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I think it's important to note that although studies of serotonin levels don't show a connection with depression (i.e. lower serotonin levels = depression), that doesn't mean that drugs which decrease reuptake/increase (by proxy) serotonin levels won't improve mood.

It's sort of a red herring to say "Depression isn't caused by a serotonin deficiency, therefore SSRIs are bunk", which is what this article seems to veer towards. SSRIs could affect a completely different body system as long as they wind up showing a statistically significant effect over placebo in a double blind study, then they are acceptable forms of treatment by our current scientific/medical standards. (Which apparently they do for most patients--so I wouldn't rule them out.).

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There seems to be a growing view that inflammation plays an important role in depression. See for example http://www.biomedcentral.com/1741-7015/11/200 .

The idea is that depression could be a feedback loop in which negative life events cause the brain to become chronically flooded by stress hormones like cortisol and epinephrine.

These are pro-inflammatory factors whose chronic presence promote run-away inflammatory responses which kill glial cells, decrease neuroplasticity, retard neurogenesis, and also contribute to a whole constellation of other health problems like obesity, diabetes, and heart disease.

What closes the feedback loop is that this inflammation-mediated form of brain damage, particularly in the hippocampus and amygdala, directly compromise a person's cognitive ability to deal with life stressors constructively. The ability to process emotion, fear, and memory degrade.

Speaking a bit poetically, you could say that a severely depressed brain is one that has rewired itself to be a stress-processing circuit.

SSRIs no doubt work for some people, and the modern thinking is that they might be promoting neurogenesis through upregulating BDNF and other growth factors; there are multiple lines of evidence, one fun one is the fact that the maturation time of new neurons roughly matches the time it takes for SSRIs to start affecting depression (3-6 weeks).

Exercise also works, seemingly about as well as SSRIs for many people with moderate depression (Googling will provide examples of studies from the last few couple decades to that affect). I haven't read much about this but I would imagine that the metabolic and cellular stresses of a bout of heavy exercise (in which millions of cells die) promotes the production of growth factors all over the body, including in the brain.

I think "negative life events" are more of a symptom than a cause. Temporary grief over loss or other genuinely bad things happening in life is normal in healthy people. What's so different about depression is that the patient seems to feel bad without a clear cause. You hear them going on about things that to a healthy person don't seem like such a big deal, or easy to fix, or so long ago a healthy person would have been over it by now. It's more a sign of the depressed brain trying to rationalize why it feels bad, and looking for outside causes to blame.

> Exercise also works, seemingly about as well as SSRIs for many people with moderate depression (Googling will provide examples of studies from the last few couple decades to that affect). I haven't read much about this but I would imagine that the metabolic and cellular stresses of a bout of heavy exercise (in which millions of cells die) promotes the production of growth factors all over the body, including in the brain.

Evidence is inconclusive for exercise; more research needed.

http://www.cochrane.org/CD004366/DEPRESSN_exercise-for-depre...

> When only high-quality trials were included, exercise had only a small effect on mood that was not statistically significant.

[...]

> Exercise is moderately more effective than no therapy for reducing symptoms of depression.

> Exercise is no more effective than antidepressants for reducing symptoms of depression, although this conclusion is based on a small number of studies.

> Exercise is no more effective than psychological therapies for reducing symptoms of depression, although this conclusion is based on small number of studies.

> The reviewers also note that when only high-quality studies were included, the difference between exercise and no therapy is less conclusive.

> Attendance rates for exercise treatments ranged from 50% to 100%.

> The evidence about whether exercise for depression improves quality of life is inconclusive.

So far a talking therapy, or a talking therapy combined with medication, are recommended for mild to moderate depression. That might change for some people with depression if we get better social interventions and lifestyle changes.

The fatal error in his reasoning is fundamentally units vs. integration. The "comprehensive" studies still show that SSRIs are effective [0], the mechanism of action is just not likely to be "because you didn't have enough serotonin."

[0] Cochrane Review: http://www.cochrane.org/CD007954/DEPRESSN_antidepressants-ve...

> The "comprehensive" studies still show that SSRIs are effective

From the article:

"Most of the studies were supported by funds from pharmaceutical companies and were of short duration."

In other words, what they are saying is that the published research papers show efficacy for SSRIs, which is completely different from saying that the research shows that SSRIs are effective.

> "Most of the studies were supported by funds from pharmaceutical companies"

Isn't that true of MOST drugs?

Yes, which, by itself, would not be a problem (of course, you would need to watch closely for conflicts of interest clouding the issue). No, the real problem is that the drug companies do not have to release all of the data associated with the trials they perform. They don't even have to publish all of the trials they perform.

Given that, I have a very hard time trusting any drug that does not show amazingly stellar clinical trial results. If you have the options of cherry picking what you publish, and your drug only "helps" 50% of the participants, I see that as random noise.

Ben Goldacre[1] is trying to shine a spotlight on this, and is doing a pretty good job. His Ted Talk[2] is well worth watching.

1. http://www.badscience.net/

2. http://www.ted.com/talks/ben_goldacre_battling_bad_science

Depression probably isn't a single illness, and so it's not surprising that meds don't work for everyone.

We've recently discovered genetic differences in medication efficiency - at some point in the future you'd have a genetic test that would tell you that meds A, B, and C probably aren't going to work for you. (Except by then we'll probably have better meds and better access to better talking therapies.) These genetic differences were not known at the time of the drug trials.

I totally agree with you about the problems of drug research and drug companies cherry picking which data to release. Goldacre's books are good.

This is already true. Both my wife and I had genetic tests done that showed which medications were likely to be more or less effective. In my wife's case it was a deficiency in an enzyme to break down folic acid and nothing to do with serotonin levels. Without the genetic test she'd still be taking the wrong medications.

I didn't realise genetic testing like this was possible - it seems unknown in the UK (esp in the NHS). Can you share more details?

here's one: http://genomind.com/

Basically they give you a report of your genetic variations and how those relate to different medications or treatments.

Generally not plants.

That is a deeply unfair misunderstanding of the pharmaceutical industry and the medical profession.

First of all, not all these studies are funded by the producers themselves. And even when they are, it is still hard or next to impossible to outright cheat. There are standards in place, and thousands of people are involved, of which hundreds would need to collude.

Has this happened? Yes, it has. And when it came out it had a devastating effect.

But ruling all scientific studies were these stakeholders foot some of the bill invalid is just unfair and dangerous!

I was under the impression that they do not have a benefit over placebo for most patients - only for the most depressed patients. And also some risk of worsening things for younger patients.

I think I got this impression from reading Bad Science, which had references IIRC. Example column from the blog version:

http://www.badscience.net/2008/01/washing-the-numbers-sellin...

http://www.amazon.com/Bad-Science-Ben-Goldacre/dp/000728487X

The key papers on this are listed here:

https://scholar.google.co.uk/scholar?q=kirsch+antidepressant...

About 70-80% of the drug effect is replicated in the placebo arm. Other things to be worried about:

- Unpublished data was much less likely to show a benefit for SSRI than published data. - SSRIs have side effects which may increase expectation of benefit in patients - Numerous studies show unblinding is very common in trials of psychoactive drugs. These studies are not a 'gold standard' by any stretch of the imagination.

Well,

Actually, I think a lot of patients and researchers do care whether a drug "corrects a problem" or merely adjust brain chemistry some other way to allow a person to function. Something that merely someone "cope" might indeed be acceptable but it's not as highly valued as something that "returns you to normal".

> that doesn't mean that drugs which decrease reuptake/increase (by proxy) serotonin levels won't improve mood.

It also doesn't mean that these mood improvements are actually useful for treating depression. (For example some studies have shown an increased suicide risk - there is no firm consensus on the topic though: http://en.wikipedia.org/wiki/Antidepressants_and_suicide_ris...)

Drug dependency on SSRI's is a very real thing - I honestly don't see how its any better than an opiate addiction.

Also Big-Pharma funding has a strong and very much negative influence on the objectivity of our scientific body of knowledge. Very often studies/research that have been funded but do not support their conclusions will simply be shelved without publication.

> Drug dependency on SSRI's is a very real thing - I honestly don't see how its any better than an opiate addiction.

Where are you getting this from? Withdrawal syndrome is a minor component in any real addition and is nothing without craving for the substance which is not present with SSRIs. As someone who has experienced both reasonably severe SSRI withdrawal and nicotine addiction I find your comparison ridiculous (no exp with opiates, but it seems safe to assume they aren't better than nicotine).

> Where are you getting this from? Withdrawal syndrome is a minor component in any real addition and is nothing without craving for the substance which is not present with SSRIs. As someone who has experienced both reasonably severe SSRI withdrawal and nicotine addiction I find your comparison ridiculous (no exp with opiates, but it seems safe to assume they aren't better than nicotine).

The issue is the way your body normalizes to the new default of higher Serotonin levels - when you suddenly return to normal the present state is worse than the it was before you started taking SSRI's (I read a few good papers on the topic a while ago, but I don't remember their titles now - wikipedia is probably a good place to start: http://en.wikipedia.org/wiki/Antidepressant_discontinuation_...).

Also lack of craving is a ridiculous justification for effectively prescribing substance abuse - for example aderol et. all are amphetamine salts - that people don't have a craving in the sense that they would for cocaine is just because the high lacks the euphoric effect -- they still can't function normally without dosing -- and it definitely doesn't mean it's fucking reasonable to prescribe to seven-year-olds.

Likewise people have cravings to watch their favorite tv-show or check their Facebook accounts - these cravings do not qualify these activities as substance abuse.

I've read my share of stuff on SSRI discontinuation, not in the last because I was experiencing it first hand. My point stands. Nothing you mentioned constitutes an addiction.

> Also lack of craving is a ridiculous justification for effectively prescribing substance abuse

What? The justification is improvement of patient's quality of life which is often unacceptably low without the treatment. Blinded by the anti-drug dogma you are unable to see that sometimes the only available alternative is endless suffering.

> these cravings do not qualify these activities as substance abuse.

Strawman. Substance abuse? No. Addictions? Absolutely.

> Strawman. Substance abuse? No. Addictions? Absolutely.

That's simply not how addiction is defined e.g.:

"Addiction is a state characterized by compulsive engagement in rewarding stimuli, despite adverse consequences"

> Blinded by the anti-drug dogma you are unable to see that sometimes the only available alternative is endless suffering.

The ad-hominem is quite unnecessary,thank you. It's certainly not the only viable alternative. I'm not saying it doesn't help some people -- but religion also helps some people; I'm saying the number of people taking clinical prescriptions greatly out-number the people that actually benefit and/or are getting the optimal treatment.

> not in the last because I was experiencing it first hand.

First-hand experience isn't a good metric.

"Which apparently they do for most patients--so I wouldn't rule them out."

They work ever so slightly, over Placebo, and only for severest cases of clinical depression. They made my anxiety worse, especially the heterocyclic drugs(Prozac).

There are many researchers who collated all the studies, and still can't find any improvement over Placebo.

I am so disgusted by this sham that was forced on Psychiatrists and patients by drug companies; I am too tired to cite links for my statements, but once you look into the efficacy of antidepressants, it is very depressing.

That said, if I was considering suicide I would see a Psychiatrist. Whatever treatment you are given, truly believe you will get better. Believe you will get better with Time.

The placebo effect is the little secret of all allopathic medicine, and alternative therapies. Most of you will get better if you just believe you will get better. In my world, the placebo effect is the only actual proof of a higher power(existence of God). I don't think there's a doctor out there who won't dissagree, with the fact that the placebo effect is the strongest healing modality they have in their arsenal?

I don't think I could find one Psychiatrist in the U.S. who honestly didn't feel most of their patients felt better because of the placebo effect, and time. If any MD wants to correct my statements; I would love to hear what you think.

(please stay off the internet medical sites because I just feel the mob can make you feel worse. See a good Psychiatrist(it's a crap shoot), and believe you will get better.

Antidotally--I have been very depressed' and anxious, and it does get better with time. I guarantee the stuff you worry about in your twenties; by the time you are in your forties, you will look back on those days and maybe--laugh. Oh yea, psychiatrists never tell young patients this; that debilitating fear of death some of you have--greatly dissipates later in life. Getting older sucks, but for some reason my anxiety and depression got better?

My only regret in seeing a psychiatrist was going on addictive drugs, but I had a complete breakdown. I went from being one of the better students in grad school--to a trembling mess. I came pretty close to being a shut in. I literally couldn't be around people without getting dizzy. The only drug that helped was klonopin, and alcohol to fight the panic attacks, and the placebo effect. I have been trying to get off the benzodiazepines, but I did stop drinking.

>I don't think there's a doctor out there who won't dissagree, with the fact that the placebo effect is the strongest healing modality they have in their arsenal?

No. I'm pretty sure almost all doctors would rate.. Say.. Penicillin, or antibiotics, much much much higher than placebo....

Or Aspirin.

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