US Pharm. 2012;37(11):39-44.
ABSTRACT: Several metabolic consequences of
antipsychotic use have been described within the literature, including
weight gain, hyperglycemia, and dyslipidemia. While the exact mechanisms
of antipsychotic-induced metabolic dysfunction are unknown, there are a
variety of proposed mechanisms. Since weight gain is considered a
precipitating factor for the development of diabetes and dyslipidemia,
monitoring of weight changes with antipsychotic treatment is an
important screening measure. As some antipsychotic agents are less
likely to contribute to weight gain, such as aripiprazole and
ziprasidone, it seems prudent to choose a lower-risk antipsychotic in
people who are at high risk for or have a preexisting diagnosis of
diabetes or in whom hyperglycemia, dyslipidemia, and/or substantial
weight gain develops.
Diabetes mellitus (DM) is the seventh leading cause of
death in the United States and is a major cause of renal failure, new
onset blindness, and nontraumatic limb amputations.1 DM
additionally places people at risk for adverse cardiovascular outcomes
and is a major contributor to the incidence of stroke and heart disease.
National estimates indicate that DM affects 8.3% of the U.S.
population, which equates to a staggering 25.8 million people, and the
incidence of DM is continuing to grow at an alarming rate.1
While the health and economic consequences of type 2 DM
(T2DM) are widely known, the contribution of medications to the
development of T2DM is sometimes less well recognized. One class of
drugs for which there are large amounts of clinical data to substantiate
a link between their use and the development of T2DM is antipsychotic
medications. This article will provide an overview of
antipsychotic-induced DM and current recommendations pertaining to its
Antipsychotic-Induced T2DM: How Common Is It?
There are many potential metabolic consequences of
antipsychotic use that have been described within the literature. Such
metabolic disturbances primarily include weight gain, hyper-glycemia,
and dyslipidemia.2-4 As a consequence of these metabolic
disturbances, the risk of comorbid hypertension and heart disease are
also reportedly increased in people using antipsychotic drugs.5
The association of antipsychotic use to T2DM development
is supported by retrospective epidemiologic studies as well as
post-marketing surveillance.5 Identifying the prevalence of
antipsychotic-induced DM versus the background prevalence of DM in
people with schizophrenia and other mental health disorders, however, is
confounded by a number of factors. Many studies to date have included
patients with schizophrenia receiving treatment with antipsychotic
therapy; thus, determining the baseline prevalence of DM in this
population in the absence of antipsychotic therapy is difficult. Data
indicate the prevalence of DM and obesity to be approximately 1.5 to 2
times higher in people with schizophrenia or affective disorders when
compared to the general population.6
In an analysis of the Clinical Antipsychotic Trials of
Intervention Effectiveness (CATIE) study, patients with schizophrenia
were found to have higher rates of T2DM (13%) when compared to age,
race, and gender-matched controls from the National Health and Nutrition
Examination Survey (NHANES) III (3%; P <.001).7
Similarly, a cross-sectional study enrolling outpatients with a
diagnosis of schizophrenia found an 11.5% lifetime prevalence of T2DM in
this patient population.5 Cases of patients developing
hyperglycemia upon initiation of antipsychotic therapy followed by the
resolution of hyperglycemia upon discontinuation of the offending
medication have also been reported.6 A cohort study of antipsychotic-naïve patients followed participants for 3 years after the initiation of antipsychotic therapy.8
After 3 years of follow-up, the incidence rate of DM was found to be
0.65% per patient-year. Of note, in older participants the time to DM
onset was significantly shorter when compared to that in younger
participants, indicating that age may be a risk factor for
People at highest risk for antipsychotic-induced DM are
those diagnosed with schizophrenia, bipolar disorder, psychotic
depression, dementia, autism, or developmental disorders.2,6
Other less common uses of antipsychotic medications, which can also
result in the development of treatment-induced metabolic disturbances,
are post-traumatic stress disorder (PTSD), delirium, personality
disorder, and aggressive behavior.6 Risk factors for the
development of antipsychotic-induced DM are complex and may involve an
interplay between sedentary lifestyle, the pharmacologic properties of
the antipsychotic agent being used (e.g., drug-specific risk of
contributing to drug-induced metabolic disturbances), worsening
metabolic homeostasis, and possible genetic causes.8,9
How Do Antipsychotics Contribute to the Development of Weight Gain, T2DM, and Dyslipidemia?
Metabolic disturbances seen with antipsychotic use
typically manifest initially as weight gain that can advance to obesity.
Cases of new onset DM associated with weight gain and independent of
weight gain have been reported in the literature.3 Second-generation
antipsychotic (SGA) therapy can contribute to rapid weight gain in the
first few months of treatment, with weight gain continuing in some
patients for up to one year. Variation in weight gain exists and can
range from gains of 0.5 to 5.0 kg after 10 weeks of antipsychotic
therapy.6 Given these risks, distinguishing the presence of
metabolic syndrome is useful to proactively identify metabolic risk in
people with mental illness. In addition to the presence of mental
illness, lifestyle factors such as increased food intake, intake of
particularly high carbohydrate content drinks and snacks, limited
physical activity, drug abuse, or tobacco smoking can all contribute to
the development of weight gain and obesity in this population.2
While the exact mechanisms of antipsychotic weight gain
are unknown, there are a variety of proposed mechanisms whereby
antipsychotics may contribute to weight gain, DM, and dyslipidemia. It
is widely believed that antipsychotic drugs contribute to weight gain
and corresponding hyperglycemia and dyslipidemia via effects mediated by
binding to serotonin (5-HT2), norepinephrine, dopamine,
and/or histamine receptors. Serotonin activity at receptor sites is a
potent satiety signal, with the most implicated receptors being 5-HT1A and 5-HT2C. Stimulation of 5-HT1A is associated with an increase in food intake whereas stimulation of 5-HT2C is related to a decrease in food intake. Antagonism of the 5-HT2C receptor can, in turn, lead to an increase in food intake, with most SGAs possessing 5-HT2C antagonist activity.10
The histamine receptor has additionally been theorized to mediate
medication-induced weight gain, with histamine receptor affinity
correlating with drug-induced weight gain in some studies.11
Olanzapine, for instance, possesses a high affinity for histamine
receptors, while agents with a lower risk of contributing to weight
gain, such as ziprasidone and aripiprazole, have lower histamine
Hyperglycemia, impaired fasting glucose, and DM are likely
caused and/or exacerbated by drug-induced insulin resistance stemming
from weight gain; however, a direct effect of antipsychotic drugs on
insulin resistance may also play a role.6 Mechanistic studies
have demonstrated both insulin resistance and increased insulin
secretion (an indirect indicator of increased insulin resistance) with
antipsychotics.3,12 Likewise, changes in body weight may also contribute to antipsychotic-induced dyslipidemia.6
With weight gain considered a key adverse effect that potentiates the
development of dyslipidemia, hyperglycemia, and DM, additional research
is warranted to unravel mechanisms contributing to the metabolic
complications associated with antipsychotic pharmacotherapy.
Recommendations for patient monitoring for the development of dyslipidemia, weight gain, and DM have been published.6
They consider the potential metabolic risks when initiating an SGA;
patient, family, and caregiver education; baseline screening; and
referral to a specialist, if needed, as key components of patient care.6
As weight gain is considered a precipitating factor for the development
of DM and dyslipidemia, monitoring of weight changes with treatment is
an important screening measure.
Baseline and follow-up monitoring is recommended by the
joint consensus statement from the American Diabetes Association, the
American Psychiatric Association, the American Association of Clinical
Endocrinologists, and the North American Association for the Study of
Obesity to help reduce the risk of developing diabetes, cardiovascular
disease, and other complications of DM.6 According to the
consensus statement, screening measures are recommended to be obtained
before or soon after the initiation of antipsychotic medication. The
recommended screening measures are summarized in TABLE 1.6
Accordingly, clinicians are encouraged to record and track
the patient’s height and weight (BMI) before and during treatment and
to encourage patients to self-monitor weight change by charting their
weight.6 Follow-up monitoring is additionally recommended at
various intervals depending on the measure being evaluated. Fasting
plasma glucose and blood pressure are assessed at baseline, at 3 months,
and then annually, while lipids are assessed at baseline, at 3 months,
and then every 5 years. If patients are at higher risk to develop DM or
hypertension, more frequent monitoring is advised. Using these measures,
clinicians can better assess patients’ baseline status for weight
(overweight defined as BMI 25-29), prediabetes (fasting plasma glucose
100-125 mg/dL) or DM (fasting plasma glucose ≥126 mg/dL), hypertension
(>140/90 mmHg), or dyslipidemia to help determine their risk status
and the contribution and/or causation of antipsychotic therapy.6
Depending on the presence of any metabolic disorders at
baseline, clinicians can make an informed decision regarding the
selection of appropriate antipsychotic therapy (see the following
section). For patients who are overweight, referral for a consult with a
nutritionist and for activity counseling is advised, especially if an
SGA with a high likelihood of contributing to weight gain is initiated.
The panel goes on to state that education is a very important aspect of
management, and all patients, caregivers, and family members should be
counseled regarding the recognition of the signs and symptoms of DM and
diabetic ketoacidosis (DKA) (TABLE 2).6 Abrupt
development of DKA as the only presenting sign of glucose abnormalities
has been reported. For patients who do develop hyperglycemia, prompt
referral to a clinician experienced in the management of DM is
For patients who do develop metabolic abnormalities
stemming from antipsychotic therapy, switching to another antipsychotic
agent associated with less hyperglycemia, weight gain, and dyslipidemia
is a potential management strategy. The consensus statement recommends
switching an agent if the patient gains ≥5% of his or her baseline body
weight with therapy.6
Are There Differences Between Antipsychotic Agents?
SGAs most implicated in leading to metabolic abnormalities
are clozapine, olanzapine, risperidone, quetiapine, aripiprazole, and
ziprasidone.10 There is variability between first-generation
antipsychotics (FGAs) and SGAs regarding their metabolic and other
adverse effects. FGAs are known to contribute to extrapyramidal symptoms
(EPS) such as dystonia, pseudoparkinsonism, akathisia, and late-onset
tardive dyskinesia.6 High-potency FGAs such as haloperidol
and fluphenazine also have higher occurrences of EPS in comparison to
other, low-potency FGAs.13 SGAs, while generally associated
with fewer EPS and better overall tolerability when compared to FGAs,
are also associated with a higher risk of contributing to metabolic
Clozapine and olanzapine are considered the worst
offenders for contributing to hyperglycemia, dyslipidemia, and weight
gain. Intermediate effects are seen with risperidone and quetiapine,
while ziprasidone and aripiprazole are considered to convey the smallest
relative risk.13 Interestingly, the relative risks of these
agents parallel their relative effects on weight gain. A report of
1-year treatment data compiled from industry-sponsored trials showed
more weight gain with clozapine and olanzapine (~12 kg) when compared to
quetiapine and risperidone (~2 to 3 kg), aripiprazole (slightly less
than quetiapine or risperidone), or ziprasidone (~2 to 3 kg weight loss).2 These differences should be considered in light of the fact that they were obtained from separate industry-sponsored trials.
While data are limited, the American Diabetes Association
states that the effects of SGA therapies on lipids are concordant with
their effects on body weight; thus, monitoring is recommended.6
Mixed findings exist for risperidone and quetiapine in regard to risk
for the development of new-onset or worsening T2DM, and they are
considered to have intermediate effects on increasing lipids.6
While ziprasidone and aripiprazole are considered to possess the lowest
risk, case studies of new-onset hyperglycemia have been reported in the
literature, including a report of aripiprazole precipitating a case of
DKA.13 A summary of the reported metabolic effects of SGAs is provided in TABLE 3.6
Overall, it seems prudent to choose a lower-risk
antipsychotic such as aripiprazole or ziprasidone for an individual who
has preexisting DM or is otherwise at high risk. If hyperglycemia,
dyslipidemia, and/or substantial weight gain develops, switching to a
lower-risk antipsychotic drug should be considered.6,14 While
data regarding potential metabolic consequences of long-term treatment
with newer SGAs (such as asenapine, iloperidone, lurasidone, and
paliperidone) are currently lacking, the relative effects of these
agents on the development of diabetes and other metabolic derangements
will become more clear with additional study and clinical experience.
DM is reaching epidemic proportions worldwide, and the
contributions of medications to the development of hyperglycemia and
other metabolic derangements is receiving more attention. Pharmacists
are in a unique position to counsel and encourage appropriate
self-monitoring in patients receiving certain drugs, such as
antipsychotics, that can contribute to the development of weight gain,
hyperglycemia, and dyslipidemia. Pharmacists can serve as a catalyst for
patients receiving antipsychotics to communicate adverse events to
other health care providers and seek therapeutic substitutions,
counseling, and/or treatment if adverse events result from treatment. As
a population, people with schizophrenia often have poor access to care
and lower levels of psychosocial support; thus, the pharmacist’s
recognition and intervention in this population have the potential to
improve quality of care.
Providers should be aware that the onset of DM can be
rapid and severe in some patients, with case reports of life-threatening
DKA reported, sometimes within weeks after starting antipsychotic
treatment.12,14 Rarely, such cases have occurred even with
low-risk SGAs such as ziprasidone and aripiprazole, so that diligence in
monitoring is warranted even with agents less likely to contribute to
weight gain, hyperglycemia, and dyslipidemia.13,15
While the exact mechanisms contributing to
antipsychotic-induced metabolic changes are unknown, research is ongoing
to pinpoint the mechanisms at play. Overall, appropriate monitoring,
reporting, and patient and clinician awareness are critical to the early
recognition and treatment of antipsychotic-induced DM.
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diabetes and prediabetes in the United States, 2011. Atlanta, GA: U.S.
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