Schizophrenia Research 70 (2004) 1 – 17

www.elsevier.com/locate/schres

The effects of antipsychotic therapy on serum lipids:

a comprehensive review
Jonathan M. Meyer a,*, Carol E. Koro b,c
a
University of California, San Diego VAMC (MC 116A), 3350 La Jolla Village Drive, San Diego, CA 92161, USA
b
GlaxoSmithKline, Upper Providence, PA, USA
c
University of Maryland, Baltimore, MD, USA
Received 10 October 2003; received in revised form 18 January 2004; accepted 21 January 2004
Available online 11 March 2004

Abstract

Objectives: The purpose of this paper is to review the literature since 1970 documenting the effects of antipsychotic agents on
serum lipids, including a discussion of possible mechanisms for the observed phenomena, the clinical significance and
recommendations for monitoring hyperlipidemia during antipsychotic therapy. Results: High-potency conventional anti-
psychotics (e.g., haloperidol) and the atypical antipsychotics, ziprasidone, risperidone and aripiprazole, appear to be associated
with lower risk of hyperlipidemia. Low-potency conventional antipsychotics (e.g., chlorpormazine, thioridazine) and the atypical
antipsychotics, quetiapine, olanzapine and clozapine, are associated with higher risk of hyperlipidemia. Possible hypotheses for
lipid dysregulation include weight gain, dietary changes and the development of glucose intolerance. Conclusions: Given the
multiple cardiovascular risk factors seen in patients with schizophrenia, great care must be exercised in the choice of antipsychotic
therapy to minimize the medical burden of additional risk imposed by hyperlipidemia. It is recommended that a lipid panel be
obtained at baseline in all patients with schizophrenia, annually thereafter for patients on agents associated with lower risk of
hyperlipidemia and quarterly in patients on agents associated with higher risk for hyperlipidemia. All patients with persistent
dyslipidemia should be referred for lipid-lowering therapy or switched to a less lipid-offending antipsychotic agent.
D 2004 Elsevier B.V. All rights reserved.

Keywords: Hyperlipidemia; Antipsychotics; Conventional; Atypical; Cholesterol; Triglycerides; Lipids; Cardiovascular risk

1. Introduction dietary choices on cardiovascular risk (Expert Panel,

Cardiovascular disease continues to be a significant
source of morbidity and mortality in westernized soci-
eties despite the development of new medications, new
technologies like stents and increased education about
the adverse impact of smoking, inactivity, obesity and
* Corresponding author. Tel.: +1-858-642-3570; fax: +1-858-
642-6442.
E-mail address: jmmeyer@ucsd.edu (J.M. Meyer).
2001). Over 70% of coronary disease mortality can be
accounted for by the traditional risk factors of hyper-
tension, hyperlipidemia, smoking and diabetes melli-
tus, with the latter two highly prevalent in patients with
schizophrenia (Davidson et al., 2001). The net impact
on mortality in the schizophrenia population can be
seen in the results of large epidemiologic studies (Osby
et al., 2000) which have noted a standardized mortality
ratio from cardiovascular disease twofold greater for
schizophrenia patients than the general population.

0920-9964/$ - see front matter D 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.schres.2004.01.014
2 J.M. Meyer, C.E. Koro / Schizophrenia Research 70 (2004) 1–17

Table 1
Summary of studies examining lipid changes during antipsychotic therapy from 1970 to 2003
Reference Study method N Daily dose Results
Atmaca et al., 6 week prospective 14 per drug, 535.7 mg quetiapine, significant increases in fasting TG were seen for
2003b study of schizophrenia 11 controls on 15.7 mg olanzapine, olanzapine (+ 31.23 F 9.87 mg/dl, p < 0.001),
patients on risperidone, no psychotropic 6.7 mg risperidone, clozapine (+ 36.28 F 5.61 mg/dl, p < 0.001) and
olanzapine, quetiapine medication 207.1 mg clozapine quetiapine (+ 11.64 F 4.58 mg/dl, p < 0.05), but
and clozapine not risperidone (+ 3.87 F 1.45 mg/dl, p = 0.76)
monotherapy
Atmaca et al., 6 week prospective 15 per drug NR serum TG increases were much greater for
2003a study of patients on olanzapine compared to quetiapine or haloperidol
haloperidol, olanzapine and for quetiapine compared to haloperidol
and quetiapine
Baymiller prospective 1-year 50 clozapine 200 – 600 mg from baseline, 54.7 F 80.4 mg/dl (41.7%) increase
et al., 2003 open-label study clozapine (mean in serum TG ( p = 0.001) and 14.4 F 24.6 mg/dl
454 F 109 mg) (7.5%) increase in TC ( p < 0.001); no significant
changes in HDL-c, LDL-c; serum TG peaked
between days 41 – 120 and declined, but still
remained elevated; use of propranolol exacerbated
increases in TC and TG
Wirshing et al., retrospective 215 total: NR clozapine associated with greatest increase in TC,
2002 comparison clozapine, 39; while risperidone and fluphenazine were associated
olanzapine, 32; with decreases; clozapine and olanzapine had
risperidone, 49; greatest increase in TG levels
quetiapine, 13;
haloperidol, 41;
fluphenazine, 41
Wetterling, case report 1 on zotepine NR maximum TG of 1247 mg/dl on zotepine which
2002 normalized upon switch to high-potency
conventional agents
Stoner et al., case report 1 on olanzapine 15 mg 42-year-old African-American male with treated
2002 hyperlipidemia had baseline lipids as follows: TC
227 mg/dl, TG 134 mg/dl, HDL-c 38 mg/dl; after
8 weeks of olanzapine serum TG 5093 mg/dl,
TC 375, with evidence of new onset type 2 DM
(fasting glucose 395 mg/dl, HbA1c 11.9%)
Meyer, 2002 retrospective chart 47 risperidone, risperidone 4.5 mg after 52 weeks, TC increased 24 mg/dl for
review 47 olanzapine olanzapine 16.7 mg olanzapine vs. 7 mg/dl for risperidone ( p = 0.029),
and fasting TG by 88 mg/dl for olanzapine vs. 30
mg/dl on risperidone ( p = 0.042); in the nongeriatric
cohort, these increases were greater: TC increased
31 mg/dl for olanzapine vs. 7 mg/dl for risperidone
( p = 0.004), and fasting TG increased 105 mg/dl for
olanzapine vs. 32 mg/dl on risperidone ( p = 0.037)
Martin and retrospective chart 22 child and 2.7 F 2.2 mg after mean exposure of 4.9 F 1.0 months,
L’Ecuyer, review adolescent risperidone no significant changes in serum TG or TC levels
2002 inpatients, were seen in the group as a whole
mean age
12.8 F 2.6 years
Leonard et al., prevalence study 13 males, 485 mg clozapine 11 patients (52%) were deemed to have
2002 8 females hypertriglyceridemia and 3 patients (14%) had
hypercholesterolemia; Mean TC 193 F 46 mg/dl
(range 131 – 309), mean TG 196 F 142 mg/dl
(range 39 – 665); of note, 29% met criteria for
obesity and 12 patients (57%) were classified as
overweight
 J.M. Meyer, C.E. Koro / Schizophrenia Research 70 (2004) 1–17 3

Table 1 (continued )
Reference Study method N Daily dose Results
Koro et al., case-control database 18,309 any conventional olanzapine use was associated with nearly a fivefold
2002 study schizophrenia or atypical increase in the odds of developing hyperlipidemia
patients, 1268 antipsychotic compared with no antipsychotic exposure and more
incident exposure than a threefold increase compared with those
cases of receiving conventional agents
hyperlipidemia
Goodnick and meta-analysis of trial 1919 patients NR meta-analysis of short-term trial data showed that
Jerry, 2002 data treated with increases in TC following aripiprazole
aripiprazole or administration were lower than for haloperidol,
olanzapine or risperidone or placebo; a 26-week trial comparing
risperidone or aripiprazole to olanzapine found significant
haloperidol or differences after 4 weeks; olanzapine increased TC,
placebo whereas aripiprazole decreased TC; data from
1-year study found that aripiprazole produced less
of an increase in TC than haloperidol
Domon and case report 1 on quetiapine 600 mg 17-year-old African-American female on quetiapine
Cargile, 600 mg/day on stable dose of metformin 100 mg
2002 PO bid for type 2 DM; TC 235 mg/dl, TG 456
mg/dl on admission; quetiapine discontinued with
complete resolution of both DM and
hyperlipidemia; after 6 weeks off of quetiapine
(and 4 weeks without metformin), TC 226 mg/dl
and TG 163 mg/dl
Shaw et al., 8-week open trial 15 adolescents quetiapine TC remained unchanged
2001 with a diagnosis 300 – 800 mg/day
of psychotic
disorder
Nguyen and case report 1 on olanzapine 5 mg 10-year-old boy with ADHD on olanzapine 5 mg
Murphy, 2001 hs for 3 months experienced 20 lb weight gain
with resulting TC 193 mg/dl and TG 183 mg/dl;
olanzapine discontinued, and 5 weeks later, TC 151
mg/dl and TG 61 mg/dl, with over 20 lb weight loss
Newcomer cross-sectional study, 63 on NR Controls had low mean serum TG 87.7 F 49.9
et al., 2001 all patients matched antipsychotics, mg/dl, vs. clozapine 177 F 152.6 mg/dl, olanzapine
for age, gender, BMI 20 controls 175.5 F 250.0 mg/dl; olanzapine cohort more likely
to have borderline high serum TG vs. controls
( p = 0.054)
Nasrallah et al., retrospective 103 olanzapine NR mean serum TG for Caucasians before olanzapine
2001 112.6 mg/dl, after olanzapine 203.1 mg/dl with no
statistically significant difference for
African-Americans; both groups experienced
increase in serum TG on olanzapine: 81% for
Caucasians, 65% for African-Americans, with
similar proportions (33% and 35%, respectively)
gaining z 100 mg/dl
Meyer, 2001a case series 12 olanzapine, 5 – 20 mg hypertriglyceridemia up to 7668 mg/dl on
2 quetiapine olanzapine, olanzapine and 1932 mg/dl on quetiapine reported;
200 – 250 mg Time to peak TG ranged from 1 to 23.5 months
quetiapine
Lund et al., retrospective cohort 2461 typicals, NR in patients aged 20 – 34 years, clozapine associated
2001 study 552 clozapine with a significantly increased relative risk of
hyperlipidemia (2.4 [95% confidence interval,
1.1 – 5.2]), but not in older patients
(continued on next page)
4 J.M. Meyer, C.E. Koro / Schizophrenia Research 70 (2004) 1–17

Table 1 (continued )
Reference Study method N Daily dose Results
Kingsbury prospective 6-week 37 ziprasidone; 62.16 F 13.97 mg serum TC decreased significantly ( 17.57 mg/dl
et al., 2001 switch study prior meds: bid ziprasidone p < 0.001) as did serum TG ( 62.38 mg/dl,
olanzapine, p = 0.018); change in serum TC was not correlated
15; risperidone, with weight change, but change in TG was,
12; typical, 10 although the effect was small: r = 0.409, p = 0.018;
r2 = 0.167)
Kinon et al., retrospective cohort 573 olanzapine, 5 – 20 mg olanzapine, median nonfasting serum TC at endpoint was
2001 103 haloperidol 5 – 20 mg haloperidol significantly higher for olanzapine-treated patients
than for haloperidol-treated patients (205.7 mg/dl
vs. 189.9 mg/dl, respectively, p = 0.002)
Domon and case report 1 on olanzapine 20 mg 15-year-old African-American male started on
Webber, olanzapine 20 mg hs; after 3 months weight, 91 kg,
2001 fasting glucose 90 mg/dl, fasting TG 155 mg/dl,
fasting TC 131 mg/dl; 5 months later (8 months
total); weight peaked at 108 kg, but subsequently
declined with development of type II DM (fasting
glucose 368 mg/dl); maximum TG was 298 mg/dl
on olanzapine; both DM and hyperlipidemia
resolved over 8 weeks after stopping olanzapine:
fasting glucose 98 mg/dl, TG 86 mg/dl,
TC 132 mg/dl
Bouchard et al., retrospective study 22 olanzapine, 12.84.4 mg/day after mean exposure of 17.9 F 8.1 months
2001 22 risperidone olanzapine (olanzapine) and 17.4 F 8.8 months (risperidone)
12.8 F 4.4 mg olanzapine-treated patients had significantly higher
risperidone plasma TG levels (185 F 115 mg/dl for olanzapine
2.8 F 1.8 mg vs. 115 F 62 mg/dl for risperidone; p < 0.01),
significantly higher very low-density lipoprotein
cholesterol levels (0.9 F 0.6 for olanzapine vs.
0.5 F 0.4 mol/l for risperidone; p < 0.03), a trend for
a higher cholesterol/HDL ratio (5.3 F 1.7 for
olanzapine vs. 4.3 F 1.4 for risperidone; p = 0.06),
as well as a trend for a lower HDL-c concentration
( p = 0.08); no significant differences in TC, fasting
glucose or insulin
Baptista et al., cross-sectional 26 women on received typical the antipsychotic-treated subjects displayed a trend
2001 cohort typical antipsychotics for for lower levels of HDL-c than controls as well as
antipsychotics, more than 6 increased insulin resistance
26 control consecutive months
women matched
for age, BMI and
day of menses
Wu et al., 2000 case report 1 variable dosages 25-year-old Chinese male demonstrated
of clozapine dose-dependent increases in fasting serum TG
and glucose
Melkersson prospective cohort 14 olanzapine 62% had hypertriglyceridemia (mean TG 273.45
et al., 2000 study monotherapy, median mg/dl) and 85% had hypercholesterolemia (mean
dose 12.5 mg TC 257.14 mg/dl) after a median duration of
5 months (range 2.4 – 16.8 months)
Henderson 5-year naturalistic 82 clozapine NR Significant changes in serum TG in patients treated
et al., 2000 study with clozapine over 60 months ( p = 0.04), (linear
coefficient = 2.75 mg/dl per month SE = 1.28)
 J.M. Meyer, C.E. Koro / Schizophrenia Research 70 (2004) 1–17 5

Table 1 (continued )
Reference Study method N Daily dose Results
Spivak et al., retrospective chart 70 clozapine, clozapine = 332.9 F mean TG level increased in the clozapine-treated
1999 review 30 typicals 168.1 mg; group and decreased in the conventional
typicals: 347.3 F antipsychotic group after 6 months of treatment
247.3 mg ( p < 0.005)
(CPZ equivalent)
Sheitman et al., prospective study 9 olanzapine After 16 months, mean increase in serum TG from
1999 19 mg 170 mg/dl (range 25 – 200 mg/dl) to 240 mg/dl
(range 135 – 369); no significant changes in TC,
HDL or LDL; five had >50% increase in TG
Osser et al., prospective cohort 25 olanzapine 13.8 F 37% increase in fasting TG (from 162 F 121 to
1999 study 4.4 mg 222 F 135 mg/dl) ( p < 0.05); fasting TC did not
increase
Gaulin et al., retrospective chart 222 clozapine NR 45% increase in serum TG in clozapine-treated
1999 review patients ( p < 0.01) and insignificant decrease in
serum TG in haloperidol-treated patients after a
mean treatment period of 590 days for clozapine
and 455 for haloperidol
Dursun et al., prospective 12 week 8 clozapine 352 F 73 small increase in TG levels (11%) but no significant
1999 study mg changes in other lipid levels after 12 weeks
Spivak et al., cross-sectional 30 clozapine, clozapine: 2950.0 F serum TG were significantly higher in clozapine
1998 study 30 typicals 165 mg; group after 1 year of treatment ( p < 0.01): clozapine
typicals: 348.9 F 202.9 F 131.1 mg/dl vs. typicals 134.4 F 51.9
298.8 mg mg/dl ( p < 0.01); no significant difference in
(CPZ equivalent) serum TC
Ghaeli and chart review 67 clozapine: serum TG were significantly higher in clozapine
Dufresne, 1109 F 397 mg; group ( p < 0.001): clozapine 264.6 F 160.5 mg/dl
1996 typicals (21 high- vs. typicals 149.8 F 78.3 mg/dl; difference was not
potency; 2 middle- explained by concomitant illness or medication,
potency; 5 low- patient age or sex; no significant difference in
potency): 626 F 817 serum TC
mg (CPZ equivalent)
Ghaeli and case series 4 clozapine increased serum TG levels in patients on clozapine;
Dufresne, 600 – 900 mg decreased upon switching to risperidone and
1995 increased upon rechallenge
Vampini et al., case report 1 on clozapine 400 mg increased TG levels after 15 months
1994
Martinez et al., survey conducted 311 schizophrenic 225 used neuroleptics neuroleptic administration was associated with
1994 in a 750-bed subjects (mainly haloperidol, changes in HDL-c and TG in males but not in
mental hospital thioridazine or females
fluphenazine) during
the 2 prior years and
86 no psychotropic
medications
Shafique et al., cross-sectional 87 male chlorpromazine TC, VLDL-c and LDL-c levels were significantly
1988 observational study schizophrenic (300 – 500 mg), elevated in patients on phenothiazines and LDL-c in
patients (35 haloperidol patients on butyrophenone; VLDL-c and LDL-c
treated with (10 – 30 mg) for levels were significantly higher and HDL-c levels
phenothiazine, 6 – 12 months lower in patients on combined therapy
30 with
butyrophenone,
22 with both
drugs) for
6 – 12 months
(continued on next page)
6 J.M. Meyer, C.E. Koro / Schizophrenia Research 70 (2004) 1–17

Table 1 (continued )
Reference Study method N Daily dose Results
Fleischhacker double-blind 6 haloperidol, means not reported; no significant differences in mean HDL-c or TC
et al., 1986 prospective 6 fluperlapine flexible titration between groups by day 28, and mean values were
6-week study within normal limits; one fluperlapine subject
developed serum TG level of 900 mg/dl on day
7 which required treatment on day 28; Plasma TG
levels of all other patients remained in the
normal range
Sasaki et al., cross-sectional study, 17 phenothiazine trifluoperazine after mean 8 years of antipsychotic exposure, no
1985 all males, excluded (trifluoperazine 5 – 30 mg, effect of butyrophenones on serum lipids, but
patients with diabetes or perphenazine), perphenazine significant elevations in fasting TG levels for the
mellitus or taking 14 haloperidol, 6 – 24 mg, phenothiazine group (163 F 65 mg/dl) compared to
lipid-lowering 14 healthy controls haloperidol 3 – 6 mg the butyrophenone group (104 F 52 mg/dl) and
medication controls (127 F 71 mg/dl); no significant
differences in TC, LDL or HDL values between the
three groups
Sasaki et al., cross-sectional chronic use of patients chronically treated with phenothiazines
1984 analysis, with phenothiazines (chlorpromazine, levomepromazine, perphenazine)
additional 10-week (8 years); new for long periods (average = 8 years), had HDL-c
prospective data to phenothiazines: levels significantly lower ( p < 0.001) than normal
on 8 new patients 8 patients controls serum TG level was significantly higher
( p < 0.05) in patients treated with phenothiazines
than in controls; serum HDL decreased 24% within
1 week following new administration of
phenothiazines in small prospective cohort (n = 8);
no significant differences were found in TC and TG
levels for 10 weeks after initiation of phenothiazine
administration
Muller- multicenter trial 43 schizophrenic fluperlapine 16 out of 28 patients TG in serum increased
Oerlinghausen, and depressed significantly during the treatment period as well as
1984 patients evaluated some impressive increases in serum TC
for lipid levels
Bell and in vitro study in in rats fed CPZ or lidocaine for 14 days, there was
Hubert, 1981 plasma from man no statistically significant change in total plasma
and experimental TC levels or the size of the plasma-free TC pool;
animals CPZ may inhibit lecithin/cholesterol acyltransferase
(LCAT) in vitro
Vaisanen et al., randomized 30 restless haloperidol (60 mg) serum cholesterol was significantly higher at the
1979 crossover trial mentally vs. thioridazine (600 end of the thioridazine than of haloperidol
subnormal mg) for 2 weeks administration ( p < 0.05)
patients
Orlandi et al., cross-sectional 43 percutaneous short-term treatment in the 3 chlorpromazine-treated patients, the rate of
1975 study liver biopsies with diazepam hepatic synthesis of cholesterol was in the normal
performed in (10 – 40 mg), range; significant increase in smooth endoplasmic
39 patients phenobarbital (360 reticulum in hepatocytes of diazepam-treated
mg), chlorpromazine patients and a positive correlation between the
(100 – 150 mg), or increased cholesterol synthesis and the formation of
diphenylhydantoin areas of nonvesicular, type 2, smooth endoplasmic
(50 – 150 mg) reticulum
Serafetinides double-blind 57 chronic haloperidol (12.3 low serum cholesterol concentrations seemed to
et al., 1972 placebo-controlled schizophrenic mg), chlorpenthixol occur more often with haloperidol, whereas
clinical trial patients (205 mg), elevated TG seemed more often to be associated
chlorpromazine with chlorpenthixol
(830 mg)
 J.M. Meyer, C.E. Koro / Schizophrenia Research 70 (2004) 1–17
Table 1 (continued )
Reference Study method N Daily dose
Clark et al., double-blind 55 chronic
1972 placebo-controlled schizophrenic
trial inpatients
Serafetinides placebo-controlled 18 male
et al., 1971 study schizophrenia
patients
Clark et al., controlled clinical 233 patients
1970 trials (156 on CPZ
and 77 on
placebo)
Most importantly, cardiovascular disease is commonly
the single largest cause of death among males and
females and, in one study, was also the main cause of
excess deaths in females (Osby et al., 2000).
While the development of the newer generation,
novel or atypical antipsychotics including clozapine,
risperidone, olanzapine, quetiapine, ziprasidone, ari-
piprazole and zotepine has reduced concern surround-
ing the short- and long-term neurological side effects
of antipsychotic therapy, a significant body of data has
accrued in the past decade about the adverse meta-
bolic consequences of atypical antipsychotic agents,
particularly the dibenzodiazepine-derived compounds
clozapine, olanzapine and quetiapine (Meyer, 2001a).
A triad of side effects has been documented in-
cluding significant weight gain, glucose intolerance or
frank type 2 diabetes mellitus (at times with metabolic
acidosis) (Lean and Pajonk, 2003; McIntyre et al.,
2001) and hyperlipidemia, primarily related to the use
of dibenzodiazepine-derived atypicals, although the
published literature on ziprasidone and aripiprazole is
relatively sparse due to the limited time these com-
pounds have been on the market (Cohen et al., 2003;
Goodnick and Jerry, 2002; Kingsbury et al., 2001;
Taylor, 2003).
While much of the literature and industry activity
has focused on weight gain and glucose intolerance,
the importance of recognizing and treating hyperlip-
idemia in schizophrenia patients cannot be overesti-
mated, given the long-term impact of untreated
7
Results
100 mg loxapine, significant increase in serum cholesterol
1000 mg concentration in the chlorpromazine and loxapine
chlorpromazine or treatment groups compared to placebo; TG also
placebo increased significantly in the CPZ group compared
to placebo; however, significant mean increases in
body weight and serum cholesterol associated with
loxapine were less than those associated with CPZ
15 mg trifluperidol the concentration of serum cholesterol was
significantly reduced in subjects receiving
trifluperidol compared to those on placebo
150 – 600 mg chlorpromazine exhibited hypercholesterolemic
chlorpromazine activity; the mean difference in serum cholesterol
concentrations between the placebo and CPZ
groups ranged from 14 to 28 mg/100 ml; this
activity was dose related in that it occurred with a
fixed daily dose of 600 mg administered for
24 weeks
hyperlipidemia on cardiovascular mortality, particu-
larly in patients with multiple CV risk factors such as
smoking (Expert Panel, 2001). For the schizophrenia
population, the likelihood that lipid abnormalities will
go undetected is much greater than in the general
population given the limited access to general medical
services and routine preventive care seen in chroni-
cally mentally ill patients (Meyer, 2003). The net
effect is an increased risk for CV disease in a
population with a known propensity for death from
cardiovascular complications.
With the accumulating literature on metabolic com-
plications of atypical antipsychotic therapy, combined
with the widespread use of atypical antipsychotics for
many disorders beyond schizophrenia and schizoaf-
fective disorder, there is thus a need for a comprehen-
sive review of the lipid abnormalities related to
antipsychotic therapy to guide the clinician in choice
of medications and appropriate monitoring strategies.
The purpose of this paper is to review the literature
since 1970, documenting the effects of antipsychotic
compounds on serum lipids, including a discussion of
possible mechanisms for the observed phenomena, the
clinical significance and recommendations for moni-
toring hyperlipidemia during antipsychotic therapy.
Although the focus of this review will be large case
series and studies, individual case reports are included
in the summary table (Table 1) and at times in the
discussion for their heuristic value. The relative pau-
city of available data on this issue compared to that
8 J.M. Meyer, C.E. Koro / Schizophrenia Research 70 (2004) 1–17
generated regarding other metabolic adverse events
makes such anecdotal cases somewhat more valuable.
2. Hyperlipidemia and conventional antipsychotics
The data generated from studies of schizophrenia
patients exposed to conventional antipsychotics illus-
trate that agents with similar modes of therapeutic
action, namely, dopamine D2 antagonism, may have
significantly different metabolic profiles. Within a
decade after the widespread use of chlorpromazine
and other phenothiazines, several studies emerged
examining the metabolic profiles of this class of
antipsychotics (Clark and Johnson, 1960; Clark et
al., 1967; Mefferd et al., 1958). In general, these
compounds were found to elevate serum triglycerides
(TG) and total cholesterol (TC), but with greater
effects on TG concentrations. Subsequent studies of
the phenothiazine chlorpromazine and related com-
pounds in 1970 and 1972 by Clark et al. (1970, 1972)
confirmed these findings that high serum TG seemed
to be the primary significant dyslipidemia, but elevat-
ed TC could also be found. What also emerged from
this early literature was the fact that not all potent D2
antagonists shared these effects on serum lipids with
phenothiazines.
Butyrophenone derivates such as haloperidol are the
most potent D2 antagonists used in clinical practice, yet
did not share the dyslipidemic effects seen with low-
potency phenothiazines. The relative neutrality of bu-
tyrophenone derivatives was first described in 1966
when Simpson and Cooper documented modest reduc-
tions in serum TC during schizophrenia trials, a finding
generally seen in most but not all studies of that era,
which were typically uncontrolled clinical data (Braun
and Paulonis, 1967; Clark et al., 1968; Simpson and
Cooper, 1966; Simpson et al., 1967). The first placebo-
controlled study published by Serafetinides et al.
(1971) found that trifluperidol significantly lowered
TC compared to the placebo-treated group. Subsequent
comparative studies between phenothiazines (chlor-
promazine and thioridazine) and butyrophenones (hal-
operidol) emerged shortly thereafter and corroborated
prior clinical reports that butyrophenones therapy was
associated with no effect on serum TG and either no
effect or lowering of TC, while the phenothiazines
tended to cause hyperlipidemia, with the primary effect
seen as hypertriglyceridemia (Serafetinides et al., 1972;
Vaisanen et al., 1979).
There was scant clinical data on the issue of lipids
and conventional antipsychotics until the publication
of Sasaki’s papers in the mid-1980s examining serum
lipids in Japanese schizophrenics (Sasaki et al., 1985,
1984). One study comparing serum TC and TG levels
among chronically hospitalized male schizophrenics
receiving phenothiazines or butyrophenones, vs. age-
and sex-matched controls, revealed negligible effects
of butyrophenones on serum lipids, but demonstrated
significant elevations in serum TG levels for the
phenothiazine group (163F65 mg/dl) compared to
the butyrophenone group (104F52 mg/dl) and con-
trols (127F71 mg/dl). There were no significant differ-
ences in TC values between the three groups, but the
phenothiazine-treated patients had significant eleva-
tions in low-density lipoproteins (LDL-c), and de-
creased high-density lipoprotein (HDL-c)
concentrations. The next published study reporting
data on lipids and conventional antipsychotic therapy
was the 1988 paper by Shafique et al. from Pakistan,
who performed a cross-sectional study of laboratory
findings in 87 male schizophrenia patients treated for
6 –12 months with antipsychotics, with 35 on haloper-
idol, 30 receiving a butyrophenones and 22 on com-
bination therapy (Shafique et al., 1988).
Hyperlipidemia in the form of elevated TC, elevated
LDL-c and elevated very low-density lipoprotein cho-
lesterol (VLDL-c) was noted in the phenothiazine
group, but increased LDL-c was also found in the
butyrophenone cohort. Martinez et al. performed com-
prehensive nutritional status assessments in 311
patients residing in a 750-bed Spanish mental hospital
and noted that neuroleptic-treated male patients
(n = 97) had significantly lower HDL-c and higher
TG than male control patients not receiving neuro-
leptics (n = 61), while no differences between treated
female patients and controls were noted. Specific
analysis on the basis of type of neuroleptic prescribed
was not performed.
3. Hyperlipidemia and atypical antipsychotics
The first reports of hyperlipidemia with the new
generation of atypical antipsychotics occurred in the
mid-1980s during the early trials of fluperlapine, a
 J.M. Meyer, C.E. Koro / Schizophrenia Research 70 (2004) 1–17
dibenzodiazepine-derived compound structurally re-
lated to clozapine, that was not released commercially.
In one open trial, 16 of 28 patients developed hyper-
triglyceridemia, while in a subsequent study, one
patient on fluperlapine developed a serum TG level
greater than 900 mg/dl by day 7, with a subsequent
decline over the next 3 weeks (Fleischhacker et al.,
1986; Muller-Oerlinghausen, 1984). Although cloza-
pine was available in Europe from the 1970s onward,
nearly a decade elapsed before the publication of
hyperlipidemia cases with clozapine, and later, the
other currently available atypical antipsychotics. In
1994, Vampini (Vampini et al., 1994) presented as an
abstract an isolated case report of hypertriglyceride-
mia associated with clozapine therapy, and then
Ghaeli and Dufresne (1995) described four cloza-
pine-treated patients with hypertriglyceridemia whose
TG normalized upon switching to risperidone. These
same authors later published a chart review comparing
serum lipids in patients receiving clozapine or con-
ventional antipsychotics (primarily butyrophenones)
for at least 1 year who had no prior history of
hyperlipidemia or use of lipid-lowering agents (Ghaeli
and Dufresne, 1996). This retrospective study found
serum TG significantly elevated ( p < 0.001) in the
clozapine group (264.0 F 160.5 mg/dl) compared to
the conventional group (149.8 F 78.3 mg/dl), but not
so for TC (clozapine 217.0 F 52.9 mg/dl vs. conven-
tional 215.0 F 43.2 mg/dl). Three cases of severe
hypertriglyceridemia (>500 mg/dl) occurred among
clozapine-treated patients. A 1998 study comparing
Israeli patients on clozapine (n = 30) or conventional
antipsychotics (n = 30) for at least 1 year confirmed
those findings of significant hypertriglyceridemia in
the clozapine group (202.9 F 131.1 mg/dl) but not the
conventional group (134.4 F 51.9 mg/dl), without
significant differences in TC (clozapine 197.1 F 46.4
mg/dl vs. conventional 194.9 F 51.5 mg/dl) (Spivak
et al., 1998). Dursun’s 12-week prospective study of
six men and two women receiving clozapine at a
mean dose of 352 mg/day also found significant
increases in serum TG only, but not TC (Dursun et
al., 1999). Two subsequent chart reviews of long-term
clozapine-treated patients, one by Spivak et al. (1999)
comparing 70 clozapine- and 30 conventional anti-
psychotic-treated patients (treated for 6 months or
more), and Gaulin’s chart review of 222 records of
long-term clozapine patients (mean 590 days of ther-
9
apy) (Gaulin et al., 1999) demonstrated mean increase
in serum TG of 41% and 45%, respectively, related to
clozapine therapy. More recent cross-sectional and
short- and long-term prospective studies have noted
the same pattern of marked elevations of serum TG
with modest increases in TC (Henderson et al., 2000;
Leonard et al., 2002; Atmaca et al., 2003a; Baymiller
et al., 2003; Wirshing et al., 2002), with significant
differences compared to baseline, and also those
receiving conventional antipsychotics (Lund et al.,
2001). It is worth noting that the 1-year prospective
study of 50 clozapine-treated patients (Baymiller et
al., 2003) found mean increases of 41.7% in serum
TG, but only 7.5% for TC, without significant
changes in HDL-c and LDL-c. Moreover, Baymiller
also commented on the phenomenology of TG
increases by pointing out that serum TG peaked
between days 41 and 120 and then declined, but still
remained elevated at the 1-year interval. As part of a
5-year naturalistic study of 82 clozapine-treated
patients with schizophrenia, Henderson et al. (2000)
found ongoing increases in serum TG ( p = 0.04, linear
coefficient 2.75 mg/dl per month), although one must
bear in mind that 7% of this cohort developed type 2
diabetes mellitus in each year of follow-up (36%
cumulative 5-year incidence), so lipid changes after
the 1-year interval may be reflective primarily of those
inherent to glucose intolerance.
The first published cases of olanzapine-associated
hypertriglyceridemia were Sheitman’s group of nine
patients followed for an average of 16 months on
olanzapine (mean age, 41 years, mean olanzapine
dose, 19 mg/day). This group experienced an increase
in serum TG from a baseline mean of 170 mg/dl
(range 25 –200 mg/dl) to a mean of 240 mg/dl (range
135– 369 mg/dl), with five sustaining >50% increase
in serum TG. There were no significant changes in TC
levels, and mean weight gain was 22 lb (Sheitman et
al., 1999). Osser et al. subsequently reported on 25
inpatients (21 males and 4 females) commencing
olanzapine therapy tracked prospectively as part of a
drug evaluation for 12 weeks. For this sample, mean
dose was 13.8 F 4.4 mg/day, and mean weight gain 12
lb. Fasting TG increased from 162 F 121 to 222 F 135
mg/dl. Both weight and TG increases were significant
( p < 0.05), and there was a significant association
between weight gain and TG change ( p < 0.02);
however, after controlling for weight, analysis of
10 J.M. Meyer, C.E. Koro / Schizophrenia Research 70 (2004) 1–17
covariance showed no independent increase in TG
(Osser et al., 1999).
Recent work involving olanzapine illustrates not
only the much greater effect on serum TG than TC, but
also the risk of severe hypertriglyceridemia. Melkers-
son followed a group of 14 schizophrenia patients on
olanzapine monotherapy for an average of 5 months
and noted that 62% had elevated fasting TG (mean
273.45 mg/dl) and 85% hypercholesterolemia (mean
257.14 mg/dl). Bouchard’s prospective comparative
study of 22 risperidone- and 22 olanzapine-treated
patients also noted significantly higher TG levels in
the olanzapine group, although the mean was still in
the high normal range (185 mg/dl). Bouchard also
found higher LDL-c and trends for higher TC/HDL-c
ratio and low absolute HDL-c levels in the olanzapine
cohort (Bouchard et al., 2001). Concern over severe
elevations in serum TG was raised by Meyer’s case
series (Meyer, 2001b) of 12 olanzapine and 2 quetia-
pine patients with fasting TG levels exceeding 500 mg/
dl, including one patient on olanzapine whose fasting
serum TG was measured at 7688 mg/dl. A similar case
of severe hypertriglyceridemia (TG 5093 mg/dl) was
subsequently reported by Stoner et al. (2002) in a
patient who also developed new onset type 2 diabetes
mellitus. Other studies have also confirmed the effect
on serum TG (Atmaca et al., 2003a,b; Wirshing et al.,
2002), with one abstract noting that approximately
one-third of patients on olanzapine will have an
increase in serum TG of at least 100 mg/dl (Nasrallah
et al., 2001). In some instances, only serum TC was
measured, but the effect was still evident, especially
when compared to metabolically neutral agents such as
haloperidol (Kinon et al., 2001).
Quetiapine and zotepine are structurally related to
clozapine and olanzapine as noted above, but there is
sparse published information on their metabolic
effects. Unlike clozapine and olanzapine, quetiapine
generally has a much lower propensity towards weight
gain (Wetterling, 2001). Nonetheless, the available
data suggest that quetiapine shares the propensity with
other benzodiazepine-derived atypical antipsychotics
to primarily elevate serum TG levels as illustrated by
case reports from Meyer and others, along with two 6-
week prospective comparative studies by Atmaca et al.
and an 8-week study by Shaw (Atmaca et al., 2003a,b;
Domon and Cargile, 2002; Meyer, 2001b; Shaw et al.,
2001). As with other dibenzodiazepine-derived atyp-
icals, there were lesser effects on TC (Shaw et al.,
2001). Zotepine is associated with weight gain similar
to that experienced with olanzapine and clozapine
(Wetterling, 2001), but the sum total of the published
literature on lipid changes during zotepine therapy is
one case report in which serum TG peaked at 1247 mg/
dl and normalized upon switch to a high-potency
conventional agent (Wetterling, 2002).
The more neutral effects of ziprasidone, aripipra-
zole and risperidone can be seen from the literature
involving these agents. While Ghaeli’s case series of
clozapine patients noted significant improvement in
serum TG when switched to risperidone (Ghaeli and
Dufresne, 1995), the effect of initial risperidone ther-
apy on serum lipids was not quantifiable until the data
generated by Bouchard and Meyer. Bouchard’s pro-
spective comparative study found markedly lower
serum TG and LDL-c in the risperidone cohort com-
pared to the olanzapine cohort, without significant
changes from baseline in the lipid parameters mea-
sured for the risperidone group. Meyer’s retrospective
review of state hospital patients treated for an average
of 1 year found the following lipid changes in patients
under 60 years of age treated with risperidone (n = 39)
or olanzapine (n = 37): TG + 104.8 mg/dl (olanzapine)
vs. + 31.7 mg/dl (risperidone) ( p = 0.037); TC + 30.7
mg/dl (olanzapine) vs. + 7.2 mg/dl (risperidone)
( p = 0.004). Another chart review by Martin and
L’Ecuyer (2002) noted that risperidone caused no
significant changes in TC or TG after 4.9 months
average exposure in 22 adolescent inpatients (mean
age 12.8 years).
Other comparative studies have tended to find the
relatively neutral effect of risperidone on serum lipids,
especially when compared to olanzapine (Atmaca et
al., 2003a p. 727; Atmaca et al., 2003b; Wirshing et al.,
2002), including Koro’s case-control database study of
1268 incident cases of hyperlipidemia among 18,309
schizophrenia patients in the United Kingdom. Koro et
al. (2002) found that olanzapine use was associated
with nearly a fivefold increase in the odds of develop-
ing hyperlipidemia compared to no antipsychotic ex-
posure (OR, 4.65; p < 0.001) and a threefold increase
compared with those on conventionals (OR, 3.36;
p < 0.001), while risperidone therapy was not associat-
ed with increased odds of hyperlipidemia compared to
no antipsychotic exposure (OR, 1.12; p = 0.72) or
conventionals (OR, 0.81; p = 0.52). Ziprasidone is the
 J.M. Meyer, C.E. Koro / Schizophrenia Research 70 (2004) 1–17
most weight neutral of the atypical agents and appears
to have even less effects on serum lipids than risper-
idone as evidenced by the statistically significant
improvement in serum TG and TC over 6 weeks when
patients were switched to ziprasidone from risperidone
(Kingsbury et al., 2001; Weiden et al., 2003). The
limited available data on aripiprazole suggest that it
also has nominal effects on serum lipids (Goodnick and
Jerry, 2002).
4. Possible mechanisms for antipsychotic-related
hyperlipidemia
The development of hyperlipidemia related to var-
ious types of drug therapy is widely reported in the
general medical literature and occurs with pharmaco-
logical agents that possess differing mechanisms of
therapeutic action (Echevarria et al., 1999). In their
comprehensive review of the subject, Mantel-Teeu-
wisse et al. (2001) note that certain diuretics, proges-
tins, beta-adrenergic antagonists, immunosuppressive
agents, protease inhibitors and even some anticonvul-
sants increase TC, LDL-c and/or TG and decrease
HDL-c. While global changes in serum lipids are
described with some medications, certain agents appear
to have specific effects on particular lipid fractions.
Isotretinoin, acitretin, certain protease inhibitors, low-
potency phenothiazines and dibenzodiazepine-derived
antipsychotics primarily elevate serum TG levels, but
these effects may vary dramatically within a class of
medications, as illustrated by the literature on protease
inhibitors (Manfredi and Chiodo, 2001).
There are several possible means by which any
agent may induce hyperlipidemia. For most agents
associated with lipid dysregulation, these mechanisms
are not clearly elucidated, and that remains the case
for antipsychotic-induced hyperlipidemia. Nonethe-
less, several biologically plausible hypotheses have
been advanced focusing on weight gain, dietary
changes and the development of glucose intolerance
to explain the high incidence of hyperlipidemia with
certain antipsychotic medications (Meyer, 2001b).
Weight gain and obesity are known to increase the
risk of hyperlipidemia, and the use of antipsychotic
medications is frequently associated with a consider-
able increase in body weight, with low-potency con-
ventional agents (e.g., chlorpromazine) and some
11
atypical antipsychotic medications associated with
greater weight gain than high-potency conventionals
or more weight-neutral atypicals (Allison et al., 1999).
This variability in the propensity to induce weight
gain is quite marked among the atypical agents
(Allison et al., 1999; Goodnick and Jerry, 2002), with
clozapine and olanzapine and possibly zotepine asso-
ciated with the greatest gains in weight, even more
than seen with low-potency conventional antipsy-
chotics (Wetterling, 2001). Several early studies
reported substantial weight gain with clozapine
(Cohen et al., 1990; Lamberti et al., 1992; Umbricht
et al., 1994; Hummer et al., 1995; Bustillo et al.,
1996), with mean body weight gains of more than
10% overall, but more than 20% seen in one-fifth of
the patients over 12 months and in up to half of
patients with longer term use (Meyer, 2001a). Inter-
estingly, weight gain was significantly correlated with
clinical response to clozapine in two studies (Lamberti
et al., 1992; Leadbetter et al., 1992). Available data on
olanzapine suggests that its effect on body weight is
similar to that of clozapine (Beasley et al., 1997), with
mean weight gain at 1 year as high as 11.8 kg seen in
clinical trials (Beasley et al., 1997). Among the new-
generation antipsychotic agents, clozapine and olan-
zapine thus appear to have the greatest potential to
induce weight gain, while risperidone, aripiprazole
and ziprasidone have the least, with 1-year studies
showing gains typically of 2.3 kg or less, with
ziprasidone being essentially weight neutral (Kings-
bury et al., 2001; Csernansky et al., 2002; Goodnick
and Jerry, 2002; Potkin et al., 2003).
Several mechanisms have been proposed for
weight gain due to the use of antipsychotics, although
their relevance to the induction of hyperlipidemia is
unclear. Histamine H1 antagonism is well known to
cause weight gain presumably through increased ap-
petite, and the association between high H1 affinity
and weight gain is found among various classes of
psychotropic agents. The affinity for this receptor also
correlates extremely well with the propensity to in-
duce weight gain among the atypical antipsychotics
(Wirshing et al., 1998; Kroeze et al., 2003). Serotonin
5-HT2c antagonism may play an additive role with the
weight gain liability of the new compounds, but the
correlation is very poor since the atypical antipsychot-
ic with the greatest affinity, ziprasidone, appears to be
the most weight neutral. One proposed mechanism for
12 J.M. Meyer, C.E. Koro / Schizophrenia Research 70 (2004) 1–17
weight gain is increased leptin secretion followed by
an increase in adiposity, although it is unclear whether
higher leptin levels measured in some patients on
clozapine and olanzapine is a consequence of the
medication, or simply the result of increased adipose
mass (Kraus et al., 1999; Hagg et al., 2001; Melkers-
son and Hulting, 2001; Atmaca et al., 2003a,b).
Obesity by itself and weight gain have a demonstra-
ble negative impact on serum lipid profiles (Itoh et al.,
1996; Colombel and Charbonnel, 1997; Pi-Sunyer,
2002), so it is not surprising that those atypical anti-
psychotics most likely to cause significant weight gain
are also correlated with the greatest impact on serum
lipids. While Eder et al. (2001) found that weight gain
during olanzapine treatment is due to increased adipose
mass, it is worth noting that multiple studies of atypical
antipsychotics have not found a strong association
between the increases in serum TG and weight gain
(Meyer, 2001a). This is particularly true for some
patients with extreme elevations in serum TG for whom
weight gain is modest (Meyer, 2001b), although it is
worth commenting that baseline weight may itself be a
risk factor (Baptista et al., 2001).
One mechanism which is operative in some patients
is the development of glucose intolerance (Meyer,
2001a), with a direct correlation found in a number of
case reports between the development of new onset
type 2 diabetes mellitus and elevated serum TG levels,
often with reversal of these problems upon discontin-
uation of the offending agent (Domon and Cargile,
2002; Domon and Webber, 2001; Ghaeli and Dufresne,
1995; Nguyen and Murphy, 2001; Wetterling, 2002).
There is, however, ample evidence that the mechanism
underlying hypertriglyceridemia related to atypical
antipsychotic therapy is generally not dependent on
glucose intolerance in light of the finding that increased
serum TG or hypertriglyceridemia is prevalent in
studies involving dibenzodiazepine-derived atypicals,
but relatively few cases of new onset diabetes mellitus
are described in these studies. This issue was also
indirectly addressed by one study examining the
changes in serum TG levels in African-Americans
and Caucasians treated with olanzapine. Although
African-Americans are at increased risk for developing
type 2 diabetes mellitus compared to non-Hispanic
white populations and appear to be overrepresented
among the more severe cases of type 2 diabetes mellitus
and metabolic acidosis related to atypical antipsychotic
treatment (Jin et al., 2002), there were no differences on
the basis of ethnicity in the prevalence or severity of
hypertriglyceridemia related to olanzapine therapy
(Nasrallah et al., 2001). It should be noted that it
usually takes years until glucose intolerance, which is
strongly linked to hypertriglyceridemia, leads to man-
ifest diabetes, so it is not surprising that few cases of
new onset diabetes are described in studies that report
hypertriglyceridemia.
Schizophrenia is also associated with poor diet and
inadequate exercise as documented by multiple stud-
ies (Le Fevre, 2001; Mortensen and Juel, 1993)
including detailed published data from a semistruc-
tured interview of 102 community dwelling middle-
aged subjects with schizophrenia who noted that their
diet was higher in fat and lower in fiber compared to
the general population (Brown et al., 1999). Dietary
changes may have an impact on serum lipids as shown
in studies comparing diet modification with lovastatin
(Jenkins et al., 2003), or in those examining the role of
diet in human immunodeficiency virus-related lip-
odystrophy (Hadigan, 2003), the marked increases in
serum TG in patients within controlled settings,
whose diet varies little on a daily basis, would argue
against this as the primary mechanism for atypical-
induced hyperlipidemia.
The structure – activity hypothesis, by an unidenti-
fied mechanism, is also attractive given the fact that
dibenzodiazepines as a class and low-potency pheno-
thiazines share the property of marked increases in
serum TG with modest effects on TC in a manner not
seen with compounds that have similar pharmacolog-
ical profiles.
5. Impact of hyperlipidemia on cardiovascular risk
Lipid elevations among mentally ill patients war-
rant the same clinical considerations as those seen for
general patient populations, consistent with good
clinical practice, but this is particularly true since
schizophrenia patients also tend to exhibit other major
risk factors for cardiovascular events, such as smoking
(Brown et al., 1999), sedentary lifestyle (Davidson et
al., 2001), diabetes mellitus (Dixon et al., 2000) and
obesity (Zimmermann et al., 2003).
The clinical relevance of elevations in TC and TG
levels has been repeatedly demonstrated for general
 J.M. Meyer, C.E. Koro / Schizophrenia Research 70 (2004) 1–17
populations and are strongly associated with an
increased risk for cardiovascular events such as
myocardial infarction and stroke (Expert Panel,
2001; Ford et al., 2002). Current therapies focus
on aggressive interventions to modify lipid levels
in general populations, and the Adult Treatment
Panel III (ATPIII) guidelines have quantified the risk
for cardiovascular events associated with increased
TC and recommend both lifestyle and pharmacolog-
ical therapies to reduce the risk (Expert Panel, 2001;
Ford et al., 2002). Epidemiologic studies provide the
largest body of evidence for the relationship between
serum TC levels and coronary heart disease (CHD)
risk. For example, in the Multiple Risk Factor
Intervention Trial, CHD rates declined progressively
with lower TC levels down to a level of 150 mg/dl
(Stamler et al., 1986). In fact, CHD events are rare in
nonsmoking populations with TC levels < 150 mg/dl
(Villablanca et al., 2000).
The extent to which elevated TG levels increase the
risk of cardiovascular disease has been debated for
many years. Observational studies using case-control
methods and most prospective cohort studies have
consistently shown a strong association of increased
TG levels with CHD (Austin, 1999; Jeppesen et al.,
1998; Rubins, 2000). When these cohort studies are
subjected to multivariate analysis, controlling for other
risk factors, such as blood pressure, HDL-c, LDL-c,
TC, physical activity and obesity, the effect of TG is
diminished, but as Jeppesen demonstrated, the effect is
still present (Jeppesen et al., 1998). For example, in the
Stockholm Ischemic Heart Disease Secondary Preven-
tion Study, there was a clear relationship between TG
levels in the treated group and beneficial change in
coronary heart disease event rates (Rubins, 2000).
The spectrum of risk factors defined as the meta-
bolic syndrome (also known as the dysmetabolic
syndrome, or syndrome X) has also received consid-
erable attention among practitioners in recent years
and is discussed at length in the ATPIII recommen-
dations because of the high risk for cardiovascular
disease seen in this population (Expert Panel, 2001;
Grundy, 1999). The main risk factors defining the
metabolic syndrome are abdominal obesity (waist
circumference >40 in. in men, >35 in. in women)
dyslipidemia (serum TG z 150 mg/dl, or low HDL
< 40 mg/dl in men, < 50 mg/dl in women), nondiabetic
levels of hyperglycemia (fasting glucose z 110 mg/
13
dl) and hypertension (blood pressure z 130/85 mm
Hg). A patient meets the diagnostic criteria for the
metabolic syndrome if they possess at least three of
the above risk factors. The metabolic effects of the
dibenzodiazepine-derived compounds unfortunately
appear to generate a group of adverse effects which
satisfies these criteria (weight gain, hypertriglyceride-
mia, impaired glucose tolerance), implying that
screening for all three conditions may be necessary
in patients receiving ongoing therapy with that class
of atypical agents (Meyer, 2002; Consensus Develop-
ment Conference, 2004).
6. Monitoring recommendations for
hyperlipidemia during antipsychotic therapy
Given the multiple cardiovascular risk factors seen
in patients with schizophrenia, great care must be
exercised in the choice of antipsychotic therapy to
minimize the medical burden of additional risk im-
posed by hyperlipidemia. Unlike diabetes mellitus or
obesity which eventually come to clinical attention,
hyperlipidemia is typically silent unless hypertrigly-
ceridemia is so severe that pancreatitis develops, but
presents the patient with enormous long-term cardio-
vascular risk. Depending on the person’s age, a
normotensive smoker exposed to a dibenzodiaze-
pine-derived atypical antipsychotic might have the
10-year risk for a major cardiovascular event (e.g.,
sudden death, acute myocardial infarction) increased
two to four times from baseline (Meyer, 2003). While
hyperlipidemia is associated with long-term cardio-
vascular consequences, various authors also com-
ment that monitoring for hyperlipidemia is not solely
a long-term issue, as severe hypertriglyceridemia
(>500 mg/dl) represents a risk for acute pancreatitis
(Meyer, 2001b).
The following guidelines are based upon prior
published recommendations (Marder et al., 2002;
Meyer, 2002; Consensus Development Conference,
2004) and the clinical experience of the authors. Some
of the considerations inherent in these recommenda-
tions include the fact that schizophrenia patients have
multiple risk factors for cardiovascular disease, that
certain antipsychotics are associated with greater
adverse effects on serum lipids, that many health care
providers outside of the psychiatric arena are as yet
14 J.M. Meyer, C.E. Koro / Schizophrenia Research 70 (2004) 1–17
unaware of the potential metabolic complications of
atypical antipsychotic therapy and that schizophrenia
patients often receive limited or no medical care
outside of that provided by the mental health practi-
tioner, so the burden of medical monitoring necessar-
ily falls upon those who prescribe antipsychotic
medications (Meyer, 2003). While the following rec-
ommendations are specific to monitoring of serum
lipids, these are understood to be part of the routine
monitoring of serum glucose and weight recommen-
ded elsewhere as part of routine medical care for those
receiving atypical antipsychotics (Marder et al., 2002;
Meyer, 2002).
7. Baseline
1. In all patients with schizophrenia, record smoking
status, patient and first-degree family history of
cardiovascular disease, hyperlipidemia and glucose
intolerance in the medical record.
2. Obtain weight, waist circumference, blood pressure
and (ideally) fasting lipid panel. Total cholesterol
and HDL-c are valid on nonfasting specimens, but
TG and LDL-c are not. This is recommended for
all patients with schizophrenia, regardless of
medication regimen, given the limited health care
access for these patients.
8. Follow-up
1. For patients on agents associated with lower risk
for hyperlipidemia (high-potency conventionals,
ziprasidone, risperidone, aripiprazole), an annual
fasting lipid panel is sufficient unless dyslipidemia
is suspected on the basis of baseline evaluation.
2. For patients on agents associated with higher risk for
hyperlipidemia (low-potency conventionals, quetia-
pine, olanzapine, clozapine), a quarterly fasting lipid
panel is necessary for the first year to pick up cases
of severe hypertriglyceridemia. This may be
decreased to semiannually if fasting TC and TG
remain normal, but should continue on a quarterly
basis in those identified with abnormal values.
3. All patients with persistent dyslipidemia should be
referred for lipid-lowering therapy, or considered
for switch to a less offending agent if possible.
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