Metabolic Syndrome: a note from Dr. Manji

Bipolar World is an active website for patients with bipolar disorder.  One of the members there actually has forged a good communication network there with the leading researcher at the National Institute of Mental Health (NIMH); and has kindly handed on to me some of his notes to that group.  Thanks to Ms. HB for this info'. 

She reports: 

I've asked Dr. Husseini Manji at the NIMH to comment on metabolic syndrome and polycystic ovary syndrome and Metformin, which we were discussing a few days ago.

Here is his response:

In the adult (generally schizophrenia) field, there is increased interest in the possibility that some individuals with excessive weight gain on atypicals [atypical antipsychotics] may develop the metabolic syndrome associated with insulin resistance. There are studies underway to determine if metformin, an "insulin sensitizer" (i.e., makes insulin have a bigger effect) will prevent/treat this. Controlled data isn't not available yet, to the best of my knowledge.

I would be very careful about using metformin unless the metabolic syndrome PCOS [polycystic ovarian syndrome] has been clearly identified. The medication has a number of potentially serious side effects [see my discussion of Risks and Side Effects-- Phelps] , and glucose regulation is something that needs to be regulated carefully. In fact lithium is also known to enhance the effects of insulin by (at least in part) inhibiting the enzyme GSK-3)...

I don't think that its outlandish to think that someone with a *true* metabolic syndrome could be lethargic, have problems concentrating, etc. I don't think that this is likely to be the case for most individuals diagnosed with bipolar disorder. Could untreated metabolic syndrome be contributing to lethargy/depressive/sluggishness symptoms in *some* cases ? -- certainly. The best well conducted study is described in "The relationship  between psychological risk attributes and the metabolic syndrome in healthy women: antecedent or consequence?"
Raikkonen K, et al, Metabolism 2002 Dec;51(12):1573-7.

But... another reason not to jump to this conclusion is because metformin activates some of the same signaling pathways as antidepressants and lithium. I don't know if this also occurs in the brain (but there are insulin receptors in the brain), but it raises the possibility that the metformin-induced improvement in the bipolar individuals was also due to activating these pathways, not necessarily simply treating an underrecognized metabolic syndrome. The next bit is *very speculative* -- as we've gotten increasing data that lithium and valproate [Depakote] affect growth factor cascades (which in many cases are the same ones that insulin uses), Ken Davis (Dean at Mount Sinai and a major schizophrenia researcher) and I have been wondering if insulin coma therapy (used years ago) actually might have worked by activating insulin pathways in the brain, not by a "coma shock". The growth factor cascades that insulin, etc utilizes in many cases are the same ones used by brain derive
d neurotrophic factor, etc.

So at this point, I think that metformin should only be considered when there is more clear evidence of PCOS or metabolic syndrome (not "just" lethargy/sluggishness). It certainly *might* help in the latter situations, but the cost/benefit may not be worth it. If there are concerns about "mild" metabolic syndrome, dietary changes (reducing carbs, frequent smaller meals) and exercise (and I know its not as simple as that, especially for someone who is depressed, but even modest resistance exercise ... has been shown to help regulate insulin release/sensitivity).

Husseini Manji, M.D.