Antidepressants have been proposed to act via their influence on emotional processing. We investigated the effect of discontinuing maintenance antidepressant treatment on positive and negative self-referential recall and the association between self-referential recall and risk of relapse.

The ANTLER trial was a large (N = 478) pragmatic double-blind trial investigating the clinical effectiveness of long-term antidepressant treatment for preventing relapse in primary care patients. Participants were randomised to continue their maintenance antidepressants or discontinue via a taper to placebo. We analysed memory for positive and negative personality descriptors, assessed at baseline, 12- and 52-week follow-up.

The recall task was completed by 437 participants. There was no evidence of an effect of discontinuation on self-referential recall at 12 [positive recall ratio 1.00, 95% CI (0.90–1.11), p = 0.93; negative recall ratio 1.00 (0.87–1.14), p = 0.87] or 52 weeks [positive recall ratio 1.03 (0.91–1.17), p = 0.62; negative recall ratio 1.00 (0.86–1.15), p = 0.96; ratios larger than one indicate higher recall in the discontinuation group], and no evidence of an association between recall at baseline or 12 weeks and later relapse [baseline, positive hazard ratio (HR) 1.02 (0.93–1.12), p = 0.74; negative HR 1.01 (0.90–1.13), p = 0.87; 12 weeks, positive HR 0.99 (0.89–1.09), p = 0.81; negative HR 0.98 (0.84–1.14), p = 0.78; ratios larger than one indicate a higher frequency of relapse in those with higher recall].

We found no evidence that discontinuing long-term antidepressants altered self-referential recall or that self-referential recall was associated with risk of relapse. These findings suggest that self-referential recall is not a neuropsychological marker of antidepressant action.

According to the cognitive neuropsychological model, antidepressants reduce symptoms of depression and anxiety by increasing positive relative to negative information processing. Most studies of whether antidepressants alter emotional processing use small samples of healthy individuals, which lead to low statistical power and selection bias and are difficult to generalise to clinical practice. We tested whether the selective serotonin reuptake inhibitor (SSRI) sertraline altered recall of positive and negative information in a large randomised controlled trial (RCT) of patients with depressive symptoms recruited from primary care.

The PANDA trial was a pragmatic multicentre double-blind RCT comparing sertraline with placebo. Memory for personality descriptors was tested at baseline and 2 and 6 weeks after randomisation using a computerised emotional categorisation task followed by a free recall. We measured the number of positive and negative words correctly recalled (hits). Poisson mixed models were used to analyse longitudinal associations between treatment allocation and hits.

A total of 576 participants (88% of those randomised) completed the recall task at 2 and 6 weeks. We found no evidence that positive or negative hits differed according to treatment allocation at 2 or 6 weeks (adjusted positive hits ratio = 0.97, 95% CI 0.90–1.05, p = 0.52; adjusted negative hits ratio = 0.99, 95% CI 0.90–1.08, p = 0.76).

In the largest individual placebo-controlled trial of an antidepressant not funded by the pharmaceutical industry, we found no evidence that sertraline altered positive or negative recall early in treatment. These findings challenge some assumptions of the cognitive neuropsychological model of antidepressant action.