Diabetes Drug Or Dieter’s Dream? Metformin and Antipsychotic-Induced Weight Gain

With the roll-out of Clozaril, in 1989, with its promise to treat recalcitrant schizophrenics, the era of the second-generation, or ‘atypical,’ antipsychotics, was born.

And there is much the atypicals offer over the first-generation antipsychotics, including freedom from fear from the worst side effects: tardive dyskinesia, with its uncontrolled involuntary movements, uncontrollable tremors, akathisia, with its inability to stay still, and the dreaded neuroleptic malignant syndrome, rarer, but potentially fatal, with fever, change in mental status, rigidity of muscles.

It seemed a new day had dawned, as Clozaril was followed by Risperdal, Zyprexa, Seroquel, Abilify and Geodon, all, it appeared, just as effective as the first generation meds, without the frightening side effect profile.

But as I’ve learned time and again, if something seems too good to be true, it often is, and several of these atypicals [geodon and abilify excluded], while treating a variety of illnesses and succeeding with some recalcitrant cases, soon turned out to have a side effect, the full danger of which would not be fully understood for several years.

If you tell someone that your illness is better on a new medicine, but you’ve put on a few pounds, you’re likely not to receive much encouragement to come off that drug. But the atypicals packed on the pounds–enough so that patients who experienced the full impact of the weight gain now were also in danger of developing metabolic syndrome, putting them at risk of developing coronary heart disease, type 2 diabetes, and stroke.

Research has not shown that exercise and dieting to have reliably positive results in containing ballooning weight.

And other medications have shown little promise. A 2005 study, “Current options in the management of olanzapine-associated weight gain” did a survey of the literature on Zyprexa, or olanzapine, arguably the atypical with the greatest risk for gain, and the use of adjunctive medications to manage the situation.

What they found wasn’t heartening. The researchers conclude:

Preliminary evidence evaluating adjunctive pharmacologic treatment for this indication [weight gain] has demonstrated minimal clinical benefit.

For some patients it can look like they’ve got to make a choice–between their physical and mental health.

And then. . .along comes metformin, generic of Glucophage. In a field where newer and more expensive are the key words of the pharmacological day, here we are, back to the oldest and cheapest drug to treat type 2 diabetes.

Now the most widely-prescribed anti-diabetic drug in the world, metformin, it appears, might just turn out to be the atpyical-takers’ dream ‘Dexatrim.’

Those who don’t understand the full scope of the problem continue to insist that if patients merely ate less and exercised more, the situation would improve. But one Dr. Wu found metformin was more helpful in reversing weight gain than lifestyle changes alone.

Ren-Rong Wu, MD, of Central South University in Changsha, China, studied 128 schizophrenic patients who had gained more than 10% of their body weight after starting treatment with an atypical. Subjects continued their medication regimen, but were assigned–randomly, this being a (what have I taught you, about the sexiest term there is for scientists? Don’t fail me now.) a randomized controlled trial–to 4 groups: metformin alone, metformin plus diet/exercise, placebo alone, or placebo plus diet/exercise.

Entitled “Lifestyle intervention and metformin for treatment of antipsychotic-induced weight gain: A randomized controlled trial,” it was the first study to put lifestyle intervention and metformin alone or in combination all in a room together and let them duke it out to see who’d knock off the most weight.

As laid out neatly in CBS news’ “Fighting Antipsychotic Weight Gain,” the following occurred

  • Those on placebo alone gained 6.8 pounds and their waist size grew almost an inch.
  • Those on placebo plus diet/exercise lost 3.1 pounds and their waist size shrank by a small fraction of an inch.
  • Those assigned to metformin alone lost 7.1 pounds, with waist size shrinking by a half-inch.
  • Those assigned to metformin plus diet/exercise lost 10.4 pounds. Waist size? It shrank by nearly an inch.

Wu’s study clearly showed that lifestyle intervention plus metformin was far more effective than lifestyle intervention plus placebo, and

metformin was superior to lifestyle intervention plus placebo in decreasing weight, BMI, waist circumference, fasting glucose, and insulin. And, additionally, Metformin alone was more effective in weight loss and improving insulin sensitivity than lifestyle intervention alone. [emphasis mine].

Concurrent with this study on whether metformin would help decrease weight gain, Wu was investigating whether it could actually prevent the significant increases in the first place. Again returning to Zyprexa (olanzapine) and its tendency to really pack on the pounds, Wu studied 40 schizophrenics randomly assigned for a 12-week segment to Zyprexa with metformin, or to a placebo pill alone.

Results of using metformin as a preventative measure were positive. Significantly fewer patients taking the metformin increased their baseline weight by over 7%, the cutoff researchers used for ‘meaningful weight gain.’ And:

The weight, body mass index, waist circumference, and waist-to-hip ratio levels increased less in the olanzapine plus metformin group relative to the olanzapine plus placebo group during the 12-week follow-up period. [emphasis mine]

Pretty good, I’d say.

As recently as 2010, researchers did a survey of the literature of medications used to treat aytpical-induced weight gain, calling it (my personal favorite) a ‘meta-analysis.’

15 medications were tested. The most familiar ones would probably be Prozac, Topomax, and Dexedrine. And, of course, metformin.

The results?

Across seven studies, subjects on metformin had significantly reduced weight compared with placebo. In addition, subjects on metformin experienced a significant decrease in BMI. . . .Sensitivity analyses revealed that metformin, given as an intervention after weight gain had occurred, yielded significantly greater weight loss than placebo. [And, in sum,] results were most robust for metformin [in ameliorating antipyschotic-induced weight gain.] [emphasis mine]

They do warn, however, that, despite metformin’s help with weight gain, it is not ‘the answer’. None of the drugs utilized in the study was

able to entirely reverse weight gain because of antipsychotics. At present, no treatment has sufficient evidence to recommend broad clinical usage.

Indeed, metformin has yet to experience ‘broad clinical usage’ in the event of atypical-induced weight gain. Many sufferers are unfamiliar with it even as an option.

The most recent study, from just March of this year, “Efficacy of metformin for prevention of weight gain in psychiatric populations: a review,” was a little more up-beat, although still cautious. They wrote, after surveying the literature,

We concluded that if weight gain occurs after second-generation antipsychotic initiation, despite lifestyle intervention, metformin should be considered. Further studies with adequate statistical power are required to determine the efficacy of metformin in those with chronic psychotic illness.

And perhaps that note of hesitance, despite all the positives, is right, after all.

Because as intriguing as an option I believe metformin is for weight reversal–and even, potentially, preventative weight control–and as much as I believe it should continue to be looked into with double-blind studies, we should remember what we started with:

If something sounds too good to be true, it probably is.

That doesn’t meant it’s not pretty darned good, though.


Newll H, et al. Efficacy of metformin for prevention of weight gain in psychiatric populations: a review. International Clinical Psychopharmacology 2012; 27(2):69–75.

Hester EK, Thrower MR. Current options in the management of olanzapine-associated weight gain. Annals of Pharmacotherapy 2005; 39(2):302-310.

Maayan L, Vakhrusheva J, Correll CU. Effectiveness of medications used to attenuate antipsychotic-related weight gain and metabolic abnormalities: A systematic review and meta-analysis. Neuropsychopharmacology 2010; 35(7):1520–1530.

Wu RR, et al.  Metformin addition attenuates olanzapine-induced weight gain in drug-naive first-episode schizophrenia patients: A double-Blind, placebo-controlled study. American Journal of Psychiatry 2008; 165:352-358.

Wu RR, et al. Lifestyle intervention and metformin for treatment of antipsychotic-induced weight gain: a randomized controlled trial. JAMA 2008; 299(2):185–93

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