Using an experimental medicine model to explore combination effects of pharmacological and cognitive interventions for depression and anxiety

Abstract

Selective serotonergic reuptake inhibitors (SSRIs) and cognitive therapies are effective in the treatment of anxiety and depression. Previous research suggests that both forms of treatments may work by altering cognitive biases in the processing of affective information. The current study assessed the effects of combining an SSRI with a cognitive intervention on measures of affective processing bias and resilience to external challenge. A total of 62 healthy participants were randomly assigned to receive either 7 days of citalopram (20 mg) or placebo capsules while also completing either an active or a control version of a computerized cognitive bias training task. After treatment, standard measures of affective processing bias were collected. Participants' resilience to external stress was also tested by measuring the increase in negative symptoms induced by a negative mood induction. Participants who received both citalopram and the active cognitive bias training task showed a smaller alteration in emotional memory and categorization bias than did those who received either active intervention singly. The degree to which memory for negative information was altered by citalopram predicted participants' resistance to the negative mood induction. These results suggest that co-administration of an SSRI and a cognitive training intervention can reduce the effectiveness of either treatment alone in terms of anxiety- and depression-relevant emotional processing. More generally, the findings suggest that pinpointing the cognitive actions of treatments may inform future development of combination strategies in mental health.

Figure 1

Study design and bias training task used. (a) Participants completed two assessment sessions, immediately before and after the period of treatment. The assessment measures completed during both sessions are listed. (b) Each participant was randomly assigned to one of four treatment groups using a factorial design. This design allows assessment of the main effects of both citalopram and training type, as well as the interaction of the two. (c) Two example trials from the attentional bias training task completed by participants. On each trial, two faces were presented, followed by a probe (one or two dots) to which participants had to respond. During positive training (shown), the probe appeared behind the more positive of the two faces on the majority of trials; the control training condition was identical in every respect other than that the probe was equally likely to appear behind either face.

Figure 2

Effects of interventions on measures of cognitive bias. (a) Emotional memory bias, calculated as the relative accuracy in the recognition of positive vs negative words. An interference pattern is seen (F=5.1, df=1,58, p=0.03); when compared with the baseline group (control placebo) both interventions, administered singly, produce a relative increase in positive memory bias, whereas the combination treatment does not. (b) The interference effect is apparent in the mean number of negative words recognized (F=12.6, df=1,58, p=0.001). Both citalopram and positive training significantly decrease recognition of negative words, whereas the combination of interventions does not differ from the baseline group and shows increased memory of negative words compared with the singly administered interventions. The results of the post hoc pairwise comparisons are shown, ^*p<0.05, ^p<0.1. (c) Emotional bias when categorizing self-referent words, calculated as the relative reaction time to classify negative vs positive words. A negative interference pattern is again seen (F=4.5, df=1,58, p=0.038), with each intervention administered singly reducing the relative reaction time difference between negative and positive words, whereas the combination of interventions again has very little effect. All graphs display mean scores with error bars reporting SE.

Figure 3

Effects of the interventions on emotional reactivity across the mood induction procedure. Measures of negative affect (negative-PANAS) were taken before and after the mood induction task. As can be seen, participants in the citalopram-treated groups (control citalopram and positive citalopram) displayed a smaller increase in negative symptoms than did those in the placebo groups (time × drug; F=6.9, df=1,58, p=0.01). Direct comparison between the two citalopram-treated groups revealed a trend level effect of training (F=3.6, df=1, 29, p=0.07). Consistent with the effects of the interventions on emotional biases, the addition of positive bias training to citalopram tended to reduce the protective effect of the drug.