Selecting another treatment after one fails
A question of clinical importance is what treatment to select when an adolescent fails to respond to an initial treatment with an SSRI. Brent and colleagues1 recently reported on the findings from a NIMH study that was designed to address this issue.
Those eligible for the study were adolescents aged 12 to 18 years with a DSM-IV diagnosis of major depressive disorder. Youths had clinically significant depression (defined as a Children’s Depression Rating Scale–Revised [CDRS-R] score of 40 or more and a Clinical Global Impression Severity [CGI-S] score of at least moderate severity, 4 or greater) while receiving treatment with an SSRI. Participants had to have taken an SSRI for at least 8 weeks, with dosages of at least 40 mg/d of fluoxetine(Drug information on fluoxetine) (or a similar agent) or 150 mg/d of sertraline(Drug information on sertraline) for the past 4 weeks. Those who could not tolerate the higher dosages could be included in the study as long as they were taking 20 mg/d of fluoxetine or its equivalent for at least 4 weeks. Therefore, patients who were enrolled in this study were considered to have clinically significant depression despite adequate dosage and duration of treatment with an initial SSRI.
Developing an Effective Treatment Protocol Psychiatric Times, February 1 2008 |
Comorbid Depression and ADHD in Children and Adolescents Psychiatric Times, September 1 2008 |
Treatment-Resistant Depression: Advances in Assessment Psychiatric Times, September 1 2008 |
In clinical practice, when an adolescent fails to respond to an SSRI, the clinician may try another SSRI or an antidepressant with a different mechanism of action. Some clinicians will add psychotherapy to the medication to see if effectiveness is improved. The study by Brent and coworkers1 was designed to determine which of the following was the most effective treatment strategy:
- Switching to a different SSRI.
- Switching to a different class of agent (ie, venlafaxine).
- Adding cognitive-behavioral therapy (CBT) to the alternative SSRI.
- Adding CBT to venlafaxine.
The 334 participants in this study were randomized to 12 weeks of 1 of these 4 treatment strategies. Dosages of paroxetine, citalopram(Drug information on citalopram), or fluoxetine could range from 20 to 40 mg/d, and venlafaxine dosage could range from 150 to 225 mg/d.
The mean age of the participants was 16 years; 70% were female and 82% were white. These adolescents had moderately severe depression for a median duration of 17 months. Most were having their first episode of depression. Approximately 59% of the adolescents had clinically significant suicidal ideation at baseline.
Clinical response was defined as at least a 50% decrease in the CDRS-R score and a CGI-S score of 2 or less (much or very much improved). The response rate was 55% among those treated with CBT and 41% among those who did not receive CBT. Response rates did not differ between the medication groups (48% in the venlafaxine group vs 47% in the SSRI group). Interestingly, there were significant differences in response to CBT depending on which site conducted the study. At some sites, medication alone produced a higher response rate than when it was combined with CBT, whereas in other sites combination treatment was more effective.
The frequency of adverse events did not differ among the treatments. Similarly, there were no differences in self-harm or suicide-related events among the treatment groups. No participants completed suicide. However, there were more skin problems (mostly itching and rash) and a greater increase in diastolic blood pressure and pulse in those treated with venlafaxine than in those treated with an SSRI.
An important finding from this study is that approximately 50% of depressed adolescents who did not respond to an SSRI did respond to an alternative treatment. This is encouraging news for both clinicians who treat depressed adolescents and for those teenagers who are depressed.
Deciding on treatment duration
Another question of clinical importance is how long to treat children and adolescents with depression who have responded to initial treatment with an antidepressant. Emslie and colleagues2 reported their findings from an NIMH study that evaluated the need for continuation treatment in youth with depression.
One hundred sixty-eight children and adolescents aged 7 to 18 years with a diagnosis of major depressive disorder participated in the acute phase of the study. To be eligible, participants had to have a CDSR-R score of 40 or more and a CGI-S score of 4 or more. Participants were treated openly with fluoxetine during a 12-week period. The dosage of fluoxetine was 10 mg/d for the first week; thereafter, it was increased to 20 mg/d. If there was minimal or no improvement, the dosage could be increased to 40 mg/d after 6 weeks of treatment. After 12 weeks of acute treatment, children and adolescents who responded were then randomized to continue to receive fluoxetine or to receive placebo for an additional 6 months.
One hundred two youths participated in the continuation treatment; of these, 50 received fluoxetine and 52 received placebo. The mean dosage of fluoxetine during the continuation treatment was 26 mg/d; dosages for adolescents were higher (30 mg/d) than those for children (23 mg/d). The mean age of the youths who entered the continuation phase was 12 years. The mean duration of depression was 13 months. The majority (73%) were experiencing their first episode of depression.
The outcome measures for this study were relapse and time to relapse. Relapse was defined as either a 1-time CDRS-R score of 40 or more, with worsening of depressive symptoms for at least 2 weeks or a clinician’s assessment that there was significant worsening in the youth’s condition (which would suggest that full relapse was imminent).
Relapse rates were significantly higher in the placebo group (69%) than in the fluoxetine group (42%) during the 6-month continuation treatment period. The median time to relapse was shorter in the placebo group (8 weeks after discontinuation of fluoxetine). However, in those who continued fluoxetine, fewer than 50% experienced a relapse by 6 months. Relapse rates were similar in children and adolescents. There were no significant differences in adverse events between the groups.
This study demonstrates the importance of continuing treatment with an antidepressant after early response or remission. Results support the need to continue antidepressant therapy for 6 to 9 months in children and adolescents with an episode of major depression.
