Based on the Wellcome Trust Case‐Control Consortium genome‐wide study, angiotensin agents were suggested as having potential in bipolar disorders. 20 A number of observations have linked angiotensin‐converting enzyme polymorphisms with depression and the serotonin and dopamine neurotransmitter systems. 21 Preclinical models further suggest that candesartan may have efficacy in models of mania. 22

There is evidence of dysregulation of the purinergic system in mood disorders as studies have demonstrated elevated levels of uric acids during mania. 18 Further, a recent meta‐analysis found some supportive effect in mania based on five randomized placebo‐controlled trials including a total of 426 patients. 19

Statins may have a role in depression due to its anti‐inflammatory effects. 15 , 16 In a Swedish register linkage study, statins seemed to reduce the risk of depression 17 but the associations with bipolar disorder have not been investigated. There are also early clinical trials of statins in depression suggesting effects similar to antidepressants in magnitude. 16

Aspirin preferentially inhibits cyclooxygenase‐1 (COX‐1) more than COX‐2 and acetylates COX‐2, thereby blocking the conversion of arachidonic acid to prostaglandins and thromboxane A2. The inhibition of COX‐1 is neuroprotective based on preclinical evidence while COX‐2 inhibition increases leukocyte recruitment into the brain exacerbating tissue damage. 13 A pilot randomized trial suggests that aspirin might impact bipolar depression. 14

Bipolar disorder has been associated with increased low‐grade inflammation indexed by increased C‐reactive protein and cytokine levels. 8 - 11 In a recent systematic review and meta‐analysis of randomized clinical trials, we identified a number of anti‐inflammatory drugs that may have an effect in bipolar disorder including N‐acetylcysteine, non‐steroidal anti‐inflammatory drugs (NSAIDs), and minocycline. 12

Drug repurposing is a process whereby a clinically used drug is shown to possess hitherto unknown potential utility in an alternative disorder. 4 , 5 This process capitalizes on the fact that the agent is safe at usually low cost in a novel niche. 4 , 6 Currently, much drug use in psychiatry is already off‐label—in bipolar disorder anticonvulsants are borrowed from epilepsy and antipsychotics from schizophrenia. We have argued that epidemiology is a viable byway to detect signals of effectiveness for repurposing agents. 5 We therefore systematically used Danish nation‐wide population‐based registers to investigate whether agents with an a priori preclinical or theoretical evidence base may have effects in bipolar disorder. This approach is based on a theoretical foundation of a common pathway of risk for many non‐communicable disorders, which include bipolar disorder, cardiovascular disorders, osteoporosis, and diabetes. These disorders have common genetic and environmental risks as well as common biological pathways particularly inflammation. 7

Bipolar disorder is a disabling mental illness with a lifetime prevalence of 1%‐2%, a high risk of recurrence of manic and depressive episodes, and is among the top 10 most debilitating illnesses in the world. 1 , 2 Despite the high prevalence and healthcare costs of bipolar disorder, the inefficient, costly and unpredictable drug development process has led to a drought in drug discovery and dwindling company pipelines of safe and efficacious drugs. 3 , 4 One of the major reasons for this decrease is the absence of clear pathophysiological targets, and an often long and costly development process with a major proportion of candidate drugs failing to reach the market due to disappointing efficacy or unpredictable adverse effects in humans. 3

Additional analyses were performed in which we also adjusted for the time‐dependent comorbidity status with additive effects of nine dummy variables indicating the nine comorbidity groups. The comorbidity status was always evaluated 10 years ago to avoid time‐interference between exposure status and comorbidity.

Risk time, events with a single manic episode/bipolar disorder or use of lithium, hazard ratios of a single manic episode/bipolar disorder or use of lithium adjusted for age, sex, employment status, and calendar year (unadjusted and adjusted for somatic diagnoses) [Colour figure can be viewed at wileyonlinelibrary.com

Separate analyses were performed to compare rates of incident mania/bipolar disorder among individuals exposed and unexposed to non‐aspirin NSAIDs, low‐dose aspirin, high‐dose aspirin, statins, angiotensin agents, and allopurinol (Figure 1 ). Similarly, separate analyses were done with the combined endpoint (incident mania/bipolar disorder or use of lithium) as the outcome measure (Figure 2 ).

Note that an individual, initially selected as a member of the random sample of the population, may change exposure status if he or she later purchased the drug under study.

The analyses included all individuals who received any of the exposure drugs in Denmark from 2005 to 2015 together with all individuals who were part of the 30% random sample of the general population in 1995. Individuals of the 30% random sample were followed from 1 January 2005, the other individuals who were part of the sample who at a point of time received one of the exposure drugs and were followed from 1 January 2005 or first purchase of the candidate drug under study (whichever date came last). Follow‐up continued until date of the event of interest, date of death, date of a diagnosis of organic mental disorders, mental disorders due to psychoactive substance use and schizophrenia (F00‐29 incl.), or 31 December 2015 (whichever date came first).

To control for confounding effects and to estimate the effect of duration of treatment, rates were compared during successive prescriptions of non‐aspirin NSAID, low‐dose aspirin, high‐dose aspirin, statins, allopurinol, and angiotensin agents, respectively, as in prior studies. 32 , 33 Thus, the category “1‐2 prescriptions” was used as reference category in all analyses. The exposure category status was continuously updated during the follow‐up separately for each subject. To achieve the cumulation of exposure categories (0, 1‐2, 3‐9, etc) in the fixed 10 years period, all analyses of the outcomes were restricted to the calendar years 2005 to 2015 (the Danish Medical Product Statistics register starts in 1995).

The association between drug exposure and the rate of incident mania/bipolar disorder was analyzed separately for each candidate drug using Poisson regression. In these analyses, the principle is that each follow‐up day where a subject is at risk for experiencing the outcome is categorized according to the current values of the drug exposure and of the potential confounders whereby the daily risk (the rate) of the outcome can be ascertained. The drug exposure on a given day during follow‐up was defined as the cumulated number of prescriptions of the candidate drug during the last 10 years in appropriate categories (number and width of categories were chosen dependent on the general usage of the candidate drug).

Somatic diagnoses were categorized within nine ICD‐8 and ICD‐10 defined somatic disease chapters (I: infections, II: neoplasms, III: diseases of the blood, IV +IX +X: endocrine, nutritional and metabolic diseases, and diseases of the circulatory or respiratory system, VI‐VIII: diseases of the nervous system, eye and ear, XI: diseases of the digestive system, XII: diseases of the skin and subcutaneous tissue, XIII: diseases of the musculoskeletal system, XIV: diseases of the genitourinary system and pregnancy, child birth, and the puerperium) and separately within each of these disease areas.

The primary outcome was a discharge diagnosis of a single manic episode or bipolar disorder (ICD codes: F30.0‐F31.6 and F38.00) given following a psychiatric contact (as inpatients or outpatients) and as identified in the Danish Psychiatric Central Register. Secondary outcome was a combined endpoint of either the primary outcome or use of lithium (ATC: N05AN).

The following individuals were excluded from the study population: individuals who purchased lithium at least once before the entry into the study (ie, before a purchase of the current candidate drug) and individuals with a diagnosis of mania/bipolar disorder prior to entry into the study (ICD codes: F30.0‐F31.6 and F38.00 and ICD‐8 codes: 296.19, 296.39 back to 1970).

All persons who purchased the exposure medications of interest at least once in the study period from 1 January 1995 to 31 December 2015 were identified in the Medicinal Product Statistics and entered into the study at the date of the first prescription. Additionally, a random sample consisting of 30% of the Danish population was identified in the Danish Medical Register on Vital Statistics among all inhabitants in Denmark who were alive at 1 January 1995.

The Danish National Hospital Register 26 contains data on all patients treated at all somatic hospitals as in‐ or outpatients in Denmark from 1 January 1977 and onwards as a part of the official Danish health survey. 31 Likewise, all psychiatric admissions have been registered in a nationwide register, The Danish Psychiatric Central Register 27 from 1 April 1970 and onwards. Since 1 January 1994, the ICD‐10 has been in use in both registers. 31

Non‐aspirin NSAIDs, statins, angiotensin agents, and allopurinol are available only by prescription, aside from low‐dose ibuprofen, which is obtainable over‐the‐counter in Denmark (but most regular users of low‐dose ibuprofen are also recorded in the database since regular users of low‐dose ibuprofen receive a 50% refund when redeeming a prescription for ibuprofen). Around 88% of the total use of non‐aspirin NSAIDs is by prescription and thus recorded in the register. 28 , 29 Low‐dose aspirin is primarily used for prevention and treatment of cardiovascular and thromboembolic events, with a daily recommended dose of 75‐150 mg. Due to the reimbursement of 50% of the cost, the vast majority (92%) of the total sales of low‐dose aspirin are prescriptions, whereas high‐dose aspirin (500 mg tablets), typically used for transient pain relief, is sold primarily over‐the‐counter in Denmark. 30

Data were obtained by linking Danish population‐based registers using the unique personal identification number that is assigned to all 5.7 million Danish persons, thus ensuring accurate linkage of information between registers, irrespective of changes in name and demographics. 23 In this way, the Medicinal Product Statistics 24 was linked with the Danish Medical Register on Vital Statistics, 25 the Danish National Hospital Register, 26 and the Danish Psychiatric Central Register. 27

Figure 1 presents risk time in years with at least one prescription of the exposure drug, events with a diagnosis of a single manic episode/bipolar disorder, HR of a single manic episode/bipolar disorder adjusted for age, gender, employment status, and calendar year (unadjusted and adjusted for somatic diagnoses). Figure 2 presents similar analyses with a diagnosis of a single manic episode/bipolar disorder or use of lithium as the outcome measure. For all drugs and in all analyses, the hazard rate of a single manic episode/bipolar disorder, and the hazard rate of a single manic episode/bipolar disorder or use of lithium, respectively, were lower during the prescription period 0 (non‐use) than during the prescription periods 1‐2 (although not statistically significantly for allopurinol and for low‐dose aspirin in analysis unadjusted for somatic illness). Further, HR decreased with the number of prescriptions of low‐dose aspirin, statins, and angiotensin agents according to both outcome measures (although for angiotensin agents and for low‐dose aspirin, HR in trend tests were not statistically significant in Figure 1 ). Continued uses of non‐aspirin NSAIDs as well as high‐dose aspirin were associated with increased rate of incident bipolar disorder on both outcome measures (although for high‐dose aspirin HR in the trend tests were not statistically significant in Figure 1 ). There were no statistically significant associations for allopurinol.

A total of 1,605,365 subjects were exposed to one of the six drugs of interest during the exposure period from 2005 to 2015. Table 1 shows the number of subjects exposed in total and for each drug (N), age and female gender proportion at first prescription.

4 DISCUSSION

Using Danish nation‐wide population‐based registers, we found that continued use of low‐dose aspirin, statins, and angiotensin agents were associated with decreased rates of incident mania/bipolar disorder. HR of incident mania/bipolar disorder were systematically decreased early after prescription of all these drugs (HR for prescription periods 3‐9 vs prescription periods 1‐2 were below 1) and continued to decrease during two or more subsequent prescription periods to a level below the rates during the unexposed periods. Continued uses of non‐aspirin NSAIDs as well as high‐dose aspirin were associated with increased rate of incident bipolar disorder. There was no effect of allopurinol, confirming the negative trial of Weiser and colleagues,34 but discordant with other trial data in mania.19

It is hard to accord the findings of decreased rates of incident mania/bipolar disorder associated with continued use of low‐dose aspirin, statins, and angiotensin agents to be a result of bias or confounding, as it would be expected that the rate of developing mania/bipolar disorder would in fact increase with the number of prescriptions and be higher among patients prescribed these drugs during longer periods reflecting a greater propensity to comorbidity with more severe physical disorder(s). This was in fact also the case for non‐aspirin NSAIDs and high‐dose aspirin for which continued use was associated with increasing rates of incident mania/bipolar disorder. In the prespecified plan of analyses, we planned to address bias or confounding by indication of use of the agent of interest in two different ways: Firstly, in the design of the study, we chose to estimate the rate of mania/bipolar disorder during successive prescription periods of the drug compared with the rate during prescription periods 1‐2. We systematically confirmed in all analyses that the prescription periods 1‐2 was associated with increased HR of mania/bipolar disorder compared with the period with the non‐use period (see Figures 1 and 2, [although not statistically significantly for allopurinol] illustrating confounding by indication since the drugs were prescribed for physical disorders associated with increased rate of developing mania/bipolar disorder including pain (NSAID35), osteoarthritis (NSAID35), prevention and treatment of cardiovascular and thromboembolic events (low‐dose aspirin36), arthritis urica (allopurinol) and other kinds of arthritis (NSAID37), hypercholesterolemia (statins38) and hypertension (angiotensin inhibitors38), and congestive heart failure (angiotensin inhibitors36). However, it is possible that low‐dose aspirin, statins, allopurinol, and angiotensin agents are more likely to be used for prophylaxis in relatively asymptomatic people, whereas as noted in the methods, NSAID and high‐dose aspirin are more likely to be used for acute and chronic pain, which are drivers of mood symptoms.

Secondly, in addition to adjustments for gender, age, employment status, and calendar period in 1‐year periods, we adjusted the analyses for a range of physical comorbidities since comorbidity with multiple diseases is normative in this population (eg, increased co‐occurrence of bipolar disorder with cardiovascular disease, diabetes mellitus, osteoporosis,39 chronic obstructive pulmonary disease, or pneumonia40, 41) and aiming to reduce unknown or residual confounding. Results from these analyses with adjustments for somatic diagnoses confirmed the results from primary analyses unadjusted for somatic illness.

Alternative study designs would be the case‐only design, which is however less suited for the kind of continues exposure in the present study, or an instrumental variable study design using the launch date as the instrument, which is less suited as a number of the investigated drugs were launched before beginning of the exposure period in 1995.

We confirmed our hypotheses regarding all the investigated drugs except continued use of non‐aspirin NSAID and allopurinol. Further as suggested, high‐dose aspirin was associated with increased rates of incident bipolar disorder—potentially a proxy of its use in a population with pain which drives mood disorders. It should be noted that high‐dose aspirin recorded in the Medical Product Statistics is likely prescribed for acute and prolonged pain conditions.30

Theoretically, higher doses of aspirin might inhibit COX‐2 and thereby increases leukocyte recruitment into the brain potentially causing tissue damage.13 The non‐aspirin NSAIDs may exert similar effects as these drugs are nonselective inhibitors of both COX‐1 and COX‐2.42, 43 Further, non‐aspirin NSAIDs are primarily used for moderate to severe pain, and, as noted, pain increases the risk of diverse mood and anxiety disorders.44

4.1 Other strengths of the study Firstly, the study included all persons in Denmark who purchased the exposure medication of interest (100%) together with a random sample of 30% of the Danish population. Secondly, two different outcome measures were included, (1) a diagnosis of a single manic episode/bipolar disorder at a psychiatric hospital contact as inpatient or outpatient and (2) a combined measure of either a diagnosis of single manic episode/bipolar disorder or use of lithium, also being prescribed in secondary care by general practitioners and private psychiatrists and mainly for bipolar disorder. Notably in this way, the study includes prescription data from all physicians in Denmark, that is, from primary care including general practise and private specialists and from secondary outpatient hospital care settings. As can be seen from Figures 1 and 2, the number of events was substantially higher with outcome measure 2 than with outcome measure 1, but the results of analyses with the two outcome measures were rather similar. In this way, the two outcome measures complement each other capturing partly different kinds of patients with bipolar disorder with findings both pointing in the same direction with decreased HR of bipolar disorder for continued use of low‐dose aspirin, statins, and angiotensin agents, (although not all reaching statistical significance in trend tests with outcome measure 1), serving to increase the internal and external validity of the findings. Thirdly, potential reverse causation is substantively excluded as only incident bipolar disorder/use of lithium were included in the analyses since we excluded individuals who were prescribed lithium (from 1995 to 2005) or had a diagnosis of bipolar disorder (back to 1970) prior to the drug class of interest. Fourthly, the follow‐up period included a 10 years period (from 2005 to 2015). Fifthly, as the first study ever we estimated associations with incident bipolar disorder in relation to the duration of treatment during successive drug prescriptions. Finally, we conducted similar analyses with depression as the outcome with broadly comparable findings.45

4.2 Limitations The primary outcome measure was not research based but based on clinical diagnoses. However, we added analyses with a combined outcome measure on a diagnosis of mania/bipolar disorder or the use of lithium and systematically confirmed results from the primary analyses. In general, we did not consider potential effects of concomitant use of two or more exposure drugs due to the considerable complexity of such effects. For example, low‐dose aspirin and statin may be prescribed in patients with coronary artery disease and hyperlipidemia. The use of statins may be influenced by co‐prescription of atypical agents that cause dyslipidaemia. As lithium interacts with angiotensin agents, this might have reduced prescriptions of either agents in patients with indications for both, which might have weakened the capacity to detect effects. It is not clear how to address such complex effects of concomitant drug use in the statistical analyses (eg, censor during intermittent concomitant use or adjustments) but this could be an objective of future register‐based drug repurposing studies. As with all other registers including nation‐wide medication data, the Danish Medicinal Product Statistics has no information on adherence or dose of the exposure drugs,24 although repeat prescriptions are a decent proxy of medication adherence.