Psychosomatics 2014:55:686–691
& 2014 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.
Case Reports Quetiapine-Induced Hyperglycemic Crisis and Severe Hyperlipidemia: A Case Report and Review of the Literature Chris Y. Wu, B.S., Shanti R. Mitchell, M.D., Lisa S. Seyfried, M.D.
Introduction Quetiapine, dispensed as Seroquel, has become 1 of the 100 most commonly prescribed medications in the United States in the past 10 years.1 It has fewer extrapyramidal side effects than first-generation antipsychotics, but it has been associated with low to moderate weight gain, hyperlipidemia/hypercholesterolemia, and new-onset diabetes, with half of these cases manifesting as diabetic ketoacidosis (DKA).2–7 We present a case of a middle-aged man who developed diabetes mellitus (DM) manifesting as hyperglycemic crisis and severe reversible hyperlipidemia. Literature on antipsychotic-associated metabolic adverse effects and clinical recommendations is presented.
Case Report Mr. H, a 39-year-old man with bipolar I disorder and hyperlipidemia, was brought to the emergency department after being found minimally responsive at his apartment. He was noted to be acidotic and severely hyperglycemic, with a pH of 7.24, a serum glucose level of 1966 mg/dL, an anion gap of 22 ([Naþ] level of 125 mEq/L, [Cl] level of 79 mEq/L, and a [bicarbonate] level of 24 mEq/L), and a significant ketonuria. Serum osmolality was 399 mOsm/kg. Medical complications at the time of admission included hypercarbia and hypoxia (requiring intubation), electrolyte abnormalities, prerenal azotemia, and a
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triglyceride level of 2942 mg/dL. He reportedly had been drinking increasing amounts of sweetened beverages in the weeks before admission, including fruit juices, sports drinks, and soda. His body mass index on admission was 38.7 (130 kg). Pertinent admission medications included 700 mg of quetiapine, 2500 mg of valproic acid, and 0.5 mg of lorazepam (all administered before bedtime). He had no history of glucose intolerance but did have a family history of dietcontrolled diabetes in his father. Before admission, he had attended weekly appointments with his outpatient psychiatrist, and no metabolic implicative signs or symptoms (such as polyuria/polydipsia or eruptive xanthomas) had been noted. Mr. H was stabilized medically, and his condition improved steadily. A lipid panel obtained on the second day of admission showed a cholesterol level of 365 mg/dL, triglycerides level of 1918 mg/dL, and high-density lipoprotein level of 16 mg/dL. His hemoglobin A1c was 14.2. Treatment with quetiapine was stopped because of metabolic concerns and medication with 15 mg of aripiprazole daily was started; no change was made to his valproic acid regimen. Treatment with 600 mg of gemfibrozil given twice a day was
Received June 16, 2014; revised July 9, 2014; accepted July 10, 2014. From Department of Psychiatry, University of Michigan, Ann Arbor, MI. Send correspondence and reprint requests to Chris Y. Wu, B.S., Department of Psychiatry, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, MI 48109-5338; e-mail: cywu@med. umich.edu & 2014 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.
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Wu et al. begun for hyperlipidemia, and administration of insulin was continued to maintain glycemic control. He was discharged after 13 days in the hospital. At outpatient follow-up, 1 week after discharge, his daily insulin dosage was decreased and his cholesterol and triglyceride levels were within the normal range. Mr. H's last hospitalization had been 16 months earlier for acute mania in the setting of medication noncompliance. During that admission, his nightly quetiapine dosage of 150 mg was increased to a nightly 800 mg dosage. At that time, his blood glucose levels were within the normal range, whereas lipids levels were elevated, with a cholesterol level of 225 mg/dL, a triglyceride level of 764 mg/dL, a high-density lipoprotein level of 43 mg/dL, and a low-density lipoprotein level of 120 mg/dL. He had been taking 800 mg of quetiapine before bedtime for 8 days before the aforementioned lipid panel was drawn. His body mass index at that time was 35.8 (120 kg). There was no evidence that laboratory metabolic monitoring was performed in the intervening 16 months between Mr. H's hospitalizations nor were medications given to lower his lipid or cholesterol levels. Discussion Quetiapine is an atypical antipsychotic originally approved in the United States in 1997 for the treatment of schizophrenia and currently also approved by the Food and Drug Administration for the treatment of bipolar disorder and major depressive disorder; its offlabel uses include generalized anxiety disorder, dementia, obsessive-compulsive disorder, and psychosis in patients with Parkinson disease.8 Quetiapine, and atypical antipsychotics as a class, has better sideeffect profiles than typical antipsychotics do and is thus much more widely prescribed. However, metabolic complications are more common with atypical antipsychotics; these typically include hyperglycemia, weight gain, hypertriglyceridemia, elevated lowdensity lipoprotein level, and decreased high-density lipoprotein level.2,4 Hypertension is another metabolic risk factor, although it is not typically mentioned secondary to atypical antipsychotics.9 These metabolic complications can be used to diagnose metabolic syndromes when 3 or more risk factors are present, with clinical significance attributed to its causal relationship with heart disease, diabetes, and stroke.9 Psychosomatics 55:6, November/December 2014
There are 2 case reports of rapid simultaneous development of hypertriglyceridemia and DM due to quetiapine usage.4,6,10 Aripiprazole and ziprasidone appear to have less metabolic risk than the other atypical antipsychotics do.5 Our case features a young white man who developed progressive hypertriglyceridemia and new-onset DM discovered during hospitalization for hyperglycemic emergency in the setting of high-dose quetiapine augmentation of valproic acid for the treatment of bipolar I disorder. In the 16 months that Mr. H was taking 700-800 mg of quetiapine nightly, he gained 10 kg and his triglyceride level increased from 764 mg/dL to 2942 mg/dL. His initial triglyceride level of 764 mg/dL suggests he was already developing metabolic complications from quetiapine at the time of the dose increase. Quetiapine usage commonly results in dyslipidemia, with increased levels of triglycerides, low-density lipoprotein, and total cholesterol and decreased highdensity lipoprotein level.4 Severe hypertriglyceridemia (4600 mg/dL) has been associated with quetiapine usage, with new-onset diabetes developing in some of these patients as well.5,6 The etiology of this severe hypertriglyceridemia is unclear.6 The highest level of triglycerides reported was 9450 mg/dL in a patient who was taking both quetiapine and olanzapine.11 There have also been several incidences of acute pancreatitis resulting from the extreme triglyceride level induced by quetiapine.4,6 Our case shows that the dyslipidemia that occurs with quetiapine usage is progressive. Mr. H's triglyceride level increased from 764 mg/dL to 2942 mg/dL in the 16 months while he was taking high dose quetiapine. His triglyceride level decreased to 1918 mg/dL after initiation of insulin therapy. In this same time interval, he also gained 10 kg and became diabetic (hemoglobin A1c of 14.2), which suggests development of more global metabolic complications that likely exacerbated his dyslipidemia. The proper characterization of Mr. H's hyperglycemic emergency is not known with absolute clarity. DKA and hyperglycemic hyperosmolar state (HHS) are nondistinct and both may result from atypical antipsychotic usage.5 In fact, patients presenting with hyperglycemic crisis have features of both in more than 30% of cases.12 DKA is defined by the clinical triad of hyperglycemia (4250 mg/dL), ketonemia, and metabolic acidosis and usually occurs with type 1 DM; meanwhile, HHS has more severe hyperglycemia (blood glucose level at an average of www.psychosomaticsjournal.org
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Case Reports 930 mg/dL), hyperosmolarity, little or no ketone formation, milder alterations in arterial pH and serum bicarbonate level, and typically occurs with type 2 DM.12 DKA also usually presents emergently, whereas HHS can present more insidiously over days to weeks.12 In Mr. H's case, the abnormalities in laboratory results and presentation have features of both DKA and HHS. His ketosis, anion gap, and metabolic acidosis suggest DKA, whereas his comatose presentation, potentially insidious onset exacerbated by sugared beverages, elevated serum osmolality, serum glucose level 4900 mg/dL, and serum bicarbonate level within the normal range suggest HHS. A plausible mechanism is that Mr. H had chronic hyperglycemia (given his hemoglobin A1c of 14.2) and developed HHS because of a lack of treatment with insulin and continued quetiapine usage. He was able to replete fluid losses from osmotic diuresis, leading to late development of ketosis and coma. Cases of acute transient β-cell failure leading to DKA in type 2 diabetics have been described with postulated mechanisms that include glucotoxicity, lipotoxicity, and genetic predisposition.12 All 3 postulated mechanisms are potentially present in our case. Additionally, although severe DKA can cause coma or stupor, it is usually associated with an arterial pH o7 and a serum bicarbonate level o10 mEq/L, both of which were not present in Mr. H.12 However, most of the published studies and case reports on hyperglycemic emergencies attributed to antipsychotics encountered during our literature review used the terminology DKA and not HHS. Mr. H had no documented history of diabetes. In fact, his blood glucose levels during admission 16 months ago were normal. New-onset hyperglycemia or exacerbation of previously diagnosed DM is a wellknown complication of several atypical antipsychotics, including quetiapine, clozapine, olanzapine, and risperdone.7 In 2002, Jin et al.13 analyzed 45 published cases of new-onset DM and DKA associated with atypical antipsychotics. They found that 20 of the 45 cases were attributed to clozapine and olanzapine use, whereas 3 were attributed to quetiapine and risperidone use. Overall, 42% of those with new-onset DM presented with DKA with most requiring intensive care.13 African Americans, patients younger than 35 years, and those with preexisting diabetes were overrepresented in the studies, 688
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and weight gain during treatment was not found to be associated with hyperglycemic complications.13 Additionally, they remarked that the co-occurrence of DKA with DM type 2 may be attributed to the antipsychotic agent acting as a metabolic stressor.13 They also concluded that DKA was a sporadic phenomenon without consistent risk factors. In a survey of quetiapine-associated cases by Koller et al.,7 the time of onset of hyperglycemia was 3 months or less for most patients, and it was usually reversed by medication withdrawal. Additionally, the mean age of newly diagnosed patients was 31.2 years, which is less than the mean age of newly diagnosed cases with type 2 diabetes in the general population.7 Proposed risk factors include African American race, male sex, age o35 years, patients with underlying β-cell defects, pre-existing obesity, poor exercise habits, exposures to other diabetogenic drugs, and previous or concomitant exposure to other atypical antipsychotic agents.7,13 Mr. H's profile of male sex, relative youth, and pre-existing obesity is consistent with the risk factors mentioned. In 2013, Ely et al.2 analyzed 17 cases of fatal DKA attributed to antipsychotic medications. They found that quetiapine was the most frequent antipsychotic, accounting for 7 of the cases. Olanzapine accounted for 6 cases, and clozapine accounted for 1 case. They found that the average age was 48 years (range: 32– 57 y), with 15 men and 2 women. Of the patients, 11 were African American. Therefore, despite olanzapine and clozapine being regarded as having more metabolic complications than quetiapine, quetiapine seems to result in fatalities more often, although this was a small study.2,4,14 Thus far, there are no reports of the number needed to harm (development of diabetes) for quetiapine because of a lack of prospective cohort incidence studies comparing quetiapine users with matched controls. In a study that compared the incidence of diabetes among users of different atypical antipsychotics, Citrome et al.15 reported an incidence rate of 18–21 events per 1000 person-years with no significant difference between quetiapine, olanzapine, risperidone, and ziprasidone users. Thus, all atypical antipsychotics demand a strict level of monitoring and vigilance for metabolic syndromes. Several mechanisms have been proposed for this medication-induced hyperglycemia, though the exact cause is likely multifactorial.16 Postulated mechanisms include drug-induced weight gain and central Psychosomatics 55:6, November/December 2014
Wu et al. adiposity leading to type 2 DM, decreased insulin secretion, antagonism of serotonin receptors, druginduced leptin resistance, dyslipidemia-mediated pancreatic β-cell damage, and hepatocyte transcription factor dysregulation.17 Although weight gain is common with antipsychotics as a class and has been causally linked to the development of type 2 DM,16 this cannot be the sole causal mechanism, as Jin et al.13 found that approximately 50% of cases of newonset DM associated with atypical antipsychotics showed no significant weight gain at the time of presentation. An additional mechanism only substantiated in animal studies is the direct alteration of glucose transporter proteins by antipsychotic agents.18 Further research on potential etiologies include activation of protein kinase C-β that results in adipogenic events in preadipocytes and musclederived stem cells19 and other adipokines, such as resistin and adiponectin, inhibition of brown adipocyte differentiation, and the role of peroxisome proliferator–activated receptors.20,21 No consensus has been reached though attribution of diabetes solely to drug-induced weight gain and adiposity is not viewed favorably.2 Our case was further complicated by the usage of valproic acid along with quetiapine. Interactions between valproic acid and quetiapine have been hypothesized, with a study showing that valproic acid increased plasma levels of quetiapine by 77%.22,23 Mr. H had been taking 2500 mg of valproic acid nightly along with high-dose quetiapine; this interaction may have elevated his quetiapine plasma levels beyond what is suggested by his dosage and further increased his risk for metabolic side effects as higher doses of quetiapine has been shown to have more effect on serum lipid levels.24 Furthermore, long-term valproic acid use has itself been directly associated with weight gain, hyperinsulinemia, insulin-resistance, hyperleptinemia, and leptin-resistance.25 We can make several recommendations based on our case. Firstly, practicing physicians, particularly psychiatrists, need to become better at recognizing the signs and symptoms of metabolic complications of atypical antipsychotics and be more responsible at ordering regular lipid and glucose laboratory tests. Mr. H saw his outpatient psychiatrist weekly in the months before admission and no symptoms of hyperglycemia, such as polydipsia/polyuria, were recognized. Additionally, monitoring of weight gain alone Psychosomatics 55:6, November/December 2014
is not sensitive, monitoring of blood glucose for outpatients should be mandatory, especially in the first 6 months of treatment.3 As a result of surveillance failures, no interventions were undertaken for Mr. H's hyperlipidemia. Thus, his medication-induced metabolic syndrome was allowed to progress to the point where he was severely decompensated. Several cases of fatal DKA have been attributed to quetiapine,2 and this risk can be lessened with more diligent monitoring. Based on the recommendations of guidelines collaboratively produced by the American Diabetes Association, American Psychiatric Associations, and others, diligent monitoring starts with baseline assessments of personal and familial risk factors for metabolic syndrome, weight and height (to calculate body mass index), waist circumference, blood pressure, fasting lipid glucose measurements, and fasting lipid profile.26 These assessments allow psychiatrists to riskstratify patients and provide referrals to the appropriate health professional for treatment (i.e., a weight management professional for patients who are overweight). Patients and families should be educated regarding nutrition and physical activity26 and be made aware of the signs and symptoms of DM and diabetic emergencies that necessitate immediate care (Table). A lesser known, but extremely specific, sign of acute severe dyslipidemia is the development of eruptive xanthomas, though this has only been reported with olanzapine and not with quetiapine.27 Those found to be at higher risk for metabolic complications can be switched to a medication with a lower metabolic risk profile, such as aripiprazole or ziprasidone.26 Surveillance monitoring includes weight assessments at 4, 8, and 12 weeks after drug initiation and quarterly thereafter.26 Weight gain Z5% should prompt intervention. Fasting glucose levels and blood pressure should be assessed 3 months after drug initiation and then annually thereafter.26 Fasting lipid levels should be obtained 3 months after drug initiation and quinquennially thereafter.26 However, it should be emphasized that the surveillance intervals provided are for screening purposes in otherwise asymptomatic patients. Those with concerning signs or symptoms or abnormalities in laboratory results should receive more frequent screening as clinically indicated, as well as receive consideration for medication adjustment and referral to proper specialists. www.psychosomaticsjournal.org
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Case Reports TABLE.
Signs and Symptoms of Diabetes and DKA/HHS
Diabetes
Diabetic emergencies
Frequent urination Excessive thirst Extreme hunger Unusual weight loss Increased fatigue Irritability Blurred vision
Nausea, vomiting, or abdominal pain Increased urination Thirst or very dry mouth Dry or flushed skin Constantly feeling tired Difficulty breathing (short, deep breaths) Fruity odor on breath Confusion or hallucinations or lethargy Fever Focal neurologic symptoms or convulsions or vision loss Stupor/coma
DKA ¼ diabetic ketoacidosis; HHS ¼ hyperglycemic hyperosmolar state. Adapted with permission from American Diabetes Association32 and Mayo Foundation for Medical Education and Research.33 It can be noted that several signs and symptoms are nonspecific and may be attributed to psychiatric illness or other medication adverse effects.
Despite the lucid simplicity of these recommendations, baseline testing rates varied from 8%–23% and annual testing rates ranged from 23%–38% in a well-cited study.28
There is evidence in the literature that metabolic effects of antipsychotics are reversible, suggesting that the patient's insulin requirements will steadily decrease.29–31 Mr. H's lipid levels normalized within 3 weeks of discharge, and he returned to work with no functional impairments. A quicker diagnosis of metabolic syndrome as an outpatient could have led to these interventions being done sooner and as an outpatient, thus avoiding the risk for morbidities and mortality (e.g., mechanical intubation, intensive care unit admission) due to DKA/HHS. Conclusion Despite quetiapine's increasing usage due to fewer extrapyramidal side effects, it can produce significant metabolic toxicity, especially when the patient is cousing valproic acid. Our case suggests that the natural history of these metabolic side effects is progressive and can become severe if quetiapine is not discontinued. Proper monitoring of metabolic variables can allow intervention before side effects become severe enough to necessitate hospitalization. Disclosure: The authors disclosed no proprietary or commercial interest in any product mentioned or concept discussed in this article.
References 1. Marlowe KF, Howard D, Chung A: New onset diabetes with ketoacidosis attributed to quetiapine. South Med J 2007; 100:829–831 2. Ely SF, Neitzel AR, Gill JR: Fatal diabetic ketoacidosis and antipsychotic medication. J Forensic Sci 2013; 58:398–403 3. Sirois F: New-onset diabetic ketoacidosis associated with quetiapine: a case report. Gen Hosp Psychiatry 2008; 30:587–588 4. Madsen KR: Fatal hypertriglyceridemia, acute pancreatitis, and diabetic ketoacidosis possibly induced by quetiapine. BMJ Case Rep 2014 [pii: bcr2013202039] 5. Newcomer JW: Second-generation (atypical) antipsychotics and metabolic effects: a comprehensive literature review. CNS Drugs 2005; 19:1–93 6. Rashid J, Starer PJ, Javaid S: Pancreatitis and diabetic ketoacidosis with quetiapine use. Psychiatry (Edgmont) 2009; 6:34–37 7. Koller EA, Weber J, Doraiswamy PM, Schneider BS: A survey of reports of quetiapine-associated hyperglycemia and diabetes mellitus. J Clin Psychiatry 2004; 65:857–863
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8. Guzman F: Quetiapine Indications: FDA-Approved and Off-Label Uses. Psychopharmacology Institute. Available from: www.psychopharmacologyinstitute.com/antipsychotics/ quetiapine/quetiapine-indications, 2013 Accessed July 3, 2014. 9. National Institute of Health, Department of Health and Human Services: What is Metabolic Syndrome? Available from: www.nhlbi.nih.gov/health/health-topics/topics/ms, 2011 Accessed July 3, 2014. 10. Yamauchi T, Tice A: Metabolic abnormalities associated with atypical antipsychotics: a case report and alert. Hawaii Med J 2007; 66:12–13 11. Carnahan RM, Reantaso AA, Teegarden BA, Pogue T: Severe hyperlipidemia associated with olanzapine and quetiapine use. Am J Psychiatry 2007; 164:1614–1615 12. Kitabchi AE, Nyenwe EA: Hyperglycemic crises in diabetes mellitus: diabetic ketoacidosis and hyperglycemic hyperosmolar state. Endocrinol Metab Clin North Am 2006; 35:725–751 13. Jin H, Meyer JM, Jeste DV: Phenomenology of and risk factors for new-onset diabetes mellitus and diabetic ketoacidosis
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associated with atypical antipsychotics: an analysis of 45 published cases. Ann Clin Psychiatry 2002; 14:59–64 Guo JJ, Keck PE Jr, Corey-Lisle PK, et al: Risk of diabetes mellitus associated with atypical antipsychotic use among patients with bipolar disorder: a retrospective, populationbased, case-control study. J Clin Psychiatry 2006; 67:1055–1061 Citrome L, Collins JM, Nordstrom BL, Rosen EJ, Nadkarni A, Kalsekar I: Incidence of cardiovascular outcomes and diabetes mellitus among users of second-generation antipsychotics. J Clin Psychiatry 2013; 74:1199–1206 Buchholz S, Morrow AF, Coleman PL: Atypical antipsychoticinduced diabetes mellitus: an update on epidemiology and postulated mechanisms. Intern Med J 2008; 38:602–606 Buchholz S, Morrow AF, Coleman PL: Atypical antipsychotic-induced diabetes mellitus: an update on epidemiology and postulated mechanisms. Intern Med J 2008; 38:602–606 Ardizzone TD, Bradley RJ, Freeman AM III, Dwyer DS: Inhibition of glucose transport in PC12 cells by the atypical antipsychotic drugs risperidone and clozapine, and structural analogues of clozapine. Brain Res 2001; 923:82–90 Pavan C, Vindigni V, Michelotto L, et al: Weight gain related to treatment with atypical antipsychotics is due to activation of PKC-β. Pharmacogenomics J 2010; 10:408–417 Oh JE, Cho YM, Kwak SN, et al: Inhibition of mouse brown adipocyte differentiation by second-generation antipsychotics. Exp Mol Med 2012; 44:545–553 Rolland B, Deguil J, Jardri R, Cottencin O, Thomas P, Bordet R: Therapeutic prospects of PPARs in psychiatric disorders: a comprehensive review. Curr Drug Targets 2013; 14:724–732 Liang CS, Yang FW, Lo SM: Rapid development of severe hypertriglyceridemia and hypercholesterolemia during augmentation of quetiapine with valproic acid. J Clin Psychopharmacol 2011; 31:242–243 Aichhorn W, Marksteiner J, Walch T, Zernig G, Saria A, Kemmler G: Influence of age, gender, body weight and valproate comedication on quetiapine plasma concentrations. Int Clin Psychopharmacol 2006; 21:81–85
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24. Ulcickas YM, Delorenze GN, Quesenberry CP Jr, et al: Association between second-generation antipsychotics and newly diagnosed treated diabetes mellitus: does the effect differ by dose? BMC Psychiatry 2011; 11:197 25. Belcastro V, D'Egidio C, Striano P, Verrotti A: Metabolic and endocrine effects of valproic acid chronic treatment. Epilepsy Res 2013; 107:1–8 26. American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, North American Association for the Study of Obesity. Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care 2004; 27:596–601 27. Chang HY, Ridky TW, Kimball AB, Hughes E, Oro AE: Eruptive xanthomas associated with olanzapine use. Arch Dermatol 2003; 139:1045–1048 28. Morrato EH, Newcomer JW, Kamat S, Baser O, Harnett J, Cuffel B: Metabolic screening after the American Diabetes Association's consensus statement on antipsychotic drugs and diabetes. Diabetes Care 2009; 32:1037–1042 29. Dibben CR, Kalavalapalli SS, Linnington HE, et al: Diabetes associated with atypical antipsychotic treatment may be severe but reversible: case report. Int J Psychiatry Med 2005; 35:307–311 30. Sobel M, Jaggers ED, Franz MA: A new-onset diabetes mellitus with the initiation of quetiapine treatment. J Clin Psychiatry 1999; 60:556–557 31. Wilson DR, D’Souza L, Sarkar N, Newton M, Hammond C: New-onset diabetes and ketoacidosis with atypical antipsychotics. Schizophr Res 2002; 59:1–6 32. American Diabetes Association: DKA (ketoacidosis) & ketones. Available from: www.diabetes.org/living-with-diabetes/ complications/ketoacidosis-dka.html, 2014 Accessed July 3, 2014. 33. Mayo Foundation for Medical Education and Research: Diabetic hyperosmolar syndrome, symptoms. Available from: www.mayoclinic.org/diseases-conditions/diabetichyperosmolar-syndrome/basics/symptoms, 2012 Accessed July 3, 2014.
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& 2014 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.
Case Reports Quetiapine-Induced Hyperglycemic Crisis and Severe Hyperlipidemia: A Case Report and Review of the Literature Chris Y. Wu, B.S., Shanti R. Mitchell, M.D., Lisa S. Seyfried, M.D.
Introduction Quetiapine, dispensed as Seroquel, has become 1 of the 100 most commonly prescribed medications in the United States in the past 10 years.1 It has fewer extrapyramidal side effects than first-generation antipsychotics, but it has been associated with low to moderate weight gain, hyperlipidemia/hypercholesterolemia, and new-onset diabetes, with half of these cases manifesting as diabetic ketoacidosis (DKA).2–7 We present a case of a middle-aged man who developed diabetes mellitus (DM) manifesting as hyperglycemic crisis and severe reversible hyperlipidemia. Literature on antipsychotic-associated metabolic adverse effects and clinical recommendations is presented.
Case Report Mr. H, a 39-year-old man with bipolar I disorder and hyperlipidemia, was brought to the emergency department after being found minimally responsive at his apartment. He was noted to be acidotic and severely hyperglycemic, with a pH of 7.24, a serum glucose level of 1966 mg/dL, an anion gap of 22 ([Naþ] level of 125 mEq/L, [Cl] level of 79 mEq/L, and a [bicarbonate] level of 24 mEq/L), and a significant ketonuria. Serum osmolality was 399 mOsm/kg. Medical complications at the time of admission included hypercarbia and hypoxia (requiring intubation), electrolyte abnormalities, prerenal azotemia, and a
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triglyceride level of 2942 mg/dL. He reportedly had been drinking increasing amounts of sweetened beverages in the weeks before admission, including fruit juices, sports drinks, and soda. His body mass index on admission was 38.7 (130 kg). Pertinent admission medications included 700 mg of quetiapine, 2500 mg of valproic acid, and 0.5 mg of lorazepam (all administered before bedtime). He had no history of glucose intolerance but did have a family history of dietcontrolled diabetes in his father. Before admission, he had attended weekly appointments with his outpatient psychiatrist, and no metabolic implicative signs or symptoms (such as polyuria/polydipsia or eruptive xanthomas) had been noted. Mr. H was stabilized medically, and his condition improved steadily. A lipid panel obtained on the second day of admission showed a cholesterol level of 365 mg/dL, triglycerides level of 1918 mg/dL, and high-density lipoprotein level of 16 mg/dL. His hemoglobin A1c was 14.2. Treatment with quetiapine was stopped because of metabolic concerns and medication with 15 mg of aripiprazole daily was started; no change was made to his valproic acid regimen. Treatment with 600 mg of gemfibrozil given twice a day was
Received June 16, 2014; revised July 9, 2014; accepted July 10, 2014. From Department of Psychiatry, University of Michigan, Ann Arbor, MI. Send correspondence and reprint requests to Chris Y. Wu, B.S., Department of Psychiatry, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, MI 48109-5338; e-mail: cywu@med. umich.edu & 2014 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.
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Wu et al. begun for hyperlipidemia, and administration of insulin was continued to maintain glycemic control. He was discharged after 13 days in the hospital. At outpatient follow-up, 1 week after discharge, his daily insulin dosage was decreased and his cholesterol and triglyceride levels were within the normal range. Mr. H's last hospitalization had been 16 months earlier for acute mania in the setting of medication noncompliance. During that admission, his nightly quetiapine dosage of 150 mg was increased to a nightly 800 mg dosage. At that time, his blood glucose levels were within the normal range, whereas lipids levels were elevated, with a cholesterol level of 225 mg/dL, a triglyceride level of 764 mg/dL, a high-density lipoprotein level of 43 mg/dL, and a low-density lipoprotein level of 120 mg/dL. He had been taking 800 mg of quetiapine before bedtime for 8 days before the aforementioned lipid panel was drawn. His body mass index at that time was 35.8 (120 kg). There was no evidence that laboratory metabolic monitoring was performed in the intervening 16 months between Mr. H's hospitalizations nor were medications given to lower his lipid or cholesterol levels. Discussion Quetiapine is an atypical antipsychotic originally approved in the United States in 1997 for the treatment of schizophrenia and currently also approved by the Food and Drug Administration for the treatment of bipolar disorder and major depressive disorder; its offlabel uses include generalized anxiety disorder, dementia, obsessive-compulsive disorder, and psychosis in patients with Parkinson disease.8 Quetiapine, and atypical antipsychotics as a class, has better sideeffect profiles than typical antipsychotics do and is thus much more widely prescribed. However, metabolic complications are more common with atypical antipsychotics; these typically include hyperglycemia, weight gain, hypertriglyceridemia, elevated lowdensity lipoprotein level, and decreased high-density lipoprotein level.2,4 Hypertension is another metabolic risk factor, although it is not typically mentioned secondary to atypical antipsychotics.9 These metabolic complications can be used to diagnose metabolic syndromes when 3 or more risk factors are present, with clinical significance attributed to its causal relationship with heart disease, diabetes, and stroke.9 Psychosomatics 55:6, November/December 2014
There are 2 case reports of rapid simultaneous development of hypertriglyceridemia and DM due to quetiapine usage.4,6,10 Aripiprazole and ziprasidone appear to have less metabolic risk than the other atypical antipsychotics do.5 Our case features a young white man who developed progressive hypertriglyceridemia and new-onset DM discovered during hospitalization for hyperglycemic emergency in the setting of high-dose quetiapine augmentation of valproic acid for the treatment of bipolar I disorder. In the 16 months that Mr. H was taking 700-800 mg of quetiapine nightly, he gained 10 kg and his triglyceride level increased from 764 mg/dL to 2942 mg/dL. His initial triglyceride level of 764 mg/dL suggests he was already developing metabolic complications from quetiapine at the time of the dose increase. Quetiapine usage commonly results in dyslipidemia, with increased levels of triglycerides, low-density lipoprotein, and total cholesterol and decreased highdensity lipoprotein level.4 Severe hypertriglyceridemia (4600 mg/dL) has been associated with quetiapine usage, with new-onset diabetes developing in some of these patients as well.5,6 The etiology of this severe hypertriglyceridemia is unclear.6 The highest level of triglycerides reported was 9450 mg/dL in a patient who was taking both quetiapine and olanzapine.11 There have also been several incidences of acute pancreatitis resulting from the extreme triglyceride level induced by quetiapine.4,6 Our case shows that the dyslipidemia that occurs with quetiapine usage is progressive. Mr. H's triglyceride level increased from 764 mg/dL to 2942 mg/dL in the 16 months while he was taking high dose quetiapine. His triglyceride level decreased to 1918 mg/dL after initiation of insulin therapy. In this same time interval, he also gained 10 kg and became diabetic (hemoglobin A1c of 14.2), which suggests development of more global metabolic complications that likely exacerbated his dyslipidemia. The proper characterization of Mr. H's hyperglycemic emergency is not known with absolute clarity. DKA and hyperglycemic hyperosmolar state (HHS) are nondistinct and both may result from atypical antipsychotic usage.5 In fact, patients presenting with hyperglycemic crisis have features of both in more than 30% of cases.12 DKA is defined by the clinical triad of hyperglycemia (4250 mg/dL), ketonemia, and metabolic acidosis and usually occurs with type 1 DM; meanwhile, HHS has more severe hyperglycemia (blood glucose level at an average of www.psychosomaticsjournal.org
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Case Reports 930 mg/dL), hyperosmolarity, little or no ketone formation, milder alterations in arterial pH and serum bicarbonate level, and typically occurs with type 2 DM.12 DKA also usually presents emergently, whereas HHS can present more insidiously over days to weeks.12 In Mr. H's case, the abnormalities in laboratory results and presentation have features of both DKA and HHS. His ketosis, anion gap, and metabolic acidosis suggest DKA, whereas his comatose presentation, potentially insidious onset exacerbated by sugared beverages, elevated serum osmolality, serum glucose level 4900 mg/dL, and serum bicarbonate level within the normal range suggest HHS. A plausible mechanism is that Mr. H had chronic hyperglycemia (given his hemoglobin A1c of 14.2) and developed HHS because of a lack of treatment with insulin and continued quetiapine usage. He was able to replete fluid losses from osmotic diuresis, leading to late development of ketosis and coma. Cases of acute transient β-cell failure leading to DKA in type 2 diabetics have been described with postulated mechanisms that include glucotoxicity, lipotoxicity, and genetic predisposition.12 All 3 postulated mechanisms are potentially present in our case. Additionally, although severe DKA can cause coma or stupor, it is usually associated with an arterial pH o7 and a serum bicarbonate level o10 mEq/L, both of which were not present in Mr. H.12 However, most of the published studies and case reports on hyperglycemic emergencies attributed to antipsychotics encountered during our literature review used the terminology DKA and not HHS. Mr. H had no documented history of diabetes. In fact, his blood glucose levels during admission 16 months ago were normal. New-onset hyperglycemia or exacerbation of previously diagnosed DM is a wellknown complication of several atypical antipsychotics, including quetiapine, clozapine, olanzapine, and risperdone.7 In 2002, Jin et al.13 analyzed 45 published cases of new-onset DM and DKA associated with atypical antipsychotics. They found that 20 of the 45 cases were attributed to clozapine and olanzapine use, whereas 3 were attributed to quetiapine and risperidone use. Overall, 42% of those with new-onset DM presented with DKA with most requiring intensive care.13 African Americans, patients younger than 35 years, and those with preexisting diabetes were overrepresented in the studies, 688
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and weight gain during treatment was not found to be associated with hyperglycemic complications.13 Additionally, they remarked that the co-occurrence of DKA with DM type 2 may be attributed to the antipsychotic agent acting as a metabolic stressor.13 They also concluded that DKA was a sporadic phenomenon without consistent risk factors. In a survey of quetiapine-associated cases by Koller et al.,7 the time of onset of hyperglycemia was 3 months or less for most patients, and it was usually reversed by medication withdrawal. Additionally, the mean age of newly diagnosed patients was 31.2 years, which is less than the mean age of newly diagnosed cases with type 2 diabetes in the general population.7 Proposed risk factors include African American race, male sex, age o35 years, patients with underlying β-cell defects, pre-existing obesity, poor exercise habits, exposures to other diabetogenic drugs, and previous or concomitant exposure to other atypical antipsychotic agents.7,13 Mr. H's profile of male sex, relative youth, and pre-existing obesity is consistent with the risk factors mentioned. In 2013, Ely et al.2 analyzed 17 cases of fatal DKA attributed to antipsychotic medications. They found that quetiapine was the most frequent antipsychotic, accounting for 7 of the cases. Olanzapine accounted for 6 cases, and clozapine accounted for 1 case. They found that the average age was 48 years (range: 32– 57 y), with 15 men and 2 women. Of the patients, 11 were African American. Therefore, despite olanzapine and clozapine being regarded as having more metabolic complications than quetiapine, quetiapine seems to result in fatalities more often, although this was a small study.2,4,14 Thus far, there are no reports of the number needed to harm (development of diabetes) for quetiapine because of a lack of prospective cohort incidence studies comparing quetiapine users with matched controls. In a study that compared the incidence of diabetes among users of different atypical antipsychotics, Citrome et al.15 reported an incidence rate of 18–21 events per 1000 person-years with no significant difference between quetiapine, olanzapine, risperidone, and ziprasidone users. Thus, all atypical antipsychotics demand a strict level of monitoring and vigilance for metabolic syndromes. Several mechanisms have been proposed for this medication-induced hyperglycemia, though the exact cause is likely multifactorial.16 Postulated mechanisms include drug-induced weight gain and central Psychosomatics 55:6, November/December 2014
Wu et al. adiposity leading to type 2 DM, decreased insulin secretion, antagonism of serotonin receptors, druginduced leptin resistance, dyslipidemia-mediated pancreatic β-cell damage, and hepatocyte transcription factor dysregulation.17 Although weight gain is common with antipsychotics as a class and has been causally linked to the development of type 2 DM,16 this cannot be the sole causal mechanism, as Jin et al.13 found that approximately 50% of cases of newonset DM associated with atypical antipsychotics showed no significant weight gain at the time of presentation. An additional mechanism only substantiated in animal studies is the direct alteration of glucose transporter proteins by antipsychotic agents.18 Further research on potential etiologies include activation of protein kinase C-β that results in adipogenic events in preadipocytes and musclederived stem cells19 and other adipokines, such as resistin and adiponectin, inhibition of brown adipocyte differentiation, and the role of peroxisome proliferator–activated receptors.20,21 No consensus has been reached though attribution of diabetes solely to drug-induced weight gain and adiposity is not viewed favorably.2 Our case was further complicated by the usage of valproic acid along with quetiapine. Interactions between valproic acid and quetiapine have been hypothesized, with a study showing that valproic acid increased plasma levels of quetiapine by 77%.22,23 Mr. H had been taking 2500 mg of valproic acid nightly along with high-dose quetiapine; this interaction may have elevated his quetiapine plasma levels beyond what is suggested by his dosage and further increased his risk for metabolic side effects as higher doses of quetiapine has been shown to have more effect on serum lipid levels.24 Furthermore, long-term valproic acid use has itself been directly associated with weight gain, hyperinsulinemia, insulin-resistance, hyperleptinemia, and leptin-resistance.25 We can make several recommendations based on our case. Firstly, practicing physicians, particularly psychiatrists, need to become better at recognizing the signs and symptoms of metabolic complications of atypical antipsychotics and be more responsible at ordering regular lipid and glucose laboratory tests. Mr. H saw his outpatient psychiatrist weekly in the months before admission and no symptoms of hyperglycemia, such as polydipsia/polyuria, were recognized. Additionally, monitoring of weight gain alone Psychosomatics 55:6, November/December 2014
is not sensitive, monitoring of blood glucose for outpatients should be mandatory, especially in the first 6 months of treatment.3 As a result of surveillance failures, no interventions were undertaken for Mr. H's hyperlipidemia. Thus, his medication-induced metabolic syndrome was allowed to progress to the point where he was severely decompensated. Several cases of fatal DKA have been attributed to quetiapine,2 and this risk can be lessened with more diligent monitoring. Based on the recommendations of guidelines collaboratively produced by the American Diabetes Association, American Psychiatric Associations, and others, diligent monitoring starts with baseline assessments of personal and familial risk factors for metabolic syndrome, weight and height (to calculate body mass index), waist circumference, blood pressure, fasting lipid glucose measurements, and fasting lipid profile.26 These assessments allow psychiatrists to riskstratify patients and provide referrals to the appropriate health professional for treatment (i.e., a weight management professional for patients who are overweight). Patients and families should be educated regarding nutrition and physical activity26 and be made aware of the signs and symptoms of DM and diabetic emergencies that necessitate immediate care (Table). A lesser known, but extremely specific, sign of acute severe dyslipidemia is the development of eruptive xanthomas, though this has only been reported with olanzapine and not with quetiapine.27 Those found to be at higher risk for metabolic complications can be switched to a medication with a lower metabolic risk profile, such as aripiprazole or ziprasidone.26 Surveillance monitoring includes weight assessments at 4, 8, and 12 weeks after drug initiation and quarterly thereafter.26 Weight gain Z5% should prompt intervention. Fasting glucose levels and blood pressure should be assessed 3 months after drug initiation and then annually thereafter.26 Fasting lipid levels should be obtained 3 months after drug initiation and quinquennially thereafter.26 However, it should be emphasized that the surveillance intervals provided are for screening purposes in otherwise asymptomatic patients. Those with concerning signs or symptoms or abnormalities in laboratory results should receive more frequent screening as clinically indicated, as well as receive consideration for medication adjustment and referral to proper specialists. www.psychosomaticsjournal.org
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Case Reports TABLE.
Signs and Symptoms of Diabetes and DKA/HHS
Diabetes
Diabetic emergencies
Frequent urination Excessive thirst Extreme hunger Unusual weight loss Increased fatigue Irritability Blurred vision
Nausea, vomiting, or abdominal pain Increased urination Thirst or very dry mouth Dry or flushed skin Constantly feeling tired Difficulty breathing (short, deep breaths) Fruity odor on breath Confusion or hallucinations or lethargy Fever Focal neurologic symptoms or convulsions or vision loss Stupor/coma
DKA ¼ diabetic ketoacidosis; HHS ¼ hyperglycemic hyperosmolar state. Adapted with permission from American Diabetes Association32 and Mayo Foundation for Medical Education and Research.33 It can be noted that several signs and symptoms are nonspecific and may be attributed to psychiatric illness or other medication adverse effects.
Despite the lucid simplicity of these recommendations, baseline testing rates varied from 8%–23% and annual testing rates ranged from 23%–38% in a well-cited study.28
There is evidence in the literature that metabolic effects of antipsychotics are reversible, suggesting that the patient's insulin requirements will steadily decrease.29–31 Mr. H's lipid levels normalized within 3 weeks of discharge, and he returned to work with no functional impairments. A quicker diagnosis of metabolic syndrome as an outpatient could have led to these interventions being done sooner and as an outpatient, thus avoiding the risk for morbidities and mortality (e.g., mechanical intubation, intensive care unit admission) due to DKA/HHS. Conclusion Despite quetiapine's increasing usage due to fewer extrapyramidal side effects, it can produce significant metabolic toxicity, especially when the patient is cousing valproic acid. Our case suggests that the natural history of these metabolic side effects is progressive and can become severe if quetiapine is not discontinued. Proper monitoring of metabolic variables can allow intervention before side effects become severe enough to necessitate hospitalization. Disclosure: The authors disclosed no proprietary or commercial interest in any product mentioned or concept discussed in this article.
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