcare provider about these distinctions, in a way that is useful to the clinician.

When I've struggled with depression, one of my biggest hurdles has often been wondering, "am I actually depressed, or am I just an under-achieving fuckup who is looking for an excuse to rationalize my under-achieving?" Similarly, I have read lots and lots of things and am still not really sure if I'm just depressed or have anxiety or am bipolar or a regular insomniac or have circadian rhythm disorder or ADHD (I think ADHD needs to be brought up at SOME point in this post because the ADHD --> overwhelmed --> failure --> depression pipeline is common, but also lots of ppl think they have ADHD and don't).

For a personal example: in Jan/feb 2020 I couldn't sleep at all, sometimes staying up 60 hours in a row, in hindsight I was definitely hypomanic, but that is the only time I can remember being any degree of manic. Am I bipolar? Or did I just have a million stressors (new job/new city/breakup/chronic back and stomach pain that was aggravated by the stress) and how should I know? What's the most productive way to talk to a clinician about it, because even though it's totally irrational, I'm convinced a doctor won't believe I have real problems because objectively I shouldn't so I must be faking?

Even within the classic symptoms if depression list it's like:

1a/b) is my low mood because of depression or because fucking Donald Trump is president and everyone seems to be in a low mood? Am I anhedonic or is there just nothing to feel good about, like objectively?

2) I have always had trouble getting to sleep, but I don't think I've always been depressed? Am I "depressed" because I'm not sleeping extra badly right now because of a constellation of outside forces or because I actually suffer from depression? How would I know?

3) loss of interest in activities: well I've never really been one for hobbies, and my interest in video games/reading books/watching tv/scrolling Twitter has always waxed and waned. Am I losing interest in activities, or have I just not found the right game/book/show/etc

4) Guilt: how do I know when I'm feeling a correct amount of guilt vs a depression amount? I try to be a decent person, but there are times I have treated people I care about poorly that I'm right to feel guilty about, how do I know if it's a symptom of depression or a functional moral compass? Everybody gets random memories of times they were embarrassed as youngsters and we talk about that as a cultural phenomenon, but other people get that about guilt, right? It's not just me, right?

5) lack of energy: is it because I've been having trouble sleeping or because of depression? Is it because I'm in my 30's now and I just have less energy, it l or depression? Is it because my job is demanding or is it depression? You know? Am I just whining about things everyone feels, or am I uniquely tired in an important way?

6) Concentration problems. So this is a personal one for me. I was a classic, "gets almost all A's, 99th percentile on every standardized test I ever took, never does homework or studies, was fine graduating 9th in his class instead of first" type of under-achiever (I also went to a very poor public high school). I always wondered if I had ADHD because my best friend did, and it seemed like our brains worked the same, and when I'd read things by ADHD people about their disorder it felt familiar, and in college I used buddies in a frat to get black market adderall and I studied much better on that. BUT: maybe school is just boring and everyone functions better on stimulants? And I worried my doctor(s) would think I was just bullshitting to get access to Adderall if I brought it up.

7) appetite problems: so many things affect appetite, it feels hard to pin it to any particular source

8) <skipping>

9) suicidal thoughts: every millennial I know "jokes" about wanting to die, when I think that is it a sign of depression or just how my generation articulates stress?

Anyway, this comment has gone on long enough, I hope you find something useful in it

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Overall this is excellent & I expect it will help me try to get treatment for my depression. Several comments:

⋅ I found a meta-analysis of controlled trials of therapies for self-control/self-motivation/mental 'energy' in particular at http://www.devcogneuro.com/Publications/J_of_DevCogNeuro_paper_in_press_2016.pdf , which concluded that there was little evidence that physical exercise by itself improved these & that improvements reported from some forms of exercise such as sports & martial arts were probably due to the mental component of the activities. Does this mean that exercise mainly helps with other aspects of depression than this, or that additional evidence that that study didn't consider contradicts its conclusions, or are they just studying something different?

⋅ In https://slatestarcodex.com/2014/06/16/things-that-sometimes-help-if-youre-depressed/ you recommended modafinil to treat some of the symptoms of depression, & based on what you've written here, if it works, I would expect it to improve self-confidence like behavioral activation does. However, I see that you have omitted it from this. Do you still think it is likely to help?

⋅ I agree with the other comments here that "Realistically, most people know if they’re depressed or not" is not always true. My depression began with anhedonia & problems with concentration & motivation, so I interpreted it as akrasia, followed by sadness about the effects of akrasia, rather than as a mental illness.

⋅ I also agree with the other comments saying that your paragraph on the dynamic system model of depression is too technical to be understood by most people. (I didn't fully understand it despite having read & understood your article explaining the idea several months ago.) The point it makes is important, but I think it would be better to explain it in a less technical way.

⋅ Regarding style: Your article is occasionally less formal than I would expect of this sort of article (e.g. "wearing rose-colored glasses and being a moron", "because the researchers were cowards"), but I'm not sure that's a bad thing: probably it makes the article more engaging to readers. Your clearly disclaimed descriptions of your personal expectations ("Secretly I suspect Zembrin probably works better than 5-HTP or St. John’s Wort, but there’s not enough evidence for me to recommend it", "I am positively predisposed to this substance because my girlfriend has used it successfully") may or may not be appropriate depending on how you intend to use this article: if it is meant primarily for your patients or prospective patients, these things are probably helpful in indicating your opinions/preferences to them, but if it's meant primarily for people looking for information on the internet, I'm not sure that they add much.

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What if I suspect my depression is caused by an unshakeable belief that the world is shit and is almost certainly getting shitter?

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For stuff like fish oil and L-methylfolate, could a person just eat foods (like fish and leafy greens) instead of supplementing? Or would you not get high enough levels of folic acid from eating a bunch of peanuts and spinach?

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This is undoubtedly amongst the best and most useful things I’ve ever read. I’m just grateful that such an amazing and helpful write up even exists. I’ll be forwarding this to a lot of my friends.

Also n=1 evidence: the claim about the Mediterranean diet is probably true. I’ve increased my consumption of fruits and vegetables, and I think it has helped my mental health a lot.

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I'm a guy in his late 20s, and many of my friends have some kind of diagnosed mental illness, and maybe this is just a factor of my artsy fartsy social cohort, but they all went through a mid-20s period of That Time My Depression Collided With Financial Self-Sufficiency And Access To Self-Regulated Cannabis and/or Alcohol. And for some people this was easier, and for some it morphed into a serious dependency or a stint in rehab, and two people killed themselves over issues that the weed or booze probably exacerbated. So, maybe to include a small section on substance abuse - specifically the most garden variety options - is unnecessary, or assumes bad faith, but this has proven so common a battle among depressed/anxious people I know, that I figured I'd be remiss in not mentioning it.

I'm probably bipolar, but for a long time I thought it was depression, and the best description I ever heard of depression was: You have a machine inside your brain that ascribes meaning to things - it renders jokes funny and sunsets beautiful and experiences good or bad - and that meaning machine is broken. The important thing is that your brain starts to miss when certain things meant "hope" or "pleasure," and to have all of those experiences that mean nothing of course becomes exhausting, but that's separate from the "lots of sadness" description I frequently see. Thanks for writing this - I think it'll help people.

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I second the comments elsethread saying that 1. this is fantastic...for Codex readers, but 2. some of the nerdier bits are likely to switch off the general public. Dumbing things down does suck, though, so...I don't know. Presumably maintaining separate pages for nerds and not-nerds is out of the question.

> Many psychiatrists refuse to prescribe this medication because they are cowards, and I don’t have a good solution to this.

I chuckled at this, but it did make me think of a (seemingly?) parallel line from the amphetamines post:

> If none of these work, a braver person than I am might try Desoxyn.

Of course, you didn't exclude yourself, so no foul.

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I don't understand how anhedonia differs from loss of interest in activities. I know that's not a list you made up, but perhaps your summary could be revised to make the distinction clearer.

Beyond that, I've always been interested in ECT as a one-stop solution, but I understood it was seldom practiced. Is it more common than I thought? Does insurance usually cover it? How expensive can I expect it to be?

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I've spent a fair bit of my early life managing and trying to dissect the cause of my MDD/GAD, so I hope this might be useful to others. Apologies in advance if this is a bit haphazard, I've accumulated various niknaks of knowledge from my own experience and others, and don't think it could all fit in a comment.

(Quick fyi: I think your page is already very comprehensive as it is)

I'll first start with things that I think might be worth adding to your page, and then discuss what has personally benefited me the most:

- There appears to be a fairly robust link between depression and inflammation, which I'm sure you're aware of but you may want to mention. A lot of the therapeutic or preventative treatments have an anti-inflammatory effect, including SSRIs (and fish oil, and exercise).

+ There's a compelling narrative that one can draw around evolutionarily advantageous genes related to infection protection and those that are implicated in depression. (This is the most comprehensive discussion I've seen on this line of research and would recommend watching it if you haven't: https://www.youtube.com/watch?v=6DtJGJWjDys).

+ Dr Raison discusses sauna as a promising method with an anti-depressant effect, and various studies which show therapeutic effect.

+ Exercise induces an acute inflammatory response, which is then followed by an even more potent anti-inflammatory response, just from felt experience I think this is a likely mechanism.

- Studies on psilocybin have been overwhelmingly positive but primarily focussed on terminally ill patients until recently. Cathart-Harris et al's recent RCT of pscilocybin vs escitalopram on people with ordinary (I believe unipolar) depression have been very encouraging, and in particular on their secondary outcomes. I would check that out if you haven't already.

+ I also think there is a very compelling narrative that can be drawn around how this fits with predictive processing and the self. (I speculate about this here: https://umais.me/writing/the-anatomy-of-wellbeing/, also links to Cathart-Harris's REBUS paper on the differential effects of psychedelics on different layers in the heirarchy)

Now, for my own personal anecdotal experience:

- Anecdotally, (mindfulness) meditation can worsen neuroticism, or self-referential thinking if you're already in the midst of a depressive episode. I recall Jon-Kabatt Zin (founder of mindfulness based CBT) mention something similar in his book Full Catastrophe Living. (there are some reasons why I think this is the case).

+ However, not all meditation is the same in my experience. Metta (loving-kindness/compassion) is a type of meditation that I believe _can_ be hugely beneficial in the midst of an episode or during anhedonia. Neurotic and self-referential thinking is a major driver for most depression, and by explicitly focussing on the happiness of others you relax this tendency. I really can not recommend it enough.

- Historically whenever I've tried using fish oil during an episode it has worsened my mood. I've tried this a couple times and was always a little confused given that I expected a placebo effect at the very least. I've read some stuff that suggests it could be oxidation of the fish oil but I was never too convinced. The Raison interview elucidates a possible mechanism that could be the reason why, at one point he mentions the apparent contradictory effect of an anti-inflammatory given _after_ inducing a depressive episode vs as a preventative before. With the former reducing cognitive symptoms but not the latter. Perhaps fish oil works as a preventative treatment, but worsens mood when experiencing the inflammation of an acute depressive episode?

There's a lot more I want to say on the topic, but it's 2am here and in the interest of sleep I'll end by just listing interventions along with my own totally arbitrary effect sizes ratings out of 10:

medication (8), exercise (7), sleep (7), compassion meditation (6.75), diet (5)

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Great recommendation for the methylfolate. I’ve heard really good things about Jarrow. If you are on a lower budget there is a Winco brand and lots of others. But the effectiveness at the dose varies directly with price (at least for my kid.) To get the same effect at half the price it was about twice the dose. So we would roll along at an affordable “okay.” As he grew he needed more to get the same effect. When he was finishing a jar every three days we tried a degreed psychiatrist, but there were weird side effects for some things including the SSRI so we stopped. Then in desperation I located some T3 thyroid and it did help. Now I just buy the bovine thyroid supplements which taste awful but help.

I used 5-HTP for a few months and it helped some although I now see I was not taking enough.

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How about ibuprofen? Or prednisone?

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Just want to put out a strong plug for Emsam: a patch version of an MAOI. It packs a bit less punch than the pills but still has quite good effects in a number of people, and crucially doesn't have significant amounts of the side effects that pill-based MAOIs have: there are effectively no documents cases of actual serious reactions from cheese/soy sauce/etc.

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In section 2.6, regimen 3a and 3b, you recommend reading "feeling great" and doing all of its exercises, but in section 2.2.2 you recommended "feeling good" and noted that you weren't familiar with the contents of "feeling great". Probably you mean to recommend the same text both times?

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"Less-well-studed "


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Separate comment on the lorienpsych site rather than the post: Your category pages (e.g. https://lorienpsych.com/category/conditions/) have a *lot* of wasted vertical space, so much so that it's not immediately obvious I'm looking at a list; on load I can only see a single item. Some of the culprits I found in CSS: a fixed height:500px assigned to .blog-card-inner; excessive fixed margin/padding on multiple items under .blog-card-group; absolute positioning on .blog-card-inner-inner (indirect issue, breaks when the height is corrected).

The general design of the category pages suggest they were built from a template intended for an image-centric blog frontpage, not a page index. It is probably better to fix that by using a more appropriate template than by hand-hacking the CSS.

(On the other hand, +9001 points for putting your nav bar on the side when the view is wide enough, and for *not* making the narrow-view top-bar obnoxiously sticky. It's nice to know that some web designer somewhere declines to commit that particular atrocity.)

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I'm just grateful to be alive at a time when we get two amazing posts on consecutive days

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Thanks for this! I enjoyed reading it, and as a family doctor will consider suggesting this read to (at least the more intellectually inclined of) my patients going through depression. Just a couple of suggestions - I haven't read all the comments so others might have mentioned already:

1. At least where I am in Canada, psychiatry access is sub-optimal and the number of patients who would probably benefit from seeing a psychiatrist is smaller than the number who can see a psychiatrist. We do a lot of primary care mental health. When I read, "If you’re not sure if you’re bipolar, talk to a psychiatrist about it before trying anything on this page," I thought, wait a second... as a family doctor I think I am generally fairly capable of screening for mania/hypomania, and if a patient who I am convinced does not have bipolar believes that they do (this is a non-negligible number of patients) and insists on talking to a psychiatrist before starting anything I recommend... the delay could extend their illness significantly. Maybe this is context dependent, but I would consider changing this to "discuss this with your doctor before trying anything on this page."

2. Is there a reason you don't go into specific light therapy recommendations for SAD? Obviously there's lots you could cover and don't need to, but I think the minutes/lux etc might be useful enough for people to know, to justify including.

3. It might be worth at least mentioning as a side comment that there are some potential downsides to psilocybin? Here they sound totally uncomplicatedly good aside from being illegal.

4. Just a thought in response to the comments about education level - I think it's fair and helpful for you to target a higher education/reading level than the average person, because there is already a reasonable amount of (admittedly, less comprehensive) reading material about depression available at a lower level to the average person. I personally find the part about attractor states to have the lowest helpfulness-to-complexity ratio so if you were going to get rid of one complex idea, I would vote for this one.

Thanks again.

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So I'm not entirely sure what you're going for or who your patients are, but as a person who has been depressed in the past: I would not get through this. I would judge I am not currently depressed at the moment and I still gave up in the nutrition area.

For me when I am depressed, this would be both (a) way too much info, and (b) way too much hedging/inconclusive statements. Also, I don't know how educated your patients tend to be, but I would also judge this as written too highly for many--it assumes a lot of base info that I don't think is common knowledge.

I find concentration very, very difficult to maintain when depressed. While it may be useful/worthwhile to have the more in-depth info somewhere, it can't be the main page. Tell me what you want me to try. That's really all the info I can process. The links are good. I would prioritize having clear, precise, easy-to-follow directions for each point.

In more general terms: I have always found "additive" solutions more useful than "subtractive" solutions. Don't underestimate the positive emotional effects of "junk" food or other vices. Changing your entire diet might work, but I'm not going to do it and neither is anyone else I've ever known with depression (unless someone volunteers to be our cook). Start small: just add some carrots or something to the dinner you were already going to have. Don't join a gym, just watch some youtube aerobics videos, or take a walk around the block. The larger the ask (and remember, to a depressed person, things like "take a shower" can be monumentally massive asks) the less likely a depressed person is going to actually complete it.

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This is excellent. This is the most informative post on a medical subject I have ever read.

A question on your suggested regimens: The only cases in which you recommend the L-methylfolate is when the person is also taking escitalopram. You recommend 5-HTP as a stand alone supplement, or L-methylfolate plus escitalopram, but you never recommend L-methylfolate as a stand alone supplement, or ever recommend taking both L-methylfolate and 5-HTP together. Is there a reason for avoiding taking both L-methylfolate and 5-HTP? Is there a reason to not take L-methylfolate as a stand alone if you can’t get escitalopram?

In the comments, a lot of people panned the ‘depression is an attractor state’ paragraph. FWIW, I found it extremely helpful— it really clarified the entire discussion for me.

A few minor suggestions

— typo ‘Less-well-studed’ should be ‘Less-well-studied’

— I’d suggest capitalizing the ‘L’ in ‘l-methylfolate’, to reduce confusion. People who have already heard of it no doubt pattern match the ‘l’ in ‘l-methylfolate’ to the letter ‘L’, but first I thought it was the number ‘one’, and then I thought it was the letter ‘I’.

—another useful item would be a list of foods high in L-methylfolate. You say it is ‘common in various vegetables’, but it would be helpful to know how much of what I would have to eat everyday to get the equivalent of the 15 mg supplement.

— word order ‘I still cannot recommend it enough’ should be ‘still, I cannot recommend it enough’

—I would highly recommend moving the link to the page on light therapy up to the first or second time you mention it, rather than all the way down in section 2.5.

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Tons of people ITT: "I enjoyed it, but who's your audience?"


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> “On the mathematical level, depression is an attractor state in a dynamical system. It looks like that dynamical system takes both life events and biochemical factors as inputs, and based on the different weights of the edges of the graph in different people (probably at least partly genetically determined), either or both of those can shift it into the new depressed attractor state.”

For content like that, consider using sidebars that more technical readers can peruse but ordinary readers can skip over without affecting flow or comprehension.

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These are mostly typos, and I'm not bothering to dedupe with other people, sorry.

The "attractor state in a dynamical system" paragraph could use a context/definition link. I know what you're talking about, but only from having read SSC/ACX.

"In a study in India" link spans too much text, and there is an extra comma at the beginning of the currently-linked text.

Add a period after "algae-derived version".

"Again, the most important answer" at the beginning of the exercise section doesn't seem quite parallel enough with the diet section to merit "again".

"If you have zero willpower, not enough enough to be the seed for a tiny investment, then you should start with medication and only pursue willpower-requiring strategies if the medication give you that first little seed of willpower": "enough" is duplicated, and "medication give" doesn't agree.

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I was hoping you'd say something about modafinil? There were a few interesting papers some years ago about them as therapies (particularly for atypical depression IIRC). My understanding from someone who tried to use it was that all normie psychiatrists laughed him out of the room asking for a script though. Do you have a strong opinion on it?

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Consider adding untreated Celiac Disease as one of the diseases that can cause depression. I had no idea I had Celiac until I did a bunch of blood work trying to figure out why I might be depressed earlier this year. Turns out a gluten-free diet was basically all I needed!

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I'm a mathematician, but I don't know what "attractor state in a dynamical system" means. I second others here: just scrap the "dynamical system" explanation, or rewrite it in layman terms.

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This may be an edge case outside the scope of this article, or it may be helpful. I'm not sure, so I'm sharing.

I'm autistic (diagnosed with Asperger's back when it was still in the DSM), and have at various points also been diagnosed with MDD and GAD. If 1 out of ~50-80 people are autistic (estimates vary), and a substantial percentage of autistic people also experience depression (estimates of percentages vary), and something like 80% of autistic people don't have full time employment (which in the US is a prerequisite for most health insurance that isn't terrible)... I think we're a demographic worth considering, especially because a lot of the lifestyle-type changes don't work for us and we are more likely to have unusual side effects from medications (probably because of our neurological differences from allistic people).

For example, it's common advice (which you rightfully repeat) for depressed people to continue seeing friends, doing enjoyable activities, getting sunlight, etc. But for autistic people (or people with other disorders of sensory processing), these things can be overstimulating and make low mood (and its close friends, autistic meltdowns and shutdowns) worse.

Similarly, it can be helpful to take medications but (anecdotally) we seem to be more likely than allistic folks to get weird side effects to psychoactive substances. Do we just... Give up sooner on meds? Try more meds and suffer through the weird side effects until we find something that works well enough (which is what I did)? I genuinely am not sure.

Maybe the obvious advice is just "don't do things that make you feel worse." But it took me a long time to realize that forcing myself to do those supposedly-helpful things wasn't helping, and that it wasn't helping because I'm autistic. And I kept trying to do those things for a long time, because I take directions too literally sometimes, because I am autistic.

Unfortunately I'm not aware of research to back up these observations; most of it comes from interacting with the autistic community and reading a boatload of essay anthologies and memoirs of autistic people.

Certain gendered language could also be rephrased to be more inclusive. E.g. "people who get heavy menstrual periods" instead of "women who get heavy periods."

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First several grammatical things, like in this paragraph:

“On the neurological level, one line of research suggests depression involves neurons forming fewer synapses, especially in the hippocampus region of the brain. *Remember*, neurons are the type of brain cells which carry thoughts and information;”

I don’t think ‘Remember’ is necessary, you introduce neurons in the previous sentence after all. Broadly it might make sense to move most of this section to a special technical area, and just leave more vague gestures towards the neurologic, biochemical and so on. I like it but worry it might be intimidating. For formatting I like the way some sites will have embedded footnotes w/in the text but don’t know if you want to get into that.

“Along with the neurological, biochemical, and cognitive levels mentioned above, there’s a fourth level on which you can try to understand depression – a mathematical level. On the mathematical level, depression is an attractor state in a dynamical system. It looks like that dynamical system takes both life events and biochemical factors as inputs, and based on the different weights of the edges of the graph in different people (probably at least partly genetically determined), either or both of those can shift it into the new depressed attractor state.”

This is difficult to visualize, I would add the 3D graph of local minima you’ve used before, maybe with an arrow to the negative point and a label “YOU ARE HERE”

“ (ie develop a negative prior on baseball skill).” Should be ‘i.e., develop a negative etc’

“ But another part of it is that knowing things isn’t enough. I know that if *I lifted weights* every day I could become very strong, I even know some more complicated body-building advice, but the advice itself is nothing” This sounds weird, suggest ‘if I were to lift weights’ or just ‘if I lift weights’.

“Either one when used for too long increases your risk of metabolic problems (eg diabetes) and various terrible movement disorders (eg you can’t stop smacking your lips, and this problem never goes away).” Twice in this one sentence it should be ‘e.g.,’ which means you overlooked four dots and two commas, that’s a lot of missing punctuation sir.

“ For one thing, you’re unconscious and don’t feel it. For another, you’re on what’s called a “neuromuscular blocking agent” which means you’re not really going to convulse (ie won’t flail your arms and legs around).” Here’s another should be ‘i.e.,’

“If your depression returns quickly again in a way that seems correlated with stopping the medication, stay on the medication indefinitely or until something important changes (eg you quit a terrible job that was making you depressed).” Probably should just find / replace the eg to e.g., at this point but I’m committed now.

Overall I think this is a really good and important article and I’m glad I read it and can hopefully make it slightly better. One other suggestion for an option if ECT hasn’t worked: neurosurgically implanted deep brain stimulators, if you’re not a coward that is. https://www.sciencedirect.com/science/article/pii/S089662730500156X

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Can you write one of these about anxiety? Also, I am wondering why you don't mention the older SSRIs.

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I think you are being a coward for putting ketamine so low, and it is not difficult to get. 63 year old psychiatrist here, longtime private practice. I am a very skeptical, rational empiricist kind of guy, but I must say I think the word "miraculous" applies to many of my depressed patients responses to ketamine. Initially I was sending them for expensive IV infusions or IM injections, but I have been using nasal spray racemic ketamine made at compounding pharmacies for about a year now-- it's inexpensive, and dosed properly has minimal side-effects, principally dizziness or imbalance for a brief period after a dose, which diminishes over time. At 100 mg/ml, and with each spray .1 ml, most of my patients end up somewhere in the one-spray-each-nostril, one to three times a day range. I've had some non-responders of course, but lots of patients say no previous med has worked as well.

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The discussion of treatments generally includes evidence from trials, but the section on ECT has only anecdotal evidence. An article on Aeon by John Read, a professor of clinical psychology, claims that trials of ECT show very limited evidence of benefits and that there can be serious and permanent side-effects.: https://aeon.co/essays/why-is-electroshock-therapy-still-a-mainstay-of-psychiatry

Is he right, or is there evidence of clear benefits from trials of ECT?

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I dont have much to add, but just reading this helps me think about it in new ways. It feels like treatment. This feels cheesy, but thank you.

I will say that sad music usually feels very validating to me, at times when no one else acknowledges that i have a reason to be sad.

I am also afraid of ECT because ive heard stories about what it was like in the 50s, and am skeptical that it has really changed that much.

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"Doctor, my friend is depressed. What do you recommend?"

Cliche aside, this is actually true. This article is patient is oriented at what a patient or treatment can do, not what to do if someone you care about may be depressed.

I am not depressed but people I care about are. Is there anything I can, or should or shouldn't do? For example I keep inviting a depressed friend to social gatherings with a friend group (while those were still a thing prior to covid). He very often cancels at the last moment, and I tell him it's not a problem. I'm pretty sure he does enjoy it a lot when he does make it. But he knows he's getting a reputation, and is always profusely apologizing afterwards. Is this a beneficial thing to do on my part? I've asked and he says he appreciates that I keep doing that, so I suppose in our case it's fine, but I don't really know any general recommendations.

So perhaps it's worth adding a paragraph titled "My friend is depressed".

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Maybe I'm just unaware of the level of acceptance predictive processing has, but to me, the part on priors, etc., seemed more speculative than a lot of the rest of the post. (I know you like this stuff, but is it really known?)

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I know someone who thought he might have depression when his actual problem was an undiagnosed auto-immune disease, due to which he was in pain. (The doctor said: "We prescribe an anti-depressant. If it works, we say it's atypical depression.") As soon as the auto-immune disease was properly controlled, he no longer felt depressed.

Maybe it's worth mentioning that what some depressed people with non-psychiatric issues need is treatment for their non-psychiatric problem.

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Hi! I'm a 19-year-old college student, and a lot of your regular readers seem more eloquent than I usually am. So excuse me if these comments are all over the place.

As someone who’s already a fan of your work and writing style and has suffered from major depression in the past (with occasional short relapses every few years), I liked this a lot. I can think of a lot of nerdy friends of mine who might find this helpful as a calm, empowering “go-to” about depression. (Sorry if the whole “nerds will really like your writing” comment is getting old. I would recommend this as a comprehensive guide to anyone because I can’t think of much else like it, but it does seem *mildly* inaccessible to people who are looking for immediate things to do rather than general information backed by studies.) In particular a lot of the comments are asking you add more detailed potential treatments - they might work if it’s been shown to help a majority of people, but I think the “cliche” treatments (life circumstances, therapy, medication, hotlines, diet and exercise) are still the most effective places to start 99% of the time.

I also loved the mentions of comorbidity with physical diseases and with other potential disorders. I thought that was handled really well, particularly in terms of what to look for in treatment.

I like that many of the suggestions are relatively achievable by oneself and don’t necessarily require professional help (though come to think of it, it might actually be useful to state the benefits of professional psychotherapy and medication a bit more, because I know very few people who have managed to single-handedly dig their way out of depression without any outside assistance, except for those where it was mostly based on one terrible life circumstance or something.)

One thought I had is that this might be less useful for people looking to support loved ones with depression - I can easily imagine an overenthusiastic family member reading this and bursting in with a bunch of ideas for potential treatment, which might not be the best place to start. The FAQ seems like a good length and well thought-out in terms of structure already, so maybe there could be a separate document for "supporting people with depression"?

Shorter notes:

-You recommend supplements for everything but creatine - could you add a reasonable creatine supplement?

-Seconding the person who wants treatment plan 3a/3b to be labeled as time/energy and doctor/no doctor.

-I feel like calling yourself a coward over ketamine is… I appreciate the straightforwardness, but I’m not sure it strikes the right tone.

-Why did the light therapy come after magnetic and ECT? I feel like since you mentioned light boxes before… I get that it makes the tone a little calmer though.

-Talking about anxiety and depression as having huge overlap then “make sure your depression isn’t caused by anxiety” in 2.6 is somewhat confusing.

-The instances in which you suggest something might work better but can’t in good conscience recommend it because of lack of evidence might give off mixed messages - desperate people might interpret it as “he’s secretly recommending the one with less evidence but is trying to be sneaky about it.”

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In part 1, I found the paragraph on the attractor state sticking out negatively. You explain most other difficult concepts in simple terms, but you expect your readers to know what you mean by an "attractor state in a dynamic system". Also, while I understand what you mean, I found this fourth description to be less helpful than the other three.

There are some abbreviation that you assume your readers to know. I guess they know OCD, but do they know PTSD and DSM? (Little confidence, non-native speaker here.)

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"On the other hand, if you really like going through checklists to figure out if you’re depressed, you can take the HAM-D, a very official depression test used in studies, and it will tell you exactly how depressed you are."

I think the HAM-D is a rating done by a psychiatrist (after some clinical interview), it's not a test that one can self-administer. So maybe consider rephrasing "take the HAM-D".

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Really interesting, but not a word about psychoanalysis in the types of therapies?

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Really enjoyed this; two thoughts I don't believe I've seen others bring up:

- The mentions of light therapy seemed a little scattered across the piece; it was a little jarring coming straight after the ECT section, and its inclusion there seemed more about providing humorous relief (a la 'arson, murder, and jaywalking' https://tvtropes.org/pmwiki/pmwiki.php/Main/ArsonMurderAndJaywalking) rather than because it fit well in that section.

- As others have mentioned the 'mathematical attractor' analogy is perhaps offputtingly-technical; an alternative analogy that captures the same broad sense could be an analogy of a surface with differently-sized holes (this is a gravity well analogy without introducing physics terminology), where some people's neurology/psychology/whatever is set up so that certain circumstances put their ball (current mental health state) near the 'depression' hole, and then it gets pulled further in; depression is one stable position of many/several. Interventions aim to bounce the ball outwards in the hope that it can find a different stable position.

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I hope you write the same guide for OCD

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(1) Everything following comes from an Irish context, therefore not universally applicable.

(2) I don't know if I have depression. I feel depressed, but at my initial (and only) assessment appointment for counselling, the counsellor said, quote, "That sounds like mood swings not depression" so I have no Official Diagnosis (my GP wouldn't even give me anti-depressants, again, quote, "We don't do prescriptions anymore" so I got shunted off to the "but now we do counselling!" route).

(3) Is there a difference between counselling and therapy? I feel like there is, but I don't know enough to say. Anyway, it was only counselling and not therapy on offer, if that makes a difference.

(4) I HATE, HATE, HATE, that in order to get help, you have to stick to acting out a script. I was ignorant of this, answered questions honestly, and as a result ended up with nothing. My own fault, I should have researched before I went in. Plus, ironically, having worked on the 'other side of the desk', I absolutely understand the requirement that "you have to sign this contract stating that you will indeed turn up for all the ten sessions of counselling", otherwise you don't get anything. I have been that public/civil service minion. I know what such schemes entail and why they have such conditions attached.

As a potential - patient? client? what is the proper term? - it felt very odd that executive dysfunction, which is a known symptom of depression, wasn't taken into account. On the very bad days, I can't even commit to getting out of bed. I can't commit to cooking a meal, even when there is food in the house and I am hungry and it will take 15 minutes tops. And you want me to sign a contract saying "yes indeedy-doo, I will definitely turn up every week on the hour bright-eyed and bushy-tailed for our session!", well like a fool, I said "I can't commit to that", so no counselling. (And I *understand* why! But it's still making me grit my teeth and scowl when the well-intentioned ads come on the radio about "help is out there!")

Help is out there *if you know the script and stick to it*.

(a) You cannot know anything about the problem. No, not even if it's something you're long-term living with. Doctors do not like it when you use medical terms; they feel like you're telling them how to do their jobs and that you're a hypochondriac who just looked up vague symptoms on the Internet and now think you have cancer. Dumb yourself down, you have to be the humble supplicant who is "oh doctor please help me, you are so wise and competent".

(b) Agree with everything (to an extent). Again, like a fool, I said "no" when asked if I was self-harming or had attempted suicide. Apparently just *thinking* about killing yourself doesn't count; unless you're self-harming or have attempted suicide, you are Not Really Depressed (Enough).

The trick here is to agree *just* enough to fit with the script, but not enough to trigger "well, better sign you into the ward for involuntary commitment". This is where the 'cry for help' attempt works best (e.g. take an overdose of something that won't actually kill you, call the ambulance, go to hospital to have stomach pumped/be kept in overnight for observation; get to see psychiatrist. Profit!). Unfortunately that won't work for me, as if I do ever get the courage to try suicide, I am not going to fuck around with 'cry for help'. I have a method that I know will work.

Anyway, next step!

(3) Agree with everything, part two. As I said above, even if you can't commit to washing your face tomorrow much less turning up every week, don't say that. Nod and smile and sign on the dotted line. Next week is a whole week away and who knows, you might even be able to turn up to the appointment on time, miracles do happen.

(4) Don't be honest. Even if when the counsellor trots out the watered-down quickie version of CBT which boils down to "think happy thoughts!", don't say anything except something along the lines of 'oh wow, I never thought of trying that". If you're like me and naturally sarcastic, bite your tongue. Sure, "think happy thoughts" won't work if your situation really *is* objectively shit, but you're not going to get anything better. It is now Gospel that CBT cures all, and if it doesn't work for you, the problem is you: you are Not Doing It Right. This is as good as you're going to get, so take it. Maybe it will help a bit.

(5) The main thing is, this is the script you have to act out to show that you are a Good and Deserving and Compliant Patient/Client. Otherwise, you get nothing plus you are tagged as a Bad and Non-Compliant Troublemaker.

I wish I had known all this *before* I went and failed to get the help that I am constantly assured is on offer, but there you go. Learn by my mistakes.

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For me, the most useful way of conceptualizing depression is to think of it as a self-sustaining cycle: depressive thoughts lead to negative emotionality, constantly feeling bad leads to bodily dysregulation, and bodily dysregulation and negative emotionality *produce* depressive thoughts.

When I was suicidally depressed, that last part was very hard to even imagine, because I used to feel like I "was" my thoughts. As in, whatever I considered to be my self, my consciousness, my will, whatever you want to call it - that it was entirely isolated and embodied in my inner voice. I was the one doing the thinking. Whenever a negative thought popped into my head, it had to have been "me" who thought it, and therefore "I" was now thinking about that depressing thing and ruminating on it and pursuing its every implication for hours and hours, over and over again in order to get to some kind of resolution, some lesson to be learned, some revelation that would improve things if I just thought about it hard enough.

I was those thoughts. It never felt like thoughts could be introduced into my consciousness against my own "will". I thought, therefore I was (depressed).

And when anti-depressants seemingly failed to do anything at all for me, I took that as further evidence that I wasn't really ill ; I had by then reasoned that my depression wasn't anything abnormal, but that it was a rational, reasonable reaction to both my own failures and the general state of *gestures vaguely at everything*. How could I not be depressed? It would have been abnormal *not* to be depressed. Not being depressed was suspect. If I were to stop being depressed, it had to be because my reasoning became faulty. I had to have somehow become a less rational person ; which is, of course, absolutely unacceptable. Therefore, my fate is to be depressed and miserable, for the entire rest of my life. And since this is also terrifying, I have no other option but to (rationally, reasonably) kill myself.

I suspect this is a trap that a lot of hyper-rationalizing introverts with a huge ego tend to fall into.

What ended up helping me in the end was not to find a better way to think about my problems, but to not entertain depressive thoughts at all. To stop trying to figure out a rational solution, and instead force myself to notice when I was thinking depressive things and then simply decide to think about something else. Doing that is, as it turns out, way harder than it sounds - things like mindfulness meditation do help you figure out which mental muscle you need to pull to make that happen - but for me, after years and years of following the same depressive thoughts to the same depressing conclusions over and over again, I had gotten so used to all of it that I barely even bothered thinking it through anymore. I just caught myself and went "yeah, I know how that goes" and simply gave up.

As it turns out, that's basically all it took. I had some fears that I was repressing my thoughts, whatever that means, and that it would somehow end up making everything ten times worse - but over the course of ~1-1.5 years, I spent less and less time thinking depressing things, and while nothing else changed in my life, I found myself physically less and less depressed, up to the point where I could just say "I'm happy" and "I want to live" out loud, and it didn't sound completely and utterly alien.

I still have leftovers from that broken mode of thinking - for example, my instinctive reading of 2.1, when you write "the most powerful treatment for depression is GETTING AWAY FROM THE DEPRESSIVE THING", is that it says I should kill myself (since I am the depressive thing, and there's nowhere for me to get away from myself). Even though I know of course that you never intended it to be read like that, I know past me would have read it like that and believed it.

It would have tremendously helped me back then if someone had suggested just trying to treat some of my thoughts as potentially adversarial and unwelcome - and given me the assurance that doing that wouldn't really turn me into a different person. I am still very much the same I was back then in many respects, my life situation isn't that different, and the world is still generally as disappointing and as exciting as it used to be. The difference is, I'm no longer depressed and no longer suicidal, I am much happier for it, and I could have been like that 8 years earlier if I had had those mental tools back then.

All that being said, it is only what worked for me. I have no idea how strongly it reflects the actual reality of depression for everyone else. I do think the model of the self-sustaining psychological/biological cycle is an extremely useful mental health tool, because once you see it that way, you can start tugging at multiple sides of the issue at once instead of treating them separately. It also goes a long way in explaining the wild differences in treatment effectiveness between individuals:

1) People who don't usually spend their time ruminating and rationalizing can still end up falling into the attractor state and be kept there from purely biochemical factors - but any effective antidepressant should also pull them right out ;

2) conversely, people who don't really have anything badly wrong with their neurochemistry outside of what's directly caused by the whole "ruminating depressive things 24/7" will probably find antidepressants ineffective, and CBT super effective.

3) In most cases, no matter which cause is predominant at the start, you still end up getting both the physical dysregulation and the negative thoughts. Once the cycle is started, either of them can and will keep fueling the depression engine - so this also accounts for why psychotherapy and medication work better together than alone.

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Maybe explain more about what an attractor state in a mathematical model is. Seems like fairly impenetrable jargon

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Great writeup overall. Some comments:

1. You avoid mentioning the term "dysthymia" (low-grade chronic depression) at all. I feel this is a very different beast than, say, a six-month major depressive episode, and lumping both under the label "depression" may be confusing. Dysthymia is both more subtle and probably more difficult to treat (in many cases, at least).

2. You mention "trauma" only in passing. I'm very interested in various trauma-oriented types of therapy (esp. somatic - Peter Levine's Somatic Experiencing, Bessel van der Kolk etc.) and IMHO this topic warrants more attention and space. It may be even more important than discussing meds. I suspect that _most_ cases of depression, esp. chronic (see item 1 above) are in this way or another related to past trauma, especially early trauma. When you write: "f you suspect that your depression is related to stress over a trauma you’re having trouble processing, I would recommend worrying about the depression only long enough to make sure you’re stable, and otherwise putting your effort into pursuing therapy for trauma.", it sounds like you're treating these two conditions as somewhat separate and independent, which I strongly believe not to be the case in a lot of situations.

3. Related to item 2, I emphatically DO NOT share the general enthusiasm about CBT-based therapies. I don't want to discard the evidence of scores of people who where helped by it. But for a certain type of people (myself included), CBT is one of the worst types of therapy available and can even be harmful. How so? In many people, a defense reaction against trauma (again, strongly correlated with depression, see 2) is some kind of dissociation, and in intellectual minded people this dissociation often takes the form of "locking oneself inside the head" (i.e. cutting oneself off from bodily sensations, emotions etc.). Mental/cognitive interventions only reinforce this pattern and keep the patient locked in their mind, despite treating emotional depression-related content on the object level (but, crucially, not on the process level!).

Much, much more can be said here, but I'll just try to highlight main points around this:

* Depression is often a surface symptom of sth else (e.g. past trauma) that requires deep transformational work to heal.

* It's impossible to do deep transformational work purely by intellectual/mechanistic means.

* As a culture, we like intellectual/mechanistic methods because: a) they have the semblance of being "scientific", so "predictable"; b) they allow us to disregard the body experience as something secondary (this is a very strong and old streak in Western culture in general, starting perhaps from Plato)

Therefore, we like CBT and tend to treat "less scientific" modalities with skepticism ("How do I know this is not some New Age bullshit? How do I know this is not placebo or anecdotal evidence?"). I don't necessarily advise doing "spiritual enrgetic DNA healing" as an antidote, and definitely there is a Pandora box of therapies that range from "not proven, but probably make sense" to "totally bogus". But consider the possibility that the scientific understanding of the body-mind relationship lags severely behind the empirical knowledge of practicioners. So "what can be proved in RCTs as of AD 2021" might not be the best indicator of what actually works, and it will take maybe 30 more years for science to catch up.

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The thyroid thing was key for me. Most of my adolescence and early adulthood I had periodic waves of anxiety and depression. I’ve had nothing like them since I started treating my thyroid. My advice on this would be to include that many common thyroid conditions are *cyclical*, so a single thyroid panel may not catch it. I had one high result on routine blood work, which is why my doctor suggested we keep an eye on it, but it took repeated tests over nearly two years to see a pattern for me.

I had no pronounced symptoms, nothing “bad enough” that I even considered seeing a doctor. So we caught it early. In retrospect things like my mild-to-moderate anxiety and depression, concentration issues and high cholesterol were probably connected to my thyroid problem, since all of those things basically disappeared once I started treating it. Not to mention that I hopefully avoided the further trashing of my endocrine system, the results of which can be damn depressing all on their own.

The medication I take has been around for decades and is very cheap- if some people can manage their depression by managing their thyroid, that’s a got to be one of the easiest and most affordable outcomes, so if more people got diagnosed early it would be a giant win. But you can’t rule it out after only one test!

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Re: 4.: My depression (or at least depression/anxiety-adjacent experience, having never been formally diagnosed) manifests itself as feeling bad -> procrastinating -> not honouring commitments and/or increasing stress due to approaching deadlines -> self loathing -> feeling bad -> … The single biggest thing that helped me was using Beeminder, which I am fairly certain I discovered as a result of your 2015 post about willpower.

It is far from a magic cure-all, but it was so instrumental in helping me finally end a self-destructive cycle of failure and shame (and thereby helped me be ready to see and seize other opportunities to improve my life) that I am not being hyperbolic when I say that I believe it saved my life.

My first two goals were to do one pomodoro a day of productive work, and to whittle down the size of my inbox by ten messages. I'm a little more ambitious now, obviously, but that was all it took to get started on turning my life around.

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I would have loved a citation or a link at the "drilling a hole into rat skulls and injecting BDNF cures their depression" mention, as well as one for how antidepressants treat good-reason-depression as well as random.

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The one thing I would try to mention very early on: "Different remedies work for different people. It's important not to give up because you tried one thing on this list and it didn't work. Any given intervention has a less than even chance of alleviating your depression, but your odds get very good if you try three or four different things."

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Why aren't biohackers playing around with TMS devices? I assume the main bottleneck is cost. A quick search suggests a TMS machine is in the $50k-200k range. But why is this? They're "just" a bunch of coils, and they seem easy and safe to operate. My best guess is that the coils need to be tiny and oriented carefully to give good spatial accuracy and precision, but even then $100k sounds like a lot. I'm quite confused.

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I've experienced depression once in my life, last year after lockdown+bad breakup. Treated with venlafaxine with no withdrawal symptom (but my doctor made me stop *very* slowly, over 3+ months). All your advice about exercise and getting out of the bad situation matches my experience. What I find incredibly helpful in your post, and would have loved to read back then, is the plurality of causes and the link with anxiety. I couldn't help asking myself: "am I just anxious and sad because of this break up? is that genuine depression? am I a fraud and just making this up to feel better about leaving my partner?" I have no clue whether the scientific part of the article is relevant, but I cannot stress enough how important are the parts removing guilt and second-guessing for the patient.

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Misc. feedback:

At one point you refer to ECT out of context. Many readers will not know/remember what you’re referring to from the acronym alone.

At another point you say people should not “try” drugs or therapy if they don’t think they’ll like it. It seems to me you should say they should not -continue- if they aren’t happy with it. (I have a relative who “doesn’t believe in” trying either one, with a predictable (lack of) results.)

I agree with other commenters that some parts are likely too technical or detailed. For instance, maybe the reader doesn’t benefit from knowing your ranked order for prescribing various drugs. As another example, the bit about attractor states doesn’t make sense without more context (context which I’ve read in your blog before), but I don’t think delving into attractor states is super helpful for the reader anyway.

The word “availabilities” is not one I’d ever use. Perhaps it’s common in your field but not in the world at large?

I found it odd that you said people might not want to do therapy because it’s boring or hard to get to...without mentioning perhaps the biggest issue, cost.

Typo: refri(d)gerator

Thanks for sharing!

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It would depend on the market you are going after. If you want to appeal to the median ACT reader then this may not be a problem. But I think for most of your potential clients this paragraph doesn't add much value. I'm more of a business/marketing person so that is the basis of my critique:

"Along with the neurological, biochemical, and cognitive levels mentioned above, there’s a fourth level on which you can try to understand depression – a mathematical level. On the mathematical level, depression is an attractor state in a dynamical system. It looks like that dynamical system takes both life events and biochemical factors as inputs, and based on the different weights of the edges of the graph in different people (probably at least partly genetically determined), either or both of those can shift it into the new depressed attractor state."

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"Realistically, most people know if they’re depressed or not and don’t need to go through a checklist to figure it out. "

I'm not sure about that. I think there might be some selection bias going on due to your being a psychiatrist. You only deal with people who are seeking treatment. It's very likely they know they are depressed. That's why they are meeting with you. It's the people who are depressed that you don't see that are going through life thinking how they feel is normal.

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Three comments:

1. I'm not sure if it's exactly on point here, but I'd like to thank you for your article about Zembrin about a month ago.

I'd been feeling depressed, but not enough to go see a therapist. Having trouble sleeping, not feeling motivated. I'd been trying to find a new job and was not successful. I guess technically I was/am feeling depressed but figured, 'this is just life and it sucks sometimes, there's nothing special that warrants help.'

After reading your nootropics article on Zembrin, I thought I'd give it a shot. I've noticed I'm sleeping better, dwell less often on negative things, and feel more motivated at work.

Even some OCD-like things I would do have stopped. For example, I often have the feeling when I leave the house that I need to go back and check that I closed the windows or that I locked the door. I would walk all the way down the driveway, get in the car, and then have to go back in to check, even though I knew it was irrational. I still sometimes get the nagging feeling, but I don't feel the compulsion. I'm able to say to myself, 'I know everything is fine' and I leave.

2. I was very interested in and surprised by the parts of this article that talk about the impact of making major changes. I had read (pop-sci type stuff) that people basically have a kind of homeostasis of happiness. Good or bad events can happen, but people usually revert to their individual mean happiness.

This always seemed like an argument against making major changes. Why make a change if you'll still just feel the same afterwards about the new thing. I know a person who is always changing jobs. They start off liking it, discover all the annoying things about it, decide they hate it, leave and then go through that cycle again at the next place.

I wonder if there is a way to discern which people will be helped by major changes and which people have more intrinsic problems.

3. Anecdotally, I have noticed that people do not know what will make them happy and should take a more empirical approach to the subject. I wonder whether there is any scientific basis for this or if it would be helpful for depression. I have made some major life decisions that I was initially reluctant to do on the reasoning of "other people have done this thing and seem very happy with their decision, so I should ignore my reservations and do it".

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On the Hamilton Depression Rating Scale, for the Hypochondriasis part of the assessment, they include in the scoring "Querulous attitude".

Ah, so *that's* where I'm going wrong! Thanks, this made me laugh 😀

Re: the bits about "ask your doctor for this medication" - this makes the American medical system sound very interesting to me. I tried asking a doctor (not my current GP) for a repeat prescription of anti-anxiety medication and got shot down with "no, it's habit-forming". The initial prescription had been for ten tablets to be taken as needed over a six-month period. After six months I had used all ten. No dice on any more because that means I'm an addict.

Do American doctors really go along with "of course, I'll write that up for you" if you go in and ask them for a particular medication at a particular strength? Is this because of your health insurance system, where the doctor is an employee (so to speak) and 'the customer is always right'?

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Thank you for the article, and thanks for mentioning that feedback about typos is welcome. I haven't found any but I'm never sure if I should mention them if I find any. I like that it's explicit here.

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Responding to your #6: I want to offer some general writing advice that I think will make this more accessible to your target audience without sacrificing the great information you've included.

1. As much as possible, limit the amount of new vocabulary a person has to learn just to understand a section. I know the point is to help your reader learn about new concepts, and you mostly do this very well. But in some places you're likely to lose people in ways that are avoidable. The routine use of words like heuristic, global, cluster, cognitions, algorithm, unipolar, allele, eosinophilic, receptors, etc will bog a lot of readers down. Many of these terms can easily be omitted or replaced.

2. Be very careful how you communicate uncertainty. Your blog readers are used to reading "I am very non-confident..." But most people feel insecure when someone in a position of authority talks like that. Alternative phrases include: "It is still unclear why", "The specifics of this topic are still being studied...", "There is some evidence that...", "Research is ongoing", you get the idea.

3. Be very careful how you talk about depressed people. I see the clinician showing through with sentences like "Depressed people are worse at simple sensory processing tasks..." The self-loathers will loath themselves more when they read that. You can easily re-phrase things compassionately, e.g. "Depressed people find it hard to..."

4. Avoid all-caps writing. Lots of people will read it as unprofessional. I think italics would work just fine.

5. Be sure to define your acronyms, even common ones like PTSD and DSM. I'm often surprised by the number of people who know nothing about PTSD. Plenty have never heard of the DSM. Perhaps you could embed some kind of pop-up definition?

Specific advice:

The short version: Do you want this to read like an abstract? You might take a different approach here and, instead of trying to list the things you cover in more detail later, just offer a few key takeaways that you want everyone who reads this article to see. I don't think you should list any medications in this section.

Simplify the "What is Depression" section. People will go straight for this section and they won't be prepared for what you've written. I think you could move a lot of the technical information to a subsection titled something along the lines of "How doctors understand depression" or "The science behind depression".

2.1.2: "But if you want secret/fancy things, the best evidence is... here". I'd rewrite the rest of this paragraph in simpler terms, eliminating the use of effect size (why introduce a new concept if you're going to talk around it?) and the discussion of good vs. bad placebo-controlled diet experiments. These sentences will confuse and derail the average reader. For someone interested in this stuff, you could include it in a more technical article.

"We still don't know much about nutrition... the researchers didn't check" is written in a fashion that will induce anxiety in anyone who is uncomfortable with uncertainty. I'd try out some alternative phrasing like "Research in nutrition is ongoing and will likely turn up new things in the future"

That said, I'm ok with how you express uncertainty regarding exercise in 2.1.3, therapies in 2.2, and supplements in 2.4 because those instances help you make your point.

2.2.1 Please include a therapy option for low-income people and those without insurance here. I don't know what the alternatives are in your area, but in mine (Southern Oregon), the low-income clinic offers really cheap therapy sessions where you're counseled by a therapist-in-training, and I know people who have benefited just from that.

2.3 If you don't have much advice to give about psilocybin, you probably shouldn't mention it until you do. I know too many people whose psychosis started with the casual decision to take mushrooms on a daily basis.

By and large, I think you've don a lot to make this piece accessible to a lot of people. Some of the most accessible sections were located later in the article. I think you could work to simplify some of the writing in the earlier sections, the sections people will likely read first, so your readers don't get discouraged early on. In general, I enjoyed it and I thank you for putting it together.

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Thank you, a very nice guide as usual!

> In a study in India, , 40% of vegetarian women vs. 7% of omnivorous women had moderate anemia, a common consequence of iron deficiency (anemia is much more common in women, but some men can get it too). Symptoms of anemia include looking pale, feeling easily exhausted, feeling an urge to eat weird things like ice or dirt, and – yes – depression.

Extra comma + 2nd sentence repeats what was already said.

> The most-studied and best-supported supplements for depression is l-methylfolate.

supplements -> supplement

Is seasonal affective disorder a subtype of depression, or more of its own thing? I suppose diet/exercise and most of therapy recommendations apply regardless, but what about medication? If you have clear and stable seasonal patterns in depression symptoms, does it make sense to try melatonine as a 1st tier (instead of or alongside prescription antidepressants/5-HTP)?

Also not directly related to this guide, but I'd like to ask a question about vortioxetine. I have a relative who uses it because she was told that it does not tend to cause cognitive problems, unlike the cheaper options (even though money is an issue for her). Do you have any information about it? I think I've found an estimate that ~20% of regular SSRI users experience cognitive problems as side effects, but - in your experience - how bad these problems tend to be, e.g. at the median level (supposedly ~10th percentile of overall users) and 5th percentile (supposedly ~1st percentile of overall users)?

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There's summer-related depression as well as winter.

I'd have thought that lack sleep from the short nights was the big issue, but there are a bunch of others. Heat, disrupted schedules, body image....


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My anecdote is that zinc was life changing for me. I realized the only two times since puberty I wasn't suicidal were when taking zinc for my acne. Did some research, saw some links between zinc, estrogen, and depression. Ran an experiment. Never retested hormones because I didn't care why it worked just that it did. Most of the time I was taking 50mg/day, but I've tested and 25mg a day is the minimum for good effects in me.

August 8th 2016 (day I started taking zinc again)

Goldberg depression: 46 (representative of my life since 2004 or 5 or so)

Estridol: 37.8 pg/mL (Apparently a little high for a 22 y/o male)

Total testosterone: 624 ng/dL

Sept 27th 2016

Goldberg depression: 17

Feb 12th 2017

Goldberg depression: 13

I later found Prometheus claims I have a gene for poor zinc absorption. Also I've switched my opinion to my "true" diagnosis being cPTSD related to ways I was touched I didn't consent to. I still have some executive dysfunction issues I'm unsure what to do about and some anhedonia symptoms but I'm no longer an active suicide risk so that's neat

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What I personally found missing in this otherwise quite extensive article is mentions of socializing. As a person with ~7 years of depression under the belt, one of the things that help a lot is making sure I don't stop meeting with people I like who like me. I think a (newly) depressed person might benefit of a lifestyle reminder that "if possible, keep socializing with people even if you feel tired, sad or useless, as long as people you're with don't make you feel worse". It definitely slipped under my radar at first

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Typo: "if the medication give you" => gives you in 2.1

"ECT" near the end of 2.3 should be expanded to Electro Convulsive Therapy (or however it's generally typed) because it takes a second to recall what that means

Attractor state paragraph ("mathematical explanation") is probably incomprehensible for people who don't already know what you're talking about (I do, because I've read your stuff for a long time), and could use more links/expansion/a picture.

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Could you annotate the article with references to primary (or other) sources wherever possible ? Maybe not at journal-publication level rigor, but perhaps at a Wikipedia level of detail.

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Section 2.1.5 - I think it's very beneficial to

1. Give examples of very low goals ("wash your face when you wake up") so that people will feel that it's ok to go that low. Also because very depressed people might have hard time thinking on goals.

2. Encourage people to undershoot in their definition of success. It seems that doing something very easy consistently is better than doing something bigger but only 80% of the time. I believe it is because: It gives you a sense of accomplishment, it build an habit (see "atomic habits"), and finishing your task with energy, it's still possible to do more if you feel like it.

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(Disclaimer: I think this post is really good overall! Just offering what I think is worth considering re: changes.)

Maybe consider explicitly flagging the potential for bipolar 2 to be mistaken for depression? One of my main personal experiences with depression is watching a friend be treated for depression for several years, then find out she actually has bipolar 2, switch medication, and improve some (it's hard for me to say how much).

My vague impression is that the bipolar 2 / depression misdiagnosis happens a lot, especially to women; and that people generally don't know about bipolar 2, because it's not "classic bipolar". If it's not actually common, then it's probably not worth including.

Probably the place to edit is "If you’re not sure if you’re bipolar, talk to a psychiatrist about it before trying anything on this page."

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Thank you for this helpful and (like all your work) compulsively readable overview. A note about tone: I like a lot of the informal style (e.g. “The procedure itself is surprisingly non-scary”), which comes across as friendly and accessible, but (like others in the comments) I think you should be more careful about the ways you express uncertainty (e.g. “Maybe this should be a second-line option and I’m being a coward by putting it so low down”). In particular I disliked asides about secrecy (“Secretly I suspect…” “if you want secret/fancy things...”). I understand the desire to be honest about how medical knowledge is incomplete and developing, but I think it’s also good to inspire or maintain some confidence in medicine. Even when the doctor is saying, “Medications that are very helpful for some people do nothing for others, so we may to have to try several different antidepressants before we find the right one for you,” you want him to say it in a tone of cheerful competence that implies he knows the process inside and out and has a reliable system. “I can’t overemphasize how much great work by brilliant scientists has gone into this question, nor how totally useless and conflicting all the results have been” strikes me as funny, knowledgeable, and frank about uncertainty, while “I have never been able to get my patients to a high enough dose to test this; they get too many side effects and give up” is rather worrying.

For me, the idea that no one really knows what works or why it works and we’re just throwing powerful chemicals at problems to see what sticks is a major argument against psychiatry; I would need either gentle, patient explanation or despair of any other solution to be persuaded to try psychiatric medication, and any flippancy about the degree of uncertainty involved would increase my hesitancy. Probably it really is a free-for-all where the treatment you get depends on the idiosyncratic preferences and pet theories of your psychiatrist and nobody should get involved without fair warning, but to overcome anxiety as an obstacle to treatment, it seems helpful to increase the salience of knowledge and expertise and decrease the salience of experimentation and trial and error, insofar as that is compatible with honesty about the facts.

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Excellent, extensive and user-friendly article. A few more eclectic possibilities here... https://devaraj2.substack.com/p/dealing-with-depression

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Weird thought: suppose we thought of depression as a weird form of prejudice or bigotry against yourself, in the manner of racism or sexism? Thats what the talk of global reduction of optimism and the need for raising your self esteem makes me think of. May not be a particularly useful perspective though.

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I have experienced depression as anger held, and found that expressing anger healthily relieves my depression. And I note that anger is not mentioned here, which angers me slightly, so I am writing this comment.

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This is a bit ambiguous: "Take 5-HTP 100 mg, increase after one week to 200 mg, increase after three weeks to 300 mg." Presumably means "increase three weeks after that to 300 mg".

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I appreciate the importance you place on lifestyle change here. The resistance to it certainly is hard to overcome when underneath the weighted blanket of depression, but I can share a nugget of success:

I had severe treatment-resistant depression, more or less preventing me from holding down a job. We tried it all: CBT, escitalpram, buproprion, fluoxetine, sertraline, strapping magnets to my head, etc etc etc. The next step was ECT, and if that didn't work, the step after that might have been pretty dire.

So, I started volunteering at a local shelter, just one night a week. Very small ask of myself, and their sheer need for volunteers meant that there were no barriers to entry. It gave me a bit of accomplishment, a bit of self-respect, and some conversation ammunition other than 'I've been miserable in my apartment all week, thanks – how're you?'

They quickly noticed that I was invested in the work, and that I had time to spare, so I was promoted to lead volunteer, two nights a week. Slightly bigger ask of myself, somewhat more of a sense of accomplishment and self-respect. I started to build a bit of a community there, and weaned myself off my SSRI soon thereafter. It went well.

Bit by bit, I eventually clambered my way up to a management position, and have now been working there for three years. I have some bad days, but my depression is effectively over.

This plugs in well with your section on behavioral activation – the trick is making gradually bigger asks of yourself, which feeds your mental health enough to take the next, bigger step, until, whammo, you don't want to kill yourself even a little bit!

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I found the stuff at the beginning about whether depression is just an emotion a bit misleading. In particular, it makes it sound like emotional states generally don't have real and profound physical and health effects. I mean, I ultimately think that the flaw is this idea that anything just in your head or your emotions isn't serious or doesn't require real treatment but wherever you identify the issue it seems mistaken to prop up the idea that emotions fall on one side of a clear divide and try and argue depression is on the other.

I don't know if I would change it since it makes sense to be more worried about people misinterpreting it in a way that is dismissive to depression but just my 2 cents.

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> 2. Sleep problems (could be anything from having unusual trouble falling asleep, to waking up too early, to sleeping too long)

Isn't that a bit of a narrow window to squeeze through ? This sounds vaguely like getting anything other than 7.892 hours of sleep per night is an indicator of depression.

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As someone in a current depressive episode, I can only say that I found both the short and long descriptions exceedingly helpful for my current situation. Though my concentration is limited right now, I was able to follow the long description and skip to items that resonated with me in particular. I appreciated the amount of information; even though I have been grappling with chronic depressive episodes for years, my depressed brain sometimes convinces me that I'm not really depressed, so having the in-depth discussion of criteria and clear, precise ways to manage it were really enlightening, even to someone very familiar with the general information and treatments. I think what I appreciated and liked the most is that you very clearly articulated how hard some of the willpower-based treatments could be, but that even small steps are helpful. (Once I was too depressed to get out of bed, but I made myself clean the top of my nightstand. It helped. The next day I was able to do a little more. I use this method now when I feel too depressed to do much, and like you said, it makes me feel successful.) Personally, I've found DBT particularly helpful as a treatment, even though it was designed more for personality disorders than depression, but the skills are concrete and easy to remember, and I would enjoy seeing your take on it. All in all, I was grateful for the post and will be bookmarking for the future.

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Also when you make claims like "On the cognitive level, depression is a global prior on negative stimuli." it sounds like you are defining the condition not offering an observation about what it involves. I mean I doubt that is part of the DSM 5 diagnostic criteria and it also has the potential downside of potentially confusing those of us who have been depressed but we're sufficiently aware of it to correct our best guesses about outcomes.

When my depression was pretty bad I could always tell my psych a reasonable probability distribution for what would happen if I took any action. It was just that the negative outcomes loomed larger and somehow were the emotionally salient aspect.

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I only have things I wish you'd add, can't find any other fault.

Within your framework about depression as a neurological disorder with easy-to-notice mood effects, I was really hoping you'd spend a couple of lines on chronic migraines because I think there's a strong link there.

You make it sound like getting away from the depressing thing is only for people who have a clear sense what their depressing thing is. And while within depression it can be hard to identify, because everything feels depressing. But this is worth a dedicated investment of time and focus on. If you can't think while stuck in your room, go somewhere else to think about that. If you can think best while talking to people, talk to people or a therapist about it. If you can think best while writing, write it out.

The depressing thing can also be a lack of something, not something that is there. Lack of an important and worthwhile task, or lack of meaningful relationships, can be sufficient.

Pretty sure low testosterone can also cause depression, and is relatively easily fixed.

Not sure why you almost don't mention drug abuse. Maybe because you don't want to lie and say they never help, but saying anything else risks your license? Regardless, I think this is important. Most depressed people I know are abusing SOMETHING and depending on what it is that can change the situation a lot. Mood-altering drugs make the obvious mood-related components a lot less obvious, which makes depressive episodes easier to suffer through but also makes depressed people not seek real help. Illegal drugs make it MUCH harder to seek help.

Needs a section on pregnant and breastfeeding women, because their treatment options are different, they get depressed a lot and mothers are extra important.

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Is it weird that my first thought when seeing MTHFR was to read it as "motherfucker"?

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Also re medication treatment I was very successfully treated by a psychiatrist (emminent addiction specialist actually) who ended up prescribing me Adderall and there are studies which back this up. I was eventually also semi-diagnosed with ADHD but even after 15 years or so the Adderall prescription for depression is still working great (tho no doubt getting older and married helped too). I don't know if you want to mention this since it obviously won't help patients to go be asking for it but it did work great for me.

I also appreciate how you remark about how ppl often give up but I think you might want to make a stronger statement on that. I know my tendency was just to take the meds the doctor gave me and not complain too much so even when Prozac was doing nothing for me I kinda just didn't want to cause a problem. I had a doc who pushed me on whether it was working and moved me on but that was a retired emminent psychiatrist and I know friends who just get lost bc they managed to get up the courage to tell a gp once get a Prozac script and then feel reluctant to complain. One of my friends even died thx to that kind of issue (semi-intentional opiate od...as in delibrate indifference and desire to die leading to risk taking).

I think that's something a number of depressed ppl struggle with (feeling like they are being a nuisance if they say still not better) so wouldn't hurt to mention.

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Ohh sorry for comment spam but one other thought. It might help to give some sense of how much more helpful it is to also mention this to your doc than to just take supplements and tell yourself you are going to start execising.

I know that many ppl who are depressed are reluctant to tell a doc or ask for help (I was when I was horribly depressed and I let myself lapse into problematic opiate use rather than raise it with a medical professional until it all kinda fell apart) and I fear one common temptation will be to see all the diet stuff and use that as an excuse not to say anything to med pro.

That might be the right call for some ppl but I fear that the impression many readers will take away is: hey there is evidence for this diet and other crap and here is a psych spending just as much space on it on their website so it's probably fine just to do that and not tell my gp. I mean yes you say it's better if you have access but that's not until much later (many ppl won't read that far) and can easily be brushed off just as: well of course a doc prefers seeing a doc.

I'd include some stronger statement about the efficacy of treatment from a good psych over just trying to change your diet on your own. I know you probably won't be able to cite a research paper on that but nothing is wrong with just conveying your impression as a working mental health pro.

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Sorry one last thing. I'd love to see some remarks on anhedonic versus the other kind of depression. I don't know if this is the right page but I know that back in the day (15 years later might be different) when my doc talked to me about anhedonic depression versus other kinds I had trouble finding much useful online at my level which explained what that meant and how it impacted treatments etc.

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If you are writing this to be read by possibly depressed and or anxious people... you might want to define stable (from the section about trauma in the 'do I have depression or something else')

"I would recommend worrying about the depression only long enough to make sure you’re stable, and otherwise putting your effort into pursuing therapy for trauma."

You know what you mean, but your reader may not. Part of the joy of your writing is it is clear, and often rises to making complex ambiguous things not ambiguous, like the adjacent 'look stop trying to decide if you are more depressed or anxious, just get you depression-anxiety treated; bit.

A depressed or anxious person (or somebody who knows one to the point they are reading your web page about depression) may be wondering, or may need to be wondering, if the depressed person is 'safe' - and if they are not, what to do. I recognize safe is hard and crisis is hard and you probably cannot write to that without clinical evaluation (and perhaps not even then easily) but when I read 'stable' it filled my head with questions.. do you mean not suicidal? Not bipolar or suffering from wildly changing levels of depression? Not... what? ... all of which is a close proxy for 'safe'.

When I was clinically (and situationally triggered) depressed/suicidal, I got real close to actual suicide before I and others around me recognized I was not only not stable I was not safe - something I should have recognized earlier (except I was, you know, depressed) and something those around me might have recognized earlier (except, of course, I had been depressed for a bit and therefore not acting normally / masking my depression / they were the trigger of my depression and were dealing with their own depression and issues / etc).

If you haven't experienced it before, you may not know when you have crossed the line between great, ok, sad, depressed, and DANGER! ACT NOW! - having been through that journey once, I feel like the odds I will recognize 'oh shit I am feeling/not feeling that way again; plus be willing to ask for help, even significant intrusive scary help like hospitals and leave from work and such, are much much greater. I worry how to communicate that effectively to other who haven't been there seen that before...

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- My own experience for context: my mom died of cancer and some other bad/tough stuff happened to my family, and then we had a baby. For somewhere between several months and 1.5 years, I was irritable, unmotivated, not much enjoying things, sleeping too much, and drinking heavily most every night. My wife told me she didn't think I was okay and asked me to try therapy, and I was resistant for a long time. Now, due to some combination of time, lifestyle changes, and therapy, I'm doing rather a lot better. The points below are based on some of what I can see in hindsight were challenges.

- If you are some combination of analytical/knowledgeable about psychology/used to being self-reliant, you may have some resistance to a "diagnosis" of "depression" - if folks close to you think you need some help, consider the possibility that they are seeing something you don't and that getting some kind of help might make sense

- Also, note that the depression-related pessimism might strike here as well: you will be less likely to think that treatment will be helpful and more likely to think that it reflects badly on you or others will think less of you for seeking treatment.

- Especially for depression brought about by a life event (like grief over the death of a loved one), know that it might take some time and that intellectually "understanding" what has happened is not the same as working through the feelings and associated physiological changes caused by the event. This can be especially troublesome if paired with the resistance to help above: you are "fine" because you've "dealt with it" on an intellectual level, which makes you even more resistant to seek out help.

- Building further on "whatever lifestyle change you will actually do", consider lowering your standards of what "counts" radically, as low as you have to to get to something: for example, you might want to do some fancy combination of high-intensity cardio and weight lifting, but you're having trouble getting out of bed. Going for a nice, easy walk while you listen to some music or a podcast might be an easier sell. With diet, rather than going for a strict modified Mediterranean diet, maybe just make sure you eat some salad once a day. You can always ramp up later, and getting something you can do consistently is more useful than getting it perfect for a few days and then finding it too hard to stick with it. You make this advice clear in your specific regimens, but as a general rule for behavior change, I've found "make it so easy you can't not do it" to be really helpful, especially when feeling unmotivated/depressed.

- Anecdotally, I've had some good results from hot and cold exposure, though hot exposure (sauna, bath) seems better for relaxing when feeling anxious (unsurprisingly), and cold exposure seems better for dealing with lethargy/lack of motivation (again, unsurprising). I've heard that there might be some studies to support this, but no idea if they're any good or what they are. I also know ice baths were a treatment for depression back in Victorian times, which was not too long ago was seen as senseless barbarism, but now some folks are like "maybe they were on to something". Wim Hof has a good program for easing into cold exposure through incrementing up how much time per shower you spend with it cold: https://explore.wimhofmethod.com/coldshowerchallenge/ . These benefits might partly or wholly be of the "I did something intentional to help myself" variety you discuss

- Take note if you are "self-medicating" in some way: common forms include frequent and/or very high consumption of alcohol, pornography, or other things that reliably create short-term feelings of well-being. This can be very sneaky: you may just feel like you "like" the substance/activity. Again, if folks close to you are concerned about it, that's an indication that it might be more than just "liking" it.

+ I see you mention psilocybin, but very passingly, for obvious reasons. My own experience is that taking psychedelics a few times, several months apart, in increasing doses, was remarkably helpful in mostly stereotypically hard-to-describe ways, but the most obvious was making it blindingly obvious that my intellectual understanding of the situation was not the same as processing it emotionally. You might point out that anyone who lives near Johns Hopkins or other universities/hospitals conducting such research could check to see if they are accepting applications to participate in studies

- Minor point: regimens 3A and 3B do not list energy/time budget, but I would guess it is "high" after the low and medium above

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Thank you for a wonderful summary and helpfully curated literature links!

I think the structure of the piece is excellent, and flows logically. It is indeed a difficult read, particularly for a depressed individual, but the subject is complex. I think it would be a mistake to dumb it down.

I love that you love tricyclics and MAOI! These agents are woefully underutilized.

It is my conviction that TCA are superior to all post prozac antidepressants for the treatment of panic attacks, and for that reason should be considered a first line agent for patients with both panic disorder and depression. Alas, I have only anecdotal evidence to support this assertion.

A related point, I would suggest you consider distinguishing panic from anxiety disorders in general.

It occurs to me this would be a great resource for concerned family and friends. Perhaps adding some links to resources, as well as suggestions on how to deal with a depressive in one's midst, might be a boon.

Other treatments not mentioned which have at least single or even multiple case report level citations in the literature include:

Modafinil augmentation

Core body temperature elevation

Augmentation with anti-inflammatory agents (which leads into the novel area of research of depression as an autoimmune disorder).

low dose buprenorphine

Your work on this constitutes a great service, potentially helpful or even life changing to many. Thanks and praise are due you.

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The first time you mention omega-3s, you say "Most studies that found supplementation helped got effects only from very high doses (around 2 g daily), more than you could realistically get from capsules – so if you are supplementing for this purpose you should consider liquid oil."

However, the second time, you link to vegan and nonvegan capsules (which it looks totally reasonable to get 2g/day from), and describe "one pill/day [as] being a low dose and two/day [as] being higher" for the nonvegan option (whose pills are 605mg each - the label says 1210mg/serving, but a serving is 2 pills).

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1.1 and 1.2.1: Are “depression”s associated with stressors and “depression”s not associated with stressors a single psychopathology or two (or more?) psychopathologies with similar symptoms? If a patient with psychological and/or physiological stressors is less likely to respond to medication, does that suggest the latter?

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In the business of prescribing different kinds of physiotherapy and doing some manual therapy myself I had to get to terms with classical massage treatment. Many people with pain issues wanted it prescribed and the insurances in Germany preferred active physiotherapy a lot. For many orthopaedic problems there are much more efficient hands-on therapy choices. The evidence said there was one sound indication for classical massage treatment: depression. Last time I checked, that hadn't changed. From an evolutionary perspective it makes sense to me. Other social primates fumble each other most of the time and those that get fumbled most happen to be the healthiest overall. They also happen to be highest in their hierarchies which may not be beside the point.

Anyway, if my schedule of training, meditation, work, personal encounters and beer should leave me too unhappy to bear it, I would get a lot of massages before taking any drug that hasn't been around before the industrial revolution.

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Great write-up! I only have two comments of note:

1. Consider turning your list items into an actual list format, and bolding the list item itself that you're describing (e.g. the drug name in the drug list, the supplement in the supplement list, ...), that should make it easier to resume reading in case one is dragged away from reading for any reason.

2. I'd personally recommend people with access to a doctor should check themselves for deficiencies before taking anti-depressants. My B12 deficiency that I keep harping on was one that nearly went undiagnosed to terrible effect, because no one thought someone under 35 years of age who wasn't vegetarian/vegan would have it, and I didn't have a corresponding folic acid deficiency, so the symptoms were masked. Meanwhile I was gradually getting dementia. I was very, very miserable, despite somehow mustering up the desperate energy to rearrange almost everything about my life (it was so, so hard - and it definitely had large payoffs, but the largest chunk was just the deficiency).

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Two very minor comments:

(1) In 2.3, after you recommend ECT after your third-line options, put a "(see section X.Y.Z below)" call-ahead. Reading it, I was wondering whether you were going to go into more detail on it. You did, but not until a couple sections later and if I was cherry-picking a section to read I might miss it.

(2) In 2.6, add the doctor access and "high time/energy budget" to 3A and 3B. Sounds dumb but my brain wants it there for completeness.

I found it a good read at the right level for me and my bubble (mostly grad students). FWIW, if you end up making a less vocab-heavy version as some commenters mentioned, could you keep this one somewhere too? I feel like I know people who will be skeptical of any depression description that *doesn't* describe it at the level you're doing.

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Regarding the bad thoughts component of depression, something that helped me with feelings of guilt specifically were parts of the Replacing Guilt sequence by Nate Soares. It's at http://mindingourway.com/guilt/ or mirrored at https://forum.effectivealtruism.org/s/a2LBRPLhvwB83DSGq

Nowadays I can still feel bad, or lethargic or something, but I hardly ever feel *guilt* for things I consider outside my control, like not meeting my own or anyone else's standards during moments of illness or fatigue.

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For a fair-minded and fairly brief discussion of the history of electroconvulsive therapy that doesn't take sides, I would recommend Electroconvulsive Therapy in America: The Anatomy of a Medical Controversy by Jonathan Sadowsky. It's a psychiatric history book that doesn't portray psychiatrists as moustache-twirling villains!

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Typos: Spelling: change refridgerator to refrigerator

2.1.5  double word: change enough enough to enough

Overall I think you struck your desired balance of pointing out good studies, anecdotes and your personal opinion.

You don’t mention postpartum depression at all. Even if this is a whole other subject it deserves a mention.

Section 2.3 

It’s a good no nonsense overview of medications and what you recommend in your practice. 

I think you should add a comment on the time that is needed for “trying” antidepressants, i.e. how long they need to be taken to determine that they work, weaning up, wean off period and then another wean on period, large ballpark is fine. This may fit well when you mention first, second, third-line strategies, etc. or more specifically stated in section 2.6 (instead of gleaned from the scenarios) or 2.7 and putting a reference to that section in 2.3.

You gave time commitment figures for the ECT and TMS, which was very helpful. I’m currently in this process and have been for 10 months. It's very long and frustrating. When deciding to start medication, I found it difficult to get a straight answer from my psychiatrist(s) on what to expect. My guess is that they didn’t want to make any promises so I wouldn’t get disappointed. I wanted best case and worst case scenarios so I could measure my expectations. I had no problem with the caveat that we don’t know because every person is different, but only being told let's give it 2-3 weeks before we make a call was frustrating. It’s a constant struggle to continue to fight the depression. Having realistic expectations for how long finding the right medicine could take would have been helpful. Depending on your audience, this information may not be needed. My experience and those of my peers (20-30s year olds in the biological research arena) and any family member I have discussed this with, antidepressants are scary and we don’t know much about them, especially real world practice (like 2.7, I really liked that section). Setting these expectations correctly from the beginning goes a long way.

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Scott, because you recommended magic mushrooms, I think you should also recommend LSD. I became quite depressed over the course of the pandemic and ended up reduced to staying in bed 80% of the day and constantly heavily drinking. I read your post on depression as an attractor state, then resolved to take acid and instantly adopt a bunch of lifestyle changes. Within a day I returned to something approximating my pre-pandemic self and started cleaning up all the life problems I created by being too depressed to do anything for six months. I cannot stress how great it was enough. It was like the acid gave me the tool box to just delete depressive thought patterns from my brain.

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There is one question which is extremely conspicuous by its absence:

Should I try to treat my depression at all?

Seriously, treatments for depression are horrifically expensive, and not just financially. Therapy will cost you thousands of dollars and tens or hundreds of hours of your life. Anti-depressants will kill your sex life, make you fat and unhealthy and disrupt your sleep. Exercise and diet changes may be generally good, but you already knew that before you were depressed and didn't do anything about it then.

There is in fact another option: do nothing. Sometimes this even works and the depression resolves itself spontaneously.

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This is a beautifully comprehensive, well-written, and helpful summary. I know some people who will benefit from this, so much appreciation for the time and energy and care that went into it. Since you asked for comments, I have a very few:

You call synapses "wires." Can you rephrase this to emphasize that they are junctions, connections? It probably doesn't matter to most people, but it reads weird to me.

You refer to a few amino acids as "chemicals" and I think it might not be bad to indicate that they are naturally-occuring amino acids, a regular part of the diet anyway, so you're not introducing something *new* to your body chemistry. That might matter to some people (it would to me, for example). And for those people who prefer to get it in a more natural way, they can go look up in what foods you could get extra tryptophan, for example.

In your discussion of CBT, and maybe therapy generally, one aspect I didn't really see covered quite as much as might be helpful in some cases is the degree of disordered thinking that is part of depression. One might think this is one of the foundations of the idea that CBT (or therapy) can help: that it may be possible by conscious effort to retrain your mind to have different habits of thought, which can help, on the grounds that some aspect of depression is misinterpretation of experience, i.e. a cognitive failure.

The reason I mention this is that I have known people who see therapy as just a mission of discovery. If I discover my mother was cold to me from ages 1-3 because of blah blah that was going on in her own life -- hey presto! the depression will go away as soon as I have this insight (and if it doesn't, that means I need some more insights -- different therapist, or another book from a best-selling author). I feel like the idea that discovery is not enough by itself, that there is work to be done to retrain your thinking patterns also, might be helpful to emphasize a little more in the context of discussion therapy. You certainly do mention it at various places, but it doesn't seem as connected to the therapy option as might be helpful, especially to people hoping that if they go to the therapist and just listen attentively, he's going to give them some explosive insight that will Fix Everything shazam -- and if he doesn't, he's a terrible therapist and/or therapy is useless.

Obviously I'm thinking of people who do not yet have a grip on their depression, and are not right now under the care of a good psychiatrist who would make all this clear -- but I am assuming these are among the people you most want to reach and help.

I found the introduction of attractors a bit weird, since they pop in but do not inform the rest of the discussion, and unless you are interested in signaling to physicists or mathematicians that you grok them it doesn't seem to do a lot of good. I wonder if you could use some more accessible analogy, like a pit with slippery sides, to emphasize (if this is what you're doing) that sometimes it's 2 steps forward 1 back, that is, that recovery from depression may not be a smooth path -- there will be setbacks, which should not be mistaken for complete failure.

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Weird point but while I love the term "priors," I don't think it's gone mainstream. Meaning, I'm not sure the majority of normies (including depressed normies) would natively understand what priors were unless you explained it upon first use.

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'Last ditch' for ECT felt like an insensitive choice of words, even if accurate?