Off-label antidepressants: limited evidence to support their use


Antidepressants are some of the most frequently prescribed drugs in the world. Their use has continued to rise, doubling in the last ten years, to an estimated 61 million prescriptions in 2015, at an estimated cost to the NHS of £780,000 per day (HSCIC 2016a; HSCIC 2016b).

There continues to be considerable debate about the value of antidepressants in the treatment of depression. Previous Mental Elf blogs have explored the use of antidepressants and a there’s a particularly good post by Samei Huda here on the benefits and harms of antidepressants.

Antidepressants are also prescribed for a range of indications (reasons) other than depression, including other mental health disorders such as anxiety, post-traumatic stress disorder (PTSD) and obsessive compulsive disorder (OCD), as well as physical health conditions including long-term pain in adults and bed-wetting in children.

Medicines are often licensed to be prescribed for certain conditions and the optimum doses are decided upon as a result of clinical trials. They can also be used for ‘off-label’ indications (MHRA, 2009). This is when a medicine may be given for a reason for which it was not originally licensed. This is often because of an absence of a robust evidence base, or as a result of a prescriber’s clinical experience. Prescribing in this way requires the clinician to be more aware of the risks and put in place more advanced monitoring.

The aims of the study by Wong et al., (2017) was to examine the off-label indications of antidepressants in primary care, and determine the levels of evidence for their use.

Antidepressants are sometimes used in a way that is different to that described in the licence, but do clinicians have sufficient evidence to use them in this way? 

Antidepressants are sometimes used in a way that is different to that described in the licence, but do clinicians have sufficient evidence to use them in this way?


Data was collected between the 1 Jan 2003 and 30 Sep 2015 for all consenting adults (>18 years old) who were prescribed an antidepressant by one of the consenting doctors in Quebec, Canada. Approximately a quarter of doctors and patients had consented for their data to be used for research purposes.

The prescribed antidepressants were reviewed and classified as on-label or off-label. Off-label prescriptions were then categorised depending on the levels of evidence to support their use. These evidence categories were:

  • Strong
  • Strong but for a similar drug
  • No evidence.


  • There were 106,850 antidepressant prescriptions for 20,920 adults, written by 174 physicians
  • Nearly a third (29%) of all antidepressants in this study were prescribed for an off-label indication
    • 40% of these were for indications where the prescribed drug did not have strong evidence, but another drug in the same class was approved or supported by strong evidence
    • For only 15.9% (95% confidence interval (CI) 13.0% to 19.3%) of all off-label prescriptions, the prescribed drug had strong scientific evidence for the respective indication
    • However, 39.6% (95% CI 35.7% to 43.2%) of off-label prescriptions another antidepressant in the same class did have strong evidence for the indication
    • Tricyclic antidepressants (TCAs) had the highest prevalence of off-label indications: 81.4% (95% CI 77.3% to 85.5%). However, most of this was accounted for through the use of amitriptyline for pain: 93% (95% CI 89.6% to 95.7%) or insomnia: 6.4% (95% CI 3.9% to 9.5%)
    • Trazodone for insomnia was the most common off-label antidepressant, accounting for 26.2% (95% CI 21.9% to 30.4%) of all off-label prescriptions
    • Followed by Citalopram for anxiety: 17.8% (95% CI 14.8% to 21.3%)
    • The evidence was stronger for TCAs: 45.7% (95% CI 37.8% to 54.0%) than for SNRIs (serotonin-norepinephrine reuptake inhibitors): 11.0% (95% CI 4.6% to 18.4%) or SSRIs (selective serotonin reuptake inhibitors): 4.7% (95% CI 2.7% to 7.2%).
29% of antidepressants prescribed in this study were given for health conditions for which the medicines do not have a licence.

29% of antidepressants prescribed in this study were given for health conditions for which the medicines did not have a licence.


The authors concluded:

We found that when primary care physicians prescribed antidepressants for off-label indications, the prescribed drug was usually not supported by strong evidence for the respective indication. However, there was often another drug in the same class with strong evidence that could have been considered. These findings highlight an urgent need to produce more evidence on the risks and benefits of off-label antidepressant use and to provide physicians with this evidence at the point of prescribing. Technologies such as indication based e-prescribing systems and electronic health records have the potential to become essential components of effective post-market drug surveillance systems for monitoring and evaluating off-label antidepressant use.


  • Clearly if drugs are being used off-license more investigation is needed into their effectiveness, safety and outcomes
  • Studies using big data like this one clearly add to the evidence base, but may not provide the evidence of effectiveness
  • It would be interesting to see if similar prescribing habits exist in other countries, as Canada’s healthcare system might have influenced prescribing practice
  • The clinical risks might not be with these common high frequency items, but for medicines that this study excluded (<150 total prescriptions), which included all MAOIs (Monoamine oxidase inhibitors). These older antidepressants can pose significant health risks if not used appropriately
  • There did not appear to be any patient involvement in the development of this study.
This descriptive study suggests that medicines are frequently used when there is no strong evidence to support the prescribing decision.

This descriptive study suggests that medicines are frequently given to patients when there is no strong evidence to support the prescribing decision.


Primary paper

Wong J, Motulsky A, Abrahamowicz M, Eguale T, Buckeridge D, Tamblyn R. (2017) Off-label indications for antidepressants in primary care: descriptive study of prescriptions from an indication based electronic prescribing system. BMJ 2017; 356 doi: (Published 21 Feb 2017)

Other references

HCSIS (2016a) Antidepressants show greatest increase in number of prescription items dispensed. 5 Jul 2016.

HCSIS (2016b) National Statistics Prescriptions Dispensed in the Community, Statistics for England – 2005-2015. 5 Jul 2016.

MHRA (2009) Off-label or unlicensed use of medicines: prescribers’ responsibilities. Medicines and Healthcare products Regulatory Agency, 1 Apr 2009.

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John Baker

John Baker was appointed to Chair of Mental Health Nursing in 2015. John's research focuses on developing complex clinical and psychological interventions in mental health settings. He is particularly interested in i) acute/inpatient mental health services and clinical interventions; ii) medicines management in mental health care; iii) the attitudes and clinical skills of mental health workers, iv) the mental health workforce. The good practice manuals which he developed have been evaluated, cited as examples of good practice, and influenced clinical practice in the UK and abroad. The training package for patients, service users and carers to promote research awareness and understanding has been cited by the MHRN and NICE as an exemplar of good practice.

John is a member of the NIHR post-doctoral panel, sits on the Editorial boards for Journal of Psychiatric and Mental Health Nursing & International Journal of Mental Health Nursing. He is a Registered Nurse Teacher with the Nursing, Midwifery Council (NMC) and is active within Mental Health Nursing Academics (UK).

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