Neuropsychological markers of antidepressant action: a secondary analysis of the ANTLER randomised controlled trial

Background 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. Methods 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. Results 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]. Conclusions 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.

Further analyses investigated potential interactions between the effect of antidepressant discontinuation on relapse risk and recall at baseline using Cox Proportional Hazards modelling.The outcome was time to relapse, and we included an interaction term between positive or negative hits at baseline and treatment allocation.
Models were adjusted for treatment allocation, medication, and potential confounders.A stratified analysis for low (below the median) and high (equal to or above the median) baseline hits was performed to illustrate interaction effects.These analyses were repeated including only participants who scored 80% or above on the ECAT at baseline.

Emotional categorisation task (ECAT)
Baseline ECAT data were available for 434 participants: 225 in the maintenance and 209 in the discontinuation group (data were missing for n = 3 participants due to technical issues).
Performance in the ECAT was good at baseline (median percent correct = 92.5%,IQR = 10%) and at 12 and 52 weeks (median percent correct = 95%, IQR = 7.5%), with no differences between antidepressant maintenance and discontinuation.Some participants failed to understand some of the words (14% scored below 80% at baseline), and 4% performed worse than chance.

Antidepressant discontinuation and self-referential recall
The results of the main analysis were unaltered after adjusting for performance on the ECAT and adherence to study medication.There was no evidence of an association between treatment allocation and positive hits, negative hits or total hits, and no interaction between treatment allocation and word valence (Tables S1 and S2).

Self-referential recall at baseline and risk of relapse
Restricting analyses to participants who scored 80% or above on the ECAT at baseline did not affect our findings on the lack of an association between recall at baseline and risk of relapse.Positive and negative hits at baseline failed to predict relapse, both before and after adjustment for treatment and potential confounding factors (Table S3).

Effect modification by self-referential recall
There was evidence of an effect modification by baseline negative recall (adjusted hazard ratio = 0.79, CI = 0.65-0.96,p = 0.02), suggesting that individuals with lower negative recall may benefit the most from maintenance antidepressants as a relapse prevention strategy (Table S4).
Consistent with this, the risk of relapse associated with discontinuation was higher for participants with low baseline negative hit scores (adjusted hazard ratio = 3.15, CI = 1.88-5.27,p < 0.001) than for those with high scores (adjusted hazard ratio = 1.66,CI = 1.15-2.41,p = 0.01).
We found no evidence of an effect modification by positive hits (Table S4).
These subgroup analyses had reduced statistical power and should be interpreted with caution.The baseline negative hits by group interaction effect was no longer significant when we excluded participants who scored below 80% on the ECAT (Table S5).
Table S1.Ratio of positive or negative hits in the antidepressant discontinuation group, relative to long-term maintenance treatment, 12 and 52 weeks after randomisation, restricted to participants who adhered to study medication and performed at 80% accuracy or above on the baseline ECAT.Note.CI, confidence interval.*Positive hits adjusted for negative hits, baseline positive hits and stratification variables (symptom severity at baseline, assessed using the CIS-R, medication and study centre).Negative hits adjusted for positive hits, baseline negative hits and stratification variables.

Positive hits
Results unaltered after adjusting for predictors of missingness.
Table S2.Ratio of total hits in the antidepressant discontinuation, relative to long-term maintenance treatment, 12 and 52 weeks after randomisation, restricted to participants who adhered to study medication and performed at 80% accuracy or above on the baseline ECAT.Note.CI, confidence interval.*Adjusted for baseline positive and negative hits and stratification variables (symptom severity at baseline, assessed using the CIS-R, medication and study centre).

Model
Results unaltered after adjusting for predictors of missingness.
Table S3.Associations between the number of positive and negative words correctly recalled at baseline and time to first depression relapse in participants who performed at 80% accuracy or above on the baseline ECAT.
Table S5.Effect modification of the association between antidepressant discontinuation and time to first depression relapse by baseline positive and negative hits in participants who performed at 80% accuracy or above on the ECAT.
Note.CI, confidence interval.*Positive hits adjusted for baseline negative hits.Negative hits adjusted for baseline positive hits.†Partially adjusted model (*) further adjusted for treatment allocation, medication, symptom severity at baseline, previous episodes of depression, duration of treatment prior to randomisation, sex, age, education.