The results of this study show that

The results of this study show that treatment of patients who have MDD with associated PPS with 60 mg/d of duloxetine for 8 weeks results in a progressive improvement of both DS and PPS, as indicated by a reduction in MADRS total scores and BPI-SF average pain scores. At week 1, the direct effect of treatment on PPS reduction was 75% and only 25% of the PPS relief was attributed to DS improvement. The large direct component on PPS relief was also present at week 2, but the balance shifted somewhat abruptly such that the indirect effect outweighed the direct effect beginning at week 4. After 8 weeks of treatment, the PPS improvement in depressed patients with PPS was largely due to the indirect effect resulting from the DS improvement (77%) and only 23% was attributed to a direct effect of duloxetine. Accordingly, the observations made in the present investigationare consistent with earlier studies on the interactions between MDD and PPS.22,28,40,48,50 Importantly, this study extends theseobservations to show that there is a marked shift in the direct effect of duloxetine on pain relief in patients with MDD over time.First, when assessing the attribution of the direct effect of treatment on PPS and the indirect effect via DS improvement during the acute phase treatment as a whole (eg, 8-9 weeks), this study showed a direct effect of duloxetine of only 23% and an indirect effect of 77%. When compared with a previous report by Fava et al22 where the direct effect of duloxetine on PPS reduction attributed 51% and the indirect effect 49%, our results indicate a lower attribution of direct effect on PPS and higher attribution on indirect effect via DS improvement. This inconsistency may be explained by the difference in population in the study. In the study by Fava et al,22 the patient population was not initially screened for PPS, resulting in a diverse range of pain severity, whereas our study used a specific population: patients with MDD and associated PPS. From a clinical perspective, these results suggest that, for the patients with MDD and with associated PPS, although the patients explicitly exhibit PPS, it is rather important to improve DS to achieve PPS improvement in the end.Second, when assessing the attribution of the direct effect of treatment on PPS and indirect effect via DS improvement during the very beginning of acute phase treatment (ie, 1-2 weeks), this study reveals a new clinical perspective. This study showed that until 2 weeks of treatment the direct effect of treatment on PPS dominated over indirect effect via DS improvement. From a clinical perspective, this result suggests that, to quickly relieve the patients with MDD with associated PPS from pain symptoms in the initial phase of treatment, it is important to count on the effect of pharmacological therapy rather than to expect DS to indirectly improve PPS. This clinical implication is underscored by the larger effect size elicited by duloxetine with regard to PPS improvement and in contrast to DS improvement at weeks 1 and 2, as shown in Figure 1. 582 E. Harada et al.•157 (2016) 577–584 PAIN® Third, the shift in dominance of the direct effect of duloxetine on PPS to the indirect effect over time is consistent with the known neurobiology of serotonin and norepinephrine reuptake inhibitors with respect to pain and depression. The pain relief obtained with duloxetine is of an immediate nature. Duloxetine engages descending pain modulation that is likely to be impaired among patients with MDD.39 Duloxetine is also clinically effective in several persistent painful conditions, such as chronic musculo-skeletal pain of the back, osteoarthritis, diabetic neuropathy, and fibromyalgia.54 These conditions are associated with dysfunction of endogenous pain modulation, and it is highly likely thatduloxetine, by enhancing noradrenergic transmission, engages descending pain modulatory systems.41,46,47,54,55 In contrast,the antidepressant action of these drugs is not immediate in onset but occurs after a considerable latency of 3 to 6 weeks.42 This latency to effect indicates that the clinical benefit is not due to an immediate elevation in the synaptic availability of norepinephrine and serotonin, but rather to neuroplastic changes that take place over time in response to the elevation in basal levels of these transmitters.44,49 Accordingly, the predominance of the direct effect of duloxetine during the initial trial period is likely due to engagement of noradrenergic pain modulatory systems, whereas the later indirect effects are due to the antidepressant mecha-nisms coming online.48 The important clinical implication here is that pain relief with a serotonin and norepinephrine reuptake inhibitor is not simply due to alleviation of depression but due to possible engagement of descending pain modulation.Finally, when the alternate path analyses was performed, it was found that after 8 weeks of treatment the direc