Antidepressant Medications in Children and Adolescents

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The Therapeutics Initiative presents critically

appraised summary evidence primarily from controlled

drug trials. Such evidence applies to patients similar

to those involved in the trails, and may not be

generalizable to every patient. We are committed to

evaluate the effectiveness of our educational

activities using the Pharmacare/PharmaNet databases

without identifying individual physicians, pharmacies

or patients. The Therapeutics Initiative is funded by

the BC Ministry of Health through a 3-year grant to

the University of BC. The Therapeutics Initiative

provides evidence based advice about drug therapy, and

is not responsible for formulating or adjudicating

provincial drug polici

 

http://www.ti.ubc.ca/pages/letter52.htm

 

Antidepressant Medications in Children and Adolescents

 

 

Evidence of effectiveness

 

A Cochrane systematic review of the tricyclic

antidepressants (TCA) in children and adolescents

shows little or no benefit for TCAs as compared to

placebo.6 Controversy about the SSRIs and SNRIs has

arisen because only a selected 6 out of 15 randomized

controlled trials (RCTs) studying these agents in

child and adolescent depression have been

published.7-11

Only the regulatory agencies have access to the full

data set from the 15 RCTs and their conclusions are as

follows. Note that a positive trial is one in which

the pre-defined primary outcome is statistically

significantly better for the drug as compared to the

placebo. Of the 15 RCTs only 3 (2 fluoxetine and 1

citalopram) were positive.2,11

Six of the 15 RCTs are published, all claiming

effectiveness: 2 pooled sertraline trials12, one

paroxetine trial13, two fluoxetine trials14,15, and

one citalopram trial.16 However, the claims in 3

published trials (1 paroxetine and 2 sertraline) were

not confirmed after independent analysis by the

regulatory agencies.2,11 In the paroxetine trial

Keller et al13 claimed efficacy for paroxetine and not

for imipramine as compared to placebo; re-analysis by

both the Medicine and Health Care Products Regulatory

Agency2 and the Food and Drug Administration11

concluded this trial was negative for both

antidepressants. The two sertraline trials were

reported as positive when pooled together.12 Upon

re-analysis, the trials were shown separately to both

be negative.2,11 The following unpublished placebo

controlled trials were negative: 2 paroxetine trials,

2 venlafaxine trials, 2 nefazodone trials, 2

mirtazapine trials and 1 citalopram trial.

In the 3 positive studies, the benefit was limited to

a modest improvement in some symptoms, not remission

of the disorder.14-16 The 2 fluoxetine trials14,15

have also been criticized on re-analysis.17

Evidence of harm

 

Determination of the true rates of harm is hampered by

inconsistent ascertainment, description and reporting

of adverse effects. For example, in the published

adolescent paroxetine trial13, 11/93 patients

discontinued paroxetine due to “serious” psychiatric

adverse effects, of which the most common was

described as “emotional lability.” This was then

further defined as “suicidal ideation/gestures,

conduct problems or hostility, e.g. aggressiveness…”

Such responses led 7.5% of the initially mildly

depressed outpatients placed on paroxetine to be

hospitalized. None of the placebo-treated patients

required hospitalization. This finding was dismissed

in the discussion. The sertraline trials did not

include a side effect checklist in the protocol, yet

the medication was described as well-tolerated.12

Rates of suicidal ideation and attempts are low in

most trials (2-3% with drug; 0-1% with placebo), and

hence seldom reach statistical significance in

individual trials. However, the direction of change is

the opposite of that predicted if the medications are

improving depression. Furthermore, observations in

clinical trials and case reports from the past 12

years indicate that up to 25% of children placed on

various SSRIs experience psychiatric adverse effects

such as agitation, disinhibition, aggression,

hyperkinesis and emotional lability.18 The recent

labeling changes by Health Canada and the Food and

Drug Administration emphasize these potential

psychiatric and behavioral adverse effects in both

children and adults.4,19

Summary

 

The published literature on this topic is an

incomplete and inaccurate representation of the

totality of evidence. The profession has had a

difficult time coming to terms with this fact.7 When

we are guided by meta-analyses carried out on biased

datasets, we are operating under the illusion of

practicing evidence-based medicine. A recent article

has termed this “evidence-biased medicine”.20

 

Clinical Implications

 

The prescription of an antidepressant to a child or

adolescent is like an open trial with up to 80% of

patients expected to improve. When improvement occurs,

it is most likely due to a placebo group response,

which includes spontaneous remission, response to

supportive care, and other components. Because of the

unfavorable harm to benefit balance for

antidepressants in this age group, first-line therapy

is multiple supportive interventions: sleep hygiene,

exercise, regular dietary patterns, consistent

parenting, and practical problem-solving regarding

schooling and life stressors.21 For those who do not

respond, individual or group cognitive behavioral

therapy or interpersonal psychotherapy should be

arranged, if possible.21,22 Medications are reserved

for add-on therapy when the first two approaches are

not working. When an antidepressant is prescribed, the

patient must be monitored for signs of deterioration:

behavioral and psychiatric changes, including

increases in suicidal thinking, as emphasized by the

new Health Canada labeling.4