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Decreased Growth During Therapy With Selective Serotonin Reuptake Inhibitors
Naomi Weintrob, MD;
Daniela Cohen, MD;
Yaffa Klipper-Aurbach, MSc;
Zvi Zadik, MD;
Zvi Dickerman, MD
Arch Pediatr Adolesc Med. 2002;156:696-701.
ABSTRACT
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Background There is no information on the effects of selective serotonin reuptake
inhibitors (SSRIs) on growth and puberty in children. We examined growth and
growth hormone secretion in 4 children treated with SSRIs for various psychiatric
disorders.
Design Case study.
Participants Four children (3 boys) aged 11.6 to 13.7 years with obsessive-compulsive
disorder or Tourette syndrome.
Main Outcome Measures Growth, pubertal progression, and hypothalamic pituitary function.
Methods The patients were treated with SSRIs for 6 months to 5 years (dosage,
20-100 mg/d). All were regularly examined for changes in height and bone age
and for pubertal progression. They also underwent evaluation of somatotrophic
axis and hypothalamic-pituitary axis function.
Results All 4 patients had growth attenuation. Three of them exhibited growth
retardation at a pubertal stage when a growth spurt was anticipated. Three
had a decreased growth hormone response to clonidine hydrochloride stimulation
and 2 to both clonidine and glucagon stimulation, and 1 had decreased 24-hour
secretion of growth hormone that normalized when therapy was stopped. The
rest of the endocrine evaluations were within reference ranges in all patients.
At follow-up, 2 patients were being treated with somatropin while continuing
SSRI therapy, and the other 2 resumed normal growth after discontinuation
of therapy.
Conclusions A decrease in growth rate, possibly secondary to suppression of growth
hormone secretion, may occur during SSRI therapy. As the use of this group
of drugs is expected to increase in the young age groups, larger studies are
warranted to investigate their effect on growth and growth hormone secretion.
INTRODUCTION
SELECTIVE SEROTONIN reuptake inhibitors (SSRIs) are a group of antidepressant
agents that have been proved effective in the treatment of various psychiatric
disorders. They were recently approved for use in children and adolescents
with obsessive-compulsive disorder, Tourette syndrome, and other psychiatric
disorders.1 The SSRIs have relatively few adverse
effects, the most common being gastrointestinal (abdominal discomfort) and
neuropsychiatric (sedation and activation).1-2
There are several anecdotal reports of increased prolactin levels, galactorrhea,
and amenorrhea.3-4 An increasing
number of studies in adults have reported decreased growth hormone (GH) response
to pharmacologic stimulation in healthy persons and in patients with psychiatric
disorders.5-9
Studies in children and adolescents have not reported on changes in growth
and puberty, either because they were short-term10-11
or because growth was not addressed, these generally being psychiatric and
not endocrinologic investigations.10-13
The main adverse effects of youth treated with SSRIs were insomnia, fatigue,
and abdominal discomfort.2, 13
Fairbanks et al10 reported sleep problems,
decreased appetite, abdominal pain, and excitement, all of them generally
transient. However, pooled analysis of weight changes during SSRI therapy
showed more weight loss during short-term treatment but more weight gain during
long-term treatment.14
We describe 4 children who showed growth attenuation and decreased GH
secretion, with normal weight gain, during treatment with SSRIs.
PATIENTS AND METHODS
Four children (3 boys) aged 11.6 to 13.7 years were treated with SSRIs
for obsessive-compulsive disorder or Tourette syndrome. The height of the
patients and their parents was measured with a stadiometer (Harpenden; Holtain
Ltd, Crymych, Wales), and growth velocity was calculated during 6-month intervals.
Auxologic results were expressed in terms of SD score (SDS) for age, based
on the standards of Tanner and Whitehouse.15
Puberty was assessed according to Marshall and Tanner16-17
and bone age according to Greulich and Pyle.18
Target height was determined according to midparental height corrected for
sex, by means of standard equations.19 The
GH stimulation tests were performed after priming with estrogen (ethynylestradiol,
40 µg/m2 per day for 2 days before testing).20
The clonidine hydrochloride test was performed with a single oral dose of
clonidine hydrochloride (Normopresan; Rafa, Jerusalem, Israel), 150 µg/m2, and blood samples were drawn at 0, 30, 60, 90, and 120 minutes for
GH determination. The glucagon stimulation test was performed with an intramuscular
injection of glucagon, 30 µg/kg (maximum, 1 mg) (Novo Nordisk, Bagsvaerd,
Denmark), and blood samples were drawn at 0, 120, 180, and 240 minutes. Pass
levels were defined as a peak GH level of 10 ng/mL (440 pmol/L) or greater.
To determine 24-hour integrated concentration of GH, blood was obtained every
30 minutes with a nonthrombogenic continuous withdrawal pump.21
The serum GH, prolactin, cortisol, and free thyroxine concentrations were
determined with a commercially available solid-phase chemiluminescent enzyme
immunoassay; thyrotropin concentration, with an immunometric assay that used
an automated analyzer (Immulite; Diagnostic Products Corporation, Los Angeles,
Calif); and 24-hour urinary free cortisol excretion with radioimmunoassay
(Diagnostic Products Corporation).
The patients' clinical and laboratory evaluations were performed as
part of the routine procedure for the diagnosis of abnormal growth.
Reasons for referral were short stature (patients 1 and 2), slow growth
rate (patient 3), and short stature and overweight (patient 4). The characteristics
of the 4 patients are summarized in Table
1 and the laboratory results in Table 2. Figure 1 shows
the individual growth velocity curves and pubertal stage before and during
SSRI and GH therapy, where applicable. In all 4 patients, the weight percentile
was consistent during SSRI therapy. None of the patients had an underlying
chronic disease, as indicated by normal findings for blood chemistry, blood
count, erythrocyte sedimentation rate, urinalysis, antigliadin antibodies,
thyroid function tests, prolactin levels, 24-hour urinary cortisol levels,
or cortisol suppression with 1 mg of dexamethasone. Brain magnetic resonance
imaging was also performed to rule out brain tumors or malformations. All
4 patients had supportive families; they functioned well at home and attended
regular public school while receiving SSRI treatment.
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Table 1. Pertinent Clinical Data in 4 Patients at Initiation of SSRI
Therapy*
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Table 2. Endocrine Evaluation During SSRI Treatment*
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Growth velocity curves of 4 patients during periodic treatment with
selective serotonin reuptake inhibitors (SSRIs) with or without the addition
of growth hormone (GH). SDS indicates standard deviation score; B, breast;
P, pubic hair; and TV, testicular volume. Breast and pubic hair were staged
according to Marshall and Tanner.16-17
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REPORT OF CASES
CASE 1
A girl was followed up in our clinic for short stature from age 9 years
8 months. She had been born at 36 weeks after an unremarkable pregnancy. Birth
length was 46 cm and birth weight, 2280 g (appropriate for gestational age).
Growth was consistent along the fifth percentile, compatible with her target
height (155 cm). At referral, the girl was prepubertal, with no abnormalities
on physical examination. Bone age was 8 years 10 months and karyotype was
46,XX. At age 11 years 7 months, therapy with fluvoxamine maleate (Favoxil;
Agis Industries Ltd, Yerucham, Israel), 50 mg/d, was initiated for Tourette
syndrome. During the 6 months of fluvoxamine therapy, the patient showed growth
arrest despite the concomitant appearance of Tanner stage 2 pubertal signs
and consistent weight gain; plasma prolactin and thyroid hormone levels were
within the reference range. The GH response to clonidine stimulation after
estrogen priming was borderline at 9.4 ng/mL (413.6 pmol/L), and insulinlike
growth factor 1 (IGF-1) level was low for pubertal stage. At age 12 years
1 month, the fluvoxamine was discontinued, and normal growth velocity of 6.6
cm/y was resumed. On a second clonidine stimulation test performed 4 months
after discontinuation of fluvoxamine treatment, GH level peaked at 18.1 ng/mL
(796.4 pmol/L).
CASE 2
A boy was referred to our clinic at age 13 years 8 months for evaluation
of short stature and overweight. He had been born at term after an unremarkable
pregnancy, with a birth weight of 2850 g. Growth was consistent along the
third percentile, compatible with his target height (162 cm). At referral,
the patient's height was at the third percentile and his weight was at the
60th percentile (body mass index [calculated as weight in kilograms divided
by the square of height in meters], 24.4). He showed Tanner 2 pubertal signs,
and results of physical examination were normal. Bone age was 11.5 to 12.0
years. Immediately after referral, the patient started treatment with fluoxetine
hydrochloride (Flutine; Teva Pharmaceuticals Industries Ltd, Netanya, Israel),
80 mg/d, for obsessive-compulsive disorder. Six months later, growth velocity
decreased to 1.4 cm/y, followed by complete growth arrest for 4 months (age
14.1-14.5 years) but with consistent weight gain. Laboratory investigation
showed normal 24-hour urinary free cortisol level, prolactin level, and thyroid
function. Peak GH level in response to clonidine stimulation was normal, but
the mean 24-hour integrated concentration of GH during fluoxetine therapy
was low at a mean ± SD of 1.51 ± 2.19 ng/mL (66.44 ±
96.36 pmol/L) (reference,  3 ng/mL [132 pmol/L]).21
The IGF-1 level was low normal at that time. Brain magnetic resonance imaging
produced normal results. Therapy with fluoxetine was stopped, and a second
GH 24-hour profile was performed 1 month later. Results showed a mean GH integrated
concentration (3.18 ± 4.48 ng/mL [139.92 ± 197.12 pmol/L]) and
an IGF-1 level within their respective reference ranges, suggesting transient
GH neurosecretory dysfunction (probably SSRI induced).22
After 6 months, growth velocity improved to 5.1 cm/y, and testicular volume
increased from 5 mL to 6 to 8 mL. Treatment with fluoxetine was resumed at
age 15 years 11 months for 6 months and then was discontinued because of a
recurrent decrease in growth velocity to 3 cm/y, concomitant with progression
of puberty from Tanner stage 3 to stage 4. After cessation of SSRI therapy,
the patient exhibited a normal pubertal spurt of 5 to 6 cm/y, corresponding
to his height percentile.15
CASE 3
A boy was referred to our clinic at age 12 years 7 months for short
stature and slow growth rate. He had been born small for gestational age at
31 weeks because of maternal preeclampsia, with a birth weight of 900 g. The
patient had received methylphenidate hydrochloride (Ritalin; Novartis International
AG, Basel, Switzerland) from age 5 to 10 years and then switched to combined
risperidone (Risperdal; Janssen Pharmaceutica, Inc, Beerse, Belgium), 1.0
to 1.5 mg/d, and fluvoxamine maleate, 100 mg/d, for treatment of Tourette
syndrome and attention-deficit/hyperactivity disorder. From age 6 to 11 years,
he grew along the 25th to 50th height percentile (midparental height, 174.5
cm). At that time, growth attenuation was first noted. At referral, he was
at the 20th percentile for height and 75th percentile for weight (body mass
index, 22.4). Results of physical examination were normal, with Tanner stage
2 pubertal signs, and bone age was appropriate for chronologic age. There
were no signs of Cushing syndrome. During 1 year of follow-up, growth velocity
decreased from 4.5 to 2.4 cm/y, with consistent weight gain, while puberty
advanced to stage 4, with an increase in testicular volume from 5 mL to 12
to 15 mL and in testosterone level from 58 to 202 ng/dL (2 to 7 nmol/L) (normal
ranges for Tanner stages 2 and 4, 17-167 ng/dL [0.6-5.8 nmol/L] and 112-476
ng/dL [3.9-16.5 nmol/L], respectively). Laboratory investigation showed normal
suppression of cortisol in response to 1 mg of dexamethasone, and normal prolactin
level and thyroid function. The postpriming peak GH levels in response to
clonidine and glucagon stimulation were subnormal (Table 2). The IGF-1 levels were low for pubertal stage. Brain magnetic
resonance imaging results were normal. As treatment with fluvoxamine could
not be stopped, therapy with somatropin was initiated at age 14.5 years, resulting
in a marked improvement in growth rate to 12 cm/y.
CASE 4
A boy was referred for evaluation of overweight at age 12 years 9 months.
Perinatal history was unremarkable, and birth weight was 3200 g. The mother
had a history of delayed puberty. Previous medical history disclosed therapy
with methylphenidate hydrochloride, 10 mg/d, for attention-deficit/hyperactivity
disorder since the age of 7 years. Growth was consistent along the 50th percentile
for height (compatible with the midparental height of 174 cm) and 90th percentile
for weight. On physical examination, he appeared mildly obese and prepubertal.
At the age of 12 years 9 months, obsessive-compulsive disorder was diagnosed
and therapy with fluvoxamine maleate, 150 mg/d, was added. It was later changed
to fluoxetine hydrochloride, 20 mg/d. Thereafter, the patient's growth rate
slowed from 5.1 to 2.6 cm/y, decreasing from the 50th to the 15th height percentile
within 1 year, with consistent weight gain. Laboratory data showed normal
thyroid, prolactin, and 24-hour urinary free cortisol levels. Postpriming
GH response to clonidine and glucagon stimulation was subnormal (Table 2). As fluoxetine treatment could
not be stopped, therapy with somatropin was initiated at the age of 14 years
4 months. Thereafter, growth rate increased to 10 cm/y. Tanner 2 pubertal
signs appeared at age 14.6 years, with progression to Tanner 4 during the
next year while the patient was receiving combined treatment with SSRIs and
somatropin.
COMMENT
The 4 patients described in this report showed growth attenuation or
arrest with normal weight gain during SSRI therapy, possibly secondary to
decreased GH secretion, with normal progression of puberty in 3 of them and
no evidence of chronic disease or abnormalities in other hypothalamic-pituitary
functions. These findings suggest a selective impairment of the somatotrophic
axis by SSRIs. Our observation is in line with the studies of Coplan et al6 and O'Flynn et al5
showing blunted GH secretion during fluoxetine treatment in adults, either
in response to clonidine stimulation in patients with remitted panic disorder
or mediated by desipramine hydrochloride (used as a GH stimulation test) in
patients with major depression. The central  2-noradrenergic
pathways serve as major stimulants of growth hormone–releasing hormone
secretion,23 and the central 2-noradrenergic receptors mediate clonidine-induced release of GH.24 Therefore, as desipramine is a known noradrenergic
reuptake inhibitor,25 these studies suggest
that SSRIs affect GH secretion via reduction of central 2-adrenoreceptor–mediated
GH release.
The new 2-site chemiluminescent assays used currently in most endocrine
laboratories for GH determination show lower GH levels, by about 30%.26 However, using this method, our group27
and others20 reported mean GH levels of 16
to 20 ng/mL (704-880 pmol/L) in prepubertal and early-pubertal children with
short stature. Therefore, we believe the low levels found on 2 primed tests
in patients 3 and 4 were true lows. An impairment of the somatotrophic axis
is further supported by the low IGF-1 levels with normal weight gain and normal
hypothalamic-pituitary imaging in the absence of evidence of any chronic disease.
Excess cortisol secretion as a cause of the growth attenuation was also ruled
out. In patients 1 and 2, the normal growth before institution of SSRI therapy
and its resumption after the drug's discontinuation, with concomitant rise
in their IGF-1 levels, suggest a causal relationship.
In contrast to the impaired somatotrophic axis in our patients, prolactin
levels and other anterior pituitary functions were normal. Indeed, elevations
in prolactin levels have been found in only a small percentage of SSRI users4 and are apparently dose dependent.3
Of note is the growth attenuation or arrest in 3 of our patients (cases 1-3)
despite the normal progression of puberty and at a point when the growth spurt
was expected. This finding is consistent with the study of Urban and Veldhuis28 showing the normal pulsatile release of luteinizing
hormone during 1 week of fluoxetine administration.
Delayed puberty might cause growth deceleration15
and transient GH deficiency.29 Among our 4
patients, only patient 4 had delayed puberty, with subnormal GH responses
on 2 postpriming stimulation tests. According to our experience and that of
others,20, 27 the probability of
a false-positive response on 2 postpriming stimulation tests is very low.
We are not aware of any studies conducted to date on the incidence of
growth attenuation in children treated with SSRIs. Our study, in 4 adolescents,
suggests an isolated effect of SSRI therapy on growth and possibly GH secretion.
Owing to their high efficacy and low adverse-effect profile, SSRI drugs have
become increasingly popular in the treatment of various psychiatric disorders,
and their use during childhood and adolescence is expected to increase.11 Therefore, knowledge of their effect on growth and
puberty is extremely important. As the large studies conducted in children
and adolescents treated with SSRIs have not addressed growth, and our study
includes only 4 patients, an individual variation in the effect of SSRIs on
the somatotrophic axis cannot be ruled out. Larger studies are needed to investigate
the effect of SSRIs on growth and GH secretion and the prevalence of disordered
growth in treated children and adolescents. These findings may also raise
awareness among psychiatrists and physicians in other fields who treat and
follow up this patient subgroup.
| What This Study Adds
Selective serotonin reuptake inhibitors have been associated with endocrinologic
adverse effects in several reports in adults, but there is no information
on their effect on growth and puberty in children. Our study of 4 patients
aged 11.6 to 13.7 years receiving selective serotonin reuptake inhibitors
for 6 months to 5 years suggests an isolated effect of therapy on growth and
possibly growth hormone secretion. These data, although limited to only 4
patients, might have important clinical implications in view of the increasing
use of these agents in the management of psychiatric disorders in younger
age groups. The findings are reported to increase the awareness of psychiatrists
and physicians in other fields who treat and follow up these patients.
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AUTHOR INFORMATION
Accepted for publication March 3, 2002.
We thank Gloria Ginzach and Melanie Kawe for their editorial and secretarial
help. We also thank Clara Weininger, RN, for performing the endocrine tests.
Corresponding author and reprints: Naomi Weintrob, MD, Institute
for Endocrinology and Diabetes, Schneider Children's Medical Center of Israel,
14 Kaplan St, Petah Tikva 49202, Israel (e-mail: nweintrob{at}clalit.org.il).
From the Institute for Endocrinology and Diabetes, Schneider Children's
Medical Center of Israel, Petah Tikva, and Sackler School of Medicine, Tel
Aviv University, Tel Aviv (Drs Weintrob, Cohen, and Dickerman and Ms Klipper-Aurbach);
and Pediatric Endocrine Unit and Laboratory, Kaplan Medical Center, Rehovot
(Dr Zadik), Israel.
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