Clinician Article

A study of the safety and harms of antidepressant drugs for older people: a cohort study using a large primary care database.

  • Coupland CA
  • Dhiman P
  • Barton G
  • Morriss R
  • Arthur A
  • Sach T, et al.
Health Technol Assess. 2011 Aug;15(28):1-202, iii-iv. doi: 10.3310/hta15280. (Original)
PMID: 21810375
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  • Psychiatry
    Relevance - 7/7
    Newsworthiness - 7/7
  • Family Medicine (FM)/General Practice (GP)
    Relevance - 7/7
    Newsworthiness - 6/7
  • General Internal Medicine-Primary Care(US)
    Relevance - 7/7
    Newsworthiness - 6/7
  • FM/GP/Mental Health
    Relevance - 6/7
    Newsworthiness - 6/7
  • Geriatrics
    Relevance - 6/7
    Newsworthiness - 6/7


OBJECTIVES: The aim of this study was to establish the relative safety and balance of risks for antidepressant treatment in older people. The study objectives were to (1) determine relative and absolute risks of predefined adverse events in older people with depression, comparing classes of antidepressant drugs [tricyclic and related antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs) and other antidepressants] and commonly prescribed individual drugs with non-use of antidepressant drugs; (2) directly compare the risk of adverse events for SSRIs with TCAs; (3) determine associations with dose and duration of antidepressant medication; (4) describe patterns of antidepressant use in older people with depression; and (5) estimate costs of antidepressant medication and primary care visits.

DESIGN: A cohort study of patients aged 65 years and over diagnosed with depression.

SETTING: The study was based in 570 general practices in the UK supplying data to the QResearch database.

PARTICIPANTS: Patients diagnosed with a new episode of depression between the ages of 65 and 100 years, from 1 January 1996 to 31 December 2007. Participants were followed up until 31 December 2008.

INTERVENTIONS: The exposure of interest was treatment with antidepressant medication. Antidepressant drugs were grouped into the major classes and commonly prescribed individual drugs were identified.

MAIN OUTCOME MEASURES: There were 13 predefined outcome measures: all-cause mortality, sudden cardiac death, suicide, attempted suicide/self-harm, myocardial infarction, stroke/transient ischaemic attack (TIA), falls, fractures, upper gastrointestinal bleeding, epilepsy/seizures, road traffic accidents, adverse drug reactions and hyponatraemia.

RESULTS: In total, 60,746 patients were included in the study cohort. Of these, 54,038 (89.0%) received at least one prescription for an antidepressant during follow-up. The associations with the adverse outcomes were significantly different between the classes of antidepressant drugs for seven outcomes. SSRIs were associated with the highest adjusted hazard ratios (HRs) for falls [1.66, 95% confidence interval (CI) 1.58 to 1.73] and hyponatraemia (1.52, 95% CI 1.33 to 1.75), and the group of other antidepressants was associated with the highest HRs for all-cause mortality (1.66, 95% CI 1.56 to 1.77), attempted suicide/self-harm (5.16, 95% CI 3.90 to 6.83), stroke/TIA (1.37, 95% CI 1.22 to 1.55), fracture (1.63, 95% CI 1.45 to 1.83) and epilepsy/seizures (2.24, 95% CI 1.60 to 3.15) compared with when antidepressants were not being used. TCAs did not have the highest HR for any of the outcomes. There were also significantly different associations between the individual drugs for seven outcomes, with trazodone, mirtazapine and venlafaxine associated with the highest rates for several of these outcomes. The mean incremental cost (for all antidepressant prescriptions) ranged between £51.58 (amitriptyline) and £641.18 (venlafaxine) over the 5-year post-diagnosis period.

CONCLUSIONS: This study found associations between use of antidepressant drugs and a number of adverse events in older people. There was no evidence that SSRIs or drugs in the group of other antidepressants were associated with a reduced risk of any of the adverse outcomes compared with TCAs; however, they may be associated with an increased risk for certain outcomes. Among individual drugs trazodone, mirtazapine and venlafaxine were associated with the highest rates for some outcomes. Indication bias and residual confounding may explain some of the study findings. The risks of prescribing antidepressants need to be weighed against the potential benefits of these drugs.

FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Clinical Comments

Family Medicine (FM)/General Practice (GP)

These are thought-provoking results, challenging the common assumption that SSRIs should be the safest option for treating geriatric depression. However, the important limitations inherent in a cohort study make it hard to know exactly what to do with these results. A randomized controlled trial, including a placebo arm, would be really helpful and this study suggests it needs to be funded!

Family Medicine (FM)/General Practice (GP)

Timely and relevant article. It will definitely have an impact on my practice.

General Internal Medicine-Primary Care(US)

It is a study that begs more definitive study such as randomized, prospective trials. The results are somewhat surprising in view of known physiological effects and known side effects.


This is a large cohort study (60,746 patients) from the QResearch primary care database to determine the adverse event profiles of anti-depressants in older adults (>65 years) over an ~11 year span. 54,038 patients received ~1.4 million antidepressant prescriptions. All the classes of drugs had increased risks in various outcomes: SSRI increase fall risk and hyponatremia, TCAs did not have the highest risk in any outcome, and other anti-depressants had higher risks for all cause mortality and fractures. No differential cost-effectiveness among the anti-depressants. No real new information here; the study focused on adverse events. No data on potential benefit from depression treatment. Not clear how dose adjustments were accounted for longitudinally. Geriatricians tend to "start low & go slow" with dosing and escalation. If I have a depressed older adult, I'm going to accept the risk and utilize the lowest effective medication dose with frequent monitoring.


Important study of a very large community based sample of depressed people age 65 and over in UK. The results report safety indicators by ADM class and by individual drug. The findings that SSRIs did not have a more benign safety profile than TCAs and that the use of some non-TCA anti-depressants was associated with serious adverse outcomes are noteworthy.

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