In the PADRE study, 80% of the depressed patients had moderate to severe overall pain at baseline. For all patients, the mean overall pain VAS score was 55.0 mm. This high pain intensity could partly result from the fact that depressed patients with pain syndromes could be overrepresented in this study because of the proven analgesic efficacy of duloxetine [14
]. However, the observed prevalence of pain in depressed patients in the PADRE study is in line with the literature reporting prevalence rates of 56% [33
], 65% [1
] and 88% [34
For 72.1% of the PADRE population, concomitant somatic diseases were documented most frequently 'muscle and skeleton diseases' (33.7%). The high prevalence of patients suffering from pain conditions may raise concern that common depression rating scales overestimate depressive symptoms in these patients, as they may score higher on somatic items because of their pain rather than because of their mood. However, Poole et al. [35
] showed a good correlation of a commonly used depression rating scale that includes somatic items (Beck Depression Inventory-II) with a structured clinical interview for DSM-IV Axis Disorders (SCID) which represents a gold standard for assessment of depressive symptomatology.
The main finding of our study is that early change in pain severity was strongly associated with a long-term reduction of depressive symptoms according to the mean KUSTA score. Pain responders also had a higher chance of achieving a 50% reduction in the IDS-C total score after 6 months.
This association of an early improvement in pain with long term depression outcomes was already seen after 2 weeks, albeit, to a smaller extent than after 4 weeks. This is remarkable, considering that 72.9% of the patients started duloxetine treatment with a dose of 30 mg/day, which is lower than the recommended starting and maintenance dose.
Patients with a VAS pain reduction of ≥ 50% after 2 and 4 weeks, showed also higher remission rates after 6 months than patients without a ≥ 50% pain reduction (Figure ).
For clinicians, it is of interest whether or not early improvement of pain is a better predictor of the long-term outcome to antidepressant treatment than early improvement of depressive symptoms. Therefore, post-hoc analyses were performed including early response in depressive symptoms after 2 and 4 weeks (as measured with IDS-C total score). Results showed that an early pain response had similar predictive value compared to early depression response for long term depressive outcomes as measured with the KUSTA scale.
The main results of the PADRE study are in contrast to a recent publication [36
], reporting a very low predictive association between analgesic and antidepressant responses in six placebo-controlled trials assessing the efficacy of duloxetine in patients with major depressive disorder. However, the studies used in these post-hoc meta-analyses were not designed to assess the relationship between antidepressant and analgesic response, and there were only few data points available for early response assessment.
Other studies support the association between early improvement in pain and long-term antidepressant response [15
]. Pooled data from two 9-week randomized, double-blind duloxetine studies showed that the remission rate for pain responders (improvement in VAS overall pain from baseline to last observation ≥ 50%) was twice that observed for pain non-responders (36.2% vs. 17.8%, p < 0.001). Improvements in pain severity were also related to improved quality of life and improved clinician- and patient-rated global health outcomes [14
]. A secondary analysis of a 12-week open-label trial with duloxetine in 249 patients [25
] found similar results. Patients who experienced clinically important pain reduction in the first week of duloxetine treatment were significantly more likely to reach remission at endpoint than the patients without this pain reduction (64.0% vs. 35.6%, p < 0.001).
The results of the PADRE study are of interest in the context of other recent research [27
]. Evidence was provided questioning the belief that antidepressant response usually appears with a delay of several weeks, and new evidence continues to accumulate that individual improvement within the first 2 weeks is a key predictor of treatment response. Lack of early response in depression symptom subscales was highly predictive of a lack of sustained remission [41
]. A lack of improvement during the first 2 weeks of therapy may indicate that changes in depression management should be considered earlier than conventionally thought [32
]. Results from PADRE also suggest that early improvements in concomitant PPS measured with simple VAS scales should be considered in treatment decisions during the initial 2-4 weeks of a new antidepressive treatment. The results of PADRE could also be important for patients with generalized anxiety disorder with or without comorbid MDD, as the clinical relevance of PPS and resulting functional impairment has been reported [43
As this was a large observational study in daily clinical practice, several methodological limitations such as the absence of monitoring or a high number of patients lost to follow-up were unavoidable and may lead to concerns with regard to data quality. However, this non-interventional approach reflects current treatment of patients with MDD by office-based psychiatrists and should therefore allow generalization of our results to clinical practice. Perhaps the most serious shortcoming of non-interventional trials is selection bias because of absence of randomization. Another limitation of the study is the lack of a control group, as only duloxetine-treated patients were included.