The complex clinical response to selective serotonin reuptake inhibitors in depression: a network perspective

Abstract

The clinical response to selective serotonin reuptake inhibitors (SSRIs) in depression takes weeks to be fully developed and is still not entirely understood. This study aimed to determine the direct and indirect effects of SSRIs relative to a placebo control condition on clinical symptoms of depression. We included data of 8262 adult patients with major depression participating in 28 industry-sponsored US Food and Drug Administration (FDA) registered trials on the efficacy of SSRIs. Clinical symptoms of depression were assessed by the 17 separate items of the Hamilton Depression Rating Scale (HDRS) after 1, 2, 3, 4 and 6 weeks of treatment. Network estimation techniques showed that SSRIs had quick and strong direct effects on the two affective symptoms, i.e., depressed mood and psychic anxiety; direct effects on other symptoms were weak or absent. Substantial indirect effects were found for all four cognitive symptoms, which showed larger reductions in the SSRI condition but mainly in patients reporting larger reductions in depressed mood. Smaller indirect effects were found for two arousal/somatic symptoms via the direct effect on psychic anxiety. Both direct and indirect effects on sleep problems and most arousal/somatic symptoms were weak or absent. In conclusion, our study revealed that SSRIs primarily caused reductions in affective symptoms, which were related to reductions in mainly cognitive symptoms and some specific arousal/somatic symptoms. The results can contribute to disclosing the mechanisms of action of SSRIs, and has the potential to facilitate early detection of responders and non-responders in clinical practice.

Fig. 1. Direct and indirect effects of SSRIs on 17 individual depression symptoms during six weeks of treatment.

a Effects after 1 week of treatment. b Effects after 2 weeks of treatment. c Effects after 3 weeks of treatment. d Effects after 4 weeks of treatment. e Effects after 5 weeks of treatment. Treatment (SSRIs over placebo) is represented by a square and individual symptoms by circles. Red edges between SSRIs and symptoms indicate beneficial treatment effects (i.e., lower symptom scores for the SSRI condition relative to placebo), whereas blue edges indicate detrimental treatment effects (i.e., higher symptom scores for the SSRI condition relative to placebo). Red edges between symptoms indicate negative associations, whereas blue edges indicate positive associations. Thicker edges represent stronger connections.

Fig. 2. The development of symptom-specific effects of SSRIs during six weeks of treatment.

a Direct effects of SSRIs. b Overall effects of SSRIs.