Tuesday, November 9, 2010

Antidepressants and Weight Gain or Loss

My focus in this blog is not on the standard medical treatments.  You can come see me in clinic or go to your own psychiatrist for that.  However, an exploration of antidepressants and weight gain can give us some insight into the processes of obesity and the brain, so I will dive on in.  It is a more complicated subject than you might expect, as the mechanisms aren't always clear, and mood disorders themselves can cause weight gain or loss.  However, the Journal of Clinical Psychiatry came out with a nice review in October, Antidepressants and Body Weight: A Comprehensive Review and Meta-Analysis

I don't always care for the Journal of Clinical Psychiatry, mostly because they put out "supplements" bound exactly like the main journal which aren't necessarily peer-reviewed and can be high-end academic commercials for drug companies (you will notice that free registration will get you access to the supplements on their website, but you need to pay to read the journal!).  If you aren't savvy, you might get tricked.  Their supplements usually end up in my trash, but the main journal has some peer reviewed good stuff.

In the antidepressant/body weight review, the researchers screened over 3000 reports, finally settling on 116 that met certain eligibility requirements (published in a respectable journal, used therapeutic doses, weighing patients prior to and at the end of the trials of at least 4 weeks, etc.).  Then the researchers configured the data so that it could be more easily compared across the different trials (not always an easy or uncontroversial task), and came up with acute weight change data (trials of 4-12 weeks) and longer-term weight change trials (>4 months).

The results?  In acute treatment, the older class of tricyclic antidepressants (with one exception) and mirtazapine were associated with more weight gain, while all SSRIs and buproprion (wellbutrin) were associated with weight loss.  Placebo was associated with slight weight gain.  In long term trials, the only one that was linked to significant weight loss was buproprion.  The SSRIs except paxil were weight neutral (though citalopram had widely varying results), and paxil, mirtazapine, and amitriptyline (elavil) were associated with weight gain.  Placebo slightly favored weight gain but was basically weight neutral also.

So what is going on?  Well, paxil, mirtazapine, and amitriptyline all have something in common.  They all have affinity for the histamine receptor and are anticholinergic.   Alpha receptor blockers are also associated with weight gain, and mirtazapine and amitriptyline have that in spades.   Drugs that cause weight loss have more affinity for dopamine and enhance serotonin function.  Several drugs have a bit of everything (imipramine, for example, is anticholinergic, but also pro-dopamine, so it seems to be weight neutral overall).   

Why does histamine promote weight gain?  Well, the H1 receptor seems to activate AMPkinase in the hypothalamus (1).  AMPKinase reverses the actions of leptin, the appetite-suppressing hormone, and AMPkinase may be activated by orexin, the appetite-inducing hormone.  Clozaril, an antipsychotic medication known for its ability to cause huge weight gain, does not cause weight gain in mice that lack the H1 receptor.  To make things even more complicated, another antipsychotic, zyprexa, also causes a lot of weight gain through the same mechanism.  There's a type of zyprexa that dissolves in the mouth called zydis - same exact drug, only a lot of it may bypass the gut and simply be absorbed into the bloodstream in the mouth - and zydis doesn't seem to cause weight gain.  This suggests that it is an interaction with these drugs and the gut that may be the real issue here.  That interaction is poorly understood.

The SSRIs are interesting in that they seem to promote weight loss in the beginning, but (except for the strong fat-inducing anticholinergic paxil) are weight neutral in the long term.  Remember, when we are low in serotonin, we crave carbs, probably because a high carb diet helps us bring more tryptophan, the serotonin precursor, into our brains for conversion to serotonin.  At the beginning of treatment, SSRIs seem to increase serotonin, which will decrease appetite and decrease carbohydrate cravings (possibly via orexin).  After a few weeks, however, the post-synaptic serotonin receptors get sucked back into the cell, more or less reducing the overall serotonin effect.  The timing of the receptor down-regulation matches the timing of when the medicine usually starts to take effect for depression or anxiety (one piece of evidence that it is not serotonin per se, but another effect of the medicine that is actually antidepressant or anti-anxiety - perhaps because they are anti-inflammatory and anti-kyurnetic?)  All of these medicines also have histamine and mild anticholinergic effects to some extent, so the serotonin weight loss effect may counterbalance the histamine.

At the far end on the weight loss side is buproprion, or wellbutrin, which isn't really a serotonin drug at all.  It maximizes norepinephrine and dopamine, and has almost no histamine or anticholinergic effect at all.  Buproprion has actually been proposed as a treatment for obesity, though given that it went generic several years ago, it may never be FDA approved for that indication.  Buproprion isn't all giggles - it can cause anxiety, anger, and seizures.

I don't want to distract from the fact that if we live a healthy life, eat "real food," and take steps to reduce our stress, and exercise, we are less likely to get depressed in the first place.  In addition, by avoiding the inflammation of depression and other mood disorders in combination with the SAD, we don't have to worry too much about weight gain, either.  But, as I said at the beginning, understanding how these medicines affect weight gain and loss can give us some insights into how the brain (and possibly even the gut nervous system) works, and that is interesting.  At least to me.


  1. very interesting stuff indeed :) i actually wanted to ask you if you know that SSREs (SSR Enhancers) apparently have the exact same anti-depressant effect as SSRIs, even tho they *reduce* the amount of serotonin available. but as you already state "one piece of evidence that it is not serotonin per se, but another effect of the medicine that is actually antidepressant or anti-anxiety" - this question just has become obsolete ;p i still wonder tho what exactly causes the effect. maybe it's just the scary fluoride atom in these molecules?

  2. 4 weeks??? Most people on anti-depressants whose depression is helped by them (a minority, obviously) may end up taking them for years or the rest of their life. Every single person I know who has taken SSRIs for more than a year has put on some weight. This is generally dismissed with talk of "well, they regained the weight they lost when depressed" or with somewhat more scientific pointing to studies that claim that people with mood disorders are more apt to gain weight.

    IMHO, it is more likely that over time, SSRIs increase carbohydrate cravings and appetite generally. It isn't (as MDs may say) that they want to eat because food tastes better than when they were depressed. It is that they have a permanent case of the munchies. Again, my admittedly unscientific survey of acquaintances, turns up the reports that all found they began craving more sweets and starches than at any time previously in their lives. We all know that eating these foods increase serotonin levels in the brain...

    But it gets missed, unlike the effects of the atypical antipsychotics, because the effects don't kick in til about six months to a year after first taking (after the initial weight loss) so are masked. ALso, the weight gain is gradual, so is usually assumed to be age-related. Or a person "mellowing".

    I also wonder about metabolism and glucose...But I am no scientist. I have seen this at first hand in too many relatives, tho, to take a study that is only 4 weeks long seriously.

    Not to get cranky or anything, as I love your blog and your commentary...

  3. Hi Retriever - I know there were about seventeen points in that post, but the meta-analysis had two sections, one of trials from 4-12 weeks, and one of trials >4 months, so the long term trials were relatively long term. I do tend to see gradual weight gain with the medicines in practice... (except buproprion) except everyone in the US seems to have gradual weight gain, so who knows? A meta-analysis like this one is certainly not bullet proof data, but it certainly seemed to follow the larger trends of what I've observed - paxil and mirtazapine, weight gain, and buproprion weight loss, everything else is pretty individual, with wide variations, case by case.

  4. I have been on Celexa since 2002 and when I have reduced the amount or quit, I gain weight. When I go back on, I lose weight. Any thoughts there? I wondered if the drug has made my thyroid dependent on it, so that when I go off it, it is crippled and doesn't function as well?

  5. Hi Melissa. I've seen " emotional eaters" lose a lot of weight with antidepressants, only to gain it back when they go off of it - which leads me to two thoughts about SSRIs and weight loss. One is that serotonin is an "anorexogenic" neurochemcial via the mechanisms described above (possibly an interaction decreasing orexin). So if, on balance, you have a positive net increase of serotonin from the meds and you aren't sensitive to the histamine aspect, it will cause weight loss. In addition, if you are happier or less anxious on the medicine, you might not crave the tryptophan (which leads to craving carbs in women on modern diets who happen to suffer atypical depression symptoms). This second theory does have a thyroid link as T3 is especially helpful for atypical depression.

    I'm not aware of an effect the medicine has directly on the thyroid or thyroid hormones.

    Despite the data above I tend to think of celexa as a mild "weight gainer" - it is a bit on the sedating side and that typically means a little more histamine. It also seems to be more weight gain promoting than zoloft or fluoxetine when compared side by side in the charts for the above study (and in many other charts I've seen along the years). On average, the weight gain from celexa did not reach statistical significance. But some people will gain, meaning some people must lose for the overall effect to be mostly neutral across the population.

  6. Hi, Dr. Emily,
    I came across your blog and I must say it's pretty good timing. First, let me congratulate you on wanting to ''figure it out''. I find most psychiatrists don't want to invest time in this area of concern. I agree it's a very complicated issue, but since it's a huge part of whether or not a patient will continue treatment or not, I find that more interest in what causes weight gain and how to manage it should be one of their main focus. It's very hard for me to understand why researchers haven't figured it out yet and come up with a solution for it. I am particularly interested in your H1 receptor explanation, bloodstream absorption via gut absorption and the inflammation theory. I would like to share some data I have put together which pertains to my experience with antidepressants and weight gain. Those with anticholinergic activity has caused me to gain weight, those without, I've had NO weight gain. Ironically, the anticholinergic antidepressants provide relief of depression, anxiety, whereas the non anticholinergic do not. So when I hear of people gaining weight on Lexapro or Celexa, there goes to show how different each one of us is and how differently our brain chemistry is and how we react to medications. This is a real piece of work for psychiatrists, at this point, it is trial and error. In my case, can we say that anticholinergics cause weight gain? I have not explored if those same medications have affinity for the histamine receptor. If Celexa does I assume Lexapro does also? If so, Lexapro caused no weight gain for me, so I would assume those with affinity for the histamine receptor does not cause weight gain for me. I also have found some information on the JNK gene and antidepressant weight gain. There seems to be a link to inflammation and weight gain. A company is working on a product/medication which is in phase 3 now. I don't know how viable this information is. I would love it if you could take a look and tell me your thoughts on this. http://www.celgene.com/pdfs/product_pipeline.pdf.

    Again, thank you for your blog. I will be looking forward to other posts. It's nice to see a professional who takes this subject seriously.

  7. Is there anything nutrition wise that people taking anticholinergic could potentially do to offset the side effects?

  8. To make a long story short while on an ssri tried them all except paxil , i gained weight in the form of fat while marathon training . six pack abs to 25 extra pounds of fat.

  9. For seven years Wellbutrin regulated my sleep schedule and weight and then 6 months ago my chronic insomnia returned and I put on about 8 lbs. Why the change? What can I do to get back these benefits of wellbutrin?

  10. You state, "At the far end on the weight loss side is buproprion, or wellbutrin, which isn't really a serotonin drug at all. It maximizes norepinephrine and dopamine, and has almost no histamine or anticholinergic effect at all."
    I believe you mean bupropion, not buproprion. I question that statement-- everything I have read indicates that Wellbutrin (bupropion) does have significant anticholinergic effects.

  11. Hi, Dr. Emily, Thanks so much for this informative and timely post. I've been scouring the internet and library trying to find an answer to this question: how much agency do I have in regards to my weight gain on a newly prescribed SSRI (Lexapro)? In other words, even if I continue to eat healthy (paleo and conscious caloric intake) and work out regularly, should I be prepared to gain weight? I've had some conflicting reports on paleo and SSRI's as well as just weight gain in general. I've long dealt with chronic generalized anxiety and really labored over this decision, but want to know what I'm dealing with and how nutrition will work out. Thank you!