In this first study of the treatment of SSRI-resistant depression in adolescents, many predictors of treatment response were similar to those identified in studies of first-step treatments. Depression severity, hopelessness,5,8,10
youth-reported family conflict,6,7
and functional impairment5,10
were associated with nonresponse. Significant moderators of CBT/combined treatment were a history of abuse and number of comorbid/co-occurring disorders, with a marginal effect for hopelessness; self-reported depression moderated response to venlafaxine versus an SSRI. We place these findings within the context of the study limitations and extant literature and then discuss clinical significance and research implications.
Although the TORDIA sample was relatively large, power was limited for tests of moderation. The geographic diversity of the sample is a study strength, although ethnic/racial diversity was limited, reducing our ability to examine ethnic/racial differences. Exclusion criteria, such as substance abuse limit generalizability to samples with these comorbidities. Because TORDIA did not include a placebo, or CBT added to the initial SSRI medication conditions, future research is needed to determine whether results were due to CBT or CBT combined with a medication switch. The study was designed to evaluate combination therapy with CBT, selected as the most established psychosocial treatment; whether our results will generalize to alternative psychosocial treatments needs examination. This study reports secondary exploratory analyses; although, in some cases, findings were replications of previously reported results, other results require replication and confirmation.
We replicated previous findings that indices of severity and chronicity predict a poorer response to treatment.5,8,9
This highlights the importance of early detection and treatment, before patients' conditions become chronic and more intractable to intervention, and also the need to develop effective interventions for severely ill youth. This could include longer and more intense treatment, augmentation of antidepressant treatment with a mood stabilizer, or use of other types of intervention that have different and more rapid mechanisms of actions.30
Additional predictors emerged for this treatment-resistant sample, where we included a broader group of more chronic and severely ill youths relative to other samples. A history of NSSI was a poor prognostic indicator. This is a marker for difficulty with emotion regulation, which often accompanies chronic depression.31
The positive prognostic power of longer duration of medication treatment may reflect a commitment and/or positive expectancy for treatment as these youths and families continued in treatment despite minimal benefits. Alternatively, the longer time in treatment may screen out youths who are likely to respond to pharmacotherapy alone, leaving a group who require a change in treatment strategy. In contrast to TADS and other first-step treatment studies,5,8
our study did not find that older age predicted poorer response, nor did our study find evidence of moderation due to family income, although substantial missing data on our income variable may have affected results.
The number of comorbid diagnoses was a positive moderator of CBT/combined treatment effects in TORDIA, with stronger CBT/combined treatment effects among youths with more comorbid disorders, ADHD, and a trend to better outcome with anxiety disorders. These results are consistent with previous results from first-step psychosocial treatment studies in which CBT was most beneficial among youths with comorbid anxiety8
but in contrast to TADS,5
in which comorbidity was a negative predictor and did not moderate treatment outcome. Perhaps, in our SSRI-resistant population, CBT provided a frame-work for dealing with difficulties associated with comorbid conditions that medication alone did not (e.g., problem solving, social skills training), which could have an impact on a range of disorders/adjustment problems. This finding supports the use of CBT/combined treatment with the more heterogeneous and complex patients seen in community settings,32
especially because comorbidity has been reported to be a negative prognostic factor and because comorbities with ADHD and anxiety are common in community clinical settings.
We found a weaker CBT/combined treatment effect among youths with histories of abuse and higher hopelessness—a measure of negative cognitions about the future and one component of the depressive triad of negative beliefs about the self, life, and future. The results regarding abuse are consistent with previous articles in depressed adolescents,11
although chronically depressed adults with maltreatment histories have been shown to preferentially respond to psychotherapy versus medication.33
These results suggest the need to better understand the seemingly greater resistance to depression-focused CBT among youths with abuse histories. The moderation of CBT/combined treatment response by hopelessness is also consistent with some, but not all, studies of CBT5,8,10
and suggests the need for interventions targeting hopelessness more specifically, such as developing a “Hope Box” with reminders of reasons for living and cues for generating more optimistic thoughts.34,35
Contrary to our prediction based on first-step treatment research,5,13,14
significant benefits of CBT/combined treatment were found for youths with the most severe depressive symptoms, as well as less severe symptoms. Thus, in the context of initial SSRI treatment resistance, the addition of CBT seems to yield benefits even among the most severely ill youths.
Exploratory analyses (meaning that formal criteria for moderation were not met4
) indicated that response to CBT was greater among older youths, perhaps because of increasing ability to use cognitive strategies with age and developmental maturation. However, TORDIA youths ranged from 12 to 18 years old; alternative psychosocial treatment strategies rooted in knowledge regarding the developmental needs/functioning of younger youths might have yielded greater gains.36–39
The CBT/combined treatment was significantly more beneficial than medication alone among whites, but these benefits were not detected among minority participants. It could be that the TORDIA CBT required adaptation to better meet the needs of minority youths.34,40
Future studies are needed with larger minority samples and to evaluate strategies for balancing the need to maintain treatment fidelity while allowing for clinical flexibility and individual tailoring to meet diverse patient needs.
Findings regarding moderators of medication response must be interpreted cautiously because of the absence of an overall effect for medication. In contrast to our prediction that a switch to venlafaxine would be overall more efficacious than a switch to an SSRI, we found similar response rates to venlafaxine and SSRIs.2
Self-reported depression on the BDI was the only variable to emerge as a significant moderator, a significant advantage for venlafaxine versus SSRIs emerged only at the lowest levels of self-reported depression (BDI <10), and SSRIs were marginally more beneficial than venlafaxine at higher BDI levels. Given our finding of more side effects with venlafaxine,2
these results support the choice of an SSRI switch in a treatment-resistant population, although this issue requires additional research.
In conclusion, treatment nonresponse is a common problem in clinical practice: first-step treatments yield minimal benefits for 40% of youths, and TORDIA results indicate that nonresponse to second-step treatments is also common. Given the greater costs involved in adding CBT to pharmacotherapy,3
it is important for patients, parents, providers, and health care organizations to know when these costs are likely to be most beneficial and when continued emphasis on medication monotherapy is likely to be equally beneficial. We found moderators of CBT/combined treatment that may aid in personalizing treatment and in highlighting areas requiring further treatment development work. Our data support the benefits of CBT/combined treatment among youths with more comorbid disorders, suggesting that this strategy may be particularly cost-effective in community settings where youths frequently present with multiple diagnoses. The poorer response to CBT/combined treatment among youths with abuse histories and high levels of hopelessness may indicate that different treatment approaches are required for youths with these features. If confirmed by future studies, our findings can contribute to a more personalized approach to the treatment of depression in adolescence.