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, Zyprexa, clozapine, Risperdal, sulpiride all increased insulin and C reactive peptide, as well as insulin resistance; but only clozapine and Zyprexa 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  Remeron (mirtazapine)  increases GLUT4 (muscle/fat) and 5(intestine) mRNA, and Haldol and Zyprexa increase GLUT5. No effect on GLUT1-3. (Contrast with Clozaril and Risperdal, below.)

The authors propose something interesting about Remeron: "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 Zyprexa and Remeron 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 Zyprexa's effect on GLUT5 (and not on carbohydrate metabolism, per se), metformin did not prevent weight gain in 40 people on 10mg Zyprexa (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.  Haldol and amisulpiride have little effect on GLUT, and were found not to induce hyperglycemia.    Risperdal had a medium effect on hyperglycemia, but at the lower doses. 

Using rat pheochromocytoma cells, clozapine and Risperdal 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, Seroquel and fluphenazine were toxic to cells; Risperdal was minimally toxic; and Zyprexa actually promoted cell growth.

Seroquel, Zyprexa and clozapine all inhibited glucose transport about the same amount, and in a dose dependent manner.  (Remember: Haldol 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  Zyprexa 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.)

Zyprexa 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 Zyprexa nor Risperdal 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 Haldol does not.

1b. Typicals are toxic to cells, atypicals less so, and Zyprexa 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 Zyprexa and Remeron.

3. Clozapine inhibits insulin release in the presence of glucose, but Haldol 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. 





I believe you may have "out... (Below threshold)

May 15, 2006 4:02 PM | Posted by Bob: | Reply

I believe you may have "outed" yourself re the authorship of this blog today. Sprechen Sie Deutsch?

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August 16, 2006 9:28 AM | Posted by Daniel Haszard: | Reply

Appreciate your blog,mental health consumers are the least capable of self advocacy,my doctors made me take zyprexa for 4 years which was ineffective for my symptoms.I now have a victims support page against Eli Lilly for it's Zyprexa product causing my diabetes.--Daniel Haszard

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May 1, 2007 11:17 AM | Posted by Harry Horton: | Reply

I believe one of the shorter authoritative pieces of atypical antipsychotic induced adverse metabolic effects come from the rapid response section of the British Medical Journal.Richard Fiddian Green , February 13, 2003, wrote a piece in this section entitled-"Schizophrenia and adverse effects of its treatments on mitochondrial metabolism" Richard Fiddian Green being the author. Energy deficits present primarily in the electron transport chain, a phenomena found in schizophrenia disorders as well as cardiovascular conditions, could be the case that gives rise to adverse metaboilic effects of atypical antipsychotic usage. ATP hydrolysis exceeding the capacity of the mitochondria to replenish ATP resynthesis pools, this condition could be more adversely affected by the harmful side effects of the atypicals. That seems to be the problem involved with these drugs. The histamine receptor 1, that is blockaded by zyprexa and clozaril in a fairly extensive manner creates the weight gain found in
the patients that use these drugs. Risperdal also blocks this receptor with less affinity, but likewise creates intermediate weight gain that is lesser than clozaril and zyprexa. The result of histamine 1 receptor blockading by the three above drugs, a research team at Johns Hopkins, involving the researcher Solomon Snyder, found, that with such blockading, AMPK activity levels were quadrupled in the hypothalamus by clozaril and zyprexa. In addition to this fact, there was some very interesting research recently over the past couple of years, that a group of researchers were close to delineating the direct substantial relationship of cAMP to AMPK dynamics. That is, a scientific confirmatory factual illustartion of such a relationship. cAMP is created by inceased hyrolysis of ATP, thus this such action, creating the synthesis of cAMP. Thus this fact leads to the inevitable result that increased AMPK activity found in the histamine 1 receptor blockading, detailed in the Solomon Snyder Johns Hopkins research of February 2007,could be a result of increase cAMP synthesis. And finally that fact simply states, increased ATP hydrolysis is most likely present in these atypical antipsychotic induced conditions, because ATP hydrolysis increase would have to be present in order to accomplish the increased cAMP activity. When one realizes that fact, increased ATP hydrolysis as such, could very well, and potentially, occur at the expense of ATP resynthesis; that is, ATP resynthesis being a healthy building of intramitochondrial ATP stores. This latter process is deleteriously affected by the drugs, and as a result one may get Richard Fiddian Green's "ATP hydrolysis exceeding ATP resynthesis", as the core condition, that gives rise to the metabolic dysregulation seen in atypical antipsychotic (AAP) usage. That is, another way of saying,"ATP hydrolysis exceeding an adequate amount of intramitochondrial ATP stores, the latter for normal running of the energy needs of the cell." The PNAS, Proceedings of the National Academy of Sciences carried the Johns Hopkins research concerning AAP blockading of the histamine 1 receptor and resultant increased AMPK activity, in one of their February 2007 reports. The following web site article-"Atypical Antipsychotics Activate Hypothalamic AMPK" Elizabeth M. Adler, (the author) Science's STKE; this article carries more detailed information on the Johns Hopkin's Discovery. Along with some very good supporting footnotes.

Admin response: you are clearly the man. Let me look into all of this.

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