8 ms·

Serotonin may not be a major factor in depression, study suggests

42 points by mmastrac 12y ago

lutusp 12y ago
Quote: "New evidence has put into doubt the long-standing belief that a deficiency in serotonin - a chemical messenger in the brain - plays a central role in depression." Let's summarize this issue: 1. Big Pharma has sold billions of dollars' worth of SSRI-based drugs, drugs whose mode of action is to regulate serotonin to control depression. Tl;dr: big influential companies, big sales, a gullible public who think psychiatry is an evidence-based medical field. 2. Studies show that the above drugs do not work for the majority of patients. In a meta-analysis conducted by the FDA that combined the results of published and unpublished studies, "antidepressant medications have reported only modest benefits over placebo treatment, and when unpublished trial data are included, the benefit falls below accepted criteria for clinical significance." Tl;dr: these drugs do not work. http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.0050045 http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fj... 3. The linked study shows that serotonin has no clear correlation with depression in an animal model. Tl;dr: because serotonin levels and depression aren't correlated, SSRI drugs could not possibly work. Guess what effect these studies, this science, is having on the sale of antidepression drugs? None whatever. The reason? Psychiatry and psychology aren't sciences, and (unlike in real medicine) ongoing drug therapies don't hinge on evidence for effectiveness. This is why the NIMH recently ruled that the DSM, psychiatry and psychology's "bible", may no longer be used as the basis for scientific research proposals -- not surprising, it has no scientific content. http://www.newyorker.com/tech/elements/the-rats-of-n-i-m-h http://www.newyorker.com/tech/elements/the-rats-of-n-i-m-h Let the downvotes begin.
- pokpokpok 12y ago
  Are there other paths of study relating to depression that have are gathering interesting evidence? Where do you believe the field should be looking?
  - thanatropism 12y ago
    Depression is atrophy of the limbic system. I understood that flooding your brain in serotonin stimulated neuron growth. (It has never been the case that depression = low serotonin. No one has ever believed that.)
    - astrange 12y ago
      > (It has never been the case that depression = low serotonin. No one has ever believed that.) Doesn't everyone who reads about SSRIs on a pop-science level believe this?
    - seiji 12y ago
      suicide tuesdays
  - md224 12y ago
    There have been some promising studies showing rapid-onset relief for major depression following the administration of ketamine. Glutamate seems to be getting more attention these days, in terms of its potential role in mental illness.
  - lutusp 12y ago
    > Are there other paths of study relating to depression that have are gathering interesting evidence? Yes. One of the most promising is Deep Brain Stimulation: http://www.nytimes.com/2006/04/02/magazine/02depression.html?pagewanted=all http://www.nytimes.com/2006/04/02/magazine/02depression.html... Quote: "As it turned out, 8 of the 12 patients he operated on, including Deanna, felt their depressions lift while suffering minimal side effects — an incredible rate of effectiveness in patients so immovably depressed. Nor did they just vaguely recover. Their scores on the Hamilton depression scale, a standard used to measure the severity of depression, fell from the soul-deadening high 20's to the single digits — essentially normal. They've re-engaged their families, resumed jobs and friendships, started businesses, taken up hobbies old and new, replanted dying gardens. They've regained the resilience that distinguishes the healthy from the depressed." I hasten to add that DBS is nowhere near ready for the clinic -- it's experimental and risky. But it shows what can happen when people are willing to consider biological explanations instead of psychological ones.
- twir 12y ago
  Ooh, here come the Scientologists! I'm as skeptical of big Pharma as the next guy, but to say with such grandiose broad-stroked generalizing that psychiatry (or, perhaps you mean instead/also neurological pharmacology) is not science is simply untrue. Anyone with Google at their fingertips can find a dozen peer-reviewed articles about serotonin's link to mood and behavior. EDIT: accidentally a word or two.
  - dllthomas 12y ago
    Do you have any evidence that Paul is actually a Scientologist, beyond his sharing - in broad strokes - one of their opinions?
  - gipp 12y ago
    They can also find a dozen peer-reviewed articles thoroughly skewering the misuse of statistics, intentional massaging and selective cherry-picking of results, weak significance testing, and general lack of replicability that are all incredibly rife in biomedical research, and particularly in psychiatric research. It's hard to know what to trust in that area at all anymore.
  - coldtea 12y ago
    >Anyone with Google at their fingertips can find a dozen peer-reviewed articles about serotonin's link to mood and behavior. And a ton of "peer reviewed" articles are crap too. Peer review aint what it used to be.
    - lrem 12y ago
      Still, it's what demarcates the boundary between "blog about your idea, show it to some smart folk" and "proper science". And we like clean demarcation lines, they allow us to categorize without actually investigating (which is infeasible if you want to get broad knowledge).
      - coldtea 12y ago
        I'd say avoid "peer reviewed" papers like the plague if you want to find out what's actually "worth investigating" and " get a broad knowledge". Instead, wait for 2-5 years to see what still floats from all the crap that has been published. Better to read slightly behind the times, but solid, university guidebooks and published books that stood out, than to read the hot, but crappy, steam of published research.
- glenra 12y ago
  Your tl;dr for #2 isn't accurate. Yes, these medications "have reported only modest benefits over placebo treatment", but the measured benefit of placebo treatment in this case is quite large and the medications work BETTER than placebo. So even if the difference between placebo and treatment is small, the difference between treatment and no-treatment is quite large and is clinically significant. As for the claim that the difference falls below accepted criteria for clinical significance, the "accepted criteria" used to reach that conclusion are pretty arbitrary and it only just BARELY falls below the arbitrary level picked (by some), depending on which studies are included. More here: http://slatestarcodex.com/2014/07/07/ssris-much-more-than-you-wanted-to-know/ http://slatestarcodex.com/2014/07/07/ssris-much-more-than-yo... http://slatestarcodex.com/2014/06/16/things-that-sometimes-help-if-youre-depressed/ http://slatestarcodex.com/2014/06/16/things-that-sometimes-h...
  - lutusp 12y ago
    > Your tl;dr for #2 isn't accurate. Yes, these medications "have reported only modest benefits over placebo treatment", but the measured benefit of placebo treatment in this case is quite large and the medications work BETTER than placebo. Yes, unless unpublished studies are included in the analysis, after which the effect falls below that required to make a claim of clinical effectiveness. That distinction is perfectly clear in the post to which you replied. > As for the claim that the difference falls below accepted criteria for clinical significance, the "accepted criteria" used to reach that conclusion are pretty arbitrary and it only just BARELY falls below the arbitrary level picked (by some), depending on which studies are included. Weasel words, words that a scientist wouldn't dream of including in a study means to generate light, not heat. Which explains why this kind of argument is absent from the FDA study. In any case, a more recent study quoted above finds no correlation between serotonin and depression. If this study bears up under scrutiny, it undermines the basis for SSRIs as a remedy for depression, for the simple reason that serotonin and depression have no relationship. It would explain why the statistics for SSRIs are so marginal -- what's being measured is a placebo response.
    - glenra 12y ago
      > Yes, unless unpublished studies are included in the analysis, after which the effect falls below that required to make a claim of clinical effectiveness. That distinction is perfectly clear in the post to which you replied. I think you are not reading carefully. Even WITH the unpublished studies included, the placebo effect far exceeds the required effect size to be considered clinically effective which means that the combination (placebo effect+treatment effect) also far exceeds the required effect size. And the claims you make are pretty clearly rebutted in the first link I provided, which gives precise numbers to the different "clinical effectiveness" strengths. (Regarding the correlation between serotonin and depression, if it bears up it will likely establish that there is some OTHER reason that Paxil is a moderately effective antidepressant.) Here's a relevant quote from that link I gave before: ( http://slatestarcodex.com/2014/07/07/ssris-much-more-than-you-wanted-to-know/ http://slatestarcodex.com/2014/07/07/ssris-much-more-than-yo... ) "They also note that Kirsch’s study lumps all antidepressants together. This isn’t necessarily wrong. But it isn’t necessarily right, either. For example, his study used both Serzone (believed to be a weak antidepressant, rarely used) and Paxil (believed to be a stronger antidepressant, commonly used). And in fact, by his study, Paxil showed an effect size of 0.47, compared to Serzone’s 0.21. But since the difference was not statistically significant, he averaged them together and said that “antidepressants are ineffective”. In fact, his study showed that Paxil was effective, but when you average it together with a very ineffective drug, the effect disappears. He can get away with this because of the arcana of statistical significance, but by the same arcana I can get away with not doing that. So right now we have three different effect sizes. 1.2 for placebo + drug, 0.5 for drug alone if we’re being statistically merciful, 0.3 for drug alone if we’re being harsh and letting the harshest critic of antidepressants pull out all his statistical tricks."
- KrisAndrew 12y ago
  My qualm isn't with the pharmaceuticals companies, oddly enough. I have issues with the psychiatrists mostly. They rely far too much on literature and don't listen to their patients. Also, the patients are overly supine and continue treatments that aren't effective (or are partially effective with significant side effects). This combination of behaviors is toxic and leads to reduced quality of life for the patient.
- simonster 12y ago
  I appreciate skepticism about the state of pharmacological treatment of depression. Point 2 is important: it is in fact the case that several meta-analyses of the effects of anti-depressant drugs show only modest benefit in moderate depression. However, the drugs do work, they just don't work very well in many cases. The study you cite does indeed find a clinically significant effect in the most severe cases, and the drugs have a smaller but statistically significant effect in less severe cases. Additionally, the brain is complicated, and just because mice genetically depleted of serotonin do not show depression-like symptoms does not mean that toying with serotonin levels in a normal brain cannot alleviate depression. Even if depression isn't brought on by lack of serotonin, it can still be the case that potentiating the effects of serotonin can reverse depressive symptoms. In fact, antidepressant treatment does alleviate depression in mice, and my understanding is that the effects of antidepressants in mouse models are actually far stronger than in humans in a clinical setting. There has been some work to track down how antidepressants work in animal models at a systems level, e.g. http://www.sciencedirect.com/science/article/pii/S0896627309002980 http://www.sciencedirect.com/science/article/pii/S0896627309... suggests that administration of antidepressants to chronic stress model mice reverses the suppressive effects of chronic stress on growth of new brain cells in the hippocampus, and this may be related to their therapeutic action.
  - dllthomas 12y ago
    "my understanding is that the effects of antidepressants in mouse models are actually far stronger than in humans in a clinical setting." Interesting. I wonder if this is a case of "you make what you measure" - since measuring effects on rats is far, far easier than measuring them on humans (and is typically a prerequisite).
  - lutusp 12y ago
    Here's what you say: "However, the drugs do work, they just don't work very well in many cases." Here's what the science says: "... antidepressant medications have reported only modest benefits over placebo treatment, and when unpublished trial data are included, the benefit falls below accepted criteria for clinical significance." Guess which source I plan to rely on until better evidence is uncovered? One theory has it that the positive statistic among the severely depressed resulted from a dosage effect -- because of the required dosage, those specific test subjects couldn't be blinded to the fact that they were taking the experimental drug, not a placebo, therefore the experimental protocol was compromised. > Additionally, the brain is complicated, and just because mice genetically depleted of serotonin do not show depression-like symptoms does not mean that toying with serotonin levels in a normal brain cannot alleviate depression. [emphasis added] First, you're overlooking the fact that the studies that got SSRIs approved in the first place relied on animal studies using the same animals. Second, imagine a scientist saying "... just because mice genetically depleted of serotonin do not show depression-like symptoms does not mean that toying with serotonin levels in a normal brain cannot alleviate depression." Surely you see the logical error you're making here -- the argument essentially says, "if it hasn't been disproven, then it might be true." It equates an absence of evidence, with evidence. To a scientist, the guiding precept is that an idea is assumed to be false until supporting evidence appears. This is commonly known as the "null hypothesis". To a pseudoscientist, the guiding precept is that an idea is assumed to be true until contradicting evidence appears. You have just aligned yourself with a pseudoscientist's outlook. http://blogs.scientificamerican.com/doing-good-science/2011/10/04/drawing-the-line-between-science-and-pseudo-science/ http://blogs.scientificamerican.com/doing-good-science/2011/... Quote: "While a pseudo-science is set up to look for evidence that supports its claims, Popper says, a science is set up to challenge its claims and look for evidence that might prove it false. In other words, pseudo-science seeks confirmations and science seeks falsifications." This passage is particularly relevant to our exchange. > In fact, antidepressant treatment does alleviate depression in mice ... Not according to the FDA's meta-analysis quoted above. Shall I say it again? "... antidepressant medications have reported only modest benefits over placebo treatment, and when unpublished trial data are included, the benefit falls below accepted criteria for clinical significance." > ... and this may be related to their therapeutic action. Apart from a well-documented Placebo effect, which therapeutic action are you alluding to? Don't you understand that the present literature, generated by investigators subject to critical review by many interested parties, argues that there is no clear clinical role for SSRIs? And that the most recent study calls into question the most basic assumption of this class of drug therapy, that depression and serotonin are correlated? We have pharmaceutical companies advocating the use of drugs to alleviate depression on slim-to-no reliable evidence, we have studies that fail to show a correlation between depression and serotonin in the same animal population used in the original drug studies, and most important of all, we have a large population of depressed people who want to believe that psychiatry has an answer to their difficulties. As it happens, there is no present reliable answer, but there are hopeful signs that lie in other directions: http://www.nytimes.com/2006/04/02/magazine/02depression.html?pagewanted=all http://www.nytimes.com/2006/04/02/magazine/02depression.html... Quote: "As it turned out, 8 of the 12 patients he operated on, including Deanna, felt their depressions lift while suffering minimal side effects — an incredible rate of effectiveness in patients so immovably depressed. Nor did they just vaguely recover. Their scores on the Hamilton depression scale, a standard used to measure the severity of depression, fell from the soul-deadening high 20's to the single digits — essentially normal. They've re-engaged their families, resumed jobs and friendships, started businesses, taken up hobbies old and new, replanted dying gardens. They've regained the resilience that distinguishes the healthy from the depressed." Is DBS a panacea? No, not at all. First, it's a lab experiment, not a therapy. It's risky and expensive. But it shows what might result from an effort to actually understand what depression is, something that psychiatrists and psychologists seem uninterested in.
- geographomics 12y ago
  Science is certainly more difficult to apply to psychiatry than other branches of medicine - due to the relatively subjective endpoints, lack of useful animal models, and conflict with profit-based motives within the pharmaceutical industry - but your assertion that there is no scientific component to it at all really is quite the overexaggeration.
  - DanBC 12y ago
    lutusp is a troll on the subject of psychiatry. Discussions with lutusp about psychiatry are unlikely to be useful.
    - geographomics 12y ago
      Are you sure he's deliberately trolling, perhaps he genuinely believes this? Distrust of psychiatry is not uncommon, and there certainly are some really awful facets of psychiatry to selectively draw an extremist position on, especially if one looks into its abuses in recent history.
      - pessimizer 12y ago
        Distrust of SSRIs is also mainstream science, although it's still mainstream practice. The meta-analysis that showed that studies don't show a significant affect on depression from SSRIs was not published in a crank journal, and has very few serious disputes or alternative ways to view the numbers. People who cite that paper and others (and this one in the future) get treated like cranks still, though. There are a lot of people that feel like they owe their lives to SSRIs, and that they will die if they stop taking them, sent back to the same mental state as they were in during a period that they will all identify as the worst in their lives. There are also a lot of people who make an enormous amount of money in encouraging that belief. I'm not against the treatment of depression, and even possible chemical treatments of depression. I just would prefer them to work better than placebo.
        glenra 12y ago
- deleted 12y ago
  [deleted]
- marincounty 12y ago
  There's no down voting here. Your summary of the "science of Psychiatry" in general is spot on. It's time people open their eyes and expose the absolute Fraud that has bee thrust upon patients and consumers everywhere. We were all lied too requarding the efficacy of of these SSRI drugs--even the Psychiatrists were lied too. I heard anecdotally that Proxac showed so little promise that it was "shelved" for years--until they started to cherry pick studies. I am now questing most drugs! When I was in college a peer reviewed, double blind study was Holy. I had no idea Anyone(on a huge scale) would screw with clinical studies. The whole Psychiarty profession needs a thorough vetting. I recently heard some describe it as, "still in the Dark Ages"; I was so fitting. A word to the High Priced Psychiatry Specialists--your patients see right through the facade. I understand the reasons why a doctor would prescribe a lousy drug--just because they want to invoke the Placebo effect. The response from the Placebo Effect is Huge. I don't charging huge sums of money to the Non-Responders. Yes--you went to med school. Yes--you picked one of the easier Specialties. No--you don't have the moral right to take advantage of societies most fragile. It 's like kicking a Homeless person? (That said, I know how frustrating your profession has become. I cringe whenever I hear something like a suicide, or missing Psychiatrist (missing in Point Reyes-now.) Your patients do care. It's time we all band together and fight these drug companies?) Yes--I went on a rant. I went on a rant because the person above me said what I have felt for a long time.
- hrktb 12y ago
  As you mention the downvotes, I guess you understand it's not so simple. First, practician already know that the effect are far from being guaranteed, and usually after the precription there is a follow-up time span where the drug effects are checked. If something has no results, you try something else. Then, there will be results sometimes, but it might be a form of placebo. But, will you stop something that seems to help the patient, just because in most cases it shouldn't really work. Usually, no, you go on because placebo or not the results are positive. All in all, the results of this study are important, but don't have any immediate impact on how current drugs are used I think.
  - lutusp 12y ago
    > As you mention the downvotes, I guess you understand it's not so simple. Yes, and more emotional than intellectual. > But, will you stop something that seems to help the patient, just because in most cases it shouldn't really work. If I had an alternative available that might actually work, that deserved more attention and research funding, I certainly would: http://www.nytimes.com/2006/04/02/magazine/02depression.html?pagewanted=all http://www.nytimes.com/2006/04/02/magazine/02depression.html... (about Deep Brain Stimulation) > All in all, the results of this study are important, but don't have any immediate impact on how current drugs are used I think. Yes, I understand. These things take time. But imagine that a cancer drug is proven to be ineffective -- guess how long before clinicians would be required to stop prescribing it?
- jules 12y ago
  Interesting. Antidepressants have a dramatic effect on my mother. I wonder if that's all placebo.
- pessimizer 12y ago
  "Why did the substance become known as serotonin rather than its first name, enteramine? The most likely explanation is that it was first synthesized and made available for research by the American drug company, Upjohn Pharmaceutical, who chose the name 'serotonin.'" http://www.nature.com/npp/journal/v21/n1s/full/1395355a.html http://www.nature.com/npp/journal/v21/n1s/full/1395355a.html
Xcelerate 12y ago
Does anyone have experience with atypical depression? That's what I have, and SSRIs seem to do almost nothing for it. Prozac made me feel spacey, and it didn't fix any of my problems (except OCD), so I quit it. I've since read a lot of articles in psychology/psychiatry journals and it appears that MAOIs (nardil, parnate), are much more effective for this condition, although they have strong side effects and dietary restrictions. MAOIs were the original antidepressants used in the 1950s and 1960s. A lot of articles indicate nardil is particularly effective for social anxiety, over SSRIs. Atypical depression is characterized by excessive sleeping, extreme rejection sensitivity, leaden paralysis (heavy limbs/fatigue), and the ability to feel happy in response to a positive event. This last characteristic is a distinguishing factor from regular (endogenous) depression, where even positive events won't make someone feel happier.
- nether 12y ago
  Aren't those all symptoms of major depressive disorder per DSM?
- anigbrowl 12y ago
  I do, similar outcomes to your experience. I haven't tried MAOIs, they were deeply out of fashion when I was first diagnosed.
- _bdog 12y ago
  You probably need something targeting dopamine, the heavy limbs/fatigue, excessive sleeping etc. are typical symptoms of dopaminergic systems not working properly. Try an NRI like reboxetine. Exercise to make it work better. Go outside for 15 minutes in the morning, if you don't do that already. A study showed that light exposure of 30 minutes per day make a 1/3 reduction in medication possible. And stop smoking cannabis, if you do, it has catastrophic effects on dopaminergic systems.
- lutusp 12y ago
  You know what? I'm not either a doctor nor a psychiatrist, but what you've described sounds like chronic fatigue syndrome, not depression. Or (second vote) hypothyroidism, which also can create some of the symptom set you describe. Both depression and CFS have no known causes, which makes their diagnosis problematic and their treatment even more problematic. But overall I would suggest that you look at CFS -- IMHO it seems to be a better fit to your symptoms. Again, I am not a doctor and this is just an off-the-cuff opinion.
ianstallings 12y ago
It's important to note that they are using the word major to substantiate. It might not be major, but I think the word important would be justified. Saying there might be other chemicals or components involved in depression seems to be obvious given our limited understanding of the topic. We just have a currently useful tool to help, SSRIs. Maybe with these type of studies we'll see more accurate medicines.
- lutusp 12y ago
  > We just have a currently useful tool to help, SSRIs. Yes, but the quoted study shows that serotonin and depression aren't correlated. If that is so, if the study bears up under scrutiny, then SSRIs cannot possibly work. The prior FDA meta-analysis shows that SSRIs don't work for the majority of patients, this new study explains why. > Maybe with these type of studies we'll see more accurate medicines. Let me suggest an alternative -- instead of searching for a better description of depression, we should seek an explanation, like in science. Armed with an explanation, we could treat depression's causes, rather than its symptoms. But we can't do this with psychiatry -- psychiatrists aren't scientists and have no respect for evidence.
coldcode 12y ago
Even with all our advanced modern knowledge we still barely understand how the brain works much less what happens when it doesn't "work" and even that depends on how you define "doesn't work". I suffered from a major depressive time about 12 years ago and taking a drug helped me get out of it and it hasn't returned. But there is no way to know what went wrong much less prove that the drug had any actual clinical effect; at least it appeared to make life possible again. Some day we might actually understand enough brain chemistry to know the exact mechanisms. Today it is still a lot of guesswork.
- meowface 12y ago
  It makes me wonder if we'll even have much more understanding of the brain in 100 years than we do now. At least, understanding at a level that lets us effectively stop the root cause of many complex mental disorders without deleterious side effects.
  - devnonymous 12y ago
    <disclaimer > This is a general statement, I do not intend it to be 'in response' to your comment in particular, your comment just provides a logical space to precede mine.< /disclaimer > . I don't understand this negative, defeatist attitude of people with regards to our 'current' understanding of anything. We certainly know a lot more about everything in this world, including the brain than what we did in the year 1914. Why then is there a doubt that 100 years hence we'd understand lesser ? Is there really a proven 'law of diminishing returns' in the field of scientific research. Also, in reference to the parent comment, sure there isn't possibly a way to be 100% certain that the drugs did indeed help but the reasoning behind manufacturing them were presumably sound scientifically speaking based on the knowledge known at the time of their creation and the experiments conducted then. Development occurs not by discarding prior knowledge but by refining it or in the worst case scenario, eliminating the factors that make it obsolete. So, in summary, I think we are in the 'discovery phase' of medicine these days, similar to what the 1600-1900s were for physics.

42 points by mmastrac 12y ago

Quote: "New evidence has put into doubt the long-standing belief that a deficiency in serotonin - a chemical messenger in the brain - plays a central role in depression." Let's summarize this issue: 1. Big Pharma has sold billions of dollars' worth of SSRI-based drugs, drugs whose mode of action is to regulate serotonin to control depression. Tl;dr: big influential companies, big sales, a gullible public who think psychiatry is an evidence-based medical field. 2. Studies show that the above drugs do not work for the majority of patients. In a meta-analysis conducted by the FDA that combined the results of published and unpublished studies, "antidepressant medications have reported only modest benefits over placebo treatment, and when unpublished trial data are included, the benefit falls below accepted criteria for clinical significance." Tl;dr: these drugs do not work. http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.0050045 http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fj... 3. The linked study shows that serotonin has no clear correlation with depression in an animal model. Tl;dr: because serotonin levels and depression aren't correlated, SSRI drugs could not possibly work. Guess what effect these studies, this science, is having on the sale of antidepression drugs? None whatever. The reason? Psychiatry and psychology aren't sciences, and (unlike in real medicine) ongoing drug therapies don't hinge on evidence for effectiveness. This is why the NIMH recently ruled that the DSM, psychiatry and psychology's "bible", may no longer be used as the basis for scientific research proposals -- not surprising, it has no scientific content. http://www.newyorker.com/tech/elements/the-rats-of-n-i-m-h http://www.newyorker.com/tech/elements/the-rats-of-n-i-m-h Let the downvotes begin.

pokpokpok 12y ago
Are there other paths of study relating to depression that have are gathering interesting evidence? Where do you believe the field should be looking?
- thanatropism 12y ago
  Depression is atrophy of the limbic system. I understood that flooding your brain in serotonin stimulated neuron growth. (It has never been the case that depression = low serotonin. No one has ever believed that.)
  - astrange 12y ago
    > (It has never been the case that depression = low serotonin. No one has ever believed that.) Doesn't everyone who reads about SSRIs on a pop-science level believe this?
  - seiji 12y ago
    suicide tuesdays
- md224 12y ago
  There have been some promising studies showing rapid-onset relief for major depression following the administration of ketamine. Glutamate seems to be getting more attention these days, in terms of its potential role in mental illness.
- lutusp 12y ago
  > Are there other paths of study relating to depression that have are gathering interesting evidence? Yes. One of the most promising is Deep Brain Stimulation: http://www.nytimes.com/2006/04/02/magazine/02depression.html?pagewanted=all http://www.nytimes.com/2006/04/02/magazine/02depression.html... Quote: "As it turned out, 8 of the 12 patients he operated on, including Deanna, felt their depressions lift while suffering minimal side effects — an incredible rate of effectiveness in patients so immovably depressed. Nor did they just vaguely recover. Their scores on the Hamilton depression scale, a standard used to measure the severity of depression, fell from the soul-deadening high 20's to the single digits — essentially normal. They've re-engaged their families, resumed jobs and friendships, started businesses, taken up hobbies old and new, replanted dying gardens. They've regained the resilience that distinguishes the healthy from the depressed." I hasten to add that DBS is nowhere near ready for the clinic -- it's experimental and risky. But it shows what can happen when people are willing to consider biological explanations instead of psychological ones.
twir 12y ago
Ooh, here come the Scientologists! I'm as skeptical of big Pharma as the next guy, but to say with such grandiose broad-stroked generalizing that psychiatry (or, perhaps you mean instead/also neurological pharmacology) is not science is simply untrue. Anyone with Google at their fingertips can find a dozen peer-reviewed articles about serotonin's link to mood and behavior. EDIT: accidentally a word or two.
- dllthomas 12y ago
  Do you have any evidence that Paul is actually a Scientologist, beyond his sharing - in broad strokes - one of their opinions?
- gipp 12y ago
  They can also find a dozen peer-reviewed articles thoroughly skewering the misuse of statistics, intentional massaging and selective cherry-picking of results, weak significance testing, and general lack of replicability that are all incredibly rife in biomedical research, and particularly in psychiatric research. It's hard to know what to trust in that area at all anymore.
- coldtea 12y ago
  >Anyone with Google at their fingertips can find a dozen peer-reviewed articles about serotonin's link to mood and behavior. And a ton of "peer reviewed" articles are crap too. Peer review aint what it used to be.
  - lrem 12y ago
    Still, it's what demarcates the boundary between "blog about your idea, show it to some smart folk" and "proper science". And we like clean demarcation lines, they allow us to categorize without actually investigating (which is infeasible if you want to get broad knowledge).
    - coldtea 12y ago
      I'd say avoid "peer reviewed" papers like the plague if you want to find out what's actually "worth investigating" and " get a broad knowledge". Instead, wait for 2-5 years to see what still floats from all the crap that has been published. Better to read slightly behind the times, but solid, university guidebooks and published books that stood out, than to read the hot, but crappy, steam of published research.
glenra 12y ago
Your tl;dr for #2 isn't accurate. Yes, these medications "have reported only modest benefits over placebo treatment", but the measured benefit of placebo treatment in this case is quite large and the medications work BETTER than placebo. So even if the difference between placebo and treatment is small, the difference between treatment and no-treatment is quite large and is clinically significant. As for the claim that the difference falls below accepted criteria for clinical significance, the "accepted criteria" used to reach that conclusion are pretty arbitrary and it only just BARELY falls below the arbitrary level picked (by some), depending on which studies are included. More here: http://slatestarcodex.com/2014/07/07/ssris-much-more-than-you-wanted-to-know/ http://slatestarcodex.com/2014/07/07/ssris-much-more-than-yo... http://slatestarcodex.com/2014/06/16/things-that-sometimes-help-if-youre-depressed/ http://slatestarcodex.com/2014/06/16/things-that-sometimes-h...
- lutusp 12y ago
  > Your tl;dr for #2 isn't accurate. Yes, these medications "have reported only modest benefits over placebo treatment", but the measured benefit of placebo treatment in this case is quite large and the medications work BETTER than placebo. Yes, unless unpublished studies are included in the analysis, after which the effect falls below that required to make a claim of clinical effectiveness. That distinction is perfectly clear in the post to which you replied. > As for the claim that the difference falls below accepted criteria for clinical significance, the "accepted criteria" used to reach that conclusion are pretty arbitrary and it only just BARELY falls below the arbitrary level picked (by some), depending on which studies are included. Weasel words, words that a scientist wouldn't dream of including in a study means to generate light, not heat. Which explains why this kind of argument is absent from the FDA study. In any case, a more recent study quoted above finds no correlation between serotonin and depression. If this study bears up under scrutiny, it undermines the basis for SSRIs as a remedy for depression, for the simple reason that serotonin and depression have no relationship. It would explain why the statistics for SSRIs are so marginal -- what's being measured is a placebo response.
  - glenra 12y ago
    > Yes, unless unpublished studies are included in the analysis, after which the effect falls below that required to make a claim of clinical effectiveness. That distinction is perfectly clear in the post to which you replied. I think you are not reading carefully. Even WITH the unpublished studies included, the placebo effect far exceeds the required effect size to be considered clinically effective which means that the combination (placebo effect+treatment effect) also far exceeds the required effect size. And the claims you make are pretty clearly rebutted in the first link I provided, which gives precise numbers to the different "clinical effectiveness" strengths. (Regarding the correlation between serotonin and depression, if it bears up it will likely establish that there is some OTHER reason that Paxil is a moderately effective antidepressant.) Here's a relevant quote from that link I gave before: ( http://slatestarcodex.com/2014/07/07/ssris-much-more-than-you-wanted-to-know/ http://slatestarcodex.com/2014/07/07/ssris-much-more-than-yo... ) "They also note that Kirsch’s study lumps all antidepressants together. This isn’t necessarily wrong. But it isn’t necessarily right, either. For example, his study used both Serzone (believed to be a weak antidepressant, rarely used) and Paxil (believed to be a stronger antidepressant, commonly used). And in fact, by his study, Paxil showed an effect size of 0.47, compared to Serzone’s 0.21. But since the difference was not statistically significant, he averaged them together and said that “antidepressants are ineffective”. In fact, his study showed that Paxil was effective, but when you average it together with a very ineffective drug, the effect disappears. He can get away with this because of the arcana of statistical significance, but by the same arcana I can get away with not doing that. So right now we have three different effect sizes. 1.2 for placebo + drug, 0.5 for drug alone if we’re being statistically merciful, 0.3 for drug alone if we’re being harsh and letting the harshest critic of antidepressants pull out all his statistical tricks."
KrisAndrew 12y ago
My qualm isn't with the pharmaceuticals companies, oddly enough. I have issues with the psychiatrists mostly. They rely far too much on literature and don't listen to their patients. Also, the patients are overly supine and continue treatments that aren't effective (or are partially effective with significant side effects). This combination of behaviors is toxic and leads to reduced quality of life for the patient.
simonster 12y ago
I appreciate skepticism about the state of pharmacological treatment of depression. Point 2 is important: it is in fact the case that several meta-analyses of the effects of anti-depressant drugs show only modest benefit in moderate depression. However, the drugs do work, they just don't work very well in many cases. The study you cite does indeed find a clinically significant effect in the most severe cases, and the drugs have a smaller but statistically significant effect in less severe cases. Additionally, the brain is complicated, and just because mice genetically depleted of serotonin do not show depression-like symptoms does not mean that toying with serotonin levels in a normal brain cannot alleviate depression. Even if depression isn't brought on by lack of serotonin, it can still be the case that potentiating the effects of serotonin can reverse depressive symptoms. In fact, antidepressant treatment does alleviate depression in mice, and my understanding is that the effects of antidepressants in mouse models are actually far stronger than in humans in a clinical setting. There has been some work to track down how antidepressants work in animal models at a systems level, e.g. http://www.sciencedirect.com/science/article/pii/S0896627309002980 http://www.sciencedirect.com/science/article/pii/S0896627309... suggests that administration of antidepressants to chronic stress model mice reverses the suppressive effects of chronic stress on growth of new brain cells in the hippocampus, and this may be related to their therapeutic action.
- dllthomas 12y ago
  "my understanding is that the effects of antidepressants in mouse models are actually far stronger than in humans in a clinical setting." Interesting. I wonder if this is a case of "you make what you measure" - since measuring effects on rats is far, far easier than measuring them on humans (and is typically a prerequisite).
- lutusp 12y ago
  Here's what you say: "However, the drugs do work, they just don't work very well in many cases." Here's what the science says: "... antidepressant medications have reported only modest benefits over placebo treatment, and when unpublished trial data are included, the benefit falls below accepted criteria for clinical significance." Guess which source I plan to rely on until better evidence is uncovered? One theory has it that the positive statistic among the severely depressed resulted from a dosage effect -- because of the required dosage, those specific test subjects couldn't be blinded to the fact that they were taking the experimental drug, not a placebo, therefore the experimental protocol was compromised. > Additionally, the brain is complicated, and just because mice genetically depleted of serotonin do not show depression-like symptoms does not mean that toying with serotonin levels in a normal brain cannot alleviate depression. [emphasis added] First, you're overlooking the fact that the studies that got SSRIs approved in the first place relied on animal studies using the same animals. Second, imagine a scientist saying "... just because mice genetically depleted of serotonin do not show depression-like symptoms does not mean that toying with serotonin levels in a normal brain cannot alleviate depression." Surely you see the logical error you're making here -- the argument essentially says, "if it hasn't been disproven, then it might be true." It equates an absence of evidence, with evidence. To a scientist, the guiding precept is that an idea is assumed to be false until supporting evidence appears. This is commonly known as the "null hypothesis". To a pseudoscientist, the guiding precept is that an idea is assumed to be true until contradicting evidence appears. You have just aligned yourself with a pseudoscientist's outlook. http://blogs.scientificamerican.com/doing-good-science/2011/10/04/drawing-the-line-between-science-and-pseudo-science/ http://blogs.scientificamerican.com/doing-good-science/2011/... Quote: "While a pseudo-science is set up to look for evidence that supports its claims, Popper says, a science is set up to challenge its claims and look for evidence that might prove it false. In other words, pseudo-science seeks confirmations and science seeks falsifications." This passage is particularly relevant to our exchange. > In fact, antidepressant treatment does alleviate depression in mice ... Not according to the FDA's meta-analysis quoted above. Shall I say it again? "... antidepressant medications have reported only modest benefits over placebo treatment, and when unpublished trial data are included, the benefit falls below accepted criteria for clinical significance." > ... and this may be related to their therapeutic action. Apart from a well-documented Placebo effect, which therapeutic action are you alluding to? Don't you understand that the present literature, generated by investigators subject to critical review by many interested parties, argues that there is no clear clinical role for SSRIs? And that the most recent study calls into question the most basic assumption of this class of drug therapy, that depression and serotonin are correlated? We have pharmaceutical companies advocating the use of drugs to alleviate depression on slim-to-no reliable evidence, we have studies that fail to show a correlation between depression and serotonin in the same animal population used in the original drug studies, and most important of all, we have a large population of depressed people who want to believe that psychiatry has an answer to their difficulties. As it happens, there is no present reliable answer, but there are hopeful signs that lie in other directions: http://www.nytimes.com/2006/04/02/magazine/02depression.html?pagewanted=all http://www.nytimes.com/2006/04/02/magazine/02depression.html... Quote: "As it turned out, 8 of the 12 patients he operated on, including Deanna, felt their depressions lift while suffering minimal side effects — an incredible rate of effectiveness in patients so immovably depressed. Nor did they just vaguely recover. Their scores on the Hamilton depression scale, a standard used to measure the severity of depression, fell from the soul-deadening high 20's to the single digits — essentially normal. They've re-engaged their families, resumed jobs and friendships, started businesses, taken up hobbies old and new, replanted dying gardens. They've regained the resilience that distinguishes the healthy from the depressed." Is DBS a panacea? No, not at all. First, it's a lab experiment, not a therapy. It's risky and expensive. But it shows what might result from an effort to actually understand what depression is, something that psychiatrists and psychologists seem uninterested in.
geographomics 12y ago
Science is certainly more difficult to apply to psychiatry than other branches of medicine - due to the relatively subjective endpoints, lack of useful animal models, and conflict with profit-based motives within the pharmaceutical industry - but your assertion that there is no scientific component to it at all really is quite the overexaggeration.
- DanBC 12y ago
  lutusp is a troll on the subject of psychiatry. Discussions with lutusp about psychiatry are unlikely to be useful.
  - geographomics 12y ago
    Are you sure he's deliberately trolling, perhaps he genuinely believes this? Distrust of psychiatry is not uncommon, and there certainly are some really awful facets of psychiatry to selectively draw an extremist position on, especially if one looks into its abuses in recent history.
    - pessimizer 12y ago
      Distrust of SSRIs is also mainstream science, although it's still mainstream practice. The meta-analysis that showed that studies don't show a significant affect on depression from SSRIs was not published in a crank journal, and has very few serious disputes or alternative ways to view the numbers. People who cite that paper and others (and this one in the future) get treated like cranks still, though. There are a lot of people that feel like they owe their lives to SSRIs, and that they will die if they stop taking them, sent back to the same mental state as they were in during a period that they will all identify as the worst in their lives. There are also a lot of people who make an enormous amount of money in encouraging that belief. I'm not against the treatment of depression, and even possible chemical treatments of depression. I just would prefer them to work better than placebo.
      - glenra 12y ago
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marincounty 12y ago
There's no down voting here. Your summary of the "science of Psychiatry" in general is spot on. It's time people open their eyes and expose the absolute Fraud that has bee thrust upon patients and consumers everywhere. We were all lied too requarding the efficacy of of these SSRI drugs--even the Psychiatrists were lied too. I heard anecdotally that Proxac showed so little promise that it was "shelved" for years--until they started to cherry pick studies. I am now questing most drugs! When I was in college a peer reviewed, double blind study was Holy. I had no idea Anyone(on a huge scale) would screw with clinical studies. The whole Psychiarty profession needs a thorough vetting. I recently heard some describe it as, "still in the Dark Ages"; I was so fitting. A word to the High Priced Psychiatry Specialists--your patients see right through the facade. I understand the reasons why a doctor would prescribe a lousy drug--just because they want to invoke the Placebo effect. The response from the Placebo Effect is Huge. I don't charging huge sums of money to the Non-Responders. Yes--you went to med school. Yes--you picked one of the easier Specialties. No--you don't have the moral right to take advantage of societies most fragile. It 's like kicking a Homeless person? (That said, I know how frustrating your profession has become. I cringe whenever I hear something like a suicide, or missing Psychiatrist (missing in Point Reyes-now.) Your patients do care. It's time we all band together and fight these drug companies?) Yes--I went on a rant. I went on a rant because the person above me said what I have felt for a long time.
hrktb 12y ago
As you mention the downvotes, I guess you understand it's not so simple. First, practician already know that the effect are far from being guaranteed, and usually after the precription there is a follow-up time span where the drug effects are checked. If something has no results, you try something else. Then, there will be results sometimes, but it might be a form of placebo. But, will you stop something that seems to help the patient, just because in most cases it shouldn't really work. Usually, no, you go on because placebo or not the results are positive. All in all, the results of this study are important, but don't have any immediate impact on how current drugs are used I think.
- lutusp 12y ago
  > As you mention the downvotes, I guess you understand it's not so simple. Yes, and more emotional than intellectual. > But, will you stop something that seems to help the patient, just because in most cases it shouldn't really work. If I had an alternative available that might actually work, that deserved more attention and research funding, I certainly would: http://www.nytimes.com/2006/04/02/magazine/02depression.html?pagewanted=all http://www.nytimes.com/2006/04/02/magazine/02depression.html... (about Deep Brain Stimulation) > All in all, the results of this study are important, but don't have any immediate impact on how current drugs are used I think. Yes, I understand. These things take time. But imagine that a cancer drug is proven to be ineffective -- guess how long before clinicians would be required to stop prescribing it?
jules 12y ago
Interesting. Antidepressants have a dramatic effect on my mother. I wonder if that's all placebo.
pessimizer 12y ago
"Why did the substance become known as serotonin rather than its first name, enteramine? The most likely explanation is that it was first synthesized and made available for research by the American drug company, Upjohn Pharmaceutical, who chose the name 'serotonin.'" http://www.nature.com/npp/journal/v21/n1s/full/1395355a.html http://www.nature.com/npp/journal/v21/n1s/full/1395355a.html

Xcelerate 12y ago

Does anyone have experience with atypical depression? That's what I have, and SSRIs seem to do almost nothing for it. Prozac made me feel spacey, and it didn't fix any of my problems (except OCD), so I quit it. I've since read a lot of articles in psychology/psychiatry journals and it appears that MAOIs (nardil, parnate), are much more effective for this condition, although they have strong side effects and dietary restrictions. MAOIs were the original antidepressants used in the 1950s and 1960s. A lot of articles indicate nardil is particularly effective for social anxiety, over SSRIs. Atypical depression is characterized by excessive sleeping, extreme rejection sensitivity, leaden paralysis (heavy limbs/fatigue), and the ability to feel happy in response to a positive event. This last characteristic is a distinguishing factor from regular (endogenous) depression, where even positive events won't make someone feel happier.

nether 12y ago
Aren't those all symptoms of major depressive disorder per DSM?
anigbrowl 12y ago
I do, similar outcomes to your experience. I haven't tried MAOIs, they were deeply out of fashion when I was first diagnosed.
_bdog 12y ago
You probably need something targeting dopamine, the heavy limbs/fatigue, excessive sleeping etc. are typical symptoms of dopaminergic systems not working properly. Try an NRI like reboxetine. Exercise to make it work better. Go outside for 15 minutes in the morning, if you don't do that already. A study showed that light exposure of 30 minutes per day make a 1/3 reduction in medication possible. And stop smoking cannabis, if you do, it has catastrophic effects on dopaminergic systems.
lutusp 12y ago
You know what? I'm not either a doctor nor a psychiatrist, but what you've described sounds like chronic fatigue syndrome, not depression. Or (second vote) hypothyroidism, which also can create some of the symptom set you describe. Both depression and CFS have no known causes, which makes their diagnosis problematic and their treatment even more problematic. But overall I would suggest that you look at CFS -- IMHO it seems to be a better fit to your symptoms. Again, I am not a doctor and this is just an off-the-cuff opinion.

ianstallings 12y ago

It's important to note that they are using the word major to substantiate. It might not be major, but I think the word important would be justified. Saying there might be other chemicals or components involved in depression seems to be obvious given our limited understanding of the topic. We just have a currently useful tool to help, SSRIs. Maybe with these type of studies we'll see more accurate medicines.

lutusp 12y ago
> We just have a currently useful tool to help, SSRIs. Yes, but the quoted study shows that serotonin and depression aren't correlated. If that is so, if the study bears up under scrutiny, then SSRIs cannot possibly work. The prior FDA meta-analysis shows that SSRIs don't work for the majority of patients, this new study explains why. > Maybe with these type of studies we'll see more accurate medicines. Let me suggest an alternative -- instead of searching for a better description of depression, we should seek an explanation, like in science. Armed with an explanation, we could treat depression's causes, rather than its symptoms. But we can't do this with psychiatry -- psychiatrists aren't scientists and have no respect for evidence.

coldcode 12y ago

Even with all our advanced modern knowledge we still barely understand how the brain works much less what happens when it doesn't "work" and even that depends on how you define "doesn't work". I suffered from a major depressive time about 12 years ago and taking a drug helped me get out of it and it hasn't returned. But there is no way to know what went wrong much less prove that the drug had any actual clinical effect; at least it appeared to make life possible again. Some day we might actually understand enough brain chemistry to know the exact mechanisms. Today it is still a lot of guesswork.

meowface 12y ago
It makes me wonder if we'll even have much more understanding of the brain in 100 years than we do now. At least, understanding at a level that lets us effectively stop the root cause of many complex mental disorders without deleterious side effects.
- devnonymous 12y ago
  <disclaimer > This is a general statement, I do not intend it to be 'in response' to your comment in particular, your comment just provides a logical space to precede mine.< /disclaimer > . I don't understand this negative, defeatist attitude of people with regards to our 'current' understanding of anything. We certainly know a lot more about everything in this world, including the brain than what we did in the year 1914. Why then is there a doubt that 100 years hence we'd understand lesser ? Is there really a proven 'law of diminishing returns' in the field of scientific research. Also, in reference to the parent comment, sure there isn't possibly a way to be 100% certain that the drugs did indeed help but the reasoning behind manufacturing them were presumably sound scientifically speaking based on the knowledge known at the time of their creation and the experiments conducted then. Development occurs not by discarding prior knowledge but by refining it or in the worst case scenario, eliminating the factors that make it obsolete. So, in summary, I think we are in the 'discovery phase' of medicine these days, similar to what the 1600-1900s were for physics.