LAUSR

OBJECTIVE While treatment with antipsychotics and antiepileptics have been associated with an increased risk of DM, lithium may have the opposite effect via inhibition of glycogen synthase kinase-3. The aim of this study was to investigate whether treatment of bipolar disorder with lithium, antipsychotics, or antiepileptics is associated with the risk of DM in a real-world clinical setting. METHODS Using nationwide registers, we identified all patients diagnosed with bipolar disorder in Danish Psychiatric Services from January 1, 1996, to January 1, 2019 (N=30,451). The risk of developing DM was operationalized via hospital diagnoses and redeemed prescriptions for glucose-lowering drugs. For lithium, antipsychotics, valproate, and lamotrigine, we calculated hazard rate ratios (HRR) for developing DM via adjusted Cox proportional hazards models. Potential cumulative dose-response-like associations were examined using the log-rank test. RESULTS During follow-up (245,181 person-years), 2107 (6.9%) patients developed DM. Compared to non-users of the respective drugs, we found no clinically or statistically significant difference in the risk of developing DM among patients receiving lithium (n=11,690; incidence rate of DM/1,000 person-years (IR)=8.87, 95%CI:8.02-9.90; HRR=0.94, 95%CI:0.84-1.06) or lamotrigine (n=11,785; IR=7.58, 95%CI:6.69-8.59; HRR=0.89, 95%CI:0.77-1.02), respectively. Conversely, for patients receiving valproate (n=5,171; IR=12.68, 95%CI:10.87-14.80; HRR=1.34, 95%CI:1.14-1.58) and antipsychotics (n=22,719; IR=12.00, 95%CI:11.14-12.94; HRR=1.65, 95%CI:1.45-1.88), respectively, there was increased risk of developing DM. For antipsychotics, we observed a clear cumulative dose-response-like association with the risk of DM. CONCLUSIONS Treatment with valproate and antipsychotics-but not with lithium and lamotrigine-was associated with increased risk of DM in a real-world cohort of patients with bipolar disorder.