Depressive Disorders

Depressive disorders are recurrent illnesses that are fairly rare in childhood, become more common after puberty, and are associated with significant morbidity and mortality.  Depression in adolescence is often preceded by anxiety disorders in childhood.  Depression in children and adolescents often presents with irritability, oppositional behavior, or aggression, with little awareness of a sense of sadness.

Epidemiology, Risk Factors, & Pathophysiology

The prevalence of Major Depression Disorder (MMDD) is 2% in children (1:1 male to female ratio) and 4-8% in adolescents (1:2 male to female ratio).

The cumulative prevalence of MDD by age 18 is 20%.

Less is known about the epidemiology of Persistent Depressive Disorder (Dysthymia) in pediatric populations.

Risk factors = Genetics + Stress

The heritability of MDD is about 40-60%.

Genetic predisposition interacts with stressful life events to lead to depressive symptoms.

Negative cognitive styles (glass half empty), losses, abuse, neglect, ongoing conflict, exposure to violence, substance use disorders (in parent or patient), untreated ADHD, anxiety disorders, medical illness, and some medications increase risk.  But remember – there does not have to be a clear trigger. 

Pathophysiology 

Biological correlations with depression include increased levels of inflammatory cytokines, altered response to reward in the ventral striatum (associated with anhedonia), and altered connectivity from the prefrontal cortex to the limbic system which may be involved in modulating emotional responses to stressors.  There are as yet no clear biomarkers for depression. 

Comorbidity & Differential Diagnosis

Up to 50% of youth with depression will have 2 or more comorbid diagnoses.  The most common are anxiety disorders and ADHD, which often precede depression.  Depression increases the risk for conduct and substance use disorders, although these may also precede depression.  Disruptive mood dysregulation disorder (DMDD) may develop into depression.  Depression also co-occurs with medical illnesses including asthma, diabetes, inflammatory bowel disease, epilepsy and migraine.

The differential diagnosis for depression includes many conditions that may also be comorbid.

  • Anxiety, substance use disorders, perimenstrual depressive disorder, untreated ADHD
  • Hypothyroidism, mononucleosis, anemia, chronic fatigue syndrome, post-concussive syndrome, and autoimmune diseases
  • Stimulants, corticosteroids

Prognosis

Major Depression is an episodic disorder, with episodes lasting from a month to over a year. The recurrence rate in adolescence is up to 70% within 5 years, and recurrence may persist into and through adult life. 

Untreated depressive illness is associated with increase risk of school dropout and unemployment, with substance use disorders, and with poor social, emotional and cognitive functioning.  

About 20-40% of young people with depression will develop Bipolar Disorder.

Suicidal thoughts and attempts, and suicide deaths are associated with depression. 

The Disorders

Major Depression Disorder (MDD)

Major depression is diagnosed when a child or adolescent experiences at least 2 weeks of low or depressed and/or persistent loss of interest or pleasure in doing things combined with at least 3 neurovegetative symptoms (SIGECAPS).  Major depression is rare before puberty. Young children can have depressed mood but less commonly will have neurovegetative symptoms.  Children and adolescents with major depression can present with marked irritability, and may not be able to express sadness, but only anger.  

DSM-5 Criteria for Major Depressive Disorder

Five or more of the following A Criteria (at least one includes A1 or A2)

A1. Depressed mood—indicated by subjective report or observation by others (in children and adolescents, can be irritable mood).

A2. Loss of interest or pleasure in almost all activities—indicated by subjective report or observation by others.

A3. Significant (more than 5 percent in a month) unintentional weight loss/gain or decrease/increase in appetite (in children, failure to make expected weight gains).

A4. Sleep disturbance (insomnia or hypersomnia).

A5. Psychomotor changes (agitation or retardation) severe enough to be observable by others.

A6. Tiredness, fatigue, or low energy, or decreased efficiency with which routine tasks are completed.

A7. A sense of worthlessness or excessive, inappropriate, or delusional guilt (not merely self-reproach or guilt about being sick).

A8. Impaired ability to think, concentrate, or make decisions—indicated by subjective report or observation by others.

A9. Recurrent thoughts of death (not just fear of dying), suicidal ideation, or suicide attempts.

The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.

The symptoms are not due to the direct physiological effects of a substance (e.g., drug abuse, a prescribed medication’s side effects) or a medical condition (e.g., hypothyroidism).

The symptoms do not meet criteria for a mixed episode.

There has never been a manic episode or hypomanic episode.

Mild: Few, if any, symptoms in excess of those required to make the diagnosis are present, and symptoms result in no more than minor impairments in social or occupational functioning.

Moderate: Symptoms or functional impairment between “mild” and “severe” are present.

Severe: Many symptoms in excess of those required to make the diagnosis, or several symptoms that are particularly severe, are present, or the symptoms result in marked impairment in social or occupational functioning.

With mixed features – at least 3 manic symptoms, but not enough for manic or hypomanic episode.

With anxious distress – anxiety symptoms combined with a major depressive episode predict a better response to combined treatment with CBT plus an SSRI.

With psychotic features – most commonly mood congruent auditory hallucinations that reinforce the negative cognitions of depression (“You’re no good.” “Nobody cares about you.”) and may include suggestions or commands to self-harm or harm others (“You should die.” “You should kill yourself.” “You should stab your brother.”) which represent a high risk.

American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Washington, DC

Persistent Depressive Disorder (Dysthymia)

Children or adolescents with dysthymia have low mood that lasts for months and years.  You may ask a dysthymic child when they last felt ok, or a little bit happy, for more than a couple of weeks at a time and they will cast their mind back to an earlier grade or a school level.   

DSM-5 Criteria for Persistent Depressive Disorder

Depressed mood for most of the day, for more days than not, as indicated by subjective account or observation by others, for at least 2 years.

Note: In children and adolescents, mood can be irritable and duration must be at least 1 year.

Presence, while depressed, of two (or more) of the following:

  • Poor appetite or overeating
  • Insomnia or hypersomnia
  • Low energy or fatigue
  • Low self-esteem
  • Poor concentration or difficulty making decisions
  • Feelings of hopelessness

During the 2-year period (1 year for children or adolescents) of the disturbance, the individ­ual has never been without the symptoms in Criteria A and B for more than 2 months at a time.

Criteria for a major depressive disorder may be continuously present for 2 years.

There has never been a manic episode or a hypomanic episode, and criteria have never been met for cyclothymic disorder.

The disturbance is not better explained by a persistent schizoaffective disorder, schizophrenia, delusional disorder, or other specified or unspecified schizophrenia spectrum and other psychotic disorder.

The symptoms are not attributable to the physiological effects of a substance (e.g., a drug of abuse, a medication) or another medical condition (e.g., hypothyroidism).

The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.

American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Washington, DC

Disruptive Mood Dysregulation Disorder (DMDD)

DMDD was introduced in DSM-5 and added to the Depressive Disorders.  We discuss it separately here:  Disruptive Mood Dysregulation Disorder

Screening & Assessment

The US Preventive Services Task Force recommends routine screening for depression in persons aged 12-18 years using a validated instrument.  See our screening page for several freely available screening tools for depression in children and adolescents. Note also that all of the screening instruments listed can be used to track progress and response to treatment for depression.

Patient Health Questionnaire-Adolescent (PHQ-9)

The PHQ-A differs only from the adult version of the PHQ-9 in the question about being able to concentrate where "while doing homework" is substituted for "reading the newspaper."   Note also that question number 9 is tricky.  It was not designed to be a suicide risk screen, but rather to assess depression severity.  It does not actually ask if the patient is having thoughts of killing themselves. Any non-zero answer for question 9 should prompt gentle clarification.

Depression severity and functional impairment

We can think about depression, like anxiety disorders, in terms of symptom burden and functional impairment.

  • Mild depression: Moderate symptom burden, still able to function in most areas
  • Moderate depression: Moderate to high symptom burden, impaired social, academic, or other functioning. A teen may be going to school, but grades are slipping, and they are limiting social interactions
  • Severe depression: High symptom burden, impairment in nearly all areas of functioning. Here a teen may be missing school, be unable to participate in previous extra-curricular activities, and cutting themselves off from friends

Workup

  • History (family history, child’s symptom history, child’s academic history, child’s medical history)
  • Consider CBC, TFTs

Treatment

  • Psychoeducation - explaining what depression is and providing written or online references.
  • If stressors at home or school can be addressed in a brief intervention, this can also help relieve symptoms of depression. For example, a depressed teen may find schoolwork piling up to the point that they feel they will never catch up. Writing a letter to the school recommending accommodations until depression resolves may help.
  • These elements may be sufficient.
  • Expect improvement in 4-6 weeks.
  • Remember, in community samples, most episodes of MDD are brief. 

Brief interventions for depression

  • Behavioral activation targets the avoidance and withdrawal that can keep depressed kids from participating in rewarding activities.  You can help your patient identify a few activities that they may enjoy (not necessarily that they feel they should do) and make a plan to try them in a specific, measured way.  Starting small is best.  Examples include: “I can get out my paints 3 times this week and see what I feel like painting.” “I have promised Emily that we will run to the lake and back on Saturdays.”
  • Open up communication. Many depressive thoughts are based on false assumptions, misunderstandings, and unmet interpersonal needs. “I can’t tell my mom my problems because she has too many of her own.”
  • Offer hope- depression is treatable.
  • Review sleep hygiene – regular bedtime, regular wake up.
  • Maintain contact. Schedule regular follow-up visits to see how things are going.
    • Clinician engagement alone has been shown to reduce suicidality.
    • Give the message that you care and want to see them again. 
  • Enlist parents:
    • Parents can support their teens by listening, staying calm, and encouraging routine sleep and activity.
    • Parents should avoid leaving depressed teens home alone for long periods.

At follow-up visits:

  • Check in on depression - use a rating scale to track progress
  • Conduct safety assessment
  • Escalate to medication and/or therapy if not improving

Therapy options with evidence base for treatment of depression in children and adolescents include:

For moderate to severe depression, it is appropriate to consider medication therapy, some form of formal psychotherapy, or both. While cognitive behavioral therapy has been the modality of choice in the large medication combination studies, there is also an evidence base for other types of psychotherapy. Interpersonal therapy, or IPT, focuses on patterns of relationships and communication that are often central to emotional distress in adolescence. Dialectal behavioral therapy, or DBT, focuses on emotional regulation and distress tolerance, and can be very helpful for teens who engage in recurrent self-destructive behaviors.

Evidence base: Treatment for Adolescents with Depression Study (TADS)

Funded by National Institute of Mental Health in 1999

439 adolescents with depression were randomized into 4 arms:

  • Fluoxetine alone
  • Fluoxetine plus CBT
  • CBT alone
  • placebo

Results: The combination of the SSRI with CBT was superior to either alone in achieving remission until about week 24 when the active treatments converged with about 60% response rate. The fluoxetine and combination groups had lower depression scores by treatment week 6 than did CBT and placebo. 

Another large NIMH-funded trial, the Treatment of SSRI-Resistant Depression in Adolescents study (TORDIA) addressed the question of appropriate next steps in a teen whose depression has not remitted with an initial SSRI. It compared another SSRI (fluoxetine, sertraline, paroxetine) with venlafaxine, which is an SNRI, and with either class combined with CBT.

Similar to the TADS, the combination of a medication switch plus CBT was superior to a medication switch alone. The response rate to combination treatment with a second medication was about 55%. Venlafaxine was not superior to the SSRIs, and venlafaxine was less well tolerated due to side effects.  

An important result of TORDIA was that those patients who were going to have remission separated out from those who would not by week 6. This suggests that if you are not getting a response to a treatment plan by week 6, it may be necessary to identify an alternate plan. 

The Rest of the Evidence Base for Pharmacologic Treatment of Pediatric Depression

The TADS study and one smaller RCT of fluoxetine vs placebo are the only non-industry funded studies of SSRIs in adolescent depression to date. In both studies, the placebo response rate was fairly high, (35% and 33% respectively), but the fluoxetine response was significantly higher (61% and 56%, respectively). 

In 1997, a law known as the pediatric exclusivity provision provided marketing incentives to manufacturers who would conduct studies of drugs in children.  This law had a limited duration and spurred many manufacturers to run antidepressant trials in pediatric depression.

The industry-funded trials all had high placebo response rates – ranging from 46 to 63%. These placebo response rates were associated with fairly low baseline severity scores – in other words, they recruited subjects whose depression was not very severe to begin with, so more got better with the passage of time, and so medication was no better than placebo. In addition, the large number of sites – up to 65 sites per study, may have resulted in heterogeneity in adherence to study protocols.  

The upshot of this is that meta-analyses of all RCTs done for pediatric depression show that medication is no better than placebo because the negative industry trials wash out the 2 significant NIMH-funded trials. Most child and adolescent psychiatry experts argue that the industry-funded trials cannot be considered negative trials; they should be considered failed trials and not included in meta-analyses. 

The bottom line is that if you are treating an adolescent with depression only – no anxiety, consider starting with fluoxetine first because it has the best evidence base. Sertraline and escitalopram are good second line choices for depression, and if the patient has anxiety as well, you are fine with any of these 3 medications.

Depression Treatment Algorithm. Click on the image above for a larger view.

This algorithm suggests a plan for treatment choices and strategies in adolescent depression. The algorithm does not include recommendations for children with depression only and no anxiety – there is a very limited evidence base for children in this category. 

For adolescent depression, start with fluoxetine, increase as tolerated to an adequate dose which is generally going to be 40 mg. If your patient does not achieve symptom response or approach remission on an adequate dose, re-evaluate the diagnosis and assess for comorbidities that may be impeding response, like a trauma history or ongoing stressors.  

While the algorithm recommends that the SSRI be combined with psychotherapy at each step, you do not need to wait for your patient to start psychotherapy to start a medication. Remember that in the NIMH-funded studies of SSRIs, fluoxetine alone was close to fluoxetine plus CBT in getting kids to remission. 

Many modalities have been proposed as adjunctive, complementary or alternative treatments for depression. Few of these have a substantial evidence base in adults; almost none have an evidence base in children or adolescents.  

We will continue to update this list with details regarding use, efficacy and safety as data become available.

  • Herbal treatments
  • Mineral treatments
  • Bright Light Therapy
  • Neuromodulation Therapies
  • Exercise, Yoga & Dance

Read more here about Bright Light Therapy.

Prevention

  • Treat maternal depression
  • Treat anxiety disorders in younger children which often precede depression
  • Promote coping strategies, pleasurable activities, and mastery

The Course of Treatment in Pediatrics

Major depressive disorder is uncommon in prepubertal children, but it does occur.  More commonly, symptoms emerge around puberty, especially around or after menarche in girls.  Depressive symptoms can emerge gradually and go undetected or unremarked for some time as the child experiences them as a new normal. Routine screening of adolescents facilitates the identification of depression in teens who may not have the language or insight to recognize the condition in themselves.  

A supportive relationship with one's primary care clinician (or specialty care clinician for youth with chronic medical conditions) is a key aspect of the management of pediatric depression.  Even after treatment or after an episode of MDD has resolved, the pediatric clinician should regularly check in on the patient's mood and ask how they are managing any symptoms that might emerge.  

Because depression is often recurrent and persists into adulthood, the pediatric clinician should advise transitional-age youth regarding monitoring their mood and accessing care as they move into adult health care.  Most primary care clinicans for adults are comfortable assessing depressive symptoms and prescribing SSRIs.  

Resources

Resources for Patients & Families

Depression: Parents' Medication Guide.  American Academy of Child and Adolescent Psychiatry.

Child Mind Institute Depression Resources

Resources for Clinicians

Adolescent Depression: Pediatric Mental Health Minute Series

References

Guidelines for Adolescent Depression in Primary Care (GLAD-PC): Part I. Practice Preparation, Identification, Assessment, and Initial Management. AAP, March 2018.

Guidelines for Adolescent Depression in Primary Care (GLAD-PC): Part II. Treatment and Ongoing Management. AAP, March 2018.

Bodden, D. H. M., Stikkelbroek, Y., & Dirksen, C. D. (2018). Societal burden of adolescent depression, an overview and cost-of-illness study. In J Affect Disord (Vol. 241, pp. 256–262). https://doi.org/10.1016/j.jad.2018.06.015

Emslie, G. J., Mayes, T., Porta, G., Vitiello, B., Clarke, G., Wagner, K. D., Asarnow, J. R., Spirito, A., Birmaher, B., Ryan, N., Kennard, B., DeBar, L., McCracken, J., Strober, M., Onorato, M., Zelazny, J., Keller, M., Iyengar, S., & Brent, D. (2010). Treatment of Resistant Depression in Adolescents (TORDIA): Week 24 outcomes. In Am J Psychiatry (Vol. 167, Issue 7, pp. 782–791). https://doi.org/10.1176/appi.ajp.2010.09040552

Fallucco, E. M., Seago, R. D., Cuffe, S. P., Kraemer, D. F., & Wysocki, T. (2015). Primary care provider training in screening, assessment, and treatment of adolescent depression. In Acad Pediatr (Vol. 15, Issue 3, pp. 326–332). https://doi.org/10.1016/j.acap.2014.12.004

Ginsburg, A. D., Stadem, P. S., Takala, C. R., Croarkin, P. E., Mattson, A. B., Billings, M. L., Brennan, R. M., & Huxsahl, J. E. (2018). An Examination of Screening Tools for Collaborative Care of Adolescent Depression. In J Clin Psychiatry (Vol. 79, Issue 4). https://doi.org/10.4088/JCP.17m11543

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Ravindran, A. V., Balneaves, L. G., Faulkner, G., Ortiz, A., McIntosh, D., Morehouse, R. L., Ravindran, L., Yatham, L. N., Kennedy, S. H., Lam, R. W., MacQueen, G. M., Milev, R. V., & Parikh, S. V. (2016). Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder. Section 5. Complementary and Alternative Medicine Treatments. Canadian Journal of Psychiatry. 61(9), 576–587. https://doi.org/10.1177/0706743716660290

Stafford, A. M., Garbuz, T., Etter, D. J., Adams, Z. W., Hulvershorn, L. A., Downs, S. M., & Aalsma, M. C. (2020). The Natural Course of Adolescent Depression Treatment in the Primary Care Setting. In J Pediatr Health Care (Vol. 34, Issue 1, pp. 38–46). https://doi.org/10.1016/j.pedhc.2019.07.002

Weersing, V. R., Jeffreys, M., Do, M. T., Schwartz, K. T., & Bolano, C. (2017). Evidence Base Update of Psychosocial Treatments for Child and Adolescent Depression. In J Clin Child Adolesc Psychol (Vol. 46, Issue 1, pp. 11–43). https://doi.org/10.1080/15374416.2016.1220310