Diminished neural processing of aversive and rewarding stimuli during selective serotonin reuptake inhibitor treatment

Abstract

Background: Selective serotonin reuptake inhibitors (SSRIs) are popular medications for anxiety and depression, but their effectiveness, particularly in patients with prominent symptoms of loss of motivation and pleasure, has been questioned. There are few studies of the effect of SSRIs on neural reward mechanisms in humans.

Methods: We studied 45 healthy participants who were randomly allocated to receive the SSRI citalopram, the noradrenaline reuptake inhibitor reboxetine, or placebo for 7 days in a double-blind, parallel group design. We used functional magnetic resonance imaging to measure the neural response to rewarding (sight and/or flavor of chocolate) and aversive stimuli (sight of moldy strawberries and/or an unpleasant strawberry taste) on the final day of drug treatment.

Results: Citalopram reduced activation to the chocolate stimuli in the ventral striatum and the ventral medial/orbitofrontal cortex. In contrast, reboxetine did not suppress ventral striatal activity and in fact increased neural responses within medial orbitofrontal cortex to reward. Citalopram also decreased neural responses to the aversive stimuli conditions in key "punishment" areas such as the lateral orbitofrontal cortex. Reboxetine produced a similar, although weaker effect.

Conclusions: Our findings are the first to show that treatment with SSRIs can diminish the neural processing of both rewarding and aversive stimuli. The ability of SSRIs to decrease neural responses to reward might underlie the questioned efficacy of SSRIs in depressive conditions characterized by decreased motivation and anhedonia and could also account for the experience of emotional blunting described by some patients during SSRI treatment.

Figure 1

(A) Sight of chocolate condition (placebo [Plac] > citalopram [Cital]). Axial, sagittal, and coronal image of increased ventral striatal activation in the placebo group compared with the citalopram group ([6 14 −8], z = 3.79, p < .001, family-wise error corrected). Paramenter estimates from 6-mm sphere centered at 14 6 −8 for citalopram, reboxetine (Rebox), and placebo.

Figure 2

(A) Chocolate in the mouth with the sight of chocolate (reboxetine [Rebox] > placebo [Plac]): axial, sagittal, and coronal image of increased medial orbitofrontal cortex/frontal pole activation in the reboxetine group compared with the placebo ([10 42 −30], z = 3.01, p = .05 false discovery rate small volume corrected). (B) Parameter estimates from 6-mm sphere centered at 10 42 −30 for citalopram (Cital), reboxetine, and placebo.

Figure 3

(A) Sight of moldy strawberries condition (placebo [Plac] > citalopram [Cital]): axial, sagittal, and coronal image of increased lateral orbitofrontal cortex activation in the placebo group compared with the citalopram group ([32 26 −4], z = 5.12, p = .002, family-wise error corrected). (B) Parameter estimates from 6-mm sphere centered at 32 26 −4 for citalopram, reboxetine (Rebox), and placebo.

Figure 4

(A) Strawberry in the mouth with the sight of moldy strawberries (placebo [Plac] > citalopram [Cital]): axial, sagittal, and coronal image of increased lateral orbitofrontal cortex activation in the placebo group compared with the citalopram group ([30 26 2], z = 4.22, p < .001, family-wise error corrected). (B) Parameter estimates from 6-mm sphere centered at 30 26 2 for citalopram, reboxetine, and placebo.