Carol Coupland Paula Dhiman Tony Arthur Richard Morriss Julia Hippisley-Cox University of Nottingham Garry Barton University of East Anglia Antidepressant use and the risk of stroke in older people

Depression in older people Depression is a common condition in older people (around 15%) It is associated with increased rates of morbidity and mortality It is mainly treated in primary care, frequently with antidepressants 2

Adverse effects of antidepressants Around 14 million prescriptions for antidepressants were issued to people aged 60+ in 2007, an increase of 10.1% compared with 2006 and 79.0% compared with 2000 Little is known about adverse effects of antidepressants in older people Some studies have shown that antidepressants may increase risk of stroke 3

Study design Cohort study carried out using QResearch primary care database. Patients were included if: they had a recorded diagnosis of depression the diagnosis was made at the age of 65 or over the diagnosis was between 1/1/1996 to 31/12/2007 they were no more than 100 years at diagnosis the diagnosis occurred at least 12 months after registration with a study practice. 4

Exposures Antidepressant prescriptions categorised as: Tricyclic and related antidepressants (TCAs) Selective Serotonin Reuptake Inhibitors (SSRIs) Monoamine oxidase inhibitors (MAOIs) Other antidepressants Combined treatment Antidepressants also categorised by dose, duration and individual drugs. 5

Analysis Outcome was diagnosis of stroke or transient ischaemic attack (TIA) during follow-up to 31/12/2008. Cox’s proportional hazards model used to calculate unadjusted and adjusted hazards ratios for antidepressant use (time varying) Adjusted for: age, sex, study year, previous diagnosis of depression, severity of depression (mild, moderate or severe), smoking status deprivation, based on Townsend deprivation score comorbidities (ischaemic heart disease, diabetes, hypertension, stroke, cancer, dementia, epilepsy, Parkinson’s disease, hypothyroidism, obsessive- compulsive disorder) use of other drugs (statins, NSAIDS, anti-psychotics, lithium, aspirin, antihypertensive drugs, anticonvulsants, hypnotics/anxiolytics). 6

Results There were 60,464 patients in the study cohort 54,038 (89.0%) received at least one prescription for an antidepressant drug during follow-up There were 1,398,359 prescriptions for antidepressants 31.6% for TCAs, 54.7% for SSRIs, 0.2% for MAOIs, and 13.5% for the class of other antidepressants. The median duration of treatment with antidepressants during follow-up was 364 days (IQR 91, 1029). 7

Stroke/TIA outcome During follow-up 5369 (9.9%) of patients had an incident stroke/TIA, during 265,410 person-years of follow-up Crude incidence rate was 202 per 10,000 person-years (95% CI (197 to 208). 8

Hazard ratios for antidepressant class *note: hazard ratios compared to periods of non-use of antidepressants 9

Hazard ratios for antidepressant dose *note: hazard ratios compared to periods of non-use of antidepressants 10

Hazard ratios for antidepressant timing *note: hazard ratios compared to periods of non-use of antidepressants 11

Hazard ratios for individual drugs *note: hazard ratios compared to periods of non-use of antidepressants 12

Excess risks For each 10,000 patients treated with: SSRIs - 38 additional people would have a stroke in one year compared with no treatment other antidepressants - 81 additional people would have a stroke in one year compared with no treatment 13

Summary of findings Stroke risk is significantly increased for SSRIs and the class of other antidepressant drugs, compared with TCAs and periods of no use of antidepressants. Little evidence of a dose response relationship. Stroke rates were highest in the first 28 days of starting an SSRI antidepressant Among individual antidepressant drugs the highest hazard ratios were for Venlafaxine Hydrochloride and Mirtazapine. 14

Strengths Large study in a primary care setting Accounted for many confounding variables One of few studies to investigate effects of individual drugs Detailed information on antidepressants prescribed 15

Limitations Difficult to distinguish effects of antidepressant treatment from effects of depression itself May be channelling bias - different drugs prescribed according to various patient characteristics Residual confounding – some stroke risk factors may not be recorded in GP records 16

Conclusions SSRIs and drugs in the class of other antidepressants may have increased risks of stroke compared with TCAs. A careful evaluation of benefits and adverse outcomes is needed when prescribing antidepressants to older people which should include consideration of TCAs 17

Acknowledgements This project is funded by the NHS R&D Programme Health Technology Assessment Programme (project number 06/42/01) and will be published in full in the Health Technology Assessment journal. See the HTA programme website for further project information. We thank the contribution of practices and patients who provide data to QResearch Department of Health Disclaimer The views and opinions expressed are those of the research team and do not necessarily reflect those of the Department of Health. 18