Diabetic Ketoacidosis Associated With Aripiprazole
Zaineb H. Makhzoumi, B.S., Leon P. McLean, M.D., M.P.H., Jefferson H. Lee, M.D., and Ada I. Ibe, M.D.Author Information
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Abstract and Introduction
Metabolic adverse effects such as hyperglycemia, alterations in insulin sensitivity, and weight gain are known to be potential complications of atypical antipsychotic therapy. In certain cases, hyperglycemia may be so profound that diabetic ketoacidosis (DKA) or hyperosmolar coma may result. Aripiprazole, approved by the United States Food and Drug Administration in 2002, appears to have fewer metabolic adverse effects than other atypical antipsychotics. We describe a 44-year-old man with no personal or family history of diabetes mellitus who was prescribed aripiprazole for schizoaffective disorder. Two weeks after starting this therapy, the patient developed DKA, which was corrected with insulin therapy and aggressive hydration. According to the Naranjo adverse drug reaction probability scale, aripiprazole was the probable trigger of his DKA. An exhaustive search for other causes of DKA was unrevealing. Administration of aripiprazole or any other atypical antipsychotic should be terminated when impaired glucose tolerance is suspected. Vigilance regarding the potential adverse effects of this class of drugs, including new agents such as aripiprazole, is crucial to preventing potentially life-threatening complications of hyperglycemia.
Over the past several decades, the pharmacologic treatment of schizophrenia has shifted from the conventional antipsychotic agents to the newer atypical antipsychotics.[1,2] Advantages of the atypical antipsychotics include more effective treatment of negative symptoms, improved mood and cognition, fewer extrapyramidal side effects, and reduced hyperprolactinemia.[2–5] Of the atypical agents, aripiprazole's once-daily administration presumably enhances patient compliance compared with agents requiring more frequent administration. Although the atypical antipsychotics are generally considered to be better tolerated than the conventional ones, significant adverse effects do occur. As a class, atypical antipsychotics have been associated with weight gain, hyperglycemia, sedation, and orthostatic hypotension.[2,3] Aripiprazole, however, reportedly causes less dramatic weight gain, dyslipidemia, and hyperglycemia than do the older atypical antipsychotics.[2–4]
Numerous case reports have linked atypical antipsychotics to hyperglycemia and new-onset diabetes mellitus, although the precise mechanism causing this effect has not been well elucidated. Two case reports have linked diabetic ketoacidosis (DKA) to aripiprazole therapy: one in a patient with a previous diagnosis of diabetes, the other in a patient with no known history of diabetes.[6,7] We describe a patient with no personal or family history of diabetes who developed DKA after the start of aripiprazole therapy.
A 44-year-old African-American man with a 16-year history of schizoaffective disorder came to the emergency department of a large urban academic medical center complaining of "hearing voices from another world." The patient's other medical history was significant only for hyperlipidemia diagnosed 3 years earlier; however, the patient reported taking no drug therapy. He had no personal or family history of diabetes, and no diagnosis of diabetes was documented in any of his previous hospital records. The patient had been admitted 3 years earlier for schizoaffective disorder and responded well to treatment with fluphenazine and valproic acid. He appeared to be experiencing an exacerbation of schizoaffective disorder and was admitted to the psychiatric service for further evaluation and management.
After the patient's admission to the psychiatric unit, treatment was started with fluphenazine 5 mg/day, which was chosen because of his previous good response. On hospital day 3, fluphenazine was increased to 5 mg twice/day, and valproic acid 1750 mg/day was added. The patient tolerated these agents well; however, he continued to experience persistent auditory hallucinations as well as respond to internal stimuli. By day 27, the patient was still having auditory hallucinations. In addition, he reported "special powers" in his abdomen that allowed him to hear voices.
Treatment was started on day 27 with aripiprazole 15 mg every evening, with plans for upward titration until the patient's psychotic symptoms were controlled. In addition to aripiprazole, the patient was receiving fluphenazine and valproic acid, benztropine for akathisia, and atorvastatin for hyperlipidemia. On day 28, he continued to experience auditory hallucinations and respond to internal stimuli. Aripiprazole was increased to 30 mg every evening. No other changes in his drug therapy were made, and monitoring was continued. By day 43, the patient had received 16 days of aripiprazole treatment. Also on that day, he experienced an episode of urinary incontinence.
Early on day 44, the patient began to refuse nutrition by mouth. He became increasingly somnolent and had difficulty moving his upper extremities. That evening, his upper extremity weakness progressed, and he lost the ability to take his drugs or drink fluids without assistance. He was confused and had difficulty communi-cating with staff, who described him as drowsy and difficult to arouse. The patient was administered intravenous fluids due to his recent decrease in oral intake. An electrocardiogram revealed sinus tachycardia but was otherwise unremarkable.
On day 45, the patient was still lethargic. He stopped communicating with staff, had difficulty walking, and had received no substantial oral intake for approximately 48 hours. Laboratory findings at that time indicated a glucose level of 813 mg/dl (normal range 70–99 mg/dl), bicarbonate 9 mEq/L (21–30 mEq/L), and an anion gap of 31 mEq/L (8–16 mEq/L; Table 1 ). Other pertinent findings included a moderate serum ketone level, valproic acid 59 B5g/ml (therapeutic range 50–100 B5g/ml), creatine kinase 199 U/L (55–170 U/L), and troponin I level less than 0.1 ng/ml (< onclick="resizeWin('Tables',500,650)" href="http://www.medscape.com/viewarticle/583143_Tables#T1" target="Tables">Table 1 ).
Intravenous insulin was transitioned to subcutaneous long-acting insulin, and the patient was transferred back to the psychiatric service after his serum glucose levels had stabilized. He was discharged receiving treatment with metformin, insulin glargine, and insulin aspart in addition to benztropine, fluphenazine, divalproex sodium, and escitalopram. Four months after discharge, the patient still required insulin.
The diagnosis of DKA requires characteristic objective derangements encompassing, but not limited to, hyperglycemia (glucose level > 300 mg/dl), low serum bicarbonate level (< 15 mEq/L), acidosis (pH < 7.30), and ketonemia and ketonuria.[8,9] Another common derangement is volume depletion resulting in acute renal failure. All the abnormalities listed above were present in our patient, including an anion gap of 31 mEq/L. These findings occurred after 2 weeks of aripiprazole administration, suggesting a causal link between this agent and DKA. The Naranjo adverse drug reaction probability scale has been used as an objective means to assess causality between a drug and a purported adverse effect. In our patient, DKA was observed after administration of aripiprazole and resolved after the agent was discontinued. Other alternative causes of DKA were ruled out through the patient's history and laboratory data. According to the Naranjo scale (score of 5), aripiprazole was the probable catalyst triggering DKA.
It is important to exclude other potential causes of DKA.[8,11,12] Before admission to the MICU, our patient had no known history of diabetes, although his elevated hemoglobin A1c suggested that he may have had previously undiagnosed diabetes mellitus. Even so, during the patient's previous hospitalizations, his serum glucose level had been less than 126 mg/dl without treatment with insulin or oral hypo-glycemic agents. During an emergency department visit more than 3 years earlier, the patient had an isolated random blood glucose level of 148 mg/dl; this elevated level was not evaluated further. Over the next 3 years, all serum chemistries obtained for our patient reflected a blood glucose level less than 126 mg/dl until DKA developed. In contrast, a patient with aripiprazole-associated DKA described in one case report had a 10-year history of type 2 diabetes mellitus requiring daily oral hypoglycemics. After starting aripiprazole, the patient developed DKA.
Preexisting impairment of glucose metabolism is probably relevant to our patient's case, as his body mass index (BMI) on admission was 43.3 kg/m2 (range for normal weight 18.5–24.9 kg/m2) and 41.1 kg/m2 during his episode of DKA. Given the strong correlation between obesity and impaired glucose tolerance, our patient may have been particularly susceptible to aripiprazole-associated DKA. The patient described in another report linking DKA to aripiprazole had increasing obesity. That patient did not have diabetes initially, and had a BMI of 32 kg/m2. He subsequently received aripiprazole for 18 months and then developed DKA, with an increased BMI of 41 kg/m. The authors hypothesized that aripiprazole therapy resulted in weight gain, which led to insulin resistance and subsequent diabetes mellitus and DKA. Our patient's BMI did not increase after aripiprazole intake, although he did have significant preexisting obesity, which probably made him vulnerable to a direct and deleterious effect of aripiprazole on glucose tolerance.
Common causes of DKA include concomitant infection, myocardial infarction, and pancreatitis. Our patient was afebrile when transferred to the MICU. His white blood cell count was minimally elevated, as was his hemoglobin level ( Table 1 ). His mild leukocytosis was likely a reflection of his volume-contracted state rather than an infectious process. Urine and blood cultures had no growth of bacteria, and a chest radiograph was not consistent with an infectious process. Myocardial infarction was unlikely given the lack of ischemic findings on the patient's electro-cardiogram and negative troponin I and creatine kinase–MB isoenzyme levels.
The role of pancreatitis was not fully assessed since serum amylase and lipase levels were not checked, and no abdominal imaging was performed. However, our patient had no history of abdominal pain; therefore, clinical suspicion of pancreatitis was low.
Since the FDA approval of aripiprazole in 2002, relatively few adverse effects associated with the agent have been reported. To our knowledge, profound hyperglycemia has been described in only three patients, including our patient.[6,7] Abnormal glucose tolerance is the unifying link in all three patients and is reflected in preexisting diabetes mellitus, weight gain after starting therapy, or obesity at baseline. These variations on a central theme point to a complex relationship between aripiprazole and glucose homeostasis. Our patient's preexisting obesity and virtually no change in BMI before and after DKA argues against the notion that aripiprazole-induced weight gain is the sole mechanism of glucose intolerance. The significant glucose intolerance and subsequent DKA in our patient may reflect the direct exacerbation of insulin resistance by aripiprazole within target tissues.
In 2004, the FDA requested that all manu-facturers of atypical antipsychotics provide a warning statement regarding the risk of hyperglycemia in patients treated with these agents. The warning states that patients with known diabetes should have their serum glucose monitored regularly. It also advises that those at risk of developing diabetes have their serum blood glucose tested before the start of treatment with an atypical antipsychotic and then checked periodically during treatment. Monitoring patients for symptoms of hyperglycemia such as polydipsia, polyuria, polyphagia, and weakness is suggested, with a fasting blood glucose test if these symptoms develop. The FDA patient information sheet for aripiprazole states that patients who have diabetes or are at risk for developing diabetes have their "blood sugar checked often."
With respect to aripiprazole, it has been suggested in the literature that aripiprazole is not associated with diabetes or the risk of developing diabetes, including a 2004 consensus statement drafted by several professional organizations.[3,4] The statement also suggests that the risk of developing hyperglycemia is decreased in patients receiving aripiprazole versus other atypical antipsychotics. Furthermore, the American Society of Health-System Pharmacists (ASHP) position statement on antipsychotics specifically recommends treatment with aripiprazole or ziprasidone in obese patients or those with preexisting diabetes. This position statement recommends monitoring fasting blood glucose level at the start of therapy every month for the first 3 months, then every 6 months. It also recommends checking blood glucose levels more frequently in patients who are gaining weight.
Both the consensus statement and the position statement recommend blood glucose monitoring for patients receiving treatment with any atypical antipsychotic; however, both also suggest that the newer atypical antipsychotics have fewer metabolic adverse effects.[3,15] These generaliza-tions may give practitioners a false sense of security regarding hyperglycemic adverse effects such as DKA in patients receiving treatment with new atypical antipsychotics such as aripiprazole.
Although DKA represents the most extreme clinical manifestation of diabetes, milder forms of glucose intolerance due to aripiprazole may be more common and less clinically evident than demonstrated in the case reports described. Given the concerns regarding hyperglycemia and diabetes associated with atypical antipsychotics, aripiprazole administration should be considered with greater caution for patients who already have or are at significant risk of developing impaired glucose tolerance.
Concern for the potential metabolic adverse effects of the atypical antipsychotics is reflected in the FDA warning statement described above. As recommended by the FDA, a heightened level of awareness of hyperglycemic symptoms such as polyuria, polydipsia, or weight change should be maintained. A low threshold for fingerstick glucose measurements is recommended if symptoms consistent with hyperglycemia appear. Administration of any atypical antipsychotic, including newer agents such as aripiprazole and ziprasidone, should be terminated when impaired glucose tolerance is suspected.The development of atypical antipsychotics has provided clinicians with a safer option for treatment of schizophrenia. Practitioners must be cognizant that even new atypical antipsychotics may be associated with metabolic adverse effects, and that severe complications may occur, as demonstrated by our patient's development of DKA associated with aripiprazole. Unfortunately, patients receiving therapy with these new agents are often treated on an outpatient basis or are hospitalized in psychiatric units, where glucose testing may be infrequent. New atypical anti-psychotics such as aripiprazole and ziprasidone are believed to have fewer metabolic adverse effects than older agents of the same class. However, this perception may reflect less clinical experience with these new agents. Vigilance regarding the potential adverse effects of this class of drugs, including the new agents, is crucial to preventing the potentially life-threatening complications associated with hyperglycemia.