Discussion
guilt, major depression, psychic anxiety, anxiety, reductions in affective symptoms, agitation, depressed mood, hypochondriasis
To the best of our knowledge, this is the first study that uses network estimation techniques to shed light on the complex clinical response of SSRIs relative to placebo over a 6-week period. The most profound direct effects of SSRIs were found for the two affective symptoms, for which the effect on depressed mood was slightly quicker and stronger than the one on psychic anxiety. Direct effects on other symptoms were weak or absent, except for two detrimental effects on genital problems and loss of weight. We observed substantial indirect effects on all four cognitive symptoms via the direct effect on depressed mood, whereas smaller indirect effects were found for two arousal/somatic symptoms (i.e., somatic anxiety and agitation) via the direct effect on psychic anxiety.It is well-established from numerous drug trials as well as from clinical experience that the antidepressant effect of SSRIs takes a few weeks to emerge and several weeks to be fully developed [To generate hypotheses regarding the potential mechanisms of clinical change during SSRI treatment, we used network estimation techniques to reveal the patterns according to which individual symptoms were related. The networks showed multiple connections (e.g., 75 unique connections at week 1 and 53 unique connections at week 6), illustrating the complexity of the clinical response to SSRIs. It is therefore unlikely that this clinical response is a consequence of a single mechanism; instead, many mechanisms are probably involved, which may also differ across individual patients. However, our network findings could be valuable in revealing pathways that potentially play a prominent role in the clinical response to SSRIs. For example, depressed mood was mainly related to cognitive symptoms at all assessments, which explains the substantially larger reductions in these symptoms in the SSRI condition relative to the placebo condition. From a clinical perspective, it is also intuitive that an improvement in mood increases, for example, a patient’s interest in work and activities and decreases his or her feelings of guilt and suicidal thoughts. Although to a lesser extent, psychic anxiety was mainly related to somatic anxiety and agitation (i.e., two arousal/somatic symptoms), suggesting that improvements in the psychological aspects of anxiety go hand in hand with improvements in physical aspects of anxiety as measured with these two symptoms; again, this makes sense from a clinical perspective.The presented networks also support the notion that the HDRS captures common side effects of SSRIs, which is in line with a recent study [A strength of the current study is that we used data of 7909 patients with major depression by combining 28 industry-sponsored, placebo-controlled SSRI trials and considered assessments after 1, 2, 3, 4 and 6 weeks. Consequently, we had sufficient statistical power to consider a broad spectrum of clinical outcomes and their complex interrelatedness.As a possible weakness of the study it should be noted that some reports have suggested the inter-rater reliability of some HDRS items to be poor [It is also important to note that regularization techniques in network estimations set very weak connections to zero [Another potential weakness of the current study is that the number of response categories of the HDRS items differ and the sensitivity to detect symptom-specific effects might be higher for items with more response categories. This was, however, not supported by our findings, as the strongest direct effects were found for the two affective symptoms (scored 0–4) and two specific arousal/somatic symptoms (scored 0–2) while only weak effects were found for, for example, hypochondriasis (scored 0–4).In conclusion, our explorative study shows that network estimation techniques are valuable in demonstrating the complexity of the clinical response to treatment and in identifying pathways that potentially play a prominent role herein. For example, we showed that SSRIs primarily resulted in reductions in affective symptoms, which were related to reductions in mainly cognitive symptoms and some arousal/somatic symptoms. This might be an important step in disclosing the mechanisms of action of SSRIs, and may also have potential in the early detection of responders and non-responders in clinical practice.