From The Last Psychiatrist - May 10, 2006

How Do Antipsychotics Cause Weight Gain?

In order for this post-- and any discussion on antipsychotic induced weight gain-- to make sense, you have to understand one thing: each antipsychotic seems to cause weight gain by a different mechanism, not varying degrees of the same mechanism. Because let me tell you right off the bat: researchers here are far from agreed.

A review of some articles:

In rat pancreatic beta cells, neither clozapine nor haloperidol had any effect on basal insulin release. In the presence of high glucose, haloperidol had no effect on the normal insulin surge, but clozapine inhibited this effect by 40%. How it did this is not clear, as clozapine, in the presence of glucose, completely suppressed electrical activity by hyperpolarizing the membrane potential (i.e. increased K+ conductance.) Haloperidol depolarized (inhibited K+ conductance). Thus, by completely suppressing electrical activity, it should have completely suppressed insulin release-- but it only inhibited 40%. Similarly, haloperidol should have increased insulin release (via depolarization) but it didn't have any effect. We don't know what would have happened if the study had been continued for a year; but note here that the effect on insulin is dependent on the presence or absence of glucose, not the other way around.

Most studies focus on the changes in serum parameters (triglyceride, cholesterol, insulin, etc) and not the mechanism for these changes.

For example, in 112 schizophrenics on meds for 8 weeks, olanzapine, clozapine, risperidone, sulpiride all increased insulin and C reactive peptide, as well as insulin resistance; but only clozapine and olanzapine increased triglycerides and cholesterol, and had a greater impact on insulin, insulin resistance, and C-peptide. What you can't tell is when this happened and what came first: did the insulin go up as a direct effect of the med, and consequently so did cholesterol, or did insulin resistance happen first, etc?

In the first study looking at the drugs' effects on GLUT1-5 mRNA, it was found that mirtazapine increases GLUT4 (muscle/fat) and 5(intestine) mRNA, and haloperidol and olanzapine increase GLUT5. No effect on GLUT1-3. (Contrast with clozapine and risperidone, below.)

The authors propose something interesting about mirtazapine: "Therefore, the increasing effects of mirtazapine on GLUT4 mRNA levels in our study might lead to a decrease in blood glucose levels and to an increase in cellular fat deposition, leading to intermittent or continuous lowering of blood glucose levels with a subsequent increased uptake of carbohydrates and other types of nutrients." In other words, better glucose uptake into cells means more fat inside cells, and less glucose outside cells (hypoglycemia)-- which is a stimulus to eat more.

This is important, so I'll repeat it: the hyperglycemia seen with olanzapine and haloperidol is here proposed to be due to the acute lowering of blood glucose (because of increased transport), and thus an increase in eating and fat deposition, and consequently insulin resistance and hyperglycemia; not a direct affect on glucose metabolism.

(Consistent with olanzapine's effect on GLUT5 (and not on carbohydrate metabolism, per se), metformin did not prevent weight gain in 40 people on 10mg olanzapine (all gained 5-6kg in 14 weeks.)

In (male C57) mice, over a 6 month period, clozapine, chlorpromazine and quetiapine induced hyperglycemia via effects on glucose transport. haloperidol and amisulpiride have little effect on GLUT, and were found not to induce hyperglycemia. Risperidone had a medium effect on hyperglycemia, but at the lower doses.

Using rat pheochromocytoma cells, clozapine and risperidone both inhibited glucose transport (i.e. GLUT3).

Desmethylclozapine (a metabolite) was an even more potent inhibitor, while clozapine-N-oxide, the other metabolite, had no effect on glucose transport. Clozapine and fluphenazine also inhibited glucose transport in (rat) muscle cells. The drugs block glucose transport in a non-competitive (i.e. allosteric) manner (and tricyclics appear to work in the same way.) What is interesting about this is that different people metabolize clozapine differently, and perhaps those who create more desmethylclozapine get more hyperglycemia than those who make less (and/or more clozapine-N-oxide.

A follow-up study tried to correlate the toxicity of these drugs to cells to their inhibition of glucose transport.

They found that clozapine, desmethylclozapine, quetiapine and fluphenazine were toxic to cells; risperidone was minimally toxic; and olanzapine actually promoted cell growth.

Quetiapine, olanzapine and clozapine all inhibited glucose transport about the same amount, and in a dose dependent manner. (Remember: haloperidol and sulpiride don't.)

However, if the cells were exposed to drug for a longer time, fluphenazine greatly inhibited glucose uptake, clozapine had no effect, and olanzapine increased glucose uptake. In other words, the toxic typicals only need a sort exposure to kill a cell, while less toxic atypicals need prolonged exposure. Also, fluphenazine increased GLUT3, and the atypicals had little or no effect (as found above.)

Olanzapine was found not to affect either the basal or the insulin stimulated glucose transport via GLUT1 or 4. (Fun fact: bovine serum albumin (or impurities therein), used to replicate the fact that olanzapine is highly (93%) protein bound, actually increased basal glucose transport, making suspicious all studies previosuly done with BSA.) This contradicts the findins of the Dwyer articles, above, where antipsychotics had inhibitory effects on glucose transport. A possible explanation could be dosing: this study used doses comparable to 20mg, while others used 20x that amount.

Another study, in humans, found that neither olanzapine nor risperidone affected acute (3 week) insulin sensitivity. Again, what happens after you get heavy is up for debate.

So what we have here is confusion, but:

1. acute, high dose in vitro studies indicate that typicals>atypicals inhibit glucose transport, but haloperidol does not.

1b. Typicals are toxic to cells, atypicals less so, and olanzapine promotes cell proliferation.

2. Normal dose and human studies show no effect on insulin dependent glucose transport (i.e. GLUT4) but there are effects on small intestine absorption (GLUT5) with olanzapine and haloperidol.

3. Clozapine inhibits insulin release in the presence of glucose, but haloperidol doesn't.

4. Acute effects may be different than chronic. i.e. even though antipsychotics may not directly affect insluin resistance or glucose transport, if they make you hungry or increase fat over time, this could result in later insulin resistance, hyperglycemia, etc.