The serotonin theory of depression: a systematic umbrella review of the evidence

pharma industry, as has the overdiagnosis of ADHD prescribing amphetamines to kids). To be fair, the actual incidence of phychiatric conditions from ADHD to autism to depression has increased, as well as autoimmune disorders, diabetes etc. although not as much as the pharma industry wants us to believe. It could very well be the result of upstream changes in nutrition (eg wild increases in sugars like fructose across the board, antibiotic overuse on factory farms, buildup of microplastics everywhere etc.), and to a large degree society (including loneliness, dating, relationships, work, etc) and medicating them downstream (eg with amphetamines or opioids) is just a bandaid. Late stage capitalism has had a direct role in exacerbating this. For example, the tech industry (which many on HN are involved in) has redefined dating, relationships, job searches, political discourse, and much more. All of these affect how people interact. A seminal book even back in 2001 was “Bowling Alone” by Robert Putnam, who noticed Americans aren’t attending communal activities like they used to. Corporations have co-opted many movements (like women’s lib) to make people work harder, neglect their kids, eat unhealthy food, become obese, develop diabetes, lose sleep, and now be part of the gig economy etc. I like to show this Cadillac commercial from 2014 as a great example of the corporate brainwashing: https://www.youtube.com/watch?v=xNzXze5Yza8

withdrawals or take on those patients because those are so severe (extreme violence, self harm, etc during withdrawal). Until Psychiatry can reform itself to become a real science, using the scientific method (repeatable, provable results and not just a "theory of how brain chemistry maybe works sorta but we're not sure"), it will continue to just be a big cash cow for Big Pharma while hooking many patients who do not need these drugs onto them for life, while failing to effect ANY cure on the things they are treating (Have you heard of someone getting "better" after taking anti-depressants and being able to come off them? No. They have to take them for life. That's not a cure.)

the CNS[0]. Since it's one of the primary neurotransmitters, it affects an enormous number of systems in the body: Memory, learning, anxiety, pain, depression, vision (and hallucinations; psychedelics bind to serotonin-2A), vasoconstriction, bone mass, heart function, vomiting, food moving through the GI system, and a LOT of other functions[1]. It's why psychoactive drugs work with such broad effects: - Cannabis has memory-altering effects because of indirect action on serotonin receptors via the cannabinoid receptors[2] - Psychedelics bind to serotonin-2A to produce the primary effects - MDMA binds to the serotonin transporter (among other things) as a reuptake inhibitor, and also causes the brain to release serotonin. MDMA also indirectly stimulates a lot of receptors[3], so it's not as simple as "MDMA -> serotonin release / reuptake inhibition -> happy :D" or similar. There's also some fairly recent research[4] that the serotonin model of depression might be wrong: > _The main areas of serotonin research provide no consistent evidence of there being an association between serotonin and depression, and no support for the hypothesis that depression is caused by lowered serotonin activity or concentrations. Some evidence was consistent with the possibility that long-term antidepressant use reduces serotonin concentration._ Many antidepressants also act on receptors other than serotonin receptors, ex. Bupropion[6] is a norepinephrine–dopamine reuptake inhibitor and doesn't touch serotonin at all. This isn't to say that serotonin activity plays no role in depression etc., but rather that it's a part of a very complicated picture. --- I imagine that the "confusion" around the topic is caused by something like: - Researchers in the 50-60s[5] think serotonin might have smth to do with depression - Medications that affect serotonin seem to work, so we go with it - We get to more-modern times, where the internet is fairly commonplace - People are prescribed SSRIs or similar for depression - People are told SSRIs increase levels of serotonin in the brain - This gets turned into "depression caused by low serotonin" - We are here [0] https://en.wikipedia.org/wiki/Serotonin [1] https://en.wikipedia.org/wiki/Serotonin#Serotonylation See table below heading [2] https://journals.plos.org/plosbiology/article?id=10.1371/jou... [3] https://en.wikipedia.org/wiki/MDMA#Receptor_binding [4] https://www.nature.com/articles/s41380-022-01661-0 [5] https://www.menningerclinic.org/news-resources/serotonin-the... Please note I am only using this as a date reference [6] https://en.wikipedia.org/wiki/Bupropion#Pharmacology

many other factors https://www.cebm.net/covid-19/masking-lack-of-evidence-with-.... I don't trust the establishment because they were wrong about everything. Fauci lied about masks, then lied about lying about masks, then lied about HCQ, then about IVM and other treatments. The NIH has provided 0 guidance on treating COVID other than vaccines. They did eventually do a study on HCQ to "disprove" it's effectiveness but started the dose at 1200mg/day! Nearly lethal. This of course started on patients that were too far advanced in disease and also had co-morbidities. It was a sham and borderline homicidal. All to protect the emergency use authorization for vaccines and Remdesivir. A course of HCQ: $10. A course of Remdesivir: $3000. Which is a more fiscally responsible opportunity for a for-profit industry that controls the NIH and FDA? The NIH staffers including Fauci (and of course the expert who is not an expert: Bill Gates) stand to make a lot of money on vaccines from Moderna and Pfizer. Fauci also lied about the NIh funding gain of function research in the Wuhan lab under oath to Congress. https://www.outkick.com/nih-admits-fauci-lied-about-gain-of-... Historically the entire medical industrial complex and APA lied about the "chemical imbalance" theory for depression for decades while making billions of dollars selling SSRIs and misleading the population for profit: https://www.nature.com/articles/s41380-022-01661-0 It is my opinion that these establishment organizations have 0 credibility anymore and I would never trust anything put forth by them at face value. 2. If masks don't prevent transmission, and mandates are intended to prevent transmission then mandates don't work. Aristotelian logic.

aiming to help people safely stop antidepressants in Canada. MPH reports royalties from Palgrave Macmillan, London, UK for his book published in December, 2021, called “Evidence-biased Antidepressant Prescription.” JM receives royalties for books about psychiatric drugs, reports grants from the National Institute of Health Research outside the submitted work, that she is co-chairperson of the Critical Psychiatry Network (an informal group of psychiatrists) and a board member of the unfunded organisation, the Council for Evidence-based Psychiatry. Both are unpaid positions. TS is co-chairperson of the Critical Psychiatry Network. RC is an unpaid board member of the International Institute for Psychiatric Drug Withdrawal.

downstream. The government specifically works with industry to allow corporations to get away with saving a buck at the expense of the wider public, while the wider public is given a medications and bandaids downstream that decades later turn out to be scams: https://magarshak.com/blog/?p=362 Once you see it, you can’t unsee it. Like when the government allows Coca Cola and Snapple bottling companies to switch to metric tons of non-biodegradeable plastic, while individuals are told they can’t have a plastic straw or bag, and can save the world by recycling plastic (a scam by the plastic industry to distract from the upstream problem, nearly all of the “recycling” consisted of shipping to China). Or how factory farms are now causing more negative externalities, which we are now finding out last month: https://amp.theguardian.com/society/2023/apr/25/use-of-antib... https://amp.theguardian.com/commentisfree/2023/mar/01/why-ar... I invite you to consider the same dynamic with autoimmune diseases and others. It’s the same question of whether kids always had this level of gender dysphoria and ADHD and autism, or did something happen in the environment, or did the industry start to overdiagnose them? The truth is probably somewhere in the middle, but activists on either side insist on their explanation being the dominant one, or perhaps the only one. Similarly to how other activists might insist on systemic sexism or racism to explain a gender pay gap, or systemic antisemitism to explain criticism of Israel, etc. (Disclaimer: I’m a Jewish straight cis male.) This is an impulse by people with a specific agenda / issue to make sure their agenda “wins”. In every case, there are real problems that need to be solved upstream, but the focus by well-meaning activists is only on downstream solutions (eg prescribing amphetamines to ADHD-diagnosed kids) rather than upstream solutions (eg shortrr school days and allowing kids to climb trees like in Finland, where ADHD has far less diagnosed). They will spend decades advocating the same thing and expect a different result — it’s not collective insanity, it is actually learned helplessness. It is common to think this way when one’s “tribe” is involved. To illustrate it, I will touch on an issue with dynamics that have affected many people on HN. I hope it’s alright to mention it, because that is the only way you’ll see that the “downstream focus” even concerns many sacred cows. So — to hit home, this even happened on HN with depression. I have seen it for years, where any attempts to attribute some diagnosed depression to upstream causes like diet and exercise and environental factors are met with “you just don’t understand, clinical depression is completely different, and you should be quiet”. In each of these issues, the science shows that the theory that promotes medical interventions downstream is often wrong, eg in 2022 we found this out when it comes to the theory of chemical imbalance / low serotonin explaining depression: https://www.nature.com/articles/s41380-022-01661-0 https://amp.theguardian.com/society/2022/jul/20/scientists-q... On the other hand there is a ton of studies on everyone from young girls to middle aged people getting far more sad and depressed: Teen girls: https://www.nytimes.com/2023/02/13/health/teen-girls-sadness... 20% of all middle-aged women is on antidepressants (surely it can’t all be explained by a chemical imbalance, right?) https://www.wkbw.com/news/local-news/cdc-states-1-in-5-women... Opioid epidemic in men, once again much of it is due to capitalism, both from an employment and a pharma industry side: https://www.cdc.gov/opioids/basics/epidemic.html But it’s easy for society to just prescribe medications to people rather than fixing systemic issues, eg implementing a UBI or 20 hour workweek overtime protections so people can spend more time with their family. In capitalism we’d rather allow companies to social problems with surveillance capitalism, social networks and AI to optimize clicks, because that’s what the market demands. On the other hand there are tons of studies and books on how the market and new technology has led to the breakdown of American social and family life. Starting with “Bowling Alone” by Robert Putnam back in the early aughts. People in big cities don’t even know their own neighbors. They live alone with their cats, order in netflix and uber eats, they stick their kids in public schools and parents in nursing homes, but hey, the economy is good right? https://www.nytimes.com/2023/04/20/opinion/microplastics-hea... Anyway to end with autoimmune diseases… notice how much more effort it would take for our society to stop producing plastics in clothes, that break down into microplastics on every wash, aren’t caught in drains and now find themselves everywhere, humans accumulate more and more microplastics. Rather than confront these environmental issues head-on (as we did once with CFCs and Toronto Protocol, the one big win for solving collective action problems) we allow the microplastics to accumulate in all biological beings, including us, throw up our hands and wonder aloud what could be causing autoimmune diseases? Meanwhile it is more convenient to open a new plastic spoon from a plastic package shipped from china, than wash a metal one. Instead of refilling bottles like our ancestors, we buy new ones every day and chuck them in the “recycling” LOL. Oh, and polyester is just so stretchy and convenient, as is teflon non-stick coating on our pans, why demand our government tell the industry to phase out nonbiodegradeable stuff and research biodegradeable alternstives? Nah that’s too hard to do as a society. So the problems get worse every year and “activists” arise who attribute it to a systemic issue like sexism or racism — they think they’re a great ally but rather than fighting each other we should band together to demand our govenrnment aggressively tax negative externalities upstream with Pigouvian taxes. Fiscal policy btw would be a great way to remove stimulus and UBI money from the economy. Certainly much nore targeted and better than crude monetary level the Fed has, raising interest rates on everyone. But our politicians are scared to raise taxes on industries, or go up against Big Ag or Big Pharma. So we as a society allow Day Zero to occur in cities, antibiotic resistant bacteria to grow, etc. all because of regulatory capture and cowardice. It will continue unless people recognize that the real problems are upstream, stop fighting each other and clearly spell out how we can organize to demand our government raise taxes on industries externalizing costs to others. If there was ever a proper role for government, it is that! PS: with AI, experts say 10% chance that humanity is wiped out… yet we can’t stop the competition and progress, and certainly when people are affected we’ll have industries to help them out downstream. Just another example, perhaps may be the biggest and fastest one soon.