special section

Diabetes and Schizophrenia

Supported by Eli Lilly and Company

MG39116 0306
 Placing the Risk of Diabetes in Context
Based on an interview with Leslie Citrome, MD, MPH
As of 2005, an estimated 20.8 million people in the
United States, or 7% of the population, have diabe-
tes; one-third (6.2 million people) are undiagnosed. In
2005, 1.5 million new cases
of diabetes were diagnosed
in people aged 20 years or
older. By 2030, more than 30
million people in the US are
expected to have diabetes.1,2
This is becoming a major
issue in the mental health-
care community, since studies
have suggested that patients
treated with antipsychotic
medications have a higher Leslie Citrome, MD, MPH
risk of diabetes than the general population. Yet as
Leslie Citrome, MD, MPH, a professor of psychiatry
at the New York University School of Medicine, ex-
plains below, the data on the possible connection
between schizophrenia, antipsychotic selection, and
diabetes are not clear-cut.
S
even percent of the American population has dia-
betes.3 Research shows that patients with schizo-
phrenia are at a higher risk of developing diabe-
tes. Rates of type 2 diabetes mellitus in patients
with schizophrenia are two to four times that in the general
population.4-7 In a recent report on the New York State
Office of Mental Health psychiatric hospital system, the
prevalence of patients with diabetes doubled from 6.9%
of 10,091 patients in 1997 to 14.5% of 7,420 patients in
2004 irrespective of antipsychotic use.8
Theories About the Schizophrenia-Diabetes Link
Several theories have been suggested to account for the
apparent connection between diabetes and schizophrenia.
One is the potential genetic link between the heritability
of diabetes and the heritability of schizophrenia. Patients
with schizophrenia have a higher rate of family history of
26 APRIL 2006 w w w.b eh av i o r a l.n e t
diabetes than the general population. Studies have reported
that 17 to 50% of people with schizophrenia have a family
history of type 2 diabetes,9,10 and a positive family history
of diabetes may increase the risk of developing diabetes in
individuals with schizophrenia and other serious and persis-
tent mental illnesses up to threefold.11
We have known, even before the availability of anti-
psychotics, that patients with schizophrenia were prone
to develop hyperglycemia. A link between schizophrenia
and diabetes was postulated in the 1920s,12 and a tem-
poral association between first-generation antipsychotic
drug treatment and hyperglycemia was first reported in
the 1950s.13
Patients with schizophrenia often are disadvantaged eco-
nomically, so they may not be able to afford healthier eating
habits. These patients also may not be aware of the risks for
diabetes or have access to adequate primary care services.
Large-scale epidemiologic studies14,15 have spawned an
increased interest in an association between second-genera-
tion antipsychotics and diabetes. Clinicians have begun to
be more concerned about diabetes in patients with schizo-
phrenia, because it has been suggested that the second-
generation antipsychotics we are using today are putting
our patients at a higher risk for developing diabetes.
Insulin resistance can take more than a decade to mani-
fest as diabetes. Someone destined to become diabetic of-
ten has alterations in his or her ability to handle glucose
that have existed for years—alterations that may remain
asymptomatic in patients who remain unaware of having
this problem until they eventually have their blood sugar
levels checked. Thus, a patient with schizophrenia may have
diabetes or prediabetes even before treatment with antipsy-
chotics. Because of this and many other factors, the poten-
tial contribution of antipsychotic treatment toward the risk
for developing diabetes mellitus is unclear.14,15
The Different Ways to Define “Risk”
Different study designs have been used to estimate the con-
tribution of antipsychotic treatment toward the risk for de-
 D i a b e t e s a nd Sc h i z o p h r e n i a
veloping diabetes in a patient with schizophrenia. All of the
large epidemiologic studies have been retrospective analyses
of large claims databases. These studies offer the advantage
of large numbers and longitudinal data. Before discussing
study design, I will discuss the types of risk these studies
try to estimate.
The odds ratio is the odds that a patient with a disease
was exposed to a risk factor versus the odds that a control
(unaffected by the disease) was exposed to the same risk
factor. The relative risk ratio represents the increased (or
decreased) likelihood of developing a disease on exposure
to one risk factor compared with exposure to something
else other than that risk factor.15 Odds ratios and relative
risk ratios help us compare the potential risk of developing
a disease in patients treated with one treatment versus an-
other, but by themselves they don’t place the results into a
clinically meaningful context and often are misunderstood.
Odds and relative risk ratios do not tell us if the event rarely
occurs overall, or if the absolute difference in risk for pa-
tients treated with different agents is small.16
Let’s go over an example to highlight the problem of just
looking at relative risk. Let’s say the incidence of green toes
occurring in patients on drug A is 0.1%, and for patients
treated with drug B, 0.13%. Effectively this means that for
every 10,000 patients treated with drug A, we would expect
10 to develop green toes; for drug B we would expect 13.
The relative risk ratio is the incidence of drug B divided by
the incidence of drug A (0.13/0.10 = 1.3). This relative risk
might be interpreted as “Drug B is 30% more risky for the
development of green toes than drug A.” This is a provoca-
tive statement because it is out of clinical context. The extra
number of cases we would expect (the attributable risk in
patients treated with drug B instead of drug A) is 3 per
10,000 patients treated (see table, p. 30). To boil it down,
relative risk helps us understand the comparative likelihood
that something will occur between two groups of exposures.
However, too often, people read “30% more risk” as “30%
more of the total number treated” rather than “30% more
of the number who developed the outcome.”
So let’s say you use drug X, a first-generation antipsy-
chotic, to treat 100 patients with schizophrenia, and drug
Y, a second-generation antipsychotic, to treat another 100
patients with schizophrenia. Over the course of a year, 1 pa-
tient treated with drug X develops diabetes, and 2 patients
treated with drug Y develop diabetes. Thus, the relative risk
of diabetes is doubled in patients being treated with drug X
compared with drug Y. But this does not describe how com-
SPECIAL SECTION
monly you could expect to see diabetes in patients treated
with these antipsychotics. It’s important to determine the at-
tributable risk: the difference in risk between patients treated
with drugs X and Y, which is 1 out of 100 (1%). This means
that if you treat 100 patients, you might expect to see one
extra case of diabetes in patients being treated with drug Y.
However, the attributable risk of developing diabetes while
being treated with drug Y is much lower when compared to
the risk of developing diabetes attributable to family history,
being overweight, or lack of exercise.9
The potential risk of diabetes must be evaluated in light of
the potential therapeutic benefits and the overall safety and
tolerability profile. Patients treated with second-generation
antipsychotics are less likely to experience treatment-emer-
gent extrapyramidal symptoms and tardive dyskinesia than
patients treated with first-generation antipsychotics.17,18
This explains their widespread adoption and preference
among many patients and providers. The second-genera-
tion antipsychotics have also demonstrated improved effi-
cacy in treating negative symptoms, mood symptoms, and
cognitive dysfunction relative to the first-generation anti-
psychotics.19-21 These gains may have helped patients to stay
on therapy longer, resulting in lower relapse rates22 and lon-
ger times to all-cause discontinuation.23
How Study Design Affects Results
In addition to different ways of defining risk, different study
designs have been used to examine the possible connection
between antipsychotic selection, diabetes, and schizophre-
nia.15 There are three ways to look at groups of people in
epidemiologic studies: cross-sectional studies, cohort stud-
ies, and case-control studies.
Cross-sectional studies. These studies “freeze time.” An
example would be looking at 1,000 people at one point in
time to see how many have schizophrenia, are taking an
antipsychotic, or have diabetes. This study design does not
tell us what came first—schizophrenia, the antipsychotic
treatment, or diabetes; there’s no causal pathway to exam-
ine. Cross-sectional study results are limited because they do
not consider patients’ baseline status. But using this study
design is a good way to assess the burden of a disease in
a population. It’s important to know that 7% of the US
population have diabetes and 1% has schizophrenia because
it helps policy makers plan how to allocate healthcare re-
sources.
Cohort studies. These studies are probably the most com-
mon epidemiologic design. In a prospective cohort study, a
BEHAVIORAL HEALTHCARE 27
 group of people is followed over time to see what illnesses
they develop and what drugs they use. These studies are
expensive and take a long time. To date, no large-scale pro-
spective cohort studies have been conducted on diabetes
and antipsychotic use.
A retrospective cohort study examines data already gath-
ered to see what diseases people developed and what drugs
they used. A researcher, using a prescription drug database,
might examine a cohort of patients receiving antipsychotic
treatment at the beginning of a year, and determine how
many of those patients received antidiabetic treatments by
the end of the year. This would allow the researcher to com-
pare the different rates of new antidiabetic prescriptions
based on which antipsychotics patients received.
Retrospective cohort studies have several limitations.
First, researchers’ results are tied to the data’s accuracy. For
example, a prescription drug database may not clearly in-
dicate whether a patient is taking multiple medications
nor does it reflect whether a patient is complying with a
prescribed regimen. The database might indicate which pa-
tients are being prescribed antidiabetic medications, but it
probably won’t show who actually has been diagnosed as
diabetic or who is controlling diabetes through diet and ex-
ercise instead of medication. Other limitations:
• The database won’t indicate people with undiagnosed
diabetes.
• The data won’t reflect incidences in the general popula-
tion (e.g., many databases include only people insured
through an employer).
• The database may not reflect how many patients in the
cohort have a family history of diabetes—perhaps one of
the strongest risk factors for the disease.24
• The database may not reflect patients’ weights or dietary
habits or other important risk factors.
Treatment assignment bias also can make it difficult to
28 APRIL 2006 w w w.b eh av i o r a l.n e t
interpret retrospective cohort studies. The factors that in-
fluence a doctor to prescribe one antipsychotic instead of
another might be based on a patient’s preexisting risk fac-
tors for diabetes (e.g., family history, obesity, lack of exer-
cise). If a physician believes that drug A is associated with
a higher risk of diabetes compared with drug B, he or she
may avoid prescribing drug A to patients who have these
risk factors. In such a case, observed case rates of diabe-
tes would be lower for drug A because it wasn’t prescribed
to high-risk patients. On the other hand, in this instance,
drug B, presumed “better” for high-risk patients, eventually
would become associated with a higher case rate of diabe-
tes.
Finally, retrospective cohort studies can be affected by
surveillance bias. For example, if a healthcare provider be-
lieves that there is less of a concern about diabetes with one
antipsychotic, there may be less likelihood of a patient on
that drug having his/her blood sugar levels checked, and
hence less of a chance of being diagnosed with diabetes.
Case-control studies. Case-control studies are, by defini-
tion, retrospective. For example, a case-control study could
examine patients with schizophrenia and diabetes based on
which antipsychotic they received. To estimate the odds ra-
tio in the study, the researcher would also need to assess
a group of patients with schizophrenia receiving the same
antipsychotic treatment but who do not have diabetes—the
control group. Comparing the case patients with the con-
trol patients yields the odds ratio. The odds ratio calculated
in case-control studies is considered a reasonable estimate
of the relative risk calculated in similar retrospective cohort
studies only if the outcome event is uncommon.25
What the Data Show
When the results of studies with different designs are taken
together, one might conclude that patients treated with
antipsychotics may have a greater risk of developing diabe-
tes than patients who are not treated with antipsychotics.
 Diabetes anD schizophrenia
“patients require individualized
management, and they should be
screened for diabetes and risk factors.”
Looking at differences between patients treated with first-
and second-generation antipsychotics is more difficult, but
there appears to be an increased association of diabetes with
second-generation antipsychotics than with first-generation
antipsychotics, although the data are mixed on this point.
This relationship, however, is not as strong or convincing as
the difference between patients being treated with an anti-
psychotic versus those who are not.
The results of studies comparing the association of dia-
betes among second-generation antipsychotics are quite in-
consistent. Not all agents in this therapeutic class have been
tested in large studies, and not all studies have led to the
same conclusions. Although the weight gain associated with
different second-generation antipsychotics can differ signif-
icantly, this difference has not translated into a substantial
difference in association with type 2 diabetes.26,27 Finally,
it’s important to remember that established risk factors for
diabetes, as outlined in consensus guidelines,26 play a great
role in predicting whether a given individual will develop
diabetes. Obesity, lack of exercise, hypertension, hyperlip-
idemia, and family history are among the most common of
these factors.
The Importance of a Holistic View
For a patient with both schizophrenia and diabetes, effec-
tive treatment of schizophrenia is a necessary prerequisite
for the successful treatment of diabetes. A person with un-
controlled schizophrenia will be unable to follow a regimen
to control diabetes. Thus, patients’ psychotic symptoms
must be controlled first, so that patients can have a chance
to manage their blood sugar levels. A person must have the
cognitive awareness to be able to understand the impor-
tance of following a diabetes management plan. Patients
with acute psychosis and paranoia may not monitor their
blood sugar levels daily or adhere to their diabetic treat-
ment. These are particularly important because of the mor-
bidity and mortality of untreated diabetes. Uncontrolled
special section
diabetes leads to substantial risks of myocardial infarction,
stroke, neurologic problems, kidney problems, blindness,
and other comorbidities.
The life expectancy of someone with diabetes is lower
than that of the general population,28 and uncontrolled
diabetes further decreases life expectancy. The life expec-
tancy of someone with schizophrenia is approximately 20%
less than that of the general population.29 So a person with
schizophrenia and uncontrolled diabetes is likely to have an
even shorter life expectancy.
Patients with schizophrenia can be difficult to treat, and
prescribers need access to all available options. If second-
generation antipsychotics are avoided because of their po-
tential diabetes risk, and first-generation antipsychotics
are preferred, this could result in poor adherence to the
treatment medication. Poor adherence is associated with
increased frequency of relapse, more intense symptoms,
and longer inpatient stays, resulting in higher healthcare
costs.30
Risk for diabetes should be monitored by taking a holis-
tic view of patients, including weighing patients, measur-
ing blood pressure, obtaining fasting glucose results, and so
on. Patients require individualized management, and they
should be screened for diabetes and risk factors. Several
organizations have proposed guidelines26,31 (“Recommen-
dations for Screening and Monitoring” and a “Tracking
Sheet for Patients on Atypical Antipsychotics” are included
at the end of this article.) It’s the least we can do for our
patients, given the number of diabetes risk factors many of
them have. This is particularly important at the community
mental health level, where many people with schizophrenia
and other serious mental illnesses receive treatment.
The general population is facing a healthcare crisis as
more and more people develop diabetes. Our patients with
schizophrenia are no exception. One must examine all the
risk factors for diabetes. Some risk factors cannot be modi-
fied, such as family history and ethnicity. However, there
behavioral healthcare 29
Table. Difference between relative and attributable risk
Incidence of patients with green toes drug A = 0.10% (10 out of 10,000)
Relative risk: 0.13/0.10 = 1.3
Drug B is 30% more risky for the development of green toes than drug A.
Attributable risk: 13-10 = 3
The extra number of cases expected when using drug B instead of drug A is 3 per 10,000 patients treated.
are modifiable risk factors, such as diet and exercise. Pa-
tients at risk can eat appropriately and increase their activity
level. We might never be able to prevent diabetes in high-
risk patients, but the longer we can delay its manifestation,
the better off our patients will be.
References
1. U.S. Centers for Disease Control and Prevention. National diabetes
fact sheet: General information and national estimates on diabetes in
the United States, 2005. Atlanta: Department of Health and Human
Services, Centers for Disease Control and Prevention, 2005.
2. Wild S, Roglic G, Green A, et al. Global prevalence of diabetes: Es-
timates for the year 2000 and projections for 2030. Diabetes Care
2004;27:1047-53.
3. American Diabetes Association. All About Diabetes. Available at:
www.diabetes.org/about-diabetes.jsp.
4. Keskiner A, el-Toumi A, Bousquet T. Psychotropic drugs, diabetes
and chronic mental patients. Psychosomatics 1973;14:176-81.
5. McKee HA, D’Arcy PF, Wilson PJ. Diabetes and schizophrenia—a
preliminary study. J Clin Hosp Pharm 1986;11:297-9.
6. Mukherjee S. High prevalence of type II diabetes in schizophrenic
patients. Schizophr Res 1995;15:195.
7. Mukherjee S, Decina P, Bocola V, et al. Diabetes mellitus in schizo-
phrenic patients. Compr Psychiatry 1996;37:68-73.
8. Citrome L, Jaffe A, Levine J, Martello D. The treated incidence,
identified prevalence, and surveillance for diabetes mellitus among
inpatients in state-operated psychiatric hospitals in New York State
1997-2004. Psychiatr Serv. In press.
9. Mukherjee S, Schnur DB, Reddy R. Family history of type 2 diabetes
in schizophrenic patients [letter]. Lancet 1989;1(8636):495.
10. Cheta D, Dumitrescu C, Georgescu M, et al. A study on the types of
diabetes mellitus in first degree relatives of diabetic patients. Diabetes
Metab 1990;16:11-15.
11. Lamberti JS, Crilly JF, Maharaj K, et al. Prevalence of diabetes melli-
tus among outpatients with severe mental disorders receiving atypical
antipsychotic drugs. J Clin Psychiatry 2004;65:702-6.
12. Lorenz WF. Sugar tolerance in dementia praecox and other mental
disorders. Arch Neurol Psychiatry 1922;8:184-96.
13. Charatan FB, Bartlett NG. The effect of chlorpromazine (largactil) on
glucose tolerance. J Ment Sci 1955;101:351-3.
14. Citrome LL, Jaffe AB. Relationship of atypical antipsychotics with de-
velopment of diabetes mellitus. Ann Pharmacother 2003;37:1849-57.
15. Citrome LL. The increase in risk of diabetes mellitus from exposure
to second-generation antipsychotic agents. Drugs of Today 2004;40:
445-64.
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drug B = 0.13% (13 out of 10,000)
16. Citrome L. Relatively speaking, how odd can hazards be? Psychophar-
macology Educational Update 2005;1(10):2-3.
17. Glazer WM. Extrapyramidal side effects, tardive dyskinesia, and the
concept of atypicality. J Clin Psychiatry 2000;61(suppl 3):16-21.
18. Kinon BJ, Jeste DV, Kollack-Walker S, et al. Olanzapine treatment
for tardive dyskinesia in schizophrenia patients: A prospective clini-
cal trial with patients randomized to blinded dose reduction periods.
Prog Neuropsychopharmacol Biol Psychiatry 2004;28:985-96.
19. Stahl SM. Selecting an atypical antipsychotic by combining clini-
cal experience with guidelines from clinical trials. J Clin Psychiatry
1999;60(suppl 10):31-41.
20. Yatham LN. Efficacy of atypical antipsychotics in mood disorders.
J Clin Psychopharmacol 2003;23(3 suppl 1):S9-14.
21. Meltzer HY, McGurk SR. The effects of clozapine, risperidone, and
olanzapine on cognitive function in schizophrenia. Schizophr Bull
1999;25:233-55.
22. Csernansky JG, Schuchart EK. Relapse and rehospitalisation rates in
patients with schizophrenia: Effects of second generation antipsychot-
ics. CNS Drugs 2002;16:473-84.
23. Swartz M, Zhu B, Ascher-Svanum H, et al. Time to all-cause discon-
tinuation of atypical versus typical antipsychotics in the naturalistic
treatment of schizophrenia. Presented at: International Congress on
Schizophrenia Research; 2005; Savannah, Georgia.
24. American Diabetes Association. The Genetics of Diabetes. Available
at: www.diabetes.org/genetics.jsp.
25. Streiner DL, Norman GR. PDQ Epidemiology. 2nd ed. Hamilton,
Ontario: BC Decker, Inc., 1998.
26. American Diabetes Association; American Psychiatric Association;
American Association of Clinical Endocrinologists; North American
Association for the Study of Obesity. Consensus development confer-
ence on antipsychotic drugs and obesity and diabetes. Diabetes Care
2004;27:596-601.
27. Lieberman JA, Stroup TS, McEvoy JP, et al. Clinical Antipsychotic
Trials of Intervention Effectiveness (CATIE) Investigators. Effective-
ness of antipsychotic drugs in patients with chronic schizophrenia.
N Engl J Med 2005;353:1209-23.
28. Kannel WB, McGee DL. Diabetes and cardiovascular disease. The
Framingham study. JAMA 1979;241:2035-8.
29. Hennekens CH, Hennekens AR, Hollar D, Casey DE. Schizo-
phrenia and increased risks of cardiovascular disease. Am Heart J
2005;150:1115-21.
30. Thieda P, Beard S, Richter A, Kane J. An economic review of com-
pliance with medication therapy in the treatment of schizophrenia.
Psychiatr Serv 2003;54:508-16.
31. Marder SR, Essock SM, Miller AL, et al. Physical health monitoring
of patients with schizophrenia. Am J Psychiatry 2004;161:1334-49.
 D i a b e t e s a nd Sc h i z o p h r e n i a SPECIAL SECTION

Recommendations for Screening and Monitoring

In 2003, based on recommendations from the FDA, a warning regarding hyperglycemia and
diabetes mellitus was added to package labeling for each of the atypical antipsychotics.
Included in the warning are FDA recommendations for diabetes screening in the high-risk
population that relies on these medications.

FDA Recommendations for Monitoring Patients

Treated With Atypical Antipsychotics
Patient with Patients with risk All patients initiated on
pre-existing diabetes factors for diabetes an atypical antipsychotic

• Monitor regularly for • Fasting blood glucose at • Monitor for symptoms of

worsening of glucose baseline then periodically hyperglycemia (polydispsia,
control during treatment polyuria, polyphagia, and
weakness)
• Fasting blood glucose in
patients who develop
symptoms of diabetes

Source: Food and Drug Administration recommendations for atypical antipsychotics, September 2003.

ADA Consensus Development Conference on Antipsychotic Drugs

and Obesity and Diabetes
Monitoring protocol for patients on atypical antipsychotics.
More frequent assessments may be warranted based on clinical studies.
Baseline 4 Weeks 8 Weeks 12 Weeks Quarterly Annually Every 5
Years
Personal/ X X
family history
Weight (BMI) X X X X X

Waist X X
circumference
Blood pressure X X X

Fasting plasma X X X
glucose
Fasting lipid X X X
profile

Source: ADA. Diabetes Care. 2004;27(2):596-601.

MG38613 1205
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BEHAVIORAL HEALTHCARE 31
 Tracking Sheet for Patients on
Atypical Antipsychotics*
Patient name
Current Medication(s) & Date(s) Started

Personal and family history (Baseline, Annually)

Weight (BMI) (Baseline + every visit for 6 months after medication initiation)
Date: / /

Waist circumference – measure at level of umbilicus (Baseline + annually)

Date: / /

Blood Pressure (Baseline + 12 weeks + annually)

Date: / /

Fasting Plasma Glucose (Baseline + 12 weeks + annually)

Date: / /

Fasting Lipid Profile (Baseline + 12 weeks + every 5 years)

Date: / /

Diet discussed. Plan:

Exercise discussed. Plan:

*ADA. Diabetes Care; 2004;27(2):596-601.

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