SSRIs, Weight Gain, and Diabetes

Yesterday I talked about the connection between antidepressant usage and diabetes. It may seem odd, at first, that antidepressants should double one's risk of diabetes, but given the pervasive involvement of serotonin in appetite and digestive processes (and the ability of antidepressants to make you fat; see discussion below), perhaps it shouldn't really come as such a shock.

To put things in perspective: Around 95% of the body's serotonin can be found in the gastrointestinal tract; only 5% is in your brain [reference]. Serotonin is the primary signalling molecule involved in motility, secretion, and vasodilation within the intestines, and just as in the brain, bioavailability of serotonin to target cells in the gut is dependent on the serotonin reuptake transporter (SERT). SERT, in turn, is the binding target of selective serotonin reuptake inhibitors. When you take an SSRI like Prozac, Zoloft, Paxil, etc., you're medicating your intestines (and your nearby reproductive system, which is highly innervated and dependent on serotonin for proper functioning); and also, your brain. So it should surprise no one that the main physiologic effects of SSRI administration are, in fact, on gut, sex organs, and brain. If you were thinking you were mainly medicating your brain, with your sex organs and gut experiencing "side effects," you've essentially got it backwards. Serotonin's main effect in your body is keeping your gastrointestinal system functioning. (It's worth noting that low-dose SSRIs have been used to treat irritable bowel syndrome, but it should also be noted that selective serotonin reuptake inhibitors increase the risk of upper gastrointestinal bleeding, particularly when used with NSAIDs.) For more on serotonin's action in the gut, see this paper and also this paper. I also recommend "Serotonin receptors and transporters — roles in normal and abnormal gastrointestinal motility," in Alimentary Pharmacology & Therapeutics ,Volume 20, Issue Supplement s7, pages 3–14, November 2004 (full article here).

Weight control is at least partially mediated through the 5-HT2c serotonin receptor in the hypothalamus. We know this is true because "knockout" mice with a targeted mutation of the 5-HT2c receptor gene engage in chronic hyperphagia (overeating), leading to obesity and hyperinsulemia [reference]. We also know this because obese humans who've been exposed to the potent 5-HT2c receptor agonist m-chlorophenylpiperazine (mCPP) experience weight loss and appetite changes. There's also very good evidence that polymorphisms in the promoter region of the 5-HT2c receptor gene play a direct role in obesity and diabetes in humans. These kinds of interactions led the authors of a report in Nature Medicine 4, 1152-1156 (1998) to state categorically that "a perturbation of brain serotonin systems can predispose to type 2 diabetes."

Finally, it's worth pointing out that some SSRIs (Prozac in particular) exhibit direct action on 5-HT2c receptors (and not just on SERT).

So bottom line, there's plenty of reason to believe that antidepressants can play a direct role in fostering diabetes.

And then there's the small matter of weight gain.

Most doctors tell their patients that weight gain is not a problem with SSRIs (that it's mainly a problem with older tricyclic drugs), but this is a myth. Drug trials of the kind that lead to FDA approval of antidepressants are far too short in duration to bring out long-term weight-change trends, which is why weight gain is hardly ever mentioned in package inserts for SSRIs. (In the rare instance when weight gain is mentioned, it's usually painted as restoration of appetite due to recovery from depression, which is self-serving nonsense, IMHO.)

In a study called "Real-World Data on SSRI Antidepressant Side Effects," published in Psychiatry (Edgmont). 2009 February; 6(2): 16–18, real-world patients taking citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac), paroxetine (Paxil), and sertraline (Zoloft) were asked about side effects. Among the 229 patients who noted specific side effects, the three most common side effects, by far, were sexual dysfunction, sleepiness, and weight gain (see graph below). All three occurred at about the same rate (56, 53, and 49 reports, respectively, out of 229 total).

Real-world SSRI users reported weight gain almost as often as sexual
side-effects. From http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2719451/

How much weight gain are we talking about? Very substantial weight gain. Long-term studies have reported mean weight gains of 15 lb (6.75 kg) for sertraline (Zoloft), 21 lb (9.45 kg) for fluoxetine (Prozac), and 24 lb (10.80 kg) for paroxetine (Paxil). Citalopram (Celexa) is often painted as being less likely to cause weight gain than other antidepressants, and yet in one trial, 8 of 18 patients reported an average weight gain of 15.7 lb (7.1 kg) after receiving citalopram for just 5 weeks. See this table for a rundown of weight-gain effects for various popular antidepressants

A Norwegian study (Raeder MB, Bjelland I, Vollset SE, Steen VM, "Obesity, dyslipidemia, and diabetes with selective serotonin reuptake inhibitors: the Horland Health Study," J Clin Psychiatry 2006; 671974-1982) found:

We observed an association between use of SSRIs as a group (N = 461) and abdominal obesity (OR = 1.40, 95% CI = 1.08 to 1.81) and hypercholesterolemia (OR = 1.36, 95% CI = 1.07 to 1.73) after adjusting for multiple possible confounders. There was also a trend toward an association between SSRI use and diabetes.

The Norwegian study involved patients taking paroxetine, citalopram, sertraline, fluoxetine, and/or fluvoxamine

The bottom line: Weight gain is a serious issue with SSRIs (not just older antidepressants), and the association of SSRIs with increased risk of diabetes is not a statistical fluke of some kind, but a very real outcome. Given what we know about serotonin's role in appetite, weight control, and gastrointestinal function, none of this should come as a surprise.