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Comment by ckosidows | Hacker News Reader

As hopeful as I am for unconventional drugs to have more medicinal uses, is it unreasonable for me to think there's no good medicinal depression cure? Is it unfounded to think depression generally has its roots in being disconnected from other people/society?

I've felt depressed before, but I've probably never had it as bad as many people. But generally I've felt depressed when my life felt too narrow. When I've felt like there was only one or two things holding me up. When I felt like nobody really understood what I was going through or I couldn't open up to others.

From what I understand, tripping on psilocybin inhibits your DMN, which apparently is the part of your brain most responsible for your sense of self and makes you feel less like there is a barrier between you and the rest of the universe.

If certain medicines help people cope with depression, I definitely don't want to detract from the progress those medicines have provided to those people. But does it go against prevailing wisdom to think the only cure to depression is other people? And that, if psilocybin gets people to connect more, it can be part of the cure. But that no drug, in and of itself, can "cure" depression?

Just thinking out loud. Please go easy on me. I'm just curious and want to know more.

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I have had treatment-resistant major depression for eight years. During that time I have had long periods with extensive, frequent social interaction and bonding. My depression encompasses most of the time I've known my now-wife, repairing a broken relationship with my father, the acquisition of one new close friend, and the coming and going of many transient relationships.

I don't know what the cure for my own case of depression is, and I'm sure if I were isolated/disconnected my condition would be worse, but the evidence available to me indicates that simply connecting with people is not what's going to fix me.

My wife and mother-in-law are both counselors, and routinely successfully treat people with depression. They have never indicated that level of social connection is either a dominant cause or reliable treatment for depression.

If you want something to read up on, a very popular treatment methodology for depression is CBT (Cognitive Behavioral Therapy). The premise is that depression is often caused by harmful thought patterns about yourself or your life, and CBT trains you to arrest those thoughts and replace them with thoughts that are constructive or more accurate (less exaggerated, etc.). It's not the treatment I need, but it works for an awful lot of people, and its solution isn't built around social connections (though it may reveal social connections as a problem in individual cases).

First, agree with everything you said (and it must be frustrating to deal with poptart* psychology like this).

>but it works for an awful lot of people

I know CBT is awfully popular on HN. But it is worth reading into the stats on CBT. Even if you take them at face value, it certainly does not work for everyone. It is of course, most effective when there is a clear cause and effect, very effective with anxiety, and also generally with children in particular. But has been shown to be ineffective or even dangerous when used with certain cohorts, ie. significant trauma background, clinical mental illness including depression, psychosis etc.

There have been more studies on CBT than any other form of therapy, and those studies suffer from the same replication crisis that the rest of social science research does.

So if it is your first exposure to getting help (and don't get me wrong, it is good to try as a first response) and it doesn't work for you, it is not your fault. You are not 'treatment resistant', more just at a 'treatment deficit'. Generally speaking, if your counsellor says you are treatment resistant, it is time to get a new counsellor and maybe if it is warranted a referral in combination with other medical expert like a psychiatrist. Each case is different though, and you are always your own best expert in yourself.

*like pop psychology, but it burns your mouth.

>There have been more studies on CBT than any other form of therapy, and those studies suffer from the same replication crisis that the rest of social science research does.

More studies showing the same results means they aren't suffering from the replication crisis, even if the exact same study isn't being replicated.

CBT isn't for everyone, that is true. And you shouldn't worry or blame yourself if it didn't work, there are more options available. But I wouldn't cast doubt's on it's overall efficacy or claim it's junk science.

Seriously?! I never claimed it is junk science.. didn't even allude to it. I certainly wasn't casting doubt on research figures where they have been replicated and proven.

Truth is, some CBT studies have repeatedly passed replication and others yet have failed. CBT studies in lots of areas where it is used have shown relatively low efficacy, but close to alternative options. Even across anxiety disorders, where is it most effective, it is with an average-ish 70-80% success, and often only a few points different with alternative options. Meta studies have shown it to be ineffective within certain sub-cohorts, even in general areas where it is shown to be effective. Lots of CBT studies are performed differently or with different cohorts to how or with whom they are instituted in practice.

None of this means it is junk science, it just means you have to be very careful to understand the precise limitations of the science. You cannot separate the outcomes you like from the replication issue, you have to test it all. You also cannot generalise the very real successes of CBT across areas where they have not been shown to be effective, or shown to be ineffective. It is worth keeping these things in mind.

This information is almost never shown to clients. Clients are told 'CBT works', with the implication (or outright claim) that if it doesn't work for you it is your fault. It is popular with clients and it is popular with the profession, because it sets expectations early, it is cheap, it is targeted, and it works for the majority of people with the majority of issues people seek counselling for (ie. anxiety and depression). If this doesn't work for you, and this is all your counsellor offers, they are doing a massive disservice.

> More studies showing the same results means they aren't suffering from the replication crisis, even if the exact same study isn't being replicated.

Not specific to CBT, but as a general point, replication crises are behind the scenes. Publication bias means only positive results get published, even if it's only the occasional lucky studies (or ones with overt cheating or innocent bad statistics) which come out positive. Researchers know about it and grumble privately, because they wasted months or years of effort before figuring out it's largely false. But this knowledge isn't generally what goes into archival publications.

> CBT trains you to arrest those thoughts and replace them with thoughts that are constructive

This part is useful to everyone well beyond the scope of depression. Simply becoming aware of one's thoughts is a revelation. Our ability to ride a stream of thoughts without being actively conscious to them is unfortunate; it must have some evolutionary reason, but it also means we can repeat and experience many bad feelings and thought patterns without recognizing that we have some choice in whether to allow them to run free or to shut them down/replace them.

> Our ability to ride a stream of thoughts without being actively conscious to them is unfortunate; it must have some evolutionary reason

I suspect that the evolutionary reason is rather mundane; introspection (thinking about thinking and feeling) is expensive, and while it may confer some small epistemic benefit toward constructing and maintaining a theory of mind, the main benefit is in masking the downsides of other traits (like neuroticism, depression, anxiety, paranoia), which, to be frank, don't usually have much in the way of an upside. Historically (and likely prehistorically) it is simpler on a population basis to select against the traits that introspection would mask, which leaves introspectiveness as a trait that isn't strongly selected for, and at least slightly selected against in most situations.

This calculation flips in any situation where neuroticism, paranoia, etc. confer an advantage, which probably happens often enough to keep those traits (and introspectiveness) from dying out, and of course much of the stress of modern living exacerbates any neurotic etc. tendencies, which may give introspectiveness a boost even as those tendencies are selected against more strongly. But on an evolutionary timescale, I'd place a bigger bet on human culture(s) becoming less stressful, rather than on people evolving to better withstand stress.

Much of this speculation, TBH, is a handwavy just-so story. And since a theory isn't much use unless it has predictive power, here is a prediction: low-trust societies are where you would expect to find some minor advantage to neuroticism associated traits and a corresponding greater advantage to an even marginally better theory of mind, so we might find a correlation to greater introspectiveness. I am not aware of any research that addresses that question (although on an individual basis, neuroticism is by definition negatively correlated with trust, since trust is a facet of agreeableness)

As someone who used to be diagnosed with clinical depression and eventually got over it with a combination of therapy and sheer determination ...

... eh, being with people is the most reliable way to trigger a depressive episode. It makes me realize how much of traditional "This will make you happy" advice just doesn't click with me. Groups of friends make me feel lonely and disconnected.

I feel my best when I'm on my own. Or with 1 or 2 very close friends for short periods followed by lots of recovery time.

Who we are with is very important. For some people (myself included), the percentage of people who are beneficial to be around is very low compared to the general population.

And since so few people result in positive experiences (and since solitude doesn't usually cause feelings of sadness, but rather freedom), I would usually choose to be alone.

Given a choice, I would like 60% total solitude, 10-20% general human interaction, and the rest ideally the good meaningful, connective relationships.

Yes, it does go against prevailing wisdom to think that the only cure to depression is other people; it's generally considered that (at least part of) cases of clinical depression can not be solved solely by psychological or social means as they involve problems with, so to say, literal brain chemistry; social and emotional connections with other people are helpful to manage symptoms and assist recovery but they aren't sufficient to fix the underlying cause. And also for psychological problems which can be helped with non-drug therapy such as CBT and the likes, "other people" are again a helpful, perhaps necessary, but not a sufficient factor, they don't replace actual treatment.

In general, the boundaries of what people call "depression" is very fuzzy and usually far wider than what doctors would call "depression". I can certainly agree that there are a lot of "what-people-call-depression" cases which could in fact be helped by a change of company and habits and literally connecting more with other people. But there are also a lot of people for whom suggesting "connect more with people" is the literal equivalent of telling a person with broken legs to "walk more", as their current ability to connect with people in a functional and rewarding way is simply not working properly right now. Unhappiness is not depression; depression can involve things like feeling subjectively unhappy or even suicidally miserable during experiences that the depressed person agrees are really rewarding and positive, it's just that their happiness/reward system is broken currently.

You’re describing situational depression. A lot of people have chronic depression, where he only hope for managing the depression involves pharmaceuticals.

As someone who used to suffer from chronic depression, that's simply not true. Treatment is difficult, and pills are the easiest solution, but claiming they're the "only hope" is bordering on industry propaganda.

Pharmaceuticals on the market today don’t have a great track record in treating chronic depression. The first time a depression victim takes a drug it has a 66% failure rate: https://www.webmd.com/depression/guide/treatment-resistant-d...

Drugs like MDMA are being evaluated as a potential treatment as well: https://www.medicalnewstoday.com/articles/mdma-depression

33% success rate on first try is better than I'd expected.

Anecdotally, I've heard it usually takes several tries to find an antidepressant that works for any given patient. But once you've found a drug that works, that helps a lot.

*clinical depression which could easily stem from long-term, chronic situational depression, life circumstances, etc.

Which is completely irrelevant in many cases. Depression can be caused by serotonin deficiencies, and once you’ve got depressed (pun intended) values, it’s difficult to return to baseline without medical support.

> clinical depression which could easily stem from long-term, chronic situational depression, life circumstances, etc.

It could as easily not stem from it.

Treatment resistant depressive here.

After three decades of trying different therapeutic treatment avenues, including many pharma and non-pharma options, I think that refractory (treatment resistant) depression is a phenomenon rooted in biochemistry. At least for me, disconnect from other people/society doesn’t play a role (plenty of connections, happily married, etc.).

In my case, pharma pretty much works, non-pharma hasn’t. This doesn’t exclude non-pharma therapies’ being effective - for example, they may modulate underlying biochem to good effect in some- but only that such treatments haven’t worked for me.

I’m following the pscilocybin work closely. So far, it’s encouraging. I plan to experiment in 2021.

I completely agree. The structure of our society actively deprives people from human connection which is essential to happiness. Individuals do suffer from depression at different rates, but it pops up the same way popcorn pops when you turn the heat on. The direct cause is the atomization of modern life, not some chemical imbalance in the brain.

The reason people treat depression as an individual problem to be addressed by individual means (medication) is that we are totally unwilling to acknowledge the complete emptiness of modern life. And also because modern life teaches us to treat everything as an individual problem. The symptom is itself the mechanism.

While lack of human connection can be one cause or contributing factor for depression in individual cases, and may make a lot of people "depressed" in the informal coloquial sense, the notion that major depressive disorder across the spectrum and across society is singularly caused by lack of human interaction (or singularly caused by anything at all) is not a notion evidenced by any literature on depression I'm aware of, and is not a notion espoused by any of mental health professionals I've encountered who routinely successfully treat people with depression.

Of course therapists don't define it that way... their definition is limited by what the treatment options are. Those options basically amount to prescribing drugs or becoming a friend for hire, not changing the structure of society.

And there are plenty of therapists (and researchers) who would definitely say that the quality of the relationship with a depressed patient makes or breaks treatment, in many cases it actually is the distinguishing factor. At the very least, it's a necessary one.

"The literature" isn't even clear on what major depressive disorder is. Well, the clinical definition is clear: literally sadness/low mood for at least 2 weeks. But what does that mean?

I guess what I really mean to say here is that we have essentially created a situation where people are pushed toward being alone. Then when a whole bunch of them feel empty about their state of being, we assign the label of "depressed" on them and give them drugs that are only barely effective. The lucky ones can afford to buy someone who basically takes the place of a close friend or parent. We have no framework to describe this state of affairs because every single one of us only has our permanently modern society as a point of reference.

It's easy to forget that the human brain is not designed to live the way we live. It's designed to spend every waking moment together with a very small group/family, always outdoors together, always doing something entirely tangible and physical together. Seeing a stranger was a rare occurrence. Imagine that!

"Sadness" happens when someone close dies. "Depression" happens when a huge number of human relationships that the brain needs get replaced by vastly inferior alternatives -- coworkers, social media, video game friends, service workers, etc. Nothing else but modern society creates this.

I think the quality of the human connection is important. The Dodo Bird Verdict[1] states that the relationship and connection between a therapist and client is the true healing factor. Indeed, a strong causal factor on client outcomes is the attitude of the therapist; whether they are warm, caring and genuine. The therapist-client relationship accounted for 7% of the variability in outcome, whereas adherence to a specific treatment accounted for 1%.

On an individual basis, the specific treatment matters, but statistically the human connection matters more. Your standard “what did you do on the weekend” friendship won’t cut it.

[1] https://en.m.wikipedia.org/wiki/Dodo_bird_verdict

> The structure of our society actively deprives people from human connection which is essential to happiness.

(Clinical) depression isn't the same as unhappiness.

The lack of energy to do anything and the general hopelessness are quite different to feeling unhappy or sad.

I believe it was the late and great George Carlin that said something along the lines of:

"Before you go on any powerful psychoactive medication, just do a quick head count of all the people around you. Are most of them assholes? You may want to just take a nice long vacation, permanently"

P.S. If anyone has the link to that part of whatever stand-up it was, that would be really great to see!

Apparently, SSRIs work really well for some people. I know a person who is night and day difference on them. She was crying a lot and sluggish without them, down right jolly with them.

As far as the default mode network, I've seen research that claims hyperactivity of the DMN causes rumination, which puts you in a downward spiral. So perhaps a bit of inhibition is good.

The problem in my opinion is that not everybody counts as the people who can help you get better. Your social needs could be related to an idealised image of yourself that you can't achieve, a desired romantic relationship, a sense of being part of a group around your age, etc. It's entirely possible that you never meet those expectations due to your specific circumstances, which makes any effort to connect with people a failure.

Someone I know well has suffered from major depressive episodes effectively since she was a baby—and no, she didn't suffer from a broken home, uncaring parents, or any of the things that could have reasonable been expected to lead to such a thing at such an age.

So yeah, tell me how depression has no neurological root, and is purely a result of a dysfunctional relationship to society, when it can affect someone effectively from birth.

She is watching the emerging study of psychedelics for mental illness with great anticipation and hope. Nothing else has done more than reduce the frequency of symptoms. (She actually started trying IV ketamine a few years ago, when it became available, and it has helped to reduce both the frequency and severity of symptoms, but not eliminate them entirely.)

"Feeling depressed" is not what we call clinical depression. Clinical depression means you just cannot function on your own anymore. Seeing it happening to someone you knew for years is eye opening.

The problem with that theory comes when people who have all of that and more get depressed. I do think you have a point in that the cause can be external but I think to see it as social is far too limited. Then there are cases where it's entirely internal as well, depression being a symptom of various illnesses. I'm not sure if you know this but a lot of theraputic work does focus on solving external problems. You might also observe that there can be quite a catch-22 effect or bootstrapping problem here as well.

To me it seems happiness is basically a big AND-expression of fulfilled needs. If someone is lonely they need community, if someone is scared they need safety, if they are malnourished they need food etc.

Quick note that depression isn't simply "I'm unhappy" (existence of a negative feeling). Depression is characterized by many/all feelings being severely diminished or completely absent. People who think everything's going right in their life still get depressed, and it's something of a trope for some depressed people to wonder how they can be depressed when they can't point to anything in their life that should be depressing.

Again, many people who are depressed have all of their needs met and more.

"Depression" is a bit of an overloaded term.

Maybe the easiest way to think of it is an electrochemical circumstance in the brain. This circumstance could come about as a result of external stimuli (or lack thereof), or through some imbalance or other more internal issue. I think the technical terms are something like situational depression vs clinical depression.

Even with situational depression, a fresh perspective can often give people the bit of confidence and hope that they need to proactively break depressive cycles.

Some things in typical medicine have their roots in unconventional medicine. For example PSK came from Shiitake (I think), oyster mushrooms and walnuts have plant sterols which statins mimic, lions mane has shown effectiveness as a nootropic, and there are currently trials on the effectiveness of turkey tail extract in combination with chemo. And don't eat shaggy mane and drink alcohol - it will mimic antabuse.

I'm an amateur mycophile, if you couldn't tell.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2948609/ is a metareview of non-drug treatment for mood disorders in adults.

However, medication is very effective especially as short term treatment or for major depression.

In terms of non-pharmaceutical medication, there is evidence supporting the use of St John's Wort:

A 2008 review of 29 international studies suggested that St. John’s wort may be better than a placebo and as effective as different standard prescription antidepressants for major depression of mild to moderate severity.

However:

St. John’s wort was no more effective than placebo in treating major depression of moderate severity, an NCCIH- and NIMH-funded study of 340 participants reported in 2002.

https://www.nccih.nih.gov/health/st-johns-wort-and-depressio...

Feeling down is not always a medical condition; if it's an adequate reaction to the conditions you're in, it's not something to be cured or treated. May be in your case, or in cases you're taking about those people felt depressed because they didn't have enough social interaction, and they fixed it by being around other people more: then it's not a condition, just your brain doing exactly what it's supposed to.

Depression, on the other hand, is feeling down without any adequate reason to do so. If your life is objectively quite okay, save for depression itself, but you constantly feel as if you've lost a loved one, then it's a medical condition. It's like feeling physical pain when you're not actually getting hurt.

> is it unreasonable for me to think there's no good medicinal depression cure

There can be, but only for some people and not others. I've seen esketamine make a night & day difference. Sadly, it has horrible side-effects as well, as in someone nearly died from that and had to discontinue the trial.

There's some hope that a particular metabolite of ketamine that works on AMPA may offer relief without the side-effects, but I haven't seen it actually in a medical trial yet and even if it was, I don't know if our doctor would go for it or not, though it allegedly does avoid the psychosis.

I use ketamine for depression. I get it by IV every 2-3 months at a clinic, and the effect seems to last about that long. Haven't had any bad side effects so far.

You're lucky. In someone prone to psycosis, it can do terrible things. Imagine feeling compelled to murder/suicide or it creating lots of new phobias.

You're right that it can basically turn off depression, though. I just want a version with that and not the rest.

Insofar as it's possible to generalise, I believe you're completely right, and what you say is very important. But IMO it's not possible to generalise completely, both because people's psychology varies so much and also because what people mean by "depression" varies so much (and yes, in "people" there I include psychologists and psychiatrists, whose approaches to diagnosis vary enormously in my experience).

As a completely unscientific anecdote, I have two friends who both happen to be microdosing right now, and the improvements to their general dispositions and engagement with daily activities are profound. It's not at all clear that the effects will be lasting however, and my friends tend to be outliers in any case.

note: they're taking far less than a recreational dose.

You've been sad. It is unreasonable to draw any conclusions about depression from that experience.

If depression really is a "software" rather than a "hardware" issue that makes it much harder to solve right?

You can't just toggle some biochemical switches and restore normal function.

But if you can rewire the software in just the right way then maybe

> If depression really is a "software" rather than a "hardware" issue that makes it much harder to solve right?

I bet you have the 3 scenarios:

- "hardware" only

- "software" only

- both

Broken computer. Could be hardware, could be sofware, could be both.

But even though there are common scenarios, each computer can also be broken in a different way.

you forgot the input data :)

Fix the source of the problem.

I imagine this drug can uncover the problem and help the person solve it.

> I imagine this drug can uncover the problem and help the person solve it.

Bang on the money there, speaking from experience with exactly this.

If DMN inhibition makes you feel more connected and less depressed, I would expect constant attention-grabbing distractions like cell phones to have the same positive effect - but they certainly don't.

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