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.