Child Psychiatry Hum Dev
DOI 10.1007/s10578-014-0524-9
SUBSTANTIVE/THEORETICAL REVIEW
Adolescent-Onset Depression: Are Obesity and Inflammation
Developmental Mechanisms or Outcomes?
Michelle L. Byrne Neil M. OBrien-Simpson
Sarah A. Mitchell Nicholas B. Allen
Springer Science+Business Media New York 2015
Abstract Depression often has its first onset during
adolescence and is associated with obesity. Furthermore,
inflammatory processes have been implicated in both
depression and obesity, although research amongst adoles-
cents is limited. This review explores associations between
depression and obesity, depression and inflammation, and
obesity and inflammation from a developmental perspective.
The temporal relations between these factors are examined
to explore whether obesity and elevated inflammation act as
either risk factors for, or outcomes of, adolescent-onset
depression. Sex differences in these processes are also
summarized. We propose a model whereby increases in sex
hormones during puberty increase risk for depression for
females, which can lead to obesity, which in turn increases
levels of inflammation. Importantly, this model suggests
that inflammation and obesity are outcomes of adolescent
depression, rather than initial contributing causes. Further
research on biological and psychosocial effects of sex
M. L. Byrne (&)
N. B. Allen
Melbourne School of Psychological Sciences, The University
of Melbourne, Melbourne, VIC 3010, Australia
e-mail: michelle.byrne@gmail.com
N. M. OBrien-Simpson
Melbourne Dental School, Oral Health CRC, The University
of Melbourne, 720 Swanston Street, Carlton, VIC 3010,
Australia
S. A. Mitchell
Faculty of Medicine, Nursing and Health Sciences, School
of Psychology and Psychiatry, Monash University,
Melbourne, VIC 3800, Australia
N. B. Allen
Department of Psychology, University of Oregon,
Eugene, OR 97403-1227, USA
hormones is needed, as is longitudinal research with children
and adolescents.
Keywords Adolescent depression
Obesity

Inflammation
Puberty
Sex differences
Introduction
Depression, Obesity, and Inflammation
Major depressive disorder (MDD) is a preeminent public
health issue [1], with lifetime prevalence rates estimated to
be 1316 % in the general population when measured
retrospectively [2], and as high as 41 % when measured
prospectively [3]. It is a debilitating disease and projected
to be the second highest cause of disease burden as mea-
sured in disability adjusted life years by 2020 [4]. In the
United States alone, the economic burden of depression
was estimated to be $83.1 billion dollars in 2000 [5]. Not
only are the symptoms and consequences of depression
undesirable and often devastating for individuals, they are
also expensive and damaging on a broader scale. For so-
ciety, depression has a heavy cost.
One of the most notable features of the epidemiology of
depression across the lifespan is the significant increase in
incidence observed during early to middle adolescence,
especially for girls [6, 7]. Point prevalence estimates of
depressive illnesses (i.e., the rate of current depression at
any one time, as measured by cross-sectional studies) in
adolescents aged 1318 years range from 2.9 to 5.8 % [6,
810], while lifetime prevalence is estimated to be from
11.7 [11] to 20.4 % [9]. Furthermore, some research sug-
gests that the first onset of depression often occurs in
adolescence [12], and that early-onset depression is
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associated with an increase in comorbidity of other mental
illnesses compared to adult-onset depression [13]. There-
fore, adolescent depression is a significant mental health
issue, and identification of risk factors for this type of de-
pression is important for developing treatments and
interventions.
Comorbidity of depression with medical conditions has
also been reported. In particular, the relation between
MDD and obesity is well documented in adults (e.g.,
[1417]. Furthermore, in many countries, rates of obesity
have been increasing over the past few decades. For ex-
ample, in the US, the prevalence of obesity, defined as a
body-mass index (BMI) score above 30 kg/m2, has in-
creased over 50 % from 19802000 [18], and 70 % of adults
are classified as overweight [19], which is defined as a BMI
score over 25 kg/m2. Similar estimates of prevalence exist in
other developed nations such as Australia [20].
Obesity is also a growing problem in children and
adolescents. The National Health and Nutrition Examina-
tion Survey in the US reported that 16 % of children and
adolescents aged 619 years were overweight or obese in
2002 [21]. A follow-up of that survey in 2010 revealed that
almost 17 % of children and adolescents were now obese
[22], suggesting that the prevalence of obesity in American
children and adolescents is increasing. Obesity is also a risk
factor for many medical illnesses such as type 2 diabetes
[23, 24], cancer [25], cardiovascular disease (CVD; [26
28]), and general mortality [29].
Finally, there is significant evidence showing that in-
flammatory processes are related to both depression (for
review, see [30, 31] and obesity [3236] in adults. For
example, inflammatory proteins such as C-reactive protein
(CRP; [37]) and cytokines interleukin (IL)-6 [38], and tu-
mour necrosis factor (TNF)-a [39], have all been shown to
be elevated in samples of adults with depression. Further-
more, injections of cytokines for treatment of certain
medical conditions can induce clinical levels of depression
in some people [40], suggesting that there may be a type of
depression that is cytokine-induced. Some research has
suggested that activation of the inflammatory and oxidative
& nitrosative stress (IO&NS) pathways contributes to
neurodegeneration and consequently, depressive symptoms
and behaviors (for review, see [41]. Finally, adipose tissue,
a connective tissue that is made up of fat cells (adipocytes),
nerve cells, and immune cells, all of which together act as
an endocrine organ [42], can release certain cytokines, such
as IL-6 [33], TNF-a [43], and CRP [44].
Why Examine These Processes in Adolescents?
Differing risk factors, both neurobiological [45] and psy-
chosocial [46], have been suggested for child-, adolescent-,
and adult-onset depressionhowever, many of these are
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Child Psychiatry Hum Dev
differences in cross-sectional associations rather than true
antecedents of depression. Additionally, obesity and in-
flammation have not yet been fully explored in terms of
their potential role as either correlates, risk factors, or
consequences of adolescent depression. While associations
between depression, obesity, and inflammation may also
exist in children and adolescents, to date there has been no
summary of these research findings. Furthermore, although
limited longitudinal research in adults has been conducted,
temporal relations between depression, obesity, and in-
flammation are not always consistent, and they have not yet
been comprehensively examined in adolescence when de-
pression often emerges.
Biological mechanisms or outcomes of adolescent-onset
depression may be especially important because obesity
and inflammation are associated with endocrine processes,
which are salient during sensitive adolescent specific de-
velopmental periods such as puberty. Therefore, mechan-
isms of depression may differ across the lifespan, and in
adolescence, may depend on pubertal stage, timing, and
tempo (or velocity). Sex differences may be especially
apparent during this period, because levels of estrogens
and androgens become strongly differentiated between
males and females at this point. In fact, in prepubescent
children, rates of depression are approximately equal for
males and females [47]. From puberty, however, there is a
dramatic shift in this pattern where females are suddenly
more likely to suffer from depression than males [48]. In
fact, one study found that negative affect in adolescent
females was associated with more rapid increases in
estradiol [49]. Additionally, the number of negative life
events (e.g., death of a parent, suspension from school)
was more strongly associated with negative affect than
levels of sex hormones were. It is likely that the rise in sex
hormones around this age interacts with changes in psy-
chosocial roles that may result in more adverse experi-
ences. One diathesis-stress model of the gender difference
in depression suggests that girls have more risk factors
prior to puberty, and stressors during puberty interact with
these risk factors to lead to depression [7]. These risk
factors are often identifiable before adolescence and in-
clude cognitive and personality factors such as excessive
empathy or compliance [50]. Many other risk factors for
depression, such as early life trauma [51] and parenting
behaviors [52], are also present before puberty. However,
this review will focus on those changes that are observable
at or after puberty. Furthermore, although other models of
increases in sex hormones leading to depression via hy-
pothalamuspituitaryadrenal (HPA) axis sensitivity exist
(e.g., [53, 54]), this review will focus on the effect of sex
hormones on psychosocial changes, inflammatory pro-
cesses, and obesity, which are in turn associated with
adolescent-onset depression.
Child Psychiatry Hum Dev
This paper aims to summarize literature within child
and adolescent samples and to highlight any longitudinal
research that may show temporal associations between
depression, obesity, and inflammation, and to determine if
obesity and inflammation are risk factors or outcomes of
adolescent-onset depression. This will allow researchers to
more comprehensively examine developmental processes
of adolescent depression, but will also assist clinicians to
identify risk factors for either depression or obesity and
inflammatory diseases in order to inform early intervention
or preventative treatments. Furthermore, this review sum-
marizes sex differences in these associations that have
been observed in adults, children, or adolescents. Finally,
we propose a hypothetical model to be tested by further
research, based on the integration of the data so far,
whereby increases in sex hormones during puberty in-
crease risk for depression, which affect adiposity, poten-
tially leading to obesity. Obesity, in turn, increases levels
of inflammation. Importantly, adolescent-onset depression
may be an antecedent of obesity and increased inflamma-
tion. We then discuss future research directions that can
test these hypotheses and further elucidate the pathways by
which depression, obesity, and inflammation influence
each other.
Depression and Obesity in Adolescence
Weight appears to be associated with depression in ado-
lescents, but it is not yet clear if being overweight, un-
derweight, or either, is a marker of depression. A study of
adolescents aged 1517 years found that obesity was cross-
sectionally associated with elevated depressive symptoms
[55]. Another study of adolescent females aged
1117 years found that BMI and percentage of body fat
were positively associated with both anxious and depres-
sive symptoms [56]. However, a study of 18-year-old
Greek students found that participants with lower BMI
scores had more depressive symptoms [57]. These seem-
ingly conflicting results may be evidence for a U-shaped
association between BMI and adolescent depression, where
both underweight and obese adolescents are more likely to
be depressed. In fact, the sample from the Matziou et al.
[57] study only included one obese participant, but had 14
underweight participants (BMI score of 18.5 kg/m2 or
less), meaning that the effect of BMI on depression may
have only been apparent for underweight adolescents,
while the effect of obesity was not able to be observed.
A U-shaped association of BMI and depression would also
be consistent with the idea that both atypical (a symptom of
which is increased appetite, and may be associated with
higher BMI) and melancholic (a symptom of which is
decreased appetite, and may be associated with lower BMI)
depression could be related to abnormal weight.
Furthermore, some longitudinal research points to evi-
dence that depression in adolescence and young adulthood
may be a risk factor for developing obesity later in life.
First, a study of university students aged 1825 found that
baseline depressive scores interacted with baseline BMI to
predict an increase in weight at a 20-year follow-up [58].
Participants who reported high levels of depressive symp-
toms at baseline gained less weight than non-depressed
participants if they initially had a low BMI score, but de-
pressed participants gained more if they initially had a high
BMI score. Additionally, participants with high levels of
depressive symptoms at both baseline and follow-up gained
more weight than those with high levels of depressive
symptoms at only one time point. Second, the National
Longitudinal Study of Adolescent Health in the US found
that baseline depressive symptoms were not associated
with being obese at baseline, and that having high levels of
depressed mood at baseline was associated with being
obese at follow-up, including for those not obese at base-
line [59]. Being obese at baseline did not predict depressed
mood at follow-up, and there were no moderating effects of
sex. Third, the Coronary Artery Risk Development in
Young Adults (CARDIA) study examined trajectories of
BMI scores and depressive symptoms over time [60] and
found that young adults aged 1830 years at baseline with
higher levels of self-reported depressive symptoms expe-
rienced a faster rate of increase in BMI and waist-to-hip
ratio (WHR; a measure of adiposity) over time compared to
young adults with lower levels of depressive symptoms at
baseline. Importantly, these investigators examined the
effect in the opposite direction and found that baseline BMI
and WHR were not associated with the rate of change in
depressive symptoms over time. Results from these three
prospective studies suggest that depression in adolescence
or young adulthood precedes obesity. Research on much
younger samples is limited, but one study also found that
depressive symptoms at 10 years old predicted waist cir-
cumference and BMI at a 3 year follow up for boys, but not
girls; however, dysthymia predicted waist circumference in
both sexes [61].
These results alone are not evidence of a causal relation
between depression and obesity. However, the mechanisms
involved in depression as a cause of obesity may be largely
embedded in lifestyle factors. Several studies have shown
an association between depression and lack of physical
activity [6264] or lower adherence to a low-fat diet [65].
It is also possible that the association between depression
and obesity is bidirectional and that obesity may have
consequences for psychological well-being. For example,
the Sjoberg et al. [55] study showing that obesity was
related to depressive symptoms in adolescents also found
that measures of shame may explain the association.
Obesity in adolescents may engender feelings of shame and
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humiliation, negative stigma, low self-esteem, or body
image dissatisfaction, all of which can in turn lead to de-
pressed mood [66, 67].
However, a direct causal relation in either direction may
not necessarily exist. It is possible that obesity and de-
pressive symptoms are both heritable phenotypes that
emerge at different times during adolescence. Without
controlling for parental or genetic factors in both of these
domains, it is not possible to conclude that depression
causes obesity or vice versa, but rather that one simply
precedes the other. One twin study found a 12 % shared
genetic contribution to both depression and obesity [68].
Future studies aiming to elucidate mechanisms of obesity
and depression should attempt to measure these variables
in parents, as well, in order to control for them in statistical
models.
The last possibility is that early-life experiences may
also contribute to both depression and obesity, which,
again, may emerge at different times over the lifespan. In
a study of adult women, childhood abuse or neglect
(measured retrospectively) was associated with higher
waist circumference and BMI [69]. Other research has
shown similar results and also effects of abuse and neglect
on levels of inflammation through BMI [70]. However, a
recent study has showed that maltreated children aged
912 did not differ in terms of the prevalence of being
overweight or obese when compared to non-maltreated
children from the same neighbourhood. In fact, for fe-
males, sexual and physical abuse was negatively associ-
ated with obesity [71]. Furthermore, for the non-
maltreated children only, depressive measures were
positively associated with obesity. Nevertheless, a recent
meta-analysis has reported that childhood maltreatment is
associated with obesity in adulthood, and not in adoles-
cence [72], suggesting a delayed effect of early-life stress
on obesity, which may not be relevant for adolescent-
onset depression, specifically. Alternatively, the discrep-
ancies could point to an effect of abuse measured retro-
spectively instead of simultaneously.
Therefore, although depression in children and adoles-
cents seems to be antecedent to obesity, it is not yet clear if
depression has a direct effect on obesity. Future longitu-
dinal studies aiming to elucidate the direct mechanisms of
depression on obesity should measure lifestyle factors such
as physical activity and diet, self-esteem and other social
factors, parental and genetic risk factors, and the effect of
early-life trauma and maltreatment.
Depression and Inflammation in Adolescence
The limited research so far suggests that immune abnor-
malities, especially elevated markers of inflammation such
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Child Psychiatry Hum Dev
as CRP, may already be present in depressed young people,
but further research in this area is required. Cross-sectional
studies have shown that inflammatory markers are elevated
in adolescents with dysthymia [73], MDD [74], and anxiety
disorders [75]. Other studies have shown that inflammatory
proteins are positively correlated with depressive symp-
toms in children aged 711 years [76]. However, some
research has found no cross-sectional association between
depressive symptoms and inflammation [7779], nor dif-
ferences in inflammation between clinically depressed and
non-depressed adolescents [80].
In adults, some longitudinal research has shown that
inflammation precedes clinical depression [81] while other
research has shown that depressive symptoms precedes
inflammation [82, 83]. Yet other longitudinal research has
suggested that the relation is bi-directional [84]. In ado-
lescents, longitudinal data has shown that cumulative epi-
sodes of MDD predicted later levels of CRP [85], but CRP
did not prospectively predict any measure of depression,
which suggests that elevated inflammation is a conse-
quence rather than an antecedent of adolescent-onset de-
pression. However, another longitudinal study of
adolescent females at risk for depression at baseline found
bidirectional associations between depression and inflam-
matory markers [86], so further research is needed to de-
termine the directionality and various pathways between
depression and inflammation in adolescents. Although
SSRIs have been shown to have anti-inflammatory effects
in adults [87], this has yet to be demonstrated in adoles-
cents, although cross-sectional research has shown that
adolescents treated with SSRIs have higher levels of the
anti-inflammatory marker IL-10 [75]. This suggests that
depression may indeed be an antecedent to inflammation in
adolescence. However, as with the relation between de-
pression and obesity, it is not yet clear if there is a direct
effect of depression on inflammation, or if other mediating
factors may play a role.
Obesity and Inflammation in Adolescence
As in research with adult samples, evidence from child and
adolescent studies also shows an association between
obesity and inflammatory markers, particularly CRP. A
school-based study of Canadian children and adolescents
aged 9, 13, and 16 years found a positive correlation be-
tween BMI scores and plasma CRP [88]. In Mexican-
American children aged 611 years, BMI and WHR were
each independently associated with serum CRP concen-
trations, as well as high-density lipoprotein cholesterol
[89]. In the Third National Health and Nutrition Ex-
amination Survey in the US, the association of being
overweight or obese with elevated serum CRP levels
Child Psychiatry Hum Dev
remained even when restricting analyses to people aged
1739 years [35]. Although CRP seems to be the main
inflammatory marker elevated in obese children and ado-
lescents, concentrations of IL-6 and TNF-a have also been
shown to be elevated in obese children compared to those
with normal weight [90]. For example, another study of
Mexican-American young people aged 1016 years found
that obesity, defined as BMI in the 95th percentile, was
associated with elevated levels of serum TNF-a [91].
Some longitudinal studies of obesity and inflammation
exist in adults, mainly as studies of weight loss. This re-
search shows a significant decrease in plasma or serum
CRP levels in both men and women [92100], regardless of
whether the weight loss is through changes in diet, in-
creases in exercise, or surgery [101]. Concentrations of IL-
6 also appear to decrease after weight loss in obese women
[102]. However, no longitudinal research has yet examined
obesity and inflammation in children or adolescents, so
developmental differences in the association of obesity and
inflammation, and the associate causal mechanisms, remain
unexplored. This is clearly an important avenue for future
research.
Sex Differences in Depression, Obesity,
and Inflammation
Some research has shown that sex differences exist in de-
pression, obesity, and inflammation. The consideration of
sex differences in adolescent-onset depression is vital,
because childhood and adolescence are critical periods for
brain development that correspond to physical develop-
ment, behavioral changes, and emergence of mental ill-
nesses, and these developmental trajectories do not always
occur similarly in both males and females [103]. In par-
ticular, studies that examine these processes in adolescents
longitudinally are necessary to examine separable effects
of pubertal stage, timing, and tempo, all of which have
been shown to play a role in depression [104106].
Rates of depression are higher in females than in males
[107]. Many mechanisms have been suggested to explain
this difference, some psychosocial, some biological, and
some a mixture of both. Men and women may experience
different psychosocial roles, such as a discrimination in the
work force or a reduction of paid employment, and women
may have more adverse experiences as a result of these
sociocultural roles or they may experience decreased self-
esteem [107], which can then lead to more depressive
symptoms or chronic stress. The inflammatory response
activates in the presence of stress, regardless of whether it
is a biological threat or a psychosocial stressor [108], so
both inflammation and depressive symptoms may increase
in response to these changing social roles, especially during
puberty. Interestingly, some research in cultural popula-
tions where more value is placed on womens roles shows
little or no difference in rates of depression between the
sexes [109].
The increase in sex hormones during puberty not only
changes an individuals pubertal stage, but also potentially
pubertal timing compared to his or her peers. In addition,
individuals may experience different rates of increase of
these sex hormones (pubertal tempo or velocity; [110].
Therefore, there may be individual differences in these
pubertal changes that affect consequences that are psy-
chosocial or directly biological.
Female sex and obesity are also related, and these fac-
tors may interact to affect depression. Adipose tissue may
be more important to measure than weight alone, as women
have a higher percentage of body fat than men overall
[111], even in pre-pubertal children [112], and adolescent
females acquire more adipose tissue than males during
puberty [113]. Other research has shown female sex to be a
moderator of the relation between obesity and depression
[114]. The heterogeneity of depressive illness may also
affect these processes. For example, obesity may be a
factor only in atypical MDD and this type of depression is
more common than melancholic MDD. If sex hormones
affect both depressed mood and an increase in appetite and/
or weight, then as expected, being female is more charac-
teristic of atypical MDD [115], as is having younger age of
onset [116]. As such, it is possible that being female is a
risk factor for this subtype of depression only, which in-
flates the overall increase in rates of depression for fe-
males. This model may also be applicable to adolescent-
onset depression.
Finally, females have a stronger immune response than
males, especially after puberty [117]. They produce more
inflammatory cytokines [118], and have higher rates of
autoimmune disease [119]. It has been shown that
symptoms of autoimmune diseases and levels of cytokine
production change at different stages of the menstrual
cycle [120]. Therefore, sex hormones such as estradiol
may modulate the mechanisms of autoimmune diseases.
Immune cells express estrogen receptors [121], and
estrogen has been shown to increase inflammation [122]
by affecting dendritic cell development and promoting the
inflammatory response [123], or by upregulating the ex-
pression of proinflammatory genes [124]. Therefore, the
reason that females are more likely to suffer from au-
toimmune diseases than males is likely due to the effect
of estrogens that cause the immune system to be more
responsive.
Within child and adolescent research, the Copeland
et al. [85] study showing that MDD prospectively predicted
levels of inflammation did control for sex, and this did not
attenuate the relation between depression and CRP.
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Another study found no association between depression
and inflammatory markers for either sex; however, for
older female adolescents only there was an association
between depression and immune cell activity [77]. Fur-
thermore, Keller et al. [76] examined children and young
adolescents, and found that the positive association be-
tween IL-6 and depressive symptoms was present only for
girls. Other research has found similar results for female
adolescents with salivary CRP and depressive symptoms
[128]. The effect of sex on depression and inflammation in
children and adolescents remains to be elucidated, but
initial findings suggest that female sex is a moderator.
An Integrated Hypothetical Model of Puberty,
Depression, Obesity, and Inflammation
Few studies have combined measures of obesity, inflam-
mation and depression in one sample. One study of adult
men aged 4574 years found an association between in-
creased CRP levels and depressive symptoms only in a
group that was obese [125]. Another study of adult men
and women found that depressive symptoms were
positively correlated with CRP levels and BMI [126].
However, after controlling for BMI, there was no sig-
nificant association between depression and CRP for each
sex separately, or for both sexes together. This suggests
that obesity mediates the association between depression
and inflammation, and does not suggest that either in-
flammation or depression has a direct effect on the other.
Adipose tissue releases inflammatory markers [33]; there-
fore, it is plausible that depression affects obesity, which in
turn affects inflammation. In fact, a study of adults with
depressive illness compared to age-, gender-, and ethnicity-
matched healthy controls found that a statistical model
specifying that depression predicted adiposity (measured
by BMI and WHR), which in turn activated an inflamma-
tory response (measured by levels of IL-6 and CRP), was a
better fit to the data than one where adiposity led to an
inflammatory response that triggered depression [127].
However, as this research is still cross-sectional in nature,
further longitudinal studies are required in order to develop
more compelling causal models of the relationship between
depression, obesity, and inflammation over time, and to
ascertain if BMI and other measures of obesity are medi-
ating factors in the association between depression and
inflammation.
Only one study of adolescents has been conducted
combining all measures. This study shows an association
between depressive symptoms and CRP for those with a
high BMI score only [128]. Furthermore, the significance
of the increase of sex hormones during puberty on this
model has not yet been examined. The effects of increased
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Child Psychiatry Hum Dev
estrogens on depression, obesity, and inflammation should
be measured in a longitudinal study of adolescents in order
to clarify whether puberty is a risk period for these out-
comes, especially for females.
Based on an integration of the literature reviewed here,
we propose a hypothetical diathesis-stress model of the
emergence of depression during adolescence that incorpo-
rates the roles of sex and obesity, with inflammation as an
outcome. This model is based on the few adolescent studies
that have examined these associations separately, as well as
adult research that has examined sex differences or longi-
tudinal associations. We hypothesize that sex hormones
affect both depression and inflammation through multiple
pathways (see Fig. 1). Firstly, a rise in estrogens for fe-
males during puberty can increase the likelihood of de-
pression in vulnerable individuals via psychosocial changes
stemming from pubertal change, especially in relation to
peers. Examples of this could include (a) an increasing
number of negative life events, where females may be
more sensitive to this change, or (b) a decrease in self-
esteem, leading to depressive symptoms.
Alternatively, an increase in sex hormones, especially a
rapid rise, may increase inflammation directly (c), possibly
through HPA axis mechanisms, or through a direct effect
of sex hormones on immune cell receptors, although the
latter remains to be tested comprehensively. However,
for individuals that are vulnerable to developing depres-
sion through psychosocial pathways discussed above, a
depressive illness could influence a change in lifestyle
factors that increases adiposity, leading to obesity (d). In
turn, this can increase levels of inflammation (e). Obesity
can also further increase depressive symptoms and be-
haviors through psychological mechanisms (f). Addition-
ally, depressive symptoms or the presence of depressive
illness can generate further psychosocial stress and activate
an inflammatory response (g). Finally, psychosocial stress
from sociocultural changes and adverse experiences
for females can also directly activate an inflammatory
response (h).
Importantly, this model suggests that, during adoles-
cence, inflammation and obesity are outcomes (and mark-
ers) of increased sex hormones and depression, rather than
initial contributing causes. This conjecture is somewhat
inconsistent with research showing that patients injected
with inflammatory cytokines often experience depressive
symptoms as a result [40], and animal research demon-
strating increased depressive-like behaviors in monkeys
injected with cytokines [129]. However, this type of cy-
tokine-induced depression may have a different etiology,
including degenerative effects through the IO&NS path-
ways, but may not necessarily be as relevant to a first
episode with an onset in adolescence. It appears that the
adolescent, first-onset depression may be an antecedent to
Child Psychiatry Hum Dev

Fig. 1 Proposed model of the

effect of sex hormones on the
association between depression,
obesity, and inflammation
during adolescence. Some
evidence suggests that obesity
mediates the relationship
between depression and
inflammation (e) rather than the
two being directly linked;
however, depressive behaviors
could potentially generate
stress, which activates an
inflammatory response (g).
Importantly, this type of model
suggests that inflammation is an
outcome, rather than a cause of
adolescent-onset depression

inflammation in adolescence, and this is supported by re-
cent prospective, longitudinal research in adolescents [85].
This type of depression may increase inflammation directly
or through obesity, and this could set an individual up for
reoccurring depression through cytokine-induced models.
In other words, adolescent-onset depression could ori-
ginate from non-inflammatory mechanisms, but once in-
flammation has increased, could result in a feedback loop.
This is not shown in our model but may be relevant for
relapse and recurrence of depression. It suggests that re-
occurring depression can be difficult to treat as there are
many complicating factors driving its etiology that may not
always be examined during treatment. However, this can-
not be confirmed without further longitudinal research
examining inflammatory, obesity, and psychosocial mea-
sures in adolescents before and after they experience their
first episode of depression.
Recommendations and Directions for Future Research
Research suggests that females are at risk for both de-
pression and elevated inflammation, which may be due to
increased sex hormones and obesity, especially during
puberty. Therefore, studies should also include enough
statistical power to be able to examine effects by sex.
Relatedly, research in this area would benefit from studies
of children and adolescents during sensitive developmental
periods where the effect of sex hormones and increases in
hormones can be measured and controlled for. This would
require longitudinal research to examine the effects of
pubertal timing and velocity. Additionally, the influence of
increasing hormones other than estrogens, prior to the onset
of puberty, may also be relevant. Adrenal androgens such
as dehydroepiandrosterone (DHEA) signify the start of
adrenarche prior to gonadarche, and have been shown to
activate the immune response [130]. Other research has
shown that DHEA [131] levels are decreased in adult pa-
tients with MDD. It seems likely that biological mechan-
isms underlying these processes differ in pre-pubescent
children that are experiencing an initial increase in adrenal
androgens compared to adults or elderly patients. There-
fore, in order to assess the effect of hormones in the pro-
posed model, adrenal androgens such as DHEA should be
also measured in pre-pubescent children alongside other
sex hormones.
In addition to multiple measures of endocrine func-
tioning, a wider range of immunological factors should be
considered. While much research has focused on inflam-
matory proteins, few have examined multiple proteins [80,

123

132, 133]. Additionally, other research has shown that de-
pression is associated with dysfunction of B cells [134], NK
cells [135], and T cells [136]. Research with younger sam-
ples is lacking, but preliminary research has shown NK cell
dysfunction in depressed children and adolescents [137].
Furthermore, the effect of the immune system on other
biological systems and vice versa can be examined via the
glucocorticoid receptor (GR) or GR gene, both of which are
implicated in MDD [138]. The GR gene in particular could
be examined in early childhood, or, conversely, early
childhood trauma is known to affect the GR gene epige-
netically [139]. Other endocrine receptors, such as sex
hormones, that are expected to have immunomodulatory
effects could also be explored in depression.
One potential method to examine multiple sex hormones
and inflammatory markers with children and adolescents is
through saliva collection. Compared with blood, saliva is
safer and easier to collect in research studies, especially
with younger samples or with participants where comorbid
blood and needle phobias are a concern. CRP has been
shown to correlate well between saliva and blood in adults
[140] and in adolescents [80]. Testosterone and estradiol
have also been successfully measured in saliva and corre-
lation of these hormones between saliva and serum is high,
especially in adolescents [141]. In fact, saliva may be a
superior medium to measure these hormones because
saliva has a higher percentage of the biologically active, or
unbound, version of these hormones, while most of the
hormones in blood are bound to other serum proteins [142].
Therefore, saliva should be considered as a useful biolo-
gical medium in which to examine many of the processes
proposed in this model.
Summary
Depression is a prevalent and serious public health issue
and has significant comorbidity with obesity in adults. In-
flammatory processes in particular, have been investigated
as potential mechanisms explaining the link between obe-
sity and depression. However, this mechanism during
sensitive developmental periods such as puberty has not yet
been fully explored, making identification of obesity and
inflammation as risk factors for adolescent depression
difficult. Initial evidence implicates the rise of estrogens in
females during puberty as a factor affecting depressive
symptoms and behaviors, which then affect obesity, and in
turn influence levels of inflammation, suggesting that
adolescent depression may actually be a risk for developing
obesity and elevated inflammation. Therefore, further re-
search with children and adolescents utilizing longitudinal
designs and combining measures of depression, obesity,
and inflammation is justified to test this hypothetical
123
Child Psychiatry Hum Dev
model. Additionally, further research on the influence of
obesity on depression, through psychological factors such
as shame or low self-esteem, and the influence of depres-
sion on general stress is needed in order to fully charac-
terize bidirectional relations in this model. Finally,
biological research examining the functioning of sex hor-
mone receptors on immune cells will shed light on the
direct influence of sex hormones on immune functioning
and inflammation. This type of research will have impor-
tant implications for understanding pubertal mechanisms in
this model, and will support intervention efforts to prevent
both inflammatory and depressive illnesses, and reduce
rates of obesity. It will also assist clinicians to identify and
screen for common comorbidity between depression, in-
flammation, and obesity in adolescents and provide an
evidence-based approach to a wider treatment plan.
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