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Introduction

This article covers epidemiology and pathophysiology of depression, as well as assessment, and treatment of depression in children and adolescents. Brief survey of major trials appears below. Properties of medications used to treat depression are covered in respective articles. Many depressed children exhibit suicidality; article on detailed assessment and management of suicidality can be found here. List of instruments appears below. Depression in pregnancy is addressed here.

Epidemiology

Lifetime prevalence of depression is around 10% worldwide; general population studies in the US recorded lifetime prevalence as high as 17%. Commorbidity is very common, particularly anxiety (40%), substance use, and personality disorders. 40% of depressed patients abuse alcohol and 30% smoke. Of personality disorders, OCPD is most common (Tassman, Hassin 2005).

As many as 15% of depressed individuals commit suicide. Two-thirds of individuals who committed suicide were depressed.

50-75% of patients who had expereinced a major depressive episode (MDE), will develop subsequent episodes in the future. 10% of patients with first MDE will go on to have symptoms of bipolar disorder, 5% with mania and 5% with hypomania.

Cardiovascular disease (CVD) has become a major focus as a comorbidity, since MDD worsens outcomes of CVDs (both, mortality and re-infarction). It is not clear if treatment of MDD with SSRIs lowers the risk. Diabetes type II and MDD also have a bidirectional positive association.

Pediatric Depression

Around 2% of children and at least 8 % of adolescents are depressed. Common comorbidities include anxiety and disruptive behavior disorders. Neglect and child maltreatment, as well as bereavement, are significant risk factors, among many others. Adolescents are at a higher risk, particularly female teenagers:

  • Childhood M:F ratio is 1:1
  • Adolescent M:F ratio is 1:2-3; this ratio persists into adulthood.
    • Female predominance emerges with Tanner stage III and is explained by increasing levels of estradiol and testosterone (Copeland JAACAP 2014)
    • STAR*D trial found that women have earlier onset and longer episodes of depression.
    • Early puberty is another risk factor in adolescent girls.
  • According to large survey of US adolescents (n=10,123, ages 13-18) 15.9% of female adolescents and 7.7% of male teens met criteria for MDD or dysthymia. (Merikangas JACAAP 2010)

In contrast, male-to-female ratio in pediatric bipolar disorder is closer to 1:1 for all age groups.

Pathophysiology and Imaging

Neuroimaging

  • reduced hippocampal volume
  • reduced volume of frontal regions (anterior cingulate, and orbitofrontal cortex)
    • reduced left subgenual prefrontal cortex is somewhat more specific for early onset and familial depression.
  • Serotonergic receptor dysfunction had been implicated in suicidal behavior.

Changes in Sleep Architecture

EEG studies showed that depression in adults is associated with reduction in slow-wave sleep (stages III and IV), shorter period before onset of REM sleep (decreased REM latency), and increased REM density. Common complaints include early morning wakening, taking longer to fall asleep, and frequent night awakenings.

In children EEG differences have not been observed. (4)

Definitions and DSM-IV-TR

A mood disorder generally refers to sustained inability to control one’s moods while having mood states that are abnormal in intensity and/or duration.

Major depressive episode is a required for diagnosis of major depressive disorder (MDD) and is defined as depressed mood, (or anhedonia, or irritability in children) and 4 additional symptoms lasting for 2 weeks with significant distress or functional impairment. DSM-IV criteria are often summarized with a mnemonic “Sig E CAPS.” The mnemonic includes one of two major criteria and all 7 minor criteria: abnormal of sleep, lack of interests (anhedonia - major criteria) and energy, poor concentration, abnormal appetite (in children, failure to gain weight), psychomotor retardation, and suicidality. The criteria are widely used in research but do not necessarily capture every depressed individual (see assessment section).

A period of depression associated with substance use or caused by a general medical condition should not be called a “major depressive episode,” and thus, does not constitute a diagnosis of MDD. For example, symptoms of depressed mood precipitated by oral contraceptives or isotretinoin use should be documented as substance-induced mood disorder. Manic-like symptoms precipitated by an SSRI should like-wise be considered a substance-induced adverse event, rather than a hypomanic episode of bipolar disorder. Bereavement should not be diagnosed as MDD, unless 2 months had passed since the loss, and moderate to severe symptoms of depression persist (DSM-IV). This is often documented as “bereavement-related major depression.” Complicated grief is typically diagnosed when distress associated with loss persists for more than 6 months.
Minor depression is a depression that does not meet the criteria for MDD; it is sometimes referred to as “sybsyndromal” or “subthreshold” depression.

Dysthymia is having depressed mood for better part of 2 years, 1 year for children, plus 2 of 6: abnormal appetite, sleep, low energy, low self-esteem, poor concentration/indecision, and hopelessness.

Assessment

Depression can manifest itself in a variety of ways; most common symptoms of depression are generally grouped in 3 symptom categories:

  1. Psychological symptoms, including anxiety, worry, feeling of helplessness, obsessiveness, cognitive difficulties, etc.
  2. Behavioral manifestations, including reduced productivity, adherence to rituals, crying spells, cutting, and other self-injurious behaviors, psychomotor retardation, anger, and substance abuse.
  3. Somatic/Physical symptoms, including pain, headaches, GI symptoms, sexual dysfunction, fatigue, sleep and appetite disturbances, and weight changes.

Note, that only a few of these common symptoms of depression are captured in the DSM-IV definition of depression.

Recognizing depression in youth

Depressed children are less likely to verbalize depressed mood and may present with irritability, temper tantrums, somatic complaints, worry, separation anxiety, and social withdrawal. They are less likely than adults to have problems with appetite, sleep, or decreased energy (Goldman, CAP clinics NA, 2012)
In teenage years, additional symptoms of anxiety, truancy/school avoidance, anger, mood swings, academic problems, and hypersomnia may be the presenting problem.

Differential diagnosis

  • Thorough history is essential in recognizing depression: in young children consider anxiety, DBDs, PDDs, lead poisoning, anemia, mononucleosis, lyme disease, and thyroid dysfunction.
  • In adolescents, substance abuse is an important consideration as a differential diagnosis and a comorbidity.
  • In all patients, contribution of traumatic experiences/PTSD, a disabling chronic illness, and bereavement resulting from loss of relative, sibling, or a friend should be investigated. Likewise, certain medication side effects commonly cause depressive symptoms, classically oral contraceptives, corticosteroids, stimulants, isotretinoin, antibiotics, and antivirals.

While seasonal affective disorder may be diagnosed in children and adolescents, its pattern may coincide with and should be differentiated from depression triggered by the increased stress and pressures of the academic school year. (ACAAP)

Finally, over 20% of depressed teens will be diagnosed with bipolar disorder; thorough investigation of symptoms of hypomania, mania, and general mood lability is essential.

Evaluation

AACAP parameter calls for screening of all children and adolescents for depression; if screening reveals depressive symptoms, the youth should undergo thorough evaluation, including safety/self-harm and bipolarity assessment. Using standardized instruments and asking the patient to keep a “feelings diary” can often be helpful. As with any evaluation, PPHx, FMHx, and social and medical histories are very important.

Screening and Assessment Instruments

  • Mood Disorder Questionnaire (MDQ) is a screening instrument for bipolar disorder (not to be used for diagnosis) available in public domain.
  • Columbia DISC Depression Scale is a self-reporting screening instrument for youth 11 years of age and older. It is available in the public domain, and contains 22 questions for the patient and the parent.
  • Beck Depression Inventory for Youth (BDI-Y) is a 20-item self-report instrument for children 7-14 y.o.; the questions are written on 2nd grade reading level.
  • Children’s Depression Rating Scale Revised (CDRS-R) is an clinician-administered 17-item screening and diagnostic questionnaire for youth aged 7 to 18 years. It is modeled after Hamilton Rating Scale for Depression.
  • Children’s Depression Inventory (CDI) is a self-report scale with 27 items for youth aged 7 to 17 years.

Treatment of Children and Adolescents

The evidence-based modalities shown to be effective in adolescents are anti-depressants, CBT, and interpersonal therapy (IPT).

How to Think about Treatment of Depression

In planning intervention it is useful to to conceptualize it in stages of acute, continuation, and maintenance treatments. Other terms that are used frequently in literature, include:

  • Response/Remission - initial symptom reduction/significant improvement lasting at least 2 weeks; the goal of the acute phase of treatment is to achieve response to treatment.
  • Recovery - significant improvement lasting at least 2 months;
  • Relapse - early return of symptoms, usually within 1-2 mo of remission; risk of relapse can decreased with continuation treatment;
    • for the purposes of the boards exam, a relapse into a major depressive episode in under 2 months of initial response is considered a continuation of the original depressive episode, i.e. the diagnosis is "MDD, singe episode," and not "MDD, recurrent."
  • Recurrence - return of symptoms following a period of recovery. Around 70% of children and adolescents with depression will have recurrence within 5years. Risk of recurrence is minimized with maintenance treatment.

Severity of depression and level of functional impairment must also be considered; these factors and many other (age, comorbidities, family environment, etc) determine which specific interventions should be offered:

  • Placebo response is uniformly high (30%-60%) in RCTs of pediatric depression, and therefore, in mild, uncomplicated depression supportive treatment alone (education, family support, supportive psychotherapy, and case management) may be sufficient (AACAP).
  • Moderate depression may respond to CBT or IPT, particularly if patient is motivated, whereas more severe cases generally require an SSRI in combination with psychotherapy. Initial response rate to SSRIs is 40%-70% across many RCTs but remission rate drops to 35%.
  • Once remission is achieved, continuation treatment is essential, for at least 6-12 months, due to high risk of relapse and recurrence (highest at 4 months).
  • Maintenance treatment should follow to prevent recurrence, especially if the patient had several relapses/recurrences or needed a while to recover. Youth with MDD and comorbid dysthymia ("double depression") may need to continue treatment for years.
  • Primary and Secondary prevention of depression in children is taking on increasing importance in literature and practice. Effective strategies include
    • CBT for at-risk youth who did not meet criteria for MDD
    • treating maternal depression,
    • treating anxiety disorders in children,
    • lifestyle modification, particularly for children with family history of depression and/or sybsyndromal symptoms.

How to Treat Depressed Children and Adolescents

Studies of psychotherapies as acute treatment showed fair response in both, children and adolescents, but recurrence rate within a year was consistently high. Thus, continuation treatment psychotherapy and/or psychopharmacological intervention are warranted in depressed youth. While effectiveness of CBT was demonstrated in many studies, in the TADS trial, CBT alone was not superior to placebo.

Efficacy of fluoxetine and (recently) escitalopram (Lexapro) has been established in several large RCTs; the two drugs have FDA indication for treating pediatric depression in youth as young as 8 y.o. in the case of fluoxetine, and 12 y.o. for escitalopram (more SSRIs are approved for OCD). While sertraline, citalopram, and paroxetine were also shown to be effective in RCTs, it is unclear if the observed risks outweigh the measured benefits of these SSRIs.

In RCTs of SSRIs (n>3000) overall rate of response was 61%, (vs placebo 50%) with NNT of 10, and NNT=5 for fluoxetine specifically. venlafaxine is more efficacious than placebo in adolescents (not children), but had higher rate of suicidal events, particularly in those at risk.(Maalof, CAP clinics of NA, 2012). There is some evidence for dose escalation if there is no response at a lower dose, prticularly with fluoxetine and citalopram.

TCAs were found to be no more effective than a placebo' in adolescent depression. They are sometimes used in augmentation. In few RCTs, Venlafaxine (Effexor) was not superior to placebo in children; adolescents did somewhat better on it. Studies of other antidepressants were likewise inconclusive.

Lithium has been studied in treatment of acute depression in teens (Lewis’s 769). This may provide faster alleviation of symptoms in adolescents with significant functionally impairments. Benzodiazapines are helpful when anxiety is a significant comorbidity or symptom. An atypical antipsychotic should be part of treatment in depression with psychotic features. ECT and light therapy likewise have a role.

SSRIs should be started at a low dose and increased slowly. Response to dose increase can be expected at 4-week intervals. However, a patient should be monitored more frequently for suicidality and other adverse effects. Psychopharmacological management strategies are adopted from adult literature due to lack of data:

  • Failure to respond to an SSRI at 8-10 weeks or development of adverse effects are reasons to switch to another one.
  • If partial response is achieved, various dose optimization and augmentation strategies can be used.

The half-life of some antidepressants (sertraline, citalopram, paroxetine, bupropion SR) is shorter in children than in adults, exposing youth to risk of withdrawal symptoms. Adverse effects of SSRIs, including suicidality, are addressed in dedicated article. MAO-I have been associated with treatment of atypical depression??

Landmark Studies and Trials

Treatment for Adolescents with Depression Study (TADS)

  • TADS was the first RCT to compare an SSRI with CBT and their combination.(5)
  • 439 adolescents were randomly assigned to four treatment groups, fluoxetine alone (FLX), CBT alone, their combination (COMB) and a pill placebo group. The treatment lasted for 12 weeks, and detailed assessments were performed then and in another 6 months.
  • CBT did not separate from placebo, and was inferior to fluoxetine alone at 12weeks; combination of fluoxetine and CBT did the best. However at 9 mo all non-placebo treatment arms merged, suggesting that CBT has a role in secondary prevention and suicidality. (Kennard BD JCAAP 2009)

Adolescent Depression and Psychotherapy Trial (ADAPT)

severely depressed patients had a 61% resonse rate by week 28 with SSRi alone, and 53% for combination of SSRI and CBT.

Treatment of Resistant Depression in Adolescent Study (TORDIA)

  • Adolescents who failed a 2-mo SSRI trial were enrolled, n=334.
    • Subjects randomized to 1. SSRI, 2. SSRI+CBT, 3. venlafaxine (150 - 225 mg), 4. venlafaxine+CBT for 12-weeks.
    • Remission in the combination treatment was superior to medication only groups (55% vs 41%)
    • Venlafaxine and SSRI groups response rates were similar at 47%, but venlafaxine groups had higher BP, HR, and more skin problems. (6)
  • In TORDIA follow-up, responders continued teatment for 24 weeks,, while non-responders had open treatment.
    • no difference between original groups, but suicidality improved faster on SSRIs than on venlafaxine.
    • trajectories of responders and non-responders diverged by week 6.
    • 61% gained remission with a successive treatment by 72 weeks.
    • 1-year relapse rate was 25% among responders, similar to youth who respond to their first SSRI.

High-yield Facts

  • Of the SSRIs, fluoxetine’s safety and efficacy in treatment of youth is backed by strongest evidence. Escitalopram is next in line.
  • TCAs are not considered an efficacious monotherapy, unlike their established role in adult depression.
  • While fluoxetine and TCAs are considered safe in pregnancy and breast-feeding, there is some evidence of association of paroxetine use and risk of congenital malformations. ECT is considered a safe treatment in severe depression.
  • While SSRIs are first line for both treatment of anxiety and depression, they are much more effective in anxiety disorders (NNT of 3 versus NNT of 9-10 for depression). This is in part due to high placebo response rate in depression studies.

Further reading

(1) AACAP 2007 Practice Parameter J. Am. Acad. Child Adolesc. Psychiatry, 2007; 46(11):1503-1526.

(2) Lewis’s Child and Adolescent Psychiatry (2007)

(3) Vitiello B. Treatment of Adolescent Depression: What We Have Come to Know. Depression and Anxiety 26:393-95(2009)

(4) Bertocci, MA et al. Subjective sleep complaints in pediatric depression: a controlled study and comparison with EEG measures of sleep and waking. JAACAP, 44:1158-66, 2005.

(5) Merikangas et al. Lifetime Prevalence of Mental Disorders in US Adolescents: Results from the National Comorbidity Survey Replication - Adolescent Supplement (NCS-A). JACAAP, 2010;49(10)980-9.

(6) Brent D. Switching to Another SSRI or to Venlafaxine w/w/o CBT for Adolescents With SSRI-Resistant Depression - The TORDIA RCT JAMA 2008

(7) Copeland WE, Angold A, Shanahan L, Costello EJ. Longitudinal patterns of anxiety from childhood to adulthood: the Great Smoky Mountains Study. JAACAP 2014 Jan;53(1):21-33.

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