Running head: INTEGRATED REVIEW 1

Integrated Review

Cameron Reynolds

Bon Secours Memorial College of Nursing

NUR 4122

On my honor, I have neither given nor received aid on this assignment or test, and I pledge that

I am in compliance with the BSMCON Honor System

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Abstract

The goal of this integrative review is to evaluate the literature regarding the occurrence of

diabetic related adverse events associated with the use of different antipsychotic medications.

Antipsychotics are routinely prescribed to treat a large variety of mental health illnesses. They

are used to treat schizophrenia, as well as bipolar mania, certain symptoms in autism, disruptive

behaviors, and other schizoaffective disorders. Within the past century, a startling trend has

emerged with mentally ill patients experiencing diabetic related adverse events. The research

design of this paper is an integrative review. The search for literature was conducted using the

computer based search engine PubMed. The search yielded 1,149 research articles and 5 met

inclusion criteria. The results and findings of the five articles clearly display strong evidence of

diabetic related occurrences with the use of atypical antipsychotics. Evidence of the use of all

antipsychotics, to include conventional antipsychotics, wasnt significant in suggesting an

association with diabetic related occurrences. Limitations to the review included the students

lack of experience, knowledge deficiency in design methods used to evaluate drug-event

associations, and limits on the allowed number of articles to conduct the review. Future research

should focus on examining the exact underlying cause of the metabolic abnormalities that

subsequently provoke diabetic related adverse events. Since the atypical antipsychotics clozapine

and olanzapine were shown consistently to have highest associations with the occurrence of

multiple diabetic related events, focused examination specifically on these drugs should be

conducted to help better understand the factors that encompass this issue.
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Integrated Review

This integrative review was conducted in an effort to examine the existing literature on

the topic of antipsychotics and their potential association with diabetic related adverse events.

Recent statistics illicit data that the risks of diabetes is two to three times greater in patients with

psychiatric disorders such as schizophrenia, bipolar disorder, and other schizoaffective disorders

when compared with the general public (Baker et al., 2009). The use of antipsychotics for

treatment of these disorders is believed to be the cause of the diabetic related adverse events.

Close attention to the literature on this topic is essential in determining different variables that

exist within these medications and diabetes. Antipsychotic medications are an essential part of

the treatment regimen for patients with psychiatric disorders such as schizophrenia. If there is an

issue with the medications that subsequently affect other aspects of the clients physical health,

then the new-found facts should be concrete and stated. If the risks are too great and the drugs

are too highly associated with potentially deadly diabetic related adverse events, then they should

be redeveloped to take out the kinks so that they are safer for widespread use. Dealing with

schizophrenia, bipolar disorder, and other schizoaffective disorders is already a very difficult

health matter to maintain, adding other complications to that could heighten the disease pattern

and make the individuals circumstances intolerable. Therefore, the proposed PICO question is as

follows: In individuals with mental illness, does the use of antipsychotics contribute to diabetic

related health issues.

Design and Search Methods

This integrative review encompasses information from the analysis of five research

articles. The articles were discovered through the use of the computer based search engine

PubMed. Key search terms included, antipsychotics, diabetes, risk factors, glycemic
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disorders, and adverse events. Different variations of the search terms yielded over 1,000

results, indicating an abundance of research on the topic. Much of the results consisted of articles

that addressed the topic in certain populations such as pregnant women and children. This

failed to address the generalized PICO question which states all individuals with mental

illnesses. To make the search more specific, the PICO question, In individuals with mental

illness, does the use of antipsychotics contribute to diabetic related health issues, was reviewed

again and the words antipsychotics, diabetes, glycemic disorders, and adverse events were

all used in the search bar. From this, the article Antipsychotics, Glycemic Disorders, and Life-

threatening diabetic events: a Bayesian data-mining analysis of the FDA adverse event reporting

system (1968-2004) was used and because it addressed the PICO question so well, the similar

articles section was consistently used as a gateway to gather the remaining articles. To narrow

the articles down to the five that were most significant to addressing the PICO question, the

inclusion criteria consisted of topic specificity, researchers with doctoral degrees, methods within

the abstracts that appeared to be most reliable and thorough, and/or articles that were current.

Findings/Results

The findings and results of the five reviewed studies display strong evidence that atypical

antipsychotics are associated with diabetes mellitus and other diabetic related adverse events

(Baker et al., 2009; Dumouchel et al., 2008; Kato et al., 2015; Nielsen et al., 2014; & Sernyak,

Leslie, Alarcon, Losonczy, & Rosenheck, 2002). Evaluation of these five research articles is

summarized in Table 1. The review is structured according to the following categories:

association of atypical antipsychotics with diabetic related occurrences and analysis of the FDA

Adverse Event Reporting System.

Association of Atypical Antipsychotics with Diabetic Related Occurrences

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There was consensus among all 5 studies that a strong association existed with the use of

atypical antipsychotics and the onset of diabetic related occurrences (Baker et al., 2009;

Dumouchel et al., 2008; Kato et al., 2015; Nielsen et al., 2014; & Sernyak, Leslie, Alarcon,

Losonczy, & Rosenheck, 2002). The 5 quantitative studies analyzed specific databases that

encompassed patients with psychiatric disorders taking antipsychotics to measure association

with diabetic related adverse events. Diabetic related adverse events is recognized as an umbrella

term within this topic and includes reports on metabolic syndrome, the development of diabetes

mellitus, hyperglycemic occurrences, diabetic ketoacidosis, diabetic coma, and many other

metabolic issues related to glycemic abnormalities within the human body. In the association

analysis conducted by Sernyak et al. (2002), schizophrenic patients who were treated with

typical and atypical antipsychotics in the Veterans Health Administration of the Department of

Veterans Affairs (VA) were examined using multiple logistics regression. The purpose of this was

to compare atypical to typical antipsychotics to see if one was more associated with the

development of diabetes mellitus. Utilizing an association strength sampling method, 38,632

patients with schizophrenia were categorized according to age, sex, income level, distance to

nearest VA hospital, comorbid diagnosis, VA service connected disability, and days hospitalized

in the previous year. All these variables were controlled when selecting the sample. For instance,

the variable distance to nearest VA hospital specifically consisted of people who were within

closer proximity to a VA hospital. This was implemented with the assumption that those

individuals had greater ease of access to a hospital to receive a diagnosis of diabetes mellitus, as

greater access to health care leads to a greater chance of picking up on a diagnosis (Sernyak et

al., 2002). The VA drug benefit management system kept record for all the medications the

patients were taken and this accompanied with VA workload databases, which had the patients
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diagnoses, were where the data was collected from. Patients receiving atypical antipsychotics

were 9 % more likely to have diabetes than those who received typical, also known as

conventional antipsychotics. Values were significant in patients less than 40 years old. The

unique approach in including people with varying demographics and other personalized

characteristics contributes to the body of literature by displaying significant associations with

diabetic related adverse events among all analyzed groups of patients taking atypical

antipsychotics.

In the nationwide twelve-year case control study conducted by Nielsen et al. (2014),

children and adolescent psychiatric patients taking antipsychotics were compared to patients not

taking antipsychotics regarding the occurrence of type 2 diabetes. The researchers aimed to

examine the issue in children and adolescents because they explained that there is far less

evidence supporting an association of antipsychotic use and diabetic related adverse events when

compared to adults (Nielsen et al., 2014). The method used was a longitudinal register linkage

case control study of diabetes in psychiatric patients in Denmark from January 1999 to June

2010. The sample included 48,299 patients under 18 years of age who had a psychiatric disorder,

with the exception of those who had eating disorders, fearing that the weight issues associated

with most eating disorders would yield inaccurate results in the study. Mental illnesses included

were substance abuse disorders, schizophrenia, behavioral disorders, emotional disorders, mental

retardation, psychologic development disorders, and mood disorders. The data was collected

from the Danish Psychiatric Central Research Register. Logistic and Cox regression analyses

were conducted, identifying type 2 diabetes diagnoses as the dependent variable, and use of

antipsychotics, sex, age, and psychiatric diagnoses as explanatory diagnoses. In addition, a post

hoc analyses which examined metformin treatment on type 2 diabetes was conducted. Other data
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analysis methods included exploratory analysis and statistical analyses. All analyses were 2 sided

with alpha set at 0.05. Significant data suggested more frequent type 2 diabetes onset in children

and adolescents taking antipsychotics who fit under the category of female and older age at

psychiatric diagnosis. Clozapine, an atypical antipsychotic, was shown consistently with highest

association to increased occurrence of diabetes. The inclusion of patients with all types of

psychiatric illnesses and the emphasis placed on significant association with clozapine and

diabetes contributes to the body of literature.

In the Bayesian signal detection analysis conducted by Baker et al. (2009), researchers

specifically evaluated the potential association between atypical antipsychotics and diabetic

related adverse events. The purpose of this was to add to already existing research on the topic

and determine if specific differences existed between atypical antipsychotics. Study methods

were categorized into data analysis from the US Food and Drug Administrations (FDA) Adverse

Event Database and drug analysis between the six atypical antipsychotics, clozapine, risperidone,

olanzapine, quetiapine, ziprasidone, and aripiprazole. Statistical analysis included systemic

disproportionality analysis, which they went on to explain is used to systematically gather

information from large drug safety databases. Examining specific atypical antipsychotics, as

these were the antipsychotics that much of the existing research suggested had highest

association with diabetic related adverse events, provided detailed data that suggested strongest

associations of diabetic related adverse events with atypical antipsychotics clozapine and

olanzapine. All of the examined atypical antipsychotics suggested significant association with

diabetic related adverse events and therefore contribute to the body of literature.

Dumouchel et al. (2008) conducted a very extensive study of the association between

diabetic related adverse events and use of different antipsychotics. The quantitative study
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collected data from the FDA Adverse Event Reporting System that spanned from the year 1968

to the year 2004. The sampling included analyzing seven antipsychotics, which included the

following: ziprasidone, aripiprazole, haloperidol, risperidone, quetiapine, clozapine, and

olanzapine in patients 45 and up compared to patients 45 and under who used the drugs and had

diabetic related adverse events occur. The study was very detailed in assessing specific diabetic

related events and listing them in their accordance with the medications in tables. The diabetic

related events included general hyperglycemia, impaired glucose tolerance, onset of diabetes

mellitus, diabetic coma, diabetic ketoacidosis, and abnormal blood glucose. Data was analyzed

using proportional reporting ratio (PRR), Bayes data-mining algorithm, also referred to as the

Multi-Item Gamma Poisson Shrinker in this article, and Logistic Regression (LR) analysis.

Association strengths and significance of diabetic adverse events and drugs varied greatly among

the different samples. By incorporating comprehensive sampling methods and employing

extensive collection and analysis methods to ensure validity and reliability while suggesting that

there is a strong association with specific atypical antipsychotics and the occurrence of diabetic

adverse events, the study greatly contributes to the body of literature.

The study conducted by Kato et al. (2015) aims to evaluate the relationship between

antipsychotic drugs and adverse hyperglycemic events using the FDA Adverse Event Reporting

System (FAERS) database from the year 2004 to March 2013. Sampling included 26

antipsychotic drugs associated with hyperglycemia. The reporting odds ratio (ROR) presented a

confidence interval of 95%, indicating signal strength with antipsychotic-induced adverse

hyperglycemic events. The study concluded that olanzapine and clozapine, both of which are

atypical antipsychotics, were highly associated with increased risk for type 2 diabetes. The study

goes further to explain evidence of polypharmacy with other antipsychotics dramatically

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increases the risks. The study also highlights an essential aspect regarding the topic which is that

the mechanisms to exactly how the hyperglycemia is occurring is not physiologically

understood; however, that atypical antipsychotics are highly associated with rapid weight gain,

and this in turn could be the cause of the new onsets of diabetic related events. Providing

information on these factors and generating hypotheses related to the topic contributes to the

body of literature.

Analysis of the FDA Adverse Event Reporting System

Three of the five research studies utilized data collected from the FDA Adverse Event

Reporting System (Baker et al., 2009, Dumouchel et al., 2008, Kato et al., 2015). Baker et al.

(2009) conducted a thorough study that aimed to evaluate an association between specific

atypical antipsychotics and diabetic related adverse events from data collected via the FDA

AERS database. This extensive database comprised 2.5 million general adverse events reported

from patients, healthcare workers, and pharmaceutical manufacturers. The database has a system

similar to a search engine called the Medical Dictionary for Regulatory Activities coding system

(MedDRA), in which specific adverse events can be narrowed down and examined per the

specific terms of interest. All six atypical antipsychotics examined had a significant association

with a diabetic related adverse event. The development of diabetes mellitus was noted as the

most common adverse event with a reported 2,784 cases. Hyperglycemia, and diabetic

ketoacidosis also had frequent reports for individuals taking atypical antipsychotics with 1,347

cases and 782 cases respectively. Statistical analysis of the drug-event reports was utilized to

indicate a potential signal. By providing focused analysis of atypical antipsychotics and

subsequent diabetic events while displaying evidence of differential associations, the study

greatly contributes to the body of literature.

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Domouchel et al. (2008) conducted a very comprehensive study utilizing Bayesian data-

mining analysis of the FDA Adverse event reporting system from the year 1968 to 2004. The

substantial amount of time analyzed suited the concepts of quantitative research to provide a

generalized approach to the study. Extensive measures were taking to provide validity to the

study. The proportional reporting ratio (PRR), Multi-Item Gamma Poisson Shrinker, and Logistic

Regression (LR) analysis display strongest and most accurate numerical correlations, responses,

and predictors, which in this case create for the best methods to strengthen the probability of the

hypothesis. Diabetic events were also broken down to specific occurrences, such as diabetic

ketoacidosis compared to diabetic coma. Many studies analyzed by the researcher didnt go to

such lengths to examine the topic. This contributed to the body of literature by putting forth

strongest and most comprehensive research pertaining to the topic.

The study conducted by Kato et al. (2015) examined data from the FDA Adverse Event

Reporting System utilizing Bayesian analysis starting from the year 2004 and ending in the year

2014. This was pertinent because it provided a more updated examination of the research on the

topic. Kato et al. (2015) explained that the FDA asked manufacturers of atypical antipsychotic

(AAP) drugs to add a warning to drug labels regarding the increased risk of hyperglycemia and

diabetes in 2004. The significance in the findings from the study was the discovery that

polypharmacy created significantly higher chances of diabetic related adverse events occurring.

The study explains the essentialness in understanding this finding because it is noted that

polypharmacy is suggested after failure of antipsychotic monotherapy (Kato et al., 2015).

Sampling included 26 antipsychotics that were examined in association with patients in the

FAERS who had an occurrence of diabetic related adverse events. The ROR of the three-drug

polypharmacy had the highest value for every antipsychotic. By displaying evidence of an
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association between atypical antipsychotics, suggesting that antipsychotic polypharmacy may

influence adverse hyperglycemic events, and explaining that clinicians should monitor for

adverse polypharmacy induced hyperglycemic events, the study greatly contributes to the body

of literature.

Discussion/Implications

The findings of the integrative review address the effects of antipsychotics on patients

with mental illnesses to determine an association with the occurrence of diabetic related adverse

events. Therefore, the review findings relate to and support the proposed PICO question. The

PICO question specifically asked in individuals with mental illness, does the use of

antipsychotics contribute to diabetic related health issues? Consistent and substantial

differences exist between diabetic related adverse events and antipsychotic use. Atypical

antipsychotics were statistically significant regarding diabetic events across all results. A trend

emerged that listed the drug clozapine as either the highest associated, or at least, second highest

associated drug with diabetic related adverse events in all studies (Baker et al., 2009; Dumouchel

et al., 2008; Kato et al., 2015; Nielsen et al., 2014; & Sernyak et al., 2002). Two of the studies

utilized types of Bayesian analysis methods of gathering data (Baker et al., 2009, Dumouchel et

al., 2015). Such methods utilize empirical means to identify confidence intervals that exists in

reports from general populations to add validity to hypotheses. All five quantitative studies

utilized some form of logarithmic reasoning to deduce trends from the extensive databases the

data was collected from. Databases served as the sole source of data collection across the five

studies, as this was the primary way to evaluate large quantities of patients to generalize drug-

event trends. With the use of three different databases, with one of those being out of the country
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in Denmark, all sources identify a strong association with atypical antipsychotics and diabetic

related adverse events.

The implications of the findings suggest the potential public health efforts to recognize

atypical antipsychotics as being highly associated with the occurrence of multiple and various

diabetic related adverse events. Atypical antipsychotics are a newer generation of antipsychotics

when compared to other antipsychotics prescribed historically. Atypical antipsychotics have

shown great efficacy in treating antipsychotics, with fewer extrapyramidal side effects when

compared to other antipsychotics. However, their use has been identified with rapid weight gain

and metabolic issues as primary side effects, and this in turn could be responsible for the strong

evidence suggesting an association with diabetic related adverse events. Some efforts have been

made to provide press coverage on the issue and mandate class label warnings on the package

inserts (Dumochel et al., 2008). Further widespread insight on the potential diabetic related

occurrences associated with use of the drugs affords researchers the opportunity to address a

growing issue among patients with mental illnesses who wish to benefit from the rewards of the

newer generation antipsychotics that have proven to be very effective in treating psychiatric

symptoms with the exception of the occurrence of diabetic related events. Metabolic monitoring

of patients who receive atypical antipsychotics for signs and symptoms of diabetes mellitus,

hyperglycemia, and other adverse diabetic occurrences must be in place.

Limitations

There are few limitations acknowledged in regards to this integrative review. The

researcher of the integrative review does not have experience in completing integrative reviews.

Much of the information on the details that encompass the methods used require in depth

understanding that goes beyond the educational objectives of the researchers undergraduate
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nursing research class. The fact that all research from all articles was solely limited to data

collected from databases served as a limitation among the studies. Many artifacts can exist

within databases, as pointed out by (Dumouchel et al., 2008). Precise measures are required to

keep studies as free from artifacts as possible to provide reliable data. The other issue with

collecting data solely from databases is that they show inconsistencies when it comes to drug-

event associations with duration of drug exposure. Dumouchel et al. (2008) explains that if the

event of concern develops only after a patient has been on a specific drug, then there will be less

evidence of an association with newer drugs. Lastly, only 1 to 10 percent of adverse events are

ever reported to the AERS database which could alter conclusions drawn from the unique

characteristics that provide the specific basis for data analyzed in certain studies.

Conclusion

The findings of this integrative review substantiate the need for recognizing that there is strong

evidence suggesting an association with the use of atypical antipsychotics and the occurrence of

diabetic related adverse events. Clozapine and olanzapine in particular displayed consistently and

significantly larger reporting ratios then other atypical antipsychotics and typical antipsychotics

in all examined databases. Such differential reporting ratios require the need for further research

on the issue to provide clarity on the specifics of how and why this is occurring. Despite clear

evidence suggesting an association of atypical antipsychotics and diabetic related adverse events,

it is unclear what the physiological mechanism exactly is. Baker et al. (2009) hypothesizes that

the rapid weight gain associated with use of atypical antipsychotics is the culprit, as rapid weight

gain could lead to insulin resistance. Introduction of atypical antipsychotics has been proven to

be very effective in reducing the classical extrapyramidal symptoms associated with many of the

antipsychotics on the market prior. However, reporting trends that are suggestive of an
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association between atypical antipsychotics and diabetic related adverse events should inspire

practitioners to evaluate the risks/benefit ratio of the drug. The general premise of medication

administration operates on a risk/reward system. Although atypical antipsychotics have been

shown to be the most effective types of antipsychotics in treating psychiatric symptoms, the

occurrence of adverse diabetic events such as diabetic coma and abnormal glycemic related

deaths place the risks far higher than the rewards. Practitioners and patients should be fully

aware of these potentially deadly consequences. Prevention strategies such as metabolic

monitoring should be implemented when the need for atypical antipsychotics is absolutely

necessary.
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References

Baker, R., Pikalov. A., Tran, Q., Kremenets, T., Arani, R., Doraiswamy, M. (2009). Atypical

antipsychotic drugs and diabetes mellitus in the US Food and Drug Administration

Adverse Event database: a systematic Bayesian signal detection analysis.

Psychopharmacology Bulletin, 42 (1), 1-21. Retrieved from:

https://www.ncbi.nlm.nih.gov/pubmed/19204649

Cronin, P., Ryan, F., Coughlan, M. (2008). Undertaking a literature review: a step-by-step

approach. British Journal of Nursing, 17(1), 39-43. Retrieved from:

https://www.ncbi.nlm.nih.gov/pubmed/18399395

Dumouchel, W., Fram, D., Yang, X., Mahmoud, R., Grogg, A., Engelhart, L., Ramaswamy, K.,

(2008). Antipsychotics, glycemic disorders, and life-threatening diabetic events: a

Bayesian data-mining analysis of the FDA adverse event reporting system (1968-2004).

Annals of Clinical Psychiatry, 20(1), 21-31. doi: 10.1080/10401230701844612

Kato, Y., Umetsu, R., Abe, J., Ueda, N., Nakayama, Y., Kinosada, Y., Nakamura, M. (2015).

Hyperglycemic adverse events following antipsychotic drug administration in

spontaneous adverse event reports. Journal of Pharmaceutical Health Care and Sciences,

1 (15). Retrieved from: https://www.ncbi.nlm.nih.gov/pubmed/26819726

Nielsen, R., Laursen, M., Vernal, D., Bisgaard, C., Jakobsen, H., Steinhauseri, H., & Correll, C.

(2014). Risk of Diabetes in Children and Adolescents Exposed to Antipsychotics: A

Nationwide 12 Year Case-Control Study. Journal of The American Academy of Child and

Adolescent Psychiatry, 53 (9), 971-978. Retrieved from:

https://www.ncbi.nlm.nih.gov/pubmed/25151420
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Sernyak, M., Leslie, D., Alarcon, R., Losonczy, M., Rosenheck, R. (2002). Association of

Diabetes Mellitus With Use of Atypical Neuroleptics in the Treatment of Schizophrenia.

American Journal of Psychiatry, 159 (4), 561-566. Retrieved from:

https://www.ncbi.nlm.nih.gov/pubmed/11925293
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NUR 4122: Nursing Research

Table of Evidence

Association of Antipsychotics and Diabetic Related Adverse Events

First Author Baker (2009) PhD, MBA. Associate Director of

(Year)/Qualifications
Background/Problem
Statement
Neuroscience, Bristol-Myers Squibb. Princeton, NJ, USA
Existing research on antipsychotic-induced diabetic related
adverse events varies between certain atypical antipsychotics.
Researchers wanted to evaluate these variations to determine
potential associations between the examined atypical
antipsychotics.

Conceptual/theoretica Not discussed.

l Framework

Design/ Quantitative Experimental

Method/Philosophical Data pertaining to diabetic adverse events extracted from the
Underpinnings FDAs Adverse Event Database.
Examining drug-event associations between the six atypical
antipsychotics, clozapine, risperidone, olanzapine, quetiapine,
ziprasidone, and aripiprazole
Sample/ 8,032 cases extracted from the FDAs Adverse Event Database
Setting/Ethical under the category of diabetic related adverse events for
Considerations individuals receiving atypical antipsychotics.
Database consisting of spontaneous reports submitted by
patients, healthcare professionals, and pharmaceutical
manufacturers.
Ethical considerations were not discussed in this article.
Major Variables Clozapine, risperidone, olanzapine, quetiapine, ziprasidone,
Studied (and their and aripiprazole, all of which are atypical antipsychotics.
definition), if Diabetic related adverse events, to include diabetes mellitus,
appropriate hyperglycemia, diabetic ketoacidosis, increased blood
glucose, diabetic coma, glycosuria, and variations of these
categories.
Measurement Medical Dictionary for Regulatory Activities coding system to
Tool/Data Collection narrow down and measure the diabetic related adverse events
Method and allow for assessment of association with atypical agents.
Data collected from FDAs adverse event reporting system.

Data Analysis Statistical analysis - Systematic disproportionality analysis,

which extracts information from large drug-safety databases.
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Logistic regression analysis. Multi-item Gamma Poisson

Shrinker data mining algorithm.

Findings/Discussion All six atypical antipsychotics examined had a significant

association with a diabetic related adverse event.
The development of diabetes mellitus was noted as the most
common adverse event with a reported 2,784 cases.
Hyperglycemia, and diabetic ketoacidosis also had frequent
reports for individuals taking atypical antipsychotics with
1,347 cases and 782 cases respectively.

Appraisal/Worth to Results suggest differential associations with use of atypical

practice antipsychotics and subsequent diabetic events.
Awareness of atypical antipsychotic-event associations could
be practiced among healthcare practitioners to ensure patients
fully understand risks.
Risk/benefits ratios should be carefully considered when
prescribing atypical antipsychotics, especially in terms of
patients with certain metabolic abnormalities/risks.

First Author Dumouchel (2008) PhD. Lincoln Technologies Inc.

(Year)/Qualifications Waltham, Massachusetts, USA.
Background/Problem There is an increasing amount of diabetic related adverse
Statement events seen in patients with mental health illnesses taking
atypical antipsychotics.
The authors explain that the statistics regarding this issue are
increasing so much that in the year 2003, press coverage over
the issue prompted the FDA to add class label warnings to
the package inserts for all atypical antipsychotic drugs
available in the United States (Dumouchel et al., 2008).

Conceptual/theoretica Not discussed.

l Framework

Design/ This quantitative analysis aims to examine diabetic associated

Method/Philosophical adverse events in relation to the use of different antipsychotic
Underpinnings medications under the US Food and Drug Administrations
(FDA) Adverse Event Reporting System.
The researchers assessed trends among certain antipsychotics
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and further investigated the hypothesis that atypical

antipsychotics are associated with diabetic adverse events by
using Bayesian analysis to examine the previous data in the
AERS database from the year 1968 through 2004.
Sample/ Tables were included on the seven antipsychotics that were
Setting/Ethical analyzed. These included the drugs aripiprazole, clozapine,
Considerations haloperidol, olanzapine, quetiapine, risperidone, and
ziprasidone.
Patients age 45 and up were compared to patients 45 and
under who used antipsychotics and had diabetic related
adverse events occur
Researchers failed to mention anything in regards to
protecting human subjects from harm. There was no mention
of IRB approval.
Major Variables The specific drugs aripiprazole, clozapine, haloperidol,
Studied (and their olanzapine, quetiapine, risperidone, and ziprasidone were
definition), if examined to determine association strength.
appropriate Quantitative measures of association strength between drugs
and adverse events examined were computed and graphed.
Measurement 14 Medical Dictionary for Regulatories Activities (MedDRA)
Tool/Data Collection Primary Terms were chosen to identify diabetic related
Method adverse events in the FDAs Adverse Event Reporting System.
Information in the FDAs Adverse Event Reporting System
spanning from the year 1968 through 2004 was examined.

Data Analysis Proportional reporting ratio, Bayes data-mining algorithm,

also referred to as the Multi-Item Gamma Poisson Shrinker in
this article, and Logistic Regression analysis

Findings/Discussion This study found that there were large, consistent, and
statistically significant differences in association strength with
glycemic related adverse events for people on the seven
different antipsychotic agents examined.
Clozapine and olanzapine carried greater risks of developing
diabetic related adverse events such as diabetes mellitus or
diabetic ketoacidosis when compared to other antipsychotics.

Appraisal/Worth to The results in this study showed greater accuracy in increasing

practice probability of certain drugs being more strongly correlated
with diabetic related adverse events when compared to most
studies due to the efforts undertaken to eliminate artifacts
(inaccurate information) within the extensive database in
addition to the keen data analysis methods utilized.
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More studies should be conducted to continue hypothesis

generation to fully understand the basis of the issue now that
extensive evidence suggesting drug-event association actually
exists.

First Author Kato (2015). Laboratory of Drug Informatics, Gifu

(Year)/Qualifications Pharmaceutical University, Gifu, Japan
Background/Problem As antipsychotics are used to treat schizophrenia and bipolar
Statement disorder, they are shown to have increased association with
the occurrence of diabetic adverse events.
Since antipsychotic polypharmacy is suggested if
antipsychotic monotherapy is ineffective multiple
antipsychotic drugs are frequently prescribed by practitioners.
Previous literature on the topic demonstrated the effects of
antipsychotic polypharmacy on the occurrence of diabetic
adverse events; however, the specific effect of antipsychotic
polypharmacy on hyperglycemia is not fully clear.
The FDA asked manufacturers of atypical antipsychotics to
add a warning to drug labels regarding the increased risk of
hyperglycemia and diabetes in 2004.

Conceptual/theoretica Not discussed.

l Framework

Design/ Quantitative
Method/Philosophical Cohort study
Underpinnings This study aims to evaluate the relationship between
antipsychotic drugs and adverse hyperglycemic events using
the FDA Adverse Event Reporting System (FAERS) database
from the year 2004 to March 2013.
Sample/ 241,478 cases of adverse hyperglycemic events were extracted
Setting/Ethical from FAERS database coded according to the terminology
Considerations preferred by the Medical Dictionary for Regulatory Activities
(MedDRA).
26 antipsychotic agents were examined and the ones with
greatest association strengths were determined to be
quetiapine, olanzapine, risperidone, aripiprazole, haloperidol,
clozapine, prochlorperazine, and chlorpromazine.
Ethical considerations were not discussed in this article.
Major Variables Characteristics of antipsychotics in the FDA adverse event
Studied (and their reporting system database
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definition), if Evaluate the effect of antipsychotic polypharmacy on adverse

appropriate hyperglycemic events using the FAERS database

Measurement Data was collected from the FDA Adverse Event Reporting
Tool/Data Collection System (FAERS)
Method The medication database DrugBank, was utilized as a
dictionary for the batch conversion and compilation of drug
names
MedDRA was used to narrow in on specific diabetic events, to
include hyperglycemia and new onset diabetes mellitus.
Tables consisting of Characteristics of antipsychotics, generic
names, and hyperglycemia were put into place to measure
associations.

Data Analysis Reporting ratios were analyzed based on administration

(monotherapy, two-drug combination, and three-drug
combination).
Disproportionality analysis
A two by two contingency table for analysis to calculate
reporting odds ratio was established.

Findings/Discussion The study concluded that olanzapine and clozapine, both of

which are atypical antipsychotics, were most associated with
increased risk for type 2 diabetes.
The study also suggests evidence of polypharmacy with other
antipsychotics dramatically increases the risks of
hyperglycemia.
Reporting ratios increased with increasing number of drugs
administered. The ROR of the three-drug polypharmacy had
the highest value for every antipsychotic. Therefore,
antipsychotic-induced adverse hyperglycemic events may be
influenced by the number of drugs administered.

Appraisal/Worth to The reporting ratios suggested an association between

practice antipsychotic drugs and hyperglycemic adverse events, and
the reporting ratio was increased with an increase in the
number of co-administered antipsychotic drugs. Clinicians
should monitor for adverse polypharmacy-induced
hyperglycemic events.
The study indicates the importance of comparing drug safety
profiles using post-marketing real-world data. This
information could be useful to improve schizophrenia and
INTEGRATED REVIEW 22

bipolar disorder management

Further epidemiological studies should be conducted to
determine the true risk of adverse hyperglycemic events.

First Author Nielsen (2014) M.D., PhD. Psychiatry, Aalborg University

(Year)/Qualifications Hospital. Aalborg, Denmark.
Background/Problem Use of atypical antipsychotics for psychiatric disorders in
Statement children and adolescents has increased within recent years.
Very little literature has been done on this patient population
compared to that of adults and it hasnt been significantly
clear what the relationships and associations for this age group
are.
In this study children and adolescent psychiatric patients
taking antipsychotics were compared to patients not taking
antipsychotics regarding the occurrence of type 2 diabetes

Conceptual/theoretica Not discussed.

l Framework

Design/ Quantitative experimental

Method/Philosophical Longitudinal register linkage case-control study of diabetes in
Underpinnings all psychiatric patients less than age 18 in the country
Denmark from the year 1999 to June 30th, 2010.
The study focused on patients in a hospital setting under the
age of 18 with a diagnosis of diabetes who were not exposed
to antipsychotics compared to those who were exposed.
Since the non-exposed group was younger at age of
psychiatric diagnoses, had far fewer females, and wasnt
diagnostically balanced with the exposed group, regression
analyses was conducted to adjust groups appropriately.
Sample/ The sample included 48,299 patients under 18 years of age
Setting/Ethical who had a psychiatric disorder according to ICD-10 criteria,
Considerations with the exception of those who had eating disorders.
All children and adolescent psychiatric patients diagnosed
with type 2 diabetes in a hospital based setting.
The Danish Data Protection Agency, National Board of
Health, and Statistics Denmark approved the use of data for
the study.
Major Variables Children and adolescents diagnosed with diabetes and a
Studied (and their psychiatric disorder who received antipsychotics versus those
definition), if who didnt receive antipsychotics.
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appropriate Inclusion criteria for studied demography consisted of age,

sex, and specific diagnoses, which included, substance abuse
disorders, schizophrenia, behavioral disorders, emotional
disorders, mental retardation, psychological development
disorders, and mood disorders.
Measurement Data on psychiatric diagnoses were extracted from the Danish
Tool/Data Collection Psychiatric Central Research Register, a system that contains
Method diagnostic data on all psychiatric inpatients and outpatients in
Denmark.
Medication data was extracted from the Danish Prescription
Database, a system that contains all prescription based
medications picked up from pharmacies in Denmark since the
year 1997.

Data Analysis Logistic regression and Cox regression analyses were

conducted with type 2 diabetes as the dependent variable and
antipsychotic drug exposure, sex, age, and psychiatric
diagnosis as explanatory variable.
Post hoc analyses was conducted to examine the effects of
metformin in patients taking this drug to control type 2
diabetes as this could alter results.
Exploratory analysis to compare type 2 diabetes within
individual antipsychotics.
Statistical analyses was conducted with STATA 12 on a
Statistics Denmark server with alpha set at 0.05.

Findings/Discussion Significant data suggested more frequent type 2 diabetes onset

in children and adolescents taking antipsychotics who fit
under the category of female and older age at psychiatric
diagnosis.
Clozapine, an atypical antipsychotic, was shown consistently
with highest association to increased diabetic occurrences.

Appraisal/Worth to Antipsychotic treatment, female sex, and older age at

practice psychiatric diagnosis was significantly associated with type 2
diabetes onset. These characteristics should be considered
carefully when prescribing these medications.
Strict cardiometabolic monitoring should be done on a routine
bases for any patient receiving an antipsychotic medication,
with very strict indications for atypical antipsychotics.
INTEGRATED REVIEW 24

First Author Sernyak (2002) M.D. Psychiatry Services, VA Connecticut

(Year)/Qualifications Healthcare System, West Haven Campus. West Haven, CT.
Background/Problem Use of Atypical antipsychotics to treat schizophrenia has been
Statement associated with weight gain, exacerbation of previously well
controlled diabetes, and onset of type 1 and type 2 diabetes
mellitus.
The purpose of this study was to compare atypical to typical
antipsychotics to see if one was more associated with the
development of diabetes mellitus.

Conceptual/theoretica Not discussed

l Framework

Design/ Quantitative experimental

Method/Philosophical Patients with schizophrenia in the Veteran Affairs
Underpinnings administrative database who were treated with typical and
atypical antipsychotics over the span of 4 months in the year
1999 were studied under ICD-9 code diabetes mellitus.
Characteristics to categorize individuality among the sample
of patients were put into place.
Sample/ Utilizing an association strength sampling method, 38,632
Setting/Ethical patients with schizophrenia were categorized according to age,
Considerations sex, income level, distance to nearest VA hospital, comorbid
diagnosis, VA service connected disability, and days
hospitalized in the previous year. Of the patients, 15,984 of
them received typical antipsychotics, and 22,648 of them
received atypical antipsychotics.
Data determining at least two outpatient encounters in a
specialty mental health outpatient clinic.
Ethical considerations were not discussed in this article.
Major Variables Patients with schizophrenia receiving typical antipsychotics
Studied (and their vs. atypical antipsychotics.
definition), if The atypical agents studied were Clozapine, Olanzapine,
appropriate Quetiapine, and Risperidone.
Demographic characteristics were studied also. This included
to age, sex, income level, distance to nearest VA hospital,
comorbid diagnosis, VA service connected disability, and days
hospitalized in the previous year
Measurement Medical records from the VA Drug Benefit Management
Tool/Data Collection System and Veterans Health Administration database were
Method reviewed over the span of four months in the year 1999.
Data from the American Hospital Association annual survey to
determine distance to nearest hospital.
The prevalence of diabetes mellitus was examined.
INTEGRATED REVIEW 25

Data Analysis Chi square tests to compare the percentage of patients with
diabetes receiving typical vs atypical antipsychotics.
Logistic regression analysis to calculate odds ratios for the
association of atypical neuroleptic prescription and the
diagnosis of diabetes within each of the age strata, controlling
for the effects of the demographic, diagnostic, and treatment
factors.
Data analysis was reanalyzed for each individual drug
assessed.

Findings/Discussion Patients receiving atypical neuroleptics were 9 % more likely

to have diabetes than those who received typical neuroleptics.
Values were highly significant in patients less than 40 years
old in terms of the development of diabetes mellitus.

Appraisal/Worth to On a national level with a very large group of patient

practice sampling, use of atypical antipsychotics was significantly
associated with diabetes mellitus.
Practitioners should prescribe typical antipsychotics when
patient conditions warrant.
If patient has metabolic risk factors that contribute to diabetes,
strong consideration should be in place to determine adequate
and safe risk/benefit ratios.
Public health prevention measures should be in place.
All patients who receive atypical antipsychotics should
undergo regular monitoring for signs and symptoms of the
development of diabetes mellitus.