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Research Article                                                                                                                                        Open Access

## Latent Classes of Symptoms related to Clinically Depressed Mood in Adolescents

Eva Henje Blom 1,2,3* , Mats Forsman 4 , Tony T. Yang 2 , Eva Serlachius 1,5 , Jan-Olov Larsson 6

1 Department of Clinical Neuroscience, Karolinska Institutet, Sweden 2 Osher Center for Integrative Medicine, Karolinska Institutet, Sweden 3 Department of Psychiatry, University of California San Francisco, USA 4 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Sweden 5 Centre for Psychiatric Research and Education, Karolinska Institutet, Sweden 6 Department of Women's and Children's Health, Karolinska Institutet, Sweden

*Corresponding author: eva.henjeblom@ki.se

## Abstract

Background: The diagnosis of major depressive disorder (MDD), according to the Diagnostic and Statistical Manual of Mental Disorders, is based only on adult symptomatology of depression and not adapted for age and gender. This may contribute to the low diagnostic specificity and validity of adolescent MDD. In this study, we investigated whether latent classes based on symptoms associated with depressed mood could be identified in a sample of adolescents seeking psychiatric care, regardless of traditionally defined diagnostic categories.

Methods: Self-reports of the Strengths and Difficulties Questionnaire and the Development and Well-Being Assessment were collected consecutively from all new patients between the ages of 13 and 17 years at two psychiatric outpatient clinics in  Stockholm, Sweden. Those who reported depressed mood at intake yielded a sample of 21 boys and 156 girls. Latent class analyses were performed for all screening items and for the depression-specific items of the Development and WellBeing Assessment.

Results: The symptoms that  were  reported  in  association  with  depressed  mood  differentiated  the  adolescents  into  two classes.  One  class  had  moderate  emotional  severity  scores  on  the  Strengths  and  Difficulties  Questionnaire  and  mainly symptoms that were congruent with the Diagnostic and Statistical Manual of Mental Disorders criteria for MDD. The other class had higher emotional severity scores and similar symptoms to those reported in the first class. However, in addition, this group  demonstrated  more  diverse  symptomatology,  including  vegetative  symptoms,  suicidal  ideation,  anxiety,  conduct problems, body dysmorphic symptoms, and deliberate vomiting. The classes predicted functional impairment in that the members of the second class showed more functional impairment.

Limitations: The relatively small sample size limited the generalizability  of  the results  of  this  study,  and  the  amount  of items included in the analysis was restricted by the rules of latent class analysis. No conclusions about gender differences between the classes could be could be drawn as a result of the low number of boys included in the study.

Conclusions: Two  distinct  classes  were  identified  among  adolescents  with  depressed  mood.  The  class  with  highest emotional symptom severity score and the most functional impairment had a more diverse symptomatology that included symptoms  that were not congruent with the traditional diagnostic criteria of MDD.  However,  this  additional symptomatology is clinically important to consider. As a result, the clinical usefulness of the Diagnostic and Statistical Manual of Mental Disorders during the diagnostic process of adolescent depression is questioned.

Keywords: Adolescent major depressive disorder, diagnostic validity, Diagnostic and Statistical Manual of Mental Disorders, latent class analysis

## Introduction

Depression  is  one  of  the  most  common  mental health disorders among the adolescent population; it has a cumulative prevalence of 25% by the end of adolescence, and the prevalence of mild to moderate  depression  seems  to  be  increasing  (1;2). Depression during adolescence results in secondary problems, such as the loss of social, cognitive, and interpersonal  skills;  social  problems;  poor  school performance; substance abuse; and difficulties with family and peer relationships. Adolescent depression is also related to a significantly increased risk of self-harm and suicide (1). The early onset of depressive  symptoms  in  general  is  known  to  be associated with increased risk for suicide, increased treatment use, and psychiatric comorbidity as compared with the adult onset of major depressive disorder (MDD) (3).

Neurodevelopmental  aspects are important to consider in relation to adolescent depression. These include  the  course  of  adolescent  brain  maturation (including pruning), the maturation of the serotonergic  and  noradrenergic  systems,  and  the mechanisms  of  hormonal  impact  on  emotional regulation and stress sensitivity, which influence the expression of depression symptoms during puberty (4;5).  In  addition,  genetic  effects  on  symptoms  of anxiety and depression are developmentally dynamic from middle childhood to young adulthood, thereby demonstrating both genetic innovation and genetic attenuation (6). A life-trajectory perspective of depression  is  important,  because  early  exposure  to environmental  factors  (e.g.,  developmental  trauma, neglect, insecure attachment) may alter normal brain development and cause the dysregulation  of  affect and attention; these factors can result in an increased risk of depression, anxiety disorders, and attention-deficit/hyperactivity disorder later in childhood and during adolescence (7;8). The diagnostic criteria of the fourth and fifth editions of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV and  DSM-5)  for  MDD  do  not  take  age into consideration, despite that fact that the symptomatology  of  depression  changes  across  the life  span  and  seems  to  have  a  specific  phenotype during adolescence that is quite  different  from  the adult clinical symptomatology.

There are specific concerns regarding the clinical use  of  DSM-IV  and  DSM-5  for  the  diagnosis  of adolescent depression:

1.  The  diagnosis  of  MDD  during  childhood  and adolescence  can  be  based  only  upon  unspecific symptom  criteria, which  may  contribute to an adverse effect on diagnostic specificity and treatment  (9).  Depressed  mood  and  anhedonia  are the  two  cardinal  symptoms  of  MDD  in  adults. However,  for  children  and  adolescents,  depressed
2. mood  may  be  substituted with irritable  mood, which is not specific to MDD. Because only one of the  cardinal  symptoms  is necessary  for  a  diagnosis of MDD according to the DSM-IV and DSM-5, the MDD  diagnosis can potentially be based on irritability and other symptoms that may occur with other psychiatric or somatic disorders as well.
2.  The  symptom  criteria  of  MDD  are  broadly defined and include reversed conditions. For example,  a  change  in  appetite  and  weight  may  be either weight loss/decreased appetite or weight gain/increased  appetite;  sleep  problems  may  be early awakening,  insomnia,  late sleep phase, or hypersomnia.  In  addition,  psychomotor  inhibition and  agitation  are  both  MDD  criteria.  The  broad definition  of  MDD  leaves  questions  unanswered with  regard  to  the  diagnostic  boundaries  of  the disorder (3).
3. Psychiatric comorbidities are especially prevalent  during  adolescence  (10).  From  a  clinical point  of  view,  it  is  often  not  clear  which  of  the symptoms presented  are  expressions  of  adolescent MDD  and  which  are  expressions  of  psychiatric comorbidities,  because  many  of  the  symptoms  are unspecific  and  overlap  among  different  diagnostic entities  (11;12).  Concentration  difficulties,  restlessness, hyperactivity, and a decrease in impulse control commonly coexist with MDD. In addition, the differential diagnosis of attention-deficit/ hyperactivity disorder and conduct disorder may be difficult, especially in children (10;13). Self-harming behavior  (14),  eating  disorders  (15),  and  substance abuse  (16)  frequently  appear  with  MDD  during adolescence. Generalized anxiety disorder and MDD  often  coexist  and  show  diagnostic  criteria overlap  with  regard  to  symptoms  such  as  fatigue, concentration difficulties, irritability, and sleep disturbances (17-19).

One example that illustrates a potentially counterproductive consequence of the clinical application of the DSM-IV and DSM-5 system for the diagnosis of adolescent psychiatric problems is the case of developmental trauma. From a neuroscientific and developmental point of view, it is  known that early diverse life events cause limbic hyperactivation and hypercortisolemia and it is hypothesized that this is linked to  damage  of hippocampal neurons and depressive illness later in life (8 ; 20-23). Following this trajectory, the pathophysiological processes involved may cause a diverse symptomatology that includes concentration difficulties, anxiety, and impulsivity. Secondary behavioral problems that are intended to self-sooth the primary problems (e.g., self-harming, behavioral problems, alcohol and drug abuse) are also common (7).  From this perspective, the DSM categorization may  not  necessarily  be  clinically  helpful;  on  the contrary,  it  may  complicate  the  situation  for  the patient with multiple psychiatric comorbidities. Future adolescent depression research should optimally aim to develop treatments that target the underlying neurodevelopmental dysfunction.

Gender-specific symptom criteria are also lacking in  the  DSM  system,  which  may  have  implications for nosology and therapeutics. Differences in genetic  risk  factors  for  anxiety and depression in males and  females  may  increase  during  development  (6). Depressive symptoms in combination with features such as emotional instability and dysregulation, low impulse control, and elevated stress reactivity demonstrate  increased  prevalence  at  the  onset  of puberty, with a major predominance in girls; this is hypothesized  to  be  related  to  estrogen  effects  and cortisol  receptor sensitivity in  the  brain  (24-27).  In Sweden, the prevalence of self-assessed anxious and depressive  symptoms  as  well  as  hospitalization  for anxiety, depression, and suicide attempts have shown a more rapid  and  dramatic  increase  among adolescent  females  as  compared  with  males  during the last decade (28). In adults, women have a higher documented frequency of comorbid depression and anxiety disorders and a three-fold higher prevalence of  atypical  depression  (29;30).  To  identify  genderspecific  trajectories  of  depressive  symptomatology and  to  define  how  the  phenotype  changes  across the life span, we need to study which symptoms are associated with the depressive core symptoms during a defined age range and across genders.

The primary aims of this study were to investigate which  psychiatric  symptoms  are  associated  with depressed mood (regardless of traditionally defined diagnostic  categories)  in  a  sample  of  adolescents seeking  psychiatric  care  and  to  investigate  whether age-specific latent classes based on these symptoms could be identified. This analysis may help to define age-specific  combinations  of  symptoms  related  to depressed mood while disregarding traditional diagnostic systems that are based on adult symptomatology.  This  may  increase  the  chance  of linking neuromechanisms to corresponding symptomatology and behavioral dysfunction, which may  ultimately  be  useful  for  the  development  of targeted and effective treatment (31 ; 32).

Our first hypothesis was that latent class analysis (LCA) could identify particular classes of individuals on  the  basis  of  their symptom  profile.  In  other words, we wanted to determine whether the symptoms may form meaningful classes, independently of prior theoretical expectations. LCA is a statistical method for identifying unmeasured class membership among subjects with the  use  of  categorical  and  continuous  observed variables.  LCA can help to define subcategories of depression,  such  as  depressed  mood  with  self- harming  behavior, depressed mood  with  eating problems, or depressed mood with sleeping problems. LCA has previously been used with both large population-based samples (e.g., to define latent classes of episodic mania-like symptoms in children and adolescents (33), to assess variations in depression symptoms over the life courses of adults (34))  and  smaller  clinical  samples  (e.g.,  to  assess treatment engagement (35), to determine diagnostic subgroups  of  patients  with  post-traumatic  stress disorder (36)). Our second hypothesis was that the identified  classes  would  be  differentially predictive of social impairment. Finally, we hypothesized that the genders would be unevenly distributed between the classes.

## Methods

Description of the sample and the data collection procedure The  diagnostic  self-assessment  data  for  this  study, which are discussed later in this article, were originally  collected  for  a  larger  project  that  took place  during  2009  and  2010.  That  study  aimed  to compare the efficacy of different intake procedures for  new  patients  seeking  help  at  the  Stockholm Child and Adolescent Psychiatry Clinic, which is a public health care setting (37).  Two  outpatient clinics  that  covered  two  geographically  different areas  of  Stockholm  were  assigned  to  let  all  new patients between the ages of 6 and 17 years old and their parents complete an intake procedure with the Strengths and Difficulties Questionnaire (SDQ) (38) and  the  Development  and  Well-Being  Assessment (DAWBA)  (39). Seven hundred and thirty-six patients and their parents were recruited consecutively  and  asked  to  complete  the  online versions of the SDQ and DAWBA at home before their first visit to the clinic. In the present study, we included  the  SDQ  and  DAWBA self-reports  from all  teenagers  between  the  ages  of  13  and  17  years who  reported  depressed  mood  (N  =  177).  The formulation  in  DAWBA  that  reflects  depressed mood is 'very sad, miserable, unhappy or tearful.' Depressed mood  was  chosen as the inclusion criteria for this study, because it is the most obvious and  specific  attribute  of  depressive  disorders  and regarded as a cardinal symptom of MDD. According to the DSM system, depressed mood can be  exchanged  for  irritable  mood  in  adolescents; however,  because  irritable  mood  is  prevalent  but non-specific  to  depression,  it  is  inadequate  as  an inclusion  criterion  (9).  Anhedonia,  which  is  the other  cardinal  symptom  of  depression,  is  highly prevalent among  depressed adolescents, but its extent is quite variable (40) and therefore also not a good  inclusion  criterion.  The  high  variability  of anhedonia  with  teenage  depression  could  result  in contrasting MDD phenotypes, which we wanted to capture in the LCA.

The Regional Ethical Review Board in Stockholm, Sweden, approved the study, and the research was conducted in accordance with the Helsinki Declaration as revised 1989.

## Measures

The  SDQ  is  a  25-item  scale  with  subscales  that reflect hyperactivity and inattention, behavior problems, emotional symptoms, peer problems, and pro-social behavior. The SDQ may also generate a total difficulties score by summarizing the scores of the  subscales  (except  the  pro-social  subscale).  The SDQ  total  impact  score  measures  overall  distress and  social  impairment  caused  by  all  mental  health problems,  specifically  in  the  domains  of  family, school, learning,  and  leisure  (41).  The  SDQ  is considered psychometrically valid  (42-44),  and  it  is frequently used in the Nordic countries (45). In this study, the SDQ  was administered before the DAWBA and used to ensure that the skipping rules were not overused (this is discussed in more detail later in this article). The SDQ was also used for the assessment of total difficulties and social impairment.

The  DAWBA  (39)  is  an  Internet-based  semistructured  interview  that  is  compatible  with  the diagnostic criteria of the DSM-IV. Detailed information  about  the  DAWBA  is  available  from http://www.dawba.info; this includes online and downloadable versions of the measures and demonstrations of the clinical rating process. In this study,  the  DAWBA  was  used  as  a  way  to  collect data  about  which  symptoms  were  associated  with depressed mood in adolescents who seek psychiatric care;  the  purpose  was  not  to  use  it  as  a  diagnostic tool. The DAWBA assesses separation anxiety; fears of  specific  things  or  situations;  panic  attacks  and agoraphobia; post-traumatic stress; compulsions and obsessions; generalized anxiety; depression; attention and activity; conduct problems; and dieting, weight, and body/shape concerns. However, it  does  not  address  psychotic  or  autistic features  or  problems  related  to  alcohol  and  drug abuse. The DAWBA focuses on current rather than lifetime problems. Each section starts with screening questions that allow the person completing  the  assessment  to  skip  to  the  next section if the screening question is answered in the negative. If the  screening  is  positive, additional specific  questions  are  asked.  Most  sections  of  the DAWBA can only be skipped if the initial screening questions  are  negative  and  if  the  relevant  SDQ score  is  close  to  average  (i.e.,  <80th  centile).  This double requirement prevents 'respondent fatigue,'

which  could  result  in  too  many  sections  being skipped (39). The depression section has screening questions for depressed mood, irritable mood, and anhedonia. If any of these three cardinal symptoms for  MDD  are  rated  positively,  specific  questions about other depression criteria follow (Table 1). The eating  disorder  section  also  has  several  screening questions about body dysmorphic symptoms, shame  in  relation  to  eating,  deliberate  vomiting, worries related to eating, and self-blame in relation to overeating.

Depressed mood  was used as the inclusion criterion  for  the  study;  irritable  mood,  anhedonia, and depression-specific items were also included as items in the analyses. Because two of the depression-specific items dealt with weight and appetite, we decided to have those two included in the LCA; in other words, not all five of the eating disorder  screening  questions  were  included  due  to limitations regarding the number of items allowed in the LCA. In summary, depressed mood was analyzed  in  relation  to  all  other  screening  items except the five eating disorder items and in relation to the depression-specific items of the DAWBA.

TABLE  1. The  probability  of  having  each  of  the  self  assessed  symptoms,  if belonging to class 1 or 2 respectively. Probabilities of >70% are marked in bold

|                                                           |   Class 1 n = 101 |   Class 2 n = 79 |
|-----------------------------------------------------------|-------------------|------------------|
| Irritability                                              |               .64 |              .89 |
| Loss of interest                                          |               .86 |              .97 |
| Tired/no energy                                           |               .88 |              .99 |
| Change of appetite                                        |               .53 |              .97 |
| Change of weight                                          |               .21 |              .86 |
| Sleeping difficulties                                     |               .62 |              .85 |
| Sleep more than normal                                    |               .29 |              .48 |
| Agitation                                                 |               .46 |              .65 |
| Feelings of worthlessness                                 |               .74 |              .96 |
| Concentration difficulties                                |               .77 |              .96 |
| Suicidal ideation                                         |               .53 |              .90 |
| Concurrent or previous thoughts or action of self harming |               .76 |              .97 |
| Specific fears                                            |               .60 |              .90 |
| Symptoms of separation anxiety                            |               .23 |              .72 |
| Symptoms of social anxiety                                |               .34 |              .77 |
| Panic attacks during the last four weeks                  |               .41 |              .79 |
| Symptoms of agoraphobia                                   |               .36 |              .72 |
| Experience of traumatic event                             |               .35 |              .53 |
| Symptoms of obsessive compulsive thoughts or behavior     |               .23 |              .51 |
| Symptoms of generalized anxiety                           |               .91 |              .96 |
| Symptoms of hyperactivity                                 |               .35 |              .52 |
| Conduct problems                                          |               .53 |              .72 |

The DAWBA has been translated to Swedish, and the Swedish version has been retranslated back into English and approved by Professor Goodman, who is  the  originator  of  the  DAWBA.  The  Swedish DAWBA  is  in clinical use in several settings throughout Sweden, but no Swedish validation studies of this tool have yet been published (37). In Norway, the DAWBA has been shown to generate realistic  estimates  of  the  prevalence  of  psychiatric illness as well as a high predictive validity when used in  public  health  settings  (46).  Good  to  excellent inter-rater reliability has been reported in Norwegian studies, with a κ value of 0.86 to 0.91 for any  diagnoses  and  a κ value  of  0.57  to  0.93  for emotional diagnoses (47). Another Norwegian study also  demonstrated  that  experienced  clinicians  can assign reliable  diagnoses and assess severity on the basis of DAWBA data that is collected online (48).

## Statistical analyses

LCA  simultaneously defines the structure and estimates the probabilities  of  membership  in  a certain  class  (49).  LCA  assumes  the  presence  of discrete classes or groupings rather than dimensions. For example, it can be used to categorize  people  on  the  basis  of  their  depressive symptoms  into  different  subtypes  of  depressive symptomatology (i.e., latent  classes).  This  can  help to define subcategories of depression, such as depressive  symptoms  with  self-harming  behavior, depressive  symptoms  with  eating  problems,  and depressive symptoms with sleeping problems. One can seek to explore the consequences of such a class membership: for instance, one may consider whether  membership  in  the  class  of  depressive symptomatology in combination with eating problems predicts other variables. There are different  indices  that  can  be  used  to  evaluate  how many classes  are  needed  to  best  describe  the  data. Nylund  and  colleagues  simulated  multiple  models and concluded that the Bayesian information criterion  (BIC)  performs  best,  irrespective  of  the number of classes and the sample size (50). BIC is a comparative measure that allows us to compare the fit of models with different numbers of classes. The model  with  the  best  fit  has  the  lowest  BIC  value. LCA  has  specific  limitations  with  regard  to  the number of included items in relation to sample size, and  these  limitations  cannot  be  exceeded.  In  the current  study,  all  individuals  included  in  the  LCA had  a  potential  probability  of  0  to  1  to  endorse  a specific item or symptom given their class membership.  The  cutoff  for  scoring  positive  on  a symptom  was  0.7  (i.e., a >70%  probability  of answering 'yes'), given class  membership.  The Student t -test was used to evaluate mean differences in emotional symptoms, conduct problems, hyperactivity,  peer  problems,  pro-sociability,  and impact on function as measured with the SDQ. The frequencies  of  having  symptoms  specific  to  eating disorders  were  calculated  for  the  total  group  to further investigate the findings of the LCA results. The relative risk ratios of having symptoms specific to eating disorders on the basis of class membership were also calculated retrospectively.

## Results

To estimate the amount of classes that best described the data, six models were tested with BIC. The  model  with  two  distinct  classes  showed  the best fit for the data (Table 2). The sample included 21 boys and 156 girls, with a mean age of 15.0 years for the boys (standard deviation, 1.38; range, 13 to 17 years) and 15.4 for the girls (standard deviation, 1.37; range, 13 to 17 years).

TABLE 2. 'Model-fit' using the Bayesian Information Criterion model (BIC) to test which amount of classes from 1 to six, that constitutes the best fit for the data  (lowest BIC score)

|   Classes |     BIC |
|-----------|---------|
|         1 | 2550.83 |
|         2 | 2416.60 |
|         3 | 2476.14 |
|         4 | 2561.74 |
|         5 | 2613.75 |
|         6 | 2705.55 |

LCA  showed  that,  if  an  individual  belonged  to Class 1 (n = 99), the probability was high (>70%) that he or she would have symptoms of generalized anxiety,  tiredness/loss  of  energy,  loss  of  interest, concentration  difficulties,  previous  or  concurrent thoughts  of  self-harming  or actual  self-harming behavior, and feelings of worthlessness in addition to the predefined depressed mood (see Table 1).

In  Class  2  (n  =  78),  there  was  an  even  higher probability  of  having  the  same  symptoms  as  those exhibited  by  the  individuals  in  Class  1.  However, what  differed  between  the  classes  was  the  higher probability  of  the  members  of  Class  2  having  a greater diversity of symptoms. In addition to depressed mood and the previously described symptoms, changes of appetite and weight, suicidal ideation,  irritability,  sleeping  problems,  symptoms of  anxiety  expressed  as  specific  fears,  separation anxiety, social anxiety, panic attacks and agoraphobia, and conduct problems were also reported among members of Class 2 (see Table 1). There was a lower probability (  64%) of problems with excessive sleeping, agitation, obsessivecompulsive  symptoms,  and  hyperactivity  in  both classes,  and  members  of  both  groups  often  selfreported  having  experienced  or  witnessed  adverse or traumatic events (see Table 1).

Symptom  scores  for  self-assessment with the SDQ  differed  significantly between  the classes. Members  of Class 2  showed higher  symptom severity for emotional symptoms, conduct problems,  hyperactivity,  and  peer  problems  and lower  scores for pro-social behavior. The  total difficulties scores and impact scores were significantly  higher  for  members  of  Class  2  (see Table 3).

TABLE  3. T-tests  showing  differences  of  mean-values  of  symptom  severity between Class 1 and Class 2 assessed by Strengths and Difficulties Questionnaire (SDQ), including the subscales, the total difficulties score and impact on function

|                        | Class 1 n = 99   | Class 2 n = 78   |         |
|------------------------|------------------|------------------|---------|
|                        | Mean (SD)        | Mean (SD)        | t-value |
| SDQ-total              | 17.2 (5.2)       | 22.7 (5.3)       | 6.9***  |
| SDQ-emotional symptoms | 5.8 (2.1)        | 8.0 (1.6)        | 8.1***  |
| SDQ-conduct problems   | 3.2 (2.0)        | 4.0 (2.1)        | 2.6**   |
| SDQ-hyperactivity      | 5.3 (2.6)        | 6.9 (2.2)        | 4.3***  |
| SDQ-peer problem       | 2.9 (2.1)        | 3.8 (2.0)        | 3.2**   |
| SDQ-pro-social         | 7.4 (1.9)        | 7.4 (2.0)        | 0.1ns   |
| SDQ-impact on function | 4.2 (2.7)        | 5.6 (2.6)        | 3.4***  |

*** p < .001, ** p < .01, * p < .05; SD=standard deviation; ns=non-significant

Because problems with appetite and weight changes, which were both assessed by the depression-specific questions, demonstrated a major difference  between  the  two  classes,  we  decided  to take a closer look at the five screening questions for eating disorders that were  not  included in the original LCA. We retrospectively analyzed how the answers to these five items were distributed between  the  two  latent  classes.  It  was  discovered that members of Class 2 had more than double the risk  of  having  body  dysmorphic  symptoms,  shame related  to  eating  behavior,  self-induced  vomiting, increased worrying about eating, and selfaccusations  involving  overeating  as  compared  with Class 1 (Table 4).

TABLE 4. Percentage of individuals in each class who has symptoms related to eating disorders and the relative risk of having the symptom when class 1 is used as reference

|                                                                                                | Class 1 N = 88   | Class 2 N = 73   | OR (95 %CI)           |
|------------------------------------------------------------------------------------------------|------------------|------------------|-----------------------|
| 1. Have you ever thought you were fat even when other people told you that you were very thin? | 59.1% (52)       | 76.7% (56) 54.8% | 2.15 (1.07-4.32) 2.53 |
| 2. Would you be ashamed if other people knew how much you eat?                                 | 31.8% (28)       | (40)             | (1.32-4.83)           |
| 3. Have you ever deliberately made yourself vomit (throw up)?                                  | 31.8% (28)       | 54.8% (40)       | 2.53 (1.32-4.83)      |
| 4. Do worries about eating (what? where? how much?) really interfere with your life?           | 36.4% (32)       | 67.1% (49)       | 3.42 (1.77-6.64)      |
| 5. If you eat too much, do you blame yourself a lot?                                           | 59.1% (52)       | 76.7% (56)       | 2.15 (1.07-4.32)      |

## Discussion

This  study  aimed  to  investigate  which  psychiatric symptoms  were  associated  with  depressed  mood, regardless of traditionally defined diagnostic categories and whether age-specific diagnostic latent classes that were based on these symptoms could be identified. This is of importance because the diagnostic entity of MDD as defined by adult DSM criteria  does  not  well  match  the  symptomatology that adolescents present in conjunction with depressed mood; in addition, the boundaries of how these  symptoms  are  expressed  among  individuals with comorbid disorders are not clear cut (10;15;51). We  investigated whether age-specific diagnostic  latent  classes  could  be  identified  on  the basis  of  a  broad  variety  of  symptoms,  including symptoms  that  are  not  traditionally  regarded  as depression criteria. Some of these have, in previous research,  been  shown  to  frequently  co-occur  with depressive problems in adolescents, such as attention-deficit/hyperactivity disorder, anxiety, and eating  disorders  (13;15;52;53).  Our  study  yielded two  main  results.  First,  LCA  of  the  psychiatric symptoms differentiated the adolescents with depressed mood  into two distinct classes that differed with regard to emotional symptom severity and  diversity  of  symptoms.  Second,  the  classes predicted  social  impairment;  Class  2  had  higher general  symptom  severity  and  greater  impact  on function  related  to  family,  school,  learning,  and leisure. Our third hypothesis that the genders would be unevenly distributed between the classes was not confirmed as a result of the relatively small number of boys included in the study.

The  results  of  the  LCA  that  included  a  broad range  of  psychiatric  symptoms  in  adolescents  with depressed mood and who were seeking psychiatric care differentiated the adolescents into two distinct classes, which supported our first hypothesis. Class 1 had symptoms that reflected the established DSM criteria for MDD, such as tiredness/loss of energy, loss  of  interest,  concentration  difficulties,  previous or concurrent thoughts of self-harm or actual selfharming  behavior,  and  feelings  of  worthlessness. Class  2,  on  the  other  hand,  had  all  of  the  same symptoms  as  Class  1  in  addition  a  more  diverse symptomatology  that  included  irritability,  suicidal ideation,  conduct  problems,  symptoms  of  anxiety expressed as specific fears, separation anxiety, social anxiety, and panic attacks and agoraphobia. Class 2 also  had  a  high  probability  of  having  vegetative symptoms, such as changes of appetite and weight and sleeping problems. Members of Class 2 also had a higher risk of having body dysmorphic symptoms, deliberate vomiting, increased worrying, and shame related  to  eating.  These  findings  are  in  line  with previous studies that have demonstrated that binge eating is related to emotional dysregulation (54) and that the comorbidity of depressed mood and eatingrelated  symptoms  is  high  in  this  age  group  (15). There was also a high probability of sleeping problems among the members of Class 2. Sleeping problems  should  be  carefully  addressed  at  intake, because they may have a reciprocal relationship with emotional dysregulation and explain the increase in self-reported tiredness and concentration difficulties (55;56).

Our second  hypothesis  that  the  latent  classes  of adolescent  depression  are  predictive  of  symptom severity  and  social  impairment  was  also  supported by our findings. Indeed, one may speculate that the symptomatology of Class 1 represents a milder form of depression, with its own trajectory, and that the more  severe  Class  2  (as  defined  by  the  emotional subscale of SDQ) describes the age-specific symptom  profile  of  melancholic  depression,  with more suicidal ideation and vegetative symptoms. If that  is  the  case,  it  is  of  clinical  importance  to recognize  the  diversity  of  symptoms  that  present with adolescent melancholic depression as compared with the typical adult features. According to our data, symptoms related to severe depression during adolescence include conduct problems, anxiety and  panic attacks, agoraphobia,  specific fears,  social  as  well  as  generalized  anxiety,  and symptoms  related  to  eating  and  sleeping.  Binge eating and deliberate vomiting often occur in adolescents  of  normal  weights;  these  features  are closely  related  to  shame  and  should  be  specifically asked  about  during  intake.  Sleep  disturbances  in adolescents are also important to identify and treat, because  they  are  related  to  an  increased  risk  of suicide (57).

It has been suggested that adolescent melancholic depression may be a discrete category at the extreme  end  of  the  depression  spectrum  (58).  If melancholic depression during adolescence is defined  by  the  symptoms  demonstrated  by  the members of Class 2, then this may be a possibility in line  with  our  findings.  Interestingly,  anhedonia  which  is  a  cardinal  symptom  of  adolescent  MDD according to DSM and regarded as a typical feature of melancholic depression in adults - occurred very frequently  in  both  classes.  However,  irritability  which  is  also  regarded  as  a  cardinal  symptom  of adolescent depression -was not reported as frequently,  and  it  was  predominantly  found  in  the members  of  the  more  severely  depressed  group. The  notion that adolescent MDD  is  a  purely dimensional  construct  (58)  was  not  supported  by our data.

Unfortunately, our third hypothesis regarding gender distribution across the classes could not be confirmed as a result of the relatively small number of boys included in the study. The ratio of boys and girls  in  the  total  sample  was  21  to  156,  which mirrors the gender distribution of depressed teenage patients  in  child  psychiatry  treatment  in  Sweden (59). It may also be the case that teenage boys with depression  have  a  different  symptom  profile  that includes  substance  abuse  as  well  as  behavioral  and conduct  problems that  make  them  less  inclined  to seek  psychiatric  care  (60).  Suicide  rates  are  four times  higher  among  boys  as  compared  with  girls between the ages of 16 and 18 years in the United States, but girls have higher rates of suicidal ideation and attempted suicide (61).

The  lack  of  adaptation  for  ontogenetic  aspects and age in the MDD diagnostic criteria of DSM-IV and  DSM-5  may  contribute  to  a  low  diagnostic specificity and validity for MDD during adolescence.  Consequently,  the  DSM  system  may have limited the opportunity to identify trajectories of  the  progression  of  depressive  problems  across adolescence into young adulthood and thus hampered  the  ability  to  estimate  prognosis  and  to develop efficient treatment (62). Furthermore, when treatments that are shown to be effective for adult MDD are applied to  adolescent  MDD  defined  by adult  criteria,  there  is  considerable  risk  that  young people  who  are  not  suffering  from  MDD  will receive antidepressant medication. In fact, selective serotonin reuptake inhibitor treatment of adolescent MDD  (as  defined  by  the  DSM  system)  has  not demonstrated  clear  evidence  of  the  reduction  of depressive  symptoms  as  compared  with  placebo, and  it  is  not  known  whether  selective  serotonin reuptake  inhibitors  decrease  the  risk  of  suicide  in this  population  (32;63).  The  situation  may  look different if new treatments for adolescent depression were targeted for populations that were defined  by  age-appropriate  symptom  profiles  and their underlying pathophysiologies.

The rationales of the  DSM-IV  and  DSM-5 diagnostic systems have recently been heavily debated, and the National Institute of Mental Health has launched a strategic plan (Strategy 1.4) to develop new ways of classifying mental disorders on the  basis  of  dimensions  of  observable  behavior  as well as neurobiological measures. (For the full text of  this  plan,  visit  http://www.nimh.nih.gov/about/ strategic-planning-reports/index.shtml.)  The  Research Domain Criteria Project of the National Institute of Mental  Health  aims  to  establish  construct  validity for  dimensions  of  psychopathology  by  promoting clinical  research  in  which  subjects  are  recruited transdiagnostically on the basis of the specific research question. Developmental and gender aspects  are  not  included  in  these  criteria,  but  it  is stated that an intended  focus  is  to  enhance  a systematic integration of developmental aspects and interactions with the environment and their relationship to specific brain circuits and functions.

A  limitation  of  this  study  is  its  relatively  small sample size. The results have to be replicated with the use of larger samples and recruited from more diverse locations to be generalizable. The relatively small sample size also limited the amount of items that  could  be  included  in  the  LCA.  The  small number  of  boys  in  the  study  made  comparisons between genders underpowered, and no conclusions could  be  drawn  regarding  symptom  differences between  boys  and  girls.  Another  limitation  is  that the DAWBA does not assess autistic and psychotic symptoms or alcohol and drug abuse. These problems may have been co-occurring among individuals  with  depressed  mood  in  this  study's cohort, but they have not been taken into consideration during our analysis.

In  summary,  LCAs  of  psychiatric  symptoms  in teenagers with depressed mood showed two distinct classes.  One  group  demonstrated  tiredness/loss  of energy, feelings of worthlessness, concentration difficulties, previous or concurrent thoughts of selfharming or actual self-harming behavior, generalized anxiety, and less functional impairment as  compared  with  the  other  group.  The  second group  had  similar  symptoms  but  greater  symptom variations, including vegetative symptoms and suicidal  ideation;  this  group's  members  also  had greater functional impairment. No conclusions about gender distribution could be drawn as a result of the small number of boys included in the study. These  findings  show  that  age-specific  symptoms outside of the traditionally defined MDD criteria are important to consider during the diagnostic process for teenage depression, and they point to the difficulty of defining adolescent MDD as a precise diagnostic  entity  when  employing  adult  DSM-IV and  DSM-5  standards.  The  clinical  utility  of  the DSM-IV and DSM-5 systems for the diagnosis  of teenage depression is limited as a result of the low diagnostic  validity  and  specificity  of  the  symptom criteria for this age group. Future studies of teenage depression should be based on dimensions of psychopathology  and  their  behavioral  aspects  as recognized by transdiagnostic investigations. However,  both  developmental  and  gender  aspects as well as interaction with the environment must be taken into consideration to gain a better understanding of the trajectories of symptom expression  and  disease  progression  across  the  life span  and,  ultimately,  to  aid  in  the  development  of targeted prevention and treatment.

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## Acknowledgements

Thank  you  to  the  patients  and  staff  of  the  clinics that  contributed  to  this  study.  Funding  for  this study  was  obtained  from  the  Swedish  Society  of Medicine,  the  Söderström-Königska  Foundation, the Stockholm Center for Psychiatric Research and Education,  the  Swedish  Research  Council  (3502012-303),  the  Brain  Foundation  (PS2012-0073), and  the  Sweden  American  Association.  None  of these  organizations  had  any  involvement  in  the collection, analysis, or interpretation of the data; in the  writing  of  the  report;  or  in  the  decision  to submit the paper for publication. All of the authors declare that they have no conflicts of interest.