This study examined how symptom dimensions of depression may predict indices of recovery among SSRI-resistant adolescents enrolled in second-step treatment as part of the TORDIA trial. Anhedonia emerged as a key dimension predicting recovery. Anhedonia predicted a longer time to remission when all five symptom dimensions of depression were included simultaneously in a predictive model. Moreover, Anhedonia continued to predict time to remission when examined simultaneous to total CDRS-R score. As the confidence intervals for the association between Anhedonia and remission, and between the CDRS-R total score and remission are non-overlapping, this suggests that the effect for Anhedonia is stronger than that for the total score in predicting time to remission. Analyses examining depression-free days revealed similar outcomes. Taken together, these data suggest that Anhedonia robustly predicts both time to remission and depression-free days above and beyond other symptoms dimensions of depression; and above and beyond total CDRS-R score.
Anhedonic symptoms may serve as an important prognostic tool for identifying youth who may be at risk for a poorer or delayed recovery. Also, these data suggest that anhedonia may be blocking or slowing remission and could represent an important target for intervention. It is also possible that anhedonic symptoms reflect a marker of severity such that these are among the last symptoms to remit, though the likelihood of this is reduced by results demonstrating that Anhedonia predicted recovery above and beyond CDRS-total score at baseline. Identifying anhedonic symptoms in depressed youth early in treatment may provide opportunities to monitor symptoms more closely and intervene more aggressively to improve outcomes. Anhedonic symptoms have been shown to be associated with underlying positive affective systems (positive emotion, appetitive motivation, and features of reward-related circuitry);23
and although positive and negative affective systems certainly interact, they also carry unique functions24
and are not simply reciprocally activating.25,26
As such, the centrality of anhedonia to recovery among treatment resistant youth, combined with evidence that systems underlying anhedonia are functionally unique, suggests that targeting anhedonic symptoms and features of underlying positive affective systems carries potential to yield unique benefit.
No interaction effects between depression symptom dimensions and CBT treatment raises the question of whether or not existing CBT approaches adequately address anhedonic symptoms. In a previous component analysis of the CBT delivered in TORDIA, the most commonly used interventions were mood monitoring and cognitive restructuring.27
Behavior activation (BA)—an approach that may more directly target anhedonic symptoms in part by increasing exposure to and reinforcement from pleasant events—was also used, but only on average 1.5 times during the course of treatment. Thus, the treatment focused more on negative affect and cognitive distortions, with relatively less emphasis on increasing positively reinforcing experiences and related pleasure. An important set of questions for future research is whether CBT treatment that is augmented or front-loaded with BA approaches (or another intervention targeting anhedonia) for youth presenting with anhedonic symptoms may help to promote a more positive and rapid trajectory of recovery, and help youth to reach a full remission status.
Future research can capitalize on advances in the field of affective neuroscience and help to refine our understanding of these results. First, clinical trials that include neuroimaging and behavioral assessments of positive emotional and motivational functioning can help to determine if targeting anhedonia can uniquely alter underlying positive affective systems, and play a distinct role in improving remission rates and recovery among youth with treatment resistant depression. Second, there may be opportunities for novel treatment development that is informed by progress in affective neuroscience revealing a deeper understanding of positive affective systems and their neural underpinnings (e.g. fronto-striatal reward-related circuitry). For example, there are growing insights into how positive affective systems change and develop during the adolescent period,28
as well as how these systems uniquely relate to the developmental pathophysiology29–31
and clinical course of depression.32–35
Importantly, positive affective systems and how they relate to clinical manifestations of anhedonia are likely complex. As one of several examples, basic science across both animal and human models elucidates distinctions between appetitive motivations (“wanting”) and consummatory pleasure (“liking”), which both fall under the broader construct of positive affect and reward-related circuitry.36
Distinctions like these may inform our understanding of anhedonic symptom presentations (e.g. motivational anhedonia vs. consummatory anhedonia) and underlying neurobiology; as well as the use of existing interventions (e.g. BA), and the potential for complementary approaches that target these and other key deficits to alter underlying developmental pathways of depression.
Limitations to the study included that the continuation treatment (weeks 12–24) was not controlled, such that depression symptom dimensions may have been related to intervening variables that impacted time to remission or depression-free days. Second, the ethnic diversity of the sample was limited, which restricts generalizability of these findings.3,9
Third, although we did examine how these findings interacted with medication versus combination treatment (medication plus CBT), a high percentage of youth were enrolled in open treatment from weeks 12 through 24 during which they may have received any treatment. As such, future research may benefit from a more controlled approach to the question of whether combination treatment is indicated for youth presenting with anhedonic symptoms. Also, while outside of the scope of the current study, it may be useful to further unpack these findings with attention to specific treatment strategies to ascertain whether treatment may be optimized by matching strategies to symptom dimensions (e.g. BA for youth with anhedonic symptoms). Finally, global measures of outcome such as those used in this study may preclude detection of several possible pathways that can result in the same final net score of symptoms.
Despite these limitations, this was the first large-scale clinical trial among youth who were resistant to SSRI treatment, and it offers important insights into severely depressed adolescents. Other strengths include multiple assessments of symptoms over a longitudinal time-course, and the use of multiple indices of recovery. This allowed us to capture important temporal features that can be overlooked by the use of single end-point categories of remission/non-remission.
Overall, anhedonia is worthy of consideration as a prognostic feature and specific treatment target among youth with treatment-resistant depression. When considered from the framework of affective neuroscience, understanding anhedonia as it relates to developmental pathways of underlying positive affect systems and reward-related circuitry may provide opportunities for treatment innovation.