Project objectives

1. Determine the relative and absolute risks of pre-defined adverse events in people aged under 65 and diagnosed with depression comparing classes of antidepressant drugs (tricyclic and related antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs) and other antidepressant drugs.
2. Determine the relative and absolute risks of pre-defined adverse events in people aged under 65 diagnosed with depression comparing individual antidepressant drugs where numbers are sufficient.
3. Examine the effects of antidepressant dose and duration of use on the risks of the adverse events.

Changes to project objectives

No changes were made.

Brief summary

Methods

Study cohort

The study used a large primary care database (QResearch) to select the study cohort. Recorded information includes data on patients’ diagnoses, symptoms, consultations, referrals, test results and prescriptions.

The study cohort comprised an open cohort of patients with a first recorded diagnosis of depression between 1/1/2000 and 31/07/2011, and made between the ages of 20 to 64. Patients were only eligible for inclusion if their diagnosis of depression occurred at least 12 months after registration with a study practice and the date of the installation of the practice computer system. Patients were eligible for inclusion whether or not they received prescriptions for antidepressant medication. Patients who received prescriptions for antidepressants but did not have a recorded diagnosis of depression were not eligible for inclusion as the prescriptions may have been for conditions other than depression. Patients were excluded from the cohort if they had a previous recorded diagnosis of depression, were temporary residents, had a diagnosis of schizophrenia, bipolar disorder or other type of psychosis or had been prescribed lithium or antimanic drugs at the study entry date. Patients were also excluded if they had received prescriptions for an antidepressant either before the study start date, before their date of registration with the practice (if later), before the age of 20 or more than 36 months before their first recorded diagnosis of depression. Participants were followed-up in the database until the earliest of: date of death, date of leaving the practice, or the end of the follow-up period (1/8/2012).

Outcomes

We identified a number of potential adverse effects of antidepressants and included these as outcome measures. Information on these outcomes was extracted from the primary care computer records of patients in the cohort and from linked death certificates for patients who died during the study period. Outcomes were only included if they occurred after the index date of entry into the study cohort. The outcomes assessed were: suicide (including open verdicts); attempted suicide/self-harm; myocardial infarction; stroke/transient ischaemic attack (TIA); arrhythmia; epilepsy/seizures; all-cause mortality; sudden death; fractures; falls; antidepressant poisoning; upper gastrointestinal bleeding; and adverse drug reactions.

The date of occurrence of the outcome used in analysis was the first recorded date of the outcome during follow-up.

Exposures

We extracted details of all individual prescriptions for antidepressants during follow-up, including the issue date, the type and dose of antidepressant, dosage instructions and quantity of tablets prescribed. We calculated the daily dose of each prescription by multiplying the specified dose of each tablet by the number of tablets to be taken each day. Antidepressant drugs were grouped for the analyses according to the major classes namely: tricyclic and related antidepressants, selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors, and other antidepressants. Duration of treatment and dose of the antidepressant drugs were examined in the analyses Individual antidepressant drugs were also assessed where numbers were sufficient.

Confounding variables

Variables considered likely to be associated with the risk of the outcome or with the likelihood of receiving treatment for different antidepressant medications were included as confounding variables. These included: age; sex; year of diagnosis of depression; severity of index diagnosis of depression; deprivation; smoking status; alcohol intake; ethnic group; various comorbidities at baseline and use of other drugs at baseline. In addition, the analysis of suicide as an outcome included attempted suicide/self-harm at baseline.

Statistical analysis

Cox’s proportional hazards models were used to assess the associations between exposure to antidepressant drugs and the different outcomes, adjusting for confounding variables. Antidepressant exposure was treated as a time-varying exposure to account for patients starting and stopping antidepressant treatment and also changing between different antidepressants during follow-up. The main analyses were based on the first five years of follow-up after study entry.

Findings

There were 238,963 patients aged 20 to 64 years with a first diagnosis of depression in the study cohort. During follow-up 87.7% (n=209,476) of patients in the cohort received a total of 3,337,336 prescriptions for antidepressants. There were 2,379,668 (71.3%) prescriptions for SSRIs, 533,798 (16.0%) for tricyclic and related antidepressants, 422,079 (12.7%) for the group of other antidepressants, and 1,791 (0.05%) for monoamine oxidase inhibitors. Citalopram was the most commonly prescribed antidepressant (1,051,360 prescriptions, 31.5% of total). The median duration of treatment was 221 days (interquartile range 79 to 590 days).

In the analyses of suicide and attempted suicide/self-harm there were 198 cases of suicide and 5243 cases of attempted suicide/self-harm during the first five years of follow-up. There was no significant difference in the suicide rate for tricyclic and related antidepressants (adjusted hazard ratio 0.84, 95% CI 0.47 to 1.50) compared with SSRI treatment, but the suicide rate was significantly increased for other antidepressants (adjusted hazard ratio 2.64, 95% CI 1.74 to 3.99). The hazard ratio for suicide was significantly increased for mirtazapine compared with citalopram (adjusted hazard ratio 3.70, 95% CI 2.00 to 6.84). There was no significant difference in the rate of attempted suicide/self-harm for tricyclic antidepressants (adjusted hazard ratio 0.96, 95% CI 0.87 to 1.08) compared with SSRI treatment but the rate of attempted suicide/self-harm was significantly higher for other antidepressants (adjusted hazard ratio 1.80, 95% CI 1.61 to 2.00). Hazard ratios for attempted suicide/self-harm were significantly increased for three of the most commonly prescribed drugs compared with citalopram, which were venlafaxine (adjusted hazard ratio=1.85, 95% CI 1.61 to 2.13), trazodone (adjusted hazard ratio =1.73, 95% CI 1.26 to 2.37) and mirtazapine (adjusted hazard ratio 1.70, 95% CI 1.44 to 2.02) and significantly reduced for amitriptyline (adjusted hazard ratio 0.71, 95% CI 0.59 to 0.85).

In the analyses of epilepsy/seizures there were 878 patients with a first diagnosis of epilepsy/seizures during the first five years of follow-up. The hazard ratios were significantly increased for all antidepressant drug classes and for 8 of the 11 most commonly prescribed drugs compared with no treatment. The highest risks in the first five years were for trazodone (adjusted hazard ratio 5.41, 95% CI 3.05 to 9.61, number needed to harm (NNH) 65), lofepramine (adjusted hazard ratio 3.09, 95% CI 1.73 to 5.50, NNH 138), and venlafaxine (adjusted hazard ratio 2.84, 95% CI 1.97 to 4.08, NNH 156).

Analyses of cardiovascular outcomes found that SSRIs were not associated with a significantly increased risk of arrhythmias compared with no antidepressant treatment, but that fluoxetine was associated with a significantly reduced risk (adjusted hazard ratio 0.74, 95% CI 0.59 to 0.92). There were no significant associations between antidepressant class and myocardial infarction over five years follow-up. There were also no significant associations between antidepressant class and stroke/TIA.

Analyses of the other outcomes found some differing patterns of risk between the antidepressant classes and different antidepressant drugs, for example SSRIs and other antidepressants were associated with significantly increased risks of fracture. Absolute risks of the different outcomes have been calculated for the different exposure groups.

Conclusions

Antidepressants are prescribed for the majority of patients diagnosed with depression in primary care.

There were varying patterns of risk for the different antidepressant classes and individual drugs across a range of adverse outcomes. Residual confounding and indication bias may influence our results, so confirmation may be required from additional studies. These findings present a comprehensive profile of the safety of antidepressants in people aged 20 to 64 diagnosed with depression, and can be used to inform prescribing guidelines and treatment decisions between patients and health professionals.

Plain English summary

Antidepressants are one of the most commonly prescribed medications worldwide, and their use is increasing. There were more than 53 million prescriptions for antidepressants in England in 2013 which is nearly twice as many as were prescribed 10 years before. Much of the increase is due to people with depression taking antidepressants for longer periods of time. However little is known about the safety of taking antidepressants, nor whether some antidepressant drugs are safer than others. There is some evidence that certain illnesses and harmful events could be caused by antidepressants, so we carried out a study to see whether antidepressants increased the risk of these illnesses and the risks were higher for some types of antidepressant.

The study used a primary care database containing data collected by general practitioners during consultations with patients to identify a large group of people diagnosed with depression and assess what antidepressants they had been prescribed. We studied 238,963 people with depression aged 20 to 64 years and found that most of these (88%) were treated with antidepressants. We found out which people in the study had new diagnoses of different illnesses and harmful events over the next five years, including epilepsy, falls, fractures, suicide, self-harm, heart attacks, stroke, abnormal heart rhythms, mortality, sudden death, antidepressant poisoning, upper gastrointestinal bleeding, and drug reactions. When we looked at which antidepressants were being taken when people developed a new illness or had a harmful event we found that some antidepressants seemed to be safer than others, but this depended on which illness was being looked at. For example we found that some types of antidepressant could increase the risk of suicide and self-harm and that the risk of epilepsy was increased for eight of the 11 most commonly prescribed antidepressant drugs. The risks of some illnesses, such as stroke, were not increased in people taking antidepressants. Some of these findings may be due to factors we could not fully account for such as differences in severity of depression between people prescribed different antidepressant drugs.

In conclusion this large study of antidepressant safety has provided information on the risks of a range of outcomes for different antidepressant medications. The results show that the risks of certain illnesses and harmful events vary depending on the type of antidepressant prescribed. The risks and benefits of different antidepressants should be carefully considered when these drugs are prescribed to people with depression.

Dissemination

Published articles

1. Coupland Carol, Hill Trevor, Morriss Richard, Arthur Antony, Moore Michael, Hippisley-Cox Julia et al. Antidepressant use and risk of suicide and attempted suicide or self harm in people aged 20 to 64: cohort study using a primary care database BMJ 2015; 350:h517.
   http://www.bmj.com/content/350/bmj.h517
2. Carol Coupland, Richard Morriss, Antony Arthur, Michael Moore, Trevor Hill, Julia Hippisley-Cox. Safety of antidepressants in adults aged under 65: protocol for a cohort study using a large primary care database. BMC Psychiatry 2013; 13: 135.
   http://www.biomedcentral.com/1471-244X/13/135

Submitted for publication

1. Trevor Hill, Carol Coupland, Richard Morriss, Antony Arthur, Michael Moore, Julia Hippisley-Cox. Antidepressant use and risk of epilepsy and seizures in people aged 20 to 64 years: cohort study using a primary care database.

Two further articles are planned and currently being drafted.

Conference presentations/posters

1. Antidepressant use and the risk of cardiovascular outcomes: cohort study using a primary care database. NIHR School for Primary Care Research Showcase 2014, Oxford. Oral presentation (Carol Coupland), plenary session.
2. Antidepressants and risk of epilepsy or seizures. SAPC annual conference, 2014 Edinburgh. Elevator pitch presentation (Trevor Hill).
3. Antidepressant use and the risk of cardiovascular outcomes: cohort study using a primary care database. SAPC annual conference, 2014 Edinburgh. Oral presentation (Carol Coupland).
4. Antidepressants and risk of epilepsy or seizures. Poster presented by Trevor Hill at the Trent Regional SAPC conference in Lincoln, 2014. Awarded best poster prize.
5. Antidepressant prescribing in adults aged under 65: cohort study using a large primary care database. Trent Regional Meeting of the Society for Academic Primary Care, Sheffield, 2013. Poster.
6. Antidepressant prescribing in adults aged under 65: cohort study using a large primary care database. SAPC annual conference, 2013 Nottingham. Poster.
7. Safety of antidepressants in adults aged under 65: cohort study using a large primary care database. SPCR Showcase event, London 2012. Poster.

Public involvement

There is an advisory board for the QResearch database overall which includes service users and practitioners, and the board gives general advice and input into research carried out using the database (see: http://www.qresearch.org/SitePages/Advisory%20Board.aspx).

The study was also informed by input from service users into a previous study of antidepressant safety in older people. We are reviewing and considering different ways of involving the public in ongoing database studies.

Impact

The first paper presenting results from the research has only recently been published. It was covered in an article in the Times newspaper and various online media outlets. We hope that this paper and further papers from this project will inform prescribing guidelines for antidepressants.

This project was funded by the National Institute for Health Research School for Primary Care Research (project number 81)

Department of Health Disclaimer

The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the NIHR School for Primary Care Research, NIHR, NHS or the Department of Health.