Drugs (2014) 74:183–194 DOI 10.1007/s40265-013-0171-7

REVIEW ARTICLE

Acute Hyperglycemia Associated with Short-Term Use of Atypical Antipsychotic Medications T. Vivian Liao • Stephanie V. Phan

Published online: 8 January 2014 Ó Springer International Publishing Switzerland 2014

Abstract The prevalence of metabolic disturbances associated with long-term use of antipsychotic medications has been widely reported in the literature. The use of atypical antipsychotics for the treatment of delirium in the intensive care unit (ICU) has gained popularity due to a lower potential for adverse effects compared with conventional antipsychotics. However, current studies evaluating safety and efficacy of antipsychotics in the ICU setting do not include metabolic parameters as a potential adverse effect that requires monitoring. It is thought that long-term adverse effects of antipsychotics may be out of context for the intensive care setting. A literature review was conducted to investigate the prevalence of acute hyperglycemia associated with short-term use of antipsychotics, with the purpose of reviewing evidence that hyperglycemia may occur even with short-term use of atypical antipsychotics. A MEDLINE search for acute hyperglycemia from short-term use of antipsychotics resulted in studies involving animal models and healthy volunteers. These studies indicate that acute hyperglycemia may occur after short-term treatment. A review of the literature shows preliminary evidence to suggest that atypical antipsychotics impact glucose sensitivity and induce insulin resistance even after a single dose. Although no studies have been conducted evaluating the impact of

T. V. Liao (&) Mercer University College of Pharmacy, 3001 Mercer University Drive, DuVall-128, Atlanta, GA 30341, USA e-mail: [email protected] S. V. Phan University of Georgia College of Pharmacy, Southwest Georgia Clinical Campus, 1000 Jefferson Street, Albany, GA 31701, USA e-mail: [email protected]

hyperglycemia in critically ill patients from the short-term use of atypical antipsychotics for the treatment of delirium, the potential to affect clinical outcomes exist and warrants further research in this area.

1 Introduction Literature has reported that delirium, an acute change or fluctuation in mental status associated with inattention, cognitive impairment, and a change in the level of consciousness, is associated with poorer clinical outcomes, including prolonged mechanical ventilation, longer lengths of stay in the intensive care unit (ICU), increased costs, higher mortality, and long-term cognitive impairment [1– 9]. The most recent clinical practice guidelines on pain, analgesia, and delirium report that the incidence of delirium occurs in as many as 80 % of patients admitted to the ICU requiring mechanical ventilation [10]. The Society of Critical Care Medicine (SCCM) recommends that all patients in the ICU should be routinely monitored for the development of delirium, regardless of mechanical ventilation [10]. Although the pathophysiology of delirium is unknown, the current hypothesis is that delirium is caused by a combination of disease-induced syndrome (e.g., organ dysfunction), iatrogenic (e.g., use of sedatives and analgesics), and environmental factors (e.g., physical restraints and immobility) [10, 11]. Strategies recommended in the guidelines to prevent and manage delirium and deliriumrelated symptoms include pharmacologic and non-pharmacologic therapy, such as sleep promotion, early mobilization, and avoidance of benzodiazepines, if possible [10]. The use of haloperidol or atypical antipsychotics for prophylaxis of delirium is not recommended [10]. Specifically for mechanically ventilated adult patients, promoting

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an analgesia-first approach with a light target level of sedation or daily interruption of sedation is recommended [10]. Management of delirium involves reducing contributing factors (e.g., infection, hypoxia, medications), treatment of co-morbid diseases, removal of iatrogenic causes (e.g., sedation/analgesia), and use of pharmacotherapy [8, 12]. Until recently, intravenous haloperidol was recommended for the past 20 years as first-line therapy for the treatment of acute agitation in both national and international guidelines despite limited evidence supporting its efficacy for treatment of delirium in the ICU [13–15]. In the 2013 version of the SCCM guidelines, haloperidol is no longer recommended since no evidence shows that it reduces the duration of delirium [10]. Although haloperidol was recommended as the drug of choice for many years, it is a medication with the potential for serious adverse effects, such as hypotension, extrapyramidal symptoms (EPS), corrected QT (QTc) interval prolongation, and neuroleptic malignant syndrome (NMS) [16]. Because haloperidol is not an ideal agent for delirium, the use of atypical antipsychotics has gained popularity in the ICU as an attractive option due to a lower liability of neurological adverse effects [17, 18]. Devlin et al. published a study that showed pharmacists often used haloperidol or an atypical antipsychotic drug as first-line therapy for treatment of delirium [19]. In fact, specific agents frequently or always used for agitated delirium were haloperidol (87 % of the time) and quetiapine (59 % of the time). With the most recent SCCM guidelines suggesting that atypical antipsychotics may reduce the duration of delirium and no longer recommending the use of haloperidol, clinicians may decide to use atypical antipsychotics as first-line pharmacologic treatment for delirium with higher frequency than before [10]. To date, studies involving the use of antipsychotics for delirium in the ICU report conflicting results regarding efficacy, and it is unclear whether atypical antipsychotics are helpful for the treatment of delirium [20–22]. Similarly to the use of haloperidol, it should be realized that adverse effects, including EPS, QTc prolongation, hypotension, and oversedation, may occur with the use of atypical antipsychotics, albeit to lesser degrees [20–22]. Additionally, hyperglycemia, seizures, and NMS are adverse effects that may be observed even with short-term administration of antipsychotics, which is commonly how the medication is used in the ICU setting [23]. The prevalence of metabolic disturbances including weight gain and glucose dysregulation (defined as blood glucose changes outside of the normal ranges in fasting and post-prandial glucose levels) associated with long-term use of antipsychotic medications for psychiatrically ill patients has been widely reported in the literature and typically occurs within weeks to months upon medication initiation

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[24–27]. Recommendations regarding monitoring and treatment for patients on atypical antipsychotic medications have been published in a consensus statement endorsed by several professional organizations [28]. The recommendations for monitoring in patients on atypical antipsychotics include obtaining baseline personal/family history, weight, waist circumference, blood pressure, fasting plasma glucose, and fasting lipid profile with additional monitoring occurring at 4 weeks for weight and at 12 weeks for the other parameters [28]. These indirect measures, though easily obtainable and commonly used clinically, may be less accurate than obtaining measures directly, such as through an intravenous glucose tolerance test. The belief that metabolic disturbances occur from longterm use of antipsychotics may be inaccurate. It is thought that long-term adverse effects of antipsychotics, particularly atypical antipsychotics, such as weight gain, dyslipidemias, and development of diabetes, may be out of context for the ICU setting where the use of antipsychotics rarely spans beyond 14 days [12, 23]. This review discusses evidence from animals and healthy human volunteers that acute hyperglycemia may occur after a single dose and within days upon initiation of atypical antipsychotic therapy. Antipsychotics are used in a variety of patient populations in which slight variations in glycemic control may have a considerable impact on outcomes even in patients without pre-existing diabetes, such as the critically ill population. No randomized controlled studies evaluating the effect of acute hyperglycemia from an atypical antipsychotic in medically ill patients have been conducted to date and may be an area for future research.

2 Mechanism Both conventional and atypical antipsychotics bind with varying affinities to an assortment of neurotransmitter receptors and transporters, any of which, alone or in combination, may be responsible for metabolic abnormalities [29]. Savoy et al. reported that despite the classification of ‘‘conventional’’ or ‘‘atypical,’’ antipsychotic drugs have varying effects on glycemic control that may be related to each drug’s unique pharmacology. Several possible mechanisms involved in causing metabolic disturbances include the histamine H1-receptor, serotonin 5-HT2C receptor, muscarinic M3 acetylcholine receptor, and glucose transporters [29]. The autonomic nervous system is involved with energy metabolism and controls blood glucose within a narrow range by means of central and peripheral mechanisms [29]. Alterations in this system could affect glucose homeostasis potentially through pancreatic insulin release (reduced due to reduced b-cell function), peripheral glucose utilization, glycogen

Acute Hyperglycemia and Short-Term Use of Atypical Antipsychotics

synthesis, and/or hepatic glucose output [29–31]. Development of insulin resistance, possibly due to changes in insulin sensitivity in peripheral and/or hepatic tissues, may also be a potential mechanism responsible for alterations in glucose homeostasis [30, 31]. Development of insulin resistance could potentially be the first step in a cascade leading to hyperglycemia and diabetes [32]. Atypical antipsychotics known to cause the most amount of weight gain include clozapine and olanzapine, while aripiprazole and ziprasidone are associated with the least amount of weight gain [33]. Data also supports that olanzapine and clozapine have pharmacologic properties that may lead to an increased likelihood of causing abnormalities in glucose homeostasis [32]. In a rat study conducted by Boyda et al. [34], it was shown that antipsychotic drugs affected glucose regulation and insulin sensitivity in a doseand time-dependent manner, with the greatest effect noted with clozapine and olanzapine. Other drugs studied, risperidone and haloperidol, also increased fasting glucose and/or insulin levels but not to the same degree as clozapine and olanzapine [34]. Because the role of clozapine is limited in the treatment of delirium due to slow titration (no role in acute treatment) and tolerability issues, further discussion of clozapine is not included in this review. Quetiapine can also potentially lead to hyperglycemia, with time of onset ranging from several days to 1 year [35]. A study by Koller et al. [35] found that of patients diagnosed with hyperglycemia, 75 % of patients were diagnosed at 6 months or less after initiation of quetiapine. For patients already diagnosed with diabetes, glucose control destabilization occurred within 3 months for 86 % of patients [35]. Reversal of hyperglycemia occurred in most patients that discontinued quetiapine therapy [35].

3 Methods Search terms in MEDLINE from inception to November 2013 included the following keywords: antipsychotic, aripiprazole, haloperidol, quetiapine, olanzapine, risperidone, ziprasidone, and hypertension, hyperglycemia, glucose, insulin resistance, fasting insulin, hyperlipidemia, weight, and waist circumference. Studies that involved only clozapine were excluded for reasons as previously described. Search results with clozapine and other antipsychotics as part of the study design were included for consideration. No language limit was applied to the search. Given that the interest was in acute changes in metabolic parameters, other search terms such as critical care, ICU, critically ill, or acute effects were used. Studies, case series, and case reports of acute changes from long-term use ([14 days) were excluded. The time period of 14 days was chosen since ‘‘acute use’’ has not been previously defined. Two

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researchers conducted a literature search independently and compiled the results.

4 Supporting Evidence for Hyperglycemia and Insulin Resistance 4.1 Animal Studies Multiple animal studies with acute changes in insulin resistance or sensitivity and glucose control were identified [32, 34–42]. In 2003, Dwyer and Donohoe reported the induction of hyperglycemia with atypical antipsychotics in a murine model [36]. After an 18-h, overnight fast, the rats were injected with a control, quetiapine, and risperidone. Blood samples were drawn 30 min and 3 h post-administration. Glucose levels, when compared with the control group, were significantly elevated at both time periods for quetiapine and risperidone. Another study to investigate acute effects of whole-body glucose disposal was conducted by Houseknecht et al. [32]. The investigators used a commonly accepted method known as the hyperinsulinemic– euglycemic clamp technique to examine acute changes in whole-body insulin sensitivity in a rat model [43]. Under physiologic conditions, insulin increases glucose disposal in the skeletal and adipose tissue and suppresses hepatic glucose production [44]. The hyperinsulinemic–euglycemic clamp method is considered a standard technique for directly measuring insulin sensitivity and resistance in vivo by suppressing hepatic glucose production and monitoring the glucose disposal rate [44]. Typically, insulin is administered at a constant rate after an overnight fast, to establish a new insulin steady state above the fasting level, thereby leading to ‘‘hyperinsulinemia,’’ while a dextrose solution is administered at a variable rate to maintain a blood glucose level within the normal range (‘‘euglycemia’’) to determine whole-body glucose disposal [44]. After a period of time, steady-state conditions are reached with no net change in the blood glucose concentration to allow the glucose infusion rate to equal the glucose disposal rate, which is an estimation of insulin sensitivity. Some researchers may utilize a radioactive glucose tracer in case there is an incomplete inhibition of hepatic glucose production and will account for it when calculating the insulin sensitivity [44]. Houseknecht et al. [32] used radioactive tracer studies to investigate which tissues were affected by glucose dysregulation and to identify the effect on glucose transport. Doses corresponding to clinically relevant dopamine D2 receptor occupancy for clozapine, olanzapine, and risperidone (0.32–32 mg/kg) were subcutaneously administered. After a single dose of clozapine and olanzapine, the rats showed significantly decreased insulin sensitivity in a dose-dependent manner within

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40–60 min when compared with the control (p \ 0.001) [32]. Ziprasidone and risperidone had no effect on insulin sensitivity, even when administered at high doses [32]. The radioactive tracers showed that hepatic glucose production increased in the groups receiving insulin and single doses of olanzapine and clozapine administered at 10 mg/kg when compared with the control group receiving insulin only (p \ 0.001), indicating that the liver was the site of the drug-induced insulin resistance [32]. The tracers indicated that administration of the medications did not affect glucose uptake into the peripheral tissues [32]. This study was the first to support acute metabolic effects after a single dose of olanzapine in healthy animals [32]. Similarly, Chintoh et al. [37] investigated the acute effects of a single dose of olanzapine in healthy rats with the hyperinsulinemic–euglycemic method and radioactive tracers. Similar basal plasma glucose levels, insulin, and C-peptide secretion between both groups were maintained at baseline. Results showed that the olanzapine-treated group had plasma glucose levels 1.5 times higher than the control group (209 ± 11 vs. 136 ± 4 mg/dL; p \ 0.001) 90 min after the injections. Furthermore, the olanzapine group had a significantly higher rate of hepatic glucose production and decreased glucose utilization than the control group (p \ 0.001). The mean plasma insulin levels and C-peptide assay for the olanzapine-treated group was significantly lower than the control group (p = 0.002; p = 0.04, respectively). Chintoh et al. [37] concluded that a single dose of olanzapine decreased whole-body insulin sensitivity and decreased insulin secretion. Olanzapine was thought to directly stimulate hyperglycemia and reduce pancreatic b-cell secretory function. Other studies reported similar findings of insulin resistance with atypical antipsychotics [38, 40–42]. Smith et al. [38] concluded that acute hyperglycemia following administration of atypical antipsychotics is due to an increase in hepatic glucose production. Additionally, hyperglycemia was attributed as resulting from an increase in glucagon secretion [38]. To address the question of whether acute effects of antipsychotics were dose dependent, Boyda et al. [34] investigated glucose sensitivity in an animal model at low and high doses. This study measured plasma glucose levels at 60, 180, and 360 min following a single dose of antipsychotic medication. The rats were randomized to receive low or high doses of the following medications and were compared to a control group: clozapine (2 or 20 mg/kg), olanzapine (1.5 or 15 mg/kg), risperidone (0.5 or 2.5 mg/ kg); haloperidol (0.1 or 1 mg/kg). Investigators reported significant dose- and time-dependent elevations in basal glucose levels following drug administration for all the antipsychotic medications when compared to the control group (p \ 0.05) [36]. Most recently, Jassim et al. [39] confirmed the findings of previous authors and found an

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initial upregulation of hepatic genes responsible for gluconeogenesis. Similar to Smith et al., their study also reported findings of increased glucagon levels after a single injection of olanzapine [39]. 4.2 Human Studies Case reports of acute hyperglycemic events have been described for psychiatric patients on long-term therapy with various atypical antipsychotics (See Table 1) [27, 45– 50]. Few studies have been conducted in humans to evaluate the onset of hyperglycemia associated with antipsychotics. Recognition of the relationship between atypical antipsychotics and diabetes came about via case reports of severe, potentially fatal, acute diabetic decompensation, such as diabetic ketoacidosis [28]. Further evidence for weight gain and lipid abnormalities, in addition to glucose abnormalities, was derived from information including case reports, MedWatch reports, and database reviews [28]. A review of the literature documenting cases of hyperglycemia onset associated with atypical antipsychotic use revealed few reports, with time to onset ranging from 3 days to 29 months [27, 49]. In most cases, patients presented to healthcare facilities due to symptomatic elevations of blood glucose levels. All case reports detailing acute elevations in blood glucose levels involved olanzapine, which is known to cause significant metabolic disturbances [28]. In a study of 26 patients with schizophrenia assigned to risperidone 2 mg/day or olanzapine 10 mg/day, though fasting glucose and fasting insulin were not found to be different at 2 weeks, insulin secretion was found to be statistically significantly different in the olanzapine group (and not in the risperidone group) [51]. Investigators hypothesized that this effect might have been due to direct impairment of pancreatic b-cell function [51]. Four human studies investigating acute metabolic effects in healthy volunteers were identified in the literature search (Table 2) [52–55]. Sacher et al. conducted a single-center, open-label, randomized study in healthy males between 19 and 41 years with body mass index (BMI) between 18 and 25 kg/m2 and fasting blood glucose \100 mg/dL [52]. None of the volunteers had a personal or family history of diabetes or alcohol or regular nicotine consumption. The volunteers did not have previous exposure to the study medications and did not have other medication intake within 2 weeks of enrollment. Prior to initiating the study medications, all volunteers fasted for at least 12 h and were administered a continuous insulin and glucose infusion to maintain a plasma glucose level between 80 and 100 mg/ dL. Potassium supplements were administered as necessary to minimize hypokalemia. Baseline laboratory tests were drawn prior to randomizing one group to receive olanzapine 10 mg daily and another group to receive ziprasidone

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Table 1 Case reports of acute hyperglycemia in patients with psychiatric indications References

Demographic

Antipsychotic

Onset of hyperglycemia

Resolution

Weight gain?

Roefaro and Mukherjee [45]

51-year-old man with post-traumatic stress disorder, bipolar disorder, alcohol abuse, hypertension, coronary artery disease, esophageal strictures

Olanzapine 5 mg po QAM, 20 mg po QPM

About 1 month after dosage increase, serum glucose 1,596 mg/dL, hyperosmolar, hyperglycemic, nonketonic coma

Resolved upon discontinuation of olanzapine (no insulin required 8 days after olanzapine discontinuation)

No

Seaburg et al. [27]

27-year-old man with schizophrenia (no diabetes mellitus)

Olanzapine 10 mg daily

Approximately 29 months before being brought to emergency department by family, BG 1,240 mg/dL

Maintained on olanzapine 15 mg daily and eventually maintained on pioglitazone alone for BG control

No, in contrast, 30 lb (13.6 kg) weight loss

Ramankutty [46]

51-year-old female with schizoaffective disorder, diabetes

Olanzapine 30 mg daily

Worsening diabetes control ‘‘within weeks’’ requiring insulin therapy

Olanzapine was tapered and discontinued over 3 weeks and pt was eventually maintained on usual doses of oral hypoglycemic agents

No

Bettinger et al. [47]

54-year-old female with history of hypertension, non-insulin-dependent diabetes (dietcontrolled, HbA1c 6.5 %), major depressive disorder with psychotic features

Olanzapine 10 mg daily

BG initially was 89–132 mg/dL and went to 246–283 mg/dL (fasting) and 276–536 (post-prandial) 12 days after olanzapine initiation; HbA1c went to 12.5 %

2 weeks after antipsychotics stopped, BG 85–163 (fasting) and 95–248 (postprandial) mg/dL; pt was discharged on insulin

Yes (initial weight was 73 kg, pt gained 13 kg after 14 weeks of olanzapine)

Ober et al. [48]

45-year-old man with diabetes (HbA1c 7.4 %), major depressive disorder

Olanzapine 10 mg daily for auditory hallucinations in May

At May clinic visit, weight was increased 25 % since last appointment and BG readings were 180–260 mg/dL; later that same month, BG was 300–400 mg/dL; BG continued trending up 380–600 mg/dL per home glucometer and 303 mg/dL serum and insulin was initiated

After 3 months, olanzapine was discontinued and BG returned to 85–155 mg/ dL; weight decreased by 15 lb (6.8 kg)

Yes

Kohen et al. [49]

89-year-old man with mixed dementia with psychosis and behavioral disturbances

Olanzapine 2.5 mg bid for psychosis; dose increased to 5 mg bid after 2 days

Initial fasting BG 114 mg/dL, after 3 days, fasting BG 138 mg/dL and fingerstick BG 325 mg/dL

After stopping olanzapine, BG 125 mg/dL

No

Goldstein et al. [50]

A case series of 7 pts without baseline diabetes: Olanzapine 10 mg daily

After 6 months, pt complained of polydipsia, polyuria, ‘‘feeling dazed,’’ decreased appetite, abdominal pain, and malaise for 3 weeks; outpatient BG was 1,274 mg/dL and 882 mg/dL at the hospital; diagnoses included DKA

Olanzapine was discontinued and insulin therapy was continued

Yes

Case 1

42-year-old woman with schizoaffective disorder

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Table 1 continued References

Demographic

Antipsychotic

Onset of hyperglycemia

Resolution

Weight gain?

Case 2

40-year-old mildly obese woman with schizophrenia

Olanzapine 10 mg daily

After 17 months, pt was admitted to a hospital poorly arousable with BG 1,160 mg/dL, diagnoses included DKA

Pt was discharged from the hospital on insulin; however, with discontinuation of olanzapine, glucose levels normalized and antihyperglycemics were no longer required

Yes

Case 3

41-year-old woman with bipolar disorder, obesity, hyperprolactinemia, and amenorrhea

Olanzapine 10 mg daily, which was discontinued initially for complaints of somnolence and pitting edema; reinitiated at 5 mg and titrated to 10 mg daily and again was discontinued due to complaints of increasing fatigue and sedation

2 weeks after olanzapine discontinuation, a high urine glucose via dipstick was noted; BG was 766 mg/dL

Insulin and troglitazone were initiated but all were eventually discontinued with normalization of BG

Unknown

Case 4

47-year-old man with schizoaffective disorder, obesity, and hypothyroidism

Olanzapine 10 mg daily, eventually increased to 20 mg daily due to increased psychosis

5 weeks after olanzapine initiation, pt had increasing somnolence, polyuria, and polydipsia; BG 878 mg/dL

Olanzapine was temporarily discontinued, but reinitiated and pt continued on insulin; BG normalized when pt became medication non-adherent; olanzapine was ultimately discontinued; however, pt still required insulin

Yes

Case 5

43-year-old white man with bipolar disorder and obesity

Olanzapine 10 mg daily

After 6 months, pt complained of polyuria and polydipsia; BG 567 mg/dL, HbA1c 10.4 %

Pt was treated with insulin and glyburide while hospitalized; however, he remained on glyburide after olanzapine was discontinued

Yes

Case 6

39-year-old man with schizoaffective disorder, obesity, elevated triglycerides, hypertension, and hypothyroidism

Olanzapine 5 mg daily titrated to 10 mg daily and haloperidol 10 mg daily (haloperidol eventually discontinued)

3.5 months after olanzapine initiation, pt complained of 3–4 weeks of polydipsia, polyuria, and blurred vision; BG 571 mg/dL

Symptoms resolved upon olanzapine discontinuation

No [weight loss 6 lb (2.7 kg)]

Case 7

38-year-old man with schizophrenia, obsessive–compulsive disorder, hypercholesterolemia, obesity

Olanzapine 5 mg daily increased to 10 mg daily

3 months after olanzapine initiation, pt complained of polyuria with urgency, polydipsia, and blurred vision for 2 weeks; fasting BG was 372 mg/ dL

Pt reported symptomatic improvement but BG remained elevated after olanzapine discontinuation and pt was referred to outpatient provider for further management

Unknown

BG blood glucose, bid twice daily, DKA diabetic ketoacidosis, HbA1c glycosylated hemoglobin, po orally, pt patient, QAM in the morning, QPM in the evening

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Table 2 Studies evaluating the effects on glucose regulation of acute (B14 days) therapy with antipsychotics References

Study design

Population

Intervention

Outcomes related to glucose regulation

Sacher et al. [52]

Open-label, randomized, singlecenter study

Healthy volunteers, N = 29, between 19 and 41 years of age, BMI between 18 and 25 kg/m2, fasting glucose level of B100 mg/dL, no history or family history of diabetes mellitus

Subjects randomized to olanzapine 10 mg/day or ziprasidone 80 mg/ day

Glucose uptake was less during hyperinsulinemic–euglycemic clamp for 120 min comparing baseline values vs. values after 10 days for olanzapine (p \ 0.001) Plasma insulin concentration during hyperinsulinemic–euglycemic clamp at baseline, 60, 80, and 100 min was greater after 10 days of olanzapine vs. baseline (statistically significant) Plasma glucose after 10 days of either olanzapine or ziprasidone during hyperinsulinemic–euglycemic clamp was no different compared with baseline

Vidarsdottir et al. [53]

Not detailed

Healthy male volunteers, N = 14, between 20 and 40 years of age with normal weight, fasting plasma glucose concentrations

Olanzapine 10 mg/day or haloperidol 3 mg/day for 8 days

Serum glucose and insulin concentrations during hyperinsulinemic–euglycemic clamp in basal condition did not change in response to either olanzapine or haloperidol. Endogenous glucose productions were not affected by either treatment Olanzapine-treated group had significantly elevated serum glucagon concentrations when compared with baseline Glucose infusion rate needed to maintain euglycemia and glucose disposal during hyperinsulinemia was significant reduced or blunted, respectively, after olanzapine treatment

Albaugh et al. [54]

Double-blind, placebo-controlled, crossover, singlecenter study

Healthy volunteers, N = 15, between 18 and 30 years of age, BMI 18.5–25 kg/m2, no history of metabolic diseases or endocrine diseases

Olanzapine 10 mg/day for 3 days

Oral glucose tolerance testing after 3 days of olanzapine or placebo showed AUC was increased by 42 % after olanzapine treatment (2,808 ± 474 vs. 3,984 ± 444 mg/ dL
min; p = 0.0105). AUC for insulin did not differ between olanzapine vs. placebo

Kopf et al. [55]

Randomized, doubleblind, placebocontrolled, crossover, singlecenter study

Healthy male volunteers, N = 10, between 24 and 30 years of age, BMI 18.5–28.2 kg/m2

A single dose of amisulpride 200 mg, olanzapine 10 mg, or placebo on different study days

After 60 min during euglycemic clamp (steady-state hyperinsulinemia), no difference was observed between amisulpride, olanzapine, or placebo with insulin sensitivity and glucose infusion rate During hyperglycemic clamp, C-peptide concentrations increased in all groups but displayed a stronger response after amisulpride administration than with olanzapine or placebo. Post hoc analysis show statistical significance for amisulpride vs. placebo at 5, 10, and 30 min and amisulpride vs. olanzapine at 10 and 30 min

AUC area under the plasma concentration–time curve, BMI body mass index

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80 mg daily for 10 days. The hyperinsulinemic–euglycemic clamp procedure was repeated after 10 days of study completion to monitor for changes in the rate of glucose uptake to indicate whole-body insulin sensitivity as the primary outcome. The mean patient demographics for the olanzapine (n = 14) and ziprasidone group (n = 15) were similar. The average patient was approximately 25 years of age, with an average BMI of 22. Average arterial blood pressure prior to initiating study medications was 83 mmHg. No difference in the mean rate of glucose uptake between the groups at baseline was observed over 120 min after initiation of the hyperinsulinemic–euglycemic clamp. The results showed that patients in the olanzapine group had a significantly reduced rate of glucose uptake after 10 days of therapy compared with baseline values (4.7 ± 0.3 vs. 5.7 ± 0.4 mL/kg/h; p \ 0.001). The ziprasidone group did not have different changes in whole body insulin sensitivity at baseline and after 10 days of therapy (5.1 ± 0.3 vs. 5.2 ± 0.3 mL/kg/h; p = not significant). Plasma insulin concentrations were also significantly increased in the olanzapine group compared with baseline values (6.22 ± 0.78 vs. 9.40 ± 1.0 lU/mL; p \ 0.02), but the ziprasidone group showed similar values (6.29 ± 0.54 vs. 5.1 ± 0.6 lU/mL; p = not significant). Also, the rate of glucose uptake at the completion of the 10-day therapy was significantly reduced for the olanzapine group compared with baseline values at 80, 100, and 120 min of the hyperinsulinemic–euglycemic challenge (p \ 0.015, p \ 0.001, p \ 0.0001, respectively). The group receiving ziprasidone did not have significant changes from baseline in the glucose uptake rate. Although not significantly different, the fasting blood glucose values were higher in the olanzapine group upon the completion of the 10-day therapy compared with baseline values. Fasting plasma glucose values compared with baseline were similar in the ziprasidone group. A significant increase in BMI in the olanzapine group, compared with baseline, was noted after 10 days of therapy: 22.0 ± 2.2 vs. 22.6 ± 1.8 (p \ 0.02). No difference in BMI was observed in the ziprasidone group. No changes in blood pressure were observed at the completion of therapy compared with baseline in either group. This study was the first in vivo evidence in humans of acute effects of olanzapine therapy on reduced glucose uptake and insulin sensitivity. This study also concluded that the metabolic effects on BMI and weight gain reflected the reduced insulin sensitivity and impaired glucose uptake rate. The impact of lifestyle in the healthy volunteers was not evaluated. The researchers did not account for differences in diet and exercise in the study design. Vidarsdottir et al. [53] also measured serum glucose and insulin concentrations in non-obese, healthy male volunteers after 8 days of antipsychotic therapy. The volunteers were treated with oral olanzapine 10 mg daily or oral

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haloperidol 3 mg daily. Using the hyperinsulinemic– euglycemic clamp technique, the researchers reported similar fasting glucose and insulin concentrations at baseline and day 8 of therapy. The effect of insulin on endogenous glucose production was not impaired in either the haloperidol or olanzapine group. Yet, the glucose infusion rate to maintain euglycemia in the olanzapine group was significantly reduced. The investigators concluded that treatment with olanzapine induced a whole-body insulin resistance and impaired glucose disposal. Similar to the animal studies, a significant increase in serum glucagon concentrations were observed at the end of the treatment period when compared with baseline values (p \ 0.05). Based on evidence of abnormalities with glucose tolerance and insulin sensitivity in animal models, Albaugh et al. [54] conducted a 3-day crossover study of olanzapine 10 mg/day in 15 healthy patients. On the morning following the last dose of olanzapine, an oral glucose tolerance test was performed and revealed that median area under the plasma concentration–time curve (AUC) for glucose was increased by 42 % after olanzapine administration and was significantly different between the olanzapine and placebo groups. The study concluded that an increase in AUC for glucose showed a decrease in wholebody insulin sensitivity. Most recently, Kopf et al. [55] investigated the effects of insulin secretion and sensitivity in ten healthy males with a single oral dose of amisulpride, olanzapine, or placebo. Interestingly, this study did not report any differences in insulin sensitivity between the medications when compared with placebo. The authors did, however, show that amisulpride had a significantly higher concentration of C-peptide than placebo and olanzapine, indicating involvement of the pancreatic b-cell. Olanzapine did not show a significant difference in C-peptide secretion. The authors concluded that this was the first study to show that a single dose of amisulpride, an atypical antipsychotic, directly stimulated insulin secretion by the pancreatic b-cell. Though insulin sensitivity and insulin secretion were not different after a single dose of olanzapine compared with placebo, the researchers cautioned against the notion that olanzapine was as safe as placebo with respect to its metabolic profile [55].

5 Discussion Based on multiple animal studies and limited human evidence, atypical antipsychotics have been shown to affect glucose regulation after short-term administration and even after a single dose. Though metabolic abnormalities have been frequently, albeit to varying degrees, reported with atypical antipsychotics, it is unclear whether the abnormalities are a result of increased risk factors (e.g., obesity,

Acute Hyperglycemia and Short-Term Use of Atypical Antipsychotics

reduced physical activity) secondary to sedative effects or a more basic mechanism [29, 51]. Possible mechanisms responsible for metabolic disturbances include damage to pancreatic islet cells, sympathetic nervous system dysfunction, or secondary to weight gain and insulin resistance [51]. Abdominal adiposity, in particular, is associated with muscle insulin resistance and type 2 diabetes mellitus [31]. While weight gain is a well-documented side effect of atypical antipsychotics that may lead to glucose dysregulation and is a risk factor for diabetes, there is evidence for glucose abnormalities that are independent of weight gain [29]. Receptor mechanisms responsible for weight gain may differ from those responsible for insulin resistance and diabetes [29]. Weight gain associated with antipsychotic use may be long-term; however, severe hyperglycemia in the absence of weight gain or shortly after antipsychotic initiation has been reported, which demonstrates that atypical antipsychotics may have a rapid and direct effect responsible for impairing insulin secretion or action [51]. Antipsychotics may also disrupt the secretion and actions of hormones involved in the regulation of glucose and fat metabolism, such as leptin, ghrelin, and glucagons [29]. Whether the metabolic effects are primarily mediated by a hepatic or pancreatic mechanism is controversial [38, 52–55]. Case reports have identified a rapid and/or sudden onset or exacerbation of diabetes or occurrence of hyperglycemic events after initiation of atypical antipsychotic therapy (Table 1) [27, 45–50]. In animal models, olanzapine led to hepatic insulin resistance and impaired compensatory upregulation of b-cell sensitivity to glucose [51]. Albaugh et al. [54] suggested that glucose tolerance may be affected within 3 days of medication initiation. Many cases of rapid or new onset of disturbances in glycemic control were reversible and resolved upon antipsychotic discontinuation [30]. This rapid onset and resolution (and recurrence with reintroduction) are further evidence that glucose control destabilization is a drug-related effect [30]. A small but significant number of patients experience metabolic abnormalities in the absence of weight gain and/or obesity, therefore showing that there is possibly a direct mechanism of glucose dysregulation [33]. Although the exact mechanism of action by which antipsychotics affect glucose metabolism is unknown, it is believed to involve hormones, such as insulin or glucagon, of energy metabolism [23]. Houseknecht et al. [32] postulate that hepatic insulin resistance may develop with acute dosing while weight gain and hyperlipidemia occur with repeated dosing. Results concluding acute metabolic effects occur based on animal studies and in patients without a history of mental illness may have important clinical implications, especially in practice settings that use antipsychotics for a short period and in patients with acute onset in mental

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disturbance, such as the ICU for delirium. Furthermore, in the critically ill population, acute metabolic changes, specifically hyperglycemia, contribute to long-term patient outcomes even in patients without pre-existing diabetes. As the use of atypical antipsychotics gain popularity in the critical care setting for treatment of ICU delirium, it is important to be aware of acute metabolic effects that may appear within days upon initiation [19, 56]. Currently, no randomized controlled trials have been conducted to evaluate acute metabolic effects from use of antipsychotics in the treatment of delirium in critically ill patients [23]. While the adverse effects reported in studies evaluating the use of antipsychotics for ICU delirium in terms of safety occurred rarely or were similar to the placebo group, metabolic parameters, specifically blood glucose readings, were either not evaluated or mentioned [20–22]. Of note, the consensus statement by the American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, and North American Association for the Study of Obesity addressing antipsychotic drugs and long-term metabolic adverse effects identified patients receiving these medications for chronic psychiatric illnesses [28]. The monitoring recommendations, therefore, are inappropriate for patients with medical conditions who are receiving short-term antipsychotics and in critically ill patients. Since the potential impact of acute hyperglycemia on patients who receive short-term antipsychotics has not been evaluated, clinicians do not routinely attribute changes in blood glucose elevations to atypical antipsychotics when patients are admitted to the ICU. Despite limited evidence suggesting that acute hyperglycemia does occur even with short-term use, it is important to investigate the clinical significance of the impact on patient outcomes. Though there are known differences among the severity and prevalence of various atypical antipsychotics to cause metabolic disturbances, evidence suggests that even those agents classified to have a low risk for metabolic disturbances may affect glucose sensitivity and tolerance [29, 34]. Also, given that the studies suggest that the glycemic impact from antipsychotics are dose related and the efficacy studies supporting the use of atypical antipsychotics for ICU delirium are not robust, it is important to manage delirium by treating the underlying cause, consider non-pharmacologic methods, and as well as actively prevent the development of delirium prior to utilizing drug therapy. The potential for antipsychotics to affect metabolic parameters, specifically hyperglycemia, is of important clinical relevance. Although the conclusions from the NICE-SUGAR (Normoglycemia in Intensive Care Evaluation and Surviving Using Glucose Algorithm Regulation) trial do not recommend intensive glucose control in critically ill patients, it is important to prevent hyperglycemia

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to minimize adverse clinical outcomes [57]. Hyperglycemia, regardless of its etiology in hospitalized patients, is associated with higher mortality and poor clinical outcomes [58–61]. It is also associated with deleterious effects on the brain structure and function, including hematoma expansion, memory impairment, and neuronal changes [62–64]. Furthermore, evidence suggests that fluctuations in blood glucose concentration affect mortality [65, 66]. One study reported the long-term risk of developing type 2 diabetes in 5 years is higher in non-diabetic patients with hyperglycemia than in hospitalized patients without hyperglycemia [67]. In addition to the risk of mortality and the development of diabetes, glucose dysregulation is a risk factor that impacts long-term cognitive and physical function post-ICU discharge and even after 1-year posthospital discharge [68, 69]. For critically ill patients, hyperglycemia and the development of delirium are established risk factors associated with long-term cognitive impairment. Recently, literature reported that the duration of delirium affects long-term outcomes [70]. Survivors of critical illness with a longer duration of delirium were associated with worse global cognition and executive function [70]. The implications of acute hyperglycemia associated with antipsychotic medications are currently unknown. Well-designed clinical trials to investigate this area are needed.

6 Conclusions Multiple animal studies conclude that disturbances in glucose regulation and metabolism as well as insulin resistance may occur acutely over several hours to days after initiation of an atypical antipsychotic medication. Limited evidence in healthy humans suggests impaired glucose regulation after days of therapy. The current studies evaluating safety and efficacy of atypical antipsychotics in patients with delirium in the ICU do not monitor or report on glycemic control. With the recent practice guidelines suggesting that the use of atypical antipsychotics may decrease the duration of delirium, no randomized controlled trials have been conducted to evaluate the clinical impact of acute hyperglycemia. Currently, the impact of atypical antipsychotics on acute glycemic control is unknown and warrants further research. Acknowledgments The authors would like to acknowledge John Papadopoulos, B.S., Pharm.D., FCCM, BCNSP for his assistance with reviewing and commenting on a draft of the manuscript. Conflict of interest statement T.V. Liao and S.V. Phan have no conflict of interest to report. No financial assistance was used to assist in the preparation of this manuscript. This work has not been presented previously.

T. V. Liao, S. V. Phan

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