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Hindawi Publishing Corporation

International Journal of Endocrinology
Volume 2015, Article ID 969182, 8 pages

Review Article
An Overview of Diabetes Management in
Schizophrenia Patients: Office Based Strategies for
Primary Care Practitioners and Endocrinologists

Aniyizhai Annamalai1 and Cenk Tek2
Departments of Psychiatry and Internal Medicine, Yale School of Medicine, 34 Park Street, New Haven, CT 06519, USA
Department of Psychiatry, Yale School of Medicine, 34 Park Street, New Haven, CT 06519, USA

Correspondence should be addressed to Aniyizhai Annamalai;

Received 5 January 2015; Revised 11 March 2015; Accepted 12 March 2015

Academic Editor: Kazuhiro Shiizaki

Copyright © 2015 A. Annamalai and C. Tek. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly

Diabetes is common and seen in one in five patients with schizophrenia. It is more prevalent than in the general population
and contributes to the increased morbidity and shortened lifespan seen in this population. However, screening and treatment
for diabetes and other metabolic conditions remain poor for these patients. Multiple factors including genetic risk, neurobiologic
mechanisms, psychotropic medications, and environmental factors contribute to the increased prevalence of diabetes. Primary
care physicians should be aware of adverse effects of psychotropic medications that can cause or exacerbate diabetes and its
complications. Management of diabetes requires physicians to tailor treatment recommendations to address special needs of this
population. In addition to behavioral interventions, medications such as metformin have shown promise in attenuating weight
loss and preventing hyperglycemia in those patients being treated with antipsychotic medications. Targeted diabetes prevention
and treatment is critical in patients with schizophrenia and evidence-based interventions should be considered early in the course
of treatment. This paper reviews the prevalence, etiology, and treatment of diabetes in schizophrenia and outlines office based
interventions for physicians treating this vulnerable population.

1. Introduction with schizophrenia and other mental illness [4], but also are
associated with poor psychiatric and functional outcomes [5].
People with schizophrenia have an increased risk of diabetes For many people with schizophrenia and other serious
and other metabolic abnormalities. A renewed interest in mental illness, the mental health center is the primary point of
this phenomenon has been sparked by the adverse metabolic contact with the health care system [6]. But there are multiple
effects of antipsychotic medications used in the treatment
barriers to adequate screening and treatment at the mental
of schizophrenia. It is now well established that people with
health centers [7]. Referrals to community medical providers
serious mental illness (SMI), including schizophrenia, have
are challenging, in part due to administrative barriers, lack
excess morbidity and mortality leading to a reduced lifespan
of 20–25 years compared with the rest of the population [1, 2]. of communication between mental health and primary care
The increased mortality is largely attributable to physical practitioners and clinics, and also poor patient experience in
illness, including metabolic abnormalities and cardiovascular medical settings. For patients with schizophrenia, psychiatric
disease, rather than factors that are directly associated with symptoms and cognitive deficits limit their social functioning
psychiatric illness such as suicide or homicide. Metabolic and a fast paced medical health care environment is difficult
syndrome occurs in one in three patients and diabetes in one to navigate. In one survey, these patients cited continuity of
in five patients [3]. These abnormalities not only confer an care and listening skills as qualities important in medical
elevated cardiovascular risk and increased mortality in those practitioners [8, 9].

4%. possibly aggravated by pharmacological effects of some These agents are now known to contribute significantly to antipsychotics [16]. though there are variations A large number of patients with schizophrenia and other in magnitude of risk between individual agents [10]. ulation and estimates of prevalence range from 10 to 15% [14]. targeted education. treatment [12]. metabolic risk in schizophrenia patients is conferred by Metabolic syndrome was seen in more than 40% of patients. susceptibility to both diabetes and schizophrenia has been Diabetes prevalence was 4-5 times higher within each age postulated based on the observation that diabetes is more group. This. The difference in diabetes prevalence between those common in family members of those with schizophrenia with schizophrenia and the general population rose linearly [22]. Interestingly. Antipsychotics are a cornerstone of the increase in prevalence with age is the same as the general treatment in those with schizophrenia.2% in has been suggested. Genetic Susceptibility to Diabetes. The following sections review briefly some mechanisms pos- The prevalence of diabetes in schizophrenia has been tulated to explain the association of diabetes with schizophre- estimated to be 2-3-fold higher than in the general pop- nia. social interventions. population. and other metabolic syndrome is higher in those with schizophrenia. A common genetic linkage between the two diseases with age from 1.5% and hyperglycemia at agents [20]. These rates were much lower when com- effectiveness of different antipsychotic medications in over pared with people with chronic schizophrenia established 1400 patients with schizophrenia. if not all.2 International Journal of Endocrinology Patients with SMI are usually on treatments that include the 55–65 age group. schizophrenia had an elevated fasting glucose (>100 mg/dl) In spite of increased awareness among mental health [17]. Skills of primary care such as empathic listening. largely due to medical illnesses. There is debate about the degree of contribution of patients with schizophrenia. A meta- There is also evidence that antipsychotics increase analysis of several studies comprising over 25. respectively. 11]. A recent comparative meta-analysis of metabolic 19% [3]. genetics and environmental factors to development of dia- betes. the study also examined physical health indicators. been a tremendous increase in use of these medications [9]. A common inherited was 6. examined the eral population [21]. obesity and metabolic syndrome. has not of treatment seen in the CATIE study. and care coordination with mental health providers for over a century. narrowed [13]. Increased awareness 3. This would imply that most. Etiology of Development of among medical providers of the high medical morbidity and Diabetes in Schizophrenia mortality in schizophrenia is critical. antipsychotic agents. the Clinical Antipsychotic Tri- with schizophrenia showed a comparable rate with the gen- als of Intervention Effectiveness (CATIE). first episode schizophrenia show impaired glucose tolerance and higher insulin resistance compared to healthy The rate of metabolic syndrome and diabetes in patients with cohorts [19]. schizophrenia and diagnosed diabetes reported not receiving The mortality gap between this patient group and the rest any antihyperglycemics. The rates of treatment were low.084 patients schizophrenia. Prevalence of Diabetes Diagnosis and antipsychotics [18]. The relative study.3% and 23. This corroborates with the low rates of the population. Some authors report abnormal glucose . Primary care providers already have the specialized medical knowledge necessary to treat medical conditions in those with schizophrenia. Diabetes was seen in 11% of patients and fasting glucose levels As can be seen. long before the use of antipsychotic medi- all have the potential to significantly improve the health of cations.1. the outcomes. abnormalities among unmedicated and first episode patients A large multisite study. psychotherapy. the prevalence of diabetes and impaired glucose tolerance 3. even among those providers of the increased prevalence of metabolic syndrome with known diabetes. in the total sample [15]. continuity A link between schizophrenia and diabetes has been known of care. A national screening program of 10. while the prevalence of psychopharmacologic agents.000 patients metabolic risks. with second-generation agents showing dif- with schizophrenia and related disorders showed an overall ferentially higher risk over time compared to first generation rate of metabolic syndrome at 32. the data on the extent to which antipsy- >100 mg/dl were seen in more than 25% of patients in this chotics confer metabolic risk are conflicting. Some studies of people with antipsychotic Treatment in Schizophrenia naı̈ve. SMI receive their psychiatric care at specialized mental health along with the increased smoking rates seen in people with settings. A category of agents. results in an increased cardiovascular risk over several of these centers showed 37% of patients with and ultimately leads to worsened mortality rates [4. schizophrenia is higher than the general population. Rates of treatment for metabolic syndrome were low contributions of genetic susceptibility and antipsychotic with more than 30% of patients with diabetes not receiving treatment to increased prevalence of diabetes are uncertain. have been used schizophrenia is not solely secondary to metabolic syndrome since the early 1990s and in the last two decades there has but there may also be an inherent vulnerability to diabetes. In addition to psychiatric on medications. Epidemiological studies show an increased risk of devel- oping diabetes in people with schizophrenia with and without 2. This suggests that the development of diabetes in known as second-generation antipsychotics. rates of screening and treatment remain poor [12]. In a study of over 400 patients with schizophrenia. Approximately 40% of patients with in SMI.6% in the 15–25 age group to 19.

But the difference between the two (b) other proposed mechanisms: action on pancre- groups of agents was not significant when clozapine and atic muscarinic receptor and leptin resistance olanzapine were excluded from the analysis. Treatment of Diabetes in Schizophrenia ergic receptors [29]. As seen above. could play a role in preventing access to healthy lifestyles. and olanzapine are second-generation antipsychotics. The following is a summary of 3.4. class of antipsychotics are different [28]. dependent on tobacco [34] and this further increases risk for cardiovascular disease. also a second-generation agent. The metabolic effects on (b) nutritional deficiencies proposed as common glucose and insulin metabolism between agents within each pathway for both diseases [25–27]. Relationship between Diabetes and Schizophrenia neogenesis. pituitary axis and high serum cortisol levels in people with schizophrenia.2. In a large meta-analysis comprising 25. Elevated serum cortisol increases gluco.9% for risperidone [3]. For example. Some the proposed common pathways between the two disease studies have reported dysregulation of the hypothalamic conditions.International Journal of Endocrinology 3 metabolism and insulin signaling in the brain of those status. 4. serotonergic. schizophrenia and vitamin D may affect insulin response to (c) common mechanism proposed for cognitive glucose stimulation [26]. lower educational level. and social isolation [30. Gestational zinc deficiency has also deficit and glucose metabolism [23]. (ii) Neuroendocrine pathways: 3. Some authors have also implicated nutritional bers of schizophrenia patients [22]. It is hypothesized that the elevated cortisol also (i) Genetic susceptibility: increases serum leptin levels with a resultant increase in (a) higher occurrence of diabetes in family mem- appetite [24]. and cognitive deficits also of a common molecular mechanism underlying both cogni. Prevention of obesity is an important part of prevent- equate physical activity [30–33]. living situation (residential with schizophrenia [19. 31. dopaminer- medications [20]. Comprehensive programs to improve diet and that contribute to poor access to healthy lifestyle choices physical activity of people with schizophrenia and other in individuals with schizophrenia are lower socioeconomic mental illnesses have been shown to be effective for clinically . It is well known increased cardiovascular risk and mortality. Antipsychotics lead (a) hypothalamic axis dysregulation and elevated to weight gain and a higher risk of obesity related com. they are at risk not simply for diabetes but also for other metabolic conditions that lead to 3. insulin resistance. serotoninergic. illnesses have unhealthy lifestyles with poor diets and inad. Neuroendocrine Pathways Increasing Diabetes Risk. and histaminergic receptors fasting glucose was more frequent in those treated with the [29]. and histamin. factors in a common pathway for development of both diabetes and schizophrenia [25]. This places them at higher ing diabetes in schizophrenia patients as in the general risk of obesity and other metabolic complications. 28. been proposed as a possible mediator of a common etiologic pathway [27]. At the three-year follow-up. The first step in that patients with schizophrenia and other serious mental diabetes management is prevention. one (iv) Environmental: in five patients with schizophrenia had hyperglycemia. impaired gic. Both clozapine [29]. There is also a suggestion such as low motivation. Risperidone is 32]. anisms mediated by their effect on hypothalamic regulation and action on dopaminergic. tive deficits such as working memory and glucose metabolism Patients with schizophrenia are also much more likely to be [23]. Symptoms of schizophrenia diabetes in schizophrenia patients. 23]. Factors population. and 27. a low level (b) abnormal glucose metabolism in schizophrenia of vitamin D during childhood may be associated with patients [19. Nonmedication Environmental Factors. these patients.3. apathy. and symptoms of metabolic syndrome. See Table 1 for a to block the pancreatic muscarinic (M3) receptor. and social isolation.992 patients. Second-generation or atypical antipsychotics had three times the rate of new (iii) Antipsychotic medications: onset metabolic syndrome compared to first generation or typical or conventional antipsychotics after three years on (a) effect on hypothalamic regulation. second-generation agents. The resulting obesity is a risk for hyper- glycemia but antipsychotics can also directly cause diabetes.2% (a) poor diet and lack of access to quality foods [30– for olanzapine. the rate of metabolic syndrome was 51. cortisol in schizophrenia [24].9% for clozapine. plications including diabetes [20]. Antipsychotics and Risk of Diabetes. 33]. Developing effective treatment programs for diabetes care is One postulated mechanism is the ability of antipsychotics imperative for people with schizophrenia. Leptin summary of recommendations for diabetes management in resistance is another proposed mechanism. (b) inadequate physical activity due to symptoms These medications cause weight gain by multiple mech. 23]. Genes involved in both glucose settings and living in areas with abundance of fast food metabolism and cognitive function may increase the risk of facilities).

Most expert recommendations argue other metabolic complications. significant weight loss [35] as well as metabolic parameters. Refer patient to dental care to prevent gingivitis. Confer with psychiatrist to change to medication with lower weight gain Medication switch potential. Treatment adherence Communicate treatment plan to family and caregivers. HbA1c is preferable to fasting blood sugar. a fasting glucose level as a screening test. adherence and follow-up may be an issue and patients who failed other antipsychotics. fluphenazine. Comorbid illnesses obstructive sleep apnea. Refer patient to structured program for weight management as lifestyle Prevention interventions are proven to work.4 International Journal of Endocrinology Table 1: Special considerations for diabetes treatment in schizophrenia patients. exacerbate diabetes symptoms and sexual dysfunction from antipsychotics and antidepressants. Screen for and treat high prevalence conditions like tobacco dependence. and hypertension. it should A targeted approach to screening should be employed in be remembered that the metabolic abnormalities are not all patients. Psychotropic side effects that mimic or Psychotropic side effects include gastric slowing from anticholinergic agents. Surgical management Refer patient to bariatric surgery if eligible by weight criteria. Metformin is a promising agent as it has the potential treating psychiatrist when a patient with schizophrenia gains for modest weight loss and improves insulin sensitivity and . then Screening every 6–12 months. Perform screening frequently: every 3 months when staring antipsychotic. As described primary care site and the psychiatrist’s office. an antipsychotic agent with lower metabolic risks. Individual clinicians can and should be considered in all patients [39]. Treat wounds aggressively if skin breakdown is present. screening should be done at baseline and with schizophrenia and other psychotic disorders to prevent then at 3-month intervals. Diabetes care Address foot care at each visit as hygiene is often poor. Also. excessive weight or develops glucose intolerance. Tailor frequency of glucose self-monitoring to patient capability. While every attempt should be made to switch to high risk regardless of age and presence of other risk factors. if clinically feasible. Also higher in those on antipsychotics. Arrange home nursing services if available. Provide simplified recommendations as cognitive impairment may limit Patient education learning. Schedule longer medical visits. If the HbA1c levels remain stable. Risperidone and quetiapine for frequent monitoring of metabolic parameters in those are next in line in terms of likelihood of causing obesity and with schizophrenia [38]. Evidence has shown that intolerance and other metabolic abnormalities. found in patients treated with antipsychotic medications Primary care physicians should also confer with the [40]. Arrange frequent follow-ups as compliance is often poor. Set flexible target HbA1c goals as hypoglycemia from tight glucose control may be difficult to self-manage. but frequency of screening will need to be always reversible with cessation of the offending agent. clozapine and olanzapine are the antipsychotics most Another key strategy in preventing diabetes is periodic likely to cause weight gain as well as hyperglycemia and monitoring of patients. thus a switch out of so glycosylated hemoglobin (HbA1c) may be preferable to clozapine may not be possible. Among antipsychotic agents. For those on Many pharmacologic agents have been studied in patients antipsychotics. In this particular patient clozapine represents a special case since its use is limited to population. Aripiprazole also provide office based counseling with specific targets for and other antipsychotics such as perphenazine. ziprasidone components. These patients should be considered diabetes. behavior change and periodic monitoring of weights and and haloperidol can be considered as second line agents metabolic parameters [37]. include both education and activity within group if the patient is on an agent that has a high risk of causing obe- settings. Pharmacologic treatment Consider metformin early as proven efficacious in this population. and complications chronic kidney disease from lithium. The treating One program showed a greater decline in fasting blood psychiatrist may not be aware of the development of glucose sugars compared to controls [36]. above. and include both nutrition and physical activity sity and diabetes. the psy- for these programs to be effective they have to be of longer chiatrist may be able to change the antipsychotic medication duration. Manualized programs may be more successful has shown to be the least likely to cause significant weight gain than unstructured interventions. This should happen at both the to switch to for attenuation of weight gain. or reverse the weight gain and metabolic abnormalities screening can be reduced to 6-month or 1-year intervals. Prescribe basal or premixed insulin for easier management.

Other novel agents used ated with acute onset of hyperglycemia and ketoacidosis [51]. Patients with diabetic patient. as with any goal is to prevent long-term complications. should be used whenever possible. schizophrenia are unknown at this time. has shown and coexisting mood disorder. should be intensive and started early. The Diabetes Prevention Study showed be referred to a structured treatment program.International Journal of Endocrinology 5 glucose regulation. gastroparesis. which symptoms such as paranoia or delusions might interfere with is similar to weight loss observed with metformin in the adherence to recommendations. In patients with schizophrenia. Some prominent side effects such as cognitive impair. the potential may be mistaken for the patient’s baseline cognitive deficit benefits both in the general population and in those with resulting in delay in detection of hyperglycemia. Providers should also recognize that weight loss compared to placebo was modest at 2 kg. schizophrenia have multiple other cardiovascular risk factors. who are obese and have evidence of glucose dysregulation. In another cohort of patients who were should arrange for frequent follow-up visits. For this reason. These medications affect sexual function through early in the course of illness in all patients with schizophrenia multiple mechanisms including elevated prolactin levels. disorders resulting in chronic kidney disease and rarely renal ment may be a deterrent for its use in schizophrenia. It has been shown to be effective in attenuating and follow-up may be even more problematic than in the weight gain on antipsychotics and improving glucose regu. such Diabetes care in those with schizophrenia should be as use of aspirin and preventive immunizations. that.2 mg/dl in the placebo group.8 in the group Adequate hygiene may be a problem in some patients and that received both metformin and lifestyle interventions so special attention should be paid to foot care. Poor dentition is frequently also shown efficacy in improving weight and metabolic profile seen in these patients and efforts should be made to obtain in patients on clozapine [46]. have been associ- prevent conversion to diabetes.2 in the placebo group. providers general population. wound care should be increased by 1. can also even if they are not on antipsychotics. Antidiabetic agents with lesser likelihood of weight gain Other conditions such as tobacco dependence and hyper. In the event of vascular complications the metformin and lifestyle interventions group while it with development of a diabetic ulcer. Similarly. for treatment of diabetes are being studied for diabetes Cognitive dysfunction associated with elevated glucose levels prevention in prediabetic patients. general population. Thus it is not clear if they can tions. Providers will also need to coordinate to lifestyle interventions but combined intervention was care with specialists for routine diabetes care such as visits for superior to either intervention alone [45]. given that the result from anticholinergic medications that are often used to reductions in weight and glucose are small. diet very specific recommendations on immediate management and exercise measures can be effective and patients should should be provided to both patients and caregivers. in the general population. issues of adherence weight gain. As in all patients. metformin is only combat adverse effects of antipsychotics. providers In people on antipsychotics. longer visits and simplified explanation of antipsychotic in the metformin trials. lorcaserin. Potential interactions between psychotropics and available weight loss agents such as orlistat. in body mass index (BMI) was about 1. In a sample of patients recommendations may be necessary. The be clearly delineated. Other measures to prevent and treat comorbidities. Similarly. the primary based on current evidence-based guidelines. None of these agents It is worthwhile to note that some antipsychotic medica- affect glucose metabolism. metformin is effective in At a minimum. especially in ini- early in the course of schizophrenia. aimed at improving eating and physical activity behavior [41]. 43]. an anticonvulsant. However. a complication of diabetes. topiramate. since these patients are tension should be aggressively treated. apnea is another cardiovascular risk factor that is highly If they are on medications that can cause hypoglycemia. dental evaluation and treatment to prevent gingivitis and Thus. metformin was superior tial stages of treatment. is a mood stabilizer used in patients with schizophrenia Besides metformin. metformin was poorly treated diabetes. which regulation in those with schizophrenia. Sexual dysfunction. including increased mortality. Due to psychiatric symptoms and cog- lation [42. report neuropathic symptoms readily and a foot exam should The fasting glucose decreased by a mean of 7. The long-term risks of with chronic schizophrenia on olanzapine. prevalent in this population [48]. if available. Attention should also be paid to psychotropic med- The bulk of the data on metabolic abnormalities and ications that can cause chronic kidney disease. and agents used to treat diabetes and comorbid hypertension and naltrexone/bupropion combination have not been adequately hyperlipidemia should also be taken into consideration [50]. should effective in reducing both weight and HbA1c levels [44]. It should be considered treatment. Lithium antipsychotics is on weight gain related to these agents. At all stages of prevention and treatment. They may not compared to an increase in BMI of 1. Other failure [49]. can also be due to antipsychotic are small as in the general population. . metformin has shown efficacy in improving glucose other infectious complications. one step in the treatment of those with glucose intolerance. As outlined above. they should be referred to a nutritionist preventing conversion to diabetes in those with impaired for specific recommendations on dietary modifications for glucose tolerance but less effective than lifestyle interventions managing diabetes. Obstructive sleep already on psychotropic medications that cause weight gain. Olanzapine is the most commonly studied nitive deficits. Metformin has aggressive with close follow-up. especially quetiapine and olanzapine. Long-term treatment with some success in treating antipsychotic related weight gain lithium is associated with a range of glomerular and tubular [47]. though the effect sizes can result from diabetes.2 mg/dl in be done at every visit. However. studied in the schizophrenia population. Mean reduction a fundoscopic eye exam. metformin has been studied should communicate with family members or other care- for both prevention and treatment of antipsychotic-induced givers.

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