Metabolic Dysregulation With Atypical Antipsychotics
Occurs in the Absence of Underlying Disease
A Placebo-Controlled Study of Olanzapine and
Risperidone in Dogs
Marilyn Ader, Stella P. Kim, Karyn J. Catalano, Viorica Ionut, Katrin Hucking,
Joyce M. Richey, Morvarid Kabir, and Richard N. Bergman
Atypical antipsychotics have been linked to weight gain,
hyperglycemia, and diabetes. We examined the effects of
atypical antipsychotics olanzapine (OLZ) and risperidone (RIS) versus placebo on adiposity, insulin sensitivity (SI), and pancreatic ␤-cell compensation. Dogs
were fed ad libitum and given OLZ (15 mg/day; n ⴝ 10),
RIS (5 mg/day; n ⴝ 10), or gelatin capsules (n ⴝ 6) for
4 – 6 weeks. OLZ resulted in substantial increases in
adiposity: increased total body fat (ⴙ91 ⴞ 20%; P ⴝ
0.000001) reflecting marked increases in subcutaneous
(ⴙ106 ⴞ 24%; P ⴝ 0.0001) and visceral (ⴙ84 ⴞ 22%; P ⴝ
0.000001) adipose stores. Changes in adiposity with RIS
were not different from that observed in the placebo
group (P > 0.33). Only OLZ resulted in marked hepatic
insulin resistance (hepatic SI [pre- versus postdrug]:
6.05 ⴞ 0.98 vs. 1.53 ⴞ 0.93 dl 䡠 minⴚ1 䡠 kgⴚ1/[␮U/ml],
respectively; P ⴝ 0.009). ␤-Cell sensitivity failed to
upregulate during OLZ (pre-drug: 1.24 ⴞ 0.15, postdrug: 1.07 ⴞ 0.25 ␮U 䡠 mlⴚ1/[mg/dl]; P ⴝ 0.6). OLZinduced ␤-cell dysfunction was further demonstrated
when ␤-cell compensation was compared with a group
of animals with adiposity and insulin resistance induced
by moderate fat feeding alone (ⴙ8% of calories from fat;
n ⴝ 6). These results may explain the diabetogenic
effects of atypical antipsychotics and suggest that ␤-cell
compensation is under neural control. Diabetes 54:
862– 871, 2005
From the Department of Physiology and Biophysics, Keck School of Medicine,
University of Southern California, Los Angeles, California.
Address correspondence and reprint requests to Marilyn Ader, PhD, Keck
School of Medicine, Department of Physiology and Biophysics, University of
Southern California, MMR 624, 1333 San Pablo St., Los Angeles, CA 90033.
E-mail: [email protected].
Received for publication 6 July 2004 and accepted in revised form
29 November 2004.
M.A. has received honoraria from Janssen Pharmaceutica. R.N.B. has
served on an advisory panel for and received consulting fees from Janssen
Pharmaceutica.
DI, disposition index; EGC, euglycemic-hyperinsulinemic clamp; FFA, free
fatty acid; HGO, hepatic glucose output; MRI, magnetic resonance imaging;
OLZ, olanzapine; RIS, risperidone.
© 2005 by the American Diabetes Association.
The costs of publication of this article were defrayed in part by the payment of page
charges. This article must therefore be hereby marked “advertisement” in accordance
with 18 U.S.C. Section 1734 solely to indicate this fact.
862
T
he introduction of atypical antipsychotics in
psychopharmacology represented a major advance in the treatment of schizophrenia, providing an effective therapy for both positive and
negative symptoms of psychosis while minimizing the
extrapyramidal effects characteristic of earlier therapeutic
options. Indeed, these medications are widely prescribed
(⬃3% of the U.S. population) for treatment of schizophrenia, as well as bipolar disorder, depression, and dementia.
In the face of their widespread use, concern has arisen
regarding treatment-associated weight gain and apparent
increased diabetes risk (1–3). It is unclear whether weight
gain is a direct effect of the drug or secondary to behavioral changes, such as increased sedation associated with
pharmacotherapy. But regardless of its causality, obesity is a
significant public health concern and is a well-documented
risk factor for type 2 diabetes as well as other chronic
diseases, such as cancer and atherosclerosis (4 – 6). Nonetheless, diabetes risk with antipsychotic use has also been
reported in the absence of significant weight gain (7–9).
Evidence linking atypical antipsychotics to metabolic
dysregulation is largely based on case reports and retrospective analyses, which note a disproportionately greater
number of patients developing fasting hyperglycemia and
new-onset diabetes or exhibiting exacerbation of preexisting diabetes soon after the initiation of atypical antipsychotic treatment (10 –15). Henderson et al. (14) reported
that ⬎30% of schizophrenic patients receiving clozapine
developed diabetes within a 5-year follow-up, and those
with preexisting diabetes required increased insulin dosing. Federal Drug Administration reports (10), based in
part on the Medwatch Surveillance Program, provide
further evidence of the excessive occurrence of new-onset
diabetes and exacerbation of preexisting disease with
clozapine compared with disease incidence in untreated
individuals. More recently, olanzapine (OLZ) and risperidone (RIS), which collectively account for ⬎80% of all
drugs prescribed of their class of atypical antipsychotics,
have also been associated with metabolic abnormalities,
though OLZ is generally linked to greater relative risk for
diabetes (11,16) and more marked obesity (3,11,17) compared with RIS (12,13,18).
It is indeed challenging to study the actions of antipsyDIABETES, VOL. 54, MARCH 2005
M. ADER AND ASSOCIATES
chotic agents. Most prospective studies (19 –21) have been
performed in subjects with psychiatric disease. However,
the use of such patients for prospective studies introduces
confounding factors, such as comedication, comorbidity,
and poorly defined effects of underlying disease per se.
With respect to carbohydrate metabolism, disease per se
can result in obesity and the associated risk for diabetes
and other ailments (22–24). One possible approach to
minimize such confounds is to study the effects of the
drugs in healthy subjects (25). However, since there are
well-known potential risks associated with administration
of psychiatric drugs to normal subjects (26), it is often not
possible to administer therapeutic drugs for extended
periods of time.
In view of the overwhelming evidence that these agents
may increase the risk for diabetes, it is incumbent to study
the effects of the agents in an appropriate animal model. Also, because of the reports of diabetic ketoacidosis
(10 –12), which most often results from severe insulinopenia, it is important to include studies of pancreatic ␤-cell
functionality. For these reasons, the present placebocontrolled study was performed in normal dogs to directly
test whether chronic treatment with atypical antipsychotics results in obesity and glucose dysregulation.
The present study represents the first prospective analysis of the metabolic effects of two widely prescribed
atypical antipsychotics in the absence of underlying disease and demonstrates clear differential effects of these
two agents on body composition and carbohydrate metabolism. Most notably, we provide the first clear demonstration of a negative effect of an atypical antipsychotic agent
on ␤-cell function.
RESEARCH DESIGN AND METHODS
Animal model: metabolic effects of antipsychotics. Procedures were
performed on 26 male mongrel dogs (28.6 ⫾ 0.6 kg). Dogs were individually
housed in the University of Southern California Vivarium under controlled
environmental conditions. At least 1 week before testing, dogs were surgically
outfitted with chronic catheters in the jugular vein (advanced into the right
atrium) for sampling of mixed central venous blood and a femoral vein for
infusions. All procedures were approved by the University of Southern
California Institutional Animal Care and Use Committee.
Diet and food intake. At least 1 week before surgery, dogs were established
on a strict feeding regimen to permit assessment of daily food intake
throughout the study to determine its contribution to any observed changes in
body weight. During baseline and treatment periods, all dogs were fed ad
libitum a diet of one can of Hill’s Prescription Diet (10% carbohydrate, 9%
protein, and 8% fat) and a known quantity of dry chow (37% carbohydrate, 26%
protein, and 15% fat) once per day. Quantity of uneaten food was removed,
weighed, and recorded daily each morning before giving the next day’s food
allotment. Any dog consuming its daily meal on 2 consecutive days was
provided with an increased amount of dry chow for all subsequent days,
although this rarely occurred since dogs were given dry chow in excess of
typical daily intake to enable virtually ad libitum feeding. Food intake was
presented as total calories consumed per week.
Study design. The study was divided into three phases: 1) baseline testing
(pre-drug), 2) drug treatment period, and 3) post-drug period. Before study
entry, dogs were randomly assigned to one of three treatment arms: OLZ, RIS,
or placebo. Predrug testing was performed in all dogs to quantify insulin
sensitivity (SI), trunk adiposity, and pancreatic ␤-cell function (see below for
details). The order of experiments was randomized and performed in each
animal over a 10-day period, with ⱖ2 days between experiments. After
pre-drug testing, dogs were placed on the drug (or placebo) regimen for 4 – 6
weeks, after which all procedures performed during pre-drug phase were
repeated (post-drug) under conditions identical to pre-drug testing. Drug (or
placebo) treatment was continued during the entire post-drug testing period.
Dogs were assigned to receive either OLZ (Zyprexa; Lilly, Indianapolis, IN;
n ⫽ 10), RIS (Risperdal; Janssen Pharmaceuticals, Titusville, NY; n ⫽ 10), or
placebo (gelatin capsules; Monterey Bay Spice, Santa Cruz, CA; n ⫽ 6). Drugs
DIABETES, VOL. 54, MARCH 2005
were administered orally once per day, 6 – 8 h after daily presentation of food
(⬃2:00 P.M.). Doses were based on those used in typical treatment of patients,
as well as on reported dopamine D2 receptor binding in the caudate nucleus
(27). The RIS dose was chosen as the midpoint between zero and the dose
associated with moderate toxicity (28). The OLZ dose was subsequently
chosen to parallel the approximate 3:1 (OLZ-to-RIS) ratio used in clinical
applications (29). Doses of each drug were stepped up to the target dose by
day 4 of treatment. The target dose for OLZ was 15 mg/day and the target dose
for RIS was 5 mg/day. All dogs (including placebo-treated animals) were
videotaped for ⬃2–5 min before and 1–3 h and 24 h after first dosing at initial
and target doses to facilitate monitoring of behavioral changes and possible
movement disorders.
Drug treatment period. During the time interval between pre- and post-drug
testing, body weight was measured and fasting blood samples drawn twice
weekly to monitor hormone and substrate changes. Blood samples were
collected percutaneously from a cephalic vein, centrifuged, and plasma
assayed for glucose and lactate with an automated analyzer (YSI Model 230;
Yellow Springs, Yellow Springs, OH). Remaining plasma was stored at ⫺80°C
for subsequent assay of insulin, free fatty acids (FFAs), glycerol, and
triglycerides. Given reports of elevated hepatic enzymes with antipsychotic
treatment (29), fasting blood samples were collected during pre- and post-drug
periods for determination of alanine aminotransferase and aspartate aminotransferase.
Experimental procedures. During pre-drug and post-drug periods, all
animals underwent three procedures performed in random order: 1) abdominal magnetic resonance imaging (MRI) to assess treatment-induced changes
in adiposity, 2) euglycemic hyperinsulinemic clamp (EGC) to quantify hepatic
and peripheral insulin sensitivity, and 3) stepwise ␤-cell stimulation test
(STEP test) to assess pancreatic ␤-cell insulin response. All procedures were
performed in overnight-fasted animals, and during all experiments (except
MRIs), dogs were fully conscious, rested comfortably in a Pavlov sling, and
were given free access to water.
Abdominal MRI. After an overnight fast, dogs were preanesthetized and
sedated. Thirty 1-cm axial abdominal images were obtained using a General
Electric 1.5 Tesla Horizon magnet. Images were analyzed by a laboratory
technician who was blinded to treatment group and phase of study (basal,
posttreatment). Analysis was performed using ScionImage software, which
quantified fat tissue (pixel value: 0 –120) and other tissues (pixel value:
121–256) in each slice. Total trunk fat and tissue were estimated as the
integrated fat or tissue across all 30 slices. Visceral fat was defined as fat
within the peritoneal cavity at ⫾5 images from the slice at the level where the
left renal artery branches from the abdominal aorta (i.e., from 11-cm abdominal range). All adiposity data are expressed in units of cm3 normalized to the
volume of nonfat tissue.
EGC. On the morning of the clamp, one intracatheter was inserted percutaneously in the saphenous vein for infusion of glucose. At t ⫽ ⫺180 min, a
primed infusion of high-performance liquid chromatography–purified 3-3Hglucose (tracer; 25 ␮Ci ⫹ 0.25 ␮Ci/min; Perkin-Elmer NEN, Boston, MA) was
initiated via indwelling femoral vein catheter. After basal blood sampling,
cyclic somatostatin (1 ␮g 䡠 min⫺1 䡠 kg⫺1) was infused intravenously to
suppress endogenous insulin secretion, and basal insulin secretion was
replaced by exogenous infusion (0.15 mU 䡠 min⫺1 䡠 kg⫺1). Hyperinsulinemia
was induced by systemic insulin (regular purified pork; Lilly) infusion at 1.0
mU 䡠 min⫺1 䡠 kg⫺1 from 0 to 180 min. Euglycemia was maintained by a variable
rate of 50% dextrose infusion spiked with 3-3H-glucose (specific activity: 2.2
␮Ci/g) to avoid large fluctuations in plasma specific activity. Blood samples
were drawn every 10 min from t ⫽ 10 to 60 min, every 15 min from t ⫽ 75 to
150 min, and every 10 min from 160 to 180 min. Plasma was stored for
subsequent assay of insulin, tracer, FFAs, glycerol, and triglycerides.
STEP test. After basal blood sampling, glucose was clamped at three
sequential glycemic levels by exogenous glucose infusion. Glucose was
targeted to concentrations of 100 mg/dl (t ⫽ 0 –59 min), 150 mg/dl (t ⫽ 60 –149
min), and 200 mg/dl (t ⫽ 150 –240 min).
Fat fed dogs: control for drug-induced adiposity. To determine the extent
to which drug-associated changes in ␤-cell function were due to increased
adiposity per se, we examined a separate group of dogs with obesity induced
by isocaloric moderate fat feeding. Dogs (n ⫽ 6; 27.5 ⫾ 1.5 kg) were fed a
weight-maintaining diet (3,885 kcal/day; 37.9% carbohydrate, 26.3% protein,
and 35.8% fat) for 2 weeks before and during baseline testing. After baseline
testing, dogs were placed on an isocaloric diet (i.e., total calories similar to
baseline) with moderate supplementation of dietary fat (⫹2 g/kg prediet body
weight of cooked bacon grease), which consisted of 3,945 kcal/day (32.9%
carbohydrate, 22.9% protein, and 44.1% fat) for a total increase of ⬃8% daily
calories from fat. This diet was maintained for 6 weeks and continued during
postdiet testing. This diet was previously shown to cause a moderate increase
in visceral and subcutaneous adiposity despite no increase in calories (30).
863
METABOLIC EFFECTS OF ATYPICAL ANTIPSYCHOTICS
TABLE 1
Effect of drug (or placebo) treatment on fasting plasma values
OLZ
Glucose (mg/dl)
Insulin (␮U/ml)
FFAs (mmol/l)
Glycerol (mmol/l)
Triglycerides (mmol/l)
Lactate (mg/dl)
RIS
Placebo
Predrug
Postdrug*
Predrug
Postdrug
Predrug
Postdrug
98 ⫾ 1
13.7 ⫾ 2.3
0.62 ⫾ 0.07
0.103 ⫾ 0.010
0.291 ⫾ 0.025
8.69 ⫾ 0.55
96 ⫾ 1†
18.2 ⫾ 3.0†
0.79 ⫾ 0.07
0.123 ⫾ 0.014
0.277 ⫾ 0.027
7.37 ⫾ 0.41
98 ⫾ 1
10.3 ⫾ 1.1
0.73 ⫾ 0.07
0.115 ⫾ 0.010
0.351 ⫾ 0.026
7.76 ⫾ 1.04
97 ⫾ 1
13.0 ⫾ 1.1†
0.58 ⫾ 0.05
0.092 ⫾ 0.013
0.297 ⫾ 0.023§
8.43 ⫾ 0.49
92 ⫾ 2‡
10.5 ⫾ 1.6
0.54 ⫾ 0.07
0.094 ⫾ 0.009
0.366 ⫾ 0.029
8.13 ⫾ 0.39
91 ⫾ 2
13.0 ⫾ 1.7†
0.45 ⫾ 0.08
0.074 ⫾ 0.007
0.332 ⫾ 0.020
7.68 ⫾ 0.70
Data are means ⫾ SE. *Values reported are mean of week 6 of drug treatment period; †P ⬍ 0.05 vs. pre-drug; ‡P ⫽ 0.015 vs. OLZ and RIS
(by ANOVA); §P ⫽ 0.011 vs. pre-drug.
Data from diet group represents a subset of results currently under review
(31). Before and after fat feeding, each dog underwent procedures described
above (MRI, EGC, and STEP test), performed in identical manner except for
insulin infusion rate during clamps (1.5 mU 䡠 min⫺1 䡠 kg⫺1).
Blood sampling. Blood samples for insulin and tracer analysis were collected
in lithium- and heparin-coated tubes to which EDTA was added. Samples for
measurement of FFAs, glycerol, and triglycerides were collected in tubes containing paraoxan (to suppress lipoprotein lipase) and EDTA. All samples were
centrifuged immediately and plasma stored at ⫺80°C for subsequent assays.
Assays. Plasma glucose was assayed online in duplicate by the glucose
oxidase technique on an automated analyzer, with intra-assay coefficient of
variation (CV) ⬍1%. Plasma porcine insulin was measured in duplicate by the
highly specific sandwich enzyme-linked immunosorbent assay (Linco Research, St. Charles, MO). The limit of detection in the enzyme-linked immunosorbent assay is 5 pmol/l, with a intra- and interassay CV of 2 ⫾ 1 and 5 ⫾
1%, respectively. Plasma FFAs were measured using kits that utilize a
colorimetric assay based on the acylation of coenzyme-A (Wako, Neuss,
Germany). Glycerol and triglycerides were measured spectrophotometrically
(GPO-Trinder; Sigma, St. Louis, MO). Measurement of [3-3H]-glucose was
performed after deproteinization of samples as previously described (32).
Data analysis and calculations. After data smoothing (33), rates of glucose
disappearance (Rd) and hepatic glucose output (HGO) during EGC were
calculated with Steele’s equations, as modified for use with labeled glucose
infusion (34). Measures of insulin sensitivity from clamps were calculated as
previously described (35). Whole-body insulin sensitivity (SIclamp; combined
actions of insulin to stimulate glucose uptake and suppress endogenous
glucose production) was defined as SIclamp ⫽ ⌬GINF/(⌬INS ⫻ GLUss), where
⌬GINF and ⌬INS are the respective increments in the glucose infusion rate
and plasma insulin measured during exogenous insulin infusion (i.e., steady
state minus basal period) and GLUss is the steady-state glucose concentration.
Peripheral insulin sensitivity (SIpclamp) was defined as ⌬Rd/(⌬INS ⫻ GLUss),
where ⌬Rd is the change in glucose uptake (Rd) from basal to steady state.
Hepatic insulin sensitivity was calculated as the absolute value of ⌬HGO/
(⌬INS ⫻ GLUss), where ⌬HGO is the observed change in endogenous glucose
production or HGO (basal minus steady state).
Pancreatic ␤-cell sensitivity to glucose was calculated from STEP tests as
the slope of the line relating plasma insulin to glucose concentrations (␤-cell
slope), using the mean of the final 20 –30 min from each glycemic period for
each variable (i.e., 40 – 60, 120 –150, and 210 –240 min). Incremental area under
the curve was calculated by the trapezoid rule. It is known that there is a
stereotypical hyperbolic relationship between insulin secretion and insulin
sensitivity, such that any reduction in sensitivity (insulin resistance) is
normally compensated by an increase in ␤-cell responsiveness (36,37). Therefore, to assess the ability of the ␤-cells to compensate for adiposity-driven
insulin resistance, we also normalized ␤-cell response to insulin sensitivity
(36), as reductions in insulin sensitivity would be expected to prompt
upregulation of ␤-cell function. Pancreatic ␤-cell function is expressed as the
disposition index (DI) (36,37) calculated as SIclamp ⫻ ␤-cell slope.
All statistics (t tests and ANOVA, with Tukey’s post hoc analysis when
overall significance was detected) were performed using MINITAB statistical
software (version 13.32; Minitab, State College, PA). Data are reported as
means ⫾ SE. Statistical significance was set at P ⱕ 0.05.
0.015 by ANOVA). In the pre-drug state, there were no
differences in fasting insulin, FFAs, glycerol, triglycerides,
or lactate among groups (P ⬎ 0.14). In response to drug
(or placebo) treatment, fasting hyperglycemia did not develop in any dog. Rather, glucose was marginally lower
after OLZ (P ⫽ 0.05) but clearly remained in the physiologic range within which counterregulatory responses are
absent. In contrast, insulin was elevated from pre-drug in
all groups (P ⫽ 0.033, P ⫽ 0.01, and P ⫽ 0.02 for OLZ, RIS,
and placebo, respectively). FFAs, glycerol, and lactate concentrations were not appreciably changed in any treatment
group, although there was a trend toward reduced FFAs
after treatment with RIS (P ⫽ 0.078). Triglycerides were
unchanged by OLZ (P ⫽ 0.44) but significantly reduced by
RIS (P ⫽ 0.011). Except for insulin, fasting plasma values
were not changed significantly by placebo treatment.
Body weight and food intake. There were modest
RESULTS
Basal values. The pre-drug characteristics of each treatment group are shown in Table 1. Fasting glucose was
similar between OLZ and RIS (98 ⫾ 1 mg/dl for both) but
was slightly lower in the placebo group (92 ⫾ 2 mg/dl; P ⫽
864
FIG. 1. Time course of body weight in dogs treated with OLZ (A), RIS
(B), or placebo (C). Week 0 represents the mean of 2 weeks before
drug (or placebo) administration and is shown as dashed line. Statistics denote comparison to respective pre-drug values. *P < 0.05; †P <
0.01; ‡P < 0.001.
DIABETES, VOL. 54, MARCH 2005
M. ADER AND ASSOCIATES
FIG. 2. Time course of total weekly food intake during treatment with
OLZ (A), RIS (B), or placebo (C). Week 0 represents the mean of 2
weeks before drug (or placebo) administration and is shown as dashed
line. Statistics denote comparison to respective pre-drug values. *P <
0.02.
changes in body weight in all groups (Fig. 1). OLZ-treated
dogs exhibited an initial decline in weight of 0.7 ⫾ 0.2
kg (⫺2.5 ⫾ 0.6% pre-drug weight) within 1 week of drug
treatment (P ⫽ 0.001; Fig. 1A), which occurred despite
increased food intake during that time (P ⫽ 0.015; Fig. 2A).
Weight normalized by week 2 and steadily increased to
maximum weight gain of ⫹1.7 ⫾ 0.4 kg (⫹5.9 ⫾ 1.2% of
pre-drug weight) at week 6 (P ⫽ 0.001 vs. pre-drug). Body
weight changes during RIS appeared similar in pattern to
OLZ though smaller in magnitude (Fig. 1B). Following
transitory weight loss after 1 week of RIS treatment (0.7 ⫾
0.2 kg, ⫺2.4 ⫾ 0.8% pre-drug weight; P ⫽ 0.016), weight
returned to basal levels within 2 weeks and exhibited a
marginal nonsignificant upward trend to maximum recorded weight by week 6 (P ⫽ 0.09 vs. pre-drug). Three
dogs exhibited net weight loss after RIS (week 6 versus
pre-drug). Placebo-treated dogs exhibited an upward trend
in body weight; by week 6, weight gain in placebo-treated
dogs was ⫹1.5 ⫾ 0.3 kg, or ⫹4.8 ⫾ 1.0% of pre-drug weight
(P ⫽ 0.006).
Changes in food intake suggest possible mechanisms of
weight gain observed in this study (Fig. 2). OLZ caused
increased food intake; dogs consumed a significant excess
of calories during treatment (16,024 ⫾ 6,240 kcal over
baseline; P ⫽ 0.031). However, such changes were similar
to that induced by placebo, as evidenced by the tendency
for increased caloric intake in control dogs (19,355 ⫾
12,885 kcal over baseline; P ⫽ 0.82 vs. OLZ). Food intake
was not appreciably altered by RIS (⫺9,599 ⫾ 6,111 kcal
over baseline; P ⫽ 0.17), suggesting that even modest weight
DIABETES, VOL. 54, MARCH 2005
changes with RIS treatment could not be accounted for by
increased consumption of calories. Food intake during RIS
was significantly lower than that observed during OLZ
treatment (P ⫽ 0.007).
Adiposity. Unremarkable changes in body weight did not
reflect substantial increases in adiposity with drug treatment (Fig. 3). Fat deposition was most dramatic in OLZtreated dogs, where total trunk fat increased in all dogs,
from 24.9 ⫾ 3.2 to 43.4 ⫾ 3.9 cm3 (P ⬍ 0.000001). Both fat
depots enlarged: the visceral adipose compartment expanded by 66% (pre-drug: 13.1 ⫾ 1.3, post-drug: 21.8 ⫾ 1.1
cm3; P ⬍ 0.000001), while subcutaneous fat increased 83%
(pre-drug: 11.8 ⫾ 2.0, post-drug: 21.6 ⫾ 3.1 cm3; P ⫽
0.0001).
Adiposity changes with RIS were less than with OLZ and
more variable (Fig. 3). RIS increased total fat by 45%, from
21.9 ⫾ 3.0 to 31.8 ⫾ 2.8 cm3 (P ⫽ 0.005), with two dogs
exhibiting reduced fat volume. Visceral fat was increased
in most dogs (group increase ⫽ ⫹52%; pre-drug: 11.4 ⫾ 0.8,
post-drug: 17.3 ⫾ 1.2 cm3; P ⫽ 0.001), while the subcutaneous adipose depot was only marginally enlarged 38%
(pre-drug: 10.5 ⫾ 2.4, post-drug: 14.4 ⫾ 1.8 cm3; P ⫽ 0.053).
Dogs given placebo exhibited increases of 27–30% in total
(P ⫽ 0.042), visceral (P ⫽ 0.046), and subcutaneous (P ⫽
0.044) fat depots.
Compared with placebo, changes in adiposity with OLZ
were markedly greater in total (P ⫽ 0.0088), visceral (P ⫽
0.025), and subcutaneous (P ⫽ 0.0078) compartments.
Changes with RIS were not different from placebo (P ⬎
0.33). Compared with RIS, OLZ resulted in a 2- to 2.5-fold
greater accumulation of total (OLZ: 18.5 ⫾ 1.8, RIS: 9.9 ⫾
2.7 cm3; P ⫽ 0.018) and subcutaneous fat (OLZ: 9.8 ⫾ 1.5,
RIS: 4.0 ⫾ 1.8 cm3; P ⫽ 0.024) and a tendency toward a
greater increase in visceral fat (OLZ: 8.7 ⫾ 0.9, RIS: 5.9 ⫾
1.3 cm3; P ⫽ 0.091). For a given observed change in body
weight, OLZ-treated dogs exhibited greater total fat deposition than dogs treated with either RIS or placebo (not
shown).
Insulin sensitivity. Before treatment, dogs exhibited a
wide range of insulin sensitivity, consistent with the wide
range of pretreatment adiposity (38). There were no
differences among groups at basal (P ⬎ 0.8). Whole-body
insulin sensitivity (SIclamp) tended to decline after both
OLZ and RIS (OLZ: ⫺6.2 ⫾ 3.6, RIS: ⫺6.9 ⫾ 5.8 dl 䡠 min⫺1 䡠
kg⫺1/[␮U/ml]; P ⬎ 0.1) but not for the placebo group
(⫹3.3 ⫾ 5.8 dl 䡠 min⫺1 䡠 kg⫺1/[␮U/ml]; pre-drug: 25.6 ⫾ 5.2,
post-drug: 28.9 ⫾ 6.2 dl 䡠 min⫺1 䡠 kg⫺1/[␮U/ml]; P ⫽ 0.6).
Peripheral sensitivity (SIpclamp; Fig. 4) was similar before
treatment (OLZ: 24.3 ⫾ 4.4, RIS: 24.7 ⫾ 6.3, and placebo:
20.1 ⫾ 4.2 dl 䡠 min⫺1 䡠 kg⫺1/[␮U/ml]; P ⬎ 0.84) and not
significantly altered by treatment in any group (OLZ:
23.3 ⫾ 6.4, RIS: 19.9 ⫾ 1.9, and placebo: 25.3 ⫾ 5.7 dl 䡠
min⫺1 䡠 kg⫺1/[␮U/ml]; P ⬎ 0.3 compared with respective
pre-drug value). However, liver sensitivity to insulin was
impaired by OLZ. Before OLZ, HGO was suppressed ⬎90%
during clamps (basal: 2.5 ⫾ 0.2, steady state: 0.2 ⫾ 0.5 mg
䡠 min⫺1 䡠 kg⫺1; P ⬍ 0.0001). Comparable hyperinsulinemia
failed to significantly suppress HGO after OLZ treatment
(basal: 2.3 ⫾ 0.1, steady state: 1.8 ⫾ 0.4 mg 䡠 min⫺1 䡠 kg⫺1;
P ⫽ 0.12). Thus, hepatic insulin sensitivity was markedly
diminished by OLZ, from 6.1 ⫾ 1.0 to 1.5 ⫾ 0.9 dl 䡠 min⫺1
䡠 kg⫺1/[␮U/ml] (P ⫽ 0.009; Fig. 5).
865
METABOLIC EFFECTS OF ATYPICAL ANTIPSYCHOTICS
FIG. 3. Differential effect of drug treatment on
adiposity. A: Abdominal MRI of representative
dogs from each treatment group. Adipose tissue is shown in yellow and is segregated into
visceral (within peritoneum) and subcutaneous (outside peritoneum) depots. B: Quantitative increase in adiposity during treatment.
OLZ resulted in markedly greater accumulation of fat in both visceral and subcutaneous
regions (compared with placebo). See text for
statistics.
Unlike OLZ, hepatic insulin sensitivity was not significantly affected by RIS (pre-drug: 4.3 ⫾ 0.8, post-drug: 3.0 ⫾
0.9 dl 䡠 min⫺1 䡠 kg⫺1/[␮U/ml]; P ⫽ 0.35). Likewise, there
was no significant change in hepatic insulin sensitivity in
placebo-treated dogs (pre-drug: 5.5 ⫾ 1.3, post-drug: 3.3 ⫾
0.4 dl 䡠 min⫺1 䡠 kg⫺1/[␮U/ml]; P ⫽ 0.12; Fig. 5), although a
trend toward liver resistance was observed in the majority
of placebo animals.
Pancreatic ␤-cell function. OLZ had little overall effect
on insulin response to graded hyperglycemia (Fig. 6A),
although post-drug insulin response was higher at first
866
glycemic target (P ⫽ 0.005). RIS treatment resulted in
greater circulating insulin during STEP tests, which was
significantly higher than the pre-drug response at the first
two glucose plateaus (P ⫽ 0.015 and P ⫽ 0.007, respectively). Insulin response was unaffected by placebo.
Changes in insulin sensitivity and adiposity should elicit
a compensatory upregulation of ␤-cell sensitivity to glucose. However, despite SIclamp reduction, treatment with
OLZ had no measurable effect on insulin response to
graded hyperglycemia (pre-drug: 1.24 ⫾ 0.15, post-drug:
1.07 ⫾ 0.25 ␮U 䡠 ml⫺1/[mg/dl]; P ⫽ 0.58; Fig. 6B), with 8 of
DIABETES, VOL. 54, MARCH 2005
M. ADER AND ASSOCIATES
SIclamp after fat feeding (⫺8.9 ⫾ 4.1 dl 䡠 min⫺1 䡠 kg⫺1/[␮U/
ml]) was of similar magnitude to that induced by OLZ (OLZ
vs. FAT: P ⫽ 0.63). Insulin resistance due to fat feeding
was associated with an impressive threefold compensatory increase in ␤-cell sensitivity to glucose (Fig. 7A). This
robust upregulation was observed in all animals, demonstrating an average increase in ␤-cell slope from 0.74 ⫾
0.21 to 2.18 ⫾ 0.57 ␮U 䡠 ml⫺1 䡠 mg⫺1 䡠 dl⫺1 (P ⫽ 0.01). This
contrasts sharply with OLZ-treated dogs, in which no
measurable change in ␤-cell sensitivity to glucose was
observed (Fig. 6B). Remarkably, despite matched changes in
adiposity and insulin sensitivity, the ␤-cell compensation for
resistance seen with fat feeding (14.4 ⫾ 2.4 vs. 32.7 ⫾ 9.2;
P ⫽ 0.053) was not observed during OLZ (35.7 ⫾ 4.2 vs.
24.8 ⫾ 6.6; P ⫽ 0.222; Fig. 7B). This disparate effect of
treatment on DI was significant (P ⫽ 0.02).
DISCUSSION
FIG. 4. Time course of Rd in dogs treated with OLZ (A), RIS (B), or
placebo (C). Predrug: closed symbols; post-drug: open symbols.
10 dogs actually demonstrating a paradoxical decline in
insulin response after OLZ. DI tended to decline with OLZ
(pre-drug: 35.7 ⫾ 4.2 vs. 24.8 ⫾ 6.6; P ⫽ 0.22). Conversely,
RIS-treated animals, faced with similar insulin resistance,
upregulated ␤-cell function by 50% (pre-drug: 0.64 ⫾ 0.11,
post-drug: 0.97 ⫾ 0.10 ␮U 䡠 ml⫺1/[mg/dl]; P ⫽ 0.038; Fig.
6B), and DI remained constant (pre-drug: 19.8 ⫾ 5.0,
post-drug: 21.8 ⫾ 2.7; P ⫽ 0.74). Insulin response to
hyperglycemia was unaffected by placebo, consistent with
no change in SIclamp. Likewise, no appreciable change in
DI was observed with placebo treatment (pre-drug: 33.3 ⫾
7.9, post-drug: 37.9 ⫾ 16.7; P ⫽ 0.80; Fig. 6B).
Diet-induced insulin resistance. We compared changes
in pancreatic function during OLZ with those observed in
a separate group of dogs with increased adiposity and
resistance induced by increased fat in the diet but no
treatment with atypical antipsychotics. Baseline (pre–fat
feeding) body weight (27.5 ⫾ 1.5 kg) and adiposity (total:
21.0 ⫾ 5.2 cm3, visceral: 13.5 ⫾ 3.1 cm3, and subcutaneous:
7.6 ⫾ 2.2 cm3) as well as fasting insulin (14 ⫾ 3 ␮U/ml)
were similar to pretreatment values of all other experimental groups (P ⬎ 0.1 by ANOVA), while fasting glucose
was lower than OLZ and RIS (ANOVA with post hoc
analysis; P ⫽ 0.001 for both comparisons) but not placebo
(P ⫽ 0.4).
Increased dietary fat (⬃8% daily calories from fat [FAT])
induced a marked truncal adiposity pattern very similar to
that observed with OLZ. Fat feeding almost doubled total
adipose tissue volume (21.0 ⫾ 5.2 vs. 35.8 ⫾ 7.3 cm3; P ⫽
0.60 vs. changes after OLZ) and enlarged visceral (OLZ:
⫹8.7 ⫾ 0.9 cm3, FAT: ⫹7.0 ⫾ 3.5 cm3; P ⫽ 0.65 between
groups) and subcutaneous truncal depots (OLZ: ⫹9.8 ⫾
1.5 cm3, FAT: ⫹7.8 ⫾ 3.2 cm3; OLZ vs. FAT: P ⫽ 0.60).
Consistent with matched adiposity, the decrement in
DIABETES, VOL. 54, MARCH 2005
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 ␤-cell defects are considered requisite for
pathogenesis of the disease. However, no prospective
mechanistic studies to examine possible drug effects on
␤-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 ␤-cell function.
Differential changes in body weight observed in this dog
study were consistent with observations in patients (rev.
in 39). OLZ-treated animals exhibited greater (⫹5.9% of
pre-drug weight) and more consistent weight gain than
more modest (⫹3.9%) weight gain observed with RIS.
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. OLZ-induced weight gain may reflect increased
consumption of calories, but such increases mirrored
those observed in control animals (Fig. 2A and C), suggesting no additional effect of drugs beyond that of placebo-treated dogs. In contrast, modest weight gain induced
by RIS over the entire treatment period occurred in the
FIG. 5. Effect of treatment on hepatic insulin sensitivity. Units of
sensitivity are dl 䡠 minⴚ1 䡠 kgⴚ1/[␮U/ml]. **P ⴝ 0.009 vs. pre-drug.
867
METABOLIC EFFECTS OF ATYPICAL ANTIPSYCHOTICS
FIG. 6. Effect of treatment on insulin response during STEP tests. Upper panels: OLZ; middle panels: RIS; lower panels: placebo. A: Insulin time
course. B: ␤-Cell sensitivity to glucose. Predrug: closed symbols and solid lines; post-drug: open symbols and dashed lines.
face of unchanged (or lower) caloric intake (Fig. 2B).
Moreover, the time courses of changes in body weight and
food intake during both OLZ and RIS treatment were
discordant. For both drugs, early weight loss was observed
within 1 week of treatment despite increased (OLZ) or stable (RIS) consumption of calories, an observation not apparent in control animals. These data suggest that weight
gain with antipsychotics reflects treatment effects on both
caloric intake and energy expenditure (20,41). Further
studies are required to determine the specific drug effects
on the components of energy balance.
Measures of body weight alone may not reveal differential effects of agents on adiposity. Despite similar changes
in weight between OLZ versus placebo and similar caloric
intake between groups, MRI analyses revealed that OLZtreated dogs developed substantial adiposity that greatly
exceeded observed changes in control animals, indicating
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.
Although published literature is replete with reports of
weight gain with antipsychotic treatment, few studies have
868
quantified adiposity. Eder et al. (19) report a small (⫹16%)
increase in adiposity, measured by bioelectric impedance,
in schizophrenics on OLZ monotherapy for 8 weeks,
although such methodology yields a questionable measure
of adiposity (43). Moreover, this study used a minimal
(3-day) washout period before OLZ treatment for the large
number of subjects with prior treatment history with other
antipsychotics. 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 study is the first to prospectively examine
the effects of OLZ and RIS on the discrete actions of insulin on Rd and HGO in the absence of prevailing disease.
Insulin stimulation of Rd was unaffected by either drug or
placebo. In sharp contrast, dogs treated with OLZ exhibited severe hepatic insulin resistance (275%). This differs
with the more modest declines with RIS or placebo. While
OLZ-induced hepatic insulin resistance may reflect a primary hepatic defect, other sites of action are also plausible. Given that visceral adipose depot was greatly enlarged
by OLZ, and this depot is insulin resistant (46), it is
possible that portal FFAs draining from visceral stores
DIABETES, VOL. 54, MARCH 2005
M. ADER AND ASSOCIATES
FIG. 7. Pancreatic ␤-cell function during matched adiposity and resistance. A: ␤-Cell sensitivity to glucose in fat fed dogs. B: ␤-Cell upregulation after fat feeding, which is absent after OLZ. Pretreatment:
closed symbols and solid lines; posttreatment: open symbols and
dashed lines. Lines represent hyperbolic fit to mean of pre- or posttreatment data. Inset represents mean treatment effect on DI.
were elevated in OLZ-treated dogs and hepatic insulin
resistance developed.
The present studies revealed a dramatic impairment in
␤-cell compensation during OLZ. OLZ and RIS induced
similar whole-body insulin resistance, yet only RIS responded with compensatory upregulation of ␤-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 ␤-cell compensatory function induced by OLZ
that was apparent only by comparing pancreatic function
under similarly “stressed” conditions of insulin resistance.
It is worth noting that during antipsychotic treatment,
DIABETES, VOL. 54, MARCH 2005
␤-cells did not lose their ability to secrete insulin in
response to hyperglycemia (Fig. 6A). Sowell et al. (25)
examined the effects of OLZ and RIS on insulin secretion
in healthy human subjects. After 2 weeks of drug treatment, subjects exhibited weight gain and fasting hyperinsulinemia. We report similar effects of 4 – 6 weeks of
treatment in healthy dogs. The Sowell studies reported no
change in the insulin response to hyperglycemia with drug
treatment, similar to the findings reported herein. However, those studies did not assess whether the observed
␤-cell response after drugs was appropriate for the prevailing degree of insulin sensitivity or adiposity. Here, we
compared the ␤-cell response to OLZ-induced adiposity
and insulin resistance with that of an independent group of
animals that developed a similar degree of obesity induced
not by OLZ but by consuming a fat-supplemented diet.
These results, illustrated in Figs. 6 and 7, are dramatic.
Although sequential steps of hyperglycemia elicited an
insulin secretory response after OLZ treatment not different from pre-drug response, it is clear by comparison with
fat-fed but unmedicated animals that the insulin response
after OLZ was severely blunted. This functional impairment of pancreatic ␤-cells by OLZ was reflected in the DI
(Fig. 7B). The effect of fat feeding versus OLZ on ␤-cell
compensation (⌬DI) was markedly different (fat feeding:
positive 18.3 ⫾ 7.3, OLZ: negative 10.9 ⫾ 8.3; P ⫽ 0.02).
That secretion remained constant in OLZ-treated animals
in the face of resistance indicates that OLZ completely prevented ␤-cell compensation. Indeed, failure to account for
changes in insulin sensitivity in previous studies (25)
may have masked the underlying ␤-cell compensatory
dysfunction.
The mechanisms underlying impairment in ␤-cell compensation with OLZ are unclear. In vitro data suggest that
OLZ does not directly impair ␤-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 ␤-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 ␤-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 ␤-cell upregulation
suggests such signaling to the ␤-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 ␤-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 contrast to OLZ, RIS treatment did not block ␤-cell
869
METABOLIC EFFECTS OF ATYPICAL ANTIPSYCHOTICS
upregulation for insulin resistance (Fig. 6), as evidenced
by a stable DI during treatment similar to that observed
in placebo-treated dogs. However, while animals receiving placebo developed adiposity of similar magnitude to
those receiving RIS, placebo treatment did not induce
comparable resistance. Additional studies are warranted
to test whether ␤-cell function during RIS is appropriate
for prevailing adiposity and insulin resistance or whether these effects may dependent on dose or duration of
treatment.
The dog model was particularly well suited to investigate the effects of atypical antipsychotics on glucose metabolism. Twenty-five of 26 dogs tolerated the drugs with
no apparent side effects, and sedation, a common problem
in treated rodents, was limited to a single dog. No deterioration of hepatocellular integrity was noted, as evidenced
by stable plasma liver enzymes alanine aminotransferase
and aspartate aminotransferase (data not shown). Feeding
behavior, similar to humans, allowed us to test direct effects of drugs on caloric intake; food intake and activity
were well controlled, and drug administration was uneventful. While the duration of treatment in the present
study is shorter than typically employed in treatment of
psychiatric patients, it is striking that such substantial
alterations in adiposity, hepatic sensitivity, and ␤-cell
function were observed in that brief period.
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 ␤-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 ␤-cell compensation for
insulin resistance. OLZ completely blocked the compensatory response with obesity and resistance seen with fat
feeding, whereas ␤-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 ␤-cell compensation. Failure of ␤-cell compensation to atypical antipsychotics provides a mechanistic basis by which diabetes
may develop in the vulnerable psychiatric population
treated with these therapeutic agents. These results underscore the importance of examining drug effects in the absence of risk factors common among psychiatric patients.
Further studies are needed to determine the mechanisms
underlying differential metabolic sequelae of these agents,
and the processes which may lead to development of diabetes in this population.
ACKNOWLEDGMENTS
These studies were funded by a researcher-initiated grant
supported by Janssen Pharmaceutica as well as the National Institutes of Health (DK29867 and DK27619 to R.N.B.).
S.P.K. and K.J.C. were supported by a National Institutes
of Health predoctoral training grant (T32-AG00093), and
870
K.H. and V.I. were supported by an American Diabetes
Association mentor-based fellowship (awarded to R.N.B.).
The authors offer their sincere gratitude to Ed Zuniga for
his gentle care and treatment of the experimental animals
and to Dr. Erlinda Kirkman for her expert veterinary care
and advice.
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