Action Potential

Antidepressants and caloric restriction, what’s the connection?

ResearchBlogging.org

If it exists, it must be a tenuous link, right? Well, at least in C. elegans, it is definitely not. Linda Buck and colleagues revealed, in a recent Nature article that drugs modulating the serotonin system in the worm can increase lifespan. Caloric restriction has been a well-documented means to enhance longevity in animals ranging from rodents to worms. We have only recently begun to mechanistically understand why eating less allows us to live longer (remember the sirtuin genes?)


In this latest study, the authors found that a compound typically used as an antidepressant, called mirtazapine and commercially known in the US as Remeron, increased lifespan in the worm by 31% through an inhibition of the 5-HT2 receptor for the neurotransmitter serotonin. This occurred in a dose-dependent manner. Several compounds in the same family (with similar modes of action) failed to increase lifespan in worms harboring mutations in genes causing a disruption of the serotonin system, like in the synthesis enzyme tryptophan hydroxylase or the serotonin reuptake transporter.

In an attempt to link these mechanisms to those typically associated with lifespan extension in the worm, Buck and colleagues demonstrated that treating worms with the antidepressant after caloric restriction failed to increase lifespan beyond that which occurred following caloric restriction alone. In addition, treatment with the drug had little effect on lifespan in worms expressing mutant proteins required to reap the benefits of caloric restriction.

Since serotonin is a neuromodulator that affects a variety of neuronal functions, including food-intake regulation, altering the serotonin system may cause the worm to enter a state of “perceived starvation” that, despite adequate food intake, would still activate the signaling mechanisms responsible for inducing an extended lifespan.

Whether or not this mechanism will hold up in humans is anyone’s guess; the only evidence that it might do so comes from reports of an increased appetite in those taking the same class of antidepressants as was used in the Nature study. If it does turn out to be an evolutionarily conserved pathway in humans, it seems like this mechanism could be a coup for Big Pharma. With antidepressants being prescribed at alarmingly high rates (as of 2002, 11% of women and 5% of men in the non-institutionalized population take anti-depressants), and with those customers living longer because of their prescription filling, Big Pharma could have what Big Tobacco never had: an addictive (at the least psychologically) product that makes more money for the company because it causes its customers to live longer.

Petrascheck, M., Ye, X., & Buck, L. (2007). An antidepressant that extends lifespan in adult Caenorhabditis elegans Nature, 450 (7169), 553-556 DOI: 10.1038/nature05991

Comments

  1. Report this comment

    Drugmonkey said:

    sigh. and here we go again

    please define “psychologically” addictive and distinguish from your other conceptualizations of “addiction”. while at it, make sure to state whether or not you are a dualist, closeted or otherwise.

  2. Report this comment

    Simon said:

    I’m not too convinced this study will hold in humans, since both sertraline (Zoloft®) and paroxetine (Paxil®) shortened the worms’ lifespan by 40% or more, which is something you’d think would get noticed if it were happening in psych patients.

    Drugmonkey: There is dualism; there is materialist; and then there is solipsism. From a materialist perspective, physical addiction is what happens to your body, and psychological addiction is what happens to your brain. If withdrawal from some drug made your arm fall off, would you really maintain that it was as psychological as physical?

  3. Report this comment

    Drugmonkey said:

    Simon, I do not maintain there is any such thing as “psychological” addiction that is meaningfully distinguished from “physical” addiction. Quite the contrary.

    Until we get some meaningful demonstrations of where the “mind” exists outside of the workings of the brain than the most subtle of urges to take drug again are surely as “physical” or “physiological” as are the oft dramatic, externally observable symptoms of acute heroin withdrawal.

  4. Report this comment

    Noah Gray said:

    Well, to be the most accurate, why don’t we just cite this. I just couldn’t pass up the opportunity to add a link to a paper from 1933. And it is actually primates to yeast.

    Regarding the second part, I’ll let you call me on that, as I do not want there to be any confusion over my position regarding mind/body. As you are aware, anti-depressants are not considered to be habit forming nor addictive (although tolerance can develop). The closest manifestations are the withdrawal symptoms that occur upon the cessation of treatment (even when “weaning off”), causing the patient to “need” the drug in order to not suffer from the definitively physical (yes, including those related to the brain) side-effects that follow. Therefore, this is not a physical addiction, but rather a choice not to suffer from physical afflictions, hence skirting (admittedly, barely) the boundaries of addiction. Regardless, sloppy word-choice and I corrected it. Thanks.

  5. Report this comment

    Drugmonkey said:

    “Therefore, this is not a physical addiction, but rather a choice not to suffer from physical afflictions, hence skirting (admittedly, barely) the boundaries of addiction.”

    not merely “skirting” but fully consistent with some aspects of addiction. aspects that some researchers (notably fleshed out in reviews from Koob and LeMoal) feel are a fundamental contributor to the essential problems in drug addiction. negative reinforcement, meaning the drug action removes or prevents the noxious stimulus. this removal (behavioralist “negative”) enhances the probability that one will continue to take the drug (reinforcement). “stimulus” in this case being the diverse ways in which someone might be in a low affective state. $64K question being what produces the drug-abuse relevant negative affective state(s), of course.

  6. Report this comment

    Simon said:

    Drugmonkey, I can agree with you that the symptoms of antidepressant withdrawal may serve to demonstrate that these drugs are “addictive.” I’m still not sure I follow you on why you don’t believe in a distinction between psychological and physical addiction. There are some effects of drug addiction that are psychological, namely, those that relate to behavior. There are some that aren’t. If you disagree with the use of the words “psychological” and “physical” (instead of “psychological” and “non-psychological”) you’re really just splitting hairs, but I’ll bite. If you believe there’s no such thing as psychology, you should join the Church of Scientology.

    Psychology is the study of behavior and mental state; psychological changes are changes in behavior and mental state. Yes, they are ultimately produced by some change in neurophysiology. If one is not a Cartesian dualist, any psychological change must be accompanied by some physical change. However, the changes in behavior and mental state, and not the neurophysiological changes, are crucial to the psychological effects of addiction. To use a philosopher’s trick, imagine that the same physiological changes took place, but did not alter behavior. Would we consider the effect to be of the same magnitude? If not, then there must be some component that does not lie within the domain of physiology.

    To bring this discussion further into the domain of philosophy: if you hold that psychological properties do not simply supervene on physical properties, but are isomorphic to them, then you must also hold that consciousness does not exist. (See David Chalmers’ The Conscious Mind for an extended argument to this effect.) While Dan Dennett believes this, and you may too, I find it hard to swallow.

  7. Report this comment

    Drugmonkey said:

    “Psychology is the study of behavior and mental state; psychological changes are changes in behavior and mental state. Yes, they are ultimately produced by some change in neurophysiology”

    My problem is that in popular use and apparently medical training (see MarkH of denialism blog and Jake of Pure Pedantry) the us of “psychological” is used in addiction and other mental disorders as a minimization technique. To suggest the problems are less “real” or somehow less serious or medically significant for patients. You seem to be saying that psychological just means the brain and behavior. So why do we never hear of “cardiac addiction” or “gastrointestinal addiction” or the like? There are both GI and cardiac symptoms of withdrawal and acute drug use, after all.

    “To use a philosopher’s trick, imagine that the same physiological changes took place, but did not alter behavior. Would we consider the effect to be of the same magnitude? If not, then there must be some component that does not lie within the domain of physiology.”

    This is an idiotic “trick”. Sure, hold all else equal, ensure that you’ve located the exact “addictive” change(s) and replicate them and see no effect and you are quite right. Just like when the Flying Spaghetti Monster shows up we’ll all have to realign our theological positions. Until then, the philosophers can propose all the “tricks” they would like, doesn’t make it correct or even probable.

    “if you hold that psychological properties do not simply supervene on physical properties, but are isomorphic to them, then you must also hold that consciousness does not exist”

    ahh, a troll. the prior comment should have alerted me. what you have done here is make a bald assertion without any argument and say “go see some book if you want the actual argument”. pretty weak. why don’t you at least give the short version?

    otherwise we can use another “philosopher’s trick”.

    If you believe in some sort of non-brain based “mind”, you must also believe in the Flying Spaghetti Monster (see venganza.org for extended argument for his existence). While NuttyHomelessGuy believes in the FSM, and you may too, I find it hard to swallow.

    see how much we really advance a discussion with such “tricks”?

  8. Report this comment

    Simon said:

    My problem is that in popular use and apparently medical training (see MarkH of denialism blog and Jake of Pure Pedantry) the us of “psychological” is used in addiction and other mental disorders as a minimization technique. To suggest the problems are less “real” or somehow less serious or medically significant for patients. You seem to be saying that psychological just means the brain and behavior. So why do we never hear of “cardiac addiction” or “gastrointestinal addiction” or the like? There are both GI and cardiac symptoms of withdrawal and acute drug use, after all.

    Obviously, it’s wrong to use the term “psychological” as a minimization technique; whether it’s in your head or in your chest, it can be just as bad for you. However, it doesn’t seem wrong to separate what individuals do voluntarily as a result of taking drugs from the effects of the individuals on various organs, especially given that most of the harm done to society comes from changes in behavior, not in the heart or gastrointestinal tract.

    Also, I never said that “psychological” meant anything about the brain. I believe that a seizure should be considered a physical withdrawal symptom, since it does not involve voluntary behavior or mental state.

    Now, to get onto more divisive issues…I don’t understand why, when discussing a topic far removed from that of the original post, referring you to a book rather than producing a detailed summary of the thesis of the book (which I didn’t have with me at the time) would make me a “troll.” Since you insist, I can copy Chalmer’s brief summary of the basic argument.

    1. In our world, there are conscious experiences.
    2. There is a logically possible world physically identical to ours, in which the positive facts about consciousness in our world do not hold.
    3. Therefore, facts about consciousness are further facts about our world, over and above physical facts.
    4. So materialism is false.

    This is Chalmers’ (in)famous “”http://en.wikipedia.org/wiki/Philosophical_zombie" rel="nofollow">zombie" argument. If you don’t like philosophical tricks, you might not be too friendly to it. Unlike Cartesian dualism and other forms of substance dualism, however, property dualism of the type Chalmers advocates is scientifically sound, and effectively identical to materialism for all purposes outside of philosophical discussion (except, apparently, when it comes to discussing the existence of psychological addiction!)

  9. Report this comment

    Rick said:

    This is certainly an interesting approach to an extended lifespan. My guess is there are serotonin receptor sites throughout the digestive tract and it may have an impact on nutrition absorption and food intake.