Objective To evaluate the clinical and prognostic significance of suicide attempts (SAs) and non-suicidal self-injury (NSSI) in adolescents with treatment-resistant depression. Method Depressed adolescents who did not improve with an adequate SSRI trial (N=334) were randomized to a medication switch (SSRI or venlafaxine) with or without cognitive-behavior therapy. NSSI and SAs were assessed at baseline and throughout the 24-week treatment period. Results 47.4% of youths reported a history of self-injurious behavior at baseline: 23.8% NSS-alone, 14% NSSI+SAs, 9.5% SAs-alone. The 24-week incidence rates of SAs and NSSI were 7% and 11%, respectively; these rates were highest among youths with NSSI+SAs at baseline. NSSI history predicted both incident SAs (HR= 5.28, 95% CI: 1.80–15.47, z= 3.04, p=.002) and incident NSSI (HR= 7.31, z= 4.19, 95% CI: 2.88–18.54, p<.001) through week-24, and was a stronger predictor of future attempts than a history of SAs (HR= 1.92, 95% CI: z = 2.29, p=.13). In the most parsimonious model predicting to time to incident SAs, baseline NSSI history and hopelessness were significant predictors, adjusting for treatment effects. Parallel analyses predicting time to incident NSSI through week-24, identified baseline NSSI history and physical and/or sexual abuse history as significant predictors. Conclusions NSSI is a common problem among youths with treatment resistant depression and a significant predictor of future SAs and NSSI, underscoring the critical need for strategies that target the prevention of both NSSI and suicidal behavior. Clinical Trial Registration Information Treatment of SSRI-Resistant Depression in Adolescents (TORDIA). URL: http://www.clinicaltrials.gov. Unique Identifier: NCT00018902.

Objective To identify symptom dimensions of depression that predict recovery among SSRI-treatment resistant adolescents undergoing second-step treatment. Method The Treatment of Resistant Depression in Adolescents (TORDIA) trial included 334 SSRI-treatment resistant youth randomized to a medication switch, or a medication switch plus CBT. This study examined five established symptom dimensions (Child Depression Rating Scale-Revised) at baseline as they predicted recovery over 24 weeks of acute and continuation treatment. The two indices of recovery that were evaluated were time to remission and number of depression-free days. Results Multivariate analyses examining all five depression symptom dimensions simultaneously indicated that Anhedonia was the only dimension to predict a longer time to remission, and also the only dimension to predict fewer depression-free days. In addition, when Anhedonia and CDRS-total score were evaluated simultaneously, Anhedonia continued to uniquely predict longer time to remission and fewer depression-free days. Conclusions Anhedonia may represent an important negative prognostic indicator among treatment resistant depressed adolescents. Further research is needed to elucidate neurobehavioral underpinnings of anhedonia, and to test treatments that target anhedonia in the context of overall treatment of depression.

Objective The authors sought to identify predictors of self-harm adverse events in treatment-resistant, depressed adolescents during the first 12 weeks of treatment. Method Depressed adolescents (N=334) who had not responded to a previous trial with an SSRI antidepressant were randomized to a switch to either another SSRI or venlafaxine, with or without cognitive behavior therapy. Self-harm events, i.e., suicidal and non-suicidal self-injury adverse events were assessed by spontaneous report for the first 181 participants, and by systematic weekly assessment for the last 153 participants. Results Higher rates of suicidal (20.8% vs. 8.8%) and nonsuicidal self-injury (17.6% vs. 2.2%), but not serious adverse events (8.4% vs. 7.3%) were detected with systematic monitoring. Median time to a suicidal event was 3 weeks, predicted by high baseline suicidal ideation, family conflict, and drug and alcohol use. Median time to nonsuicidal self-injury was 2 weeks, predicted by previous history of nonsuicidal self-injury. While there were no main effects of treatment, venlafaxine treatment was associated with a higher rate of self-harm adverse events in those with higher suicidal ideation. Adjunctive use of benzodiazepines, while in a small number of participants (N=10) was associated with higher rate of both suicidal and nonsuicidal self-injury adverse events. Conclusions Since predictors of suicidal adverse events also predict poor response to treatment, and many of these events occurred early in treatment, improving the speed of response to depression, by targeting of family conflict, suicidal ideation, and drug use may help to reduce their incidence. The relationship of venlafaxine and of benzodiazepines to selfharm events requires further study and clinical caution.

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Objective To review the studies that test treatments targeting adolescent suicidal ideation, suicide attempts, or self-harm, and to make recommendations for future intervention development. Method The extant randomized clinical trials that aim to reduce the intensity of suicidal ideation or the recurrence of suicide attempts or self-harm were reviewed with respect to treatment components, comparison treatments, sample composition, and outcomes. Results The majority of studies that showed any effect on suicidal ideation, attempts, or self-harm had some focus on family interactions or non-familial sources of support. Two of the most efficacious interventions also provided the greatest number of sessions. Some other treatment elements associated with positive effects include addressing motivation for treatment and having explicit plans for integrating the experimental treatment with treatment as usual. In many studies, suicidal events tend to occur very early in the course of treatment prior to when an effective “dose” of treatment could be delivered. Important factors that might mitigate suicidal risk such as sobriety, healthy sleep, and promotion of positive affect were not addressed in most studies. Conclusion Interventions that can front-load treatment shortly after the suicidal crisis, e.g., while adolescent suicide attempters are hospitalized, may avert early suicidal events. Treatments that focus on the augmentation of protective factors, such as parent support and positive affect, as well as the promotion of sobriety and healthy sleep, may be beneficial with regard to the prevention of recurrent suicidal ideation, attempts, or self-harm in adolescents.