Research

Original Investigation

Antipsychotics and the Risk of Type 2 Diabetes Mellitus

in Children and Youth
William V. Bobo, MD, MPH; William O. Cooper, MD, MPH; C. Michael Stein, MB, ChB; Mark Olfson, MD, MPH;
David Graham, MD, MPH; James Daugherty, MS; D. Catherine Fuchs, MD; Wayne A. Ray, PhD

Supplemental content at
IMPORTANCE The increased prescribing of antipsychotics for children and youth has jamapsychiatry.com
heightened concerns that this practice increases the risk of type 2 diabetes mellitus.

OBJECTIVE To compare the risk of type 2 diabetes in children and youth 6 to 24 years of age
for recent initiators of antipsychotic drugs vs propensity score–matched controls who had
recently initiated another psychotropic medication.

DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study of the Tennessee Medicaid
program with 28 858 recent initiators of antipsychotic drugs and 14 429 matched controls.
The cohort excluded patients who previously received a diagnosis of diabetes, schizophrenia,
or some other condition for which antipsychotics are the only generally recognized therapy.
Author Affiliations: Department of
Psychiatry, Vanderbilt University
MAIN OUTCOMES AND MEASURES Newly diagnosed diabetes during follow-up, as identified School of Medicine, Nashville,
from diagnoses and diabetes medication prescriptions. Tennessee (Bobo, Fuchs);
Department of Pediatrics, Vanderbilt
University School of Medicine,
RESULTS Users of antipsychotics had a 3-fold increased risk for type 2 diabetes (HR = 3.03 Nashville, Tennessee (Cooper);
[95% CI = 1.73-5.32]), which was apparent within the first year of follow-up (HR = 2.49 [95% Division of Clinical Pharmacology,
CI = 1.27-4.88]). The risk increased with cumulative dose during follow-up, with HRs of 2.13 Department of Internal Medicine,
Vanderbilt University School of
(95% CI = 1.06-4.27), 3.42 (95% CI = 1.88-6.24), and 5.43 (95% CI = 2.34-12.61) for
Medicine, Nashville, Tennessee
respective cumulative doses (gram equivalents of chlorpromazine) of more than 5 g, 5 to 99 (Stein); Department of Psychiatry,
g, and 100 g or more (P < .04). The risk remained elevated for up to 1 year following Columbia University College of
discontinuation of antipsychotic use (HR = 2.57 [95% CI = 1.34-4.91]). When the cohort was Physicians and Surgeons, New York,
New York (Olfson); US Food and Drug
restricted to children 6 to 17 years of age, antipsychotic users had more than a 3-fold Administration, Silver Spring,
increased risk of type 2 diabetes (HR = 3.14 [95% CI = 1.50-6.56]), and the risk increased Maryland (Graham); Division of
significantly with increasing cumulative dose (P < .03). The risk was increased for use Pharmacoepidemiology, Department
restricted to atypical antipsychotics (HR = 2.89 [95% CI = 1.64-5.10]) or to risperidone of Preventive Medicine, Vanderbilt
University School of Medicine,
(HR = 2.20 [95% CI = 1.14-4.26]). Nashville, Tennessee (Daugherty,
Ray).
CONCLUSIONS AND RELEVANCE Children and youth prescribed antipsychotics had an Corresponding Author: Wayne A.
increased risk of type 2 diabetes that increased with cumulative dose. Ray, PhD, Division of
Pharmacoepidemiology, Department
of Preventive Medicine, Vanderbilt
JAMA Psychiatry. doi:10.1001/jamapsychiatry.2013.2053 University School of Medicine, 1500
Published online August 21, 2013. 21st Ave S, Ste 2600, Nashville, TN
37212 (wayne.ray@vanderbilt.edu).

I
ncreasing antipsychotic use among children and youth1-4
raises the concern that this practice increases the risk of type
2 diabetes mellitus in this vulnerable population.5-7 For
adults, there is considerable evidence linking antipsychotic use
to increased risk of type 2 diabetes. Several antipsychotics have
metabolic effects, such as weight gain, increased glucose level,
and insulin resistance, that are thought to be precursors to
diabetes. 8 Epidemiologic studies have confirmed an in-
creased risk for type 2 diabetes for individuals using some types
of antipsychotics, particularly the atypical antipsychotic
drugs.9-11 However, the evidence for children and youth is less
extensive. Although metabolic studies of children suggest that
antipsychotic use might increase the risk of type 2 diabetes,12,13
epidemiologic data are more limited.5-7 Obstacles to studies of
this population include the lower incidence of type 2 diabe-
tes, the need to distinguish between type 1 and type 2 diabe-
tes, and the identification of appropriate comparison groups.
Prior to the introduction of the atypical antipsychotic
drugs, the primary indications for antipsychotics in pediatric
or adolescent populations were schizophrenia and other psy-
chotic disorders. Subsequently, use expanded to include bi-
polar disorders, affective disorders, and symptoms related to
behavior and conduct, which now account for the majority of
prescriptions.2-4,14 There are other well-recognized alterna-

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 Research Original Investigation
tive medications for each of these conditions; indeed, anti-
psychotics are often a secondary or off-label therapeutic
choice.14-17 Thus, an increased risk of diabetes conferred by an-
tipsychotic medications would be an important component of
risk-benefit evaluation.
To better define the relationship between antipsychotic use
and newly diagnosed type 2 diabetes among children and
youth, we conducted a retrospective cohort study of the Ten-
nessee Medicaid program. The cohort included recent initia-
tors of antipsychotics who had received no diagnosis for which
antipsychotics were generally the only recognized pharmaco-
therapy and a propensity score–matched control group of re-
cent initiators of other psychotropic medications.
Methods
Sources of Data
Study data were obtained from the computerized files of the
Tennessee Medicaid program, augmented with linkage to a
statewide hospital discharge database and computerized birth
certificates.18,19 Study files (enrollment, pharmacy, hospital,
outpatient, nursing home, and linked death certificates) al-
lowed for the identification of the study cohort, the classifi-
cation of baseline comorbidity, the tracking of medication use,
and the ascertainment of diabetes.
Antipsychotics and other study medications were identi-
fied from Medicaid pharmacy files. These included the date
that the prescription was dispensed, drug name, quantity, dose,
and days of supply. Computerized pharmacy records are an ex-
cellent source of medication data because they are not sub-
ject to information bias19 and have a high level of concor-
dance with patient self-reports of medication use.20-22 Residual
misclassification should be limited and, if nondifferential,
should bias toward the null.18
Antipsychotic Users
The study population included children and youth 6 to 24 years
of age enrolled in Medicaid for at least 1 year between Janu-
ary 1, 1996, and December 31, 2007. The lower age limit is the
youngest age for which there are material numbers of case re-
ports of type 2 diabetes; the upper age limit corresponds to the
World Health Organization's definition of youth.23 Cohort eli-
gibility (eAppendix and eTables 1 and 2 in Supplement) re-
quired that, during the past year, there was adequate enroll-
ment and health care utilization to ensure availability of data
for study variables, no evidence of life-threatening illness or
institutional residence, no evidence of diabetes, and no evi-
dence of pregnancy (gestational diabetes might be misdiag-
nosed) or polycystic ovarian syndrome (treated with oral hy-
poglycemics). Cohort members could not have been in the
hospital in the past month because changes in the medica-
tion regimen cannot be identified until up to 30 days follow-
ing hospital discharge.
Cohort antipsychotic users had recently initiated antipsy-
chotic therapy by filling an antipsychotic prescription on a day
of cohort eligibility. The first such prescription during the study
period was the qualifying prescription. They could have non-
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Antipsychotics and the Risk of Type 2 Diabetes
qualifying use of antipsychotics in the 90 days preceding the
qualifying prescription (allowed inclusion of patients start-
ing an antipsychotic shortly before meeting cohort eligibility
criteria) but had to have a prior period of 365 days free of an-
tipsychotic use. The cohort was restricted to recent users to
include cases of diabetes that occurred early in therapy and
to ensure that baseline covariates were unaffected by chronic
antipsychotic effects.19
We excluded patients with diagnosed conditions for which
antipsychotics generally are the only recommended treat-
ment. These included schizophrenia or related psychoses, or-
ganic psychoses, autism, mental retardation, Tourette syn-
drome, or other tic disorders. We also excluded patients
prescribed clozapine or long-acting injectable preparations—
usually indicators of schizophrenia or related psychoses—as
well as those with parenterally administered drugs, typically
given for transient agitation.
Controls
Potential controls were recent initiators of other psychotro-
pic drugs, defined as for antipsychotics, with no antipsy-
chotic use in the 365 days preceding the qualifying prescrip-
tion. Control drugs included mood stabilizers (lithium or
anticonvulsant mood stabilizers [absent evidence of a neuro-
logic indication]), antidepressants with a psychiatric diagno-
sis, psychostimulants, α-agonists with diagnosed attention-
deficit/hyperactivity disorder (ADHD) or other problems of
behavior/conduct, and benzodiazepines with a psychiatric di-
agnosis (eAppendix and eTable 3 in Supplement).
From the pool of potential controls, we calculated the pro-
pensity scores,24 the conditional probability of being an anti-
psychotic user, given the study covariates. These were fac-
tors that might be directly or indirectly related to both
antipsychotic use and the development of type 2 diabetes (eAp-
pendix and eTable 4 in Supplement). The 115 covariates in-
cluded demographic characteristics, psychiatric diagnoses and
medications, metabolic disorders and related conditions (eg,
diagnosed obesity), obstetric-gynecologic conditions (eg, ab-
sent/irregular menstruation), cardiovascular disease (eg, hy-
pertension), respiratory disorders (eg, sleep apnea), muscu-
loskeletal symptoms (eg, joint pain), other somatic conditions,
and intensity of health care utilization (medical surveillance)
for both psychiatric and somatic comorbidity. The estimation
of the propensity scores was stratified according to the pres-
ence of a bipolar disorder (diagnosis or mood stabilizer pre-
scription) because the propensity score coefficients differed
for patients with this disorder.
The final control group included 1 control for every 2 an-
tipsychotic users, frequency-matched25 with the antipsy-
chotic users according to propensity score to ensure baseline
comparability with regard to study covariates. Because we
sought a control group highly comparable to the antipsy-
chotic users, we required that the controls be matched within
centiles (1%) of the antipsychotic propensity score distribu-
tion. The 1:2 matching ratio was established by a preliminary
analysis of the potential control pool, indicating that there were
too few controls to permit such close 1 to 1 matching (eAppen-
dix and eTable 5 in Supplement).
jamapsychiatry.com
 Antipsychotics and the Risk of Type 2 Diabetes
Follow-up
Follow-up began on t0, the day following the filling of the quali-
fying prescription for the antipsychotic or control drug, which
permitted exclusion of participants based on medical care on
the prescription fill date (eg, schizophrenia diagnosis). Fol-
low-up ceased (eAppendix and eTable 6 in Supplement) with
the end of the study, owing to a failure of the participant to
meet study inclusion/exclusion criteria, a diagnosis of diabe-
tes, or the death of the participant or 365 days following the
last day of antipsychotic/control drug use. Follow-up for con-
trols also ended with an antipsychotic prescription. Antipsy-
chotic users or controls who left the cohort could reenter if they
subsequently met the study eligibility criteria, unless fol-
low-up terminated because of diabetes.
Antipsychotic Exposure Variables
The primary exposure variable was antipsychotic use status
(user or control) on t0, the first day of follow-up. Because base-
line exposure status did not change during follow-up, the analy-
sis provided a conservative assessment of antipsychotic ef-
fects. At baseline, antipsychotic users were also classified
according to daily dose on t0, expressed as chlorpromazine
equivalents (eAppendix and eTable 7 in Supplement).
We defined time-dependent antipsychotic exposure vari-
ables in order to study antipsychotic cumulative dose and ces-
sation of use. Cumulative dose on a given follow-up day was
the sum of all previously dispensed antipsychotic doses (chlor-
promazine equivalents). A follow-up day was considered “re-
cent use” if the prescription days of supply indicated use on
that day or within the preceding 90 days. The “former use” of
antipsychotics was defined as more than 90 days without use
of an antipsychotic.
Diabetes
Newly diagnosed cases of diabetes during study follow-up were
identified from medical care encounters using an algorithm that
was validated in a sample of the study cohort.26 A primary dis-
charge diagnosis of diabetes met the case definition. Other-
wise, we required both a diagnosis of diabetes and a prescrip-
tion for an antidiabetic medication within a 120-day period.
We required confirmation because single outpatient diabetes-
related medical care encounters often were false positives. Out-
patient diagnoses of diabetes in the absence of an anti-
diabetic medication prescription frequently indicated
subthreshold hyperglycemia, whereas prescriptions for oral hy-
poglycemics in the absence of a diagnosis of diabetes were of-
ten considered the treatment of choice for polycystic ovarian
syndrome. The presumed date of the diagnosis was that of the
earliest diabetes-related medical encounter. Type 1 diabetes
was indicated by exclusive treatment with insulin; other cases
were considered type 2 diabetes.
In the validation study,26 84% of cases identified by our
computer algorithm as having type 2 diabetes were con-
firmed as being true cases, 10% had subthreshold hypergly-
cemia, 3% had type 1 diabetes, and 3% had polycystic ovarian
syndrome.26 The positive predictive value for type 2 diabetes
did not differ materially between antipsychotic users (82%) and
controls (85%).
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Original Investigation Research
Analysis
The statistical analysis compared the adjusted incidences of
diabetes according to antipsychotic exposure status. Relative
risk was estimated with the hazard ratio (HR), calculated from
Cox regression models with a robust sandwich estimation of
variance to account for persons reentering the cohort.27 There
was no evidence of interaction between time and antipsy-
chotic use status (HR for interaction, 1.00; P < .30), indicating
that the proportional hazards assumption was satisfied. Re-
gression models included the baseline propensity score
(deciles), to adjust for residual confounding,24 as well as age
and calendar year during follow-up. Other time-dependent co-
variates were not included in the primary analysis because
these might be on the causal pathway for development of dia-
betes (eg, new diagnosis of obesity).
For the analyses of antipsychotic dose, the propensity score
may not control for confounding,28 given that the distribu-
tion of study covariates could vary according to dose. Thus,
models for these analyses included a disease risk score (the
probability of type 2 diabetes, conditional on no antipsy-
chotic use), expressed as deciles. 29 Tests for the dose-
response relationship used a single degree of freedom orthogo-
nal polynomial contrast for linear trend.
An a priori subgroup analysis was performed for children
6 to 17 years of age, with follow-up ending on the day before
their 18th birthdays. Subgroup analyses also were performed
according to sex, the presence of a bipolar disorder (the most
common labeled indication for antipsychotics in the cohort),
use of psychostimulants (which can possibly limit weight gain),
and a diagnosis of ADHD or conduct disorder.
Given that since 2004 guidelines have recommended rou-
tine glucose monitoring for antipsychotic users,30 we per-
formed several analyses to assess the potential effect of dif-
ferential screening during follow-up. Thus, follow-up time was
classified according to the presence of a metabolic panel with
glucose or other screening test in the past year. The screening
variable was lagged 90 days to exclude the tests associated with
the diagnosis of diabetes in the cases. We also performed an
analysis that excluded person-time subsequent to 2004, which
should be little affected by screening recommendations.
Additional analyses modeled possible clustering effects in-
troduced by the frequency matching, restricted the cohort to
new users of antipsychotics and control medications, did not
allow antipsychotic users to reenter the cohort, and utilized
an alternative definition of type 2 diabetes. All analyses were
performed with SAS version 9.2 (SAS Institute Inc). All P val-
ues are 2-sided. The institutional review board at Vanderbilt
University and the Tennessee Bureau of TennCare and the De-
partment of Health approved our study, which was funded by
grants from federal agencies with no role in study conduct or
reporting.
Results
Cohort Characteristics at Baseline
The cohort included 28 858 children and youth who had re-
cently initiated antipsychotic therapy (eAppendix and eTable
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 Research Original Investigation Antipsychotics and the Risk of Type 2 Diabetes

Table 1. Characteristics of Cohort on the First Day of Follow-upa Table 2. Demographic Characteristics of Cases of Diabetes Mellitus
Indentified During Follow-up
Antipsy-
chotic Cases of Diabetes, %
Characteristic Controls Usersb
Type 1 Type 2
Total No. 14 429 28 858 Characteristic (n = 21) (n = 106)
Mean calendar year t0 2002.8 2002.8 Age at t0,a mean, y 13.0 16.7
Duration of prior qualifying drug use, mean, d 5.6 5.5 White race, % 47.6 73.6
Age at t0, mean, y 14.5 14.5 Male sex, % 61.9 36.8
White race, % 73.5 72.8 Standard metropolitan 61.9 74.5
statistical area, %
Male sex, % 55.9 56.0
Medicaid enrollment 28.6 34.0
Standard metropolitan statistical area, % 66.7 67.1 disabled, %
Medicaid enrollment disabled, % 26.1 26.6 a
First day of follow-up.
Psychiatric diagnoses in past year, %
Bipolar disorder 18.4 18.3
trols had initiated use of the study psychotropic drug within
Depression 19.5 19.3
a mean of fewer than 6 days prior to cohort entry.
Other mood disorder 32.5 33.3
Cohort members had a mean age of 14.5 years, and 56%
Attention-deficit/hyperactivity disorder 38.3 38.9
were male participants (Table 1). The most frequently re-
Conduct disorder 24.9 25.3
corded psychiatric diagnoses were mood disorders (includ-
Anxiety 19.9 20.6
ing bipolar disorder), ADHD, and conduct disorder. Metabolic
Alcohol abuse 3.3 3.1 disorders and other factors potentially associated with diabe-
Other substance abuse 9.3 8.9 tes were relatively infrequent, although 23% of cohort mem-
Psychiatric inpatient stay 13.8 14.5 bers had had a diagnostic test that included glucose measure-
Psychiatric medications in past year, % ment administered in the year preceding t0.
Lithium 4.1 4.2 The median starting dose for cohort antipsychotic users
Valproate 9.3 9.5 was 67 mg (interquartile range, 33-100 mg) of chlorproma-
Lamotrigine, carbamazepine, oxcarbazepine 9.0 8.8 zine equivalents. Of antipsychotic users, 87% were pre-
Other mood stabilizer 1.8 1.8 scribed an atypical agent (eAppendix and eTable 8 in Supple-
Selective serotonin reuptake inhibitor 46.6 47.0 ment); use of typical antipsychotics was largely restricted to
Heterocyclic antidepressant 14.3 14.9 the earlier study years. The most frequently prescribed indi-
Psychostimulant 33.7 34.1 vidual antipsychotic was risperidone (n = 10 718; 37% of an-
α-Agonist 14.2 14.6 tipsychotic users), followed by quetiapine fumarate (n = 5807;
Benzodiazepine 12.6 12.4 20% of antipsychotic users) and olanzapine (n = 5671; 20% of
Conditions associated with metabolic disorders antipsychotic users). Risperidone users were younger, more
in past year, % likely to be male, had greater prevalence of diagnosed ADHD,
Menstruation absent or infrequent 3.7 3.8 and were started at lower doses than were users of other atypi-
Menstruation disorder, other 5.0 4.9 cal antipsychotics.
Diagnosed obesity 3.9 3.8
Metabolic disorderc 2.1 2.1 Antipsychotics and the Risk of Diabetes
Blood chemistry panel with glucose 22.5 22.9 The cohort had 55 984 person-years of follow-up, during which
Diabetes-screening procedures 5.9 5.5 there were 21 cases of type 1 diabetes (3.8 cases per 10 000 per-
Hyperlipidemia-screening procedures 8.4 8.5 son-years). These cases consisted of persons who had a mean
Cardiovascular conditions in past year, % age of 13 years, 62% were male, and 29% had Medicaid enroll-
Hypertension 2.5 2.6 ment related to disability (Table 2). Antipsychotic users had no
Other diagnosed cardiovascular disease 4.2 4.5 significantly increased risk for type 1 diabetes (HR = 1.13 [95%
a CI = 0.43-3.00]).
Unless otherwise noted, all demographic characteristics are as of the first day
of follow-up (t0), and other factors for the year preceding t0. There were 106 incident cases of type 2 diabetes (18.9 cases
b
None of the differences are statistically significant except for “Psychiatric per 10 000 person-years) during cohort follow-up. The mean
inpatient stay” (P = .03). age of the persons was 16.7 years, 37% were male, and 34% had
c
Hyperglycemia, insulin resistance, acanthosis nigricans, and hyperlipidemia. Medicaid enrollment related to disability (Table 2).
Antipsychotic users had a 3-fold increased risk for type 2
diabetes (Figure 1 and Table 3; HR = 3.03 [95% CI = 1.73-
1 in Supplement). There were 14 429 propensity score– 5.32]). The increased risk was apparent within the first year of
matched controls who had recently initiated a control psycho- follow-up (HR = 2.49 [95% CI = 1.27-4.88]). Risk did not vary
tropic drug and who were selected from 122 738 potential con- significantly according to baseline dose but did increase with
trols. By virtue of the matching, the baseline characteristics cumulative dose during follow-up (Table 2). The HR for co-
of the controls were entirely comparable to those of the anti- hort members with a cumulative dose of 100 g or greater of
psychotic users (Table 1). Both antipsychotic users and con- chlorpromazine equivalents was 5.43 [95% CI = 2.34-12.61],

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 Antipsychotics and the Risk of Type 2 Diabetes Original Investigation Research

Figure 1. Cumulative Incidence of Type 2 Diabetes Mellitus, According to Baseline Antipsychotic Use and Using
the Kaplan-Meier Method
.014
Control medication HR =3.03 (95% CI=1.73-5.32)
.012 Antipsychotic drug

Probability of Type 2 Diabetes

.010

.008

.006

.004

.002

0
0 1 2 3 4
Years of Follow-Up
No. of Children and Youth at Risk
Control medication 14 417 7799 2504 1074 485
Antipsychotic drug 28 825 17 803 5066 2188 972
HR, hazard ratio (adjusted).

Table 3. Risk of Type 2 Diabetes Mellitus by Antipsychotic Exposure Status

Person- Rate per 104
Status Years Cases Person-Years HR (95% CI)
No antipsychotic use in nonuser control group 17 963 14 7.8 1 [Reference]a
Antipsychotic use at baseline for all 24.2
38 022 92 3.03 (1.73-5.32)
antipsychotic users
Antipsychotic users, according to baseline daily
dose of antipsychotic
<50 mg 12 777 22 17.2 2.65 (1.69-5.77)
50-99 mg 11 991 30 25.0 3.07 (1.63-5.78)
≥100 mg 13 254 40 30.2 3.13 (1.33-5.30)
Antipsychotic users, according to cumulative
dose of antipsychotic during follow-upb Abbreviations: HR, hazard ratio
<5 g 13 634 27 19.8 2.13 (1.06-4.27) (adjusted).
a
5-99 g 21 734 56 25.8 3.42 (1.88-6.24) Reference for all comparisons is the
33.9 nonuser control group.
≥100 g 2654 9 5.43 (2.34-12.61)
b
Antipsychotic users, according to continuity P < .04 (test for dose-response
of use during follow-upc relationship).
c
Former (use ceased for >90 d) 11 388 26 22.8 2.57 (1.34-4.91) Follow-up persisted for 365 days
following last dispensed day of
Recent (use within past 90 d) 26 634 66 24.8 3.19 (1.77-5.74)
antipsychotic medication.

whereas the HR for those with a cumulative dose of less than
5 g of chlorpromazine equivalents was 2.13 [95% CI = 1.06-
4.27] (P = .04). The risk remained elevated for up to 1 year fol-
lowing the discontinuation of antipsychotic use (HR = 2.57 [95%
CI = 1.34-4.91]). Although this was less than that for cohort
members who continued to use antipsychotics (HR = 3.19 [95%
CI = 1.77-5.74]), the difference was not statistically signifi-
cant.
When the cohort was restricted to children 6 to 17 years
of age, antipsychotic users had more than a 3-fold increased
risk of type 2 diabetes (Figure 2; HR = 3.14 [95% CI = 1.50-
6.56]). For these children, the incidence increased with in-
creasing cumulative dose (Figure 2), from an HR of 2.00 (95%
CI = 0.76-5.30) for cumulative doses of less than 5 g to an HR
of 7.05 (95% CI = 2.63-18.89) for cumulative doses of 100 g or
more (P = .03).
We examined the risk for atypical antipsychotics, which
were used by 87% of cohort users, and for individual atypical
drugs. The risk for type 2 diabetes increased with the cumu-
lative dose of all atypical antipsychotics, including risperi-
done, which drug was used by approximately 40% of the co-
hort antipsychotic users (eAppendix and eTable 9 in
Supplement). Significantly increased HRs were present for
other atypical antipsychotics; the difference between HRs for
risperidone and HRs for aripiprazole was statistically signifi-
cant (P < .001).
We examined several subgroups defined by baseline co-
hort characteristics (Figure 3), including age, sex, presence of
a bipolar disorder, psychostimulant use, and a diagnosis of
either ADHD or conduct disorder. For each of these sub-
groups, the risk of type 2 diabetes was significantly increased
for antipsychotic users, and the estimates for the subgroups
defined by the individual factors did not differ statistically.
We also assessed the risk of type 2 diabetes according to
screening for elevated glucose levels in either the year pre-
ceding t0 or during follow-up (Figure 3). For the controls, 28%
of the follow-up person-time had such screening, as did 33%
of the person-time for the antipsychotic users. Both expo-

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 Research Original Investigation Antipsychotics and the Risk of Type 2 Diabetes

Figure 2. Adjusted Annual Incidence of Type 2 Diabetes Mellitus Among Children and Youth 6 to 17 Years
of Age, According to Cumulative Antipsychotic Dose

P < .03
60

Type 2 Diabetes per 10 000 Person-Years

40

20

0 The vertical bars represent 95% CIs.

Control <5 g 5-99 g ≥100 g
The P value is for the test for the
Cumulative Antipsychotic Dose, Chlorpromazine Equivalents
dose-response relationship. Adjusted
incidence was calculated by
Diabetes cases: 8 15 33 8 multiplying the incidence in the
Person-years: 13 536 10 154 16 786 2076 control group by the hazard ratio,
with an analogous calculation for the
95% CIs.

Figure 3. Risk of Type 2 Diabetes Mellitus for Antipsychotic Users Within Subgroups Defined by Baseline Cohort Characteristics
Controls Antipsychotic Users

P-y No. P-y No. Hazard ratio

(95% CI)
13 536 8 29 015 56 3.14 (1.50-6.56) Age, y <18
4427 6 9006 36 2.95 (1.23-7.02) ≥18

11 071 4 23 793 35 3.86 (1.39-10.74) Sex Male

6892 10 14 229 57 2.67 (1.36-5.23) Female

4538 2 11 265 32 6.66 (1.58-28.14) Bipolar disorder Yes

13 425 12 26 756 60 2.41 (1.29-4.50) diagnosis No

7420 2 15 540 25 5.71 (1.35-24.07) Stimulant use Yes

10 543 12 22 482 67 2.65 (1.43-4.91) No

10 817 6 23 236 48 3.57 (1.52-8.36) ADHD/conduct Yes

7146 8 14 786 44 2.62 (1.23-5.62) disorder No
diagnosis

4985 8 12 306 46 2.44 (1.15-5.18) Glucose screen Yes

12 978 6 25 715 46 3.64 (1.55-8.50) (baseline or No
during follow-up)

3359 6 8892 39 2.54 (1.08-6.00) Glucose screen Yes

14 603 8 29 129 53 3.17 (1.51-6.68) (follow-up only) No
0 1 5 10 20 30
Antipsychotic decreases risk Antipsychotic increases risk

Hazard Ratio

No., number of cases of type 2 diabetes; P-y, person-years of follow-up.

sure groups had increased HRs for type 2 diabetes, and these The increased risk of type 2 diabetes among antipsy-
did not differ significantly according to screening status. Simi- chotic users persisted in several sensitivity analyses that as-
lar results were present in an analysis according to the pres- sessed study assumptions (eAppendix and eTable 10 in Supple-
ence of a screening test during follow-up (there was a mean ment). These analyses included control for possible clustering
number of 0.35 tests during follow-up for the controls and of induced by the frequency matching (HR = 3.07 [95% CI = 1.74-
0.51 tests for the antipsychotic users). An analysis that ex- 5.39]), restriction of the cohort to new users of antipsychotics
cluded person-time subsequent to 2004 (the year of the first and control psychotropic medications (HR = 3.05 [95%
publication of guidelines recommending screening of antipsy- CI = 1.70-5.46]), not permitting antipsychotic users who left the
chotic users30) also demonstrated increased risk for antipsy- cohort to reenter (HR = 2.86 [95% CI = 1.55-5.26]), and use of
chotic users (HR = 2.73 [95% CI = 1.35-5.53]). an alternative definition for type 2 diabetes that required a pre-

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 Antipsychotics and the Risk of Type 2 Diabetes
scription to confirm a diagnosis, except in the case of a pri-
mary inpatient diagnosis (HR = 3.11 [95% CI = 1.74-5.57]). In
each of these analyses, the risk for type 2 diabetes increased
with cumulative antipsychotic dose (eAppendix and eTable 10
in Supplement).
Discussion
In this cohort of children and youth who had recently initi-
ated use of an antipsychotic or a control psychotropic drug, an-
tipsychotic users had a risk of newly diagnosed type 2 diabe-
tes 3 times greater than that for propensity score–matched
controls. The excess risk occurred within the first year of an-
tipsychotic use, increased with cumulative antipsychotic dose,
and was present for children 6 to 17 years of age. The in-
creased risk persisted for up to 1 year following cessation of
antipsychotic use.
Study cases of type 2 diabetes were identified from diag-
noses from clinical practitioners and prescriptions for antidia-
betic drugs. Thus, there was the potential for false positives.
However, a validation study conducted in a cohort sample
found that the case definition had a positive predictive value
of 84% and that this did not differ materially according to an-
tipsychotic use status. These data suggest that the errors made
by clinical practitioners in the diagnosis of diabetes are un-
likely to explain the study findings.
Another type of misclassification that may have affected
our findings was the incomplete identification of type 2 dia-
betes in the cohort. In routine practice, many children and
youth may not undergo the testing necessary for this diag-
nosis. This could introduce bias if the diagnostic scrutiny of
the antipsychotic group was greater than that for controls.
To minimize this potential bias, we sought to ensure compa-
rability of medical surveillance for both groups. Thus, anti-
psychotic users and controls had recently initiated psycho-
tropic drug therapy and were closely matched at baseline
according to glucose or diabetes screening tests, as well as
recent medical care utilization, which is an indicator of
diagnostic scrutiny.
However, guidelines published in 2004 recommending
routine glucose monitoring for antipsychotic users could have
led to differential surveillance during follow-up. Thus, we per-
formed several analyses to assess this possibility. When data
were analyzed according to the presence of a screening test,
either at any time or only during follow-up, the increased risk
was present for both those who were and those were not
screened. This analysis should be conservative, given that
screening could be triggered by antipsychotic-related weight
gain. Furthermore, in an analysis that excluded person-time
subsequent to the year of guideline publication, the magni-
tude of the increased risk for antipsychotic users was little
changed.
We could not directly control for obesity, which is
closely linked to the development of type 2 diabetes.31 How-
ever, a material difference in body mass index between anti-
psychotic users and controls seems unlikely, given that con-
trols were very closely matched according to 115 study
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Original Investigation Research
covariates, many of which either are plausibly associated
with increased body mass or might mediate an association
between obesity and antipsychotic use. These included
diagnosed obesity, disorders or diagnostic testing linked to
excess weight, psychiatric diagnoses, psychotropic drug
use, and demographic characteristics. The observed dose-
response relationship is further evidence that the study
findings were not due to confounding by obesity.
For adults, the risk of type 2 diabetes conferred by anti-
psychotics is most pronounced for atypical antipsychotics32
and may vary according to specific drug.10,33 In the study
cohort, 87% of antipsychotic users received atypical drugs.
Study findings were largely unchanged when the cohort was
restricted to this group or to risperidone, the most fre-
quently prescribed individual drug. Olanzapine, quetiapine,
ziprasidone, and aripiprazole were used less frequently, but
each had a significantly elevated HR. However, this post hoc
finding must be interpreted cautiously. There was marked
variation in the baseline characteristics of users of specific
antipsychotics. Our study was not designed to study the
comparative risk of individual drugs, given that sample size
did not permit a propensity score match for specific antipsy-
chotics. Furthermore, it is possible that high-risk patients
may have been recommended a drug perceived to have
greater metabolic safety.34
Both the pathophysiology and the epidemiology of type
2 diabetes indicate that its development is a chronic process.35
Although the risk of type 2 diabetes did increase with cumu-
lative dose of antipsychotics, which is consistent with a chronic
process, we also found that a significantly increased risk was
present during the first year of therapy. Cases of early-onset
antipsychotic-associated diabetes have been reported for
adults. In one series,36 the majority of cases occurred within
6 months of drug initiation. Although there are fewer case re-
ports in the literature for children, early-onset cases also have
been described.37,38 Further study of the pathophysiology of
antipsychotic-associated diabetes is needed.
In the study cohort, there were an estimated 15.8 addi-
tional cases of type 2 diabetes per 10 000 person-years of
antipsychotic exposure, or a number needed to harm of 633.
However, this number should be applied cautiously in clini-
cal practice because the baseline risk for a child or youth will
vary substantially according to age and body mass index. Fur-
thermore, the study cohort consisted of Tennessee Medicaid
enrollees (approximately 40% of the state's children), which
also limits the generalizability of study findings, given that the
incidence of type 2 diabetes in children covered by Medicaid
may be elevated owing to economic and social factors, as well
as to a greater prevalence of behavioral risk factors, 39,40
disability,41 and chronic illness.42,43
In conclusion, in the study cohort of children and youth
between 6 and 24 years of age, those recently initiating an
antipsychotic medication had a 3-fold greater risk of newly
diagnosed type 2 diabetes than did propensity score–
matched controls. Risk was elevated during the first year of
antipsychotic use, increased with increasing cumulative
dose, and was present for children younger than 18 years of
age.
JAMA Psychiatry Published online August 21, 2013 E7
 Research Original Investigation
ARTICLE INFORMATION
Submitted for Publication: September 11, 2012;
final revision received December 2, 2012; accepted
January 21, 2013.
Published Online: August 21, 2013.
doi:10.1001/jamapsychiatry.2013.2053.
Author Contributions: All authors had full access
to all of the data in the study and take responsibility
for the integrity of the data and the accuracy of the
data analysis.
Study concept and design: All authors.
Acquisition of data: Bobo, Cooper, Daugherty, Ray.
Analysis and interpretation of data: Bobo, Cooper,
Stein, Olfson, Graham, Ray.
Drafting of the manuscript: Bobo, Ray.
Critical revision of the manuscript for important
intellectual content: All authors.
Statistical analysis: Graham, Ray.
Obtained funding: Ray.
Administrative, technical, or material support:
Cooper, Daugherty.
Study supervision: Cooper, Ray.
Conflict of Interest Disclosures: Dr Bobo has
received research support from Cephalon and
served on speaker bureaus for Janssen
Pharmaceutica and Pfizer. Dr Olfson has received
support from a research grant to Columbia
University from Eli Lilly (end date June 20, 2010)
and one from Bristol-Myers Squibb (end date
January 31, 2010). No other disclosures are
reported.
Funding/Support: This study was supported by the
Agency for Healthcare Research and Quality,
Centers for Education and Research on
Therapeutics cooperative agreement (grant
HS1-16974).
Disclaimer: The views expressed are solely the
responsibility of the authors and do not necessarily
represent the official views of the US Food and
Drug Administration.
Additional Information: The first draft of the
article was written by Drs Bobo and Ray, who vouch
for the data and the analysis.
Additional Contributions: We gratefully
acknowledge the Tennessee Bureau of Medicaid
and the Department of Health, which provided
study data.
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