Q: What are your thoughts on the effects of obesity and/or metabolic parameters on cognition in adults with MDD?

The moderational effect of these things on cognition in adults with MDD has not been sufficiently studied. There have actually been more studies of individuals with bipolar disorder and schizophrenia, in whom excess weight quite significantly accounts for deficits in cognition, broadly defined and measured. Depending on the study, it could be as much as 30% to 40%. It’s not simply another variable with a 0.05% contribution; it’s a major
player. And this isn’t really surprising, because if we step out of Psychiatry and walk into an obesity clinic, or a diabetes clinic, there are very highly replicated findings of cognitive deficits in this group. Proof of the principle that this is not merely some association but rather some type of Bradford-Hill causative direction is provided by bariatric surgery. Bariatric surgery has turned out to be one of the most powerful procognitive interventions you can do to somebody, so that’s a very important part of this story.

When we think about inflammation and metabolism and cognition, we get into hot cognition and cold cognition, and that is really important, because when we are talking about cold cognition, we know that obesity “metastasizes” to the brain.

But one can also go the other way around. For example, the report last year, the meta-analysis by Kooij and colleagues in the American Journal of Psychiatry, showed that adults and children with ADHD have significantly elevated rates of obesity—and that’s not just because of a reward disturbance but also because of impulse-control problems.

Adiposity is clearly only a piece of the broader picture of MDD and cognition. Cognitive impairment is recognized as a principal mediator of psychosocial impairment in MDD, although antidepressant medications have not generally been shown to improve measures of cognitive control and executive function; vortioxetine is an exception in that it is a multimodal antidepressant that has been shown to improve performance in objective measures of cognition.

Q: Is weight gain associated with selective serotonin reuptake inhibitors (SSRIs) relevant here? Are there any “worst offenders” to avoid, if you are concerned about a patient’s weight?

I believe there is sufficient meta-analytic evidence, looking across studies, that paroxetine is associated with more weight gain, and I believe fluoxetine was associated with less weight gain, than the other SSRIs. Now, these differences may be attributable to secondary or tertiary effects, within the SSRIs; however, for a given patient, there is no better predictor than actually weighing him or her at the beginning of treatment and then at the 2nd, 4th, and 6th weeks of treatment. If patients are not showing weight gain in those first 6 weeks, then it becomes very unlikely. I think that rather than worrying about some of the more subtle differences in weight gain within classes, the better thing to do is to be very careful and vigilant with your patient to ensure that, even if it is an uncommon side effect, it doesn’t happen to him or her.

With the earlier SSRIs, there is also the artifact from the failure to prospectively measure these outcomes, including weight gain and sexual dysfunction. If you look in the Physician’s Desk Reference, for instance, you will see rates of 1% or 2% of anorgasmia with fluoxetine, simply because these were all spontaneous reports, since it wasn’t asked about and no one measured it. So I think it’s hard to know from, say, registration trials, what the true changes are and the timeframes for changes in metabolic parameters or weight, and so we are left with more recent, observational studies, which are often confounded. That is, subjects were often taking multiple agents, and there was confounding by indication (eg, you put heavy people on drugs you think might help them lose weight, like bupropion, and lighter people might go on something with more anticholinergic effects, such as paroxetine).

With regard to weight gain, I would think that clinicians each have individual perceptions of differences among agents; I do not, myself, perceive a huge difference among the SSRIs. I believe I have seen patients both lose and gain weight with all of them. It’s a fairly short list of the weight-neutral ones; maybe here we come back to noradrenergics, bupropion, and I might even mention nortriptyline, as drugs that are less apt to cause some of the cognitive dulling, maybe even have some cognitive benefits, with less weight gain perhaps and more of an activating, positive effect on motivation, as compared with some of the other compounds.