Patients with schizophrenia receive medication to alleviate various symptoms, but some efficacious second generation antipsychotics, particularly olanzapine, can cause obesity, dyslipidemia, and diabetes mellitus. It has been generally considered that olanzapine contributes to the development of diabetes by inducing obesity and subsequent insulin resistance. In this study, we examined the effect of olanzapine and risperidone, another second generation antipsychotic, on a hamster pancreatic β cell line, and found that both evoked mild endoplasmic reticulum (ER) stress, as evidenced by mild activation of the ER stress sensor molecule PERK. Surprisingly, only olanzapine induced marked apoptosis. Phosphorylation of the α subunit of eukaryotic initiation factor 2, an event immediately downstream of PERK activation, was not observed in cells treated with olanzapine, protein synthesis continued despite PERK activation, and ER stress was thereby sustained. Secretion of insulin was markedly inhibited, and both proinsulin and insulin accumulated inside olanzapine-treated cells. Inhibition of protein synthesis and knockdown of insulin mRNA, which result in less unfolded protein burden, both attenuated subsequent olanzapine-induced apoptosis. Given clinical observations that some patients taking olanzapine exhibit hyperlipidemia and hyperglycemia without gaining weight, our observations suggest that damage to pancreatic β cells may contribute to the undesirable metabolic consequences of olanzapine treatment in some cases.

Second-generation antipsychotics are widely used to medicate patients with schizophrenia, but may cause metabolic side effects such as diabetes, which has been considered to result from obesity-associated insulin resistance. Olanzapine is particularly well known for this effect. However, clinical studies have suggested that olanzapine-induced hyperglycemia in certain patients cannot be explained by such a generalized mechanism. Here, we focused on the effects of olanzapine on insulin biosynthesis and secretion by mouse insulinoma MIN6 cells. Olanzapine reduced maturation of proinsulin, and thereby inhibited secretion of insulin; and specifically shifted the primary localization of proinsulin from insulin granules to the endoplasmic reticulum. This was due to olanzapine’s impairment of proper disulfide bond formation in proinsulin, although direct targets of olanzapine remain undetermined. Olanzapine-induced proinsulin misfolding and subsequent decrease also occurred at the mouse level. This mechanism of olanzapine-induced β-cell dysfunction should be considered, together with weight gain, when patients are administered olanzapine.

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We encountered a case of syndrome of inappropriate antidiuretic hormone secretion (SIADH) caused by duloxetine, serotonin and norepinephrine reuptake inhibitor (SNRI). A 74-year-old woman complaining of severe lethargy was transferred to our emergency department. Her serum sodium level was 109 mEq/L. Plasma hypo-osmolality with urine normo-osmolality was observed, indicating SIADH. Her essential hypertension had long been treated with telmisartan, and she had just started duloxetine 20 mg/day for chronic musculoskeletal pain 4 days prior to admission. On prescribing duloxetine in the primary care setting, clinicians should be aware of the possibility of duloxetine-induced hyponatremia, particularly in combination with telmisartan.

A 35-year-old woman, diagnosed as schizophrenia and treated with olanzapine for nearly 30 months, consulted our department because of severe hyperglycemia. The use of antipsychotics, switching from olanzapine to risperidone, and a one-month introduction of insulin therapy resulted in the decrease of pre-prandial blood glucose levels and the increase of insulin levels (269 to 128 mg/dL, 5.6 to 21.8 μU/mL). A higher level of insulin resistance as measured by HOMA-IR after the improvement of hyperglycemia (3.6 vs. 6.8) suggested that the long use of olanzapine reduced insulin secretion. Based on this case, impairment of pancreatic β-cells caused by olanzapine might be reversible.