The use of SSRIs in children and adolescents

Sarah E. Hetricka, Joanne E. McKenzieb and Sally N. Merryc

a

Orygen Youth Health Research Centre, Centre for Youth Mental Health, Faculty
of Medicine, Dentistry and Health Services, The University of Melbourne, Parkville,
Victoria, bMonash Institute of Health Sciences Research, Monash University,
Melbourne, Australia and cWerry Centre for Child and Adolescent Mental Health,
Department of Psychological Medicine, Faculty of Medical and Health Sciences,
University of Auckland, Auckland, New Zealand
Correspondence to Sarah E. Hetrick, MA, DPsych, Orygen Youth Health Research
Centre, Centre for Youth Mental Health, Faculty of Medicine, Dentistry and Health
Sciences, The University of Melbourne, Parkville, Victoria 3052, Australia
E-mail: shetrick@unimelb.edu.au
Current Opinion in Psychiatry 2010, 23:5357

Introduction
Depressive disorders are prevalent among young people
[1,2] and are frequently untreated or inadequately treated
[3]. The use of antidepressants in the management of
depression in children and adolescents is contentious.
Selective serotonin reuptake inhibitors (SSRIs) had been
widely used in paediatric depression until warnings about
their use were issued following concerns that children and
adolescents who had participated in trials evaluating the
effectiveness of SSRIs were at an increased risk of selfharm. This resulted in comprehensive reviews of the trials
by government regulatory agencies which all concluded
that only fluoxetine should be recommended for use in
children and adolescents with depressive disorders [47].
Claims and counter claims about the effectiveness of
SSRIs and risk related to their use have followed [8
13]. Concerns have been raised that if antidepressant use
is limited young people could be deprived of effective
treatments for a condition that carries with it considerable
morbidity and mortality [8,9,14]. Recent research has
suggested that pessimism about effective treatments
has resulted in reluctance on the part of patients to seek
help [15]. Further, lower rates of depressive disorder
diagnoses [15] may indicate that clinicians are reluctant
to make this diagnosis, perhaps due to uncertainty about
effective treatments.
The two key questions when considering the use of
SSRIs in the treatment of children and adolescents with
depressive disorder are, do they work and are they well
tolerated? Answering these questions requires consideration of the evidence.

Do selective serotonin reuptake inhibitors

work?
We undertook a Cochrane systematic review to evaluate
the evidence about the effectiveness and risk of this class
of medication for children and adolescents [16].
0951-7367 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins

Twelve trials met the inclusion criteria for our review.

The outcome response was reported in all trials. This
was a binary outcome created from a cut-point on a
continuous depression scale. Both the scale and cut-point
varied between trials. The pooled treatment effect of all
SSRI compounds on the outcome response demonstrated that a greater percentage of participants receiving
SSRIs responded compared with those receiving placebo
[relative risk (RR) 1.28; 95% confidence interval (CI)
1.17, 1.41] (Fig. 1).
There was evidence that effectiveness of SSRIs on
response varied by compound (with 81.3% of the
variation across SSRI compound effect estimates due
to heterogeneity rather than chance; P 0.001). There
was a statistically significant difference in the percentage of children and adolescents who responded when
receiving fluoxetine compared with placebo (RR 1.86;
95% CI 1.49, 2.32). The percentage of those responding while on fluoxetine ranged between 41 and 61%
compared with a range of 2035% in those on placebo.
Depressive symptom scores [Childrens Depression
Rating Scale-Revised scale (CDRS-R); range 17113]
were also statistically significantly lower for those
receiving fluoxetine compared with placebo at the
end of treatment [ranging between 8 and 12 weeks
of treatment; treatment effect 5.63 (95% CI 7.38,
3.88)].
For paroxetine, there was no statistically significant
difference in the percentage of children and adolescents
who responded to paroxetine compared with those who
responded to placebo (RR 1.09; 95% CI 0.95, 1.26).
There was a lack of consistency for both sertraline and
citalopram. There was no statistically significant difference in response rate between the sertraline and control
groups (RR 1.17; 95% CI 1.00, 1.36). However, depressive
symptom scores were significantly lower in the sertraline
group (treatment effect CDRS-R 3.56; 95% CI 6.69,
0.42). There was a statistically significant difference
in the percentage of children and adolescents who
responded when receiving citalopram/escitalopram
(RR 1.30; 95% CI 1.02, 1.67), compared with placebo
but no significant difference in depressive symptom score
(CDRS-R).
Functioning is perhaps the most relevant outcome for
young people as it measures their ability to sustain school/
work, interpersonal relations, and social functioning on a
day-to-day basis [17]. There was no evidence that SSRIs
were effective in improving functioning.
DOI:10.1097/YCO.0b013e328334bc92

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54 Psychiatry forum

Figure 1 Relative risk of response to selective serotonin

reuptake inhibitors compared with placebo

meaningful improvement on these scales. In addition,

varying cut-points for dichotomizing a continuous measure may also be indicative of a form of within study
selective reporting bias in which the most favourable
cut-point is chosen on the basis of the results [20].

Statistical versus clinical significance

The size of the difference in improvements between
groups is of questionable clinical significance. For
example, for fluoxetine, the average CDRS-R score at
follow-up was 5.63 lower for those in the treatment group
compared with the placebo group, with both groups
improving substantially. A difference of 25 points on
the CDRS-R scale has been shown to differentiate
clinical and nonclinical groups, whereas a difference of
19 points has been shown to differentiate clinical groups
with and without depressive disorder [21].

Internal validity

Statistical pooling used fixed effects statistical model for this outcome
and bars indicate 95% CIs. Test for heterogeneity x2 18.80, degrees
of freedom (df) 8 (P 0.02), I2 57%. SSRIs, selective serotonin
reuptake inhibitors.

What are the strengths and weaknesses of

the evidence base?
It is important to be cautious when interpreting the
results of our review. The interpretation of the outcome response, the selection of patient outcomes,
the clinical significance of treatment effects, and other
issues of internal and external validity all need consideration.

Outcome measurement
In the search for effective treatments, the ideal goal is a
resolution of symptoms (i.e., remission) and a return to
normal function. In the trials in our review, remission or
functioning were inconsistently reported, not reported, or
not collected. Most trials reported response which
equated to a reduction in symptoms that fell short of
remission. Inconsistencies in the choice of measurement scale used between trials coupled with varying
definitions of response (e.g., [13,18,19]) make it difficult to interpret this outcome. It highlights a lack of consensus over both the most appropriate measurement
scale to use in trials, and what is considered a clinically

There was generally limited information reported about

the conduct of the trials, so it was difficult to assess their
internal validity. However, two methodological components which were reported, attrition and blinding,
provided cause for concern. These have empirically been
shown to be associated with bias ([22], chapter 8, pp. 217
221). High attrition rates were observed in all trials;
ranging from 17 to 46% in the control groups and 17
40% in the intervention groups. The bias associated with
this attrition may be substantial. In the included trials,
the clinicians were also the outcome assessors for the
primary outcomes. It is possible that clinicians and
participants may have been able to guess whether the
participants were on active treatment or placebo from
side effect profiles.

External validity
Generalizability of the included trials is limited. Most
trials excluded placebo responders, those with complex
comorbidity, and those at risk of suicide so that participants were not typical of those seen in clinical practice.
It is unclear how effective these medications would be
for such young people. In addition, the trials were of
short duration, spanning only 712 weeks. Therefore,
the effectiveness and risks of these medications over a
612 month time period, which is the typically recommended treatment duration [23,24], is unknown. It is
possible, for example, that functioning may take a longer
period of time to return to normal, but these trials have
not evaluated this.
In conclusion, the effectiveness of SSRIs in patients
typical of those presenting in clinical practice is unknown.
For those young people with uncomplicated depression
there may be a small advantage to using fluoxetine in the

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The use of SSRIs in children and adolescents Hetrick et al. 55

short-term. However, there is no evidence that treatment

with fluoxetine will improve their function.

Are selective serotonin reuptake inhibitors

well tolerated?
There is conflicting evidence about the link between
SSRIs and suicidality. Consistent with US Food and Drug
Administration (FDA) findings and other meta-analyses
[25,26], our review showed an increased risk of suicidal
ideation and behaviour in those receiving an SSRI compared with those receiving a placebo (RR 1.80; 95% CI
1.19, 2.72). However, compared with rates found in
community studies [2731], the rates of these phenomena were very low (Fig. 2). This is likely to be because of
the exclusion of those most at risk. These phenomena
were measured in various ways across trials, or not
reported at all. The Treatment for Adolescents with
Depression Study (TADs) trial was the only one to report
suicidal ideation using a validated questionnaire (Suicide
Ideation Questionnaire [32]), and in contrast to the
Figure 2 Relative risk of suicide-related outcomes on a selective serotonin reuptake inhibitors compared with placebo

increased risk of suicidal ideation behaviours observed

across other trials, participants receiving fluoxetine had
lower suicidal ideation at follow-up than at the start of
treatment and compared with those in the placebo group
[33]. Although there were no reports of completed
suicide in a total sample of 2240 children and adolescents
included in our review; suicide is rare, the trials were of
short duration, and were not powered to assess suicide
risk from SSRIs. Although appropriate caution is required
in interpreting the risk of suicidal ideation and behaviours
due to inconsistency in reporting of this outcome across
trials, the increased risk for those receiving SSRIs raises
concern. Adding to this concern is the fact that the risk
may be different, perhaps larger, if SSRIs are used in a
population of patients who are typical of those seen in
clinical practice.
In contradiction to the FDA findings [26] and other
reviews of SSRIs [16,25], evidence from routinely collected data show a different story. In the decades prior
to 2004, internationally, there was an increase in the
prescribing rates of SSRIs. If SSRIs do increase suicidal
behaviours, an increase in suicide rates might be expected.
However, one study suggested that increased prescribing
of antidepressants in those years was associated with
reduced suicide rates in some countries [34]. Further,
since 2004 there has been a reduction in SSRI prescriptions
for young people due to regulatory warnings, and over the
same period of time an increase in the suicide rate in the
Netherlands and the United States of America with claims
that these two phenomena are related [35]. The low overall
rates of suicide make these claims questionable [36] with
the link between antidepressant medication use and
suicide rates contested [37].

Discussion

Statistical pooling used fixed effects statistical model for this outcome
and bars indicate 95% CIs. Test for heterogeneity x2 5.09, df 8
(P 0.75), I2 0%. SSRIs, selective serotonin reuptake inhibitors.

Our meta-analysis [16] showed that there was limited

evidence of efficacy of SSRIs. Fluoxetine was the only
SSRI for which there was consistent evidence of its
effectiveness in improving response and depressive
disorder symptoms in children and adolescents compared
with placebo. Most children and adolescents who participated in the trials were not typical of those presenting for
treatment; they had low rates of comorbidity and were at
low risk of suicide or self-harm. Those who responded to
placebo had been screened out, maximizing the chance of
showing a difference between placebo and medication.
Despite this, even for fluoxetine the improvement is
modest. There was evidence of an increased risk of
suicidal ideation and behaviour for those on an SSRI,
although rates were low. However, one included trial
showed a reduction in suicidal ideation for those
prescribed fluoxetine and evidence from studies using
routinely collected data have shown an inverse relationship between SSRI prescription and suicide.

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56 Psychiatry forum

Clinical implications
When deciding treatment options, all interventions
should be considered including psychotherapies and
other antidepressants.
When beginning treatment, interventions of least risk
should be considered first. Standard care, typical of most
child and adolescent mental health services, may be
sufficient for some to recover. Consideration to psychotherapies can also be given. There is some evidence that a
range of psychotherapeutic interventions may be effective, at least in the short-term [38].
Antidepressants potentially pose greater risks. Our systematic review examined the evidence of SSRIs [16].
However, a recent review included trials comparing all
classes of antidepressant medications with placebo [39].
Within this review, the authors undertook a metaregression to examine whether a drug class was predictive
of treatment effect for the outcome response and concluded that there was no statistical evidence to support
the hypothesis that SSRIs were more effective than
tricyclic antidepressants.
It is possible that medications are effective for some
individuals including those with more severe and complex presentations. However, only a few trials (e.g. [40])
have included these participants, so there is limited
evidence about the effectiveness and risks of treatments
in these subgroups.
Decisions on treatment options should always be made in
consultation with the young person and their families.
Given the equivocal evidence base about the effectiveness and risks of the treatments, there is a particular need
to provide accurate information about the limits of the
evidence base and elicit treatment preferences of the
young people and their family; allowing them to be
actively involved in their treatment decision [16,4145].

Research priorities
The results of our systematic review, and others (e.g. [39]),
have identified the need for further research. This
could include a systematic review that allows for direct
and indirect comparisons of various treatment options;
including antidepressant medication and psychotherapeutic interventions. This may necessitate the need for a
large head-to-head trial testing those interventions
demonstrated to be the most effective in the systematic
review. Such a trial should include young people similar
to those seen in clinical practice and should be of at least
612 months duration. Consideration should be given to
adequately powering the trial to test whether the effectiveness of the treatments differs by severity of depressive disorder.

Finally, it is evident from the variation in measurement

instruments used between trials included in our review
that there is a need to establish a standard set of outcome
measures. This has been successfully done in rheumatology [46]. Additional research may need to be undertaken
to establish what outcomes are important to children
and adolescents.

Conclusion
Untreated depressive disorder is associated with morbidity and mortality; however, the argument that SSRIs
should be used to reduce the morbidity and mortality
associated with depressive disorders is not well founded
[16,47]. Our systematic review, along with others [16,39],
has demonstrated the limited effectiveness of SSRIs
and, furthermore, the limited information about their
effectiveness in young people typically seen in clinical
practice. Evidence regarding the risk of self-harm on
SSRIs is conflicting. The search for effective treatments
for depressive disorders in young people is not over
[47].
In the meantime, it is essential that optimism and an active
approach are maintained in the treatment of depressive
disorders in children and adolescents. Depressive disorders in young people need to be detected, and actively
managed, first utilizing interventions of least risk. Many
will respond to simple remedies [40]. There is considerable heterogeneity in young people who present with
depressive disorder and SSRIs may be effective for subgroups of these young people, which are not yet defined.
For young people who have not responded to other interventions, or those with a particularly severe or disabling
disorder, a trial of medication could be considered after
discussing the risks and limited evidence of effectiveness
with the young person and their family. Close monitoring
of symptoms and side effects is always crucial, but particularly once medication is utilized. Guidelines, although
varying, consistently recommend such an approach, including more judicious use of medication [10,23,24,48]. We
would support this.

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