Is aspirin useful in patients on lithium? A pharmacoepidemiological study related to bipolar disorder.
OBJECTIVE
Administration to rats of mood stabilizers approved for bipolar disorder (BD) downregulates markers of the brain arachidonic acid (AA, 20:4n-6) metabolic cascade, including phospholipase A(2) (PLA(2)) and cyclooxygenase (COX) expression. We hypothesized that other agents that target the brain AA cascade, nonsteroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids, also would ameliorate BD symptoms.


METHODS
Medication histories on subjects who had been prescribed lithium were collected from the Netherlands PHARMO Record Linkage System. Data were stratified according to drug classes that inhibit PLA(2) and/or COX enzymes, and duration of use. Incidence density (ID) of medication events (dose increase or substance change) was used as a proxy for clinical worsening. ID ratios in patients with the inhibitors plus lithium were compared to ratios in patients using lithium alone.


RESULTS
Low-dose acetylsalicylic acid (aspirin) significantly reduced the ID ratio of medication events, independent of use duration. The ID ratios of NSAIDs and glucocorticoids did not differ significantly from 1.0 if prescribed for > or =180 or > or =90 days, but exceeded 1.0 with shorter use. Selective COX-2 inhibitors had no significant effect and multiagent administration increased the ID ratio above 1.0.


CONCLUSIONS
Low-dose aspirin produced a statistically significant duration-independent reduction in the relative risk of clinical deterioration in subjects on lithium, whereas other NSAIDs and glucocorticoids did not. These tentative findings could be tested on larger databases containing detailed information about diagnosis and disease course, as well as by controlled clinical trials.
Stolk
Pieter
P
Division of Pharmacoepidemiology and Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, Netherlands.
Souverein
Patrick C
PC
Wilting
Ingeborg
I
Leufkens
Hubert G M
HG
Klein
Donald F
DF
Rapoport
Stanley I
SI
Heerdink
Eibert R
ER
D000293:Adolescent; D000328:Adult; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000627:therapeutic use; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001241:Aspirin / Q000008:administration & dosage / Q000627:therapeutic use*; D001714:Bipolar Disorder / Q000188:drug therapy* / Q000523:psychology; D015331:Cohort Studies; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D016208:Databases, Factual; D018450:Disease Progression; D004359:Drug Therapy, Combination; D004363:Drug Utilization; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D005938:Glucocorticoids / Q000008:administration & dosage / Q000627:therapeutic use; D006801:Humans; D008094:Lithium / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D017891:Pharmacoepidemiology / Q000379:methods; D064801:Phospholipase A2 Inhibitors; D055815:Young Adult
D000894:Anti-Inflammatory Agents, Non-Steroidal; D014150:Antipsychotic Agents; D052246:Cyclooxygenase 2 Inhibitors; D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D064801:Phospholipase A2 Inhibitors; D008094:Lithium; D001241:Aspirin