The current study is the first to examine reward-related brain function as a predictor of treatment response in adolescent depression. In a sample of young people with major depressive disorder and high degree of anxiety disorder comorbidity, growth curve models indicated that participants improved over time: During treatment, depressive symptoms, anxiety symptoms, and severity decreased (albeit at a trend level for depressive symptoms), and clinician-rated improvement increased. Greater reward-related striatal function before treatment was associated with higher overall clinical severity at the end of treatment, lower anxiety symptoms at the end of treatment, and faster improvement in anxiety symptoms. Greater reward-related medial PFC function before treatment was related to slower improvement in anxiety symptoms. Reward-related brain function predicted final overall severity level, final anxiety symptom level, and rate of improvement of anxiety symptoms. This study is also unique in using fMRI in combination with growth curve modeling to account for patterns of change during treatment—including both final severity levels and slope of outcome measures over time—and their relation to brain function.
Heterogeneity in reward-related brain function among young people with depression may provide information on which people or which symptoms are likely to improve with treatment. Given that heterogeneity in response to treatment is considered the norm in depression (Brent et al., 2008
), understanding the physiological markers that characterize potential responders could inform the development of new treatments or the personalization of existing treatments.
Findings that reward-related brain function predicted lower final anxiety symptoms and faster-decreasing anxiety symptoms are consistent with the hypothesis that higher, and potentially more adaptive, reward-related brain function before treatment is associated with better treatment response. A possible explanation for this is that flexible reward responding, with its implications for affiliative behavior (Bora, Yücel, & Allen, 2009
), could serve as a mechanism in effective engagement in CBT. Such engagement could be expressed in the social, cognitive, or behavioral aspects of CBT. An adolescent with depression and comorbid anxiety who also responds to rewards might respond more collaboratively to the therapist, have optimism that the treatment will be helpful, be more motivated to try techniques suggested in treatment, experience more positive affect to behavioral activation, and have more awareness and enjoyment of positive changes in mood and experiences that occur with treatment. Along with an earlier study's findings on the positive clinical prognostic value of subjective positive affect in adolescents with depression (Joiner, Lewinsohn, & Seeley, 2002
), the current findings support the hypothesis that relatively higher positive affect could be protective in youth with depression and anxiety.
The current findings about the association between reward-related brain function and anxiety symptoms parallel, in some ways, other studies' findings that affect-related brain function predicts treatment response. Most of the previous studies have focused on neural response to negative affect (Chen et al., 2007
) or on threat-related brain systems (McClure et al., 2007
), and although the current findings focus on reward-related rather than threat-related brain systems, the regulation of both systems is postulated to be altered in depression (Clark & Watson, 1991
; Fowles, 1988
). Interestingly, anxiety is postulated to differ from depression in its weaker association with alterations in positive affect (Clark & Watson, 1991
), a construct that includes reward responding. That conceptual view is not supported by the current findings or by other findings on reward processing in anxiety traits or disorders (e.g., Forbes et al., 2006
; Guyer et al., 2006
). Perhaps appropriate affective responding rather than blunted affective response, regardless of stimulus valence, promotes the ability to benefit from treatment. This hypothesis must be tested by examining both reward-related and threat-related brain function in a single sample and, ideally, in a single task. Our task did not allow this, so this question must be addressed by future studies.
Notably, depressive symptoms were not associated with reward-related brain function. The MFQ, our measure of depressive symptoms, is valuable as a depression screening tool and is more effective at detecting depressive than anxiety disorders (Katon et al., 2008
). It is thus unlikely that the instrument measured anxiety symptoms better than depressive symptoms. In growth curve models, low variability in slope for depressive symptoms over time limited our ability to test the relation between reward-related brain function and rate of change in depressive symptoms, and thus we could not report associations between brain function and slope for depressive symptoms. This low variability could reflect a fairly uniform pattern of improvement in depressive symptoms among the adolescents in the current sample, and this similarity in pattern of improvement leaves little room for identifying factors related to improvement. In the current sample, anxiety symptoms had a more variable slope across time than did depressive symptoms, which could have been related to the presence of comorbid anxiety disorders in some participants. In addition, the difference between depressive symptom change and anxiety symptom change perhaps reflects the presence of more potential sources of influence on the improvement of anxiety with treatment.
The literature on anxiety disorders provides little context for our findings with anxiety symptoms. Because no previous studies have examined reward-related brain function as a predictor of treatment response in anxiety, and few theoretical models of anxiety postulate alterations in reward functioning, it is difficult to interpret the association of reward-related brain function with change in anxiety symptoms. A possible explanation is that reward-related brain function is related to general affective psychopathology rather than to depression in particular. Alternatively, the functioning of putative reward-related brain areas such as the striatum has yet to be determined definitively, and the striatum might be critical in some ways to the pathophysiology of anxiety. With the current pattern of findings, we cannot rule out the possibility that reward-related brain function is related more to treatment change involving anxiety than depression. Greater striatal reactivity has been reported in studies of adolescents with anxiety-related temperament (Guyer et al., 2006
) or disorders (Forbes et al., 2006
), and the next step in this line of research will be to directly compare the relation of reward-related brain function to treatment response in adolescents with anxiety only, depression only, and comorbid anxiety and depression.
The relation of reward-related medial PFC reactivity to slower rate of improvement in anxiety symptoms is consistent, to some extent, with findings on medial PFC involvement in depression. In adults with depression, medial PFC reactivity to affective stimuli is enhanced (Sheline et al., 2009
), and decreased resting medial PFC activity is associated with improvement after CBT (Goldapple et al., 2004
). Also, adolescents with depression exhibit greater reward-related medial PFC reactivity (Forbes, Hariri et al., 2009
). Because the medial PFC is part of the default-mode network, the association of mPFC reward-related reactivity with less rapid improvement in anxiety suggests that difficulty disengaging from the usual, self-focused mental state interferes with response to treatment in adolescents with depression. The current association of medial PFC reactivity and change in anxiety symptoms could indicate that anxiety (at least in the context of comorbidity with depression) confers similar functional alterations to regions in the default mode network.
In contrast, the finding that greater overall clinical severity at the end of treatment was associated with higher striatal reactivity to reward was unexpected, and it does not support our hypothesis that greater reward-related responding predicts better treatment outcome. This correlation was not mirrored in the association between brain function and adolescents' symptoms: Reward-related brain function was unrelated to higher depressive symptoms at the end of treatment, and it was inversely related to anxiety symptoms. A difference between these measures is that overall clinical severity was rated by treatment providers, while symptoms were rated by the adolescents themselves. Treatment providers and adolescents could have different perspectives on the adolescents' symptoms and functioning, and differences in the instruments used for these variables are likely to lead them to capture different aspects of affective problems. It is also possible, of course, that higher reward-related brain function is related to the expression of distress to others even if that distress is not experienced as meaningful by a young person. Furthermore, final severity was associated with striatal reactivity during the outcome condition. Adolescents who exhibit greater response to winning money might respond strongly to external stimuli in general, and as a result, they might be judged as having greater general clinical severity.
Our pattern of findings suggests that it is important to assess brain function in response to both reward anticipation and reward outcome when examining its predictive utility for treatment response. Greater anticipation-related brain function was associated with lower anxiety symptom level at the end of treatment and faster change in anxiety symptoms during treatment. Improvement in anxiety might thus be particularly associated with reward anticipation, which is thought to represent motivation or “wanting,” rather than “liking” of rewards (Berridge & Robinson, 2003
Improvement in self-reported symptoms was generally similar to that for clinician-rated severity and improvement, but greater reward-related striatal reactivity predicted higher clinician-rated severity and lower self-reported anxiety. However, severity was related to BOLD response during reward outcome, and anxiety was related to response during reward anticipation. It is possible that these two aspects of reward processing—reward anticipation reflecting motivation, and reward outcome reflecting enjoyment—are related to severity and anxiety in opposite ways.
Our findings must be considered in light of some limitations. Several of these were related to our small sample size. First, the sample size may have resulted in Type I errors in finding associations between brain activation and symptom scores and change (Maas & Hox, 2005
). In addition, not all participants completed treatment, and missing data created a challenge for analyzing data for all time points for all participants. This was a result of dropout, and although we made extensive efforts to contact participants and encourage completion of treatment, it may be valuable for future studies to use more creative methods to retain participants. Second, we were not able to compare psychosocial and combined psychosocial and pharmacotherapy treatments comprehensively. We could not include medication status in growth curve models, for example. Previous studies of adult depression have revealed that CBT and pharmacotherapy are associated with different patterns of treatment-related changes in brain function (Goldapple et al., 2004
). It will be important for research on predictors and mechanisms of treatment response in young people to address possible differences in treatment modalities. Third, we had restricted ability to compare adolescents with and without comorbid anxiety disorders. We have found that depressed adolescents with anxiety disorders are similar in their reward-related brain function to those without comorbid anxiety disorders (Forbes, Hariri et al., 2009
), but we have also found, in a different sample, that anxiety symptoms are related to reward-related brain function independently of depressive symptoms (Forbes et al., 2006
). It is important to examine comorbidity effects in the prediction of treatment response, and also to consider the possibility that comorbidity of anxiety and depression represents greater severity than the presence of depression alone.
We acknowledge that our sample size is on the small side for growth curve modeling, but we also note that the number of time points in our study makes growth curve modeling the most appropriate approach to examining change in symptoms, severity, and improvement over time. To address possible power issues for this technique, and guided by the small literature on sample size in multilevel modeling (Maas & Hox, 2005
), we conducted a Monte Carlo simulation in Mplus to examine the power to find significant variance estimates for the mean and variance components for the intercept and slope. We included the exact study characteristics from the present data to simulate 100 data sets to provide power estimates for the relevant parameters. Across outcome variables, power estimates for the intercept values, standard error of the intercept values, slope values, and standard error of the slope values were .92, .37, .84, and .34, respectively. Thus, the current study was sufficiently powered to find significant intercept and slope values but had little power to identify significant variance in the intercept and slope parameters. Thus, it is impressive that we found significant variance in four of the eight growth parameters.
Several aspects of the study design also limit the scope of our findings. We only collected fMRI data before treatment, so we were not able to examine change in brain function with treatment. This issue is important in understanding the possible roles of reward-related brain function in both the pathophysiology of depression and the mechanisms of treatment response. One study has reported that reward-related areas have impaired functioning both before and after treatment in adult depression (Fu et al., 2007
), which suggests that altered reward processing, at least in adults, is trait-like. Our study did not include a wait-list control group, which prevents us from concluding that change in severity reflects response to treatment rather than spontaneous recovery. Also, the high ratio of therapists to participants left us unable to examine potential therapist effects that could have contributed to variability in treatment response. Finally, treating clinicians, rather than independent evaluators, provided assessments of improvement and severity. Thus, some biases may have been present in their responses, even though ratings were performed without knowledge of the fMRI results.
Research on the pathophysiology and treatment of depression has indicated that development plays an important role in the disorder's onset and course. Findings in adolescents have not provided an exact replication of findings in adults, and developmental psychopathologists have postulated that the biological features of the disorder are different early in life (Kaufman, Martin, King, & Charney, 2001
). Even though we did not find that age contributed to treatment response, the broad age range of participants could have introduced other developmental effects into our study. We have found, in a different sample, that striatal response to reward decreases with pubertal maturation in healthy adolescents (Forbes et al., under review
), and development of reward-related systems during adolescence could influence the onset, course, and treatment of depression. Therefore, future treatment studies of adolescents should employ designs that allow the careful examination of developmental factors in both the response to treatment over time and the prediction of treatment response from affect-related brain function.
In summary, this study yielded preliminary findings on reward-related brain function as a predictor of treatment response in adolescents with depression, many of whom had comorbid anxiety disorders. The findings point to the potential importance of reward-related brain function in the treatment of depression, not simply in its pathophysiology. With a more complete understanding of the types of affect-related brain function that indicate which young people with depression will likely have a favorable response to treatment, it will become more possible to improve the efficacy of existing treatments or to develop biologically guided treatments that are personalized.