Chapter 38. Depressive Disorders (in Childhood and Adolescence)

DSM-IV-TR Diagnostic Criteria

Major Depressive Episode

1. Five (or more) of the following symptoms have been present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure.

   Note: Do not include symptoms that are clearly due to a general medical condition, or mood-incongruent delusions and hallucinations.

   1. depressed mood. Note: In children and adolescents, can be irritable mood

   2. loss of interest or pleasure (anhedonia)

   3. significant weight loss when not dieting or weight gain, or decrease or increase in appetite. Note: In children and adolescents, can be failure to make expected weight gains

   4. insomnia or hypersomnia

   5. psychomotor agitation or retardation

   6. fatigue or loss of energy

   7. feelings of worthlessness or inappropriate/excessive guilt

   8. diminished ability to think or concentrate, or indecisiveness

   9. recurrent thoughts of death or suicide

2. The symptoms do not meet criteria for a mixed episode.

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

4. The symptoms are not due to the direct physiological effects of a substance (e.g., drug of abuse) or a general medical condition (e.g., hypothyroidism).

5. The symptoms are not better accounted for by bereavement (i.e., depressive/grief symptoms lasting less than 2 months).

(Reprinted, with permission, from the Diagnostic and Statistical Manual of Mental Disorders, 4th edn., Text Revision. Copyright 2000 American Psychiatric Association.)

In this chapter, we describe the characteristics and epidemiology of unipolar depressive disorders in children and adolescents, etiologic risk factors for depression onset and recurrence, and assessment and differential diagnosis of depressive disorders. We review recommended psychosocial and pharmacological treatments, and in conclusion, suggest areas for future investigation.

Child and adolescent depressive disorders are common, often recurrent, and generally continue into adulthood. These disorders are often familial, and are associated with additional morbidity and mortality from comorbid substance abuse and from suicide and suicidal behavior. Patients also suffer educational and later occupational underachievement as well as relationship difficulties. Therefore, early identification and treatment of these conditions are important public health issues.

Epidemiology

The estimated prevalence of MDD is 2% in children and 4–8% in adolescents. After puberty, the risk for depression increases two- to fourfold, with 20% incidence by the age of 18 years. The gender ratio in childhood is 1:1, with an increase in the risk for depression in females after puberty, when the male/female is estimated at 1:2. This may be related to higher rates of anxiety in females, changes in estradiol and testosterone at puberty, or sociocultural issues related to female adolescent development.

It is important to differentiate childhood-onset from adolescent-onset depression. Depressive disorders in adolescence are much more likely to be recurrent into adulthood. In the context of significant family adversity, prepubertal depression is most often comorbid with behavioral problems. A less common form of childhood prepubertal depression is associated with strong familial loading for depression, high rates of anxiety, high risk for bipolar outcome, and recurrent mood disorder into adolescence and adulthood.

Etiology

Early-onset depression is multifactorial, including, but not limited to, familial factors, early life events, neuroendocrine changes, and genetics. Twin studies show the importance of genetic and environmental factors, particularly in interaction. Familial risk factors for recurrent depressive disorders in youth include early-onset parental mood disorder. Non-familial depression has as risk factors parental substance-abuse disorder, parental criminality, family discord and low family cohesion. Abuse may also be related to an earlier onset of depressive symptoms, as well as many other comorbid conditions. The contribution of early adverse life events is much greater in the setting of familial genetic risk factors.

Genetics

The strongest single factor for developing MDD is familial loading for the disorder. The majority of studies including twin, adoption and high-risk studies have shown a familial pattern with interaction of environmental and genetic factors. Family studies show a two- to fourfold increased risk for depression in offspring of depressed parents. Twin studies show a heritability for depression of 40–65%. Evidence from twin studies shows greater genetic concordance in adolescent-onset depression than in childhood-onset depression, suggesting that very early onset depression is more related to environmental factors.

One model of the interaction of genes and environment indicates a strong cotransmission for depression and anxiety, with heritability of greater than 60%. Genes imparting risk for anxiety may lead to youth depression by increasing sensitivity to adverse life events, another example of gene–environment interaction. This model is further supported by the association of the genetic variant of the serotonin receptor that is less functional, contributing to early-onset depression in interaction with stressful life events.

Signs and Symptoms

Depressive symptoms in childhood include consistent sad or depressed mood, anhedonia, change in appetite (increase or decrease), sleep disturbance, anergia, amotivation, irritability or agitation, worthlessness or guilt, poor concentration, and morbid ideation or thoughts of suicide. Children and adolescents may present with psychomotor retardation, but more often present with disabling irritability.

Children and adolescents presenting with depressive symptoms may be classified on the basis of impairment, severity, persistence of illness, and symptom profile. In the absence of a stressor leading to time-limited adjustment disorder, depression not otherwise specified (NOS) is diagnosed when full criteria for an MDD are not met. Dysthymic disorder is pervasive and chronic, lasting at least 1 year, with fewer symptoms than MDD. Dysthymia may be complicated by major depressive episodes, and is then often referred to as “double depression.” Dysthymic disorder or “minor depression,” and subsyndromal depression can be disabling, and may be precursors to MDD.

Major depression involves depressed mood, irritable mood, or anhedonia, plus four other symptoms. It is the most severe of the depressive disorders, and can be associated with psychosis. Psychosis presents as auditory hallucinations of a derogatory and mood-congruent nature, but may also include morbid visual hallucinations or delusional thinking in severe cases.

Psychological Testing

No psychological test is diagnostic of major depressive disorder. A comprehensive psychiatric diagnostic evaluation is the most useful tool to diagnose depressive disorders in children and adolescents. The Mood and Feelings Questionnaire (short-form) can be used to screen for depression and also to monitor treatment.

Laboratory Findings

No laboratory studies are diagnostic of major depressive episode, however, laboratory findings are abnormal in some patients with MDD symptoms. Provocative studies of noradrenergic, hypothalamic–pituitary adrenal axis, and serotonergic systems have been found to be abnormal in depressed child and adolescent patients, but this is particularly true of patients exposed to trauma or severe life stressors.

Subclinical hypothyroidism, anemia, diabetes, and vitamin deficiencies including B12 and folate are associated with depressive symptoms. While these are more common in adults, screening laboratories including thyroid function testing, complete blood count, electrolytes, blood sugar, and B12 and folate levels may be indicated, in cases of chronic or unresponsive depression.

Neuroimaging

Differences in morphometric and functional magnetic resonance imaging (fMRI) have contributed to our understanding of the neural circuitry underlying the development of depressive disorders. Structural imaging studies have revealed reduced volume of the left subgenual prefrontal cortex of both adolescents with depression and adults with family history of depression and early-onset of their own disorder. A review of imaging studies of adolescent and young adult twins suggested that this structural difference is genetically transmitted and may partially mediate the heritability of depression. Depressed adolescents also were found to have increased third and fourth ventricular volume in addition to decreased prefrontal cortical volume. In an fMRI study, depressed adolescents, like depressed adults, showed increased activity within the ventromedial prefrontal cortex and rostral anterior cingulate gyrus. Other fMRI studies have shown abnormalities in response to fearful faces, with increased amygdala activation in anxious children, and decreased amygdala activation in depressed children. In addition, MDD subjects had poorer memory for faces, and subjects who successfully encoded faces had higher activation of the left amygdala. The similarity of some of these findings to those in adults may indicate that neural circuitry contributing to depression is present in adolescence, and persist through development to adulthood.

The average duration of major depressive episode in community samples is 3–6 months, with slightly longer duration in referred samples of 5–8 months. Approximately 1 in 5 adolescents will have resistant depression lasting greater than 2 years. In contrast, depressive episodes may remit spontaneously without treatment. Comorbidity, especially with dysthymic disorder, increased severity, presence of suicidal ideation, parental depression, and absence of a supportive environment contribute to longer duration and intractability of episodes.

Depression is a chronic and recurrent disorder. While childhood depression is less common, there is high likelihood of recurrence during adolescence. Adolescents remain at risk for recurrence into adulthood. Estimates of the risk for childhood recurrence from one study indicate 40% relapse by year two of remission and over 70% relapse within 5 years. Estimates of recurrence for adolescent depression are between 30–70% in 1–2 years of follow-up. Children in whom there is incomplete symptom remission, presence of dysthymia, history of abuse, continued social impairment, or parental history of early depression are more likely to experience recurrence. Children and adolescents with persistent depression are at risk for a myriad of complications including suicidal behavior, personality disorders, substance-use disorders, psychosocial dysfunction, obesity, and underachievement. Bipolar outcome occurs in 10–20% of clinical referred samples of child and adolescent depression and is most common in psychotically depressed patients and those with a strong family history of mania.

The majority of children and adolescents presenting for treatment of depression has a co-occurring disorder. Commonly, patients suffer from comorbid anxiety disorder, which can predate the onset of depressive symptoms. This should be differentiated from dysphoria, which resolves with removal of stress. Children with a history of childhood abuse are predisposed to development of depression. In these children, posttraumatic stress disorder and other disorders of extreme stress are prevalent. Substance-use disorders can lead to depression and, conversely, self-medication of depression and anxiety can lead to substance abuse or dependence. Disruptive behavior disorders and impulse control disorders are often comorbid with depression, and can be misdiagnosed if depression is not identified. ADHD, in particular, is often diagnosed in depressed youth and may be coheritable in some families. There is evidence that depression leads to conduct disorder and the reverse.

The most serious concern in children and adolescents with depression is their increased risk for suicide and suicidal behavior. All patients should be assessed for the presence of suicidal ideation. Depressed youth with suicidal ideation require additional monitoring and treatment targeting improvement of suicidality. If suicidal ideation is present with intent, the patient requires treatment in an inpatient, restrictive setting.

In light of the high degree of comorbidity in child and adolescent depression, differential diagnosis is both crucial to appropriate care, and challenging. Identification and treatment of the disorder contributing to the greatest impairment is indicated. For example, treatment of a preexisting anxiety disorder may result in the resolution of depressive symptoms. Patients may not initially disclose anxiety symptoms, particularly in cases of ongoing trauma or obsessive–compulsive disorder. Such disorders require intervention beyond usual treatment for depression. Untreated ADHD may result in depressive symptoms because of its functional impairment and interpersonal difficulty. In this disorder, treatment of symptoms of inattention and impulsivity may alleviate symptoms attributed to depression. Substance-use disorders, particularly involving depressogenic substances, such as alcohol and opiates, may appear as a depressive disorder, but patients may be euthymic after detoxification and substance-abuse treatment. In the setting of psychotic disorders, affective flattening and the patient's unwillingness to share symptoms of psychosis can contribute to a misdiagnosis of depression. Finally, differential diagnosis should always include consideration of bipolar diathesis, as risk for this diagnosis in the setting of early-onset depression is as high as 10–20%. Children with a bipolar diathesis may present with decreased need for sleep, increased energy levels including marked change in behavior, flight of ideas, rapid speech, hypersexuality, grandiosity, or psychosis. In the depressed phase, some studies suggest depressive symptoms of hyperphagia, hypersomnia, and psychosis are predictive of bipolar outcome.

Treatment approach to and response of children and adolescents with depression may vary with severity, duration, and comorbidity of the presenting illness. Treatment should always include an acute and a continuation phase, with the availability of maintenance treatment. Psycho-education, support, and involvement of family and school are fundamental to any treatment plan, and in cases of very mild depression, may be adequate. In cases of more severe depression, use of psychotherapy, pharmacotherapy, or a combination is indicated.

Psychopharmacologic Interventions

In the consideration of psychopharmacologic treatment of depressed children and adolescents, it is important to note a high-placebo response rate of 30–60%. Nevertheless, there is evidence of efficacy of selective serotonin reuptake inhibitors (SSRIs) with response rates of 50–70%. Fluoxetine is the only medication approved by the FDA for the treatment of child and adolescent depression. It is the best studied and has demonstrated the greatest difference between medication and placebo. Moreover, there is evidence that fluoxetine has greater efficacy than cognitive–behavioral therapy (CBT), though combined treatment was found to have the greatest rate of response except in more severe cases, when it was equivalent to medication alone.

There are published studies demonstrating efficacy for citalopram and sertraline, though there are also unpublished negative studies. A meta-analysis of all available clinical trials, both published and unpublished, revealed that SSRIs are more efficacious than placebo, with response rates of 60% versus 49%. In some studies there are significant effects for adolescents but not for children. In addition, while tricyclic antidepressants show excellent response rates in adults, evidence does not support their use for the treatment of depression in children and adolescents.

Dosing recommendations for children and adolescents are to start at half the usual adult starting dose for 1 week (i.e., the equivalent of 10 mg of fluoxetine) and to then increase the dose to 20 mg of fluoxetine or equivalent for another 3 weeks. Dosing increases should occur at no less than 4-week intervals to allow the medication to reach steady state. Children and adolescents may require relatively higher doses of citalopram, sertraline, or fluvoxamine, based on pharmacokinetic studies. There is evidence that, in order to prevent relapse, treatment should be continued for at least 6 months after complete symptom remission, in the case of a first episode of MDD, and for at least 12 months after a recurrent episode.

In view of its more extensive efficacy data, fluoxetine should be used as a first-line agent. In depression that has been refractory to monotherapy with adequate doses of at least two SSRIs, augmentation strategies can include buproprion, lithium, or lamotrigine. Undiagnosed comorbid conditions or misdiagnosis should first be ruled out. Psychotherapy, if not started previously, is also indicated. Other considerations in the pharmacotherapeutic treatment of depression include the management of contributing comorbidity. Milder cases may respond to psychoeducation alone or in combination with brief psychotherapy.

Psychotherapeutic Interventions

Cognitive–Behavioral Therapy

CBT has been shown to be one of the most efficacious psychotherapies for the management of child and adolescent depression, with or without concomitant use of pharmacotherapy. CBT is based on the premise that depressed individuals have distorted information processing, thoughts, and core beliefs. Distortion manifests itself in a negative attributional style and beliefs that lead to, exacerbate, or perpetuate depression, particularly during times of stress. CBT uses cognitive techniques and skills building to attenuate cognitive distortions and maladaptive processing. The content of various CBT treatments varies widely, ranging from the highly structured CWD-A (Coping with Depression for Adolescents), to much less structured treatments like those based on Beck's CBT, to hybrids like that used in the Treatment of Adolescent Depression Study (TADS).

Based upon TADS, CBT alone or in combination with pharmacotherapy may be best for less severe cases of depression. Predictors of poorer response to CBT, from TADS and other studies, include greater severity, history of sexual abuse, parental depression, older age of onset, and greater hopelessness.

Interpersonal Therapy

Interpersonal Therapy (IPT) is predicated on the exploration and recognition of precipitants of depression including interpersonal loss, role disputes and transitions, social isolation, and social skills deficits. IPT for adolescents (IPT-A) is an adaptation of IPT. It begins with an “interpersonal inventory” that includes the patient's interpersonal relationships. This inventory allows therapist and patient to make collaborative decisions about goals for treatment. IPT-A may be successful because it addresses role transitions, interpersonal difficulties with peers and family, and the development of social skills—all important developmental tasks of adolescence.

In some measures of depression and functional impairment, IPT has been shown to be superior to CBT. IPT-A has been shown to be superior to “care as usual” in treatment of depression, as in regard to improvement in social adjustment, and functional status.

Family Therapy

Family therapy is often used as an adjunct to other treatments for depression. There have been both positive and negative studies regarding the use of family therapy. Interventions such as the management of parental depression, improvement of family communication, the reduction of criticism, and the enhancement of support, are likely to be of benefit.

Other Interventions

Light therapy has been shown to be beneficial for seasonal affective disorder and as an adjunct for MDD with a seasonal component. Light therapy involves the daily use of full spectrum light in the early morning hours to help with potential abnormality of the hypothalamic–pituitary axis. Light therapy is initiated in fall and winter months to counteract reduced daylight.

Electroconvulsive Therapy

Although there is little controlled evidence about the use of electroconvulsive therapy (ECT) in adolescent depression, documented clinical experience supports a role for ECT in depression that is refractory to pharmacological and psychosocial management, as well as in severe psychotic depression, and life-threatening depression. There is evidence that ECT may not be effective in the case of comorbid Axis II personality disorders. It may be most efficacious in bipolar depression.

One of the primary concerns in the prescription of SSRI medications in children and adolescents has been the FDA “black-box warning” concerning risk of suicidal behavior with use of these medications. FDA analysis has shown a higher rate of suicide-related events on SSRI than on placebo (at a rate of 4% compared to 2%). These adverse events occurred relatively early in treatment and did not involve any actual suicides, and few suicide attempts. In the TADS study, adverse suicidal events were almost four times more likely to occur with fluoxetine than with placebo.

In addition to concern about suicide-related behavior, antidepressants can cause side effects such as agitation, akathisia, serotonin syndrome (particularly in combination with other agents), headache, dizziness, gastrointestinal symptoms, sleep cycle disturbance, sexual dysfunction, and platelet inhibition leading to bruising. Additionally, in children at risk for bipolar disorder, it is important to consider that the risk of SSRI-induced mania has been reported as particularly high in children younger than 14 years of age. Other physicians involved in the care of child and adolescent patients should be made aware of the use of any medication. Due to platelet inhibiton, SSRIs should be stopped prior to surgery. Medications such as fluoxetine interact with many medications via the CYP-450 system, and this should be considered with each medication change or in cases of coprescription.

Depression is a chronic and disabling illness that often starts in childhood or adolescence. It contributes to increased risk for suicide, substance use, and other psychiatric sequelae, and interferes in the child or adolescent's personal development. While some success has been experienced in the treatment of early onset depression, up to 40% of youth with depression remain depressed at the end of clinical trials, and a higher proportion are still symptomatic. Many children and adolescents do not experience complete recovery, and all remain at risk for relapse. Further information is needed about our current methods of treatment, the management of very early onset depression, the neurobiology of depression, and the interaction of genetic and environmental contributors to depression.