Lynn DeBar

Switching to Another SSRI or to Venlafaxine With or Without Cognitive Behavioral Therapy for Adolescents With SSRI-Resistant Depression: The TORDIA Randomized Controlled Trial

CONTEXT Only about 60% of adolescents with depression will show an adequate clinical response to an initial treatment trial with a selective serotonin reuptake inhibitor (SSRI). There are no data to guide clinicians on subsequent treatment strategy. OBJECTIVE To evaluate the relative efficacy of 4 treatment strategies in adolescents who continued to have depression despite adequate initial treatment with an SSRI. DESIGN, SETTING, AND PARTICIPANTS Randomized controlled trial of a clinical sample of 334 patients aged 12 to 18 years with a primary diagnosis of major depressive disorder that had not responded to a 2-month initial treatment with an SSRI, conducted at 6 US academic and community clinics from 2000-2006. INTERVENTIONS Twelve weeks of: (1) switch to a second, different SSRI (paroxetine, citalopram, or fluoxetine, 20-40 mg); (2) switch to a different SSRI plus cognitive behavioral therapy; (3) switch to venlafaxine (150-225 mg); or (4) switch to venlafaxine plus cognitive behavioral therapy. MAIN OUTCOME MEASURES Clinical Global Impressions-Improvement score of 2 or less (much or very much improved) and a decrease of at least 50% in the Childrens Depression Rating Scale-Revised (CDRS-R); and change in CDRS-R over time. RESULTS Cognitive behavioral therapy plus a switch to either medication regimen showed a higher response rate (54.8%; 95% confidence interval [CI], 47%-62%) than a medication switch alone (40.5%; 95% CI, 33%-48%; P = .009), but there was no difference in response rate between venlafaxine and a second SSRI (48.2%; 95% CI, 41%-56% vs 47.0%; 95% CI, 40%-55%; P = .83). There were no differential treatment effects on change in the CDRS-R, self-rated depressive symptoms, suicidal ideation, or on the rate of harm-related or any other adverse events. There was a greater increase in diastolic blood pressure and pulse and more frequent occurrence of skin problems during venlafaxine than SSRI treatment. CONCLUSIONS For adolescents with depression not responding to an adequate initial treatment with an SSRI, the combination of cognitive behavioral therapy and a switch to another antidepressant resulted in a higher rate of clinical response than did a medication switch alone. However, a switch to another SSRI was just as efficacious as a switch to venlafaxine and resulted in fewer adverse effects. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00018902.

Prevention of depression in at-risk adolescents: a randomized controlled trial.

CONTEXT Adolescent offspring of depressed parents are at markedly increased risk of developing depressive disorders. Although some smaller targeted prevention trials have found that depression risk can be reduced, these results have yet to be replicated and extended to large-scale, at-risk populations in different settings. OBJECTIVE To determine the effects of a group cognitive behavioral (CB) prevention program compared with usual care in preventing the onset of depression. DESIGN, SETTING, AND PARTICIPANTS A multicenter randomized controlled trial conducted in 4 US cities in which 316 adolescent (aged 13-17 years) offspring of parents with current or prior depressive disorders were recruited from August 2003 through February 2006. Adolescents had a past history of depression, current elevated but subdiagnostic depressive symptoms, or both. Assessments were conducted at baseline, after the 8-week intervention, and after the 6-month continuation phase. INTERVENTION Adolescents were randomly assigned to the CB prevention program consisting of 8 weekly, 90-minute group sessions followed by 6 monthly continuation sessions or assigned to receive usual care alone. MAIN OUTCOME MEASURE Rate and hazard ratio (HR) of a probable or definite depressive episode (ie, depressive symptom rating score of > or = 4) for at least 2 weeks as diagnosed by clinical interviewers. RESULTS Through the postcontinuation session follow-up, the rate and HR of incident depressive episodes were lower for those in the CB prevention program than for those in usual care (21.4% vs 32.7%; HR, 0.63; 95% confidence interval [CI], 0.40-0.98). Adolescents in the CB prevention program also showed significantly greater improvement in self-reported depressive symptoms than those in usual care (coefficient, -1.1; z = -2.2; P = .03). Current parental depression at baseline moderated intervention effects (HR, 5.98; 95% CI, 2.29-15.58; P = .001). Among adolescents whose parents were not depressed at baseline, the CB prevention program was more effective in preventing onset of depression than usual care (11.7% vs 40.5%; HR, 0.24; 95% CI, 0.11-0.50), whereas for adolescents with a currently depressed parent, the CB prevention program was not more effective than usual care in preventing incident depression (31.2% vs 24.3%; HR, 1.43; 95% CI, 0.76-2.67). CONCLUSION The CB prevention program had a significant prevention effect through the 9-month follow-up period based on both clinical diagnoses and self-reported depressive symptoms, but this effect was not evident for adolescents with a currently depressed parent. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00073671.

Predictors of Spontaneous and Systematically Assessed Suicidal Adverse Events in the Treatment of SSRI-Resistant Depression in Adolescents (TORDIA) Study

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 self-harm events requires further study and clinical caution.

Treatment of Selective Serotonin Reuptake Inhibitor-Resistant Depression in Adolescents: Predictors and Moderators of Treatment Response.

OBJECTIVE To advance knowledge regarding strategies for treating selective serotonin reuptake inhibitor (SSRI)-resistant depression in adolescents, we conducted a randomized controlled trial evaluating alternative treatment strategies. In primary analyses, cognitive-behavioral therapy (CBT) combined with medication change was associated with higher rates of positive response to short-term (12-week) treatment than medication alone. This study examines predictors and moderators of treatment response, with the goal of informing efforts to match youths to optimal treatment strategies. METHOD Youths who had not improved during an adequate SSRI trial (N = 334) were randomized to an alternative SSRI, an alternative SSRI plus CBT, venlafaxine, or venlafaxine plus CBT. Analyses examined predictors and moderators of treatment response. RESULTS Less severe depression, less family conflict, and absence of nonsuicidal self-injurious behavior predicted better treatment response status. Significant moderators of response to CBT + medication (combined) treatment were number of comorbid disorders and abuse history; hopelessness was marginally significant. The CBT/combined treatment superiority over medication alone was more evident among youths who had more comorbid disorders (particularly attention-deficit/hyperactivity disorder and anxiety disorders), no abuse history, and lower hopelessness. Further analyses revealed a stronger effect of combined CBT + medication treatment among youths who were older and white and had no nonsuicidal self-injurious behavior and longer prestudy pharmacotherapy. CONCLUSIONS Combined treatment with CBT and antidepressant medication may be more advantageous for adolescents whose depression is comorbid with other disorders. Given the additional costs of adding CBT to medication, consideration of moderators in clinical decision making can contribute to a more personalized and effective approach to treatment.

Treatment of Resistant Depression in Adolescents (TORDIA): Week 24 Outcomes

OBJECTIVE The purpose of this study was to report on the outcome of participants in the Treatment of Resistant Depression in Adolescents (TORDIA) trial after 24 weeks of treatment, including remission and relapse rates and predictors of treatment outcome. METHOD Adolescents (ages 12-18 years) with selective serotonin reuptake inhibitor (SSRI)-resistant depression were randomly assigned to either a medication switch alone (alternate SSRI or venlafaxine) or a medication switch plus cognitive-behavioral therapy (CBT). At week 12, responders could continue in their assigned treatment arm and nonresponders received open treatment (medication and/or CBT) for 12 more weeks (24 weeks total). The primary outcomes were remission and relapse, defined by the Adolescent Longitudinal Interval Follow-Up Evaluation as rated by an independent evaluator. RESULTS Of 334 adolescents enrolled in the study, 38.9% achieved remission by 24 weeks, and initial treatment assignment did not affect rates of remission. Likelihood of remission was much higher (61.6% versus 18.3%) and time to remission was much faster among those who had already demonstrated clinical response by week 12. Remission was also higher among those with lower baseline depression, hopelessness, and self-reported anxiety. At week 12, lower depression, hopelessness, anxiety, suicidal ideation, family conflict, and absence of comorbid dysthymia, anxiety, and drug/alcohol use and impairment also predicted remission. Of those who responded by week 12, 19.6% had a relapse of depression by week 24. CONCLUSIONS Continued treatment for depression among treatment-resistant adolescents results in remission in approximately one-third of patients, similar to adults. Eventual remission is evident within the first 6 weeks in many, suggesting that earlier intervention among nonresponders could be important.

Association of FKBP5 Polymorphisms With Suicidal Events in the Treatment of Resistant Depression in Adolescents (TORDIA) Study

OBJECTIVE The authors sought to assess the relationship between candidate genes and two clinical outcomes, namely, symptomatic improvement and the occurrence of suicidal events, in a sample of treatment-resistant depressed adolescents. METHOD A subsample of depressed adolescents participating in the Treatment of SSRI-Resistant Depression in Adolescents (TORDIA) trial, 155 of whom were of European origin, were genotyped with respect to 21 polymorphisms on 12 genes that have a reported association with depression, treatment response, or suicidal events. Participants had not responded to a previous adequate trial with an antidepressant and were randomized to receive either another selective serotonin reuptake inhibitor or venlafaxine, with or without cognitive-behavioral therapy (CBT). Single-nucleotide polymorphism (SNP) analyses were conducted using PLINK with permutation procedures. RESULTS No relationship was observed between any polymorphism and response to treatment. The FKBP5 (which codes for a protein causing subsensitivity of the glucocorticoid receptor) rs1360780TT and rs3800373GG genotypes were associated with suicidal events (N=18), even after controlling for treatment effects and relevant covariates. These two SNPs were in significant linkage disequilibrium (r=0.91). CONCLUSIONS The FKBP5 genotypes associated with suicidal events in this study have been reported by others to cause the greatest degree of glucocorticoid receptor subsensitivity. These results are consistent with those of other studies linking alterations in the hypothalamic-pituitary-adrenal axis with suicidal behavior. The small number of events and lack of a placebo condition make these results preliminary. Replication with a larger sample and a placebo condition is needed to assess whether these events are related to treatment.

Randomized Effectiveness Trial of an Internet, Pure Self-Help, Cognitive Behavioral Intervention for Depressive Symptoms in Young Adults

This study evaluated an Internet-delivered, cognitive behavioral skills training program versus a treatment-as-usual (TAU) control condition targeting depression symptoms in young adults aged 18 to 24 years. Potential participants were mailed a recruitment brochure; if interested, they accessed the study website to complete an online consent and baseline assessment. Intervention participants could access the website at their own pace and at any time. Reminder postcards were mailed periodically to encourage return use of the intervention. The pure self-help intervention was delivered without contact with a live therapist. The primary depression outcome measure was the Patient Health Questionnaire, administered at 0, 5, 10, 16, and 32 weeks after enrollment. A small but significant between-group effect was found from Week 0 to Week 32 for the entire sample (N = 160, d = .20, 95% confidence interval [CI] 0.00–0.50), with a moderate effect among women (n = 128, d .42, 95%C1 = 0.09–0.77). Greater depression reduction was associated with two measures of lower website usage, total minutes, and total number of page hits. Although intervention effects were modest, they were observed against a background of substantial TAU depression pharmacotherapy and psychosocial services. Highly disseminable, low-cost, and self-help interventions such as this have the potential to deliver a significant public health benefit.

Group Cognitive-Behavioral Treatment for Depressed Adolescent Offspring of Depressed Parents in a Health Maintenance Organization

OBJECTIVE A randomized, controlled effectiveness trial of group cognitive-behavioral therapy (CBT) for depressed adolescent offspring of depressed parents in a health maintenance organization (HMO) was conducted. METHOD Potential adult cases were found by reviewing antidepressant medication prescriptions, mental health appointments, and medical charts. Introductory study letters signed by each parents treating physician were mailed to the appropriate adults. Eligible offspring aged 13 to 18 who met current DSM-III-R criteria for major depression and/or dysthymia were randomly assigned to either usual HMO care (n = 47) or usual care plus a 16-session group CBT program (n = 41). Assessments were conducted at baseline, after treatment, and at 12- and 24-month follow-up. RESULTS Using intent-to-treat analyses, the authors were unable to detect any significant advantage of the CBT program over usual care, either for depression diagnoses, continuous depression measures, nonaffective measures, or functioning outcomes. CONCLUSIONS Group CBT does not appear to be incrementally beneficial for depressed offspring of depressed parents who are receiving other mental health care. However, given that many other studies have found positive effects of CBT for youth depression, this single study should not be viewed as evidence that CBT is ineffective overall.

Health services use in eating disorders

BACKGROUND This study examined healthcare services used by adults diagnosed with an eating disorder (ED) in a large health maintenance organization in the Pacific Northwest. METHOD Electronic medical records were used to collect information on all out-patient and in-patient visits and medication dispenses, from 2002 to 2004, for adults aged 18-55 years who received an ED diagnosis during 2003. Healthcare services received the year prior to, and following, the receipt of an ED diagnosis were examined. Cases were matched to five comparison health plan members who had a health plan visit close to the date of the matched cases ED diagnosis. RESULTS Incidence of EDs (0.32% of the 104,130 females, and 0.02% of the 93,628 males) was consistent with prior research employing treatment-based databases, though less than community-based samples. Most cases (50%) were first identified during a primary-care visit and psychiatric co-morbidity was high. Health services use was significantly elevated in all service sectors among those with an ED when compared with matched controls both in the year preceding and that following the receipt of the incident ED diagnosis. Contrary to expectations, healthcare utilization was found to be similarly high across the spectrum of EDs (anorexia nervosa, bulimia nervosa, and eating disorders not otherwise specified). CONCLUSIONS The elevation in health service use among women both before and after diagnosis suggests that EDs merit identification and treatment efforts commensurate with other mental health disorders (e.g. depression) which have similar healthcare impact.

Long-term outcome of adolescent depression initially resistant to selective serotonin reuptake inhibitor treatment: a follow-up study of the TORDIA sample.

BACKGROUND 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. METHOD 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. RESULTS 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. CONCLUSIONS 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. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00018902.