Diminished Neural Processing of Aversive and Rewarding Stimuli During Selective Serotonin Reuptake Inhibitor Treatment

Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford OX3 7JX, United Kingdom.
Biological psychiatry (Impact Factor: 10.26). 03/2010; 67(5):439-45. DOI: 10.1016/j.biopsych.2009.11.001
Source: PubMed


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.
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.
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.
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.

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    • "Furthermore, anhedonia in MDD is a predictor of proximal (within 1 year) suicide completion (Fawcett et al., 1990). Additionally, mounting evidence suggests that standard antidepressants may possess minimal efficacy in relieving anhedonia (Nutt et al., 2007) and may even induce emotional blunting (McCabe et al., 2010; Opbroek et al., 2002; Price et al., 2009) and sexual dysfunction (Hindmarch, 1998). Despite the importance of this symptom in psychiatry, and particularly in MDD, there is currently no approved medication specifically targeting anhedonia. "
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    • "Clinically, SRIs are less effective in managing the anhedonic symptoms of depression (Nutt et al., 2007; Lane, 2014) and in fact provoke cognitive and emotional blunting (Sansone and Sansone, 2010). These SRI-associated effects have been ascribed to 5-HT 2C -mediated suppression of frontal DA function (Barnhart et al., 2004; Wongpakaran et al., 2007; McCabe et al., 2010; Sansone and Sansone, 2010) (Figure 2). By not promoting 5-HT release, agomelatine will bolster and/ or sustain DA function (by limiting 5-HT 2C activation of GABA inhibitory neurons), or it can temper DA release via NA activation of α 2 -heteroreceptors on DA neurons (Figure 2). "
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    • "Research has primarily examined serotonin reuptake inhibitors (SSRIs) and serotonergic–noradrenergic reuptake inhibitors (SNRIs) indicating that SNRIs are superior to SSRIs at improving certain cognitive functions (Herrara-Guzman et al., 2009). In contrast, SSRI antidepressants such as citalopram have been suggested to diminish neural processing of aversive and rewarding stimuli in healthy individuals (McCabe et al., 2010), suggesting the possibility that antidepressants may exert negative effects on neuropsychological function during antidepressant treatment of depressed patients. Other antidepressants that have been examined and seem to have improving effects on neuropsychological functioning in depression include selective serotonin reuptake enhancers (SSREs), tricyclic antidepressants (TCAs), and other specific drugs (Allain et al., 1992; Nickel et al., 2003; Gallassi et al., 2006; Holtzheimer et al., 2008; Katona et al., 2012; Levkovitz et al., 2012); however, their mechanisms of action on cognitive processes remain to be fully understood. "
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