# Abstract

 

## Background Negative attentional biases are thought to increase the risk of recurrence in depression, suggesting that reduction of such biases may be a plausible strategy in the secondary prevention of the illness. However, no previous study has tested whether reducing negative attentional bias causally affects risk factors for depressive recurrence. The current experimental medicine study reports the effects of a computerized attentional bias modification (ABM) procedure on intermediate measures of the risk of depressive recurrence (residual depressive symptoms and the cortisol awakening response) in patients with recurrent depression. 

## Methods Sixty-one patients with at least two previous episodes of depression who were currently in remission were randomized to receive either an active (positive) or placebo computer-based ABM regime. The ABM regime presented either pictures of faces or words. Residual depressive symptoms, measured using the Beck Depression Inventory and the cortisol awakening response were measured immediately before and after completion of the bias modification and then again after 4 weeks' follow-up. 

## Results Positive, face-based ABM reduced both measures of recurrence risk (Beck Depression Inventory and cortisol awakening response). This effect occurred during the month following completion of bias modification. Word-based modification did not influence the outcome measures. 

## Conclusions Positive face-based ABM was able to reduce intermediate measures of recurrence risk in previously depressed patients. These results suggest that ABM may provide a "cognitive vaccine" against depression and offer a useful strategy in the secondary prevention of the illness. # Results 

## Group Demographics, Baseline Measures, and Compliance As can be seen from [Table 1](#), the groups were well matched on baseline demographics, IQ, and measures of illness severity. Patients had been depressed on an average of three previous occasions. Compliance was generally high with only eight patients completing fewer than 25 sessions of ABM and no difference in compliance between the groups. 

## The Effect of ABM on Residual Symptoms Positive, relative to placebo, ABM influenced the residual depressive symptoms reported by patients using the BDI, but this effect depended on whether the ABM used faces or words \[ABM type × ABM stimuli × time; *F*(2,112) = 3.7, *p* = .03\]. There was no general ABM type × time effect \[*F*(2,112) = 1.1, *p* = .35\]. As can be seen from [Figure 2](#) positive, face-based ABM lead to a reduction of symptoms compared with placebo ABM \[[Figure 2](#)A; *F*(2,56) = 3.7, *p* = .03\], whereas word based ABM had no significant effect \[[Figure 2](#)B; *F*(2,56) < 1, *p* = .4\]. Interestingly, the beneficial effect of positive face ABM displayed a time lag; symptoms did not change across the 2 weeks of ABM \[ *F*(1,28) < 1, *p* = .5\]; rather, they reduced during the follow-up period \[*F*(1,28) = 5.9, *p* = .02\] with this change resulting from a significant drop in symptoms reported by the positive face ABM group \[*t*(15) = 2.4, *p* = .03\] and no significant change seen in the placebo face ABM group \[*t*(13) < 1, *p* = .4\]. Observer reported depressive symptoms, measured using the HRSD, revealed an identical ABM type × ABM stimuli × time interaction \[[Figure 2](#)C and [2](#)D; *F*(2,112) = 3.4, *p* = .04\]; however, in this case, the post hoc tests of the interaction for face training was significant only at a trend level \[*F*(1,28) = 2.9, *p* = .09\]. Symptoms of anxiety, measured using the trait subscale of the STAI displayed the same specific effect of positive face ABM as that seen for the BDI \[[Figures 2](#)E, F; *F*(2,112) = 3.3, *p* = .05\] with the beneficial effect again occurring during follow-up \[ *F*(1,28) = 5.2, *p* = .03\] and being driven by a significant reduction of anxious symptoms in the positive face ABM group \[*t*(15) = 2.4, *p* = .03\]. 

## The Effect of ABM on the CAR Analysis of the CAR response revealed a significant ABM type × ABM stimuli interaction \[*F*(1,53) = 4.3, *p* = .04\], which was present across the three time points \[ABM type × ABM stimuli × time; *F*(2,106)\<1, *p* = .4\]. In keeping with the effects on residual symptoms, face-based ABM influenced the CAR \[[Figure 3](#)A; *F*(2,54) = 4, *p* = .02\], whereas word-based ABM did not \[[Figure 3](#)B; *F*(2,52) < 1, *p* = .8\]. Specifically, positive relative to placebo face ABM caused a reduction of the CAR across the follow-up period \[*F*(1,27) = 5, *p* = .03\] with no change being seen during ABM \[*F*(1,27) < 1, *p* = .9\]. This relative reduction was produced by a nonsignificant decrease in the positive ABM group during follow-up \[*t*(14) = 1.7, *p* = .1\] and a nonsignificant increase in the placebo group \[ *t*(13) = 1.5, *p* = .2\]. 

## The Effect of ABM on Attentional Function Positive relative to placebo bias modification produced a differential effect on attentional bias ([Figure 4](#)), as measured by the word based visual-probe task \[ABM type × time; *F*(2,112) = 3.1, *p* = .05\]. However, unlike the previous results, this effect did not significantly differ between the face- and word-trained groups \[ABM type × ABM stimuli × time; *F*(2,112) < 1, *p* = .9\]. The effect of ABM was seen across the bias modification period \[ *F*(1,57) = 8.3, *p* = .006\] with no significant change occurring across follow-up \[*F*(1,56) < 1, *p* = .4\]. When considering the within group effects produced, positive-face ABM led to a significant increase in positive bias across the modification period \[*t*(15) = 3.7, *p* = .002\], whereas face placebo ABM did not change the bias \[*t*(13) < 1, *p* = .9\]. Interestingly, the effect of word ABM was driven by a trend level decrease in bias in the placebo word group \[*t*(14) = 2.1, *p* = .051\] with no effect seen for positive word ABM \[ *t*(15)\<1, *p* = .5\]. The correlation between change in attentional bias across the bias modification period and reduction in BDI or CAR across the follow-up period in the positive face-ABM group was not significant \[ *r*(16) = .37, not significant, and *r*(15) = .34, not significant, respectively\]. Additional analysis is provide in [Supplement 1](#). Attentional bias, assessed using face stimuli, was insensitive to the effect of the ABM interventions \[*F*(2,112)\<1, *p* = 1\]. This remained the case when analysis was restricted to those who had completed face based ABM \[*F*(2,56) < 1, *p* = .7\]. <figure> <p><img src="" /></p> <figcaption>Study design and attentional bias modification (ABM) task used. <strong>(A)</strong> Patients completed three assessment sessions, immediately before and after 2 weeks of ABM and then again a month later. The assessment measures completed during both sessions are listed. <strong>(B)</strong> 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 ABM type and the stimuli used in ABM as well any interaction between the two. <strong>(C)</strong> Two example trials from the ABM task completed by patients. On each trial two stimuli were presented, followed by a probe (one or two dots) to which the patients had to respond. During positive ABM (shown) the probe appeared behind the more positive of the two stimuli; the placebo ABM condition was identical in every respect other than that the probe was equally likely to appear behind either stimulus. The stimuli used during ABM were either faces (shown) or words.</figcaption> </figure> <figure> <p><img src="" /></p> <figcaption>The effects of attentional bias modification (ABM) on residual symptoms of depression measured using the BDI <strong>(A, B)</strong> and the HRSD <strong>(C, D)</strong> and on symptoms of anxiety measured using the trait-STAI <strong>(E, F)</strong>. Symptoms, which are displayed as a change from baseline of the mean scores, were measured at three time points; before bias modification, after bias modification, and after 1-month follow-up. The symptoms of both depression and anxiety were significantly altered by face- but not word-based ABM. The effect of ABM occurred during follow-up with no difference in groups seen during the bias modification period. Solid line, positive ABM; dashed line, placebo ABM. Error bars represent SEM. \*<em>p</em> < .05 for post hoc test of interaction. BDI, Beck Depression Inventory; HRSD, Hamilton Rating Scale for Depression; Trait-STAI, the trait subscale of the Spielberger State-Trait Anxiety Inventory.</figcaption> </figure> <figure> <p><img src="" /></p> <figcaption>The effects of attentional bias modification (ABM) on cortisol awakening response (CAR). Results display the change from baseline of the mean CAR measured before bias modification, after bias modification, and after 1-month follow-up. Face-based ABM <strong>(A)</strong> produced a significant effect on CAR, whereas word-based ABM <strong>(B)</strong> had no effect. Again, the effect of face ABM was seen during the follow-up period. Solid line, positive ABM; dashed line, placebo ABM. Error bars represent standard error of the mean. \*<em>p</em> < .05 for post hoc test of interaction.</figcaption> </figure> <figure> <p><img src="" /></p> <figcaption>The effects of attentional bias modification (ABM) on attentional vigilance to word stimuli measured using the visual probe task. Vigilance is calculated so that a greater positive number represents increased vigilance for the positive stimulus, whereas a negative number represents vigilance for the negative stimulus. Results display the change from baseline of the mean attentional bias measured before bias modification, after bias modification, and after 1-month follow-up. Positive face-based ABM <strong>(A)</strong> produced a significant increase in vigilance toward the positive stimuli, whereas placebo word-based ABM <strong>(B)</strong> resulted in a trend-level decrease in vigilance. Unlike the measures of recurrence risk (<a href="#">Figures 2 and 3</a>), the effect of ABM was seen during the bias modification period. Solid line, positive ABM; dashed line, placebo ABM. Error bars represent standard error of the mean. \*<em>p</em> < .05 for post hoc test.</figcaption> </figure> ::::table-wrap

::: caption
Participant Demographic and Clinical Information
:::

```
                                                   Positive ABM       Neutral ABM                                              
```

______________________________________________________________________

```
                                                   Faces (*n* = 16)   Words (*n* = 16)   Faces (*n* = 14)   Words (*n* = 15)   *p*[a](#)
```

Age, Mean (SD), Years 34.6 (12.2) 40.9 (11.3) 37.8 (11.5) 40.9 (13.5) .14
Sex, *n*, F:M 10:6 10:6 10:4 10:5 .59[b](#)
Years of Education, Mean (SD) 16.8 (3.8) 16.9 (4.0) 17.4 (3.0) 16.2 (1.7) .43
VIQ (NART), Mean (SD) 114.6 (7.1) 114.6 (7.2) 117.6 (5.5) 117 (6.3) .17
No. of Previous Episodes, Mean (SD) 3.6 (1.9) 3.1 (1.1) 3 (1.0) 3 (1.2) .22
Total Illness Duration, Mean (SD), Months 22.3 (12.7) 31.9 (45.2) 32.8 (34.7) 21.6 (23) .21
Time Since Last Illness Episode, Mean (SD), Months 22.3 (21.3) 41.6 (41.2) 48.6 (80.6) 38.4 (86.8) .36
BDI Score, Mean (SD) 5.9 (6.9) 6.3 (5.4) 4.3 (3.7) 3.8 (4) .14
Trait-STAI, Mean (SD) 45.3 (6.6) 44.4 (15) 44.1 (12) 43.9 (11.5) .86
HRSD, Mean (SD) 3.1 (4.1) 2.9 (2.5) 1.8 (2.1) 3.1 (2.9) .33
Compliance with ABM, *n*, Compliant:Noncompliant 14:2 14:2 13:1 12:3 .5[b](#)

ABM, attentional bias modification; BDI, Beck Depression Inventory; F,
female; HRSD, Hamilton Rating Scale for Depression; M, male; NART,
National Adult Reading Scale; Trait-STAI, the trait subscale of the
Spielberger State-Trait Anxiety Inventory; VIQ, Verbal Intelligence
Quotient.

The *p* value reported is the lowest of the three comparisons: main
effect of ABM stimuli, main effect of ABM type, or the stimuli × type
interaction.

Statistical analysis performed using logistic regression model; a
univariate analysis of variance was performed in all other analyses.::::


Extracted trial result:
Outcome: Difference of cortisol on waking and the highest level of following samples (continuous)
Intervention: Word-based attentional bias modification
Comparator: Placebo
Intervention group size: 16
Comparator group size: 15
Notes: F-values given, cant use for point estimates, and values in figure