Pancreatitis associated with metformin used for management of clozapine-related weight gain

To the Editor

A 17-year-old male with treatment resistant schizophrenia and moderate intellectual disability treated with clozapine and metformin presented with 3 months of intermittent nausea and vomiting. Metformin had been commenced 9 months earlier during trials of other antipsychotics, to manage associated weight gain.

Metformin was initiated at 500 mg mane when the patient weighed 77 kg (body mass index [BMI] 24) and was increased to 500 mg BD over a 6-month period. Clozapine was then commenced after lack of response to other antipsychotics with an associated weight increase from 83.1 kg (BMI 26.5) to 88.4 kg (BMI 28) over 6 weeks. Metformin was titrated to 1500 mg BD over this period and maintained at this dose for 3 months.

Two weeks after the increase of metformin to 3000 mg/day, the patient experienced nausea and vomiting. The patient had a neutrophilia (white cell count [WCC] 13.9 × 10⁹/L [3.5–10], neutrophils 11.2 × 10⁹/L [1.5–6.5]) with evidence of inflammation (C-Reactive Protein 17 mg/L [0–10]), and lipase was elevated to 232 U/L (0–70), while abdominal x-ray and ultrasound were unremarkable. Gastrointestinal symptoms persisted and lipase was monitored monthly and remained within normal range until 3 months later when it elevated again to 115 U/L, with an associated neutrophilia (9.57 × 10⁹/L), but unremarkable abdominal x-ray. At this time, metformin was decreased to 500 mg PO BD. Since this reduction, no further gastrointestinal symptoms were reported, and lipase, haematological and inflammatory markers have remained within normal range. The patient was provisionally diagnosed with intermittent pancreatitis secondary to high-dose metformin.

Discussion

There is strong evidence for the efficacy of metformin in managing antipsychotic-associated weight gain (Zheng et al., 2015), and psychiatrists are increasingly prescribing metformin for this purpose. It is therefore important that psychiatrists are aware that pancreatitis is a well-described, albeit rare, side effect of metformin at higher doses, more commonly seen in patients with renal insufficiency. The pathogenesis of metformin-induced pancreatitis is not known and metformin is not known to interact with antipsychotic medications (Giorda et al., 2014).

We recommend metformin be prescribed at the recommended doses for managing antipsychotic-associated weight gain of no higher than 1.5–2.0 g/day (Taylor et al., 2015) and should not be further increased should weight gain continue. Recommended doses for the treatment of diabetes mellitus have a higher maximum (3 g/day), but these should not be used for the treatment of antipsychotic-associated weight gain. In patients experiencing nausea and vomiting while prescribed metformin, pancreatitis should be considered and appropriately investigated.