Antidepressant tolerance is not trivial

To the Editor

Every clinician treating mood disorders is familiar with patients requiring escalating doses of antidepressants with diminishing results, then trialling new antidepressants with a similarly rapidly declining benefit. There has been hesitancy in applying the term ‘tolerance’ to antidepressants despite the fact that in a percentage of patients there is clearly diminishing efficacy with use, and in many patients there are also withdrawal symptoms of varying severity.

A systematic review of 14 studies found an average 56% incidence of withdrawal symptoms, often for over 2 weeks and not uncommonly lasting months. Almost half received the highest severity rating (Davies and Read, 2019). The incidence of antidepressants’ loss of efficacy remains poorly researched. At 12 months only 6% of STAR D participants remained in remission (Hengartner, 2020).

Long-term antidepressant use is often due to their perceived benefit in relapse prevention. These studies, which take patients off their antidepressants, likely confuse depression relapse with withdrawal (Hengartner, 2020).

If a certain percentage of our patients will experience tolerance to antidepressants, then should we curtail their use as we do with benzodiazepines or opiates? Opiate use can lead to hyperaesthesia and benzodiazepines a rebound anxiety. Fava (2020) hypothesises that, similarly, antidepressants lead to a homeostatic resetting of receptors he calls ‘oppositional tolerance’ – a mechanism which counteracts the antidepressant effect. In his numerous papers, Fava describes ‘rebound symptoms’ whereby the original symptoms return at a greater intensity and ‘persistent post-withdrawal disorders’ – the appearance of new symptoms subsequent to antidepressant cessation. Moreover, antidepressants ‘may propel depressive illness into a refractory phase’ (Fava, 2020).

STAR D demonstrated that relapse rates are higher in patients who have received several antidepressants. There is a correlation between antidepressant use and worse depression outcomes in long-term observational studies (Hengartner, 2020).

Short-term efficacy, confusing withdrawal with relapse, and the perception of a lack of harm, all contribute to widespread use of antidepressants. The evidence that antidepressants can lead to worse illness in the medium to long term has not been collected. Yet the hypothesis is plausible and concerning. There is an urgent need for further research and leadership from the Royal Australian and New Zealand College of Psychiatrists (RANZCP). Psychiatrists and general practitioners (GPs) need to be aware that antidepressants may cause iatrogenic harm, and the risk–benefit ratio is particularly questionable in maintenance and long-term treatment.