"Depression is probably not caused by a chemical imbalance in the brain"

Here's an excellent article which reports on the findings of a recent study. If you click on the link and read the article from the website itself, you can access the hyperlinks embedded in it.

https://theconversation.com/amp/depression-is-probably-not-caused-by-a-chemical-imbalance-in-the-brain-new-study-186672

Depression is probably not caused by a chemical imbalance in the brain – new study

Joanna Moncrieff, Mark Horowitz, UCL

Published: July 20, 2022 6.12am BST

Updated: July 21, 2022 11.32am BST

For three decades, people have been deluged with information suggesting that depression is caused by a “chemical imbalance” in the brain – namely an imbalance of a brain chemical called serotonin. However, our latest research review shows that the evidence does not support it.

Although first proposed in the 1960s, the serotonin theory of depression started to be widely promoted by the pharmaceutical industry in the 1990s in association with its efforts to market a new range of antidepressants, known as selective serotonin-reuptake inhibitors or SSRIs. The idea was also endorsed by official institutions such as the American Psychiatric Association, which still tells the public that “differences in certain chemicals in the brain may contribute to symptoms of depression”.

Countless doctors have repeated the message all over the world, in their private surgeries and in the media. People accepted what they were told. And many started taking antidepressants because they believed they had something wrong with their brain that required an antidepressant to put right. In the period of this marketing push, antidepressant use climbed dramatically, and they are now prescribed to one in six of the adult population in England, for example.

For a long time, certain academics, including some leading psychiatrists, have suggested that there is no satisfactory evidence to support the idea that depression is a result of abnormally low or inactive serotonin. Others continue to endorse the theory. Until now, however, there has been no comprehensive review of the research on serotonin and depression that could enable firm conclusions either way.

At first sight, the fact that SSRI-type antidepressants act on the serotonin system appears to support the serotonin theory of depression. SSRIs temporarily increase the availability of serotonin in the brain, but this does not necessarily imply that depression is caused by the opposite of this effect.

There are other explanations for antidepressants’ effects. In fact, drug trials show that antidepressants are barely distinguishable from a placebo (dummy pill) when it comes to treating depression. Also, antidepressants appear to have a generalised emotion-numbing effect which may influence people’s moods, although we do not know how this effect is produced or much about it.

There has been extensive research on the serotonin system since the 1990s, but it has not been collected systematically before. We conducted an “umbrella” review that involved systematically identifying and collating existing overviews of the evidence from each of the main areas of research into serotonin and depression. Although there have been systematic reviews of individual areas in the past, none have combined the evidence from all the different areas taking this approach.

One area of research we included was research comparing levels of serotonin and its breakdown products in the blood or brain fluid. Overall, this research did not show a difference between people with depression and those without depression.

Another area of research has focused on serotonin receptors, which are proteins on the ends of the nerves that serotonin links up with and which can transmit or inhibit serotonin’s effects. Research on the most commonly investigated serotonin receptor suggested either no difference between people with depression and people without depression, or that serotonin activity was actually increased in people with depression – the opposite of the serotonin theory’s prediction.

Research on the serotonin “transporter”, that is the protein which helps to terminate the effect of serotonin (this is the protein that SSRIs act on), also suggested that, if anything, there was increased serotonin activity in people with depression. However, these findings may be explained by the fact that many participants in these studies had used or were currently using antidepressants.

We also looked at research that explored whether depression can be induced in volunteers by artificially lowering levels of serotonin. Two systematic reviews from 2006 and 2007 and a sample of the ten most recent studies (at the time the current research was conducted) found that lowering serotonin did not produce depression in hundreds of healthy volunteers. One of the reviews showed very weak evidence of an effect in a small subgroup of people with a family history of depression, but this only involved 75 participants.

Very large studies involving tens of thousands of patients looked at gene variation, including the gene that has the instructions for making the serotonin transporter. They found no difference in the frequency of varieties of this gene between people with depression and healthy controls.

Although a famous early study found a relationship between the serotonin transporter gene and stressful life events, larger, more comprehensive studies suggest no such relationship exists. Stressful life events in themselves, however, exerted a strong effect on people’s subsequent risk of developing depression.

Some of the studies in our overview that included people who were taking or had previously taken antidepressants showed evidence that antidepressants may actually lower the concentration or activity of serotonin.

The serotonin theory of depression has been one of the most influential and extensively researched biological theories of the origins of depression. Our study shows that this view is not supported by scientific evidence. It also calls into question the basis for the use of antidepressants.

Most antidepressants now in use are presumed to act via their effects on serotonin. Some also affect the brain chemical noradrenaline. But experts agree that the evidence for the involvement of noradrenaline in depression is weaker than that for serotonin.

There is no other accepted pharmacological mechanism for how antidepressants might affect depression. If antidepressants exert their effects as placebos, or by numbing emotions, then it is not clear that they do more good than harm.

Although viewing depression as a biological disorder may seem like it would reduce stigma, in fact, research has shown the opposite, and also that people who believe their own depression is due to a chemical imbalance are more pessimistic about their chances of recovery.

It is important that people know that the idea that depression results from a “chemical imbalance” is hypothetical. And we do not understand what temporarily elevating serotonin or other biochemical changes produced by antidepressants do to the brain. We conclude that it is impossible to say that taking SSRI antidepressants is worthwhile, or even completely safe.

If you’re taking antidepressants, it’s very important you don’t stop doing so without speaking to your doctor first. But people need all this information to make informed decisions about whether or not to take these drugs.

Here's the study itself:

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

https://www.nature.com/articles/s41380-022-01661-0

I'm speechless Lapis2, thank you so much for finding this, wow!

You're welcome, Pamster! I'm always happy to share something that's written by Dr. Joanna Moncrieff. I have so much respect for her. I'm less familiar with Dr. Mark Horowitz, but I've certainly come across him in my online travels as well. I'm so glad these doctors and their colleagues have done this important work.

Thank you Lapis 2, im super glad someone shared this. I actually just logged in to see if this was posted.

Rumors have been floating around for years but it's impossible to get anyone's attention without mainstream news covering it. So far, I am only seeing "one side" of the media covering it.    *eye roll*.

Fonz

Psychiatrists that pay any attention to drug studies have either deduced this or suspected it for some time now.

When you look at RCTs (Randomized Controlled Trials) of anti-depression drugs like SSRIs, SNRIs, etc., it is frequently found that the drug under study just barely outperforms the placebo arm of the study. Usually just enough to achieve statistical significance - which itself doesn't mean that the drug works but merely that a signal above the noise threshold has been identified.

With the study drug and the placebo returning such similar results, there is always the chance that the patient who is supposed to be blinded to whether they are receiving the active drug or placebo can actually identify that they are in fact receiving the study drug because they are having side effects which are real that the placebo doesn't have.

So, if you're an observant patient in a study you might notice that you're getting some nausea, or dry mouth, or sexual side effects, etc. and correctly deduce you are receiving the active compound - which may well make you more susceptible to the placebo effect.

So this slight difference between SSRIs/SNRIs and placebo might be nothing more that the fact that study patients can tell they are receiving the study drug and therefore are not truly blinded.

Also, some of us took these medications and only had a multitude of negative side effects without any of the anticipated positive effects.  I regret taking them. But I remember the doctor who prescribed them drawing a picture of a synapse in order to show me how the medication would affect my serotonin levels. I wasn't convinced at the time, but I took them anyway. As time went on and the side effects worsened, I felt scared and angry. My withdrawal period was awful.

It seems like some people find them beneficial, so I usually keep my opinions on them to myself when talking to others. However, this article validates my own personal experience.

I got injured by antidepressants just as bad if not worse as by benzo. I did find them beneficial just up to the point when they stopped working and started giving me horrendous adverse reactions, but when I tried to stop taking it I've gotten even worse due to withdrawal.

The fact that a patient finds a drug beneficial isn't a good argument for the drug I think - there are many people that would say that they find taking extasy or heroin beneficial, but we as outside observers know that they are doing harm to themselves.

I was diagnosed with depression on the start of my psychiatry journey and I curse the day when it happened, I've ended a really toxic relation and were using illicit drugs then, I have no doubt in my mind that my symptoms were due to these 2 things and if I was just told that I am doing lasting harm to myself, need to stop and stabilise, maybe get 6 months of sick leave and check then if I still feel as bad all this suffering never would have happened...

My personal opinion is that there is no such thing as idiopathic mental illness, if mental break isn't due to reasons like mine (destabilisation with psychotropic substance use) then there are many chronic illnesses that can produce such symptoms when body's immunity gets overwhelmed (h pylori, toxoplasma, lyme and other tickborne illnesses and more, and probably like hundreds more that we yet don't know about) some can be treated for example h pylori, I had it and was a part of Reddit forum and have seen many people reporting really bad mental symptoms which resolved after succesful treatment, sadly not in my case.

Hello @[Va...], welcome to BenzoBuddies.

I'm so sorry you've had to go through this, but thank you for adding your experience.

@[Pa...]

My personal opinion is that the SSRI drugs do help to alleviate SXs of depression just like benzos do for anxiety and panic but after these synthetic chemicals are able to get past the BBB and affect mood, the brain becomes aware that these things are not native to its biochemistry  and the process of dependence and tolerance is set into motion with repeated use. In a nutshell, they help in the short-term to alleviate SXs (only) but they often hurt in the long-term after the brain becomes tolerant and addicted.

Depression, anxiety, panic, etc....these mental health conditions are real and they can seriously disrupt your life before drugs are ever introduced. The etiology for these disorders is still unclear and debatable but they are real. No one (most ppl I should say) wants to start taking SSRIs and Benzos for recreational reasons.

Welcome to BB btw @[Va...].

@[An...]

Hi,

I understand that You believe that they do help with depression, sadly the data doesn't prove it:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4172306/

Even in trials where antidepressants are more effective than placebo, the difference is laughably low, like in this one:

"Of 15 clinical trials of gepirone for major depressive disorder submitted to the United States Food and Drug Administration (FDA), three were excluded for methodological reasons, three were deemed "failed" and "uninformative", seven were deemed negative and did not demonstrate effectiveness, and two were deemed positive and did show effectiveness.[6] Two positive trials are needed for FDA drug approval, with this being the case regardless of the number of negative trials.[7] In the two positive trials of gepirone for depression, the drug significantly outperformed placebo in terms of depressive symptom reduction and showed effect sizes similar to those of other approved antidepressants.[1][8] In both trials, gepirone reduced depressive symptoms by about 2.5 points more than placebo on the 52-point Hamilton Depression Rating Scale"

https://en.m.wikipedia.org/wiki/Gepirone

2,5 points on 52 point scale and 2 out of 15 clinical trials, the fact that this is allowed should be criminal and this drug is no outlier in psychiatry.

Yes, this is what I believe but read what I wrote very carefully. They help by suppressing SXs. They do nothing about the root cause b/c we really don't know what the root cause is. They may not help some ppl but to say they don't help anyone is not borne out by the data unless you think all ppl who report feeling better are experiencing a placebo effect.

https://www.ncbi.nlm.nih.gov/books/NBK361016/

Professor Ashton wrote this and I personally agree>>>

Quote

 

Antidepressants. Antidepressants are the most important adjuvant drugs to consider in withdrawal. 

There is a school of thought, mainly amongst ex-tranquilliser users, that is opposed to the taking of any other drugs during withdrawal. But suicides have occurred in several reported clinical trials of benzodiazepine withdrawal. If depression is severe during benzodiazepine withdrawal as in any other situation, it seems foolhardy to leave it untreated.

Antidepressants not only alleviate depression but also, after 2-3 weeks, have anti-anxiety effects. They are in fact a better long-term treatment than benzodiazepines for anxiety, panic and phobic disorders, and may in some cases actively help the benzodiazepine withdrawal process.

 

 

@[An...]

You completely ignored studies that I've linked and sent an article that muddles the truth based on succesful drug trials.

The infographic saying that "about 20 people reports feeling better on antidepressants" is just so dishonest. I just presented what they mean by feeling better - 2 points on 52 point scale and its only based on succesful trials. Most antidepressants fail most of their trials so why would we calculate benefits only using succesful trials?

And don't forget grueling withdrawal which is no different than benzos:

https://pubmed.ncbi.nlm.nih.gov/30292574/

"Withdrawal incidence rates from 14 studies ranged from 27% to 86% with a weighted average of 56%. Four large studies of severity produced a weighted average of 46% of those experiencing antidepressant withdrawal effects endorsing the most extreme severity rating on offer."

Think about these numbers 25% of ALL people withdrawing from antidepressants say their symptoms are 10/10 in severity.

Citing Ashton in this regard is pointless, when she said that, medical community thought that there is no such thing as antidepressant withdrawal, now we know that ADs are no different than benzos in this regard. 

https://www.benzoinfo.com/estimates-of-patients-experiencing-withdrawal/#:~:text=According to the American Psychiatric,80% of patients experience withdrawal.

"According to the American Psychiatric Association’s Benzodiazepine Task Force on Benzodiazepine Dependence, Toxicity, and Abuse 40-80% of patients experience withdrawal."

There is no meta analysis like the one on ADs but look at the numbers and tell me that this isn't the same.

And lastly natural course of depression because doctors should do no harm in the first place.

https://www.cambridge.org/core/journals/the-british-journal-of-psychiatry/article/duration-of-major-depressive-episodes-in-the-general-population-results-from-the-netherlands-mental-health-survey-and-incidence-study-nemesis/406A1D35C7346CB742DFF42A90DE2462

"The median duration of MDE was 3.0 months; 50% of participants recovered within 3 months, 63% within 6 months, 76% within 12 months and nearly 20% had not recovered at 24 months."

Clearly according to the data drugs should be considered at the earliest a year in depression as most people will recover by then, half would recover in 3 months, but no, with psychiatric "treatment" they will get drugs that make them feel better by 4% and after that 50% chance to get withdrawal lasting months and 25% for their suffering to be indescribable by words.

I don't really get it, how can You get severely injured by a psychotropic with really selective action (benzo) and think that other psychotropic with much less selective action (SSRI) is better and safe. 

And lastly I am not talking about people in withdrawal, maybe in some cases AD can stabilise a person, but You then end up in the same situation as when on benzo, sooner or later tachyphylaxis (tolerance withdrawal) will kick in but now You have a wrecked GABA and glutamate system from benzo AND serotonin, norepinephrine, dopamine and probably some more from an AD so withdrawal will be even worse. And most if not all ADs work on glutamate too so I don't see how an injury there can go back to normal in abnormal drug induced state.

And as a fun fact, You know how an infographic like the one in AD article You linked would look for benzos? 

It would say 100 out of 100 people experience reduction in anxiety symptoms while taking a benzo. So benzo good?

I am simply saying in a nutshell some ppl claim to be helped by ADs (including myself). I believe these ppl. I also believe ppl like you that have been harmed by these drugs. Don't get me wrong, I dislike all drugs esp. those that ppl take chronically for medical management. All drugs come with side-effects, not just psychiatric ones.

You even said>>>

Quote

 

 I did find them beneficial just up to the point when they stopped working and started giving me horrendous adverse reactions, but when I tried to stop

 

OP said>>>

Quote

Citing Ashton in this regard is pointless, when she said that, medical community thought that there is no such thing as antidepressant withdrawal, now we know that ADs are no different than benzos in this regard. 

I am sorry but I simply disagree with you here. Maybe, this was true for you but it is not for me. YMMV as they say. I have taken ADs for many years on and off and have had very little difficulty other than some brain zaps coming off them, unlike benzos. Like Ashton said, if you can get them to work, they are much better to use for long-term medical management for those who choose to do so rather than benzodiazepines.

My or Yours anecdotal experience doesn't and shouldn't matter in medical setting. All that matters is that studies prove they are a few % over placebo and can induce horrid withdrawal.

As I said there are tons of people that would argue that taking heroin helps them, their opinion also doesn't matter.

But alas we can agree to disagree, You can't see that You only defend AD's because they didn't harm You personally, which is shortsighted when we are discussing medicine. Go onto survivingantidepressants and You will see hundreds of people that only took AD's and have the same or worse experience with wd that You have here with benzo's. Difference there is no one is arguing that only AD's are bad and other psychotropics are good.

We really are talking about 2 different things in a sense, You speak from Your experience and opinion of one medical professional and I speak from a broad perspective of study data.

35 minutes ago, [[V...] said:

My or Yours anecdotal experience doesn't and shouldn't matter in medical setting. All that matters is that studies prove they are a few % over placebo and can induce horrid withdrawal.

As I said there are tons of people that would argue that taking heroin helps them, their opinion also doesn't matter.

But alas we can agree to disagree, You can't see that You only defend AD's because they didn't harm You personally, which is shortsighted when we are discussing medicine. Go onto survivingantidepressants and You will see hundreds of people that only took AD's and have the same or worse experience with wd that You have here with benzo's. Difference there is no one is arguing that only AD's are bad and other psychotropics are good.

We really are talking about 2 different things in a sense, You speak from Your experience and opinion of one medical professional and I speak from a broad perspective of study data.

Ok, peace. We simply disagree. This site is primarily dedicated to helping those get off benzos, not ADs. I did not say that ADs were good and w/o side effects. I did say that they are better to use than benzos if one chooses to use psychoactive drugs like benzos and ADs for long-term medical management.

Yes, I understood that was Your point and didn't agree.

You are so dead on with that Vasherr. Great insight!!!!!!!!!

I have seen this too from Yosef Witt Doering vids and even Mark Horowitz himself started developing these hyperbole curves due to SSRI's and the suffering he went through at their helm. 

SSRI'S  ARE NOT TO BE TAKEN LIGHTLY AND ARE NO JOKE!!!!!!!!!!