We identified three classes of symptom response in treatment-resistant depressed adolescents using latent classification analysis. One class, “GO,” showed a rapid initial response and a short time to remission, around 3 months. A second class, “SLOW,” showed a slower response, with a median time to remission of 6 months. The third class, “NO,” consisted predominantly of participants who were unlikely to attain remission even 72 weeks after intake. These trajectories were well established after 6 weeks of treatment. In addition to depression severity, anxiety, hopelessness, and family conflict, sub-syndromal manic symptomology emerged as a predictor and correlate of trajectory. Higher baseline manic symptoms predicted a slower rate of remission. Over time, an increased number of manic symptoms were associated with the “NO” class and with lack of remission, even after those few participants who became hypomanic were excluded from the analyses.
To our knowledge, this is the first study in adolescent depression to report that sub-syndromal manic symptoms may contribute to poor outcome in adolescent depression treatment. While baseline MRS scores only discriminated SLOW from GO, higher MRS scores over time were found in both NO and SLOW, compared to GO, and were associated with lack of remission. Although this is a novel finding in adolescents, it is convergent with a growing literature in adults linking sub-syndromal bipolar symptoms to treatmentresistant depression (Correa et al., 2010
), with initial reports on this topic as long as 2 decades ago (Akiskal and Mallya, 1987
). Later studies showed that the rate of bipolar spectrum disorders can reach more than 50% in treatment-resistant populations diagnosed with unipolar MDD when in-depth assessments and modified criteria are used, especially in referred samples (Hantouche et al., 1998
; Sharma et al., 2005
). Even epidemiological studies have reported that as many as 40% of participants with a history of MDD had a history of subthreshold hypomanic symptoms, which in turn was associated with a younger age at onset, more episodes of depression, and higher rates of comorbidity (Angst et al., 2010
). These findings in adults complement epidemiological studies of adolescents showing that as much as 6% of community youth have “soft” bipolar symptoms with markedly greater rates of comorbidity, suicidal behavior and functional impairment compared to unipolar depressed adolescents without manic symptoms (Lewinsohn et al., 1995
). In the present study, the mean MRS scores for the three classes were between 3 and 5, well below the clinical cut-off score (=12) for bipolar disorder in children and adolescents (Axelson et al., 2003
). In addition, DSM-IV bipolar spectrum disorder was an exclusion criterion for TORDIA. These findings suggest that the presence of manic symptoms, even below the level that we currently consider clinically significant, may characterize a subpopulation of adolescents with treatment-resistant depression who are unlikely to respond to the currently available evidence-based depression treatment. Studies using mood stabilizers, either alone or as an augmenting agent are worth strong consideration in this population. However, similar to the findings of Lewinsohn et al. (2000)
, family history of bipolar disorder was not related to the number or severity of manic symptoms in this sample.
These findings also provide additional support for the importance of the first few weeks of treatment in determining long-term outcome, which appears to be true both in treatment resistant adolescent samples, as well as in those who were treatment naïve (Asarnow et al., 2009
; Tao et al., 2009
; Vitiello et al., 2010
). A slower pace of response is clinically significant because the slower the treatment response, the greater the likelihood of the occurrence of a suicidal event. Since the majority of suicidal events occur early in the course of treatment, acceleration of initial treatment response may not only improve the rate of remission, but also decrease rate of suicidal events, as is suggested by the findings in TADS as well as experimental studies to accelerate treatment response in suicidal adult patients with treatmentresistant depression with ketamine (Price et al., 2009
). In addition, the characteristics of the treatment refractory group, such as high rates of family conflict anxiety, non-suicidal self-injury, and high hopelessness, could also suggest additional treatment targets to improve the response and remission rates.
This sample of treatment resistant depressed adolescents is one that was unlikely to remit spontaneously, both because they had been ill a median of two years prior to entry into the study, and because to enter the study, participants had to have two assessments and demonstrate symptom stability prior to randomization. Therefore, these findings may be particularly relevant for chronically ill, treatment resistant depressed adolescents. These findings indicate that while our current treatments, including combination of antidepressants and cognitive behavior therapy, were able to help most treatment resistant adolescents, a sub-group, with particularly high baseline CDRS-R scores, often did not respond to evidence-based treatments, similar to findings in other large clinical trials (Goodyer et al., 2007
; March et al., 2004
Limitations of this study include a high rate of open treatment by the end of the follow-up period, making it difficult to draw clear inferences about the long-term impact of initial randomization. There was also a fairly high rate of attrition, especially from 24 to 72 weeks of follow-up. Since the three-class solution was also found when limiting the analyses to the first 24 weeks, when we had good (78%) participant retention, we can infer that these findings were not unduly influenced by drop-out. In addition, in the Mplus implementation of LCGA, missing data are handled in accord with the approach of Little and Rubin (2002)
. Missing data are modeled as missing at random (MAR). Simulation studies byCollins et al. (2001)
show that the MAR assumption gives results with modest degrees of bias and loss of efficiency even when the missingness is not at random (MNAR). Therefore, the results that we report have taken into account and are likely robust to the effects of attrition.
Another limitation is that there may be other important domains for which we had no formal assessment that could determine trajectories of symptoms in resistant depression. For example, domains such as neurocognitive deficits have been shown to be present in pediatric depression and to predict treatment response in depressed adults (Dunkin et al., 2000
; Maalouf et al., 2011
In summary, we identified three classes of trajectories of depressive symptoms in TORDIA participants using latent classification analysis (LCGA): rapid remitters, slow remitters, and those who were unlikely to remit. Depression severity, lower level of functioning, longer duration of depression and presence of manic symptoms predicted membership in a class with less favorable outcome. In addition, suicidal adverse events were more likely to occur in members of the trajectories with less favorable course. These findings may have important clinical and research implications. Clinicians who are treating adolescents with treatment-resistant MDD should assess for the presence of manic symptoms at baseline and during the treatment course even in individuals in whom the diagnosis of bipolar disorder has been ruled out. Although prospective studies of bipolar youth have already challenged the time criteria currently in use for defining clinically significant manic symptoms (Birmaher et al., 2009
), it is important to emphasize that the presence of sub-syndromal manic symptoms in youths does not necessarily indicate the presence of bipolar disorder per se (Findling et al., 2010
). Indeed, in the Longitudinal Assessment of Manic Symptoms Study (LAMS) sample, not all children with elevated manic symptoms had bipolar disorder although those with persistently elevated manic symptoms were more likely to have bipolar spectrum disorders (Frazier et al., 2011
). In conclusion, this study supports the importance of understanding the clinical significance of sub-syndromal manic symptoms and the need for further research into the use of mood stabilizers for the management of treatment resistant depression in adolescents.