Antidepressants, stress, and bodyweight.

Mar 16 2011 Published by under Behavioral Neuro, Uncategorized

I'd heard for a long time that various antidepressants (usually the SSRIs or TCAs) caused weight gain. Then again, I'd heard they caused weight LOSS as well. Same thing with sleep, with eating behavior, with anxiety, etc. Some people experience weight gain, some experience weight loss. Some sleep more, some sleep less. Some are more anxious than before, some less. But all of this is anecdotal, and no matter how many anecdotes you hear, it's not data.

But it turns out there IS data on this. A couple of studies have shown that long term antidepressant treatment has a side effect of weight gain in about 15-25% of patients, depending on the drug (weight gain is defined at an increase of more than 7% of your body weight. So if you were a 200lb guy, you'd have to gain 14 lbs). So there is a side effect here. The question is, how much of a side effect IS it, and how is it affected by other stuff going on in the patient's environment (such as stress, and access to a high fat diet). And of course there's the question of how long the effects last, as many patients discontinue their medications on their own (PSA: it's not a good idea to do this. Many of the current antidepressants on the market have withdrawal effects associated with them, such as refractory depression, vomiting, headaches, and more, and if you're going to discontinue use, you need to know how to do it safely. So ask your doctor. Don't just drop the pills.). So we have questions here about whether environmental factors affect the weight gain effects of antidepressants, and how long effects like this can last.

OR, you can just forego all those sensible questions and ask, as these guys did:

Could the current dramatic
increase in obesity be attributed at least in part to
exposure to antidepressants?

I rather wish I were kidding. Granted, I'm more than usually my grumpy Sci-self this morning (it's 5 am and I'm on my first cup of coffee), but...really?

Mastronadri et al. "Long-term body weight outcomes of antidepressant–environment interactions" Molecular Psychiatry, 2011.

To answer the question of whether or not the obesity epidemic could be caused by antidepressant exposure, they took a bunch of young rats, still growing. First they gave a group of rats fluoxetine (that's Prozac) for 5 weeks, and tracked body weight. They report lack of weight gain compared to saline (resulting in lighter rats), but unfortunately don't graph it with the rest of their conditions. But here's the rest of the conditions:

The conditions are: NR-CC, which is no stress, control diet. NR-CF, no stress, high FAT diet (you can see those guys gained weight compared to the straight up control in grey). R-C, which is chronic restraint stress in the rats (wrap 'em up like a burrito or put them in a clear restrainer for 6 hours) and a high fat diet. They say the animals in this condition ate less and gained less weight during the testing, but it looks like they gained it back and then some later on on the high fat diet. R-IMI is the stress as well as treatment with the antidepressant imipramine (not used in this clinic so often anymore, it's one of the TCA's and I think is still marketed as Tofranil) AND a high fat diet, and R-FLX is stress with treatment with fluoxetine (Prozac) AND the high fat diet. There was no stress (or stress with antidepressant) WITHOUT a high fat diet, which is a control I really wish they had looked at.

Now, what's interesting about this is that the measurements you're looking at extended out to 175 days, while the restraint stress itself was limited only to the first SEVEN days. The antidepressant treatment was ALSO given only for the first SEVEN days. The high fat diet was started immediately afterward. DURING the stress and antidepressant treatment, all the animals ate less.

However, AFTER the stress when the rats were put on the high fat diet, the antidepressant treated animals ate more. They also got bigger (though not by a lot, they got significant results but the animals are, on average 1.5 g heavier and their femurs are 0.1 cm longer), but did not get FATTER, just bigger. They also looked at open field activity (give a rat an open field, and the rat will stay to the edged where its darker, it's a measure of anxiety. On anti-anxiety drugs, the rats will go into the center more often), and saw that the rats treated with antidepressants showed anti-anxiety-like activity long AFTER the treatment with antidepressants had ended.

So what can we conclude from this? Me? I conclude that the effects of short term antidepressant treatment (7 days is considered pretty short term, most chronic studies treat for at least two weeks before they see many effects) cause an anti-anxiety phenotype and appear to make the rats eat more on a high fat diet. I would want to know whether the open field test results translated to other results which are more associated with an antidepressant phenotype (like tail suspension, forced swim, or sucrose preference). Open field testing like they did is not generally thought to be a good measure of antidepressant activity. I would want to know whether the mice treated with antidepressants were stress resistant, by measuring stress-related hormone levels during stress and treatment with antidepressants, and seeing how they reacted to a subsequent stress afterward. I would want to see how these animals differed from those fed a chow diet, and how stress and antidepressant treatment interacted with stress and a high fat diet later in life. I would want to see what the stress results and antidepressant results look like when the rats are on a high fat diet DURING the stress. I would want to look at mice treated with these measures later in life.

I would want to know all of those things, and I would probably conclude that stress and antidepressant treatment can interact even in short periods of time, possibly ameliorating the effects of stress, and resulting in some weight gain when on a subsequent high fat diet.

What I would NOT do is say this:

Alarmingly, SSRI drugs have become so
popular that they are already been called ‘lifestyle’
drugs. In the United States, obesity rates started
to increase markedly in the late 1980s, which
coincides temporally with the introduction of SSRIs.
Yearly increases in the rates of antidepressant
dispensing seem to parallel increases in obesity
rates; however, detailed analyses of those trends at
the population level are required to establish a
clinical association.

In conclusion, we propose here that antidepressant
treatment, occurring in the context of conditions of
high stress and high-fat intake, might be a covert,
insidious and long-lasting contributor to weight gain...

Evil, covert and insidious. Because, you know, it's not like people NEED these "lifestyle drugs". It's not like people could be...you know...depressed or something, and have difficulty functioning. It's not like these drugs could be given for longer periods of time and the effects on weight might be extremely different (just 7 days? Even with low compliance rates, most people do better than that). I don't doubt the data that they found, but when you start out with a question like whether the obesity epidemic is caused by antidepressants...well. Sure, it could contribute in some SMALL part, but I really think it's a bit much to assume, as only 5.8% of the US population is on antidepressants at any given time. Of course the lifetime prevalence rate is 20%, and the US obesity rate is indeed around there, but do those two groups overlap entirely?! Of course not. Not only that, it's been established in the literature that only 15-25% of those who TAKE antidepressants will experience weight gain as a side effect. And what about those who were overweight to begin with? What about those who gain weight, but do not become OVERweight (for example, I could gain 7% of my body weight right now, and still be at a "normal" weight for my height)? Not to mention the many other factors surrounding obesity which were not touched upon in the study, things like sedentary activity and genetic factors.

To include a line like this, connecting the obesity epidemic to antidepressant use, well, it seems alarmist to me. Let's see that again:

Alarmingly, SSRI drugs have become so
popular that they are already been called ‘lifestyle’
drugs. In the United States, obesity rates started
to increase markedly in the late 1980s, which
coincides temporally with the introduction of SSRIs.
Yearly increases in the rates of antidepressant
dispensing seem to parallel increases in obesity
rates; however, detailed analyses of those trends at
the population level are required to establish a
clinical association.

Ah yes. Obesity increased starting in the 1980's, and SSRI's came out in the 80s!!! You know what, autism onset is around age 2. So is the MMR vaccine. But as a long and troubled history there has shown: CORRELATION IS NOT CAUSATION. You gotta prove it to me first. And while they have shown that rats gain weight when stressed and given antidepressants and then exposed to a high-fat diet, they have NOT proven that this accounts for any percentage of the obesity epidemic. The rats aren't FATTER. They are BIGGER. How does that translate to humans obesity? I for one have no idea.

So does this warrant further study? Absolutely. Does it say something interesting about the interactions between antidepressant treatment and stress when on a high fat diet? 100%. Does it explain, even in part, the obesity epidemic? ...probably not.

Mastronardi, C., Paz-Filho, G., Valdez, E., Maestre-Mesa, J., Licinio, J., & Wong, M. (2010). Long-term body weight outcomes of antidepressant–environment interactions Molecular Psychiatry, 16 (3), 265-272 DOI: 10.1038/mp.2010.122

5 responses so far

  • Sue W says:

    Thanks for this. It is tiresome to see pronouncements like this made for or against various medications (or indeed technologies).

    The paper seems to be going for a quotable sound bite. Perhaps that will help them get their next grant.

  • Vicki says:

    For that matter, if there is a causal relation, it might be fatness -> depression -> use of antidepressants. Between medical worries about being fat, nonmedical worries ("I'll never get a date" is not a medical worry), and discrimination, it seems likely that fat people are more likely to be anxious or depressed than thinner people.

    But mostly, yes, correlation is not causation. And two things that they-the-researchers think are bad, even if correlated, do not necessarily have any causal relationship.

  • James Kornell says:

    "Let's take a complex mereonymic jumble and say ONE THING is the cause." Awesome, dudes. It's good and necessary to try to isolate factors and study them -- it's what we do -- but to then conclude GIANT SWEEPING PRONOUNCEMENTS from tiny and pretty much artificial data -- urg. (Almost as bad as dropping in social judgment terms like "lifestyle drugs" without taking an responsibility for biasing the argument by your word choice even before you make the argument.)

  • FiSH says:

    I would like to point out that the onset of the obesity epidemic also coincides with the Reagan Presidency, so I think he should get the blame.

  • OleanderTea says:

    I agree with FiSH -- Reagan's presidency is to blame, not antidepressants. 😀

    As someone with lifelong depression/anxiety problems who's taken every SSRI out there (and a couple of TCAs, and now an SNRI), I'd much rather be fat than go back into that deep, black, life-sucking, brain-numbing, mind-fuzzying depression I've slid into a few times in my life.

    Also, is it a lifestyle drug if it allows one to function and have a life? If so, we need to be calling a whole lot of other medications out there "lifestyle drugs".

    *ahem*

    [/soapbox]

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