Antidepressants, as I pointed out yesterday, is the most widely use prescription drug in America. Hence you could say it is likely one of the most used brain hacks. According to an independent 2005 study 11% of American females, and 5% of men take antidepressants (this data set is excluding the institutionalized population). However, what is understudied in the consequences of long term use of antidepressants.
Here is a classic example of it is hard to know what to believe.
Antidepressants and life span – take I.
Petrascheck et. al., in a 2007 Nature paper tested 88,000 compounds to finds ones that increase life span in C. elegans. Talk about high throughput science. The C. elegans were grown on a liquid medium in 384-well plates and starting on day 1 the animals were exposed the one of the compounds. From this big screen they found 1,083 compounds they wanted to retest and report that 115 compounds statistically improved life span. One of these compounds that increased life span was related to a certain class of antidepressants, that are known to influence intracellular serotonin (5-HT) signaling.
Now the researchers realizing that antidepressants were already widely tested and approved for human use they went on to further test 20 different compounds that affect serotonin signalling. Four of these compounds increased life span by 20 to 33% (mianserin, mirtazapine, methiothepin and cyproheptadine). All four of these are antagonist to the 5-HT 2 receptor. Both mianserin and mirtazapine are used to treat depression in humans.
Interestingly, though they don’t discuss it much in the paper the other antidepressants they tested caused a drastic reduction in life span including some of the well known ones you have all heard of:
SSRI (selective serotonin reuptake inhibitors)
Fluoxetine: -11 to -48 % decrease
Sertraline: -76 to -80% decrease
Paroxetine: -42 to -76% decrease
This does not bode well for the humans on antidepressants (but obviously they have a need for them – though it is argued antidepressants are over prescribed).
But let for a moment stick to the positive story that the other class of antidepressants – the 5-HT 2 receptor antagonists improved lifes pan. The researchers perform a number of other experiments to conclude:
We found that C. elegans life span is increased by giving adult animals mianserin, a drug used as an antidepressant in humans. This effect requires the presence of serotonin as well as two neurotransmitter receptors: the SER-4 serotonin receptor and the SER-3 octopamine receptor. Similar to its antagonistic action on human serotonin receptors, mianserin inhibits both SER-4 and SER-3. Serotonin and octopamine are thought to serve as physiological antagonists that signal the presence of food (serotonin) versus starvation (octopamine) in C. elegans11,16,25. It may be that these two neurotransmitters exist in a dynamic equilibrium that is tipped in the direction of a starvation response by mianserin, possibly because of the greater inhibitory effect of mianserin on SER-4 than SER-3. In this way, mianserin might potentially create a ‘perceived’ state of starvation that, despite adequate food intake, would activate mechanisms of lifespan extension downstream of dietary restriction. Interestingly, one side effect of mianserin in humans is increased appetite, suggesting a possible evolutionary link between appetite and lifespan in C. elegans and humans27
Now here is where things get interesting. Basically what they are saying is that the antidepressant, mianserin, is inducing the same effect as dietary restriction (which we know from repeated testing over the last 90 years extend various organisms life span). I need to point out that according to the authors arguments the organisms receiving mianserin were not calorie restricted and when they combined mianserin with dietary restriction the animals only lived an extra 4% beyond just dietary restriction. Therefore, they conclude that life span increase induced via mianserin is not because of dietary restriction (though it might be using similar mechanisms – the sense of being in starvation mode).
But I wonder since humans that take these antidepressants have an increased appetite (they feel starved) then why didn’t the C. elegans also increase their eating and possibly wipe out not only their hunger response but possibly the increase in life span?
Antidepressant and life span – take II.
New paper – trying to replicated the above one:
Well a new paper just came out by Zarse and Risow 2008 (PLOS one, freely available). Inspired by the original nature paper I just outlined above. The researchers set off to replicate the results in C. elegans using the two main antidepressant drugs from the previous paper (mianserin and methiothepin). However, they didn’t use a liquid based medium, but instead used what they argue is the more “standardized and widely accepted agar-based assay”.
What they found was that both mianserin and methiothepin DECREASED life span and increased fat (which is the same that is found with humans). The authors suggest that on a liquid based diet the organisms are kept in an “a priori state of calorie restriction”. They point out that they replicated the increase fat gain in C. elegans as previously seen with humans on the same antidepressant, and that other drugs that increase life span in these organisms result in a decrease of fat mass (but certain genetic manipulations (e.g. insulin/IGF-1 receptor disruption) that extend life span report an increase in fat mass).
So you can see that a certain type of antidepressant had completely opposite effects on life span depending on the simple difference between liquid base medium and a solid agar-based medium. The question then is which one is more applicable to the human condition. Based on the weight gain seen in humans taking these type of antidepressants suggests the agar-based medium is more appropriate and therefore could lead to a reduced life span.
(Also note in the original study the whole class of the widely used SSRI (Fluoxetine, Sertraline, Paroxetine) antidepressant also dramatically reduced life span of C. elegans. Note Prozac is Fluoxetine.)
Now obviously there is an important need to treat people with depression. Anything to reduce the suffering caused by depression is urgently needed. Recent meta-analysis raises questions about the efficacy of anti-depressant drugs beyond a placebo effect and I am sure this a hot debate in the field (see yesterday`s post regarding the possible benefits of the placebo affect and the difficulty in producing this positive effect without actually prescribing the drugs).
Do antidepressants effectively decrease depression and hopefully prevent suicide? I do not know the answer, but something needs to be done to prevent the suffering and possible tragedy. If antidepressants are actually effective then maybe the potential reduction in life span is not too high of a cost to pay. However, if they are not effective (or only in very limited situations – see yesterday’s post) and they reduce life span the pharmaceutical industry should re-evaluate their whole approach including their moral and ethics.
Update: if you want to learn out more check out this pieces: do antidepressant work just because they increase your hunger