1. Serotonin is a very basic, very old transmitter found in all bilateral animals. Humans have two sites of serotonin-production, one in the body, one in the brain. 90% of serotonin resides in the body.

2. Serotonin in general regulates "activity". It affects hunger, gut-movement, sleep, cell-growth, mood, body-temperature, blood-pressure and many other things. Any drugs changing serotonin-levels also affect these areas, that is why there are so many adverse effects.

3. SSRIs help exactly one group of people: those who have too low levels of serotonin. When their serotonin is boosted, circuits in the brain like the connection between thoughts and emotions start to work properly, hence they get more in touch with themselves.

4. People who have too little serotonin can show the exact same symptoms like people whose serotonin levels way too high (!!). Prescribing SSRIs to those people will worsen their state and may even lead to life-threatening conditions.

5. The level of serotonin can be tested properly by exactly one method: laboratory blood/urine sampling, which costs a couple hundred dollars, but is available. These doctors generally also know about amino-acid therapy, which consists of nutritional supplements which help the body in manufacture the missing transmitter. This can lower the need for medication, but needs proper testing first.

6. People can have proper serotonin levels and still be sad/angry/depressed. The question still is which brain-circuit is malfunctioning. If the problem is the connection between emotions and thought, serotonin helps. If the malfunctioning circuitry concerns attention regulation [0], like with people who have a genetic disposition towards ADHD, then dopamine helps.

7. People can have all their neurotransmitters adjusted to proper levels and still not be perfectly well. We are talking about signalling inside mutable structures here. Changes in signalling affect the structure, changing the structure affects the signalling.

Fixing neurotransmitters makes someone able to use all of his brain. He still has to use it properly though, to get better.

[0] https://en.wikipedia.org/wiki/Frontostriatal_circuit

Point 3 and 4 are wrong. There is no evidence that SSRIs work by fixing a chemical imbalance.

There are multiple metananlyses in top tier journals that indicate that SSRIs have an irrelevant clinical effect. SSRIs are almost all placebo with the downside of causing serious side effects. The small effect that isn't due to placebo is probably not clinically relevant.

The only cogent defense of SSRIs I have read is http://slatestarcodex.com/2014/07/07/ssris-much-more-than-yo.... The author is a practicing psychiatrist. The main disagreement he has with the large metaanalyses is that even though the effect size is small it's better than nothing.

I asked her how accurate these tests were and she said that, while you can't read everything off a sheet, there are patients, where she can already guess the result of the tests from the bodily symptoms the patient is describing (energy level at which times of the day, feeling of hunger, insomnia etc.).

Quite often serotonin is low and once it has been boosted (verified by an additional test a couple of month later) the patient is feeling a lot better.

Which, like I said, doesn't imply that that's all there is to mental well-being.

These tests also measure stress hormones, which usually are out of bounds as well.

> There is no evidence that SSRIs work by fixing a chemical imbalance.

I don't even know how one would define "chemical imbalance" in such a complex system as the human body.

All I know is that there are average ranges for transmitters and the more somebody's results are inside these ranges, the better he typically feels.

  An important point I want to start the conclusion section
  with: no matter what else you believe, antidepressants are 
  not literally ineffective. Even the most critical study – 
  Kirsch 2008 – finds antidepressants to outperform placebo 
  with p < .0001 significance. An equally important point: 
  everyone except those two Scandinavian guys with the long 
  names agree that, if you count the placebo effect, 
  antidepressants are extremely impressive. The difference 
  between a person who gets an antidepressant and a person 
  who gets no treatment at all is like night and day. The 
  debate takes place within the bounds set by those two 
  statements. Antidepressants give a very modest benefit 
  over placebo. Whether this benefit is so modest as to not 
  be worth talking about depends on what level of benefits 
  you consider so modest as to not be worth talking about. 
  If you are as depressed as the average person who 
  participates in studies of antidepressants, you can expect 
  an antidepressant to have an over-placebo-benefit with an 
  effect size of 0.3 to 0.5. That's the equivalent of a diet 
  pill that gives you an average weight loss of 9 to 14 
  pounds, or a growth hormone that makes you grow on average 
  0.8 to 1.4 inches.

All of our emotions are useful signals and it's often our learned responses to those emotions that are the problem.

Of course antidepressants can cause side-effects as do all other types of drug treatments. It's inevitable, medication effects are extremely complex and unpredictable as interaction with body systems covers a huge gamut of possibilities. Furthermore, most effects of drugs haven't studied even when they are known and a great deal more is not known than is known.

Also bear in mind that drugs in the form prescribed may not be the the chemical that produces the biggest therapeutic effect. This is the phenomenon of active metabolites which are often the drivers of favorable and unfavorable effects.

So we see how quickly these factors yield immense complexity and the reason behind the fact that drugs often have a huge array of side-effects common and rare.

BTW a side-effect occurring in 1% of recipients is considered a common adverse event. 0.1% is infrequent. Maybe 0.01% is getting rare, but definitely not implausibly drug-related.

The bottom line is that taking several drugs even one at a time for more than a few days means there's a surprisingly high probability of have an uncommon or rare side effect. It's happened to me a handful of times, including a couple of pretty serious reactions.

Interesting when I tell my physicians about these reactions. There's a certain look they get on their faces, like "what are you talking about? You're kidding me, that really didn't happen, did it?" Well, yes doctor, it really did, as though I wouldn't know a bad reaction when it's there or I just made the whole thing up.

This is perfectly consistent with what patients reported to me over the years. A long time ago I'd come to believe that people weren't making stuff up, unusual side-effects are ultimately an everyday reality among patients and all reports of AEs must be taken seriously, exactly my policy I put into practice.

Remember this little rule, it will save everyone a lot of trouble: any drug can cause any side-effect at any time.

Are these rates determined in the same conditions as the medications are prescribed?

Are there methods put in place to continue to gather side effect data after a medication is prescribed?

Since the plural of anecdote is data, I'll share my story. I struggle with depression. I've kept it at bay for a long time now, but I had a big wave this year. It turns out that was ~1wk after a Rx refill and I realized the pharmacist refilled at half the dosage. Fixing the dosage got me on track in a couple of days.

I know I'm not above a placebo effect. The placebo theory could explain my recovery, but I'm not sure how it could explain regressing when my dosage was messed up.

These type of articles follow a couple of archetypes:

1. I beat depression by (insert value-signaling method here). These people are usually in denial and/or in the initial positive rush of a life change. The latter produces transient changes that are far outlasted by internet posts.

2. SSRI's don't work and have horrible side-effects. The side-effects trash-talk causes a nocebo effect. Sexual or sleep related side effects are produced in the general population by gusts of wind, and now you read mainstream papers talking about them. The meds work as well as therapy for far less money and opportunity cost. Poor and even middle income people don't have therapy as an option for mental illness. Check out: http://slatestarcodex.com/2014/07/07/ssris-much-more-than-yo...

The best that a knowledgeable and well intentioned doctor can do is prescribe them in a trial and error fashion, maybe with a tiny bit of guidance from prominence of patient symptoms. But it's largely just prescribe, wait 6 weeks, rinse and repeat. I happen to be one of the 'treatment resistant' types, in that SSRIs don't do jack-squat for me (well, except for when there's a drug-drug interaction, and that's definitely not the 'good kind' of effect).

The medical literature suggests SSRIs are only just barely more effective at treating depression than placebo. There's also an interesting (and in my view, plausible) explanation behind why SSRIs might cause an initial increased suicide risk. A common symptom of depression is 'psychomotor retardation': "a slowing-down of thought and a reduction of physical movements in an individual" (https://en.wikipedia.org/wiki/Psychomotor_retardation). If SSRIs have any positive effect, they occur gradually.

So the hypothesis goes: a patient might be suffering from suicidal depression, but the psychomotor symptoms prevent suicide. When they are prescribed SSRIs, and those SSRIs start having a positive effect, they lift the psychomotor retardation just enough that the patient is finally able to kill themself. It probably sounds a bit strange, but I can attest to how debilitating 'psychomotor retardation' can be.

She says as soon as she started taking them, she instantly felt better. No more randomly bursting into tears.

But, she is no longer the wife I had. Her conversation is so slow. She regularly forgets what she was talking about, repeats herself. Basic chores are just forgotten about. She drinks more than ever, has started smoking. Her diet is awful. If she can be bothered to eat it is probably a chocolate bar at lunch time. She has gained about 4 stones in weight.

She never took up the counselling that she felt she needed before starting on the SSRIs.

She tried cutting down on her medication a little while ago, but this made her incredibly paranoid. So instead she has had to increase it.

All I see from it is an ever decreasing spiral into ruin.

One of the (unfortunately common) ways people learn that they have bipolar is by being mis-diagnosed with unipolar depression, being prescribed SSRIs, and suddenly finding themselves experiencing 'dysphoric mania'. Not the "everything's great, let's have sex with random strangers" type, but rather the "let's destroy every piece of furniture in the house" type.

But I don't know your situation other than what you've described, and I'm definitely not qualified to tell you what to do. The best I think you can do is to get a second opinion from a competent psychiatrist.

The "let's destroy every piece of furniture in the house" is exactly what happened with one of my parents, it's not a fun thing to witness but they eventually got the bipolar under control with lithium but the toxicity on that stuff is pretty horrible, regular blood tests for the rest of your life horrible.

First off, good advice is found in the mental health hotlines. 1-800-950-NAMI (6264) if you are in the states. They can let you know options that I might not realize.

I was lucky enough that my ex kept his meds up (mostly) and went to the doctor - and that I had an invitation from his psychiatrist to call the hospital if I had any issues. Unfortunately, you don't have this. However, this doesn't preclude you from talking to her doctor. Even if he or she doesn't give you feedback information. He might be willing to change course with her or offer.

You might be able to change tactics and talk to her as well, explaining that you aren't sure this med is doing well for her and about the changes you have seen. She might be willing to go to a psychiatrist with you under the view of saving the relationship.

You also might be able to speak to a psychiatrist or therapist yourself to get some ideas on how to get through to her.

And good luck to you both. I truly understand your sort of struggle, even if I don't understand the specific flavor of it.

* Do these drugs genuinely help or is it just a strong placebo response?

* If the anecdotal evidence increases the odds from 1 in 100 to 1 in 4, would this be considered normal in medicine?

Of course the symptoms could be attributed to the wrong thing here but they sound pretty horrific. My initial reaction was that in the future we'll look back at these drugs as barbaric, similar to how we view lobotomies today.

Edit: formatting

It is my firm conviction that a lot of people would benefit from small adjustments to their brain chemistry. I'm lucky to have found something that works for me.

ADHD has by far the most successful medical treatment of any mental illness. Something like 90% of cases get positive response out of medication, with 35-40% of people having all their symptoms handled.

My understanding is that for treatment of clinical depression, medication helps around 75% of cases, but that most people continue to have symptoms even when under medication due to the nature of the illness.

In both cases, though, treatment is understood to be a continuous process. You cannot be cured of these illnesses, you can only cope with the side effects.

The treatments are like a prosthetic leg: No matter how much you use it, removing it will bring you back to square one.

There's a lot of research showing the positive effects of medication (and in ADHD's case, the futility of non-medication-based treatments), but there's still a major fight for acknowledging the validity of this form of treatment. Major parts of the population do not think these illnesses are even real!

But it's all pretty dangerous. We have some understanding of how brains work around these illnesses thanks to the research gone into it, but there's a lot of complex interactions going on. Not that physical medicine is much different.

Is this really relevant considering the extremely rapid rise in prescription and use of ADHD medication?

In my anecdotal experience with friends who take these pills, they very quickly create a reliance on the substance and have significant side effects in the long term. I honestly believe they can be quite harmful to a person's mind.

Now, for ADHD there unfortunately aren't good non-medication treatments. But depression is a completely different matter - making lifestyle changes as simple as going for a hike every weekend can easily be as effective or more effective than any medication.

Regardless of my personal experience or your personal experience the evidence does not show that stimulants increase grades in the medium or long term.

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

I am still trying to find the studies that indicate that stimulants might increase high school drop out. But there is pretty clear consensus that they don't increase grades over the long term.

https://www.nber.org/papers/w19105

They "worked" for someone I know when they were in a very dark place, but the price was a permanent dulling of their emotions, even after they stopped taking them.

Someone else I know underwent extreme personality changes on a different antidepressant, becoming more aggressive and basically an asshole, and I had to beg them to stop taking it.

Your mileage may vary. They are very serious things.

The safe profile is one of the reasons they're probably over prescribed, along with the high profitability. Many doctors give them out like candy, even though many people probably don't suffer from the physiological ailments that the drugs target.

There is little debate, though, on the statistical efficacy of the older (less profitable, off patent) tricyclics and especially MAOI class of drugs. Unfortunately, the side effects of these drugs are far more serious. Most GPs will not even prescribe them, as only psychiatrists will have experience. But for someone with lifelong treatment resistant depression, they can be a God-send.

Asd as far as barbaric, realize that the most effective treatment for depression is still electric shock therapy.

Personal experience with Sertraline - it doesn't make you happy or feel better or anything. It just numbs you, and you're really susceptible during this time. It's part of the reason why therapy is also really important in addition to the drugs to help get down to the core of what you're having issues with.

The old Zoloft "sad blob" to "happy blob" commercials are a real disservice to modern anti-depressant medicine since it is a very incomplete picture. Aside from glossing over the side effects of the medication, the pills themselves don't do much except stop the feeling of absoutely horribleness for awhile. They don't make you feel better - they don't make you feel much of anything. But things at least stop seeming hopeless after awhile, and hopefully you can begin to address the underlying issues.

In the case of true chemical imbalances like it's suspected I have, during this time you help find non-drug related coping mechanisms. Finding ways to help create a strong positive part of your life so the imbalances are offset and don't hit as hard. A lot of this comes just through therapy or at least a counselor while you work.

My first few times on SSRIs were the result of rather serious and dangerous break downs where those around me had pretty good reason to think I was a threat to myself. But these cases were mishandled pretty heavily since the doc just wrote a prescription for Sertraline and sent me on my way. Therapy wasn't even discussed, and our insurance at the time certainly didn't cover it since it was a non-essential medical procedure.

It wasn't until many years later and many changes of drugs later that I was finally in a position when I could do both therapy and have the drugs to assist that I actually made some progress -- the counselor and the psychiatrist worked in tandem; the counselor worked and would constantly try to see how I was when we lowered the dosage, the psychiatrist spent time making sure that the dosage was enough to keep me level, not pushing either way and consulting with the counselor to ensure they had a source of info that wasn't me.

I hope we find something better since looking back at the SSRI period, it was not a very good time in my life and I was lucky enough to get to a situation where I could get proper mental healthcare. I can't imagine how many others were just tossed on an SSRI without the proper monitoring and assistance necessary to actually make use of the effect, or worse, who weren't watched at all as the more dangerous side effects kicked in.

We wouldn't say the same if it was your arm was broken...

"You can just come up with non-surgical ways of coping with the fact your arm is broken"

Brain chemistry and "fixing" it is more voodoo than science right now. There are many underlying causes of depression and it's pretty unlikely there's going to be a fix that's surgically precise and accounts for even a large number of cases with one solution.

My point wasn't that SSRIs are bad or don't work, but it does usually take more than just popping pills to mitigate and help depression. Pills aren't the full solution. They're part of a working solution but not the entirety of it.

"Since the consumption of omega-3 fatty acids from fish and other sources has declined in most populations, the incidence of major depression has increased."

https://www.youtube.com/watch?v=DiJcSoo3C4Q

Along these lines (overprescription, overdiagnosis, disease mongering) "Saving Normal" by Frances Allen may be a good read as well.

> Several plants contain serotonin [...] These compounds do reach the brain, although some portion of them are metabolized by monoamine oxidase enzymes (mainly MAO-A) in the liver.

This makes me wonder: will people with a homozygous defect in the MAO-A gene (quite a large percentage of the population) end up with the problem that lots of endogenous serotonin may reach the brain?

The only things that come close to that are the psychedelics -- psilocybin, MDMA, LSD, etc. They have been outlawed but of course, the underground therapy community has been keeping them alive and we should see legalization for the treatment of things like PTSD within the next 5 years.

I kind of think that many recreational psychedelics are both over-hyped by advocates and over-demonized by naysayers. Recreational experiences are fine and dandy, but I haven't seen much evidence so far that serotonergics do anything for depression. MDMA for PTSD remains experimental (worth a study I'm sure though).

One psychedelic is an exception: the observation that ketamine actually rapidly helped some depressed patients has sparked a whole lot of research in the last decade, has led many to question the whole monoamine hypothesis behind current depression treatment, and may lead to non-psychedelic treatments that work better (or at least on a different subset) than SSRIs. (http://www.economist.com/news/science-and-technology/2170865...).

So, if you are a fan of the psychedelic experience and want to try something a bit out of the medical norms to alleviate depression, the ketamine clinic has the most medically backed potential at the moment, in my opinion (although I'll add that from what I understand ketamine clinic treatment is not at all similar to recreational usage as the dosage is much less). Alternatively, you could wait for the non-psychedelic versions or even rather unrelated derivatives (mentioned above) to progress, that for all we know might actually be better in the end. As the Economist article rightly alludes to, the brain is a seriously complex organism, and science has not reached a neat simple conclusion about depression yet.

There is good evidence for the efficacy of ketamine in treatment resistant depression.

The psychedelics are not well studied.

SSRIs are not useful and may be harmful.

ECT works but causes amnesia.

Most depression gets better on its own.

The side effect profile is sufficiently minimal that if it turns out I'm just a lucky beneficiary of a placebo effect, I really don't mind.

[1] https://en.wikipedia.org/wiki/Neuroactive_steroid#Role_in_an...

There are some good articles in the Boston Globe's archives about Prozac, circa 2000. "Prozac, Revisited", etc [2]. Robert Whitaker [3] worked for the Boston Globe, before he wrote Mad in America and Anatomy of an Epidemic.

[2] http://www.narpa.org/prozac.revisited.htm (the boston globe's official archives site is not so easy to use, but I've previously verified that these stories exist)

[3] https://www.madinamerica.com/robert-whitaker-new/

The first patient in this BBC article could also have been diagnosed as 'exhausted':

> She had begun taking [SSRIs] while caring for her seriously ill mother and studying for her final exams at Cambridge University, but suffered severe side-effects after her GP prescribed a stronger dose of tablet. (emphasis added)

I think 'exhaustion' is a frequent cause behind the symptoms labeled "depression".

In May of this year, I watched Lexapro (an SSRI) destroy all the progress I'd made with my girlfriend... She'd asked for this drug a month after she'd escaped from her court-ordered tranquilization, because she thought it had helped her years ago. Really it just helped her relapse on cocaine then. This time it caused rapid heartbeat, and much anxiety. Her last benzodiazepine turned her into an anxious wreck... The psychiatrists got hold of her again, and they're making sure that she will never recover.

About a week ago I went through videos on my phone... and found one of my girlfriend about a week before she was taken to the hospital. The video proves, beyond any doubt, that she is not "persistently" disabled, that the symptoms that originally put her in the hospital were entirely due to quitting her addictions cold-turkey, and not due to 'defective genes' or other pseudo-scientific rationalization for forcing her to use palliative drugs.

Honestly, her coke habit is the lede here, not the scare story that might turn other people off to treatments that work for them.

I didn't say that, I said that "increasing serotonin" is not why these drugs sometimes help people feel better.

> Honestly, her coke habit is the lede here,

Yes. In the long term, cocaine use wrecks the mitochondia, which contributes to exhaustion. The proper therapy in this case is to restore the mitochondria density. Etiology (" a branch of medical science concerned with the causes and origins of diseases") is thrown out the window when a patient is prescribed an SSRI.

> not the scare story that might turn other people off to treatments that work for them.

The BBC story that this submission links is about how SSRI treatments sometimes wreck people's lives. You should read it. My comment was that adverse effects of these defective drugs (SSRIs) have been known from the very beginning, and I said a few words about alternatives that work better.

In mice, when given super high doses. The data for humans is much shakier and the effects of this are unknown, or if there are any, or if it even matters. AFAIK, none of the long term studies from reputable sources have shown long term effects on wakefulness or motivation past the initial withdrawal syndrome. This is just some new "meth neurotoxicity" hysteria bullshit to scare people into thinking drugs are bad.

Yes it is. Only some people don't have too little serotonine.

One of the things that we're reasonably sure can cause depression is decreased levels of serotonin. That doesn't mean there's not other things which cause more-or-less the same set of symptoms.

EDIT: On a note related to your girlfriend... people can appear externally happy while being seriously depressed. From talking to me irl, you'd likely never guess that I self-harm, have no motivation to do anything, and wish I were dead. You can't blame someone for wanting an escape from that.

But trying to say they're all bad because they didn't work on your girlfriend, whom appears to have had some serious issues long before using an SSRIs, is disingenuous.

There are millions of people who are helped with SSRIs, and even some who'd long ago have been dead were it not for the use of MAOIs and others that work when absolutely nothing else will.

But I do agree that SSRIs can have powerful effects, and they're over prescribed to the general population which demands easy solutions to tough problems.

I started the comment with generalities, offered supporting references and links, then mentioned my girlfriend as a case-study. I have other case studies too.

> There are millions of people who are helped with SSRIs, and even some who'd long ago have been dead were it not for the use of MAOIs and others that work when absolutely nothing else will.

MAOIs are generally safe enough to use temporarily, to get someone out of an intense depressive funk. SSRIs are modern snake oil: they are addictive palliative drugs that do not address fundamental problems. Sometimes they seem to help, but not for the reasons given.

Getting excess serotonin under control is much more beneficial than increasing serotonin levels.

Doctors aren't in the business to kill people. SSRI do save lives. We just know they kill a tonne of people as well.

The SSRIs are modern snake oil. I gave a reason why they seem to work for some people. Other people think that they're helped, but really their SSRI has only helped them "not care" about circumstances in their life that they're not happy about. I've posted this link in earlier comments.

> Doctors aren't in the business to kill people.

Pharmaceutical companies are in business to pay dividends to their shareholders. Their researchers are employed to make new patent drugs, not to figure out fundamental causes of disease. For these businesses, killing people is par-for-the-course: not the ideal outcome, not unexpected. Doctors' credibility is just collateral damage.

> SSRI do save lives. We just know they kill a tonne of people as well.

Robert Whitaker disagrees with you - he's found that, over the long term, most psychiatric medications are very harmful. Look at his website [1], read his books, and get back to me with specific reasons why he's wrong.

[1] https://www.madinamerica.com/

Every medicine has side effects. Every medicine has contraindications and is not suitable to a subset of the population which may want to use it. It looks like antidepressants are no different.

My daughter was given Montelucast/singulair for treatment of asthma; now it turns out that it can have severe side effects with kids - anxiety and suicidal behavior [1]. The funny thing is that these side effects are not listed on the medication guide, as these are supposed to be 'known risks'. What exactly were they thinking when they omitted this information from the medication guide?

https://www.ncbi.nlm.nih.gov/pubmed/26620206

Singulair is a preventive treatment, it is supposed to prevent asthma attacks before they happen, however the side effects of induced anxiety made it too costly for us.

""" if you suffer a psychotic breakdown, your odds of complete, treatment-free recovery are much, much better if you are treated in a third-world country that cannot afford psychotropic medication """

https://aeon.co/essays/treating-acute-psychosis-with-drugs-c...

> Missing a night of sleep seems to horrify some people but it's quite safe. Just don't operate heavy machinery.

Most of us drive to work most of the time. Yes, most of us operate heavy machinery every day, often in busy areas.

People worry all the time about guns and planes and other potentially dangerous things; people don't worry nearly enough about transportation accidents. If you didn't sleep, call a cab (or a rideshare, or a friend) - don't risk the lives of everyone around you.

We also know that sleep hygiene helps fix sleep problems.

"Skipping a night of sleep" isn't compatible with sleep hygiene.

In general suggesting made up bollocks to "treat" an illness which is potentially fatal isn't a good idea.