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7th October 2021
Depression is a global problem thought to affect around 280 million people or 5% of adults. The causes of depression are multifactorial and can involve a complex interaction between social, psychological, and biological factors. Treatment can be achieved through cognitive behavioural therapy as well as the use of antidepressants.
However, among those prescribed antidepressants, once a patient feels better in themselves, should they stop treatment or continue? This was the question posed by a UK team of researchers who looked at primary care patients who considered that they were now well enough to stop antidepressant treatment. The team recruited adults prescribed conventional doses of three commonly used antidepressants: citalopram, sertraline and fluoxetine. In addition, eligible patients were those who had reported at least two prior episodes of depression or who had been taking antidepressants for more than two years. Patients were then randomised 1:1 to either maintenance of their current antidepressant (maintenance group) or tapering and discontinuing (discontinuation group). Treatments were provided in identical bottles so that patients were unaware of whether they were assigned to the maintenance or discontinuation arm. In the discontinuation arm, the dose of antidepressant drug was reduced over a two month period so that by the third month they were taking placebo. The primary outcome was the first relapse of depression during a 52 week follow-up period. There were eight secondary outcomes including depressive symptoms using the Patient Health Questionnaire 9-item (PHQ-9), as well as measures of anxiety and quality of life.
A total of 478 patients with a mean age of 54 years (75% women) were enrolled and randomised to either maintenance (238) or discontinuation of therapy. By week 52, relapse had occurred in 39% of those in the maintenance group but more than half, 56%, in the discontinuation group (hazard ratio, HR = 2.06, 95% CI 1.56 – 2.70, p < 0.001). The secondary outcomes were all generally in the same direction.
The authors concluded that even though all patients believed that they were well enough to discontinue with their antidepressants, doing so resulted in a higher risk of depression relapse. In addition, quality of life and symptoms of depression and anxiety were all worse in those who stopped treatment.
Lewis G et al. Maintenance or Discontinuation of Antidepressants in Primary Care. N Eng J Med 2021
6th October 2021
Treatment-resistant depression (TRD) can be defined as a major depressive disorder (MDD) in adults who failed to respond to at least two different antidepressant treatments in their current moderate-to-severe depressive episode. It is a common problem with a prevalence estimated from one analysis to affect 30.9% of patients. Although the efficacy of an antidepressant in clinical trials is assessed by comparison against placebo, a common problem is the large and positive placebo response often observed. The magnitude of average placebo response in studies of major depression has been found to be 29.7%, but ranged between 12.5 and 51.8%. Moreover, in an analysis of 252 antidepressant controlled trials with 26,324 patients assigned to placebo, a placebo response was seen in 35 to 40% of patients, although the analysis did not specifically examine treatment-resistant depression.
However, what remains uncertain, is the magnitude of the placebo response in patients with TRD who are exposed to a range of different modalities. This prompted a team from the Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada, to not only assess the size of the placebo response in patients with TRD, but to also identify relevant factors associated with the placebo response. The team undertook a comprehensive literature search and included studies that were parallel-arm, double-blind and placebo-controlled, specifically recruiting patients with treatment-resistant depression. They set the primary outcome as the Hedges g value, which is a measure of the effect size, for the placebo response. The value of Hedges g indicates the extent to which two groups differ, based on the size of the standard deviation, e.g., a value of 1 indicates that groups differ by one standard deviations, 2 denotes two standard deviations and so on. As a secondary outcome, the team used meta-regression to explore potential moderators of the placebo effect.
A total of 50 clinical trials with 3228 patients, with a mean age of 45.8 years (20.7% women), where included in the final analysis. The placebos included pills, liquids, parenteral injections and several sham procedures such as sham transcranial magnetic stimulation, transcranial direct current stimulation or invasive brain stimulation. The pooled placebo effect size for all treatment modalities was large (Hedges g = 1.05, 95% CI 0.91 – 1.1) although this did vary with the type of placebo intervention. For example, with pill placebos, g = 1.14, parenteral placebo, g = 1.33. The pooled placebo response rate in all trials was 21.2% with a pooled remission rate of 13%.
In the TRD trials, meta-regression revealed that industry-sponsored trials, year of publication and studies with an open-label prospective phase before randomisation, all had a significantly higher placebo effect.
Discussing these findings, the authors felt that their results offered future researchers a benchmark for expected placebo responses in TRD trials. They concluded by calling for more consistent reporting of data, an agreement on the definition of TRD, and an assessment and reporting of participant’s expectations and experiences within a clinical trial.
Jones BDM et al. Magnitude of the Placebo Response Across Treatment Modalities Used for Treatment-Resistant Depression in Adults: A Systematic Review and Meta-analysis. JAMA Netw Open 2021