Female belly fat and clozaril/clozapine

JohnClay · August 10, 2012, 4:07am

Background:
Hi I have a friend who wants to lose weight and has kept a stable weight while watching what she eats. She used to be extremely athletic as a kid but now doesn’t exercise. She used to be called “the body” due to her nice body but in the past few years she’s put on a lot of belly fat. She’s 33 and her arms, legs, hips, and butt are very lean (she has virtually no butt or hips).

Her “waist” (belly) measurement is 42 inches, she’s 5’8" and 200 lbs.

She’s on antipsychotic medication called clozaril/clozapine and it commonly puts weight on.

I’ve talked to a doctor and a psychiatrist but they don’t have any ideas about why her weight is in the place it is rather than the typical female areas like the hips, butt and thighs.

I suggested that it might be hormones or something…

Does anyone know of any possible causes?

thelurkinghorror · August 10, 2012, 5:34am

I’m no expert, but isn’t it partially genetic? Honestly, she sounds somewhat fortunate if it is only in the stomach as opposed to everywhere. Obviously she should exercise along with the diet, but I’m not one to judge there. And as we age it gets harder.

I don’t know that particular drug but most psychiatric ones cause weight gain, if anything. Welbutrin I believe is a rare exception.

md2000 · August 10, 2012, 2:38pm

I’ve seen some girls/women who appear to have a different weight distribution - they put it on in the belly and as a “spare tire”, just above the hips all the way around. They have thinner legs and upper body than you would expect from the weight, and in front much of the weight is in lower abdomen.

I’ve seen this pattern on several females; I specifically remember watching one girl I knew develop this from a fairly normal thin body shape between ages of about 14 and 17 (puberty-related?). So my guess is that it’s genetic. From the small and rough sampling of large-belly females I know, I also wonder if the shape is related to PCOS?

Michael63129 · August 10, 2012, 7:21pm

Actually, it is better to have fat elsewhere and not all in the stomach, which is abdominal obesity and is highly correlated with adverse health outcomes, much more so than fat elsewhere:

DSeid · August 10, 2012, 8:37pm

That drug is one of the so-called “atypical antipsychotics” and is one the ones most strongly associated with “metabolic syndrome” - defined as having 3 of the following: central obesity (waist circumference over 35 inches in women); elevated triglycerides (over 150); low HDL (less than 50 in women); high BP (over 135/85); and elevated fasting plasma glucose (over 110).

Here is a good review for you. (pdf)

It may be at least partly because these meds have particular affinity for certain receptors that trigger off central obesity (5-HT2C and histamine H receptors as particular suspects). It may also be that those who are prone to the conditions that warrant atypical antipsychotic drug use are also particularly prone to develop central obesity when they gain fat mass. The article also talks up the association of schizophrenia and related conditions with lifestyles that are associated with metabolic syndrome but I cannot see that as the major factor in causing central obesity and the rest of metabolic syndrome so much more so than the level of obesity alone would more usually be associated with.

The increase in abdominal obesity associated with these medications being used does seem to occur more commonly in women than men.

I hope she is also getting her lipids and glucose checked regularly and she minimally should be strongly encouraged to take up exercising regularly again. And no smoking.

JohnClay · August 11, 2012, 1:26am

http://www.measureup.gov.au/internet/abhi/publishing.nsf/content/home

Women:
80cm - increased risk
88cm - greatly increased risk

Men:
94cm - increased risk
102cm - greatly increased risk

and my friend is about 106cm…

DSeid · August 11, 2012, 1:56am

The question is a very interesting one.

I’ve also found this study. They studied the effects of two different antipsychotics on fat accumulation, insulin sensitivity, and pancreatic function in dogs. First it was notable that the two (risperdone and olanzapine) had very different effects. But olanzapine’s (OLZ in the study) effects were of particular note:

Recently, the use of atypical antipsychotics has been clouded by reports of drug-associated development of pronounced weight gain and diabetes. Increased incidence of diabetes suggests these agents may also impair pancreatic function, as β-cell defects are considered requisite for pathogenesis of the disease. However, no prospective mechanistic studies to examine possible drug effects on β-cell function, glucose metabolism, and body composition in the absence of underlying psychiatric disease have been published to date. The present studies not only reveal differential effects of two atypical antipsychotics on adiposity and hepatic insulin resistance but also show for the first time a substantial effect of one antipsychotic to impair pancreatic β-cell function. …

… Although drug-induced weight gain is often attributed to stimulatory effects of drug on food intake or appetite (20,40), in the current study, observed body weight changes are not explained solely by alterations in food intake … weight gain with antipsychotics reflects treatment effects on both caloric intake and energy expenditure …

… OLZ caused preferential deposition of energy into adipose tissue. Total trunk fat stores nearly doubled with OLZ, reflecting proportional increases in subcutaneous and visceral depots. RIS caused more modest increases. While the role of specific receptor subtypes (e.g., H1 receptors) have been implicated in antipsychotic-induced weight gain (42), the mechanism for this substantial difference in adiposity between tested medications remains to be determined. …

… Induction of central obesity by atypical antipsychotics has also been inferred from cross-sectional studies (44,45) reporting waist-to-hip ratios. Clearly, the present studies are unique in that they provide the first accurate measures of adiposity during antipsychotic treatment and support the idea that adiposity may be increased considerably more than is reflected in body weight alone. …

… The present studies revealed a dramatic impairment in β-cell compensation during OLZ. OLZ and RIS induced similar whole-body insulin resistance, yet only RIS responded with compensatory upregulation of β-cell sensitivity. Appropriate compensation was also observed in dogs fed an isocaloric moderate fat diet, attaining adiposity matched to that of OLZ. These results demonstrate a substantial defect of β-cell compensatory function induced by OLZ that was apparent only by comparing pancreatic function under similarly “stressed” conditions of insulin resistance. … The mechanisms underlying impairment in β-cell compensation with OLZ are unclear. In vitro data suggest that OLZ does not directly impair β-cell insulin release (47), although treatment duration was brief (3 h). Since insulin secretion can be neurally regulated (48,49), the possibility exists that negative effects of OLZ on β-cell compensation may be mediated by its known central actions as a dopamine antagonist (50), although it is unknown if a similar dopamine-mediated neuropancreatic axis exists for pancreatic endocrine secretion. It is also possible that impairment of β-cell compensation reflects derangement in the signaling pathway by which the pancreas senses insulin resistance and elicits the appropriate secretory response. The effect of OLZ to completely block β-cell upregulation suggests such signaling to the β-cell may be under neural control, involving parasympathetic and/or sympathetic pathways (48,49) or via known OLZ antagonism of muscarinic receptors (29). In fact, stimulation of vagal efferents emanating from the dorsal motor nucleus increases acetylcholine at the β-cell via muscarinic receptors, opening sodium channels and augmenting intracellular calcium influx during hyperglycemia, leading to hypersecretion of insulin. In addition, several dopamine receptor subtypes are also present in the dorsal vagal complex (51), and their antagonism by OLZ may contribute to impaired insulin secretion during treatment. Finally, OLZ-mediated norepinephrine increase in the prefrontal cortex (52) may cause diminished islet function by inhibiting adenylate cyclase (53). …

… In conclusion, this study is the first demonstration of the intrinsic effects of the most widely prescribed atypical antipsychotics on weight, adiposity, insulin sensitivity of the liver and peripheral tissues, and pancreatic β-cell function. There were clear differences in the effects of OLZ and RIS. OLZ caused significant weight gain and marked increases in total trunk adiposity, reflecting marked expansion of both visceral and subcutaneous adipose depots and severe hepatic insulin resistance. RIS had modest effects on adiposity that did not differ from the effects of placebo. Most importantly, the present studies reveal a significant effect of OLZ to impair β-cell compensation for insulin resistance. OLZ completely blocked the compensatory response with obesity and resistance seen with fat feeding, whereas β-cell function during RIS appears intact. The mechanisms by which these actions of antipsychotics occur are not known, but these data suggest that drugs may impede possible neural regulation of β-cell compensation.

Since that 2005 study this one came out last year:

So the brain regulatory systems seem to be a main driver of the metabolic dydfunctions which likely include the tendency to central obesity. Which does not mean that peripheral effects cannot also be main drivers too.

Yes, your friend is at risk. There are reasons that these meds are used despite their known risks. The benefits are significant and other meds have their own risk profiles. Of course I am not her doctor and would not give anything but generic advice. Even given that I will state again, adequate monitoring for those metabolic and blood pressure issues, and adding regular exercise to her attempts at nutrition management, are unquestionably good ideas. She really should discuss this with her doctor.