Long-Term Outcome of Adolescent Depression Initially Resistant to Selective Serotonin Reuptake Inhibitor Treatment: A Follow-Up Study of the TORDIA Sample

Division of Services and Intervention Research, National Institute of Mental Health, Room 7147, 6001 Executive Blvd, Bethesda, MD 20892-9633, USA.
The Journal of Clinical Psychiatry (Impact Factor: 5.5). 11/2010; 72(3):388-96. DOI: 10.4088/JCP.09m05885blu
Source: PubMed


We examined the long-term outcome of participants in the Treatment of SSRI-Resistant Depression in Adolescents (TORDIA) study, a randomized trial of 334 adolescents (aged 12-18 years) with DSM-IV-defined major depressive disorder initially resistant to selective serotonin reuptake inhibitor (SSRI) treatment who were subsequently treated for 12 weeks with another SSRI, venlafaxine, another SSRI + cognitive-behavioral therapy (CBT), or venlafaxine + CBT. Responders then continued with the same treatment through week 24, while nonresponders were given open treatment.
For the current study, patients were reassessed 48 (n = 116) and 72 (n = 130) weeks from intake. Data were gathered from February 2001 to February 2007. Standardized diagnostic interviews and measures of depression, suicidal ideation, related psychopathology, and level of functioning were periodically administered. Remission was defined as ≥ 3 weeks with ≤ 1 clinically significant symptom and no associated functional impairment (score of 1 on the adolescent version of the Longitudinal Interval Follow-Up Evaluation [A-LIFE]), and relapse, as ≥ 2 weeks with probable or definite depressive disorder (score of 3 or 4 on the A-LIFE). Mixed-effects regression models were applied to estimate remission, relapse, and functional recovery.
By 72 weeks, an estimated 61.1% of the randomized youths had reached remission. Randomly assigned treatment (first 12 weeks) did not influence remission rate or time to remission, but the group assigned to SSRIs had a more rapid decline in self-reported depressive symptoms and suicidal ideation than those assigned to venlafaxine (P < .03). Participants with more severe depression, greater dysfunction, and alcohol or drug use at baseline were less likely to remit. The depressive symptom trajectory of the remitters diverged from that of nonremitters by the first 6 weeks of treatment (P < .001). Of the 130 participants in remission at week 24, 25.4% relapsed in the subsequent year.
While most adolescents achieved remission, more than one-third did not, and one-fourth of remitted patients experienced a relapse. More effective interventions are needed for patients who do not show robust improvement early in treatment. Identifier: NCT00018902.

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Available from: Joan Asarnow, Oct 10, 2015
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    • "The rate of response was also shown to be critical in adolescents in the treatment of serotonin-selective reuptake inhibitor (SSRI)-resistant depression in adolescents study. Individuals who respond early (first 6 weeks of treatment) are more likely to achieve full remission (Emslie et al. 2010; Vitiello et al. 2011). Even among responders, residual symptoms are common. "
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    ABSTRACT: Insomnia is evident in the majority of youth with depression, and is associated with poorer outcomes. There are limited data on the impact of insomnia in response to acute treatment, which is particularly relevant with serotonin-selective reuptake inhibitors, given their tendency to worsen sleep architecture. Three hundred nine children and adolescents (ages 7-18 years) were randomized to fluoxetine (n=157) or placebo (n=152) for 8-9 weeks (Emslie et al.1997, 2002). Substantial insomnia at baseline was defined as a child's depression rating scale-revised [CDRS-R] sleep item ≥ 4. Outcome measures were CDRS-R, response, and remission. Insomnia was reported in 172/309 (55.7%) youth, and was associated with higher depression severity and greater fatigue, suicidal ideation, physical complaints, and decreased concentration. While response rates were similar in those with or without insomnia overall (51.7% vs. 55.7%), there is a significant difference by age group. Among adolescents, those with insomnia were less likely to respond to fluoxetine (39.2%; 20/51) than those without (65.9%; 27/41; p=0.013), while in children on fluoxetine, those with insomnia were more likely to respond to fluoxetine (69.4%; 25/36) than those without insomnia (41.4%; 12/29; p=0.027). Insomnia did not impact the response to placebo in either age group. Within adolescents, the overall least squares means for CDRS-R total score (across the 8 weeks of treatment) were significantly different between those who had insomnia versus those who did not within the fluoxetine group (43.65 [SE=1.31] vs. 36.58[SE=1.45], F=12.69, df=1, 169, p=0.0005; d=0.82), but not within the placebo group (44.91[SE=1.34] vs. 43.75[SE=1.68], F=0.29, df=1, 179, p=0.591; d=0.15). While adolescents reporting substantial insomnia were less likely to respond to antidepressant treatment than those without insomnia, children were more responsive to fluoxetine when they had insomnia. Additional intervention targeting sleep disturbance may be warranted in adolescents.
    Journal of child and adolescent psychopharmacology 02/2012; 22(1):21-8. DOI:10.1089/cap.2011.0096 · 2.93 Impact Factor
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    • "Further, the persistence of residual symptoms puts patients at higher risk of relapse (Brent et al. 2001; Emslie et al. 2010). Sleep disturbance is the most common residual symptom in adolescent depression in responders who failed to remit in the acute phase treatment (Kennard et al. 2006; Vitiello et al. 2011). "
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    ABSTRACT: In the Treatment of Resistant Depression in Adolescents, study participants who received medication for sleep had a lower response rate. This report sought to clarify this finding. Depressed adolescents who had not responded to a previous adequate serotonin-selective reuptake inhibitor (SSRI) trial were randomly assigned to another SSRI, venlafaxine, another SSRI+cognitive behavior therapy (CBT), or venlafaxine+CBT. Augmentation with sleep medication was permitted as clinically indicated. Youth who received trazodone were six times less likely to respond than those with no sleep medication (adjusted odds ratio [OR]=0.16, 95% confidence interval [CI]: 0.05-0.50, p=0.001) and were three times more likely to experience self-harm (OR=3.0, 95% CI: 1.1-7.9, p=0.03), even after adjusting for baseline differences associated with trazodone use. None (0/13) of those cotreated with trazodone and either paroxetine or fluoxetine responded. In contrast, those treated with other sleep medications had similar rates of response (60.0% vs. 50.4%, χ(2)=0.85, p=0.36) and of self-harm events (OR=0.5, 95% CI: 0.1-2.6, p=0.53) as those who received no sleep medication. These findings should be interpreted cautiously because these sleep agents were not assigned randomly, but at clinician discretion. Nevertheless, they suggest that the use of trazodone for the management of sleep difficulties in adolescent depression should be re-evaluated and that future research on the management of sleep disturbance in adolescent depression is needed. The very low response rate of participants cotreated with trazodone and either fluoxetine or paroxetine could be due to inhibition of CYP 2D6 by these antidepressants.
    Journal of child and adolescent psychopharmacology 02/2012; 22(1):29-36. DOI:10.1089/cap.2011.0027 · 2.93 Impact Factor
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    • "The design, methods, and results of TORDIA have been reported in detail elsewhere (Asarnow et al., 2009; Brent et al., 2008, 2009; Emslie et al., 2010; Vitiello et al., 2010). In brief, TORDIA was a 6-site trial that randomized 334 participants with unipolar major depression that had not responded to one adequate trial of SSRI to one of four treatments for 12 weeks: a switch to another SSRI; a switch to venlafaxine; a switch to another SSRI with CBT, or a switch to venlafaxine with CBT. "
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    ABSTRACT: To identify distinct depressive symptom trajectories in the TORDIA study and determine their correlates. Latent Class Growth Analysis (LCGA) using the Children's Depression Rating Scale-Revised (CDRS-R) through 72 weeks from intake. 3 classes were identified: (1) little change in symptomatic status ("NO"), comprising 24.9% of participants, with a 72-week remission rate of 25.3%; (2) slow, steady improvement ("SLOW"), comprising 47.9% of participants, with a remission rate of 60.0%, and (3) rapid symptom response ("GO"), comprising 27.2% of participants, with a remission rate of 85.7%. Higher baseline CDRS-R (p<0.001) and poorer functioning (p=0.03) were the strongest discriminators between NO and GO. Higher baseline CDRS (p<0.001) and scores on the Mania Rating Scale (MRS) (p=0.01) were the strongest discriminators between SLOW and GO. Other variables differentiating GO from both NO and from SLOW, were better baseline functioning, lower hopelessness, and lower family conflict. Both NO and SLOW showed increases on the MRS over time compared to GO (ps ≤ 0.04), and increasing MRS was strongly associated with lack of remission by 72 weeks (p=0.02). High rate of open treatment by the end of the follow-up period creates difficulty in drawing clear inferences about the long-term impact of initial randomization. Along with depressive severity, sub-syndromal manic symptoms, at baseline, and over time emerged as important predictors and correlates of poor outcome in this sample. Further research is needed on the treatment of severe depression, and on the assessment and management of sub-syndromal manic symptoms in treatment resistant depression.
    Journal of Affective Disorders 01/2012; 138(1-2):86-95. DOI:10.1016/j.jad.2011.12.021 · 3.38 Impact Factor
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