6 ms·

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 t

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 antidepressant medications have reported only modest benefits over placebo treatment, and when unpublished trial data are included, the benefit falls below accepted criteria for clinical significance."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.
- simonster 12y ago
  Okay, I'll bite: > 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." With all due respect, read the paper you linked to! Here's what it says in the places you didn't quote: "Meta-analyses of antidepressant efficacy based on data from published trials reveal benefits that are statistically significant, but of marginal clinical significance [1]." "Although the difference between these means easily attained statistical significance (Table 2, Model 3a), it does not meet the three-point drug–placebo criterion for clinical significance used by NICE." "Although drug type and duration of treatment were unrelated to improvement, the drug versus placebo difference remained significant, and amount of improvement was a function of baseline severity (Table 2, Model 1a)." "The difference between drug and placebo exceeded NICE's 0.50 standardized mean difference criterion at comparisons exceeding 28 in baseline severity." > 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. SSRIs were approved several decades ago, but studies in the last decade still show the same effects, e.g. the study I linked to above, which was conducted in 2009 using fluoxetine, which was approved in 1987. The lifespan of a mouse is around a year, so there is zero chance that any of the animals are the same. In Figure 1, it reproduces the result that antidepressants reduce depressive behaviors in mouse models on a variety of tests. This is not an isolated result; basically all of the rodent studies show similar findings. > 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. This is in response to your claim that "the drugs could not possibly work." The drugs can work even if serotonin-depleted animals are not depressed. And as I've stated, there is an abundance of evidence that the drugs do work in mice, even though serotonin-depleted mice are not depressed. > > In fact, antidepressant treatment does alleviate depression in mice ... > Not according to the FDA's meta-analysis quoted above. That meta-analysis is in humans. Mice are not humans! That is a big reason why it's so hard to develop good antidepressants in the first place. > Apart from a well-documented Placebo effect, which therapeutic action are you alluding to? The therapeutic action in mice, which is replicated in the study I linked to and many others. As far as DBS goes, one of the problems with determining if DBS actually works for depression is that most studies have not been placebo controlled. Also, the largest study that I'm aware of was recently shut down by the FDA for lack of efficacy: http://neurocritic.blogspot.com/2014/01/broaden-trial-of-dbs-for-treatment.html http://neurocritic.blogspot.com/2014/01/broaden-trial-of-dbs...

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.

simonster 12y ago
Okay, I'll bite: > 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." With all due respect, read the paper you linked to! Here's what it says in the places you didn't quote: "Meta-analyses of antidepressant efficacy based on data from published trials reveal benefits that are statistically significant, but of marginal clinical significance [1]." "Although the difference between these means easily attained statistical significance (Table 2, Model 3a), it does not meet the three-point drug–placebo criterion for clinical significance used by NICE." "Although drug type and duration of treatment were unrelated to improvement, the drug versus placebo difference remained significant, and amount of improvement was a function of baseline severity (Table 2, Model 1a)." "The difference between drug and placebo exceeded NICE's 0.50 standardized mean difference criterion at comparisons exceeding 28 in baseline severity." > 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. SSRIs were approved several decades ago, but studies in the last decade still show the same effects, e.g. the study I linked to above, which was conducted in 2009 using fluoxetine, which was approved in 1987. The lifespan of a mouse is around a year, so there is zero chance that any of the animals are the same. In Figure 1, it reproduces the result that antidepressants reduce depressive behaviors in mouse models on a variety of tests. This is not an isolated result; basically all of the rodent studies show similar findings. > 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. This is in response to your claim that "the drugs could not possibly work." The drugs can work even if serotonin-depleted animals are not depressed. And as I've stated, there is an abundance of evidence that the drugs do work in mice, even though serotonin-depleted mice are not depressed. > > In fact, antidepressant treatment does alleviate depression in mice ... > Not according to the FDA's meta-analysis quoted above. That meta-analysis is in humans. Mice are not humans! That is a big reason why it's so hard to develop good antidepressants in the first place. > Apart from a well-documented Placebo effect, which therapeutic action are you alluding to? The therapeutic action in mice, which is replicated in the study I linked to and many others. As far as DBS goes, one of the problems with determining if DBS actually works for depression is that most studies have not been placebo controlled. Also, the largest study that I'm aware of was recently shut down by the FDA for lack of efficacy: http://neurocritic.blogspot.com/2014/01/broaden-trial-of-dbs-for-treatment.html http://neurocritic.blogspot.com/2014/01/broaden-trial-of-dbs...