Drug‐drug interactions as a determinant of elevated lithium serum levels in daily clinical practice

Abstract

Objective: Lithium is a drug with a narrow therapeutic window. Concomitantly used medication is a potentially influencing factor of lithium serum concentrations. We conducted a multicentre retrospective case‐control study with the aim of investigating lithium‐related drug interactions as determinants of elevated lithium serum levels in daily clinical practice. Methods: Cases were patients with an increase of at least 50% in lithium serum concentrations resulting in an elevated lithium serum level of at least 1.3 mmol/L, and who were not suspected of a suicide attempt. Controls were patients who showed stable lithium serum levels within the therapeutic range. Use and start of non‐steroidal anti‐inflammatory drugs, diuretics, renin–angiotensin inhibitors, theophyllin and antibiotics were investigated as potential determinants of the elevated lithium serum levels. Irregularity in lithium dispensing pattern, change in lithium dosing regimen, age, gender, prescribing physician and laboratory parameters were investigated as potential confounders. Results: We included 51 cases and 51 controls in our study. Five (9.8%) controls and 15 (29.4%) cases used potentially interacting co‐medication [OR of 3.83 (95%CI 1.28–11.48)]. Start of potentially interacting co‐medication was observed in eight (15.7%) cases and in zero (0%) controls resulting in an OR of 20.13 (95% CI 1.13–359). After adjustment for co‐medication, irregularity in lithium dispensing pattern, change in lithium dosing regimen, and age, the statistically significant association was lost. We report an OR of 2.70 (95% CI 0.78–9.31) for use of concomitant medication, with a large contribution of antibiotic agents, and an OR of 3.14 (95% CI 1.15–8.61) for irregularity in lithium dispensing pattern. Conclusion: Use of co‐medication, especially antibiotics, tends to be associated with elevated lithium serum levels.

The impact of environmental temperature on lithium serum levels

“…Finally, we have not been able to correct for other important patient characteristics that have previously been demonstrated to be related to lithium serum levels, such as comorbidity, current mood phase of BD, diarrhea, vomiting, infections or renal insufficiency, concomitantly used medication, pregnancy, changes in diet, alcohol use or weight, and higher rates of perspiration due to exercise or visits to saunas (2, 36–38).…”

Epidemiology and characteristics of adverse drug reactions caused by drug–drug interactions

“…Interactions involving drugs with a narrow therapeutic range (e.g., warfarin, cyclosporine, clozapine, lithium, digoxin, phenytoin, and theophylline) have more frequent and serious clinical consequences than those involving drugs with a wide therapeutic range [84][85][86][87]. The dosage of the interacting drug may also be critical [88].…”

Temporal association as a prerequisite factor of valsartan‐induced lithium toxicity

“…For example, it was shown that even a simple switch from one ACE-I to another (fosinopril to lisinopril) can provoke lithium toxicity (26). Whatever the exact mechanism may be, an increase in the serum lithium level is often observed with the introduction of ACE-I or AT 1 blockers (7,22). Once the lithium concentration has reached equilibrium, such a drug combination can be relatively safely maintained, although caution is still needed when the dose of ACE-I/AT 1 blockers is increased (23).…”