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Abstract

  1. Top of page
  2. Abstract
  3. Method
  4. Results
  5. Conclusion
  6. References

The aim of this paper was to review the longitudinal relationship between early-onset depression and disruptive behaviour and adult body weight. A systematic review of prospective longitudinal studies was conducted of articles in which (1) initial assessment occurred during childhood or adolescence (<18y); and (2) the primary outcome reported as body mass index (BMI), overweight (BMI>25–<30kg/m2), obesity (BMI≥30kg/m2), or depression; and (3) validated assessment measures for assessment of depressive symptoms or disruptive behaviour problems were employed. A total number of 16 articles were identified for review. Obese adolescent females are more likely to develop depressive illness in adulthood than their non-obese peers. Conversely, depressed adolescent females, and possibly males, are more likely to become overweight adults than non-depressed adolescents. There are insufficient data addressing future depression risk among overweight, non-obese, adolescents to evaluate the potentially interactive nature of this relationship. Studies to date are consistent in reporting that children with behaviour problems are at increased risk of future overweight, though whether this risk is conferred by conduct symptoms, ADHD symptoms, or both, is less clear. Care providers of children with disruptive behaviour problems and depressed adolescents should monitor weight gain. Among obese adolescent females, mood should be followed.

What this paper adds
  • Prospective longitudinal studies confirm that subgroups of individuals with early-onset mental illness are at increased risk of greater adult body size.
  • Children with disruptive behaviour and adolescents with increased depressive symptoms should be monitored for weight gain.
  • Research examining the association between depression/disruptive behaviour and weight gain is needed.

Current public health initiatives recognize that obesity, a leading cause of morbidity and mortality, is increasing to epidemic proportions in developed countries.[1] The rising prevalence of overweight and obesity in recent years has resulted in a rapid increase in costs for health care in North America, estimated at 4.6% and 5.7% of the national health expenditures in Canada and the United States respectively.[2, 3] In addition, obese individuals experience decreased quality of life,[4-6] greater activity restriction and increased levels of occupational dysfunction, leading to significant lost productivity costs.[3] Despite growing awareness of nutritional and physical activity patterns that contribute to the development of obesity, effective treatments are limited, leading to an increased focus on prevention strategies in at-risk populations, including adolescents. In keeping with the view of obesity as a developmental, progressive condition,[7-11] targeting childhood factors that predict increases in body mass index (BMI), a measure of overweight and obesity, may result in the development of more effective prevention interventions.

The purpose of this investigation is to review present knowledge with respect to: (1) the longitudinal relationship between depression and overweight where either disorder is first detected in childhood; and (2) the association between childhood- or adolescent-identified disruptive behaviour and adult body weight.

Method

  1. Top of page
  2. Abstract
  3. Method
  4. Results
  5. Conclusion
  6. References

MEDLINE and PubMed searches of English language articles published between 1966 and 2012 were conducted using the search terms ‘depression’, ‘attention deficit hyperactivity disorder’, ‘conduct disorder’, ‘behaviour problems’, ‘disruptive behaviour’, cross-referenced with ‘body mass index’, ‘overweight’, or ‘obesity and augmented with manual review of reference lists. Using this strategy, 164 articles were identified. Articles selected for review were limited to human studies and were based on the following inclusion criteria: prospective longitudinal study design; initial assessment occurring during childhood or adolescence (participants <18y); primary outcome reported as BMI, overweight, obesity, or depression; use of validated assessment measures for assessment of depressive symptoms or disruptive behaviour problems. Retrospective studies in which participants were asked to recall childhood exposures were not included. Using these criteria, 14 articles were selected for review. Manual review of reference lists subsequently identified two additional studies for inclusion, yielding a total number of 16 articles (Tables 1-3) included for review.

Table 1. Child and adolescent overweight/obesity and adult depression: prospective studies included in review
Study no.First author, country, yearAge-base-line (y)Age at follow-up (y)Female (%)Final sample sizeWeight variable assessed at baseline (m/s)Psychological symptoms assessed at baseline (measure)Psychological variable at follow-up (measure)Results (+/−)
  1. a

    Parent report of height/weight at baseline, participant self-report for participants thereafter. m, measured; s, self-report; +, positive association reported; −, no association reported; CAPA, Child and Adolescent Psychiatric Assessment;[52] K-SADS-PL, The Schedule for Affective Disorders and Schizophrenia for school-age children – Present and Lifetime version;[37] HSCL-25, Hopkins Symptom Checklist-25;[53] DISC, The Diagnostic Interview Schedule for Children;[36] MDD, major depressive disorder; SCID, Structured Clinical Interview for DSM-IV Disorders.[54]

1Mustillo, USA, 2003[24] 91644991Obesity (m)+(CAPA)CAPA

−Females

+Males

2Boutelle, USA, 2010[25] 11–1514–18100488

Overweight

Obesity (m)

+(K-SADS-PL)Depressive symptoms/Depression (KSADS-PL)

Overweight:

−depressive symptoms

−depression diagnosis

Obesity:

+depressive symptoms

−depression diagnosis

3Herva, Finland, 2006[26] 1431528451Obesity (s)HSCL-25

+Females

+Males

4Anderson, USA, 2007[27] 9–1828–3953661Obesity (s)a+(DISC)MDD (SCID-IV)

+Females

−Males

Table 2. Child and adolescent depression and adult overweight/obesity: prospective studies included in review
Study no.First author, country, yearAge-base-line (y)Age at follow-up (y)Female (%)Final sample sizePsychological measure used: variable type (categorical/continuous)BMI assessed in adolescence (m/s)Outcome at follow-up (m/s)Results (+/−)
  1. a

    Parent report of height/weight at baseline, participant self-report for participants >13 years thereafter. K-SADS, Schedule for Affective Disorders and Schizophrenia for school-age children;[37] BMI, body mass index; categorical, MDD diagnosis; continuous, depressive symptoms; m, measured; s, self-report; +, positive association reported; −, no association reported; DISC, Diagnostic Interview Schedule for Children;[36] CES-D, Center for Epidemiological Studies–Depression scale.[38]

1Richardson, New Zealand, 2003[28]11–152648881DISC: categorical+(m)Obesity (m)

−Females

−Males

2Pine, USA, 1997[29] 9–1817–2852644DISC: continuousBMI (s)/Obesity (s)

+(BMI)

− (obesity)

3Franko, USA, 2005[30]1621–231001554CES-D: continuous+(m)

BMI (s)

Obesity (s)

+Females (BMI)

+Females (Obesity)

4Goodman, USA, 2002[31]12–1813–19499374CES-D: categorical+(s)Obesity (s)+Males and females (data not presented separated by sex)
5Bardone, New Zealand, 1998[32]1521100459DISC: categorical+(m)BMI (m)−Females
6Anderson, USA, 2006[33] 9–1828–4053661DISC: categorical+(s)BMI (s)a

+Females

−Males

7Pine, USA, 2001[35] 6–1716–32 177K-SADS: categorical+(m)BMI (s)+Overall (no effect of sex)
8Wickrama, USA, 2009[34]12–1918–255211,404CES-D: continuous+(s)Obesity (s)−Overall (data not presented separately by sex)
Table 3. Child/adolescent behavioural problems and adult overweight/obesity: prospective studies included in review
Study no.First author, country, yearAge-base-line (y)Age at follow-up (y)Female (%)Final sample sizePsychological measure usedBMI assessed at baseline (m/s)Outcome variable at follow-up (m/s)Results (+/−)
  1. aHeight and weight measured at age 10 years. bObesity defined as BMI>28.5 kg/m2. m, measured; s, self-report; +, positive association reported; −, no association reported; BMI, body mass index; DISC, Diagnostic Interview Schedule for Children;[36] CD, conduct disorder; ODD, oppositional defiant disorder; BPI, behavioural problems index;[59] CBCL, Child Behaviour Checklist.[60]

1Pine, USA, 1997[29]9–1817–2852644DISC (CD symptom count)BMI/Obesity (s)

+BMI

+Obesity; analyses by sex not presented

2Bardone, New Zealand, 1998[32]1521100459DISC (CD or ODD diagnoses)+(m)BMI (m)−Females (decreased BMI in females with CD/ODD)
3Lumeng, USA, 2003[42]8–1110–1347629BPI (behavioural problems >90th centile)+(m)Overweight+ (78% m; 22% s)+Overall, analyses by sex not presented
4Mamun, Australia, 2009[44]521Not described2278CBCL (behavioural problems >90th centile)+(m)

BMI

Obesity (m)

+Child-onset (BMI and Obesity)

−adolescent-onset, (BMI and Obesity); analyses by sex not presented

5White, UK, 2012[45]534Not described7356Parent report subset of Rutter Questionnaire; Abridged Conners Scale[57, 58] (hyperactivity and/or conduct problems ≥1SD above mean)+(m)aObesity (s)b

+Conduct

+Hyperactivity, analyses by sex not presented

6Duarte, Finland, 2010[43]818–2302209Rutter Questionnaire[55] (hyperactivity and/or conduct problems >50th centile)[56]Overweight+ Obesity (m)

+Conduct (overweight and obesity)

−Hyperactivity (overweight and obesity)

In order to improve the quality of the present review, only those studies of prospective longitudinal design were included. Studies reviewed were cohort studies classified as providing level 2 evidence as defined by the Oxford Centre for Evidence-based Medicine.[12]

Results

  1. Top of page
  2. Abstract
  3. Method
  4. Results
  5. Conclusion
  6. References

Depression and overweight

Numerous cross-sectional investigations have detected an association between psychological distress and BMI in both child and adult samples. In particular, investigation of the relationship between depression and obesity (BMI>30kg/m2) in adult populations has been the topic of numerous individual studies and literature reviews.[13-17] Depression is a clinical illness, characterized by one or more depressive episodes, that is associated with poor functional and health outcomes, including increased mortality.[18-20] A recent meta-analysis of 17 (primarily cross-sectional) studies of the relationship between depression and obesity in community-based adult samples included a total of 204 507 participants.[21] In this study, de Wit et al. found a significant overall association between depression and obesity (OR 1.26; 95% confidence interval [CI] 1.17–1.36). Subgroup analyses indicated possible differences between males and females, however, with stronger positive associations found in females (OR 1.28; 95% CI 1.17–1.39) than in males (OR 1.05; 95% CI 0.87–1.28). Interestingly, while the female comparisons were homogeneous, the male participants showed considerable heterogeneity (I2=55.8), indicating that it may be possible to identify subgroups of males at greater risk.

In examining the association between depression and overweight (BMI 25–30kg/m2), the cross-sectional data have provided useful information. However, cross-sectional studies are clearly limited in their ability to evaluate a temporal association between the variables of interest. Investigation of a directional association between psychological distress and BMI using longitudinal methods of study is necessary to elucidate mechanisms of association. With respect to adolescent-onset predictors of adult outcomes, investigators have generally taken one of three approaches: examining either (1) the association of early-onset obesity with adult depressive illness; (2) the association of early-onset depression with adult BMI; or (3) the possibility of a bidirectional relationship between the two illness states. The literature is discussed under these headings below.

Association of BMI in adolescents with adult depression

In probing the directionality of the relationship between depression and obesity reported in cross-sectional studies, researchers have tested the hypothesis that the presence of obesity increases an individual's risk for depressive illness. Although studies of this question have been few, results from adult samples have reported a positive association.[22, 23] In adolescent samples, the longitudinal research is limited to four prospective studies, summarized in Table 1, which provide conflicting results. In a sample of rural, Caucasian participants of the Great Smoky Mountains Study who were followed from 9 to 16 years of age, Mustillo et al.[24] found that chronically obese males were at greater risk of depression at 8-year follow-up than non-obese males. The same association was not found for females in the study. Conversely, Boutelle et al.[25] reported an increased risk of depressive symptoms for obese adolescent females, followed for a 3-year period to a mean age of 16 years. In contrast, two studies of large, representative community samples that were followed for at least 15 years into adulthood demonstrated greater agreement in their findings with respect to females: both Herva et al.[26] and Anderson et al.[27] found adolescent obesity to be associated with the adult development of depression. In a sample from the longitudinal Northern Finland 1966 Birth Cohort Study, Herva et al.[26] found that high BMI at age 14 years was associated with depressive symptoms at age 31 years for both males (OR 1.97, 95% CI 1.06–3.68) and females (OR 1.64, 95% CI 1.16–2.32). In comparison, Anderson et al.[27] assessed adolescent participants of the upstate New York Children in the Community study at three time points, over a 20-year period, and showed that that the risk of depression was present for obese adolescent females only (HR 3.9, 95% CI 1.3–11.8).[27] The different findings with respect to sex may be due in part to the different methods used to assess depression status in these studies: Herva et al. assessed depressive symptoms using a standardized self-report measure as compared with the structured diagnostic interview used by Anderson et al. In using a diagnostic interview to make depression diagnoses, Anderson et al. may have obtained a more accurate estimation of psychiatric illness. However, men in the Anderson study may also have under-reported depressive symptoms, as research suggests that males may be less likely to endorse depressive symptoms in interviews as compared with self-report measures, depending on the sex of the interviewer.[24] As a result, an under-identification of depression may have occurred, leading to a lower likelihood of detecting an association between adolescent obesity and adult depression among men. In addition, by defining the outcome to symptoms at or above the diagnostic threshold for major depression, the study by Anderson et al. may have limited the relationship to that of more severe depressive pathology compared to the outcome of depressive symptoms, as measured by Herva et al. The discrepant findings by sex may also be due, in part, to differences in the studies' ability to retain participants over these long periods of time. Herva et al. achieved a 74% rate of follow-up, in contrast to a 96% rate of follow-up in the study by Anderson et al. As Herva et al. did not report demographic data for the missing individuals, it is not possible to make inferences about this group compared with those that continued in the study. It may be, for example, that non-depressed males were more engaged in their daily activities at the time of the follow-up survey and less likely to participate in the ongoing study assessment, thereby overestimating the association of early overweight with later depression in this study. Despite these caveats, however, the evidence to date suggests that while it is unclear if obese males are at greater risk for future depression, obese females are more likely to experience depression in adulthood than their normal-weight peers.

Association of depression in adolescents with adult BMI

To date, eight longitudinal studies of major depression among adolescents and later overweight or obesity exist[28-35]; these are summarized in Table 2. Of these, three assessed depressive symptoms as a continuous measure using a positive symptom count, while the remaining five dichotomized the variable into either the presence or absence of a diagnosis of depression (Table 2). Interviewer administered measures such as the Diagnostic Interview Schedule for Children-Revised Version (DISC-R)[36] and the Schedule for Affective Disorders and Schizophrenia for school-aged children (K-SADS)[37] identified the presence of clinically relevant symptoms using the assessment of a trained interviewer. Self-administered measures, such as the Centre for Epidemiologic Studies Depression Scale (CES-D),[38] assess the presence and severity of symptoms based on participant self-report; these use validated threshold scores for diagnosis of depression, as described by the DSM-IV,[39] which are specific to the instrument.

Studies examining the association between adolescent depression and BMI at follow-up, rather than obesity per se, have yielded an overall more consistent picture (Table 2), with four of five studies determining that adolescents with greater depressive symptoms or diagnoses of depression have increased BMI at follow-up, and one study reported no association between these factors. Among studies reporting a positive association, all reported a positive association between adolescent depressive symptoms[30] or diagnosis of depression and future BMI for affected females. Data regarding the outcome of depressed adolescent males are less consistent (Table 2). In a clinic-based sample of 90 depressed and 87 age- and sex-matched non-depressed participants, Pine et al.[35] did not find an effect of sex in the association of early onset depression and increased BMI at the 10- to 15-year follow-up assessment. In contrast, Anderson et al.[33] found that among a representative community sample of 661 adolescents in the United States, depression in adolescence was associated with increased self-reported BMI at ages 28 to 40 years for affected females only; depression was not associated with increased adult BMI among males. The methodological limitations of previous research on this topic include use of short periods (1–6y) of follow-up into later adolescence or young adulthood[30-32] the ascertainment of racially non-diverse, primarily Caucasian, study samples, and the inability to examine the specific effect of depression in samples with comorbid anxiety disorders.[33] Moreover, only one study followed participants past the age of 28 years,[33] such that longer-term data with respect to slowly accumulating weight gain are limited. Examination of study findings based on the methodological strength of the measures employed, however, does not yield further clarity (Fig. 1). With the exception of that of Wickrama et al.[34], studies also maintained comparable rates of participant follow-up (85–95%). Although the rate of follow-up in the study by Wickrama et al.[34] was significantly lower (70%), the study investigators found little difference between adolescents with missing and complete data on examination of key study variables. Thus, existing research indicates that depression in adolescence confers increased risk of increased BMI among affected adolescent females. Data examining the risk of increased adult BMI among depressed adolescent males is limited to three studies and yield a conflicting picture, suggesting that further research into the health outcomes of depressed adolescent males is needed.

image

Figure 1. Studies of adolescent major depressive disorder and future risk of overweight or obesity for females: outcomes by study design.aStudies that did not examine outcomes separately for females and males. (+), positive association observed; (−), = no association observed; OWT, overweight; OBS, obesity.

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Out of the five studies that examined a relationship specifically with obesity, two studies that included relatively shorter follow-up periods found that adolescents with increased depressive symptoms or threshold level depression are at increased risk of obesity. Franko et al.[30] reported that adolescent participants of the National Heart, Lung and Blood Institute Growth and Health Study (NGHS) in the United States with greater depressive symptoms at age 16 years were at increased risk of obesity at age 21 years (OR 3.11; 95% CI 1.13–5.12) in a study limited to female participants. Goodman and Whitaker[31], however, reported that an increased risk for later obesity was present for both males and females who had met diagnostic thresholds for depression in adolescence (OR 2.05; 95% CI 1.18–3.56). In contrast, three previous studies of the relationship between adolescent depressive symptoms or depression and adult obesity have not found an association between these problems, regardless of participant sex. Thus, research regarding the association of adolescent depression with future risk of obesity among either females or males is less conclusive than that of body size, which may be due in part to the relatively long periods of follow-up required to allow for examination of the outcome of interest.

Increases in the prevalence of depression and obesity from adolescence to adulthood noted in recent years may obscure the examination of the temporal association between the two disorders. In particular, the prevalence of overweight and obesity significantly increases during the prepubertal and pubertal years, making the examination of depression in the absence of the outcome variable of interest more challenging. Thus, investigating the relationship between earlier, childhood-onset psychopathology and adult overweight and obesity may be of specific value in determining whether these factors are indeed early correlates of later obesity. Of the eight studies, four included childhood psychopathology (Table 2). Pine et al.[35], in a case–control study of a clinical sample of children and adolescents with major depressive disorder (mean age 11y), found depression during childhood to be positively associated with adult BMI. This association was not explained by a number of potential confounding factors. Three additional studies included children less than 12 years of age in their predominantly adolescent study samples, but did not analyse the pre-adolescent subgroup separately. Further research examining the association between childhood-onset depression and adult BMI in prospective, longitudinal studies in representative community samples are needed.

Bidirectional association of depression and BMI

The above data have prompted some investigators to consider the possibility of a bidirectional relationship between the two disorders. Although research aimed at answering this question is limited, several authors have undertaken secondary data analyses in an attempt to address the concept of bidirectionality. In a recent meta-analysis of longitudinal studies, Luppino et al.[40] concluded that evidence of a reciprocal relationship between depression and obesity exists and further, that the association between depression and obesity (OR 1.58; 95% CI 1.33–1.87) is stronger than the association between depression and overweight (OR 1.20; 95% CI 0.87–1.66). Although the magnitude of the relationship was similar regardless of directionality in this meta-analysis, the studies included for analysis were predominantly based on adult samples. Subgroup analyses among individuals younger than 20 years of age was undertaken, and consisted of only two studies of primarily adolescent participants within the overweight/obese exposure subgroup, thereby making definitive comments regarding bidirectionality among adolescents difficult.

Although a study of bidirectionality among child and adolescent aged populations has not been published, Goodman and Whitaker[31] have included data addressing this issue. In the examination of 1-year follow-up data of 9374 participants of the National Longitudinal Study of Adolescent Health, adolescent depressed mood was found to predict obesity at follow-up among participants who were non-obese at baseline (OR 2.05; 95% CI: 1.04–4.06).[31] In contrast, baseline obesity did not predict follow-up depression (OR 1.16; 95% CI: 0.81–1.65).[31] These findings must be interpreted with caution, however, given the brief 1-year study period and the use of a non-diagnostic, self-administered measure of depressive symptoms (CES-D)[38] to determine the dichotomous outcome of presence of depressed mood. With respect to the adult literature, however, the findings of Luppino et al.[40] echo those investigating the relationship between depression and obesity-related conditions, including diabetes mellitus,[41] in noting that the interaction between the two complex, multifactorial pathological processes is likely to be reciprocal in nature.

Disruptive behaviour and overweight

Research exploring the association of childhood behaviour problems and later body size or obesity has been generally consistent in reporting an increased risk of later obesity for affected adolescents regardless of sex (Table 3); however, the studies are limited by young age at follow-up,[42] and the inability to make clinical diagnoses.[42-45] In a Finnish population-based cohort of males, Duarte et al.[43] found that Rutter questionnaire-detected[46] conduct problems at age 8 years were associated with increased risk of measured obesity at 18 to 23 years of age (OR 1.9; 95% CI 1.2–2.8). In this study, childhood hyperactivity symptoms also initially appeared to predict later obesity, but this association did not persist after adjustment for conduct problems. Two prospective, interview-based studies of adolescent psychopathology and later obesity have been conducted with divergent results. In an American population based study, Pine et al.[29] found that conduct disorder in adolescence (mean age 14y) predicted early adult obesity (mean age 22y) among both male and female participants. These findings are in contrast to those of Bardone et al.[32] in a New Zealand based cohort of adolescent females, in which conduct disorder at age 15 years was associated with lower BMI at age 21 years. Although both studies utilized the DISC interview to determine diagnoses of conduct disorder, only the study by Bardone et al.[32] used measured (vs self-reported) height and weight to determine BMI. Of note, Bardone et al. included adolescent females with a diagnosis of oppositional defiant disorder in their conduct disorder sample. In doing so, the investigators may have diluted the psychopathology present in the sample, thereby obscuring the ability to see a relationship between adolescent conduct disorder and later obesity. Summarizing these six studies, research indicates that early onset non-specific behavioural problems are associated with increased body weight in adolescence/young adulthood for affected males, and possibly for affected females. Further research investigating the independent associations between conduct symptoms, hyperactivity symptoms and future body weight is needed in order to determine whether conduct symptoms are indeed the primary contributor to this relationship.

While the inclusion of only prospective, longitudinal design studies increases the strength of this review and its findings, there are a few limitations of the data to consider. First, there is considerable variability between studies with respect to both study duration as well as the measures used to assess depressive and disruptive symptoms. Despite the large number of non-clinical participants included in many of the included studies, this variability in study design may affect the strength of the overall conclusions. Also, not all studies were able to assess BMI by direct measurement, using self-report values for BMI determination. Using participant-reported, rather than measured, weight and height data raises the question regarding the accuracy of the figures provided and the resultant validity of the BMI data included in the analyses. Research examining the acceptability of self-report weight and height has confirmed that these data are generally accurate when compared with measured values in population-based adolescent and adult samples in the United States,[17, 47] the Netherlands[48] and Scotland.[49] No differences in reporting height and weight have been identified among those with a depressed mood compared with those without.[31, 50] These findings suggest that the use of self-reported data, while not ideal, does not compromise our findings.

The effect of medication use on the association between early psychopathology and adult BMI was considered in some, but not all, studies and so its potential impact on the relationship was unable to be fully explored. However, including the effect of medication use is unlikely to have had a significant impact on the study findings. Although antidepressant use may induce weight gain among some individuals with depression, many of the included studies were of community-based samples in which rates of treatment are known to be low.[51] In contrast, stimulant treatment of ADHD is associated with anorexia, rather than weight gain, such that current evidence does not support a plausible mechanism by which treatment of ADHD in childhood might affect adult increased body weight. Further, the results of those studies that did assess the influence of medication use[33, 35, 42] were not different from the results of those that did not.

Conclusion

  1. Top of page
  2. Abstract
  3. Method
  4. Results
  5. Conclusion
  6. References

Current evidence suggests that obese adolescent females are more likely to develop a depressive illness in adulthood than their non-obese peers. Conversely, depressed adolescent females, and possibly males, are more likely to become overweight adults than non-depressed adolescents. There are insufficient data addressing future depression risk among overweight, non-obese, adolescents to evaluate more fully the potentially interactive nature of this relationship. Studies to date are consistent in reporting that children with behavioural problems are at increased risk of future overweight, though whether this risk is conferred by conduct symptoms, ADHD symptoms, or both, is less clear. These findings are important for clinical practice. Care providers of children with disruptive behavioural problems and depressed adolescents should monitor weight gain. Among obese adolescent females, mood should be followed. Future research examining the mechanism of association between these key public health problems is needed in order to identify targets for intervention and effective concurrent treatment strategies.

References

  1. Top of page
  2. Abstract
  3. Method
  4. Results
  5. Conclusion
  6. References