Treatment-Resistant Depression in Adolescents Needs Earlier Intervention

Megan Brooks

May 28, 2010

May 28, 2010 — In a study of adolescents with treatment-resistant depression who failed to respond initially to serotonin reuptake inhibitor (SSRI) therapy, switching to another SSRI or venlafaxine, with or without cognitive behavioral therapy (CBT), helped nearly 40% achieve remission after 6 months.

That's according to 24-week outcomes of the Treatment of Resistant Depression in Adolescents (TORDIA) study, published online May 17 in the American Journal of Psychiatry.

"These findings suggest that current clinical guidelines, which recommend pursuing a given treatment strategy for at least 8-12 weeks, may need to be revisited. Instead, our data support more vigorous intervention earlier in the course of treatment for nonresponding patients," the study authors write.

The 6-center TORDIA study was designed to examine second-step interventions in adolescents (n = 334), aged 12 to 18 years, with moderate to severe major depressive disorder that persisted despite treatment with an SSRI for at least 8 weeks, the last 4 of which were at a dosage equivalent of at least 40 mg of fluoxetine.

At week 12 of the study, responders (n = 159) could continue in their assigned treatment, whereas nonresponders (n = 175) were randomly assigned to 1 of 4 second-line approaches for an additional 12 weeks: switch to another SSRI, switch to venlafaxine, switch to another SSRI plus CBT, or switch to venlafaxine plus CBT.

The 12-week outcomes, published previously, showed that 47.6% of adolescents responded to treatment, with greater response to a switch in medication plus CBT (54.8%) than to medication switch alone (40.5%). There was no significant difference in the response rate between the 2 medication switch strategies.

"Similar to STAR-D [Sequence Treatment Alternatives to Relieve Depression[ trial in adults, TORDIA demonstrated that in nonresponders, an additional 50% will respond to additional interventions," first study author Graham J. Emslie, MD, of the Division of Child and Adolescent Psychiatry, University of Texas Southwestern and Children's Medical Center, Dallas, told Medscape Psychiatry.

"The goal of treatment, however, should be remission of symptoms — that is, no or minimal depressive symptoms. The 24-week paper shows that remission is possible in those who don't improve with an initial antidepressant, but remission rates are still low after 6 months," said Dr. Emslie.

Specifically, of the 334 study subjects, "38.9% achieved remission by 24 weeks and initial treatment assignment did not affect rates of remission," the study team notes.

Adolescents who had a clinical response by 12 weeks had a greater than 3-fold increased likelihood of remission at 24 weeks than those who did not (61.6% vs 18.3%). Time to remission was also quicker in those who responded by 12 weeks.

Of those who responded by week 12, 19.6% had a relapse of depression by week 24. Greater clinical severity of depression predicted both failure to remit and, among responders, greater likelihood of relapse, the study authors note. Family conflict, drug and alcohol use, and anxiety disorder also predicted failure to remit.

This suggests that "broadening treatment targets to include comorbid anxiety, alcohol and substance use, and family conflict may be important in achieving remission and preventing relapse," the investigators write.

"Patients who are going to remit are identifiable early," said Dr. Emslie, "so it may be important to provide additional interventions in those not showing significant improvements during the first 6 to 12 weeks of treatment."

However, the study authors note the study is not without limitations. The fact that roughly 20% of participants did not complete the week 24 assessment or had unknown medication status is 1 limitation. Lack of a placebo comparison group is another. It is also difficult to evaluate the relationship between initial treatment and outcome because many patients were in open treatment by week 24.

Dr. Emslie and colleagues recommend further research to "identify both promising intervention strategies and the optimal time for their implementation when a depressed adolescent is not responding to current treatment."

The TORDIA study was funded in part by grants from the National Institute of Mental Health. Dr. Emslie and several coauthors report receiving research support from several pharmaceutical companies that make antidepressant medications.

Am J Psychiatry. Published online May 17, 2010.