1 3Eur Child Adolesc Psychiatry (2016) 251287–1295DOI 1.docx

1 3
Eur Child Adolesc Psychiatry (2016) 25:1287–1295
DOI 10.1007/s00787-016-0849-y
ORIGINAL CONTRIBUTION
Clinical characteristics associated with the prescribing of SSRI
medication in adolescents with major unipolar depression
Lesley Cousins1,9 · Kirstie J. Whitaker1 · Barry Widmer1 ·
Nick Midgley2,8 ·
Sarah Byford3 · Bernadka Dubicka4,10 · Raphael Kelvin1,9 ·
Shirley Reynolds5 ·
Christopher Roberts6 · Fiona Holland6 · Barbara Barrett3 ·
Robert Senior7 ·
Paul Wilkinson1,9 · Mary Target2,8 · Peter Fonagy2,8 · Ian M
Goodyer1,9
Received: 21 August 2015 / Accepted: 7 April 2016 / Published
online: 28 April 2016
© The Author(s) 2016. This article is published with open
access at Springerlink.com
consider severity of depression in boys as an indicator for
antidepressant prescribing. Self-injury in girls appears to be
utilised as a prescribing aid which is inconsistent with past
and current revised UK NICE guidelines.
Keywords Adolescents · Depression · Antidepressants ·
SSRIs · Risk · Self-harm

Introduction
MD is a significant health problem affecting a substantial
proportion of the adolescent population worldwide [1]. The
estimated 12 month period prevalence of MD in teenagers
is 7.5 % affecting around twice as many girls as boys and
around 1 in 4 of these will have a severe clinically referable
condition [2, 3]. The long term consequences of adoles-
cent emergent MD can include suicide, anxiety disorders,
substance misuse and failure to both achieve education-
ally and in the work place [4]. These negative outcomes
come at great economic cost to the UK and other national
economies and therefore, ensuring that we manage MD
Abstract Unipolar major depressions (MD) emerge
markedly during adolescence. National Institute for Health
and Care Excellence (NICE) UK recommends psychologi-
cal therapies, with accompanying selective serotonin reup-
take inhibitors (SSRIs) prescribed in severe cases only.
Here, we seek to determine the extent and rationale of SSRI
prescribing in adolescent MD before entering a randomised
clinical trial. SSRI prescribing, together with their clinical
characteristics was determined in 465 adolescent patients
with MD prior to receiving a standardised psychological
therapy as part of the Improving mood with psychoana-
lytic and cognitive therapies (IMPACT) clinical trial. Over-
all, 88 (19 %) had been prescribed antidepressants prior
to psychological treatment. The clinical correlates varied
by gender: respectively, depression severity in boys and
self-harming behaviours in girls. Prescribing also differed
between clinical research centres. Medical practitioners
Improving mood with psychoanalytic and cognitive therapies
(IMPACT) Clinical trial number: ISRCTN83033550.
Electronic supplementary material The online version of this

article (doi:10.1007/s00787-016-0849-y) contains
supplementary
material, which is available to authorized users.
* Ian M Goodyer
[email protected]
1 Developmental Psychiatry Section, University of Cambridge,
Douglas House, 18b Trumpington Road, Cambridge CB2
8AH, UK
2 Anna Freud Centre, University College London, London, UK
3 Centre for the Economics of Mental and Physical Health,
Kings College London, London, UK
4 Institute of Brain and Behaviour and Mental Health,
University of Manchester, Manchester, UK
5 School of Medicine, University of East Anglia, Norwich, UK
6 Biostatistics Group, Institute of Population Health,
University of Manchester, Manchester, UK
7 The Tavistock and Portman NHS Foundation Trust, Tavistock
Centre, London, UK
8 Research Department of Clinical, Educational and Health
Psychology, University College London, London, UK
9 Cambridgeshire and Peterborough NHS Foundation Trust,
Cambridge, UK
10 Lancashire Care Foundation Trust, Preston, UK
http://crossmark.crossref.org/dialog/?doi=10.1007/s00787-016-
0849-y&domain=pdf
http://dx.doi.org/10.1007/s00787-016-0849-y

1288 Eur Child Adolesc Psychiatry (2016) 25:1287–1295
1 3
effectively in this age group should be a priority for public
mental health policy and practice.
The UK NICE guidelines are one of the few focused
and standardised recommendations available for the man-
agement of adolescent MD within Europe and indeed
worldwide. These standards have recently undergone revi-
sion. Previous guidance promoted the use of evidence-
based psychological therapies as first line treatment, with
SSRIs antidepressants constituting the pharmacological
treatment of choice only if psychological therapies have
first been tried without response, and only then, in combi-
nation with psychological therapy. The 2015 amendment
to these guidelines allow combined SSRI and psychologi-
cal therapy first line but continue to warn against the use of
SSRIs on their own [5]. Both state that depression should
be moderate to severe to warrant SSRI prescribing. Given
that this guidance has recently been reviewed, we deter-
mined whether the current management of adolescent MD
adheres to these guidelines, either revised or in their origi-
nal form.
IMPACT is a pragmatic, multicentre randomised con-
trolled trial of adolescents with MD [6]. It is designed to
investigate the effectiveness of three different psychologi-
cal interventions (short term psychoanalytic psychotherapy,
cognitive behavioural therapy and manualised specialist
clinical care) in reducing the risk of symptomatic depres-
sive relapse in the medium term 12–18 months after begin-
ning treatment. A clinical audit of NHS notes documenting

prior treatments and medication prescribing in a sub-sam-
ple (n = 80) of participants prior to randomisation revealed
that a marked proportion of audited cases had already been
prescribed SSRI antidepressants prior to receiving their
psychological intervention.
Given this apparent deviation in adherence to NICE
guidelines, we wished to investigate the clinical ration-
ale underlying this pre-trial prescribing of antidepressants
across the whole of the trial cohort.
Our investigations were underpinned by four principle
hypotheses; firstly, we hypothesised that pre randomisa-
tion prescribing would be based on severity or chronicity
of clinical presentation. Secondly, we considered whether
prescribing was based on perceived functional impair-
ment or subjective quality of life rather than clinical signs
and symptoms. Thirdly, we hypothesised that prescribing
would be associated with overt risk behaviours such as self-
harm and antisocial behaviour. We reasoned that practition-
ers may perceive such hazardous behaviours to be proxy
indices of depression severity or consider such behaviours
as requiring rapid pharmacological management. Finally,
given previous findings of the importance of site-specific
effects within RCTs, we investigated the importance of
the research site individuals derived from, both in terms of
SSRI prescribing and sample characteristics.
Methods
Improving mood with psychoanalytic and cognitive
therapies (IMPACT) participants
IMPACT is a pragmatic randomised control trial which
aims to determine if one of two specialist treatments, cog-
nitive behavioural therapy (CBT) or short term psycho-

analytic psychotherapy (STPP) are superior to a reference
practice-based brief psychosocial intervention (BPI), at
preventing recurrence of clinically meaningful levels of
depressive symptoms indicating potential relapse in adoles-
cents who enter the trial with MD [6].
The study was conducted over three regions within the
UK, East Anglia, North London and the North West of Eng-
land incorporating 16 routine Child and Adolescent Mental
Health (CAMH) clinics. Individuals were recruited to the
study with moderate to severe depression and aged between
11 and 18 years. Exclusion criteria included generalised learn-
ing difficulties or a pervasive developmental disorder, preg-
nancy, currently taking another medication that may interact
with an SSRI and being unable to stop this medication, sub-
stance misuse, primary diagnosis of Bipolar Type I disorder,
schizophrenia or eating disorder. Of the 561 individuals who
were referred and had baseline assessments, 470 were con-
sidered eligible with 5 later withdrawing consent, resulting in
the recruitment of 465 overall. As part of the screening pro-
cess prior to enrolment, individuals were asked if their current
depressive illness was a first episode or a relapse. At this point,
demographic information including their ethnicity was col-
lected. Ethical approval was by the Cambridgeshire 2 research
Ethics Committee, Addenbrooke’s Hospital Cambridge, UK
and is therefore, in accordance with the ethical standards laid
down in the 1964 Declaration of Helsinki and its later amend-
ments. Follow up was undertaken with repeated reassessments
at up to 86 weeks after randomisation to evaluate recurrence of
clinical level depressive symptoms. The further characterisa-
tion of the sample will be available with the publication of the
IMPACT trial during 2016 [7].
Assessment instruments
SSRI prescribing

Antidepressant prescribing prior to entering the study was
determined using the Child and Adolescent Service Use
Schedule (CA-SUS) [8]. The CA-SUS is an interview-
based measure to collect data on service use and was
designed for use within mental health populations, includ-
ing young people with depression [8]. As well as ascertain-
ing the current prescribing of psychotropic medication, it
includes information on the individual’s accommodation,
1289Eur Child Adolesc Psychiatry (2016) 25:1287–1295
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education, use of hospital and community based health and
social services, and any criminal activity or criminal justice
sector contacts. Baseline prescribing information was avail-
able for 457 individuals of the 465 recruited to the study
(98 %). Subsequent analyses presented here excluded par-
ticipants for whom this information is not available.
Interview measures
Schedule for affective disorders and schizophrenia
for school aged children, present and lifetime version
(K‑SADS‑PL) [9]
We hypothesised that SSRI prescribing may be associ-
ated with depression severity, psychiatric comorbidity or
chronicity. This was investigated using the K-SADS-PL.
With regard to depressive symptoms, this refers to the 22
items used to establish the diagnosis of current depression
in the K-SADS-PL. A score of 3 or ‘threshold’ within the
K-SADS-PL was used to define a symptom being present.

The comorbid diagnoses considered, according to DSM-IV
criteria, were panic with and without agoraphobia, separa-
tion anxiety, avoidant disorder, specific phobias, general
anxiety disorder, obsessive compulsive disorder, post-trau-
matic stress disorder, anorexia nervosa, bulimia nervosa,
attention deficit disorder, oppositional defiant disorder,
conduct disorder, alcohol abuse and substance and alco-
hol dependence. Psychotic symptoms were also recorded
but individuals with a diagnosis of mania or schizophrenia
were excluded from the study. These data were available
for all the trial participants. Using the K-SADS-PL, the age
of onset of depressive illness was also compared between
groups [data available for 282 individuals (62 %)]. The
K-SADS-PL has been shown in numerous studies to have
high inter-rater reliability and construct validity [9].
Self‑report measures
Moods and feelings questionnaire (MFQ) [10]
The MFQ was also used to investigate if depression sever-
ity was associated with SSRI prescribing prior to randomi-
sation in the IMPACT study. It is a 33 item self-report
measure of depressive symptoms consisting of a list of
descriptive phrases with subjects being asked to rate their
symptoms over the past 2 weeks. Re-test reliability and
criterion validity are reported to be high [11]. Cronbach’s
alpha within our study was 0.92. Items are scored from 0 to
2 (never = 0, sometimes = 1, mostly or always = 2), yield-
ing a maximum score of 66. These data were available for
462 out of the 465 study participants (99 %).
Health of the nation outcome scales for children
and adolescents (HONOSCA) [12]
The HONOSCA is a measure of a young person’s total

mental health problems. It measures 15 items includ-
ing psychiatric symptoms, behaviours, family, social and
school functioning. Each item is scored from 0 to 4 where
0 indicates no problems and 4 very severe problems. It is
known to be reliable, sensitive to change and correlates
well with the clinician’s judgement of the young person’s
outcome [13]. HONOSCA data were available for 432 of
the study participants (93 %).
Euroqol 5 dimension (EQ‑5D) questionnaire [14]
The EQ-5D was used to investigate whether SSRI pre-
scribing prior to randomisation in the IMPACT study was
associated with functional impairment or quality of life. It
is a standardised measurement of health status and health-
related quality of life. The EQ-5D-3L version was used
which consists of five dimensions (mobility, self-care,
usual activities, pain/discomfort and anxiety/depression),
recorded on one of three levels (no problems = 1, some
problems = 2, extreme problems = 3). This allowed indi-
viduals to be classified into one of 243 health states. For
example, 11,111 representing no problems in any dimen-
sion and 33333 representing extreme problems in all five
dimensions. A summary index value was derived by apply-
ing general population weights to each health state [15].
The summary scores range from 1 (perfect health) to 0
(death) with negative scores indicating states considered to
be worse than death. The EQ-5D was available for 436 of
the individuals (94 %).
Modified risk taking and self‑harming inventory
for adolescents (RTSHIA) [16]
The RTSHIA, a self-report instrument for assessing life-
time self-harm and risk taking behaviour in adolescents,
was used to investigate whether SSRIs are prescribed to

adolescents based on hazardous or risk-taking behaviour.
The version used differs from the original in that 3 ques-
tions were omitted regarding risky sexual behaviour. The
version used contained 31 items answered on a Likert scale
(3 = many times, 2 = more than once, 1 = once, 0 = never)
and scored as a total for hazardous behaviour ranging from
0–93. Subscales for risk taking and self-harming were
examined as well as the total score. Examples of questions
that related to risk taking but not self-harm included drug
and alcohol use, staying out late without parental knowl-
edge and actively placing oneself in risky situations such as
cheating at school and shop lifting. Cronbach alpha scores
for each component of the RTSHIA within our study were;
1 3
total = 0.90, risk taking = 0.80, self-harming = 0.90. This
was available for 436 individuals of those entered into the
trial (94 %).
Behavioural checklist [17]
We also considered if antisocial behaviour may be con-
sidered a hazardous behaviour associated with prescrib-
ing. This was investigated using the Behavioural Check-
list, an 11-item screen for current symptoms of antisocial
behaviour derived from DSM-IV criteria and converted to
a self-report format. It is scored on a 4 point Likert scale
(always = 3, mostly = 2, sometimes = 1, never = 0) with
a range of 0–44. Within our study, Cronbach alpha for the
Behavioural Checklist was 0.79. The Behavioural Checklist
was completed by 450 of the study participants (97 %).

Statistical analysis
Many of the measures we collected were found to be non-
normally distributed. Therefore, statistical tests between
two groups were completed using the Wilcoxen Mann–
Whitney test. The Chi-squared statistic was used to com-
pare groups based on gender, research centre and ethnicity.
To address the issue of missing data, scores for the MFQ,
behavioural checklist and RTSHIA total and sub-scores
were pro-rated.
Comparison of prescribing between research centres
was also undertaken using logistic regression. A multino-
mial logistic regression analysis was undertaken to inves-
tigate the potential effects of research centre on the popu-
lation characteristics with regard to gender, quality of life
(EQ5D), HONOSCA score, self-harm, depression severity
(as measured by MFQ), age and ethnicity. The relationship
between SSRI prescribing and the predictors mentioned
above, including research centre, was also tested using
logistic regression analysis. Prior to this, we undertook a
logistic regression using gender as a predictor to ascertain
if there were gender effects on the parameters measured.
Based on this, the model was split by gender to establish
if there were differences in the predictors for prescribing
between males and females.
Data were analysed using STATA Version 13 [18] for
Windows PC.
Results
Demographics
Data regarding antidepressant prescribing prior to randomi-

sation were available for 457 out of the 465 individuals
recruited to the IMPACT trial. Of these, 89 (19.5 %) had
been prescribed an antidepressant before entering the trial.
The only antidepressants that had been prescribed were
SSRIs with the majority (83 %) taking fluoxetine, as per
NICE guidelines. The remaining individuals were pre-
scribed citalopram (10 %) or sertraline (6 %). One individ-
ual was documented as taking an SSRI but the type of SSRI
was not reported.
Prior to entering the study, individuals were asked if this
was their first episode of depression. This information was
available for 396 (85 %) of the study’s participants. There
was no difference in any of the demographic variables (age,
gender, ethnicity, MFQ score, age of onset of depression,
number of depressive symptoms and number of comorbid
disorders) measured between those for whom this informa-
tion was available and those for whom it was not. Of those
with available information, 370 (93.4 %) reported their cur-
rent depressive illness as a first episode, the rest reporting
a recurrence. Of the 77 individuals prescribed antidepres-
sants for whom screening information was available, 73
reported their current depressive illness as being the first
episode (94.8 %).
As shown in Table 1, individuals did not differ with
regard to age, gender or ethnicity (white vs non-white)
regardless of whether or not they were prescribed SSRIs.
There was, however, a main effect of treatment centre,
which will be discussed in more detail below.
Illness severity
The severity of the young person’s current depressive ill-
ness was compared between those who had been prescribed

antidepressants before entering the IMPACT study and
those who had not been using both observer and self-rated
measures (Table 2).
No significant difference between groups was observed
in self-reported depression scores, the number of inter-
view reported depressive symptoms (K-SADS PL), or
the number of comorbid disorders associated with their
depressive illness. There was also no difference in the age
of onset of depressive illness obtained from the K-SADS
PL.
Quality of life/functional impairment
Individuals who had been prescribed an SSRI reported a
lower level of health-related quality of life than those who
were not taking antidepressants, as measured using the
EQ5D (Table 2). They also reported higher HONOSCA
scores, suggesting an overall poorer mental health status
(Table 2). Together, these findings suggest that individu-
als who had been prescribed SSRIs subjectively perceived
themselves as more functionally impaired.
1 3
Hazardous behaviour
Individuals who had been prescribed antidepressants had
higher self-reported lifetime histories of hazardous behav-
iour overall, as measured using the RTSHIA (Table 2).
When analysis of hazardous behaviour was split into risk

taking and self-harm components, there was no difference
between the groups with regard to risk taking behaviour,
however, those who had been prescribed antidepressants
had higher lifetime histories of self-harming behaviours.
Antisocial behaviour
This hazard-related prescribing led us to the question of
whether other forms of risky but non-depressive behaviour
were also associated with antidepressant prescribing
(Table 2). Surprisingly, individuals who had been pre-
scribed antidepressants before entering the IMPACT study
had fewer symptoms of self-reported antisocial behaviour
compared with those who had not been prescribed antide-
pressant medication. It should be noted, however, that the
median scores for each group are low in both, given the
scale range (0–33).
Prescribing differences across research centres
Prescribing rates of SSRI antidepressants differed signifi-
cantly across the three UK research centres from which
they were recruited (Table 1). Descriptively, 30 % of indi-
viduals recruited from East Anglia had been prescribed
Table 1 Baseline demographic
for individuals prescribed SSRI
antidepressants compared with
those who were not
a Derived from K-SADS-PL—schedule for affective disorders
and schizophrenia for school aged children
present and lifetime
No SSRI prescribed

(N = 368)
SSRI prescribed
(N = 89)
Statistic p
Median IQR Median IQR
Age (years) 15.6 14.6–16.8 15.7 15.0–16.8 z = 1.1 0.27
Age of onset of depressiona 14.0 12.0–15.0 14.0 13.0–15.0 z =
0.1 0.89
n % n %
Research centre
East Anglia 126 34.2 54 60.6 χ2 = 21.3 <0.000
London 112 30.4 14 15.7
North West 130 35.3 21 23.6
Gender
Boys 89 24.2 27 30.3 χ2 = 1.1 0.29
Ethnicity
White 281 76.4 74 83.1 χ2 = 1.4 0.23
Table 2 Comparison of depression severity, functional
impairment, hazardous behaviour and antisocial behaviour
scores between individuals
prescribed SSRIs and those who were not
a Derived from K-SADS-PL—schedule for affective disorders
and schizophrenia for school aged children present and lifetime

No SSRI prescribed
(N = 368)
SSRI prescribed
(N = 89)
Mann–Whitney U
(z score)
p Effect size
(Cohen’s d)
Median IQR Median IQR
MFQ score 46.0 38.2–54.0 50.0 42.0–55.7 1.8 0.072
No of depressive symptomsa 8.0 7.0–10.0 8.0 7.0–11.0 0.6 0.53
No of comorbid disordersa 1.0 0.0–2.0 1.0 0.0–2.0 0.6 0.54
EQ5D 0.7 0.4–0.8 0.4 0.3–0.7 2.6 0.008 −0.32
HONOSCA 18.0 14.0–22.0 20.0 16.1–24.0 2.3 0.024 0.24
RTSHIA hazardous behaviour total 18.0 9.0–29.0 20.0 11.8–
33.2 2.0 0.043 0.25
RTSHIA—risk taking 5.0 2.0–9.0 5.0 1.0–11.2 0.05 0.96
RTSHIA—self-harm 12.0 5.0–21.0 15.5 7.0–24.2 2.19 0.028
0.28
Antisocial behaviour 3.0 1.0–5.0 2.0 0.0–4.0 2.3 0.021 −0.31

1 3
SSRIs prior to entering the study, compared with 11.1
and 13.9 % from London and the North West of England,
respectively. Participants in East Anglia were, therefore,
2.7 (z = 3.4, p = 0.001) times more likely to be prescribed
an SSRI compared with those recruited from the other two
research centres.
These prescribing differences, however, did not explain
the observed relationship between medication prescribing,
quality of life/functional impairment and risky behaviour
(Table 3). The pattern of quality of life, self-harming and
antisocial behaviour scores were the same across research
centres with the group who had been prescribed SSRIs
prior to entering the study exhibiting lower EQ-5D scores
(poorer health-related quality of life), higher HONOSCA
scores (poorer overall mental health outcomes), higher
self-harm/suicidality levels and lower antisocial behaviour
levels, compared with those who had not been prescribed
antidepressant medication.
We tested for potential effects of centre on sample char-
acteristics using a multinomial logistic regression (Supple-
mentary Table 1). This showed that individuals recruited
from London and the North West displayed lower self-harm
scores compared with those recruited from East Anglia
[median score (IQR): East Anglia: 16.0 (9.0–26.0), Lon-
don: 13.0 (5.0–21.0), North West: 10.0 (4.0–20.5)]. Indi-
viduals from London were also slightly older [median age
(IQR): East Anglia: 15.5 (14.7–16.3) years, London: 16.1
(14.8–17.2) years, North West: 15.6 (14.6–16.7) years]
and more likely to be of a non-Caucasian ethnicity (East
Anglia: 90 % Caucasian, London: 53 % Caucasian, North

West: 84 % Caucasian). Adolescents from the North West
had significantly lower HONOSCA scores compared with
the East Anglian population [median score (IQR): East
Anglia 19.2 (16.0–24.9), London: 20.0 (14.4–25.8), North
West: 17.0 (13.0–21.3)].
Gender differences in SSRI prescribing predictors
A logistic regression using gender as an interaction term
allowed for any potential effects of gender on each of the
univariates predicting SSRI prescribing to be investigated
(Supplementary Table 2). Depression severity (as measured
by MFQ) was added to the model as the difference between
the two groups approached significance. Age was also
added to the model in case this was shown to be a prescrib-
ing predictor when other interactions were controlled for.
This showed that SSRI prescribing appeared to be more
likely in girls with higher self-harm scores and boys with
greater depressive symptoms (as measured by MFQ).
This was confirmed by a further logistic regression analy-
sis examining for main effects and interactions between
SSRI prescribing and the possible predictors; quality
of life, total mental health problems (as measured by the
HONOSCA), self-harm, antisocial behaviour, depression
severity, research centre and ethnicity. Given the findings
from our first model, this analysis was undertaken for boys
and girls separately and the results are presented in Table 4.
They confirmed that the main predictor for prescribing dif-
fered based on gender. For girls, prescribing was associated
with a history of self-harming behaviour. In contrast, pre-
scribing for boys was associated with depression severity
at randomisation. The area boys were recruited from also
appeared to play a role as to whether they were prescribed
SSRIs or not, they were more likely to be prescribed anti-
depressants if they came from East Anglia as opposed to

London or the North West of the UK.
Discussion
We set out to explore the clinical characteristics that may
account for the prescribing of antidepressants to adoles-
cents with moderate to severe depression prior to enter-
ing the IMPACT study. To do this, we studied the baseline
clinical characteristics of individuals including the severity/
chronicity of depression, quality of life/functional impair-
ment, self-harming/suicidality and other risk related antiso-
cial behaviours.
The majority of individuals (>90 %) were experienc-
ing their first episode of depression and did not report at
recruitment receiving any formal psychological treatment
before entering the trial. Therefore, at least 19 % of the
study population received an SSRI without a concurrent
psychological treatment.
Table 3 Relationship between SSRI prescribing, EQ5D,
HONOSCA, hazardous behaviour, self-harm and antisocial
behaviour across research
centres
East Anglia London North West
No SSRI mean (SD) SSRI mean (SD) No SSRI mean (SD) SSRI
mean (SD) No SSRI mean (SD) SSRI mean (SD)
EQ5D 0.59 (0.25) 0.48 (0.25) 0.56 (0.30) 0.48 (0.30) 0.59
(0.27) 0.53 (0.26)
HONOSCA 18.9 (5.2) 19.9 (5.6) 18.8 (6.5) 22.9 (6.6) 17.1 (6.4)
17.2 (5.7)

RTSHIA—self-harm 17.1 (10.8) 17.5 (11.1) 13.1 (9.8) 15.5
(10.6) 11.2 (9.7) 16 (13.7)
Antisocial behaviour 3.5 (3.2) 2.2 (2.3) 3.8 (3.3) 3.4 (3.3) 3.2
(3.4) 2.6 (2.7)
1 3
So what are the clinical characteristics underlying the
prior antidepressant prescribing in those adolescents with
MD recruited subsequently to the trial? Within the total
population, significant differences were noted in non-
depressive symptoms and behaviours: those who had been
prescribed SSRIs prior to entering the IMPACT study
reported a reduced quality of life, higher subjective total
mental health problems and higher levels of self-harm
compared with those not prescribed. Unexpectedly, young
people who had been prescribed SSRIs also reported lower
antisocial behaviour symptoms. Perhaps, low antisocial
behaviour in a presumed depressed adolescent is a con-
tributory factor to SSRI prescribing. However, it should be
noted that scores were low across the cohort, making inter-
pretation of this result unclear.
We also identified significant differences between SSRI
prescribing and the area within the UK the young person
came from. Individuals from East Anglia were more than
twice as likely to receive antidepressants compared with
those from London or the North West of England, as well
as being more likely to report greater life-time histories of
self-harm. In an attempt to understand how the differences
we found between individuals who had and had not been

prescribed SSRIs interacted, we included all the variables
where differences were seen within a logistic regression
model predicting SSRI prescribing The results suggested
that the rationale underlying SSRI prescribing in adoles-
cents differed based on gender; self-harm being the main
predicting factor for SSRI prescribing in girls, whilst sever-
ity of depressive illness predicted prescribing in boys.
If, as it seems, NICE guidelines, within the UK, are not
being systematically followed, the question must therefore
be why not? It is possible that issues such as low diagnos-
tic accuracy, a lack of familiarity with current guidelines,
insufficiently available adequately trained adolescent men-
tal health practitioner and inadequate psychological ser-
vices available in secondary and tertiary care [19], may all
compromise the chances of such guidance being followed.
It is also possible that some psychiatrists disagree with
NICE guidelines so chose not to follow them.
It may be argued that in a number of adolescents with
severe depression, SSRIs should be the treatment of first
choice with psychological therapies added, as remission
ensues to aid recovery and prevent relapse [20]. However,
the evidence for the effectiveness of SSRIs is derived from
studies where they have been prescribed based on depres-
sive symptoms and severity [20, 21]. Little is known
regarding their effectiveness when prescribed on the basis
of non-depressive hazardous risk behaviour and it is pos-
sible that they may be less effective in this population.
Why do the clinical characteristics for prescribing appear
to differ between boys and girls? One possibility is that as
depression is more common in girls, perhaps, clinicians are
wary about prescribing for these symptoms alone and see
self-harming behaviour (more common in girls [22, 23]) as

a marker of high risk warranting SSRIs. It is possible that
Table 4 Logistic regression
analysis, demonstrating
the relationship between
quality of life, self-harm,
antisocial behaviour and
centre as predictors for SSRI
prescribing at baseline
a Compared with East Anglia
Odds ratio S.E. z p 95 % C.I.
Girls
EQ5D—quality of life 0.50 0.63 −1.10 0.27 −1.92–0.54
HONOSCA—total mental health problems 1.05 0.03 1.57 0.12
−0.01–0.11
RTSHIA—self-harm 1.03 0.02 2.00 0.045 0.001–0.065
Behavioural checklist—antisocial behaviour 0.89 0.06 −1.78
0.076 −0.24–0.01
MFQ—depression severity 0.99 0.02 −0.71 0.48 −0.052–0.024
Age 1.17 0.13 1.19 0.23 −0.10–0.41
Research Centre: Londona 0.44 0.46 −1.77 0.076 −1.70–0.09
Research Centre: North Westa 0.61 0.37 −1.35 0.18 −1.23–0.23
Ethnicity 1.25 0.45 0.50 0.61 −0.65–1.10
Boys
EQ5D—quality of life 0.64 1.10 −0.41 0.68 −2.60–1.71
HONOSCA—total mental health problems 1.00 0.05 0.10 0.92
−0.09–0.10
RTSHIA—self-harm 0.95 0.03 −1.39 0.17 −0.12–0.02
Behavioural checklist—antisocial behaviour 0.86 0.09 −1.67

0.095 −0.34–0.03
MFQ—depression severity 1.07 0.03 2.04 0.042 0.002–0.13
Age 1.32 0.18 1.53 0.13 −0.08–0.63
Research Centre: Londona 0.12 0.86 −2.52 0.012 −3.84 to
−0.48
Research Centre: North Westa 0.15 0.66 −2.91 0.004 −3.22 to
−0.63
Ethnicity 0.78 0.75 −0.34 0.74 −1.72–1.08
1 3
as fewer boys present with depression, clinicians feel they
require a lower threshold of risk to prescribe.
Limitations
The main limitation of this study is that we have no clini-
cal measurements available regarding illness severity and
quality of life when assessed by the clinicians who pre-
scribed prior to ranodmisation. Therefore, it is theoretically
possible that SSRI cases were more severely depressed
when first assessed as suffering from MD than their non-
SSRI counterparts, when seen before entering the trial. It
should be noted that a case-note audit of 80 participating
individuals from one of the clinics involved in the study
showed that 75 % of the cases had been prescribed medi-
cation for less than 3 months prior to randomisation, and
more than half of these had received medication for less
than 1 month. Although it is possible that there may be
some signs of improvement this early on in treatment [24],
we believe that this would be unlikely to change the out-

come of the study. Indeed, we argue that if this were the
case, assessment at the time of prescribing would lead to
greater effects in terms of the differences seen. It should
be noted that the measurements of risk behaviour and self-
harm are based over the lifetime and are, therefore, unlikely
to be susceptible to change within this time frame.
We do, however, accept that our study should be consid-
ered as correlative rather than indicative.
We believe that the data presented reflects the poten-
tial rationale for prescribing SSRIs prior to psychological
therapy. When asked prior to randomisation if they had
received any previous psychological therapy or counsel-
ling, only nine individuals (2 %) reported that they had and
only three of these were prescribed SSRIs. However, fur-
ther questioning by trial therapists suggests that although
participants do not appear to have received any evidence-
based psychological therapy, a number have had access to
certain types of talking therapy including counselling ser-
vices. This raises the possibility for poor reliability with
regard to the recall of previous therapy.
We recognise that some aspects of our findings may be
UK specific and our findings would benefit from replica-
tion within other international healthcare systems. How-
ever, our study uses internationally recognised methods for
recruiting adolescents with MDD and therefore, we believe
our sample to be comparable with patient groups through-
out Europe and worldwide.
It is also possible that there are characteristics of the
individuals or their environmental context including family
history of mental illness that may account for these find-
ings. Finally, this is a relatively small sample of adolescent

patients and is particularly biased towards females, mean-
ing that our findings regarding the prescribing rationale for
boys may be associated with a type one or type two error.
The participants were also recruited and consented to take
part in a randomised controlled trial and therefore, may not
be entirely representative of the general population of ado-
lescents with depression. As this may affect the generaliz-
ability of our study, these findings require replication in an
independent study.
Currently, we conclude that pragmatic SSRI prescribing
in the NHS may be based on depressive severity for boys
but overt hazardous behaviour for girls. This suggests that
there may be greater adherence to NICE guidelines by cli-
nicians treating boys as opposed to girls but this remains to
be established. In addition, it appears that prescribing dif-
fers in distinct areas of the country. The NICE guidelines
have recently been reviewed, however, we believe that
before they can be seriously implemented, it is necessary
to understand how adolescent MD is currently managed in
everyday clinical practice.
Clinical implications
• The NICE guidance for the treatment of adolescent MD
has recently been reviewed, however, to aid our under-
standing of the optimal management of this debilitating
condition, we need to be aware of the reasons clinicians
depart from these guidelines. Trial evidence and clini-
cal guidelines should be considered together along with
a better understanding of what takes place currently in
clinical practice.
• Positive reasons should be recorded in the notes for pre-
scribing SSRIs along with any previous failure of an
adequately given psychological treatment. These might

explain why clinicians in the UK seem not to be adher-
ing to NICE guidelines.
• Self-harming behaviour should not on its own prompt
SSRI prescribing. Instead, prescribing is warranted
when suicidality and risk behaviour is combined with
moderate to severe depressive symptoms.
• Different reasons may be used for prescribing SSRIs for
girls and boys, despite there being no evidence that this
is correct practice.
Acknowledgments RCT Study supported by a grant to IMG
(Chief
Investigator) from the NIHR-HTA (trial number
ISRCTN83033550,
Grant Number 06/05/01).
Compliance with ethical standards
Conflict of interest The authors declare they have no conflict of
interests.
1 3
Open Access This article is distributed under the terms of the
Creative Commons Attribution 4.0 International License
(http://crea-
tivecommons.org/licenses/by/4.0/), which permits unrestricted
use,
distribution, and reproduction in any medium, provided you
give

appropriate credit to the original author(s) and the source,
provide a
link to the Creative Commons license, and indicate if changes
were
made.
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http://dx.doi.org/10.1098/rstb.2012.0407Clinical characteristics
associated with the prescribing of SSRI medication
in adolescents with major unipolar depressionAbstract
IntroductionMethodsImproving mood with psychoanalytic
and cognitive therapies (IMPACT) participantsAssessment
instrumentsSSRI prescribingInterview measuresSchedule
for affective disorders and schizophrenia for school aged
children, present and lifetime version (K-SADS-PL) [9]Self-
report measuresMoods and feelings questionnaire (MFQ)
[10]Health of the nation outcome scales for children
and adolescents (HONOSCA) [12]Euroqol 5 dimension (EQ-5D)
questionnaire [14]Modified risk taking and self-harming
inventory for adolescents (RTSHIA) [16]Behavioural checklist
[17]Statistical analysisResultsDemographicsIllness
severityQuality of lifefunctional impairmentHazardous
behaviourAntisocial behaviourPrescribing differences
across research centresGender differences in SSRI prescribing
predictorsDiscussionLimitationsClinical
implicationsAcknowledgments References
Psychology in the Schools, Vol. 46(9), 2009 C© 2009 Wiley

Periodicals, Inc.
Published online in Wiley InterScience
(www.interscience.wiley.com) DOI: 10.1002/pits.20426
USE AND IMPACT OF ANTIDEPRESSANTS IN THE
SCHOOL SETTING
CHAD A. NOGGLE
Southern Illinois University, School of Medicine
RAYMOND S. DEAN
Ball State University
Depression-based presentations constitute some of the most
commonly seen psychiatric manifes-
tations within the school-age population. In conjunction with
increased numbers of children and
adolescents being diagnosed with depressive symptomology
over the past 2 – 3 decades, there has
been seen a concurrent increase in the amount of antidepressant
agents being prescribed within
this group. This increase is largely related to the development
of the newer class antidepressants,
the selective serotonin reuptake inhibitors and serotonin-
norepinephrine reuptake inhibitors, which
have demonstrated preferred efficacy and adverse effect profiles
over the older monoamine oxi-
dase inhibitors and tricyclics. This article discusses the primary
differences between the various
forms of antidepressants, including their utility and efficacy.
Positive and negative impacts are also
reviewed, including potential impact on schooling. C© 2009
Wiley Periodicals, Inc.

It has been reported that major depressive disorder (MDD) and
variants of depressive syndromes
effect up to 10% – 15% of children and are associated with
substantial short- and long-term morbidity
and mortality (Fleming, Offord, & Boyle, 1989; Pataki &
Carlson, 1995). Functional impairments
oftentimes correspond with deficits in school and work
performance (Rao, Ryan, & Birmaher, 1995;
Rohde, Lewinsohn, & Seeley, 1994) related to aspects of
cognitive dysfunction (Noggle, Neal, Hall,
Hiller, & Dean, 2006; Ravnkilde et al., 2002) as well as lack of
motivation and vigilance (Easau,
Petermann, & Reynolds, 1999) among other factors. Although
children and adolescents demonstrate
some overlap in functional outcomes associated with depression
in adults, behavioral differences
tend to exist (Poznanski & Mokros, 1994), which has in the past
distorted the clinical picture. In
the past 35 years, information has been gathered regarding the
presentation, course, epidemiology,
and family factors of depression in childhood and adolescence
that has begun to clarify the clinical
picture. As this information has been synthesized, in addition to
refining knowledge about the
presentation of depression in children and adolescents, there has
been a concurrent advancement of
intervention and treatment strategies for depression within this
age group. Although behavioral and
psychotherapeutic techniques have demonstrated substantial
utility in this population, the efficacy
of pharmacological intervention continues to be debated. In
fact, antidepressants are frequently
prescribed in children and adolescents (Safer, 1997), and the
use of these agents within this age
group, especially the selective serotonin reuptake inhibitors
(SSRIs; Ma, Lee, & Stafford, 2005;

Murray, de Vries, & Wong, 2004), has increased significantly
over the past decade (Zito, Safer,
Dosreis, 2000, 2002). Given this prevalence, professionals
working with children and adolescents in
the schools would likely benefit from a general understanding
of these agents. As such, this article
provides an overview of the different forms of antidepressants,
differences and similarities between
them, including clinical indications for them, their impact on
children and adolescents, both positive
and negative, and how they correspond with outcomes in the
school.
PREVALENCE OF DEPRESSION IN CHILDREN AND
ADOLESCENTS
Epidemiological research has estimated the point prevalence of
depression in children and
adolescents (4 – 17 years of age) to be between 0.92% and 4.6%
(Angold, Erkanli, Farmer, Fairbank,
Correspondence to: Chad A. Noggle, Southern Illinois
University, School of Medicine, Department of Psychiatry,
901 W. Jefferson Street, P.O. Box 19642, Springfield, IL 62794.
E-mail: [email protected]
857
858 Noggle and Dean
Burns, et al., 2002; Canino, Shrout, Rubio-Stipec, Bird-Hector,
Bravo, et al., 2004; Ford, Goddman,
& Meltzer, 2003). However, research has also demonstrated a
trend in which point prevalence rates
climb the older the pediatric population. For example, in

adolescents older than 13 years, point
prevalence is between 4% and 8% (Birmaher, Ryan, &
Williamson, 1996). Overall, the lifetime
prevalence rates of depression in adolescents range from 15% to
20% (Birmaher et al., 1996).
However, in past years it has been suggested, and it likely holds
true today, that numbers rendered
through epidemiological investigation, in the case of depression
in children and adolescents, are
likely an underestimation (Lewisohn et al., 1994) as one may
assume the percentage of children
and adolescents experiencing soft depressive symptoms or “mild
depression” are even higher.
Furthermore, increases in rates as well as earlier symptom onset
in children and adolescents have also
been outlined by research (e.g., Murphy, Laird, Monson, Sobol,
& Leighton, 2000), thus numbers are
always changing. Regardless, what is clear is that there is a fair
amount of children and adolescents
who present with depressive manifestations in the schools, and
thus continued refinement of our
understanding and treatment of these presentations is warranted,
especially given the relatively broad,
negativistic impact that depression may have on day-to-day
functioning in children and adolescents.
FUNCTIONAL IMPACT AND PRESENTATION OF
DEPRESSION IN PEDIATRIC POPULATIONS
It has long been noted that although children and adolescents do
exhibit symptoms of depres-
sion, the signs and symptoms present differently in this
population than in adults (Cytryn & McKnew,
1974; Malmquist, 1977). For example, whereas adults may
exhibit the traditional depressed mood
and tearfulness, children may instead become more irritable,

angry, or aggressive. Compared to
adults, depressed adolescents are more likely to report feelings
of worthlessness and/or guilt and
less likely to report weight/appetite changes and thoughts of
death or suicide (Lewinsohn, Rohde,
& Seeley, 1998). Depressed children, in contrast, are less likely
to display extensive motor retarda-
tion, hypersomnia, cognitive disorientation, and chronically
disrupted appetite than are depressed
adolescents, adults, and elderly patients (Lewinsohn et al.,
1998). This has even been cited in the
text revision of the Diagnostic and Statistical Manual of Mental
Disorders, Fourth Edition – Text
Revision (American Psychiatric Association [APA], 2000), in
which it is stated that “In children
and adolescents, an irritable or cranky mood may develop rather
than a sad or rejected mood.” In
prepubertal children, depression is less common, equally
distributed among boys and girls, and less
likely to evolve into adult depression (Harrington, 2002)
whereas somatic complaints, psychomo-
tor agitation, hallucinations, and comorbidities are more
common (Ryan, Puig-Antich, Ambrosini,
1987). Adolescents are more likely to experience hopelessness
and vegetative symptoms, and have
a higher incidence of substance use and suicidal behavior than
do prepubertal children (Ryan et al.,
1987).
In addition to the mood symptoms, most commonly thought of
when discussing depression,
decreased energy, tiredness, fatigue, diminished ability to think
and concentrate, decreased vigilance
and interest in activities, and social withdrawal may all
manifest secondary to depression (APA,
2000). The ramifications of these symptoms are broad in terms

of functional compromise. For
the child or adolescent, mood disturbance may be just the tip of
the iceberg as he or she is at
substantial risk for cognitive disturbance and diminished school
performance as well as disruptions of
relationships with peers, family, and school personnel, which,
in turn, increases risk of victimization,
truancy, and delinquency (Kovacs, Feinberg, Crouse-Novak,
1984a,b; Rao et al., 1995). Oftentimes
we may fail to appreciate the true scope of impairment that may
manifest secondary to presentations
in children and adolescents, and depression is no different. In
response, there is substantial utility in
continually educating psychological professionals who work
with this age group about advances
in research that have developed our understanding of the
presentations with which they work, but
also, and possibly even more importantly, provide updated
reviews of the advances in addressing
Psychology in the Schools DOI: 10.1002/pits
Antidepressant Medications 859
those issues in clinical practice. With regard to depression, one
area in which empirical knowledge
is constantly growing, which, in turn, corresponds with an ever-
changing landscape of treatment,
is in the utilization and efficacy of pharmacological
intervention and practices. The fact that the
vast majority of psychological professionals do not have
prescription privileges does not suggest an
acceptability of a lack of understanding of the practice, the
agents commonly used, and the functional

outcomes. In fact, psychological professionals within the school
may be in a position to have some of
the most dramatic impacts on pharmacological practice by
serving as primary consultants monitoring
the clinical efficacy in the children and adolescents being
treated. For further discussion along this
line, see the last article of this special issue entitled “Future
Trends in the Application and Impact of
Psychopharmacology within the School Setting.”
USE OF ANTIDEPRESSANTS BY CHILDREN AND
ADOLESCENTS
Based on reported prescription rates by child psychiatrists, as
well as other medical professionals
who see children and adolescents, it is clear that antidepressant
medications have become central
to management of depression within this age group (Wong,
Besag, Santosh, & Murray, 2004).
However, literature still suggests that the decision to use this
method of treatment comes only after
a period of careful observation and after nonpharmacological
therapy options have been exhausted
(Garland, 2004). Regardless, there has never been a time when
antidepressants have been more
frequently prescribed in children and adolescents than is
presently the case (Zito, Safer, dosReis,
2000, 2002). While this reflects the prevalence of
antidepressant use overall, this involves the
summation of different classes of agents. The term
“antidepressant” reflects a general description of
the agents that fall under this umbrella. Medications termed
antidepressants are generally classified
into one of four groups: monoamine oxidase inhibitors
(MAOIs), tricyclic antidepressants (TCAs),
SSRIs, and selective norepinephrine reuptake inhibitors

(SNRIs). Although each of these classes
includes individual agents that are termed antidepressants due
to their resulting impact, they differ
substantially in their chemical makeup, which corresponds with
discrepancies in clinical indications,
efficacy, and adverse effects. Together this speaks to their
general utility and appropriateness for
use in children and adolescents. In the following section we
discuss key features of each class of
antidepressant individually.
CLASSES OF ANTIDEPRESSANTS AND THEIR IMPACT
MAOIs
Although the MAOIs fall under the umbrella of antidepressant
agents, they are used consider-
ably less than other classes due to their prominent adverse
effect profiles, especially in children and
adolescents. Although significant discrepancies between the rate
at which MAOIs are prescribed in
comparison to other groups (i.e., TCAs, SSRIs, SNRIs) are quite
prominent, this is not necessarily
due to significant differences in efficacy, but rather related to
significant adverse effects commonly
associated with MAOIs (Riederer, Lachenmayer, & Laux, 2004).
In fact, whereas early studies sug-
gested that MAOIs were less effective than other
antidepressants, more recent studies have demon-
strated that, when prescribed in adequate dosages, some of the
MAOIs (e.g., phenelzine [Nardil]
and tranylcypromine [Parnate]) demonstrate efficacies
comparable to select TCAs and SSRIs. How-
ever, again, the side effects can be severe. The most frequent
adverse effects of irreversible MAOIs
are orthostatic hypotension, sleep disturbances, and

nervousness/agitation (Riederer et al., 2004).
Furthermore, the chemical makeup of MAOIs creates for
dangerous interactions with tyramine-rich
foods and sympathomimetic and serotonergic substances
(Ballenger, Wheadon, Steiner, Bushnell,
& Gergel, 1998). To avoid such interactions, patients must
remain strongly compliant with dietary
restrictions, which can be variable, and thus dangerous in
children and adolescents.
860 Noggle and Dean
Given the aforementioned risk for adverse effects and concerns
of negative interactions, utiliza-
tion of MAOIs, as suggested, is limited. The main indications
for the classical irreversible MAOIs
are subgroups of depression such as atypical depression and/or
dysthymia or for patients who do
not respond to reuptake inhibitors. For example, high doses of
tranylcypromine, an MAOI, has
been shown to be effective in the treatment of therapy-resistant
depressions (Riederer et al, 2004).
However, these studies have been of adults only, and have been
strictly on an inpatient basis so to
assure dietary compliance and monitor possible adverse
reactions.
Although nonselective, irreversible MAOIs, including those
noted earlier in text, carry signif-
icant adverse effects that correspond with the prominent
infrequency of their use, moclobemide
(Aurorix), a newer MAOI, has little effect on the cardiovascular

system and does not demonstrate
as great a risk for interaction due to tyramine sensitivity
(Riederer et al., 2004). In addition to a
more favorable adverse effect profile, some research has shown
moclobemide to be equivalent to
TCAs in efficacy and tolerated just as well, if not better.
Furthermore, long-term follow-up studies
demonstrated continued effectiveness of moclobemide over the
treatment period of 1 year, with
more than 60% of patients having continued response (Riederer
et al., 2004). Of concern is research
suggesting that adequate efficacy of moclobemide is dependent
upon higher dosages, especially in
cases of moderate to severe cases of depression, which may
negate some of its previously noted
superiority in tolerability over other MAOIs.
Although additional research on newer variants of the MAOIs
(e.g., moclobemide) may demon-
strate advanced efficacy in their treatment of depression, in
comparison to other antidepressants there
remain substantial concerns about the degree of adverse effects
associated with their use. This latter
point has and will likely continue to prominently limit the
amount of MAOIs used in children and
adolescents.
TCAs
TCAs represent a second class of antidepressants that, in
comparison, are used far more of-
ten than MAOIs, especially within the pediatric population.
Although TCAs are widely used in
the clinical management of depressed children and adolescents,
published studies have failed to
produce a repeatable pattern of efficacy (Emslie & Judge,

2000). In fact, Geller, Cooper, Mc-
Combs, Graham, and Wells (1989) found that, when compared
to placebo, nortriptyline, a TCA,
did not demonstrate significant improvement in depressive
symptomatology in a sample of patients
5-12 years old. In a follow-up study, they found similar results
in a sample of patients 12 – 17 years
old (Geller, Cooper, Graham, Marsteller, & Bryant, 1990).
Although these studies focused on the
efficacy of nortriptyline (Aventyl), additional investigations
have called into question the efficacy of
imipramine (Tofranil; Puig-Antich, Perel, & Lupatkin, 1987;
Ryan, Puig-Antich, Cooper, 1986) and
desipramine (Norpramin; Kutcher, Boulos, & Ward, 1994) in
the pediatric population. These studies,
in addition to others like them, have contributed to meta-
analyses that have concluded that TCAs
appear no more effective than placebo in the treatment of
depression in children and adolescents
(Hazell, O’Connell, Heathcote, Robertson, & Henry, 1995). In
addition to questionable efficacy,
empirical research has documented the prominent adverse
effects of TCAs when used in children
and adolescents. These negative effects include dry mouth,
constipation, urinary retention, blurred
vision, sinus tachycardia, sedation, impaired motor functioning,
weight gain, hypotension, imbal-
ance, impaired coordination, orthostatic hypotension, and
cognitive dysfunction (Kasper, Hoflich,
Scholl, & Moller, 1994; Kuzel, DeWester, & Richardson, 1996;
Nemeroff, 1994). In compari-
son, the SSRIs have a milder side-effect profile and are better
tolerated than the TCAs (Edwards,
1992; Edwards, Inman, Wilton, & Pearce, 1994; Grimsley &
Jann, 1992; Murdoch & McTavish,
1992).

Although failure to demonstrate adequate effectiveness beyond
that seen in placebo may in and
of itself question the utility of TCAs in the treatment of
depression in children and adolescents, when
compared to that for SSRIs, the outlook for TCAs diminishes
further. In head-to-head comparisons,
SSRIs have largely demonstrated superior efficacy in the
remediation of depressive symptomatology
in children and adolescents in comparison to TCAs (e.g., Colle,
Belair, DiFeo, Weiss, & La Roche,
1994; Emslie, Rush, & Weinberg, 1997) while also
demonstrating lower rates of discontinuation
compared to the TCAs (Beasley, Bosomworth, & Wernicke,
1990). Furthermore, SSRIs present with
a more preferential adverse event profile compared to TCAs
(Jain, Birmaher, Garcia, Al-Shabbout,
& Ryan, 1992). The specifics of SSRIs, including their utility
and possible adverse reactions, are
discussed later in this chapter. Although the potential for
aforementioned adverse effects is troubling,
risk for cardiovascular events and cognitive dysfunction are
particularly concerning. To date, the
TCAs have been associated with a number of sudden cardiac
deaths in children and adolescents
(Nemeroff, 1994). In terms of cognitive performance, the TCAs
have been more prominently linked
to cognitive skill impairments as well as degradation of
psychomotor ability than have the SSRIs
(Peretti, Judge, & Hindmarch, 2000). Much of this impact has

been related to the effects of TCAs
on cholinergic, histaminergic, and adrenergic receptors. A
number of studies have demonstrated
the negative impact TCAs have had on cognition in comparison
to placebos and/or SSRIs (e.g.,
Fairweather et al., 1996; Hindmarch, 1997). When seen in
children and adolescents, the secondary
detriment this may create in school performance may be
substantial. As a result, any student taking
a TCA, likely because there has been poor response to SSRIs,
should be monitored closely to detect
any possible degradation along these lines as soon as they begin
to present.
SSRIs and SNRIs
By far, the SSRIs and SNRIs are the most commonly used
antidepressants in children and
adolescents. The basis for this is twofold. First, SSRIs and
SNRIs have demonstrated a general
efficacy in the management of depression in children and
adolescents, in comparison to placebo
(Emslie, Walkup, Pliszka, & Ernst, 1999). This positive finding
is seen in conjunction with findings
that have demonstrated a lack of benefit of TCAs and MAOIs
within this same population (Hazell,
O’Connell, & Heathcote, 2002). Second, in comparison to both
the TCAs and the MAOIs, the SSRIs
and SNRIs have presented with a far better safety record (van
Laar, van Willigenburg, & Volkerts,
2002). Although evidence appears largely in support of the use
of SSRIs and SNRIs in the treatment
of depression in children and adolescents (Emslie et al., 1999),
there are findings in opposition to
this suggestion.

When discussing the efficacy of the SSRIs one may offer a
generalized coverage as there has
been some report that there is little evidence to suggest
differentiation among these agents (SSRIs)
in the overall efficacy of treating depression (e.g., Hansen,
Gartlehner, Lohr, Gaynes, & Carey,
2005; Kroenke et al., 2001; Papakostas, Thase, Fava, Nelson, &
Shelton, 2007). Furthermore, when
comparing SSRIs and SNRIs, although a few individual studies
have reported differences between
these agents, no study has shown convincing improvements of
efficacy or a preferential adverse
effect profile of one over the other (Olver, Burrows, & Norman,
2001). Nevertheless, there are
some who would disagree with this suggestion (e.g.,
Mallinckrodt et al., 2007; Papakostas, Petersen,
Sklarsky, et al., 2007). For example, there are some studies that
have suggested increased efficacy
of the SNRIs, due to their dualistic impact on serotonin as well
as norepinephrine, as opposed to the
SSRIs, which inhibit only one monoamine (Stahl, Entsuah, &
Rudolph, 2002; Thase, Entsuah, &
Rudolph, 2001). However, other findings have failed to support
this difference (APA, 2000; Hansen et
al, 2005). In terms of supporting this claim, investigations into
the treatment of mild depression have
appeared to demonstrate slightly greater efficacy of duloxetine
(Cymbalta), an SNRI, in comparison
862 Noggle and Dean
to SSRIs (Mallinckrodt et al., 2007). This finding does not

suggest that the SSRIs were not beneficial,
rather, that in this grouping, duloxetine may be slightly better.
As depression was more moderate
to severe, this discrepancy dissipated to some extent. Across
groupings, there was found a general
efficacy of the SSRIs in comparison to placebo. A second part
of this study (Mallinckrodt et al.,
2007), demonstrated that duloxetine may not be as effective as
the SSRIs when there is prominent
comorbid anxiety, which can be a common manifestation in
depression. The overall findings of this
study suggest that differences between SSRIs and duloxetine, a
prominent SNRI, exist, although
minimally, and likely correspond to differences between agents
in their responsiveness to symptom
type and severity and that these differences do not play out in
such a way as to demonstrate
favorability of one agent over the others (Mallinckrodt et al.,
2007). This point has been reiterated by
others as well. Specifically, Fava and Rush (2006) report that
mindfulness of subtle differences of the
responsiveness of certain depressive subtypes to different
agents is essential in increasing chances
for symptom relief and possible remission. Nevertheless, the
overall clinical picture suggests utility
of SSRIs and SNRIs in the treatment of depression in children
and adolescents, although differences
exist between these classes, not consistently favoring one over
the other.
Although the efficacy of the SSRIs and SNRIs appears
relatively positive, and, in comparison
to MAOIs and TCAs, these groups demonstrate a preferred
adverse risk profile (van Laar et al.,
2002), they are not without possible negative effects. Truly,
they are associated with fewer adverse

effects than are other classes (Nutt, 2003; Peretti et al., 2000),
and are relatively free from cognitive
and psychomotor impairment (Peretti et al., 2000). Most studies
also suggest that SSRIs produce
fewer cardiotoxic, anticholinergic, and antihistaminergic side
effects than do TCAs (Pacher &
Ungvari, 2001). However, other studies have called some of
these claims into question. SSRIs
and SNRIs have been linked to increased fatigue (Papakostas,
Thase, et al., 2007), and some
have suggested a link between their use and cognitive
impairment. However, the suggestion of
“cognitive” impairment suggests too broad of an impact. In
reality, positive findings along this
front have merely suggested memory problems associated with
SSRIs and SRNIs (Joss, Burton,
& Keller, 2003). In terms of this link with specific SSRIs and/or
SNRIs, fluoxetine (Prozac; Joss
et al., 2003) and paroxetine (Paxil; Furlan et al., 2001)
represent those previously associated with
memory impairments, yet they have also been linked with
memory improvement (Schmitt, Jorissen,
& Sobczak, 2001). Without question, studies have shown that
depression itself can impair cognitive
functioning (Alvarez-Rueda, Guiterrez-Aguilar, Rosales,
Martinez, & Lablache, 2001), including
memory (Landro, Stiles, & Sletvold, 1997). In fact, within the
geriatric population, cognitive deficits
associated with depression may manifest in such a way that,
clinically, they appear similar to
those impairments associated with neurodegenerative courses
(Noggle, 2006). Such manifestations
tend to reflect impaired retrieval skills as well as slowed
cognitive processing, impaired attention,
and higher-order/abstract reasoning (Noggle, 2006). It has also
been proposed that, as depressive

symptoms are relieved, concurrent improvements in cognition
may be seen as well (Harmer, Shelley,
Cowen, & Goodwin, 2004; Zobel, Schulse-Rauschenbach, & von
Widdern, 2004). This has led to the
cognitive impairment associated with depression being viewed
as one form of reversible dementia.
In fact, some researchers have suggested that the link between
SSRIs and/or SNRIs and cognitive
disturbances are more an artifact of (as yet) ineffectively
treated anxiety or depression (Hemmeter,
Heimberg, Naber, Hobi, & Holsboer-Trachsler, 2000). Kent,
Coplan, and Gorman (1988) reiterated
this suggestion by noting that changes in cognitive processing
associated with SSRIs may occur
earlier in treatment than the therapeutic effect can occur,
suggesting that changes in psychological
function precede the improvement in psychopathology (Harmer
et al., 2004). This suggestion is
similar to that of Wadsworth, Moss, Simpson, and Smith (2005)
in which they state that recall may
be impaired among those taking SSRIs whose symptoms have
not (yet) resolved, leading to fewer
words correctly recalled, and more false alarms made. However,
among those taking SSRIs whose
symptoms are controlled, fewer words may be recalled
correctly, but fewer false alarms are also
made. In other words, there is improvement following SSRIs
and/or SNRIs, but it may not be of such
a degree to alleviate all noted impairment. Further investigation

along these lines is likely warranted,
but at the present time, although there may be some studies that
oppose this suggestion, far more
studies appear to suggest no detrimental effect on cognition by
SSRIs or SNRIs than those that do.
This includes, but is not limited to, the SSRIs/SNRIs having no
detrimental effect on psychomotor
speed, momentary inefficiency, speed of focus of attention,
speed of encoding of new information,
organization of response, mood, or perceived work performance
(Peretti et al., 2000). In terms of
this subject matter in children and adolescents, the best advice
is to remain vigilant in follow-up
with them during pharmacological intervention, so as to identify
any negative impact as soon as it
begins to appear.
While raised concerns of the impact that SSRIs and SNRIs may
have on cognitive functioning
may be unsupported to a certain degree, adverse behavioral
effects may represent the negative
outcomes of greatest concern. Agitation, irritability and
behavioral disinhibition, emotional lability,
increased conduct problems, and hostility as well as
aggressiveness have all been linked to the use
of SSRIs and/or SNRIs (Garland, 2004). However, some
researchers have questioned whether this is
a manifestation of the medications or merely secondary to
unresolved symptomology. Of additional
concern are suggestions of increased suicidal ideation and
gesturing in the use of SSRIs and/or
SNRIs. Following a review of research along these lines, the
Medicine and Healthcare products
Regulatory Agency of the British Department of Health
(MHRA) has warned against the use of
paroxetine as well as venlafaxine (Effexor)or any SSRI or SNRI

other than fluoxetine in pediatric
MDD patients, due to data suggesting some possible increase in
suicidal behavior and thoughts.
However, in a more thorough evaluation done on the various
SSRIs and SNRIs, it was revealed that
venlafaxine was the only individual drug with a statistically
significant increased risk of suicidality
(Hammad, Laughren, & Racoosin, 2006). In fact, when used in
the depressive states of bipolar
disorder, venlafaxine has been linked to the induction of mixed
states. In this situation, there may be
a substantial increase in energy and grandiosity while mood
remains depressed, and there possibly
remains a degree of hopelessness as well. Within such a
psychological/behavioral constellation as
this, an individual may not only have the will to commit
suicide, but then also have the energy and
disinhibition/impulsivity that will carry it through. Although
this may represent one link between
the use of specific SSRIs and/or SNRIs, there is also a link
between suicidal ideation and a lack
of pharmacological intervention (Cheung, Emslie, & Mayes,
2006). For further review of issues
surrounding suicidal ideation and pharmacological intervention,
see the article by Pierson (in this
issue) (2009). What appears to be the most effective is
concurrent utilization of pharmacological and
psychotherapeutic techniques. In fact, the American Academy
of Child and Adolescent Psychiatry
(AACAP) recommends psychosocial and pharmacologic
intervention for depression. However, it
also recommends psychotherapy as the preferred initial
treatment for most adolescent patients, with
the induction of pharmacological efforts only coming after there
is seen a lack of responsiveness to
therapeutic endeavors (Kane, Fagan, & Wolf, 2007). It is within

this situation (i.e., lack of response
to nonpharmacological interventions) that physicians could
choose an SSRI that has been approved
for use in children and adolescents, such as fluoxetine (Garland,
2004) and then, upon doing so,
continue to offer psychotherapeutic interventions. Research
along this line has supported this clinical
suggestion. In an investigation of the effectiveness of flouxetine
and cognitive behavioral therapy
(CBT) together as well as in comparison to each other
singularly, the combination of pharmacological
and psychotherapeutic treatment was found to be statistically
superior to unipolar techniques (Kane
et al., 2007), although fluoxetine alone outperformed CBT
alone.
The only other drawback of SSRIs is their failure to
demonstrate desired levels of effectiveness
in more severe forms of depression. Findings from meta-
analyses have suggested that SSRIs are
864 Noggle and Dean
significantly less effective than TCAs in more severe depression
(Anderson, 1998). Parker, Roy,
Wilhelm, and Mitchell (2001) further support this finding in
suggesting that, in the treatment of
severe depression of the melancholic subtype, electroconvulsive
therapy (ECT), TCAs, and MAOIs
are the most effective treatments and that SSRIs are less
effective (Gillman, 2007). Of note, this
was determined in an adult sample; thus, MAOIs and definitely

ECT are substantially less viable
options. It has also been suggested that venlafaxine may be
more effective than SSRIs in such cases
as well (Smith, Dempster, Glanville, Freemantle, & Anderson,
2002); however, as previously noted,
venlafaxine has also been associated with increased risk of
suicidal ideation. Given the fact that
suicidal thoughts and gestures are most commonly seen in
severe depressive forms, questions may
be raised about whether this proposed use may be
contraindicated. Further empirical investigation is
likely warranted along these lines. For example, expansions of
research incorporating other agents
such as sertraline (Zoloft), escitalopram (Lexapro), and
citalopram (Celexa), to name a few, continue
to be needed as these too have shown some efficacy in early
trials, yet the number of studies remains
too few in comparison to those previously noted.
IMPACT ON SCHOOLING
Antidepressants’ impact on schooling may be grouped into two
categories, either positive or
negative. Determination of these reactions is related to outcome
assessment, which psychological
professionals within the school or those who work with this age
population are likely most capable
of performing. Specifically, following administration of an
antidepressant agent, an essential role of
psychological professionals is to assess responsiveness and
outcome. This outcome may be positive,
negative, or a mixture of the two. With regard to positive
outcome, this involves assessment of the
emotional and behavioral changes that appear to manifest
secondary to the usage of the medication.
Although we use the term “positive,” not all medicinal

responses will necessarily be of such a nature.
Notation of behavioral/emotional depletion may be seen as well.
Of particular concern is an increase
in suicidal ideation. As previously noted, venlafaxine (Effexor)
was the only individual drug with a
statistically significant increased risk of suicidality in a larger
scale investigation of the links between
antidepressants, particularly SSRIs and SNRIs, and suicidal
thoughts and gestures (Hammad et al.,
2006). This finding does not suggest that such manifestations
are not possible when using other
medications, merely additional agents assessed were not related
to significantly increased suicidal
risk. Continued evaluation of suicidal ideation is recommended
in all cases of depression, with
particularly close attention paid to changes in presentation
along these lines in the acute stages of
medicinal use.
In addition to assessing the responsiveness of behavioral and
emotional symptoms to antide-
pressants, attention may be paid to the evaluation of the
remediation of secondary symptoms as well.
This may include, but is not necessarily limited to, improved
attention and concentration, increased
energy (make note of induced mania if seen), decreased
irritability and agitation, increased social
interaction, improved sleeping and eating habits, and improved
academic achievement. Although
improvements may be seen across these aforementioned
domains, it may not be of such a level
that it is deemed adequate. Clinical determination of these
shortcomings may assist in medicinal
management while also indicating areas in which
psychotherapeutic or behavioral services may be
focused. As previously discussed, in comparison, combined

treatment that incorporates pharmaco-
logical treatment and psychotherapeutic services has been found
to be superior to the singular forms
(Kane et al., 2007), leading the AACAP to support such an
approach.
In terms of negative outcome, this involves
recording/documenting the adverse reactions to
pharmacological interventions. Determination of utility can vary
from person to person and is
usually seen as a numbers game. Specifically, how much do the
positive outcomes outweigh the
negative? It may be the case that behaviorally there is clinical
improvement, but if it is viewed as
minimal to low-moderate (yet there are seen significant
disruptions of sleep, decreased appetite and
weight, increased anxiety, etc.), then the positive
responsiveness may be dwarfed by the negative
reactions. Just as positive outcomes may be used to determine
medicinal management, so too can
the negative reactions. Data may suggest a need to change the
medication altogether, alter dosage,
or supplement with other agents to remediate secondary
symptoms. The article by Roberts, Floress,
and Ellis (2009) within this issue delves further into the issue of
school impact.
SUMMARY

It is undeniable that MDD and variants of depressive syndromes
are seen in children and
adolescents. Furthermore, it is evident that the primary,
secondary, and tertiary manifestations of
these presentations correspond with substantial impairment as
well as increased morbidity and
mortality over both the short and long term (Pataki & Carlson,
1995; Rao et al., 1995; Rohde et al,
1994). As a means of fighting back against this psychiatric
opponent, utilization of antidepressant
medication has become a major player in the management of
depression in children and adolescents
(Wong et al., 2004). There are four primary classes of
antidepressants including MAOI, TCAs,
SSRIs, and SNRIs, and research investigating efficacy and
adverse effect profiles have led to the
most prominent support for use of the latter two groups (i.e.,
SSRIs and SNRIs) in pediatric
populations. Although superior to placebos in terms of efficacy,
the SSRIs and SNRIs are not
without flaws. They have shown diminished effectiveness in the
remediation of severe depression
and have been, at times, associated with adverse effects that can
include increased fatigue as well
as behavioral changes including irritability, aggression, and
externalizing behaviors. There have
been suggestions of these agents being linked to increases in
suicidal ideation, but this has been
more prominently linked to venlafaxine, an SNRI, and even in
this instance, situational factors
play prominent roles (i.e., depressive state in bipolar compared
to severe MDD). Still yet, lack of
pharmacological intervention has been related to far greater
suicidal ideation in severe depressive
cases, thus the argument may be somewhat moot. Finally,
although efficacy is seen in the use of

these agents, research demonstrates that a combined utilization
of pharmacology and psychotherapy
still remains superior. These findings are of clinical importance
as they demonstrate the need for
psychological professionals working with these children and
adolescents to remain vigilant in their
therapeutic and behavioral offerings. It is essential to continue
to maintain a supportive dialogue with
the child, parents, and teachers even after the start of
antidepressant treatment, to not only continue
to offer therapeutic services, to alleviate the many common
behavioral manifestations associated
with depression that may not be remedied medicinally, but also
to assist in tracking the effects of
the antidepressant agent, both positive and negative. Although
medical professionals have superior
training in the prescription of such agents, the work of
psychological professionals, especially in
the schools, provides them with the opportunity to be essential
consultative resources for medical
personnel in managing chosen pharmacological interventions. In
the treatment of depression in
children and adolescents, this is a role that psychological
professionals in the schools should strive
to perform.
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