medRxiv preprint doi: https://doi.org/10.1101/19001719; this version posted July 8, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. Antihypertensive medications as repurposed treatments for mood disorders: analysis of linked healthcare data for 1.8 million patients. Authors: Richard J Shaw,1 Daniel Mackay,1 Jill P. Pell,1 Sandosh Padmanabhan,2 David S. Bailey,3 Daniel J. Smith1 1. Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK 2. Institute of Cardiovascular and Medical Sciences, University of Glasgow, UK 3. Information Services Division, NHS National Services Scotland, Edinburgh, UK Financial support This project was supported by The Chief Scientist Office of Scotland award (D.J.S, D.M, J.P.P, S.P., grant number 173162-01) and the UK MRC Mental Health Data Pathfinder Award (D.J.S., J.P.P., grant number MC_PC_17217). Conflicts of interest None. Word Count: 3,876 Correspondence to: Dr. Richard Shaw Address: Institute of Health and Wellbeing, University of Glasgow, Public Health, 1 Lilybank Gardens, Glasgow, G12 8RZ, UK. Telephone : +44 (0) 141 330 2334. Email: [email protected]. NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. 1 medRxiv preprint doi: https://doi.org/10.1101/19001719; this version posted July 8, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. Abstract Background: Recent work suggests that antihypertensive medications may be useful as repurposed treatments for mood disorders. Using large-scale linked healthcare data we investigated whether certain classes of antihypertensive, such as angiotensin antagonists and calcium channel blockers, may have potential as repurposed treatments for Major Depressive Disorder (MDD) and bipolar disorder. Method: Two cohorts of patients treated with antihypertensives were identified from Scottish prescribing (2009-2016) and hospital admission (1981-2016) records. Eligibility for cohort membership was determined by receipt of a minimum of four prescriptions for antihypertensives within a 12-month window. One treatment cohort (n=538,730) included patients with no previous history of mood disorder, whereas the other (n=262,278) included those who did. Both cohorts were matched by age, sex and area deprivation to untreated comparators. Associations between antihypertensive treatment and new-onset MDD or bipolar episodes were investigated using Cox regression. Results: For patients without a history of mood disorder, antihypertensives were associated with increased risk of new-onset MDD. This was most marked for beta-blockers, with a hazard ratio (HR) of 2.68 (95%CI 2.45-2.92). For angiotensin antagonist monotherapy, the HR for new-onset MDD was 1.17 (95%CI 1.04-1.31). Some classes of antihypertensive were associated with protection against bipolar disorder, particularly angiotensin antagonists (HR 0.46; 95%CI 0.30-0.70). For patients with a past history of mood disorders, all classes of antihypertensives were associated with increased risk of future episodes of MDD. Conclusions: There was no evidence that antihypertensive medications prevented new episodes of MDD but angiotensin antagonists may represent a novel treatment avenue for bipolar disorder. 2 medRxiv preprint doi: https://doi.org/10.1101/19001719; this version posted July 8, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. Introduction Major depressive disorder (MDD) and bipolar disorder (BD) are leading causes of disability globally (Ferrari et al., 2016, Vos et al., 2016). More than one third of MDD patients will not respond to first- line antidepressants (Linde et al., 2015) and BD is challenging to treat, with antidepressants ineffective for most patients (Sidor and Macqueen, 2011). In recent years there has been very little progress in the development of new medications for mood disorders but there is currently considerable interest in the possibility of repurposing medications from other areas of medicine. For example, it has been suggested that certain classes of antihypertensive medication (particularly calcium-channel blockers, CCBs and angiotensin antagonists, AA) may have a role as repurposed treatments for MDD or BD (Harrison et al., 2016, Harrison et al., 2019, Saavedra, 2017, Vian et al., 2017). To date, the evidence for repurposing antihypertensive drugs to treat MDD is limited (Chowdhury et al., 2019, Vian et al., 2017). AAs have been reported in small observational studies to be associated with better mental health outcomes (Ahola et al., 2014, Boal et al., 2016, Brownstein et al., 2018, Johansen et al., 2012, Nasr et al., 2011, Williams et al., 2016). However, a recent large linkage study found that although initial prescriptions for AAs were associated with increased risk of depression and bipolar disorder, people receiving longer-term prescriptions for AAs were not at increased risk (Kessing et al., 2019a, Kessing et al., 2019b). Since the 1980s, CCBs such as verapamil have been suggested as possible treatments for mania (Celano et al., 2011). This was not supported by a review of six double-blind randomised studies and 17 observational studies which found that no evidence for efficacy of CCBs in mania (Cipriani et al., 2016). Nonetheless, despite the relatively limited evidence base to date, CCBs remain candidates for repurposing in BD because of their biological plausibility (Cipriani et al., 2016). There is very little published work supporting the repurposing of other antihypertensive drug classes for MDD or BD. Case reports and some clinical trials have found that beta-blockers (BB) (particularly propranolol) may be associated with increased depressive features (Luijendijk and Koolman, 2012, Verbeek et al.) (although recent observational work suggests that BBs have little influence on mood disorder outcomes (Boal et al., 2016, Johansen et al., 2012, Ko et al., 2002, Luijendijk and Koolman, 2012, Nasr et al., 2011, Ranchord et al., 2016, Verbeek et al.)). It is possible that depressogenic effects are restricted to more lipophilic BB (such as propranolol) which cross the blood-brain barrier (Thiessen et al., 1990, Verbeek et al.). For other antihypertensive drugs, such as diuretics and centrally acting agents, almost no evidence of any influence on mood disorder outcomes has so far 3 medRxiv preprint doi: https://doi.org/10.1101/19001719; this version posted July 8, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. been described (Celano et al., 2011, Coyne et al., 2002, Hayes et al., 2019, Huffman and Stern, 2007, Nasr et al., 2011, Williams et al., 2016). Our primary goal was to use Scottish national-level routine healthcare data on over 1.8 million individuals (representing more than 6 million person-years of follow-up) to assess whether patients treated with specific classes of antihypertensive medication as monotherapy were less likely to experience new-onset mood disorder episodes. Methods Data Sources Within the National Services Scotland Safehaven, we created two datasets of cohorts and comparison groups by linking data from: the Community Health Index; Scottish Morbidity Records (SMR) datasets including SMR00 (Outpatient Attendance) from 1997 to 2016, SMR01 (General/Acute Inpatient and Day Case) from 1981 to 2016, and SMR04 (Mental Health Inpatient and Day Cases) from 1981 to 2016; the Prescribing Information System (PIS) from 2009 to 2016; and the National Records of Scotland death certificates from 1981 to 2016. Cohort 1 included patients treated with new-onset antihypertensive treatment who had no previous record of mood disorder. Cohort 2 included patients with new-onset antihypertensive treatment plus a past record of mood disorder. Ethical approval for the project was obtained from the Public Benefit and Privacy Panel at National Health Services Scotland Information and Statistics division. Time periods in which potential participants were eligible for inclusion were defined on the basis of prescriptions for antihypertensive medications, as well as prescriptions and hospital admission records for psychiatric disorders. To define the cohorts, we initially used PIS data from January 2009 to December 2016 to identify individuals who had a minimum of 4 prescriptions for antihypertensives (defined using British National Formulary (BNF)(Joint Formulary Committee, 2019) sections and paragraphs 2.2, 2.4, 2.5.5, and 2.6.2) within a window of up to 12 months, preceded by 6 months of no antihypertensive treatment record. Patients were then excluded from cohort 1 and included in cohort 2 if they had been prescribed psychiatric medication (indicated by BNF sections 4.1, 4.2, 4.3) within the same window. Following that, we also excluded people from cohort 1 and included them in cohort 2 if they had been admitted to hospital for psychiatric treatment (as indicated by a clinic appointment with the general psychiatry speciality in SMR00 database, ICD10 codes F10-F48, X60-X84 and Z91.5 and ICD9 codes 290-301 and 303-305 in the SMR01 database and a record in the SMR04 databases) during the antihypertensive treatment window and for the preceding 10 years. At this stage, the number of potential cohort 1 members was 968,930 for cohort 4 medRxiv preprint doi: https://doi.org/10.1101/19001719; this version posted July 8, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.