Metabolic Syndrome -- Causes Mental Health Symptoms?
(Update Jan 2004) 

How?  What's the connection?

Drs. Raikkonen, Mathews and colleagues recently published an investigation into the relationship of metabolic syndrome and mental health factors.  In this article Raikkonen , they emphasize that there seems to be a "two-way street" between the syndrome and factors like depression, anger, and tension.  

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 (by NHLBI criteria) 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, psychological 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.  

[Update July 2003:   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.]

[Update January 2004:  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?]

[Update August 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-JarvinenIn 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 (try a pretty readable summary of some of that work from that Center for the Advancement of Health ).  And it now appears that abdominal weight gain can be a part of getting "metabolic syndrome" and the psychological symptoms that may go along with that syndrome (note: "may" -- this is only just now getting studied, and Dr. Mathews and colleagues are among the leaders in this work).  

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 there could be a what engineers call a "positive feedback loop".  This term refers to a machine or system that creates more of itself as the process continues.  It's like a good movie:  one person sees it, tells three people who each see it and tell three more, and so on.  Pretty soon the whole town knows about this movie.  

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 (such as we see in Bipolar II).   Depakote and Zyprexa are famous for this kind of unbelievably fast weight gain, and both have been implicated in causing metabolic syndrome.  For Depakote, here's a frequently updated summary of that literature; for Zyprexa, see e.g. Gianfrancesco .  Others of the new "atypical" antipsychotics have also been implicated, including quetiapine and, famously, clozapine, the weight gain king of them all.   Personally I think a couple of the antidepressants can do this, notably Paxil, sometimes perhaps even Prozac, and probably old amytriptyline (Elavil).  Basically anything that's known to clearly cause weight gain could start the cycle.  

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.  Take the following link if you'd like more information on that metabolic shift and how it seems to affect women more than men.  

However, there is some good news here:  some preliminary evidence shows that this metabolic shift can be reversed by a medication commonly used in treatment of diabetes.  More on this below.  

Before we go, let me just emphasize once more:  research on the mental health aspects of metabolic syndrome is just beginning, effectively.  It's as though the mental health community is just beginning to find out about what the heart and diabetes research communities have been studying for years.  Dr. Mathews is one of the rare links between the two.  It is too early yet to start looking everywhere for metabolic syndrome in people with mental health problems, and treating it.  But it is worth thinking about, and watching, and sometimes even using the treatment described below when things are desperate enough to merit taking some steps into unknown territory. 

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?  Yes: 

 a) for a description of how a researcher's work on this 25 years ago has emerged to inform us on this, read this story

b)  for the data from that research 25 years ago, read a summary of Dr. Hicks' work

c)  But how about now?  has anybody tried this recently?  is there any recent publication on this?  

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 the modern version of the medication Dr. Hicks was using.  This medication is called metformin.  The trade name is Glucophage.  

Can Glucophage treat mental health symptoms?  Do we have any new data on that since Dr. Hicks' work?  Just a bit:  several patients have written about their experiences; here are their stories.  Otherwise, no, to my knowledge this has not been tested.  

How about my patients?  Since I've learned all this stuff you've been reading, I've been trying Glucophage frequently for patients who appear to have metabolic syndrome.  Usually there are too many variables going on to know whether it really "worked", but I'm pretty convinced some people respond well.  At least it seems to stop weight gain, more than half the time, and some folks have definitely lost weight, similar to the results of Morrison and colleagues. 

Here's one story:  at least one woman appeared to have a really stunning response:  it might even have cured her night-eating disorder and her profound 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 what looked like bipolar disorder, and still is; but these had not seemed to induce the improvement, only the Glucophage.  Now they maintain the gains she got with a medication she's been able to discontinue.  She hasn't let me try tapering some of those bipolar med's yet...  

If you haven't been there yet, it's probably time to go read the full  metformin information.  You'll find there the discussion of the risks, which is crucial in deciding whether to take a medication approach like this that has so little data supporting its use.

How am I using it now?  Well, for starters I've gotten better at helping patients avoid getting diarrhea, which was the main limiting factor by far at first.  Primary care colleagues gave some good hints to help out there.  Now the diarrhea is not really limiting (start low, increase slow is the key).  Quite a few patients are taking full dose Glucophage (probably 20 as of Jan 2003).  I'm using it to accompany full dose Zyprexa, which otherwise seems to cause weight gain far too often, and of this potentially "metabolic syndrome" type. e.g.Ananth   

I just told a colleague today (Feb 2003) that I'm now putting just about everybody who's going to stay on Zyprexa on Glucophage at the same time -- shooting for prevention now, not just treatment.  It almost seems like Glucophage has to be started before too much time has passed gaining weight, or the Glucophage approach doesn't work.  Or maybe the people with the most severe symptoms, who've been on Zyprexa the longest, simply have the most severe stressors too, to keep the syndrome going.  You can tell this is all very early guessing.  

I haven't heard of anyone else who's using glucophage in this way.  For comparison, here is the view of a very smart bipolar researcher, Dr. Manji at the NIMH:  in brief, he says you have to weigh the risks of Glucophage, that the idea does make some sense and has some basic research to explain how it might work, and that it's far too early to go using Glucophage just to treat bipolar disorder symptoms -- unless they look like metabolic syndrome symptoms too, in which case he's moderately positive on the idea.  Here's the full text of his note,  which is a little technical.  

revised March 2003






The rest below is my junk pile for rewriting, don't bother...JP

Here is one more small bit of evidence that body fat matters in mood syndromes:   Dr. Fagiolini and his colleagues at the University of Pittsburgh, one of the main centers for research in bipolar disorder treatment, noted that among more overweight patients, recurrence of bipolar episodes occurred more frequently and for a larger number of patients in that group. Fagiolini  Their data do not speak to the question of whether weight makes symptoms worse, or symptoms make weight worse; they simply notice the association of the two.