February 28, 2008 — In a large clinical trial, 55% of teens with moderately severe, chronic depression who had not responded to initial treatment with a selective serotonin reuptake inhibitor (SSRI) did achieve an adequate clinical response when they switched to another antidepressant and added cognitive behavioral therapy (CBT).
This and other findings from the National Institute of Mental Health–funded Treatment of SSRI-Resistant Depression in Adolescents (TORDIA) trial are published in the February 27 issue of the Journal of the American Medical Association.
"If an adolescent hasn't responded to an initial treatment, go ahead and switch treatments," Graham Emslie, MD, from the University of Texas Southwestern Medical Center in Dallas, Texas, and a principal investigator in the study, said in a press release issued by the university. "If the patient hasn't had a good response with antidepressants, definitely add cognitive behavioral therapy, since having them work together is probably the most beneficial," he added.
Dr. Emslie, the first psychiatrist to demonstrate that antidepressants are effective in children and adolescents with depression, urged, "It's important that the adolescent not give up."
Up until now, clinicians had no empirically based guidelines for dealing with adolescents with depression who did not respond to an antidepressant, lead author David Brent, MD, at Western Psychiatric Institute and Clinic, in Pittsburgh, Pennsylvania, told Medscape Psychiatry. "Now we know that a switch to another SSRI and addition of CBT psychotherapy is the logical next move. A switch to venlafaxine is not indicated, since the efficacy was the same as a switch to another SSRI and there were more side effects on venlafaxine."
Failure to Respond to Initial Therapy is Common
Adolescent depression is common, and when it is untreated, it has a negative impact on school performance and interpersonal relationships at a critical stage of development and increases the risk for suicidal behavior, the group writes. Only approximately 60% of adolescents show an adequate clinical response to an initial course of SSRIs, psychotherapy, or both, and there is a lack of empirical studies to suggest treatment of adolescent patients who do not respond to an initial treatment with an SSRI.
The TORDIA trial was developed to address the clinical management of these patients. The trial was conducted at 6 US academic and community clinics from 2000 to 2006.
Participants were 334 adolescents aged 12 to 18 years who had moderate to severe major depressive disorder, many with suicidal ideation. The study subjects had had depression for an average of 2 years despite currently being treated with an SSRI for at least 8 weeks at a sufficient dosage.
Patients were randomized to switch from their current SSRI to 12 weeks of 1 of 4 treatments:
Venlafaxine alone (n = 83)
Venlafaxine plus CBT (n = 83)
Another SSRI (fluoxetine, paroxetine, or citalopram) alone (n = 85)
CBT plus another SSRI (fluoxetine, paroxetine, or citalopram; n = 83)
A switch to another SSRI, which is recommended in clinical guidelines, was compared with a switch to venlafaxine, which was shown in some studies to be superior to an SSRI for treatment-refractory adult depression.
The mean doses at 12 weeks were 33.8 mg/day for an SSRI and 205.4 mg/day for venlafaxine.
The 2 primary outcomes were as follows:
"Adequate clinical response," defined as a Clinical Global Impressions-Improvement Subscale score of 2 or less and an improvement in the Children's Depression Rating Scale-Revised (CDRS-R) score of at least 50%
The trajectory of the CDRS-R with time
"Clinicians Should Convey Hope"
A higher proportion of patients treated with CBT plus switched medication vs switched medication alone showed an adequate clinical response. There was no difference in response rate between groups that were prescribed venlafaxine vs a switch to a second, different SSRI.
Table. Adequate Clinical Response at 12 Weeks*
Treatment% of Participants With Adequate
Clinical Response (95% CI)P
Medication switch plus CBT54.8 (47 - 62)-
Medication switch alone40.5 (33 - 48).009
Venlafaxine48.2 (41 - 56)-
A different SSRI47.0 (40 - 55).83
*Adequate clinical response indicates a Clinical Global Impressions-Improvement Subscale score of 2 or less and an improvement in the CDRS-R score of at least 50%; CBT, cognitive behavioral therapy; SSRI, selective serotonin reuptake inhibitor.
There were no differential treatment effects on CDRS-R scores, self-rated depressive symptoms, or adverse events including self-harm and suicidal ideation. Compared with SSRI treatment, venlafaxine treatment resulted in greater increases in diastolic blood pressure and pulse and more frequent occurrence of skin problems.
"The clinician should convey hope to the adolescent with depression and his or her family that, despite a first unsuccessful treatment for depression, persistence with additional appropriate interventions can result in substantial clinical improvement," the group concludes.
These results are similar to research findings from the University of Texas Southwestern-led Sequenced Treatment Alternatives to Relieve Depression study on adult depression that demonstrated that 1 in 3 to 4 adults who did not achieve full remission of symptoms with 1 antidepressant became symptom-free after changing or adding a second medication.
"One major question of psychiatrists is whether depression is different in adolescence," Dr. Emslie said. "This research suggests this disease is present in adolescence and very similar to what happens in adulthood. It's important to identify and treat depression early."
Dr. Brent has not disclosed any financial relationships. Dr. Emslie has disclosed receiving research support from Eli Lilly, Organon, Shire, Somerset, Forest Laboratories, and Biobehavioral Diagnostics Inc. He reports consulting for Eli Lilly, GlaxoSmithKline, Wyeth-Ayerst, Shire, and Biobehavioral Diagnostics Inc, and is on the speakers' bureau for McNeil. The complete list of disclosures is available in the original article.