Our findings are the first to show that 7-days treatment with an SSRI diminishes the neural processing of both rewarding and aversive stimuli. This is consistent with the proposal that SSRI treatment might produce a general constraint of emotional response (8
) rather than simply decreasing the emotional impact of aversive stimuli. Such an effect could underlie the postulated modest antidepressant efficacy of SSRIs in patients whose depression is characterized by loss of motivation and pleasure (4
) in whom abnormalities in neural reward mechanisms have been demonstrated in functional imaging studies (33,34
). It has been suggested that such patients may benefit more from the use of catecholamine-potentiating antidepressants (4,10
), which agrees with the effects of reboxetine seen here to increase some aspects of reward processing.
As expected, citalopram treatment had less BOLD activation to the aversive stimuli, consistent with the ability of SSRIs to diminish negative affect across a range of psychiatric disorders (4,10
). Interestingly, reboxetine, seemed to have less effect on aversive responses than citalopram. This is in line with clinical observations that catecholamine-potentiating agents appear less effective than SSRIs at reducing distress and negative affect and have less overall utility, for example, in the management of anxiety disorders (5,35
The ability of SSRIs to limit the neural activation to reward may therefore support the clinical reports that SSRI treatment is associated not only with experiences of diminished negative affect (less sadness, less ability to cry) (36
) but in some patients also with diminished positive affect (decreased sexual pleasure and feelings of joy) (6,7
). In SSRI-treated clinical populations who report diminished positive affect, it is difficult to disentangle possible effects of subclinical depressive symptomatology or trait disturbances in reward mechanisms from those of concomitant SSRI treatment. For example, we have shown that unmedicated, clinically remitted depressed patients demonstrate blunted striatal responses to chocolate reward (13
). However, the present study of healthy subjects indicates that SSRI treatment can itself attenuate the neural processing of reward as well as that of aversive stimuli. It is conceivable, however, that in acutely depressed patients, SSRI treatment might produce a different effect on the neural processing of reward than that seen in healthy volunteers. Further studies are necessary to explore this possibility.
The time course of our study (7 days) was limited compared with the duration of clinical treatment with antidepressants, and it is therefore also relevant to study the effect of SSRIs on the neural basis of reward after longer treatment periods. However, a meta-analysis of clinical trials has shown that, relative to placebo, SSRIs significantly decrease depressive symptomatology after 1 week of treatment (37
), and indeed the effect size of active treatment relative to placebo is numerically greater during the first week of therapy than in subsequent weeks. Further, we have demonstrated in healthy volunteers that 7-day treatment with both citalopram and reboxetine produces positive biases in measures of emotional perception and memory, suggesting that therapeutically relevant changes in neuropsychological function are indeed apparent during the first week of antidepressant administration (38
Our participants showed no subjective sense of impaired reward to chocolate administration as judged by their ratings of “wanting” or “liking,” even though the corresponding neural response was substantially diminished. This suggests that impaired neural processing of reward does not necessarily become the subject of conscious awareness, although it could still presumably influence behavior. For example, longer-term SSRI treatment is associated with significant weight gain in clinical populations (39
) which would not be predicted from the known effects of serotonin on appetite (40
). However, using an experimental paradigm similar to our own, Stice et al.
) showed an association between obesity and decreased neural response in striatum to food reward, suggesting that obese subjects might overeat to compensate for the reward deficit. A similar mechanism could explain SSRI-induced weight gain during continued treatment.
Our findings indicate that the undoubtedly clinically useful effects of SSRIs in a wide range of psychiatric conditions characterized by painful and disabling negative affect (42,43
) may need to be balanced against their inhibitory effects on the neural responses to reward. As noted earlier, it could be the case that in depressed patients, in whom neural responses to reward appear to be lowered before treatment, SSRIs might in some way produce different effects on reward processing than those seen here in healthy participants. Larger studies in depressed patients and healthy control subjects, employing a within-subject design (pre- and posttreatment) are necessary to test this proposal.
Another relevant point is that although our data agree with plausible neurobiological hypotheses concerning the differential roles of serotonin and catecholamines in antidepressant action (4,10
), clinical studies in patients have not revealed consistent differences between serotonin and noradrenergic potentiating antidepressant in their ability to treat specific symptom domains in depressed patients (44
). In addition, the important functional interactions between serotonin and catecholamine pathways means that effects of pharmacologically selective agents will not be confined to a single neurotransmitter system (45
). Nevertheless, recent pooled analyses suggest that although the catecholaminergic antidepressant bupropion may be slightly less effective than SSRIs in treating depression associated with high levels of anxiety, it appears superior in resolving symptoms of sleepiness and fatigue (46,47
). Finally, although SSRI treatment has been associated with emotional blunting in some patients (6,40
), it is not established that the incidence of this phenomenon is greater with SSRIs than with other antidepressants acting through contrasting pharmacologic mechanisms.
If it is, in fact, the case that the inhibitory effect of SSRI treatment on neural responses to reward limits the potential effectiveness of SSRIs in the management of depression, it might be possible to improve the efficacy of SSRIs through the recruitment of pharmacologic mechanisms that enhance neural responses to reward as well as diminishing responses to aversive stimuli. A straightforward way to achieve this could be the use of serotonin and noradrenaline reuptake inhibitors (SNRIs) such as duloxetine and venlafaxine. Another strategy would be to add a drug such as bupropion to SSRI therapy. However, although these strategies may produce some benefits over SSRI monotherapy (48,49
), overall their effectiveness appears modest (50,51
). In this respect, it is not clear that noradrenergic or dopaminergic potentiation has the ability to “reverse” the major inhibitory effect of SSRI treatment on neural reward mechanisms demonstrated by our study. Further investigations examining the effects on reward of SNRIs as well as SSRI combination treatments are needed to address this question.