Metabolic Syndrome Causes Mental Health Symptoms?

(updated 12/2014)

How? What’s the connection?

Recent reviews emphasized that there seems to be a “two-way street” between metabolic syndrome and factors like depression, anger, and tension.Raikkonen, Mansur

Women in their study who had those three symptoms — depression, anger, and tension — were more likely that those who did not have them to develop metabolic syndrome during 7 years of study observation. However, in addition, women who had metabolic syndrome  at the beginning of the study were more likely than those without the syndrome to develop symptoms of anxiety and anger even when those were not present at the beginning of the 7-year period.

In other words, mood symptoms are associated with developing the syndrome; and the syndrome is associated with developing symptoms, at least anxiety and anger. Exactly how this association works is not clear. Whether the symptoms themselves somehow cause the syndrome; or whether the symptoms come along with some other condition, such as severe sustained stress, which causes the metabolic changes — that question has not been addressed yet.

Here’s one more case report which strengthens the connection: Dr. Rasgon at Stanford presents a case of a depressed woman with the metabolic syndrome variant called PCOS, whose severe depression responded not to an antidepressant but to treating her PCOS.Rasgon

Want one more sliver of evidence? Read a report from a woman whose husband gets mood symptoms when he “slips” off his Atkins diet — interesting, right?]

In 2004 Dr. McElroy and colleagues reviewed the relationship between weight and mood and concluded:

(1) depression with atypical symptoms [more common in bipolar disorder, which itself was associated with overweight] in females is significantly more likely to be associated with overweight than depression with typical symptoms;

(2) obesity is associated with major depressive disorder in females;

(3) abdominal obesity may be associated with depressive symptoms in females and males; but

(4) most overweight and obese persons in the community do not have mood disorders.

A common theme in metabolic syndrome research is “stress” e.g.Keltikangas-Jarvinen. In that context, isn’t this interesting: the more education a woman has, the less likely she is to get metabolic syndrome (almost three times less likely).Wamala

One of the leading theories in this research is that sustained stress leads to high levels of stress hormone release that can lead to increasing abdominal fat.e.g Bjorntorp There’s something different about that abdominal fat, versus fat that accumulates on your thighs and buttocks. Somehow abdominal fat leads to heart problems and diabetes.  And, it appears that abdominal weight gain can be a part of getting “metabolic syndrome” and the psychological symptoms that may go along with that syndrome.

The Snowball Effect
Note that if psychological symptoms are associated with developing the syndrome; and the syndrome is associated with the development of those same symptoms somehow; then the whole process could snowball, growing on itself.  This is what engineers call a “positive feedback loop”. The term refers to a machine or system that creates more of itself as the process continues. It’s like enthusiasm about a sports team:  they score, enthusiasm increases, and the team is inspired to score again, increasing enthusiasm yet further, and so on.

In a “positive feedback” medical syndrome, the more the problem develops, the more it can lead to conditions which cause the syndrome to develop further. The problem builds on itself. In the case of metabolic syndrome, starting from weight gain or starting from stress hormones or starting from a medication-induced metabolic change, the syndrome seems to become one which builds on itself. Weight gain causes increased abdominal fat; that fat changes insulin sensitivity; insulin resistance changes the hormone control of ovaries, and estrogen; and somehow out of this comes increased male hormones — and out of all this mess comes further weight increase! That’s a positive feedback loop. Such loops can multiply all the factors involved very quickly — which seems especially to be the case if the stressors that contributed to starting this problem are still there.

This “positive feedback loop” seems to go along with what patients describe: at some point, often associated with some hormonal event like ovary-removal and starting on replacement estrogen; or in association with a really severe stress; women report “my weight just took off”. After that, despite eating even less than before, and no change in physical activity, there can be a 40 or 50 pound weight gain. This seems to occur in women around their late 30’s or early-to-mid 40’s, in my practice, as though it had something to do with approaching and entering perimenopause.

Even more concerning, it seems possible that medications can begin this kind of weight gain cycle, the very medications that we use to treat anxiety, depression, and anger. In particular, divalproex/Depakote and olanzapine/Zyprexa are famous for this kind of unbelievably fast weight gain, and both have been implicated in causing metabolic syndrome.  Others of the “atypical” antipsychotics have also been implicated, including quetiapine and, famously, clozapine, the weight gain king of them all.

Unknown to many doctors, nearly the all antidepressants can also cause weight gain, as shown in a recent long-term study. Looking at the experience of thousands of patients, it shows that weight graphs after starting antidepressants go steadily up over time, faster than on known weight-neutral medications.  Some antidepressants, like paroxetine/Paxil, are worse than others.  The only curve that did not go up was that of  bupropion/ Wellbutrin. Blumenthal  

Basically anything that’s known to clearly cause weight gain could start the cycle of weight gain leading to more weight gain.   Many patients say that once they gained that weight, they couldn’t lose it despite using diets that had worked for them before, as though they were somehow metabolically different after this medication-induced weight gain. Their bodies act as though there was some sort of metabolic shift induced by the medications that then has become self-sustaining.

What does this mean if it’s true?

A skilled psychologist from Pennsylvania called me to wonder out loud about whether some people who are diagnosed as having “bipolar II” could actually have PCOS. That’s the first time I’ve heard somebody say this, having wondered so also. We agreed there are women who might otherwise look “bipolar” whose symptoms came on only after they also began having symptoms that look like PCOS. In her view this is potentially a very large number of women.

If she is even partly right, then psychiatry may have been diagnosing some women who really have a hormonal problem as having a “mental health problem” (as though the two are completely different — they are not. However, one carries a lot more stigma than the other, no?). Of course, the better we psychiatrists get at understanding some of these things, the more we’ll look bad for the way we described them in the past, right? And, it turns out that metabolic syndrome may have, at least in part, a “psychological” cause, namely stress, as described above. What matters at this point is how these diagnostic distinctions affect treatment. That leads us to the last section of this story.

Treatment implications

Sorry, I have to say it: first of all, consider the role of exercise (and therapy). There is absolutely no doubt that exercise can treat metabolic syndrome: exercise is well known to reverse the insulin resistance that is at the core of the syndrome. Of course, you gotta do it. That’s the problem. Here’s a full discussion of exercise, including some ideas on how to make it more possible, more likely.

Would a successful exercise program alone have an impact on anxiety or anger symptoms associated with metabolic syndrome? We have no data on that at all. We certainly know exercise can have an impact on mood, as you’ll see if you follow that link above. Simply from the physiology of the syndrome, it seems that exercise could have a direct, reversing effect on the whole problem. At minimum we could say that if you’re going to consider a medication approach, you absolutely should consider accompanying the medication with an exercise approach.

Similarly, psychotherapy should strongly be considered to address stress factors that are probably necessary to keep the cycle going, and are also probably capable of starting the whole thing again if not addressed.

If you treat metabolic syndrome, will it help mental health symptoms?

Has anybody tested that idea?  Not exactly. Metabolic syndrome is not typically treated as a target by itself. However, its close cousin PCOS (what’s the relation?) is routinely treated now with a medication called metformin/Glucophage. See that page for the evidence that it can halt and sometimes lower weight gain: the answer is clearly yes, but unfortunately not spectacularly well.  To my knowledge there is no work on metformin itself and mood.

Here’s one story: at least one woman appeared to have a really stunning response.  Metformin might even have stopped her night-eating pattern and her severe circadian problems (up all night, sleep from 8 am to 4 pm). Even more provocative: after less than a year she stopped the medication and her symptoms did not recur. She was on multiple medications for bipolar disorder, and still is, but they weren’t working.   With metformin, the mood stabilizers worked. And then they kept working even after metformin was stopped — as though metformin had induced some metabolic change.  She hasn’t let me try tapering some of those bipolar med’s yet…

Naltrexone: a better story?

Metformin sounds good but as my summary page shows, it doesn’t work all that well for most people. Recently another weight  control option has shown up that may have specific value in treatment of metabolic syndromeI: naltrexone.  The good news is that this stuff has been around for a long time, so it’s not a brand new medication expensive, unknown risks).    Naltrexone has been known to affect insulin secretion, a central issue in metabolic syndrome, since way back in 1995.Fulghesu But it’s getting lots of attention now that FDA approval has been granted for a weight loss drug that combines naltrexone and bupropion/Wellbutrin, the only antidepressant that doesn’t induce weight gain.

(The trade name will be Contrave, but it will be cheaper to use a the two generics in combination.  In bipolar disorder, it would be better to focus on naltrexone alone and stay away from the bupropion part anyway — because any antidepressant can be destabilizing.  For more on that issue, see Antidepressant Controversy #3).

Naltrexone alone has shown remarkable benefits in one trial in patients taking weight-gain medications.Tek But this was not found in a different research study, with patients on olanzapine  Maybe the weight-gain producing effects of that particular medication, which are know to be more severe than other medications in that class, were just too much for naltrexone to work against.Taveira

So, they final word is not in yet on naltrexone. Like metformin, which was a logical thing to try, naltrexone might look good for a while then fade in the stretch…