A case report and literature review of olanzapine-associated hyperglycemia with previous history of gestational diabetes

Olanzapine (Zyprexa) is a second-generation antipsychotic (SGA) FDA-approved for schizophrenia and bipolar 1 disorder as monotherapy or in combination with lithium or valproate.¹  The American Psychiatric Association 2020 Schizophrenia Guidelines state antipsychotic medications, particularly clozapine and olanzapine, are associated with an increased risk of hyperglycemia and diabetes mellitus.²  Due to these risks, the FDA states physicians should consider the risks and benefits when prescribing SGAs to patients with an established diagnosis of diabetes mellitus or borderline increased blood glucose level (fasting 100-126 mg/dL, nonfasting 140-200 mg/dL).¹ 

Studies have shown that receiving antipsychotics during pregnancy may increase the risk of gestational diabetes mellitus (GDM). A study by Park et al³  supports this claim and found continuation of olanzapine or quetiapine during pregnancy had an increased risk of developing GDM. It is unknown if a history of GDM increases the risk of olanzapine-associated hyperglycemia. Therefore, all patients taking SGAs should be regularly monitored for uncontrolled hyperglycemia regardless of risk factors. Fasting blood glucose testing is recommended at the beginning of treatment and periodically thereafter.² 

A case of olanzapine-associated hyperglycemia in a 33-year-old female with history of GDM is discussed. A literature review summarizing previous case reports is also presented.

A 33-year-old female was admitted for suicidal ideations and acute psychosis. She had a past medical history of bipolar disorder, cocaine and amphetamine use disorder, hypertension, and GDM. She weighed 63.9 kg with a body mass index of 24 kg/m², blood pressure of 141/94 mm Hg, and heart rate of 108 beats/min at admission. She had 2 random blood glucose levels of 146 mg/dL and 90 mg/dL on day 1 and 3, respectively. Urine drug screen was positive for amphetamines, marijuana, and cocaine. Her only home medication was hydrochlorothiazide 25 mg PO daily.

Upon admission to inpatient psychiatry, she required an emergency treatment order of chlorpromazine 100 mg intramuscular and lorazepam 3 mg intramuscular because of acute psychosis, severe agitation, and an attempt to elope and attack staff. Because of minimal improvement in severity of psychotic symptoms, on day 3 she was initiated on olanzapine 5 mg PO at bedtime and subsequently titrated to olanzapine 5 mg every morning and 20 mg PO at bedtime. Iron studies were completed on day 3 and ferrous sulfate 325 mg PO 3 times daily was initiated. Amlodipine 5 mg PO daily was initiated on day 6 and titrated to 10 mg daily on day 12 because of elevated blood pressure. On day 15, she complained of frequent urination and unquenchable thirst for the last 2 days. Blood glucose was checked, and she had 2 critical readings >500 mg/dL. No other blood glucose readings were taken after olanzapine was initiated; therefore, the onset of hyperglycemia was unknown. She was transferred to the emergency department and admitted to the inpatient hospital for further management. Table 1 shows olanzapine total daily dose, blood glucose readings, and units of insulin administered throughout her admission.

On day 16, her hemoglobin A1c (HbA1c) was 8% and insulin aspart sliding scale and insulin detemir 15 units subcutaneously twice daily were initiated. Olanzapine was continued by the hospitalist and psychiatry was consulted. Additionally, hydrochlorothiazide 25 mg PO daily was resumed, and ferrous sulfate was reduced to 325 mg PO daily. On day 17, the psychiatric pharmacist recommended to the psychiatrist to discontinue olanzapine as this may have contributed to her sudden onset of hyperglycemia and to initiate an alternative antipsychotic. The psychiatrist discontinued olanzapine; however, no alternative antipsychotic was initiated during the medical admission. There were no overt manic symptoms, psychosis, or suicidal or homicidal ideation documented in the psychiatry progress notes. Additional medication changes on day 17 included 1 dose of as needed hydroxyzine pamoate 25 mg, lisinopril 10 mg PO daily which was increased to 40 mg on day 19. Increasing amounts of insulin were required, despite discontinuing olanzapine and initiating a 45-gram consistent carbohydrate diet on day 18. Her blood glucose stabilized on insulin detemir 60 units subcutaneously twice daily and insulin aspart 15 units subcutaneously 3 times daily with meals in addition to sliding scale insulin aspart. On day 22, she was transferred back to inpatient psychiatry, and a 3 kg weight increase was noted from day 1.

Once she transferred back to inpatient psychiatry, she was largely at baseline and no longer experienced symptoms of acute psychosis, mania, or suicidal ideation. She agreed to begin ziprasidone 20 mg PO twice daily with meals for bipolar disorder maintenance therapy because of the lower metabolic risk compared to olanzapine. On day 24, her fasting blood glucose was 159 mg/dL, and she was discharged from inpatient psychiatry. Discharge diagnoses included bipolar disorder, amphetamine and cocaine use disorder, hypertension, microcytic anemia, and new onset diabetes mellitus. The discharge medication list included ziprasidone 20 mg PO twice daily with meals, insulin detemir 60 units subcutaneously twice daily, insulin aspart 15 units subcutaneously 3 times daily, lisinopril 40 mg PO daily, amlodipine 10 mg PO daily, hydrochlorothiazide 25 mg PO daily, and ferrous sulfate 325 mg PO daily. No follow up on blood glucose control could be obtained after discharge.

A review of the literature was completed using PubMed to identify previous case reports of olanzapine-induced hyperglycemia to establish whether a history of GDM was a known risk factor. Keywords searched included olanzapine, hyperglycemia, diabetes mellitus, and gestational. Similar article results and references of included cases were searched to identify additional case reports. No date restrictions were applied and only case reports available in English were included.

A total of 47 previous cases^4-35  of olanzapine-induced hyperglycemia were identified, and they are summarized in Table 2. Age ranged from 16 to 89 years (mean = 40.8 years, median = 40.5 years). Ethnicity was primarily White (n = 16) and African American (n = 14), however ethnicity was not reported in 13 cases and listed as “other” in 4 cases. Additionally, most cases were male (n = 35) and either overweight (n = 11) or obese (n = 12).^4-35  Only 4 cases^6,20,22,26  reported a history of diabetes mellitus, 2 of which were female with no known history of GDM.^22,26  One case⁹  of GDM was identified, the diagnosis occurred during a fourth pregnancy while taking olanzapine.

Olanzapine daily dose ranged from 5 to 30 mg (mean = 16.5 mg). Onset of hyperglycemia after initiating olanzapine ranged from 3 days to 3 years (mean = 6.5 months, median = 3 months). Most cases required treatment for hyperglycemia with insulin, although a small proportion were managed on oral diabetes medications.^4-35  Olanzapine was continued in 9 cases, most commonly because of significant improvement in psychiatric symptoms or well-controlled blood glucose with oral diabetes medications or low dose insulin.^{7,12,14,19,25,33,34}  Olanzapine was discontinued in 34 cases and an alternative antipsychotic was initiated in 27 cases, the most common alternatives were risperidone (n = 7) and quetiapine (n = 7).^4-35  Once the antipsychotic was switched from olanzapine, some cases were able to reduce insulin dosing or discontinue diabetes treatment altogether.^* Three case reports^16,30,32  included a rechallenge of olanzapine, and all reported a recurrence of hyperglycemia.

There are several proposed mechanisms of olanzapine-induced hyperglycemia, all of which are not fully understood. Antipsychotics may cause hyperglycemia by reduced insulin secretion and increased insulin resistance. It is well known SGAs may cause a rapid weight gain within 6 to 8 weeks of initiation, which may contribute to insulin resistance and subsequently hyperglycemia. Additional mechanisms are thought to be present because of cases where hyperglycemia develops rapidly with minimal to no change in weight.³⁶  In addition to weight gain causing insulin resistance, antipsychotics likely have a direct effect by inhibiting insulin signaling pathways.³⁷  Antipsychotics may also reduce insulin secretion involving effects on multiple receptors including dopamine, serotonin, muscarinic, and alpha-adrenergic receptors.³⁷  They may further reduce insulin secretion by direct damage to pancreatic beta-cells causing impairment or cell death.^36-38  In women who develop GDM, similar mechanisms may cause hyperglycemia including dysfunction of pancreatic beta-cells because of excessive insulin production as well as insulin resistance.³⁹  Pregnancy itself is an insulin resistant state, and additional risk factors for developing GDM include multiple pregnancies, increasing maternal age, obesity, and a family history of diabetes mellitus.⁹ 

In the case presented, the onset of hyperglycemia was faster compared to many previously identified cases of olanzapine-induced hyperglycemia; however, it is possible hyperglycemia was identified and treated earlier since she was hospitalized. She was not overweight nor obese, however, she had a prior history of GDM. GDM is an independent risk factor for developing type 2 diabetes mellitus later in life and is a common complication affecting approximately 15% of pregnancies worldwide.^39,40  GDM is diagnosed when hyperglycemia is present in a woman with no known history of diabetes mellitus, as measured by an oral glucose tolerance test performed at or after 24-weeks gestation.⁴¹  Risk factors for development of GDM include obesity, age, and family history of diabetes.³⁹ 

Additionally, a recent systematic review and meta-analysis⁴²  reported an increased risk of GDM in women using antipsychotics during pregnancy; however, more research is needed to stratify the risk of various antipsychotics. This literature review identified 1 case⁹  of GDM development during a fourth pregnancy while taking olanzapine. Olanzapine was continued throughout the affected pregnancy, and GDM was treated with metformin. She delivered via emergency cesarean section due to severe euglycemic ketoacidosis precipitated by vomiting. Hyperglycemia persisted after delivery, and metformin was continued. During her previous pregnancies she was not taking antipsychotics, and the pregnancies were not complicated by GDM. Furthermore, GDM occurred in 1 case⁴³  involving the use of clozapine. Clozapine was continued during pregnancy, and blood glucose was controlled with insulin.

In this case, ziprasidone was initiated after olanzapine was discontinued because of lower metabolic risk. A case report by Spivak et al⁴⁴  suggests ziprasidone as a potential alternative for patients who develop olanzapine-associated hyperglycemia, however 3 case reports^45-47  of ziprasidone-associated hyperglycemia have been reported. Previous literature reviews have also identified case reports of hyperglycemia induced by aripiprazole, clozapine, quetiapine, and risperidone.⁴⁸  Given their collective metabolic risks, SGA selection in any patient should consider a variety of factors including patients' diagnoses, past medication trials, medication allergies, comorbidities, and past medical history, including GDM.

This case report further contributes to reports of olanzapine-induced hyperglycemia and identifies a history of GDM as an additional risk factor. A Naranjo score of 5 was calculated, indicating a probable adverse drug reaction. The score was calculated based upon previous conclusive reports (+1), the adverse event appeared after suspected drug was administered (+2), the adverse reaction improved when the drug was discontinued or a specific antagonist was administered (+1), and the adverse event was confirmed by objective evidence (+1). All other questions on the probability scale scored zero. A notable limitation of this case report is the possibility of undiagnosed type 2 diabetes mellitus, as evidenced by the patient's insulin needs at discharge and an inpatient HbA1c of 8%. It is possible olanzapine exacerbated underlying hyperglycemia. Therefore, this case emphasizes the importance of obtaining baseline laboratory monitoring for all patients beginning SGAs, especially those with a history of GDM.

There are several previous case reports of olanzapine-induced hyperglycemia, however this is the first case report to identify GDM as a potential risk factor. This case emphasizes the importance of obtaining baseline glucose monitoring for all patients beginning olanzapine treatment, especially those with a history of GDM. If hyperglycemia develops, olanzapine may need to be discontinued and/or treatment with oral diabetes medication or insulin may be necessary. Pharmacists are well positioned to identify a history of GDM as a potential risk factor for developing olanzapine-induced hyperglycemia and recommend appropriate adjustments to treatment.