A pilot study of antidepressant-induced mania in pediatric bipolar disorder: Characteristics, risk factors, and the serotonin transporter gene.
ABSTRACT Antidepressant-induced mania (AIM) has been described in bipolar disorder (BD) and has been associated with the short-allele of the serotonin transporter gene (5-HTT). We wished to investigate the frequency of and risk factors for AIM in pediatric patients with or at high risk for BD.
Fifty-two children and adolescents (30 with BD and 22 with subthreshold manic symptoms, 15.1 +/- 3.4 years old), all with a parent with BD, were interviewed with their parents for manic/depressive symptoms occurring before and after past antidepressant treatment. The 47 subjects with serotonin reuptake inhibitor (SSRI) exposure were genotyped for the 5-HTT polymorphism.
Fifty percent of subjects were AIM+ and 25.5% had new onset of suicidal ideation. The AIM+ and AIM- groups did not differ significantly in relation to allele (p = .36) or genotype (p = .53) frequencies of the 5-HTT polymorphism. The AIM+ subjects were more likely to have more comorbidities (3.2 vs. 2.4; p = .02) and be BD type I (p = .04) than AIM- subjects.
Youth with or at high risk for BD may be particularly vulnerable to SSRI AIM and thus should be monitored if given SSRIs. In this preliminary study, we did not find that the 5-HTT polymorphism significantly influenced vulnerability to AIM.
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ABSTRACT: Smaller amygdalar volumes have been consistently observed in pediatric bipolar disorder subjects compared to healthy control subjects. Whether smaller amygdalar volume is a consequence or antecedent of the first episode of mania is not known. Additionally, smaller volume has not been localized to specific amygdala subregions. We compared surface contour maps of the amygdala between 22 youths at high risk for bipolar disorder, 26 youths meeting full diagnostic criteria for pediatric familial bipolar disorder, and 24 healthy control subjects matched for age, gender, and intelligence quotient. Amygdalae were manually delineated on three-dimensional spoiled gradient echo images by a blinded rater using established tracing protocols. Statistical surface mesh modeling algorithms supported by permutation statistics were used to identify regional surface differences between the groups. When compared to high-risk subjects and controls, youth with bipolar disorder showed surface deformations in specific amygdalar subregions, suggesting smaller volume of the basolateral nuclei. The high-risk subjects did not differ from controls in any subregion. These findings support previous reports of smaller amygdala volume in pediatric bipolar disorder and map the location of abnormality to specific amygdala subregions. These subregions have been associated with fear conditioning and emotion-enhanced memory. The absence of amygdala size abnormalities in youth at high risk for bipolar disorder suggests that reductions might occur after the onset of mania.Bipolar Disorders 09/2013; · 4.62 Impact Factor
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ABSTRACT: Depressive and anxiety disorders are common in youth who are at risk for bipolar disorder (i.e., youth who have at least one parent with bipolar disorder) and antidepressants are commonly prescribed as treatment. However, there are few data regarding the safety and tolerability of antidepressants in this population. Therefore, we sought to prospectively examine the effects of these medications in children and adolescents who are diagnosed with depressive or anxiety disorders and have a parent with bipolar I disorder. Youth aged 9-20 years, with at least one parent with bipolar I disorder [high risk (HR)], were recruited (n = 118) and assessed using semi-structured diagnostic interviews. Participants were prospectively evaluated using a modified version of the Longitudinal Interval Follow-up Evaluation to assess changes in affective and anxiety symptoms and were treated naturalistically. Over the course of 43-227 weeks (mean duration of follow-up: 106 ± 55 weeks), 21% (n = 25) of youth had antidepressant exposure and, of these, 57% (n = 12) had an adverse reaction (e.g., irritability, aggression, impulsivity, or hyperactivity) that led to antidepressant discontinuation. Those patients who experienced an adverse reaction were significantly younger than those who did not (p = 0.02) and discontinuation of antidepressant therapy secondary to an adverse event occurred at an average of 16.7 ± 17.4 weeks (median: 11 weeks, range: 2-57 weeks). Cox proportional hazard analyses yielded a hazard ratio of 0.725 (p = 0.03), suggesting that there is a 27% decrease in the likelihood of an antidepressant-related adverse event leading to discontinuation with each one-year increase in age. Antidepressant medications may be poorly tolerated in youth with a familial risk for developing mania. Controlled studies further assessing treatments for depression and anxiety in HR youth are urgently needed.Bipolar Disorders 08/2013; · 4.62 Impact Factor
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ABSTRACT: Background The relationship between psychomotor agitation in unipolar depression and mood-switching from depression to manic, hypomanic and mixed states has been controversial. We investigated the future risk of initial mood-switching as a function of psychomotor agitation in unipolar depression. Methods We identified 189 participants diagnosed with major depressive disorder (MDD). We divided all patients with MDD into two categories (1) agitated patients (n=74), and (2) non-agitated patients (n=115). These groups were prospectively followed and compared by time to mood-switching. Kaplan–Meier survival curves, log-rank test for trend for survivor functions, and Cox proportional hazard ratio estimates for a multivariate model were conducted to examine the risk of mood-switching by psychomotor agitation. Results During follow-up, mood-switching occurred in 20.3% of the agitated patients and 7.0% of the non-agitated patients. In the Kaplan–Meier survival estimates for time to incidence of mood-switching with agitated or non-agitated patients, the cumulative probability of developing mood-switching for agitated patients was higher than those for non-agitated patients (log-rank test: χ2=7.148, df=1, p=0.008). Survival analysis was also performed using Cox proportional hazards regression within a multivariate model. The agitation remained significantly associated with incidence of mood-switching (HR=2.98, 95% CI: 1.18–7.51). Limitations We did not make a clear distinction between antidepressant-induced mood-switching and spontaneous switching. Conclusions The main finding demonstrated that MDD patients with agitation were nearly threefold as likely to experience mood-switching, suggesting that psychomotor agitation in MDD may be related to an indicator of bipolarity.Journal of Affective Disorders 01/2015; 170:185–189. · 3.71 Impact Factor
A Pilot Study of Antidepressant-Induced Mania in
Pediatric Bipolar Disorder: Characteristics, Risk
Factors, and the Serotonin Transporter Gene
Fiona M. Baumer, Meghan Howe, Kim Gallelli, Diana Iorgova Simeonova, Joachim Hallmayer,
and Kiki D. Chang
Background: Antidepressant-induced mania (AIM) has been described in bipolar disorder (BD) and has been associated with the
short-allele of the serotonin transporter gene (5-HTT). We wished to investigate the frequency of and risk factors for AIM in pediatric
patients with or at high risk for BD.
Methods: Fifty-two children and adolescents (30 with BD and 22 with subthreshold manic symptoms, 15.1 ? 3.4 years old), all with
a parent with BD, were interviewed with their parents for manic/depressive symptoms occurring before and after past antidepressant
treatment. The 47 subjects with serotonin reuptake inhibitor (SSRI) exposure were genotyped for the 5-HTT polymorphism.
Results: Fifty percent of subjects were AIM? and 25.5% had new onset of suicidal ideation. The AIM? and AIM? groups did not differ
significantly in relation to allele (p ? .36) or genotype (p ? .53) frequencies of the 5-HTT polymorphism. The AIM? subjects were more
likely to have more comorbidities (3.2 vs. 2.4; p ? .02) and be BD type I (p ? .04) than AIM? subjects.
Conclusions: Youth with or at high risk for BD may be particularly vulnerable to SSRI AIM and thus should be monitored if given
SSRIs. In this preliminary study, we did not find that the 5-HTT polymorphism significantly influenced vulnerability to AIM.
Key Words: Bipolar disorder, child, adolescent, antidepressant-in-
duced mania, suicide, serotonin transporter gene
depression than in mania or hypomania (Ghaemi et al 2000).
Children and adolescents with BD also commonly have depres-
sive symptoms and often present with coincident manic and
depressive symptoms (Geller and Luby 1997). Thus, treating
depressive episodes is arguably the most important component
of the clinical management of BD; unfortunately, it may also be
more challenging than treating mania. Since mood-stabilizing
medications are not always effective in suppressing depressive
symptoms (Biederman et al 2000), patients with BD are often
prescribed antidepressants. Antidepressant therapy, however,
carries with it the risk of a quick switch in polarity, known as
antidepressant-induced mania (AIM).
Antidepressant-induced mania has been documented in both
major depressive disorder (MDD) and BD, but it seems that the
risk of AIM is significantly elevated in patients with BD (Angst
1985; Post et al 1997). Though AIM has been primarily studied in
adults, the existing pediatric research suggests that children with
BD are also particularly susceptible to AIM. In a 4-year follow-up
of children with major depressive disorder, AIM was highly
predictive of an eventual bipolar outcome (Strober and Carlson
1982). Additionally, retrospective chart studies of children al-
ready carrying a bipolar diagnosis have reported high rates of
treatment-induced manic symptoms. A study of 82 outpatients
with BD reported that 44% of those that received antidepressants
experienced AIM and an additional 14% had a stimulant-induced
mania (Faedda et al 2004). Biederman et al (2000) made the more
epressive episodes in bipolar disorder (BD) may be the
most devastating aspect of the illness (Gijsman et al
2004), and adults with BD typically spend more time in
specific observation that youths with BD who received selective
serotonin reuptake inhibitors (SSRIs) were three times more
likely to develop manic symptoms by the next follow-up visit
than subjects who did not receive an SSRI; risk of manic relapse
was not predicted by other types of antidepressants.
Since switches in polarity are intrinsic to BD, there is contro-
versy in the literature over whether such retrospective chart
reviews (Faedda et al 2004; Biederman et al 2000) adequately
account for the natural progression of the disorder (Brent 2004).
This distinction is especially problematic in pediatric BD, where
mixed episodes and rapid cycling are common (Craney and
Geller 2003). Indeed, Geller et al (2002), in a prospective
follow-up of 89 children with BD, reported that antidepressant
use did not predict relapse into mania. Furthermore, some
studies of adults with BD indicate that AIM is usually less severe
than spontaneous mania and resolves quickly once the antide-
pressant is discontinued (Stoll et al 1994). Therefore, it is still not
clear how common true AIM is in children with BD.
In contrast to research focusing on pediatric BD, studies of
children with other psychiatric diagnoses have not reported high
rates of AIM. In a study of 259 pediatric psychiatric inpatients,
only 2% of who had BD, the rate of drug-induced behavioral
disinhibition was 7.5% (Carlson and Mick 2003). Since these data
were gathered in the early 1990s, medications commonly pre-
scribed to children today, especially SSRIs and atypical antipsy-
chotics, were not thoroughly studied (i.e., SSRIs were used in
only 1.7% of treatment weeks). A more recent study (Wilens et al
2003) investigated adverse responses, primarily related to mood
disturbances, in 82 children and adolescents receiving SSRIs for
depressive disorders or obsessive-compulsive disorder (OCD).
Twenty-two percent of this group had a negative reaction to
SSRIs, with only 7% of this population experiencing manic
symptoms. While the sample of subjects with BD was fairly small
(23%), there was a nonsignificant association between BD and
adverse responses to SSRIs (p ? .1).
Given that children with BD appear to have a higher inci-
dence of AIM than children with other psychiatric diagnoses and
that this trend seems to be mirrored in adult psychiatric patients,
the subject of AIM in pediatric BD warrants further investigation.
Developing a better understanding of the factors that influence
From the Department of Psychiatry and Behavioral Sciences, Stanford Uni-
versity School of Medicine, Stanford, California.
Address reprint requests to Kiki D. Chang, M.D., Stanford University School
of Medicine, Division of Child and Adolescent Psychiatry, 401 Quarry
Road, Stanford, CA 94305-5540; E-mail: firstname.lastname@example.org.
Received November 3, 2005; revised May 2, 2006; accepted June 8, 2006.
BIOL PSYCHIATRY 2006;60:1005–1012
© 2006 Society of Biological Psychiatry
susceptibility to AIM would be of great clinical relevance, as it
would help physicians differentiate between medications that
should be immediately discontinued because they aggravate the
disorder from those that warrant a longer trial. Reliable demo-
graphic and clinical risk factors for AIM have not been consis-
tently identified in adults. Henry et al (2001) found that neither
gender, age, nor bipolar disorder type (I vs. II) were associated
with AIM. In pediatric BD research, one study reported that
female gender combined with early-onset anxiety was associated
with AIM (Faedda et al 2004). Additionally, a large-scale study of
a health maintenance organization (HMO) database found that
age was inversely related to an individual’s risk of having a first
episode of mania induced by an antidepressant (Martin et al
2004). The study was limited, however, by the fact that the
authors classified all manic episodes after antidepressant trials as
AIM, rather than assessing whether or not these manias may have
been due to the natural progression of the illness (Brent 2004).
Despite the limited findings to date, treatment of children with
BD would be improved if a biological variable with a more
specific and stronger correlation to AIM were to be identified.
It has been hypothesized that individual differences in the
serotonin transporter (5-HTT) may account for varying responses
to antidepressants, and therefore these differences could be used
as a biological predictor of AIM. A common polymorphism in the
serotonin transporter gene (SLC6A4) is a 44-base pair (bp)
deletion/insertion in the upstream promoter region, known as
the 5-HTT-linked polymorphic region (5-HTTLPR) (Heils et al
1996). The long (l) variant leads to greater transcriptional activity
of the 5-HTT gene than the short (s) variant (Lesch et al 1996).
Theoretically, an ss or ls individual would have a relatively lower
membrane concentration of serotonin transporter protein and
thus could have a higher proportion of reuptake proteins
blocked by antidepressants than an ll individual, leading to a
greater concentration of serotonin in the synapse and possibly an
exaggerated response to antidepressants (Mundo et al 2001).
The three studies that have investigated this correlation with
AIM in adults with BD have had conflicting results. Mundo et al
(2001) compared the allele frequencies in a group of 27 bipolar
patients (36.3 ? 8.5 years) who had experienced AIM (AIM?
group) with those in a matched population of 29 bipolar patients
(36.3 ? 7.7 years) who had never experienced AIM (AIM?
group). They reported an excess of the s allele and the ss
genotype in the AIM? group compared with the AIM? group.
The later studies of Rousseva et al (2003) (AIM? group with 83
subjects, 26.7 ? 11.5 years; AIM? group with 149 subjects, 25 ?
11.7 years) and Serretti et al (2004) (AIM? group with 169
subjects, 46.68 ? 13.80 years; AIM? group with 247 subjects,
42.93 ? 14.45 years) did not find a significant difference at this
polymorphism between subjects with and without AIM. How-
ever, the cohort of patients with AIM used by Mundo et al (2001)
had a relatively earlier mean age at onset of BD (19.8 years) than
those used by Rouseseva et al (2003) (26.7 years) and Seretti et al
(2004) (32.0 years). There have been no previous studies exam-
ining the association of AIM and the 5-HTT gene in pediatric
Given the paucity of research on AIM in pediatric BD and the
inconclusive findings regarding the role of 5-HTTLPR in adult
AIM, we wished to characterize AIM in children with or at high
risk for BD and investigate potential risk factors of AIM, including
the s allele, in this population. Based on the preceding evidence
of AIM in children with BD, we hypothesized that there would be
a high rate of AIM and also a significant level of suicidal ideation
following antidepressant treatment in our sample. Despite the
limitations highlighted by Brent (2004), we considered the Martin
et al (2004) data and predicted that antidepressant exposure at an
earlier age would confer greater risk for AIM. Furthermore, since
Mundo et al (2001) had significant results using a relatively
early-onset cohort, we hypothesized that in our pediatric popu-
lation, having the s allele would be a risk factor for AIM and that
there would be a greater frequency of the s allele and the ss
genotype in subjects with AIM compared with subjects without
this adverse response.
Methods and Materials
The subjects for this study were drawn from a larger popula-
tion of 225 children and adolescents participating in a longitudi-
nal study at the Stanford Pediatric Bipolar Disorders Program.
Families were recruited through the Adult and Pediatric Bipolar
Disorders Clinics at Stanford and through general referral from
clinicians and parents in the community. Written and verbal
informed consent was obtained from parents of subjects, and the
study was approved by the Stanford Panel on Human Subjects in
Medical Research. All patients in this population had at least one
parent with bipolar I or II disorder as diagnosed by the Structured
Clinical Interview for DSM-IV Axis I Disorders (SCID-I) (First et al
1995). Each child was evaluated by the affective disorders
module of the Washington University in St. Louis Kiddie Sched-
ule for Affective Disorders and Schizophrenia (WASH-U-KSADS)
(Geller et al 1996), as well as the Schedule for Affective Disorders
and Schizophrenia for School-Age Children-Present and Lifetime
(K-SADS-PL) (Kaufman et al 1997), during which a thorough
history of psychotropic medication exposure was obtained.
These interviews were performed by trained masters-level clini-
cians and/or a board certified psychiatrist, all of whom had
established interrater reliability. Based on the WASH-U-KSADS,
children were classified as having either: 1) bipolar I or II
disorder; 2) subsyndromal BD (significant symptoms of atten-
tion-deficit/hyperactivity disorder [ADHD] and mood symptoms
as indicated by a minimum Young Mania Rating Scale [YMRS]
[Young et al 1978] score of 12 or a Children Depression Rating
Scale-Revised [CDRS-R] [Poznanski et al 1984] score of 30); or 3)
unaffected. Furthermore, blood samples were being collected
from participants and their families for genetic analysis.
Of those already participating in the genetic research, a group
of 52 bipolar and subsyndromal subjects (ages 7.6–22.0, 15.1 ?
3.4 years old) who had current or past treatment with at least one
antidepressant were identified. Antidepressants included selec-
tive serotonin reuptake inhibitors (fluoxetine, paroxetine, sertra-
line, citalopram, fluvoxamine, and escitalopram) and atypical
antidepressants (bupropion, venlafaxine, trazadone, and ser-
For all subjects, information about age at antidepressant
exposure, duration of exposure, class of antidepressant, and
concurrent use of mood stabilizers or antipsychotics was gath-
ered. The following demographic and clinical variables were also
collected from the WASH-U-KSADS and SCID-I: gender, ethnic-
ity, bipolar or subsyndromal status, age at BD diagnosis and
diagnostic subtype of BD if applicable, comorbid Axis I diag-
noses, presence or absence of psychotic symptoms during mood
episodes, and family history of mood disorders and ADHD. We
obtained family history of mood disorder using the Family
History-Research Diagnostic Criteria (FH-RDC) (Andreasen et al
1977) and parental history of ADHD using the behavioral disor-
ders supplement from the K-SADS-PL (Kaufman et al 1997).
1006 BIOL PSYCHIATRY 2006;60:1005–1012
F.M. Baumer et al
Assessment of AIM
Interviews about the subjects’ experiences on antidepressants
were conducted with both the parent and child, if the subject was
older than 12 years at the time of antidepressant exposure, or
with only the parent, if the subject was younger than 12 years.
During these interviews, the subject and/or parent were asked to
describe any psychologically adverse reactions that had arisen
within 3 months of introducing a new antidepressant or increas-
ing the dose of a currently used one (heretofore referred to as
changing antidepressant status). To prevent any reporting bias,
the families were only told that we were collecting information
about reactions to antidepressants, and the nature and hypothe-
ses of the study were not mentioned.
Subjects who did not report a poor reaction to medication
were questioned regarding their earliest exposure to an SSRI or
to any other antidepressant if there was no SSRI exposure. If a
subject had an adverse reaction to more than one antidepressant,
a reaction to an SSRI was evaluated over a reaction to other
classes of antidepressants, due to our interest in effects of
serotonergic differences on AIM. If further clarification was
required, the earliest reaction would be evaluated over later
ones. The elapsed time between changing antidepressant status
and onset of the poor reaction was noted.
Mood effects of antidepressant exposure were measured
using the YMRS. Parents and children were directly interviewed
using the YMRS, and a composite score reflecting the interview-
er’s overall impression of score for each item was used. The
YMRS is an 11-item interview which queries the core symptoms
of mania in the child, including elevated mood, irritability,
psychomotor agitation, hypersexuality, and aggressive behavior.
Originally designed for use with bipolar adults, the YMRS has
been adapted for use with children and is considered one of the
best available instruments for assessing pediatric mania (Carlson
et al 2003). The YMRS has been widely used in phenomenolog-
ical (Rajeev et al 2003) and treatment outcome studies of youth
with subsyndromal and syndromal BD (Chang et al 2003; Find-
ling et al 2003). However, the validity of this instrument in
retrospective use beyond the previous week has not yet been
Each subject’s moods and behaviors were rated with the
YMRS for the week before antidepressant status was changed
and then again either during the negative reaction or 1 month
after change in status if no negative reaction occurred. Onset of
suicidal ideation was investigated and was defined as a score of
4 or above on question 13 of the CDRS-R, along with a report that
this ideation began only after medication was started. The YMRS
and CDRS-R scores were verified with trained masters-level or
doctoral-level clinicians or a board certified child psychiatrist,
who all achieved interrater reliability on these measures at a
kappa of .8.
Subjects were first broadly classified based on whether or not
they had a severe negative reaction to antidepressants. Those
placed in the reaction positive group (RXN?) reported that their
mood became noticeably more elevated, expansive, or irritable,
to an extent that disturbed daily function, within the first 3
months of changing antidepressant status; those without such a
change were classified as reaction negative (RXN?). Subjects in
the RXN? group were then further assessed to see if they
experienced enough additional symptoms to qualify as having
mania. Antidepressant-induced mania was defined as an expan-
sive, euphoric, or irritable mood, plus three other cardinal
symptoms of mania (four if the mood was only irritable), as
delineated by the DSM-IV. In addition, if subjects were found to
be manic or hypomanic before a change in antidepressant status,
then they were evaluated for worsening of manic symptoms on
the antidepressants, as indicated by an increase of at least 4 on
the YMRS along with reports from parents and subjects.
This information was discussed with a board certified child
psychiatrist blind to type of antidepressant exposure and genotype.
The duration used to qualify AIM was at least 1 day and not the 4 to
7 days required by DSM-IV criteria, because many subjects stopped
taking antidepressants within 1 to 4 days of onset of manic
symptoms. Given this modified time period, we did elicit for
possible environmental causes of mood fluctuation (i.e., making the
cheerleading squad), which the child psychiatrist took into account
in assessing the reactions. If a change in mood was thought to be
due to environmental events, it was not considered to be AIM.
had a new manic episode or worsening of a preexisting one after
antidepressant status changed and negative for induced mania
(AIM?) if this did not occur.
DNA was extracted from 200 ?L of frozen blood using the
Qiagen DNeasy Kit (Qiagen, Hilden, Germany [Cat. #69506]).
Oligonucleotide primers flanking the 5-HTT-linked polymorphic
region and corresponding to the nucleotide positions -1416 to
-1397 (stpr5, 5’-GGC GTT GCC GCT CTG AAT GC) and -910 to
-888 (stpr3, 5’-GAG GGA CTG AGC TGG ACA ACC AC) of the
5-HTT gene 5’-flanking regulatory region were used to generate
484 bp or 528 bp fragments. Polymerase chain reaction (PCR)
amplification was carried out in a final volume of 30 ?L
consisting of 50 ng of genomic DNA, 50 ng each of sense and
antisense primers, 15 ?L of Taq PCR Master mix (Qiagen, Cat.
#201445), 10% dimethyl sulfoxide (DMSO), and 1 mol/L betaine.
Annealing was carried out at 61°C for 30 seconds, extension at
71°C for 1 minute, and denaturation at 95°C for 30 seconds for a
total of 35 cycles. The PCR products were electrophoresed
through 5% polyacrylamide gel (acrylamide/bis-acrylamide ratio
19:1) at 60 V for 60 minutes. A 100-bp marker was used to
measure the PCR product size for l and s allele. Alleles were
called by raters blind to clinical status of the participant.
Exploratory analyses were done to compare the AIM? and
AIM? groups across certain demographic and clinical variables.
Our primary hypothesis was that a younger age at antidepressant
exposure would be associated with AIM; thus, for our two
age-related comparisons our alpha was set at .025, using a
Bonferroni correction for two tests. Our remaining nongenetic
comparisons between the AIM? and AIM? groups were explor-
atory to generate further hypotheses, so no correction for
multiple testing was used for these tests. The t test (two-tailed)
for independent samples was used for continuous variables (age
at onset and number of comorbid Axis I disorders) and the
Pearson ?2test was used to compare categorical values (gender,
bipolar diagnosis [BD type I, BD type II, or subsyndromal], age
group at onset of AIM, and concurrent use of a mood stabilizer or
For the genetic analysis, the 47 subjects who had exposure to
proserotonergic compounds were included, while the 5 subjects
who only had exposure to the dopaminergic antidepressant
buproprion were excluded. The allele and genotype frequencies
at the 5-HTTLPR were compared between the AIM? and AIM?
groups using the Pearson ?2test, as well as the Armitage trend
test (due to non-Hardy-Weinberg equilibrium [HWE] of allele
F.M. Baumer et al
BIOL PSYCHIATRY 2006;60:1005–1012 1007
frequencies/genotypes). The time from change in antidepressant
status to onset of AIM was compared across the genotypes using
the Pearson ?2test. An analysis of covariance (ANCOVA) was
used to covary for exposure to mood stabilizers and/or antipsy-
chotic medications during the antidepressant trial. To determine
age effects on AIM, a binary logistic regression was used to test
if AIM could be predicted based on age at antidepressant
exposure along with either genotype or presence of the s allele.
All statistical analyses were performed using the Statistical
Package for the Social Sciences, version 12.0 (SPSS Inc., Chicago,
Illinois). The level of significance was set at .05 unless otherwise
In this sample, 64.4% of subjects reported a negative reaction
to antidepressants (RXN?). Fifty percent of subjects were AIM?,
with 20 (38.5%) having a new manic episode and 6 (11.5%)
having worsening of a preexisting episode. Of the 47 subjects
informative on suicide, 12 (25.5%) had onset of suicidal ideation
within the first 3 months of antidepressant use.
To thoroughly characterize antidepressant response, subjects
were classified broadly (as RXN? or RXN?) and specifically (as
AIM? or AIM?). Most subjects who were RXN? but not AIM?
experienced extreme irritability after antidepressant exposure
but not additional symptoms of mania. The main demographic
and clinical variables of the RXN?/RXN? and AIM?/AIM?
groups are summarized in Table 1. Neither age at onset of mania
nor age at time of AIM was associated with the presence of AIM
(Table 1). In our exploratory analyses, only two comparisons
were significant: the subjects in the AIM? group had more
comorbidities (3.2 ? 1.2) than those in the AIM? group (2.4 ?
1.2) (t ? 2.39, df ? 50, p ? .02), and more AIM? subjects were
BD type I than subsyndromal BD or BD type II (Pearson ?2?
6.44, df ? 2, p ? .04). Data collected on the period of
antidepressant exposure are presented in Table 2. There were no
significant differences between groups in the frequency of
concurrent use of mood stabilizers (lithium, carbamazepine,
valproate, or oxcarbazepine) and/or antipsychotics (risperidone,
olanzapine, and quetiapine) during the period of antidepressant
exposure, but information about doses and plasma levels was
Only the 47 subjects who had taken proserotonergic com-
pounds were used for the allelic comparisons, because it was
hypothesized that the polymorphism at the 5-HTTLPR influenced
AIM by modulating serotonergic pathways. Five subjects who
had only been exposed to buproprion were excluded. Two
subjects considered RXN? due to poor reactions to buproprion
were considered AIM? in the genetic analysis, because they later
had uneventful exposure to SSRIs. Furthermore, since it was
hypothesized that the interaction between antidepressants and
the s allele would lead to mania, the genetic data were only
compared between the AIM? and AIM? groups. The demo-
graphic and clinical data on medication exposure were similar to
that in the larger group.
As shown in Table 3, there was no significant difference
between the allele (Pearson ?2? .84, df ? 1, p ? .36) or
genotype (Pearson ?2? 1.29, df ? 2, p ? .53) frequencies across
the AIM? and AIM? groups. An Armitrage trend test similarly
Table 1. Demographic and Clinical Variables in Subjects with and without Negative Reactions to Antidepressants and with and without
Two-Sided p Yes (n ? 34)No (n ? 18) Yes (n ? 26) No (n ? 26)
Age at Participation, Mean (SD)
Ethnicity, No. (%)
Bipolar Diagnosis, No. (%)
Age at Bipolar Onseta, Mean (SD)
Axis I Disorders, Mean (SD)
Axis I Disorders, No. (%)
Major Depressive Disordersb
Oppositional Defiant Disorder
Posttraumatic Stress Disorder
Psychosis, No. (%)
Family History, Mean (SD)c
26:8 10:819:7 17:9.55
14.7 (3.6)16.2 (3.0)15.0 (3.4) 15.4 (3.6)
0 1 (5.6)
0 1 (3.8)
AIM, antidepressant-induced mania.
aAge of onset of bipolar disorder only. The 30 subjects with bipolar disorder, but not the 22 subjects who are subsyndromal, were counted.
bSince having bipolar disorder precludes having major depressive disorder, this category only applies to the 22 subsyndromal subjects.
cData was unavailable for two subjects.
1008 BIOL PSYCHIATRY 2006;60:1005–1012
F.M. Baumer et al
revealed no significant differences (?2? .84, p ? .36; ?2? 2.20,
p ? .33, respectively). However, all three subjects with the ss
genotype responded negatively to antidepressants, and two were
in the AIM? group.
Within the AIM? group, the time from change in antidepres-
sant status to onset of AIM was divided into three groups: onset
within 1 week (n ? 12), onset between 1 week and 1 month
(n ? 5), and onset between 1 month and 3 months (n ? 5). Time
to onset was not affected by presence of the s allele (Pearson
?2? 1.12, df ? 2, p ? .57) or genotype (Pearson ?2? 2.75,
df ? 4, p ? .60).
Concomitant use of mood stabilizers or antipsychotics did not
limit antidepressant-induced mood destabilization in regard to
presence of the s allele (Pearson ?2? .52, df ? 2, p ? .77) or
genotype (Pearson ?2? .87, df ? 3, p ? .83).
The age at antidepressant exposure did not significantly
change the risk of AIM. Moreover, the interaction between age at
antidepressant exposure and either the presence of the s allele
(?2? 3.746, df ? 2, p ? .154) or the interaction between age at
exposure and genotype (?2? 3.828, df ? 2, p ? .147) could
This is the first study of which we are aware to assess AIM in
children with and at high risk for BD by direct interview and the
first study to investigate the relationship between the 5-HTT gene
and AIM in a pediatric sample. In our sample of children with
either subthreshold or fully diagnosable BD and a family history
of the disorder, most subjects had a poor response to antidepres-
sant treatment, with AIM and new suicidal ideation frequently
occurring within 1 month of treatment. Subjects who experi-
enced AIM were more likely to be BD type I than BD type II or
subsyndromal and tended to have a greater number of Axis I
diagnoses than patients who did not experience AIM, though
these findings should be considered preliminary, as we did not
correct for multiple comparisons in our exploratory analyses.
Neither gender nor age at onset of mania was associated with
AIM. Exploratory analyses also did not find use of concurrent
antipsychotic or mood stabilizer to decrease the incidence of
AIM. Regarding our genetic findings, neither the presence of the
5-HTT s allele nor the ss genotype was a risk factor for AIM. There
was no association between age at antidepressant exposure and
incidence of AIM, and age at exposure combined with genotype
at the 5-HTTLPR did not predict AIM.
These naturalistic data suggest that in children with a family
history of BD, those who have a diagnosis of BD or have
subthreshold manic symptoms frequently develop AIM at some
point in their treatment. The high incidence of treatment-emer-
gent problems in this sample is much greater than the 22%
reported by Wilens et al (2003) among children with depressive
disorders or OCD and on par with the 44% in children with BD
reported by Faedda et al (2004). These results are also in
concordance with the literature on adults, which consistently
demonstrates a higher incidence of AIM in patients with bipolar
type I disorder than those with major depressive disorder
(Papolos 2003). However, most studies have reported lower
overall rates of AIM in adults with BD, ranging from approxi-
mately 20% to 40% (Goldberg and Truman 2003).
Unfortunately, these studies (including ours) are all retrospec-
tive, as prospective data on AIM in pediatric BD does not
currently exist. Geller et al (2002) did publish prospective data on
natural relapse rates in childhood BD and reported that antide-
pressant use did not predict recovery from or relapse into mania.
This study did not specifically elicit AIM events, however, but
instead considered only manic symptoms that lasted for at least
2 weeks. Any cases of AIM that led to termination of the
antidepressant trial and subsequent resolution of manic symp-
toms within that 2-week window would not be counted. There-
fore, the rate of antidepressant-related problems may be under-
reported in this study.
A bipolar diagnosis also seems to be associated with an
increased risk of antidepressant-emergent suicidality. The inci-
dence of postantidepressant increases in suicidal thoughts or
gestures in our sample (25.5%) was higher than the rate previ-
ously reported in a retrospective study of children with BD (14%)
(Faedda et al 2004) and considerably higher than the 4%
Table 2. Antidepressant Exposure Information in Subjects with and
without Negative Reactions to Antidepressants and with and without
(n ? 26)
(n ? 26)
Age at Antidepressant Exposure,
5.0–9.9 years old
10.0–14.9 years old
15.0–20.0 years old
Type of Antidepressant, No. (%)
Duration of Antidepressant Trial
(years), Mean (SD)
Change in YMRS Score, Mean (SD)
Concurrent Mood Stabilizer and/
or Antipsychotic,aNo. (%)
AIM, antidepressant-induced mania; SSRI, selective serotonin reuptake
inhibitor; YMRS, Young Mania Rating Scale.
aData was unavailable for two subjects.
Table 3. Allele and Genotype Frequencies in the Subjects with and without Antidepressant-Induced Mania
Polymorphisms Total Sample (n ? 47)AIM? (n ? 22)AIM? (n ? 25)
Alleles, No (%)
Genotypes, No (%)
33 (66.0) .835 (1).36
AIM?, experience antidepressant-induced mania; AIM?, did not experienced antidepressant-induced mania.
F.M. Baumer et al
BIOL PSYCHIATRY 2006;60:1005–1012 1009
frequency reported by the U.S. Food and Drug Administration
(FDA) for depressed children and adolescents (U.S. Food and
Drug Administration 2004). Therefore, children with BD or with
subsyndromal symptoms may have a significantly higher proba-
bility of developing suicidal ideation on antidepressants than
children who suffer from MDD.
In reviewing the demographic data, several observations
indicated that the likelihood of experiencing AIM might be
directly correlated with the severity of BD. First, the AIM? group
tended to have more comorbid Axis I diagnoses than the AIM?
group, an indirect indication of severity of illness (McElroy et al
2001). Second, there was a higher frequency of AIM in subjects
with BD type I than subjects who were subsyndromal or had BD
type II. If clinical severity does modulate antidepressant re-
sponse, it might explain why certain subjects tolerated antide-
pressants at younger ages but then developed a negative re-
sponse at later exposures, once the disease had progressed. This
hypothesis, however, would need to be investigated more
thoroughly in a study carefully defining clinical severity.
Our hypothesis that the s allele and ss genotype would be
genetic risk factors for AIM was not supported. In our sample, the
frequency of the s allele was not significantly elevated in the
AIM? group (Pearson ?2? .835, df ? 1, p ? .361). The effect
size was extremely small (R2? .021); to have 80% power to
detect a difference between s allele frequencies of .43 (AIM?)
versus .34 (AIM?), we would need a sample of 240 cases and the
same number of control subjects.
Moreover, there were a similar percentage of ls individuals in
the AIM? and AIM? groups, suggesting that there was no
relationship between the heterozygous genotype and AIM.
Though we found no correlation between the ss genotype and
AIM, this negative finding was limited by only having three
subjects with the ss genotype. Perlis et al (2003) reported that
only the ss genotype was associated with treatment-emergent
physical adverse effects. In our sample, all three of our ss subjects
did have negative reactions to antidepressants, with two experi-
encing AIM. It is possible that in a larger sample, a significant
correlation between AIM and the ss genotype would be found,
but with an effect size for genotype as small as .027, it is difficult
to predict that from these results.
Our results are in concordance with two studies of AIM in
adults with BD (Serretti et al 2004; Rousseva et al 2003) and
discordant with the findings of Mundo et al (2001). We originally
predicted that our results would be more similar to those of
Mundo et al (2001), because our sample also had an early age of
BD onset. Nonetheless, we did find a higher rate of the s allele in
AIM?, and we only had a 65% chance to replicate the finding by
Mundo et al (2001), assuming the risk increase found in that
study. One problem is that the genotypes are not in Hardy-
Weinberg equilibrium, as we would have expected a total of six
to seven subjects with an ss genotype but found only three.
However, we still did not find significant differences between
groups when using the Armitage trend test, which is valid if
genotypes are not in HWE, whereas the standard chi-square is
not. Thus, it is also possible that other genetic factors that
contribute to this earlier, familial form of the disorder or the
environmental stressors associated with having a parent with BD
could strongly modulate the reaction to antidepressants and
thereby overwhelm the more subtle influence of the serotonin
Furthermore, we were not able to fully support our hypoth-
eses that there would be a higher incidence of AIM in younger
patients and that an interaction between age at antidepressant
exposure and the s allele could predict AIM. Our results resem-
bled those published by Martin et al (2004), which showed the
highest risk of AIM in peripubertal patients between the ages of
10 and 14. In our sample, there was a trend toward higher
incidence of AIM among patients with younger age at antide-
pressant exposure. Of those in our group who had AIM, 50%
experienced it for the first time between the ages of 10 and 14; an
additional 42.3% switched between the ages of 5 and 9. Only two
of the nine subjects first exposed to antidepressants in later
adolescence (15–20 years old) had AIM. However, it has been
noted that Martin et al (2004) may have overestimated AIM,
especially in the younger age groups, because they did not
account for the natural course of BD and therefore some of the
switches attributed to antidepressants could have occurred re-
gardless (Brent 2004). In contrast, the study could have under-
estimated the incidence of AIM in older children, because it
defined AIM as a new diagnosis of BD, thereby excluding any
child who experienced AIM after receiving a bipolar diagnosis.
Lastly, though genotype combined with age could not predict
AIM, the two ss individuals with AIM were in the youngest age
category (6–9 years old) at the time of switching. The small
sample size in each age group as well as the small number of ss
subjects may have obscured a true interaction between the two
variables. Therefore, while the data are inconclusive, it still might
behoove clinicians to be especially vigilant when prescribing
antidepressants to younger children.
Despite our negative genetic findings, the high rate of AIM in
our sample has important implications for the management of
children and adolescents with BD or subsyndromal BD. Clini-
cians might first consider alternate agents to treat symptoms of
depression and/or anxiety in this population. Though there have
been few studies of agents for the treatment of bipolar depres-
sion in children and adolescents, lamotrigine (Kusumaker and
Yatham 1997; Chang et al 2006) or lithium (Patel et al 2006) may
eventually prove effective in this population. The high rate of
antidepressant-emergent suicidality in our cohort is also impor-
tant, given the current concern that antidepressant use may
increase suicidality in children in general; it is possible that onset
of suicidality following SSRI treatment is more of a concern for
young patients with BD than for those with MDD. Finally,
antidepressants have also been reported to cause “behavioral
activation” in children with MDD or BD (Bhangoo et al 2003;
Guile 1996), a phenomenon presumably falling short of full
mania. Thus, all children, particularly those with BD, should be
carefully assessed after beginning antidepressant treatment for
emergence of mania and/or suicidal symptoms, and these symp-
toms should be carefully differentiated from uncomplicated
Future research should work to isolate other predictors of
AIM. It may be valuable to determine if AIM represents an
exaggeration of normal antidepressant response or if it is biolog-
ically related to spontaneous mania. If the latter is true, AIM
could be a valuable model for studying the origins of mania.
Several limitations in the study design must be considered.
Foremost, this study was retrospective and therefore confounded
by issues such as the quality of subjects’ memory and limited
data. The objectivity of our informants may have been compro-
mised by the widespread, negative media coverage of antide-
pressant use in children going on at the time of these interviews.
Though the subjects were not told our hypotheses, they may
have been more likely to report problems with the antidepres-
1010 BIOL PSYCHIATRY 2006;60:1005–1012
F.M. Baumer et al
sants, especially in relation to increased suicidal ideation. De-
spite the limitations of our study regarding retrospective recall
and reporting, our study has an advantage over past retrospec-
tive chart and database reviews (Biederman et al 2000; Carlson
and Mick 2003; Faedda et al 2004; Wilens et al 2003) in that we
were able to gather additional information and clarify data
directly with the subjects and their families.
Additionally, if the child was younger than 12 when they
experienced AIM or first received antidepressants, we chose to
interview only their parents, even though Tillman et al (2004)
found poor agreement between parent and child reports for
symptoms of prepubertal mania. Our justification for this choice
in informants was that it would be difficult for young children to
remember accurately the details of a sudden-onset switch that
happened in the past, especially if it resolved quickly. Also, the
Tillman et al (2004) study showed that children report more of
the symptoms that differentiate BD from ADHD (such as
elation and grandiosity); so in speaking only with the parents,
we reasoned our data would be a more conservative estimate
As the design of our study was naturalistic and not case-
controlled, AIM? and AIM? groups differed significantly across
some clinical variables. Also, since treatment occurred in the
community, doses and duration of antidepressants were not
controlled and trials were not necessarily stopped upon the
appearance of manic symptoms. Therefore, as seen in Table 2,
the duration of antidepressant trials was highly variable and fairly
long, even for the subjects who had adverse reactions. The
naturalistic nature of the data, along with the fact that there was
not a control group of subjects with BD without antidepressant
exposure, make it impossible to say definitively that the reported
manic or suicidal symptoms were caused by the antidepressants
and not a natural part of the disease. It seems probable that most
of these manic reactions were correlated with medication treat-
ment, however, as half the instances of AIM occurred within the
first week of antidepressant use and the majority occurred within
The methodology is also limited by the fact that the YMRS has
not been validated for use in this retrospective manner. How-
ever, there are no prospective, controlled studies of AIM in
children that we are aware of, probably due to the ethical
problems and logistic difficulties in conducting such an investi-
gation. Furthermore, as there is not a universally accepted set of
criteria for AIM, our study used the YMRS to elicit information in
a nonbiased yet methodologically rigorous manner to increase
the validity of the data. For example, we began the interview
with open-ended questions regarding response to antidepres-
sants, and when no exposure was more problematic than
another, we assessed reaction to the first SSRI the child was
prescribed. We specifically assessed for symptoms of mania by
DSM-IV criteria and used a well-established qualitative measure
of pediatric mania (the YMRS) to back up our categorical
decisions. When possible, we also interviewed both the parent
A possible limitation in our genetic data was that subjects
from a variety of ethnic backgrounds were included in this study.
The prevalence of the s allele can vary widely across ethnicities
and even across different groups of Europeans (Gelernter et al
1999). Though our sample was predominantly Caucasian, the
allele and genotype frequencies could still have been heavily
influenced by ethnic stratification and therefore not been as
informative regarding AIM. Also, given that AIM is a complex
behavioral outcome, it is unlikely that only one gene would be
responsible for this outcome. However, given the past literature,
it remains possible that singe-gene polymorphisms may be
determined to confer a small but measurable risk for AIM.
The next logical study would utilize a prospective design, in
which antidepressant doses and exposure to mood stabilizing
agents would be carefully controlled and include a control group
matched for all demographic and clinical variables. In such a
study, the sample size for the genetic analysis would also be
expanded considerably beyond the current 47 subjects. How-
ever, given that our data had such a small effect size for the
presence of the s allele on AIM (R2? .021), it is unlikely that
controlling for these limitations would change the results signif-
icantly. The effect size of genotype on AIM (R2? .027) is also
small, but given the paucity of ss subjects, it could be valuable to
replicate this study with a larger sample size to test for genotypic
Finally, a theoretical limitation to this study is that the
hypothesized relationship between the s allele and AIM was not
based on strong cellular evidence but rather on inferences made
in hopes of finding a useful clinical predictor of AIM. Currently
not enough knowledge exists regarding the specifics of serotonin
neurotransmission or the way in which antidepressants bring
about mood elevation to outline a strong molecular mechanism
by which antidepressants interact with the 5-HTTLPR to initiate
AIM. Therefore, more complex genetic, cellular, or environmen-
tal interactions may be responsible for induced mania.
This work was supported by a grant for the Heinz C. Prechter
Fund for Manic Depression and National Institutes of Health
(NIH) Grant MH64460-01 (KDC).
We gratefully acknowledge the genotyping assistance of
Xiaoyan Lin and Jessica Yee.
Presented at the “Collaborative Pediatric Bipolar Disorder
Conference,” April 16, 2005, Coral Gables, Florida. The confer-
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