Dr Shock MD PhD: adolescents depression cbt antidepressants cognitive therapy children

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Tuesday, July 15, 2008

Antidepressants have Limited Efficacy in Juvenile Depression

A recent systematic review and meta-analysis shows that at worse antidepressants are not effective for juvenile depression and at best better research might proof this conclusion wrong.
Juvenile meaning depression among children and adolescents.

The figure above is the forest plot of this systematic review:Forest plot of rate ratios (RR, with 95% CI) of responses to drug or placebo in 30 randomised double-blind placebo-controlled comparisons of rates of ‘response’ to antidepressants v. placebo, with overall pooled RR (1.22; 95% CI 1.15–1.31; blue diamond).

Antidepressants of all types showed limited efficacy in juvenile depression, but fluoxetine might be more effective, especially in adolescents. Studies in children and in severely depressed, hospitalised or suicidal juvenile patients are needed, and effective, safe and readily accessible treatments for juvenile depression are urgently required.

there were 30 contrasts arising from 29 randomised controlled trials for meta-analysis

All studies included provided drug doses consistent with contemporary paediatric practice, based on body-weight-adjusted daily dosing (mg/kg) considered standard for treating adult major depressive disorder

average exposure time of 8.7 weeks (median=8, range 1–12)

primary outcomes for meta-analysis a priori as responder status, based on changes in clinical ratings from intake to last observation point (as defined in each trial) involving substantial improvement, typically a 50% or greater reduction in symptomatic ratings of depression on standardised scales. This is a weak outcome measure, remission should be the aim of treatment mostly defined as a score of 7 or lower on the Hamilton Depression Rating Scale

pooled overall effect size, based on meta-analysis to determine a pooled rate ratio and its confidence interval for all 30 trials, yielded a value of 1.22 (95% CI 1.15–1.31)

There was no difference in efficacy between different antidepressant classes such as SSRI's or TCAs. Moreover analysis fail to support the possibility that SRIs may be superior in efficacy to tricyclic antidepressants

The three age groups yielded an interesting progression in rate differences and corresponding decreases of NNT by age (about 21 for children, 10 juveniles of mixed ages and 8 for adolescents)

Explanations for the disappointing results:

Relatively high rates of response to placebo or other non-specific interventions

Age-inappropriate or insufficiently sensitive outcome measures

Inadequately powered trials

Adverse case selection (e.g. minimally ill, uncertain or heterogeneous diagnoses, previous treatment failures, poorly cooperative participants)

Incomplete control of substance misuse

Inadequate dosing or duration of treatment

Simple lack of efficacy in juvenile v. adult mood disorders

My opinion is that selection of juveniles with relatively heterogeneous illnesses can explain the lack of efficacy. Maybe only juveniles with melancholic or psychotic depression respond to antidepressants. This is comparable to depression in adults.

sampling of young patients with depression may include a high proportion of relatively mildly ill patients, who have most probably never received in-patient treatment, and who are more likely to improve spontaneously with or without additional effects of placebo treatment

Moreover, it remains to be seen whether the brain of juveniles is as susceptible to antidepressants as with adults. Depression in a developing brain may be different from depression in an adult brain and the influence of antidepressants on a developing brain might be lacking. This is supported by the finding in this meta-analysis that older juveniles respond better than younger ones. Here is a video about teens and their developing brain, thanks PsychCentral

Importantly, prepubertal children with depression may differ biologically from adolescents or adults, and it remains unclear whether depression in prepubertal children is a substantially different disorder from that found in adolescents or adults, perhaps including developmental differences in either the pharmacodynamics of antidepressants or in their clinical effects.

Tsapakis*, E.M., Soldani*, F., Tondo, L., Baldessarini, R.J. (2008). Efficacy of antidepressants in juvenile depression: meta-analysis. The British Journal of Psychiatry, 193(1), 10-17. DOI: 10.1192/bjp.bp.106.031088

Wednesday, April 9, 2008

Finally some good news about antidepressants and adolescents

Continuation treatment with fluoxetine was superior to placebo in preventing relapse and in increasing time to relapse in children and adolescents with major depression.

This is the conclusion of a randomized placebo controlled trial after a 12-week open-label acute treatment period with 10–40 mg of fluoxetine. Those who responded at the end of 12 weeks of acute treatment were randomly assigned to receive fluoxetine or placebo for an additional 6 months. 102 patients were randomized.Those in the fluoxetine group received the same dose they were receiving in acute treatment. In the placebo group, fluoxetine was not tapered given its long half-life.

Relapse occurred more frequently in participants in the placebo group than in the fluoxetine group (N=36 [69.2%] and N=21 [42.0%], respectively. Even using a stricter definition, relapse was more frequent in the placebo group than in the fluoxetine group (N=25 [48.1%] and N=11 [22.0%], respectively). These differences were statistically significant.

Some practical consequences of these findings:

This suggests that the adult guidelines recommending 6–9 months of overall treatment for major depression would apply equally to children and adolescents. It also reinforces the fact that early-onset depression is associated with high rates of relapse, even though the majority of participants in this sample were in their first episode of major depression.

In another study with adolescents with depression the focus was on the question to what degree do patients not responding to acute anti depressive treatment consisting of fluoxetine, Cognitive Behavioral Therapy or the combination of both subsequently achieve response during continuation and maintenance therapy?

And among those that achieve response during acute anti depressive therapy, how many maintain their response during continuation and maintenance therapy?

Among 95 patients (39.3%) who had not achieved sustained response by week 12 (29.1% combination of fluoxetine and cognitive behavioral therapy, 32.5% fluoxetine alone, and 57.9% Cognitive Behavioral Therapy), sustained response rates during stages 2 and 3 were 80.0% COMB, 61.5% FLX, and 77.3% CBT (difference not significant). Among the remaining 147 patients (60.7%) who achieved sustained response by week 12, CBT patients were more likely than FLX patients to maintain sustained response through week 36 (96.9% vs 74.1%; P = .007; 88.5% of COMB patients maintained sustained response through week 36). Total rates of sustained response by week 36 were 88.4% COMB, 82.5% FLX, and 75.0% CBT.

Thus the majority of adolescents who had not achieved response by week 12 achieved response by week 36: 80% with the combination of fluoxetine and CBT, 61.5% on fluoxetine and 77.3% with CBT alone. These outcomes were not significantly different from each other. Overall adolescents with depression who have not fully responded after 12 weeks of acute treatment three-quarters of them will experience sustained response with further treatment.

Those who had responded by week 12 the majority (82.3% of 147 patients) maintained their sustained response throughout week 36. 15% failed to maintain their acute response with rates differing as a function of treatment modality: 11.5% combination treatment, 25.9% fluoxetine alone and 3.1% CBT alone.

Conclusions
I am jealous, this is excellent research especially the placebo controlled one. These are findings that are easily applicable to practice. We in adult psychiatry have to do with a lot less evidence as far as placebo controlled trials for continuation and maintenance therapy are concerned.
CBT monotherapy in the acute phase has a lower response rate, nevertheless during follow-up only 3.1% failed to sustain that response. A larger proportion of patients respond on fluoxetine but the sustained response is not as enduring as with CBT. Further research could focus on augmenting response on fluoxetine with CBT for enduring this response.

Related articles on this blog about adolescents and depression

Emslie, G.J. (2008). Fluoxetine versus placebo in preventing relapse of major depression in children and adolescents. American Journal of Psychiatry, 165(4), 459-467.

Rohde, P. (2008). Achievement and maintenance of sustained response during the treatment for adolescents with depression study continuation and maintenance therapy. Archives of General Psychiatry, 65(4), 447-455.

Thursday, March 20, 2008

SSRIs Effective in Depressed Adolescents and Children?

Little attention is being payed to the efficacy of SSRIs for depressed children and adolescents. Most of the attention is on suicidal ideation and attempts due to these antidepressants.

The number of patients needed to be treated to gain an additional improvement was 9 for all SSRIs compared to placebo. For fluoxetine only it was 5. A number needed to treat of 9 is high and comes close to no use. A number of 5 tough sounds promising and is comparable to those reported for SSRIs in adults. Sertraline and citalopram showed only a moderate degree of efficacy and the other SSRIs a weak degree of efficacy.

This conclusion is based on a meta-analysis of 11 randomised controlled trials on the effect of SSRI treatment in children and adolescents with depression.
The randomised controlled trials were different in methodological approaches: enrolled population, sample size, diagnostic and outcome measures, and applied treatment schedule.

Nevertheless, with all these limitations SSRIs especially fluoxetine might be of benefit for severe or resistant depression in children and adolescents. Moreover, combination therapy with cognitive behavioral therapy in adolescents with moderate to severe depression is superior to medication or CBT alone. To my opinion this combination is the optimal treatment for severe or treatment resistant depression in adolescents and children.

The FDA black box warning for paroxetine in October 2004 resulted in a nonsignificant decline in antidepressant treatment of adolescents, including a significant deceleration in the rate of treatment with SSRIs other than paroxetine.

This outcome of a recent study published in the Archives of General Psychiatry of January 2008 neutralizes the concern expressed mostly by drug company supported publications about putting depressed youth at risk due to excessive decline in antidepressant prescribing.

USALA, T., CLAVENNA, A., ZUDDAS, A., BONATI, M. (2008). Randomised controlled trials of selective serotonin reuptake inhibitors in treating depression in children and adolescents: A systematic review and meta-analysis. European Neuropsychopharmacology, 18(1), 62-73. DOI: 10.1016/j.euroneuro.2007.06.001