Pediatric Depression 

Updated: Nov 15, 2017
Author: Angelo P Giardino, MD, MPH, PhD; Chief Editor: Caroly Pataki, MD 

Overview

Practice Essentials

Pediatric depression is a relatively common psychiatric condition that generally continues episodically into adulthood. Whether damaging experiences or biologic processes trigger depressive episodes remains subject to debate; however, the final common pathways to depression involve biochemical changes in the brain.

Signs and symptoms

A major depressive episode in children and adolescents typically includes at least 5 of the following symptoms (including at least 1 of the first 2) during the same 2-week period:[1]

  • Depressed (or irritable) mood

  • Diminished interest or loss of pleasure in almost all activities

  • Sleep disturbance

  • Weight change, appetite disturbance, or failure to achieve expected weight gain

  • Decreased concentration or indecisiveness

  • Suicidal ideation or thoughts of death

  • Psychomotor agitation or retardation

  • Fatigue or loss of energy

  • Feelings of worthlessness or inappropriate guilt

Symptoms must cause significant distress or impairment of important functioning and must not be attributable to the direct action of a substance or to a medical or other psychiatric condition.

Depression may occur with or without the following:

  • Psychotic symptoms

  • Chronicity

  • Melancholic features

  • Catatonic features

  • Seasonality

Depression may also have atypical features, including mood reactivity and at least 2 of the following for at least 2 weeks:

  • Increase in appetite or significant weight gain

  • Increased sleep

  • Feelings of heaviness in arms or legs

  • A pattern of long-standing interpersonal rejection sensitivity that extends far beyond the mood disturbance episodes and results in significant impairment in social or occupational functioning

Medical evaluation is always indicated to rule out organic etiologies that may imitate a depressive disorder, such as the following:

  • Infection

  • Medication

  • Endocrine disorder

  • Tumor

  • Neurologic disorder

  • Miscellaneous disorders

See Presentation for more detail.

Diagnosis

No specific laboratory evaluations that identify depression, but other potential etiologies must be ruled out. Workup may include the following:

  • Complete blood count (CBC) with differential

  • Serum electrolytes

  • Blood urea nitrogen (BUN)

  • Creatinine clearance and concentration

  • Urine osmolality

  • Drug monitoring (if relevant)

Other tests that may be indicated or helpful include the following:

  • Electroencephalography (EEG)

  • Electrocardiography (ECG)

  • Liver and thyroid function tests

  • Children’s Depression Inventory

See Workup for more detail.

Management

Interventions to be considered include the following:

  • Cognitive-behavioral therapy (CBT)

  • Psychodynamic psychotherapy

  • Interpersonal therapy

  • Behavior therapy

  • Family therapy

  • Supportive psychotherapy

  • Group psychotherapy

  • Pharmacotherapy

Overall, the choice of the initial acute therapy depends on the following factors:

  • Severity

  • Number of prior episodes

  • Chronicity

  • Subtype

  • Age of the patient

  • Contextual issues

  • Adherence to treatment

  • Previous response to treatment

  • Motivation of the patient and family for treatment

In mild-to-moderate cases, psychosocial interventions are often recommended as first-line treatments; in more severe cases, the addition of pharmacotherapy is often recommended. Pharmacotherapy is insufficient as the only treatment.

Factors that appear to be related to the response to psychotherapy include the following:

  • Age at onset of depression

  • Severity of depression

  • Presence of comorbid psychiatric disorders

  • Presence or absence of social support

  • Parental psychopathology

  • Family conflict

  • Exposure to stressful life events

  • Socioeconomic status

  • Quality of treatment

  • Therapist’s expertise

  • Motivation of the patient and therapist

Studies on pharmacotherapy for youths with major depressive disorder are few. Agents that have been used or proposed for use include the following:

  • Tricyclic antidepressants (TCAs)

  • Selective serotonin reuptake inhibitors (SSRIs)

  • Other antidepressants – Heterocyclics (eg, amoxapine and maprotiline), monoamine oxidase inhibitors (MAOIs), bupropion, venlafaxine, and nefazodone (found useful in adults)

See Treatment and Medication for more detail.

Background

Pediatric depression in the form of childhood and adolescent major depressive disorder (MDD) is a relatively common psychiatric condition that generally continues episodically into adulthood.

Childhood depression seems to be evident at earlier ages in successive cohorts and often occurs with comorbid psychiatric disorders, increased risk for suicide, substance abuse, and behavior problems. Children and adolescents with depression frequently have poor psychosocial, academic, and family functioning. (See Etiology.)

Whether damaging experiences or biologic processes trigger depressive episodes remains the topic of some debate. However, the final common pathways to depression involve biochemical changes in the brain. (See Pathophysiology and Etiology.)

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM5), uses the same basic criteria to diagnose depression in adults and children. (See Presentation.)

The choice of initial acute therapy depends on the following factors:

  • Severity

  • Number of prior episodes

  • Chronicity

  • Subtype

  • Patient age

  • Contextual issues - Eg, family conflict, academic problems, exposure to negative life events

  • Ability to adhere to treatment recommendations

  • Previous response to treatment

  • Patient's and family’s motivation for treatment

In mild cases, psychosocial interventions and psychotherapies are often recommended as first-line treatments, whereas, in the most severe cases, medication in addition to psychotherapeutic intervention is often recommended. (See Treatment.)

Cognitive-behavioral therapy (CBT) has been shown in multiple randomized, clinical trials to be effective in the treatment of mild MDDs in children and adolescents. For moderate-to-severe depression, psychotherapies and psychopharmacologic treatment are recommended. Hospitalization should be considered for severely depressed patients for whom an effective safety plan and supervision cannot be provided at home and for those patients and families unable or unlikely to adhere to treatment recommendations.[2, 3] (See Treatment and Medication.)

Go to Depression for complete information on this topic.

Pathophysiology

Brain abnormalities

Several areas of the brain are involved in mood functions. Sleep, appetite, and memory are commonly disturbed in persons with depression. Except for the pituitary, all cerebral components responsible for these functions are broadly considered to be a part of the limbic system; all components normally receive signals from neurons that secrete serotonin or norepinephrine or from neurons of both types. Reductions in the activity of circuits that use serotonin and norepinephrine may contribute to depression.

One abnormality that was discovered in an area of the brain that helps to control emotional reactions has contributed to a new understanding of why some people develop depression and other affective disturbances. Using positron emission tomographic (PET) scanning, researchers found an area of the prefrontal cortex with abnormally diminished activity in patients with unipolar depression and bipolar depression.[4] This region is related to emotional response and has widespread connections with other areas of the brain.

These other areas of the brain are responsible for the regulation of dopamine, noradrenaline, and serotonin, which have important roles in the regulation of mood. PET imaging provides the means for the study of receptor volume and the effect a compound may have on receptors; however, PET is problematic for use with children and adolescents because it requires radiation.

Magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), and magnetoencephalography (MEG) are best suited to study the structural, physiologic, and developmental brain abnormalities in youths because they do not involve ionizing radiation or radioactive isotopes. To date, few neuroimaging studies have been performed in depressed youths using these modalities.[5]

Steingard et al, in a study using MRI, compared 65 latency-aged children and adolescents who were hospitalized with depression with 18 hospitalized psychiatric controls who did not have a depressive disorder. The authors found that depressed youths had a significantly smaller ratio of frontal lobe volume to total cerebral volume and a significantly larger ratio of lateral ventricular volume to total cerebral volume,[6] suggesting these alterations in cerebral volumes may signal a role for the frontal lobes in the development of early-onset depression.

Tutus et al used single-photon emission computed tomography (SPECT) to examine associations between perfusion indices and clinical variables. Significant differences between perfusion index values were found when comparing 14 adolescent outpatients (aged 11-15 y) with MDD and 11 age-matched controls.[7]

These differences in perfusion index values were indicative of relatively reduced perfusion in the left anterofrontal and left temporal cortical areas. The investigators suggested that adolescents with MDD may have regional blood flow deficits in left anterofrontal and left temporal cortical regions, with greater right-left perfusion asymmetry than healthy controls have.

Neuroendocrine abnormalities

Neurotransmitter system abnormalities are being investigated to understand the biology of depression. Nobile et al found that human platelet 5-hydroxytryptamine (5-HT; serotonin) uptake is differentially influenced in nondepressed and depressed children by a common genetic variant of the promoter region of 5-HTT.[8]

Birmaher et al found that before the onset of affective illness, high-risk children had the same pattern of neuroendocrine response to 5-hydroxy-L-tryptophan (L-5-HTP) challenge as did children with MDD.[9] These findings could lead to identification of a trait marker for pediatric depression.

De Bellis et al, in a study examining nocturnal secretion of adrenocorticotropin (ACTH), cortisol, growth hormone (GH), and prolactin in a group of prepubertal children who were depressed and a control group, reported that prepubertal children who were depressed had lower cortisol secretion during the first 4 hours of sleep than did children in the control group.[10] ACTH, GH, and prolactin secretion did not differ between the 2 groups.

Etiology

Biologic versus nonbiologic causes

Psychosocial stressors are posited to be mediators for the development of depression. The final common pathways to depression involve biochemical changes in the brain. (See Pathophysiology.)

Genetic factors

Several studies of adults who are depressed, such as those reported by Akiskal and Weller[11] and Weissman et al[12] suggest a genetic component in the etiology of depressive disorders.

Parent-child relation model

The parent-child relation model conceptualizes pediatric depression as the result of poor parent-child interaction. Adults with depression report low paternal involvement and high maternal overprotection during early childhood. Troubled relationships with parents, siblings, and peers are common in children and adolescents with affective illness.[13] A child who is affectively ill often has a parent who is affectively ill. It is not uncommon for children to report abuse and/or neglect by the parent or parents who are affectively ill.

Hammen et al reported a significant temporal association between maternal and child stress and depression.[14] They found that children with substantial stress exposure who also had a symptomatic mother were significantly more depressed than children who were exposed to comparable levels of stress only.

Cohort effect

Klerman and Gershon reported a progressive increase in the lifetime cases of major depression over the last 70 years. They found high rates of affective disorders among relatives, with a younger age of onset in successive cohorts.[15]

New media screen time

Increased time spent using electronic devices (e.g., cell phones, tablets, computers, etc.) may have played a role in the increased rates of depression and suicide observed between 2010 and 2015, especially among girls, according to one study. Researchers found that adolescents who spent more time on new media (including social media) were more likely to report mental health issues, and adolescents who spent more time on nonscreen activities (in-person social interaction, sports/exercise, homework, print media, and attending religious services) were less likely. Although the study demonstrates a correlation between long hours of daily screen time and symptoms of alienation, it does not prove that one causes the other.[16]

 

Epidemiology

Occurrence in the United States

Reported US prevalence rates for depression in children and adolescents vary. Differences may be due to different populations sampled and variable criteria used. Studies have demonstrated that the occurrence of depression is not rare and is encountered regularly in pediatric and psychiatric practice.

Birmaher et al found the incidence of depression to be approximately 2% in children and 4-8% in adolescents.[3]

Garrison et al conducted a study of adolescents aged 11-16 years in the southeastern United States and found that the 1-year incidence of major depression was 3.3%.[17]

International occurrence

Available data on the international incidence of major depression in children and adolescents are sparse. Reported adult prevalence rates generally mirror those of the United States.

Helgason examined the entire Icelandic birth cohort of 1895-97 with periodic follow-up until cohort individuals reached age 74-76 years. The lifetime estimates of risk for any affective disorder were 14.8% for females and 9.8% for males.[18]

In 2000, Murphy et al, using data from the Stirling County Study of adults in Atlantic Canada, found that the overall prevalence of depression remained stable at 5% across 3 separate samples in 1952, 1970, and 1992.[19] The investigators also reported a redistribution in the most recent sample, indicating that prevalence had shifted from older to younger persons and that the female-to-male ratio had increased. The Stirling County Study, which began shortly after World War II, offered a 40-year perspective of the prevalence and incidence of psychiatric disorders among an adult population in Atlantic Canada.

A European study by Copeland et al, which sought to assess the prevalence of depression in 9 European nations in order to design intervention for elderly persons who were depressed, found widely ranging prevalences in the study centers.[20] Prevalence for females was higher than for males. There was no constant association between prevalence and age. Meta-analysis revealed an overall prevalence of 12.3% and sex frequencies of 14.1% for females and 8.6% for males.

According to Jablensky, the World Health Organization (WHO) collaborative study on the assessment of depressive disorders examined depressive patients in Canada, Iran, Japan, and Switzerland and found considerable similarity in depressive symptomatology across cultures.[21]

Age-related demographics

Evidence suggests that the presentation of some symptoms may change with age. Symptoms such as somatic complaints, irritability, and social withdrawal are more common in children, whereas psychomotor retardation, hypersomnia, and delusions are less common prior to puberty than they are in adolescence and adulthood.[22, 23, 24, 25]

Sex-related demographics

A report recently released by the Substance Abuse and Mental Health Services Administration (SAMHSA) indicates that sex differences in depression rates emerge at 12-17 years. The report states that girls aged 12-17 years are 3 times more likely than boys aged 12-17 years to have had a major depressive episode in the last year.[26]

During this period, the increase of the overall rates of depression and the onset of new cases of depression peak. The rates of depression increase dramatically for both sexes, and the rate of depression in females grows to 3 times the prevalence rate for males. No sex differences are noted for depression symptom severity or recurrence.

A study of a randomly selected sample of high school students revealed that 22.3% of females and 11.4% of male high school students reported 1 current or lifetime episode of unipolar depression.[27] The percentage of male and female students with 2 or more episodes was 4.9% and 1.6%, respectively.[17]

Race-related demographics

Cultural norms associated with differing racial and ethnic groups can affect the experience and reporting of symptoms of depression. In some cultures, for example, depression may be experienced largely in somatic terms, in place of sadness or guilt. Several studies point toward the role of culture in childhood and adolescent depression. For example, the stress of acculturation was found to have a role in the increased incidence of depressive symptoms and suicidal ideation among Hispanic youths.[28]

In an epidemiologic study of youths aged 12-17 years in Los Angeles County in 1998, Siegel et al found that Hispanic youths reported more symptoms of depression, independent of socioeconomic status, when compared with white, African American, or Asian American adolescents, using the Children’s Depression Inventory (CDI).[29] This study also found significant effects of social class on depression. As income decreased, the average level of depression increased.

More extensive studies of ethnic subpopulations of adolescents who are depressed are needed. The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM5), states that a symptom should not be dismissed because it is part of a cultural norm.[1] Likewise, culturally distinctive experiences (eg, fear of being hexed or bewitched; experience of visitations from the dead) should be distinguished from actual hallucinations or delusions that may be part of a major depressive episode with psychotic features.

Prognosis

A 2014 World Health Organization (WHO) report, “Health for the World’s Adolescents: A Second Chance in the Second Decade,” states that depression is the most frequent cause worldwide of illness and disability in persons aged 10-19 years, with the rate being highest in females.[30, 31] The report also states that as many as half of all mental disorders arise by age 14 years but are usually not recognized. Suicide is listed as the third leading cause of death among adolescents, behind road injuries and HIV/AIDS.

Risk of future depression

According to the American Academy of Child and Adolescent Psychiatry, practice parameters for depressive disorders in childhood and adolescence, a history of a previous depressive episode, subsyndromal symptoms of depression, dysthymia, and anxiety disorders increase the risk for future depression.[32]

In a study of an epidemiologic sample of 776 adolescents, Pine and associates found that symptoms of major depression in adolescence strongly predicted adult episodes of major depression.

Risk of suicide

There were 41,149 deaths from suicide in 2013. In 2015, the CDC reported suicide as the third leading cause of death among persons aged 10-14 years and the second among persons aged 15-34 years.[33]

Because mood disorders, such as depression, substantially increase the risk of suicide, suicidal behavior is a matter of serious concern for clinicians who deal with the mental health problems of children and adolescents. The incidence of suicide attempts reaches a peak during the midadolescent years, and the mortality rate from suicide increases steadily through the teenage years, with suicide being the third leading cause of death in that age group.

Risk factors for completed suicide include the presence of a major mood disorder, recent life stressor, occurrence of command auditory hallucinations, use of substances, and evidence of specific plans and an attempt to prevent discovery, as well as patient perception of failure of the issues that precipitated suicidal thinking to change. This lack of action tends to escalate the patients’ sense of hopelessness.

The Clinical Trial Registration Information–Treatment of SSRI-Resistant Depression in Adolescents (TORDIA) study noted that a history of nonsuicidal self injury (NSSI) can be predictive of future NSSI and suicide attempts in adolescents with treatment-resistant depression.[34]

Another study noted a significant NSSI rate (3,000 in 10,000) among Native American youths aged 10-14 years, specifically the White Mountain Apache tribe. Females reported a higher rate of NSSI than males; severe substance abuse was also noted among both boys and girls. While NSSI is largely unaddressed among the White Mountain Apache Tribe and likely other reservation communities, it is important to recognize that this mental health issue could serve as a precursor to suicide in this population.[35]

Patient Education

Educating parents about children’s emotional problems is very important. Education is known to result in better compliance with treatment and to improve parents’ understanding toward their children. Patients should be educated in a manner congruent with individual development, level of impairment, and clinician judgment.

The clinician should instruct parents and others in the homes of depressed youths to remove firearms or other lethal weapons from their homes to decrease the risk of suicide. Household medications also should not be accessible to depressed youths.

For patient education resources, see the Depression Center, as well as Depression, Substance Abuse, and Antidepressant Medications.

 

Presentation

History

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM5), uses the same basic criteria to diagnose depression in adults and children.[1]

The DSM5 defines a major depressive episode as a syndrome in which at least 5 of the following symptoms have been present during the same 2-week period:

  • Depressed mood - For children and adolescents, this also can be an irritable mood

  • Diminished interest or loss of pleasure in almost all activities

  • Weight change or appetite disturbance - For children, this can be failure to achieve expected weight gain

  • Sleep disturbance

  • Psychomotor agitation or retardation

  • Fatigue or loss of energy

  • Feelings of worthlessness or inappropriate guilt

  • Decreased concentration or indecisiveness

  • Suicidal ideation or thoughts of death

At least 1 of the 5 must be diminished interest/pleasure or depressed mood. Symptoms must cause significant distress or impairment of functioning in social, occupational, or other important areas. Depression should not have been precipitated by the direct action of a substance or the result of a medical condition and should not be better explained by bereavement or schizoaffective disorder. The depressive episode should not be superimposed on schizophrenia, schizophreniform disorder, delusional disorder, or a psychotic disorder not otherwise specified.

Depressive disorders can be rated as mild, moderate, or severe. The disorder can also occur with or without psychotic symptoms, which can be mood congruent or incongruent. Depressive disorders can be determined to be in full or partial remission. When an episode lasts more than 2 consecutive years, the depression should be diagnosed as chronic. Depression may also have melancholic features. Either a loss of pleasure in almost all activities or a lack of reactivity to usually pleasurable stimuli is present. Additionally, at least 3 of the following are required:

  • A depressed mood that is distinctly different from the kind felt when a loved one is deceased

  • Depression that is worse in the morning

  • Waking up 2 hours earlier than usual

  • Observable psychomotor retardation or agitation

  • Significant weight loss or anorexia

  • Excessive or inappropriate guilt

Seasonal mood disorder

The seasonality of a depressive disorder can also be specified. To diagnose a seasonal mood disorder, a regular temporal relationship should exist between the depression and a particular time of year. An individual should have demonstrated at least 2 episodes of depressive disturbance in the prior 2 years, and seasonal episodes should substantially outnumber nonseasonal episodes.

Diagnosing seasonal affective disorder in children is difficult because they experience the recurrent universal stressor of beginning school every autumn. In addition, a young child might present with an apparent seasonal depressive disorder but not yet have had prior episodes.

Atypical features in depression

A depression may also be identified as having atypical features. Characteristics of this subtype are mood reactivity and exclusion of melancholic and catatonic subtypes in addition to 2 or more of the following for a period of at least 2 weeks:

  • Increase in appetite or significant weight gain

  • Increased sleep

  • Feelings of heaviness in arms or legs

  • A pattern of long-standing interpersonal rejection sensitivity that extends far beyond the mood disturbance episodes and results in significant impairment in social or occupational functioning

Family history

Familial, social, and environmental factors appear to play significant roles in the course of depressive illness in children and youths. Good evidence indicates that depression can be recurrently noted in families from generation to generation.[36] Thus, a thorough family history is also quite important.

Physical Examination

A complete mental health evaluation should always include a medical evaluation. Organic etiologies that may imitate a depressive disorder must be ruled out. Conditions believed to mimic depressive disorders fall into major general categories, including the following:

  • Infection

  • Medication

  • Endocrine disorder

  • Tumor

  • Neurologic disorder

  • Miscellaneous disorder

 

DDx

Diagnostic Considerations

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM5), diagnostic criteria for depressive disorders are the same for children and adolescents as for adults.[1]

Major depressive disorder (MDD) is diagnosed when the required DSM5 symptoms are present and other disorders have been ruled out. Symptom clusters, such as seasonality, atypical symptoms, psychosis, or hypomania, characterize different subtypes of depression. Identify these subtypes because they require different modes of treatment.

It is important to be alert to changes in the patient that might signify a switch from a depressive state to a manic state. Childhood-onset depression is commonly a precursor of bipolar disorder. In youths, manic and depressive symptoms may be mixed (mixed episode), which is a common presentation of bipolar disorder among youths. Hypomanic symptoms may be quite brief at the onset of bipolar disorder and may be disregarded.

Comorbid symptoms of attention deficit hyperactivity disorder (ADHD), anxiety, posttraumatic stress disorder, substance abuse, and sleep disorders are often overlooked and require careful assessment and treatment. Consideration should be given to the diagnosis and treatment of youths with subclinical depression, because these children are at high risk to develop depression, and early intervention may be beneficial.

Health-risk behaviors such as smoking, marijuana use, early sexual debut, and hard drug use begin earlier in adolescents who have higher depressive symptoms when compared with their peers. Intervention and instituting treatment programs during early adolescence may help to prevent these risk behaviors later in adolescence.[37]

Other conditions to be considered include medication reaction, substance abuse, and organic disease presenting as depressive disorder.

Differential Diagnoses

 

Workup

Approach Considerations

There are no specific laboratory evaluations that identify depression. However, other potential etiologies must be ruled out, guided by clinical presentation. Workup includes laboratory evaluation along with additional, selected tests. Include a complete blood count (CBC) with differential in the initial laboratory evaluation to rule out infection and anemia. Assay electrolytes, blood urea nitrogen, creatinine clearance, creatinine, and urine osmolality to exclude renal disorders.

When using tricyclic antidepressants (TCAs) or lithium carbonate, monitor plasma levels to measure compliance and to avoid toxicity. Evaluate urine osmolality and creatinine clearance periodically during lithium treatment.

Other tests that may be indicated or helpful include the following:

  • Electroencephalography - For patients with a history or presentation that is suggestive of seizure disorder

  • Electrocardiography - For patients who will be treated with a TCA

  • Liver function tests and thyroid function tests (triiodothyronine [T3], thyroxine [T4], and thyroid-stimulating hormone [TSH]) to rule out thyroid disease

  • Children’s Depression Inventory - A simple self-report survey that may assist in determining the severity of childhood depression

 

Treatment

Approach Considerations

Current evidence-supported interventions include cognitive-behavioral therapy (CBT), pharmacotherapy, or a combination of both should be offered as treatment for children and adolescents with major depressive disorder (MDD). Safety is always the first concern in the evaluation of MDD in children and adolescents. Risk assessment of patients who are depressed should be ongoing. Documentation should support clinical decision-making.

Cognitive-behavioral therapy has been shown in multiple randomized, clinical trials to be effective in the treatment of mild to moderate MDDs in children and adolescents. Evidence from randomized, clinical trials suggests efficacy in the treatment of moderate to severe MDD using 3 selective serotonin reuptake inhibitors (SSRIs): fluoxetine,[38] sertraline,[39, 40] and citalopram.

Overall, the choice of the initial acute therapy depends on the following factors:

  • Severity

  • Number of prior episodes

  • Chronicity

  • Subtype

  • Age of the patient

  • Contextual issues - Eg, family conflict, academic problems, exposure to negative life events

  • Adherence to treatment

  • Previous response to treatment

  • Motivation of the patient and family for treatment

In mild cases, psychosocial interventions are often recommended as first-line treatments, whereas, in the more severe cases, medication in addition to psychotherapeutic intervention is often recommended.

Treatment of a child or adolescent who is depressed should occur within a biopsychosocial context. Such an approach includes the psychotherapies (eg, individual, family, group), medication management, social skills training, and educational assessment and planning. The clinician should choose a treatment setting prior to initiation of a treatment plan.

The clinician must carefully assess the risk for suicide in any child who is depressed. If a child is preoccupied with thoughts of suicide or has definite plans, or has other significant risk factors for suicide, the patient must be hospitalized. The clinician should weigh factors such as the child’s ability to function and the stability of the family, plus any history of previous suicide attempts, when determining whether or not a child or adolescent should be hospitalized.

Psychotherapy

Psychotherapy appears to be a useful initial acute treatment for mild to moderate depression. Several factors appear to be related to the response to psychotherapy, including the following:

  • Age at onset of depression

  • Severity of depression

  • Presence of comorbid psychiatric disorders - Eg, anxiety, dysthymia, substance abuse

  • Presence or absence of social support

  • Parental psychopathology

  • Family conflict

  • Exposure to stressful life events

  • Socioeconomic status

  • Quality of treatment

  • Therapist’s expertise

  • Motivation of the patient and therapist

Psychodynamic psychotherapy, interpersonal therapy, cognitive-behavioral therapy, behavior therapy, family therapy, supportive psychotherapy, and group psychotherapy have all been used for the treatment of youths with MDD.[41] Particular elements of several such approaches may be brought together in the best interests of the patient. Such combined treatment increases the likelihood not only of mitigating depressive symptomatology but also of improving self-esteem, coping skills, adaptive strategies, and family and peer relationships.

Brent et al reported that individual supportive treatment was considerably less efficacious than cognitive-behavioral therapy in adolescents who were depressed.[42] More studies that compare the complementary and differential effects of the various types of psychotherapy in children and adolescents with depression are needed.

A Cochrane Database of Systematic Reviews study found that both targeted and universal depression prevention programs may effectively prevent the onset of depressive disorder in children and adolescents when compared with no intervention. While allocation concealment was unclear in most studies and heterogeneity was noted in the findings, these results are encouraging, as prevention would be an important advance in public health.[43, 44]

Cognitive-behavioral therapy

Cognitive-behavioral therapy (CBT) is one of the most frequently studied psychotherapy treatments.[45] Its use in treating MDD is based on the premise that patients who are depressed have a distorted view of themselves, the world, and the future. These cognitive distortions contribute to their depression and can be identified and corrected with cognitive-behavioral therapy.

In a well-done review of 16 methodologically rigorous meta-analyses, cognitive-behavioral therapy was found to be effective for a wide range of diagnoses in the adult and pediatric populations.[46]

In most clinical samples, cognitive-behavioral therapy was found to be superior to other manualized treatments, including relaxation training and family and supportive therapy; however, all clinical studies of cognitive-behavioral therapy found a high rate of relapse on follow-up, suggesting the need for continuation treatment. Given the high rate of relapse and recurrence of depression, continuation therapy is recommended for all patients for at least 6-12 months.

During the continuation phase, observe patients at least monthly, depending on clinical status, functioning, support systems, environmental stressors, motivation for treatment, and the presence of comorbid psychiatric disease or other medical disorders. In this phase, psychotherapy can be used not only to consolidate the skills learned during the acute phase and help patients cope with the psychosocial sequelae of the depression but also to address the antecedents, contextual factors, environmental stressors, and intrapsychic conflicts that may contribute to a relapse.

If the patient is taking antidepressants, psychotherapy can be used to foster medication compliance. The only continuation study in depressed youths suggests that monthly cognitive-behavioral therapy sessions may be effective in preventing relapses of depression in adolescents.[47]

A study by Garber et al also suggested that cognitive-behavioral therapy can prevent depression from relapsing in adolescents but indicated that this is not the case in patients whose parents suffer from depression. The investigators studied 316 adolescents whose parents were diagnosed with current or prior depressive disorders.[48] The adolescents had a past history of depression; current elevated, but subdiagnostic, depressive symptoms; or both. The objective was to determine if the effects of a group cognitive behavioral prevention program prevented depression onset compared with usual care.

Rate and hazard ratio were lower among adolescents participating in a cognitive-behavioral program than in those who underwent usual care. Adolescents participating in a cognitive behavioral program also self reported greater improvement in depressive symptoms than those who underwent usual care. These effects were not observed in adolescents with a currently depressed parent, and, in these adolescents, the cognitive behavioral program was not shown to be more effective than usual care in preventing depression.[48]

Psychodynamic psychotherapy

Many clinicians have found psychodynamic psychotherapy to be useful in the treatment of depression in youths. Controlled studies using psychodynamic psychotherapy for the treatment of depression in children and adolescents are particularly difficult to design and expensive to conduct but are greatly needed. Psychodynamic psychotherapy can help youths to understand themselves, identify feelings, improve self-esteem, change maladaptive patterns of behavior, interact more effectively with others, and cope with ongoing and past conflicts.

Interpersonal therapy

Interpersonal therapy focuses on problem areas of grief, interpersonal roles, disputes, role transitions, and interpersonal difficulties. Mufson and Fairbanks found that interpersonal therapy may be useful in the acute treatment of adolescents with MDD.[49] They also found the rate of relapse to be relatively low after acute interpersonal therapy treatment.

General Considerations in Antidepressant Pharmacotherapy

Studies on pharmacotherapy for youths with major depressive disorder (MDD) are few, and some have methodologic problems. Additionally, very few pharmacokinetics studies have been performed in children. The few studies in children have focused on the effects of tricyclic antidepressants (TCAs), rarely addressing selective serotonin reuptake inhibitors (SSRIs). Other antidepressants, including heterocyclics (eg, amoxapine, maprotiline), monoamine oxidase inhibitors (MAOIs), bupropion, venlafaxine, and nefazodone, have been found to be effective in treating depressed adults.

A study of antidepressants versus placebo in the general population found that antidepressants for mild or moderate depression may be no more successful than placebo. The study noted that antidepressants are still considered the best treatment for major depression but that the same result may not be replicated in patients with depression of less severity.[50, 51]

Antidepressant medications may be indicated for children and adolescents with nonrapid-cycling bipolar depression, psychotic depression, depression with severe symptoms that prevent effective psychotherapy, and depression that does not respond to psychotherapy; however, given the psychosocial context in which depression occurs, pharmacotherapy is insufficient as the only treatment.

Even when the patient’s mood has been stabilized using a medication-only treatment, evidence suggests that the environmental and social problems associated with MDD remain, preventing the necessary full stabilization.

The clinician needs to inform parents and patients about adverse effects, the dose, the timing of therapeutic effect, and the danger of overdose of the administered drugs, particularly in the case of TCAs, before initiating pharmacologic treatment. Parents should take responsibility for medication storage and administration, especially parents of younger children or of children at risk for suicide. Because of the potential of TCAs to induce a fatal overdose, the clinician must carefully determine the exact amount of medication to be prescribed at each appointment.[52]

The TCAs require a baseline electrocardiogram (ECG), resting blood pressure, and pulse. Weight should also be frequently documented. No laboratory tests are currently indicated before or during the administration of the SSRIs. No other tests are indicated in a healthy child before starting antidepressants.

TCAs are no longer considered a first-line treatment for depression, due to their unfavorable adverse effect profile and lethality in overdose.

Dosing considerations

In a prospective cohort study using population-based healthcare utilization data on 162,625 individuals with depression (age range, 10-64 years), Miller et al found that patients aged 10-24 years who were started on high-dose antidepressant therapy were more than twice as likely to engage in acts of deliberate self-harm when compared with similarly aged patients who were started on typical modal-dose therapy.[53, 54, 55] In individuals aged 25 years or older, however, the antidepressant dose had essentially no effect on the frequency of deliberate self-harming behavior.

Selective Serotonin Reuptake Inhibitors

Because of reports that selective serotonin reuptake inhibitors (SSRIs) are effective in the treatment of youths with MDD and because of reports that SSRIs have a relatively safe adverse effect profile, very low lethality after overdose, and only once-daily administration, SSRIs are the most commonly used medications for depression.

Open studies, such as those by Leonard et al[56] and Rey-Sanchez and Gutierrez-Casares,[57] have reported a 70-90% response to SSRIs in the treatment of adolescents with MDD. Also, Emslie et al conducted an 8-week, double-blind study of the treatment of a large sample of youths with MDD and showed that children and adolescents responded significantly better to fluoxetine than to placebo (58% vs 32%).[58] Despite the significant response to fluoxetine, however, many patients had only partial improvement; only 31% achieved full remission.

A possible explanation for this partial response is that the effective treatment may involve variation in dose or length of treatment. In addition, the ideal treatment likely involves a combination of pharmacologic and psychosocial interventions. Except for lower initial doses, the administration of SSRIs in children and adolescents is similar to the treatment protocols used for adult patients.

The results from one study noted that depressed adolescents who received fluoxetine realized a greater treatment response when the therapy ended during summer vacation compared with those whose treatment ended during the school year. These results suggested a significant association between school difficulties and treatment response; the time of year should be taken into account when formulating a treatment plan.[59]

The clinician should treat patients with adequate and tolerable doses for at least 4 weeks. At 4 weeks, if the patient has not shown even minimal improvement, the clinician should consider increasing the dose. If, at this time, the patient shows improvement, the dose can be continued for at least 6 weeks. On the other hand, if no improvement is apparent at 6 weeks, other treatment strategies should be considered.

The clinician must apply this recommendation cautiously; whether longer trials with SSRIs increase the number of patients with late improvement is not clear. The SSRIs possess a relatively flat dose-response curve, suggesting that maximal clinical response may be achieved at minimum effective doses; therefore, adequate time must be allowed for clinical response and frequent early dose adjustments must be avoided. Blood levels are rarely indicated in clinical settings, but they may help to clarify concerns about toxicity or medical compliance.

The adverse effects of all SSRIs in children are similar to those in adults. They are dose-dependent and may subside with time. SSRIs may induce mania, hypomania, and behavioral activation, in which patients become impulsive, silly, agitated, and daring. Other adverse effects include gastrointestinal symptoms, restlessness, diaphoresis, headaches, akathisia, bruising, and changes in appetite, sleep, and sexual functioning. The long-term adverse effects of SSRIs are not yet known.

SSRIs and suicidality

A small number of case reports, such as those by King et al[60] and Teicher et al,[61] have described a putative association between SSRI administration and increased suicidality (perhaps linked to behavioral activation or akathisia). In this context, physicians are advised to be aware of the following information and to use appropriate caution when considering treatment with SSRIs in the pediatric population.

In December 2003, the UK Medicines and Healthcare Products Regulatory Agency (MHRA) issued an advisory that most SSRIs are not suitable for use by persons younger than 18 years for treatment of “depressive illness.” After review, this agency decided that the risks to pediatric patients outweigh the benefits of treatment with SSRIs, except fluoxetine, which appears to have a positive risk-benefit ratio in the treatment of depressive illness in patients younger than 18 years.

In October 2003, the US Food and Drug Administration (FDA) issued a public health advisory regarding reports of suicidality in pediatric patients being treated with antidepressant medications for an MDD. This advisory reported suicidality (both ideation and attempts) in clinical trials of various antidepressant drugs in pediatric patients. The FDA has asked that additional studies be performed because suicidality occurred in treated and untreated patients with major depression and, thus, could not be definitively linked to drug treatment.

In September 2004, the results of an FDA analysis suggested that the risk of emergent suicidality in children and adolescents taking SSRIs was real. The FDA advisors (Columbia University) recommended the following:

  • A “black-box” warning label be placed on all antidepressants, indicating that they increase the risk of suicidal thinking and behavior (suicidality)[62]

  • A patient information sheet (Medication Guide) be provided to the patient and their caregiver with every prescription

  • The results of controlled pediatric trials of depression be included in the labeling for antidepressant drugs

The committees recommended that the products not be contraindicated in the United States, because access was important for those who could benefit from them. For more information, see the FDA Statement on Recommendations of the Psychopharmacologic Drugs and Pediatric Advisory Committees.

Some studies have shown that the FDA warnings regarding suicide in children on antidepressants may have had the unintended result of a decrease in the rates of diagnosis and treatment of depression, as well as dosing adjustments by physicians.[63] It has also been noted that monitoring of these patients did not increase following the warnings.[64, 65]

This remains a controversial issue. Although SSRI therapy may have been associated with increased suicidality in a small number of cases, several studies suggest that SSRIs, like other antidepressants, generally reduce the risk of suicide in adult patients who are depressed. Some studies have argued that a decline in youth suicide rates coincided, to a striking extent, with significant increases in the prescription of antidepressants (mostly SSRIs) to adolescents.[66, 67]

The Treatment for Adolescents with Depression Study (TADS) also lends support for fluoxetine’s efficacy in adolescent depression, notably the combined use of fluoxetine with cognitive-behavioral therapy.[68] Data from the TADS study also suggested a possible protective effect of cognitive-behavioral therapy against suicidality when used in combination with fluoxetine.

Additionally, a study of more than 65,000 children and adults treated for depression by the Group Health Cooperative in Seattle found that suicide risk declines, not rises, with the use of antidepressants. This is the largest study to date to address this issue.

Currently, evidence does not suggest that obsessive-compulsive disorder (OCD) and other anxiety disorders treated with SSRIs are associated with an increased risk of suicide.

Drug withdrawal

Abrupt discontinuation of SSRIs with shorter half-lives, such as paroxetine, may induce withdrawal symptoms, some of which may mimic a relapse or recurrence of a depressive episode (eg, tiredness, irritability, severe somatic symptoms). The withdrawal symptoms can appear after as few as 6-8 weeks of SSRI treatment.

For clinical practice and education, the FDA has recommended that physicians who prescribe these medications should closely monitor patients with observation that “would generally include at least weekly face-to-face contact during the first 4 weeks of treatment,” with specific visit intervals specified after those 4 weeks.

Drug interactions

Awareness of possible interactions with other medications is important. To varying degrees, the SSRIs inhibit the metabolism of several medications that are metabolized by the diverse clusters of hepatic cytochrome P450 isoenzymes (eg, TCAs, neuroleptics, antiarrhythmics, benzodiazepines, carbamazepine, theophylline, warfarin, terfenadine [removed from US market]).

In addition, interactions of SSRIs with other serotonergic medications, particularly monoamine oxidase inhibitors (MAOIs), may induce the serotonergic syndrome, marked by agitation, confusion, and hyperthermia. SSRIs also have a high rate of protein binding, which can lead to increased therapeutic or toxic effects of other protein-bound medications. MAOIs should not be administered less than 5 weeks after discontinuation of fluoxetine and less than 2 weeks for other SSRIs. In addition, the clinician should not prescribe SSRIs within 2 weeks after stopping the MAOIs.

Tricyclic Antidepressants

Although open studies using tricyclic antidepressants (TCAs) suggest their usefulness in treating youths with major depressive disorder (MDD), several randomized, controlled studies have shown 50-60% response to TCAs (nortriptyline, desipramine, amitriptyline) and placebo. Consider these results with caution because of methodologic limitations, including small sample sizes, short-duration trials, and inclusion of patients with mild depression and comorbid disorders that may have had good responses to placebo.

TCAs are no longer considered the first-line treatment for youths with depressive disorders; however, individual cases may respond better to TCAs than to other medications.[69, 70, 71] TCAs may also be useful for youths with comorbid attention deficit hyperactivity disorder (ADHD), enuresis, and narcolepsy, as well as for augmentation strategies. TCAs should not be used as a first-line treatment for patients with suicidal ideation.

Electrocardiography should be performed before TCA therapy is started. Because of individual variations in the pharmacokinetics of TCAs, monitoring plasma concentration is helpful in determining optimal dosage, assessing compliance, and preventing toxicity. A plasma level of 150-250 mg/mL is considered the range of therapeutic effectiveness, although an upper level in children has not been established.

Indications for Hospitalization

Major depression with psychotic features, especially command auditory hallucinations, places an individual at increased risk of harm to themselves or others and is an indication for hospitalization. The real possibility and potential for suicide with concrete planning by the patient warrants hospitalization. Suicide recidivism is another potential cause for hospitalization.

The clinician must have a safety plan in place for patients with suicidal ideation that includes no access to medications, weapons, or other means of self-harm plus constant supervision. Consider hospitalization for patients for whom an effective safety plan and supervision is not feasible and for those patients and families unable or unlikely to comply with treatment recommendations.

The failure of the family support system when confronting depression with suicidal ideation again may be a strong indicator for temporary hospitalization in an attempt to stabilize and improve family functioning.

 

Medication

Medication Summary

Several classes of antidepressants, including selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), heterocyclics (eg, amoxapine, maprotiline), monoamine oxidase inhibitors (MAOIs), bupropion, venlafaxine, and nefazodone, have been used in the treatment of depression, although not all have been studied in the pediatric population. Of these, the types most frequently used in the pediatric population are SSRIs.

SSRIs are greatly preferred over the other classes of antidepressants. Because the adverse-effect profile of SSRIs is less prominent, improved compliance is promoted. SSRIs do not have the cardiac arrhythmia risk associated with TCAs. Arrhythmia risk is especially pertinent in overdose, and suicide risk must always be considered when treating a child or adolescent with mood disorder.

Antidepressants, SSRIs

Class Summary

Selective serotonin reuptake inhibitors (SSRIs) are a relatively new group of medicines used to treat emotional and behavioral problems, including depression, panic disorder, obsessive-compulsive disorder, bulimia, and posttraumatic stress disorder in adults. These medications are beginning to be used to treat the same problems in children and adolescents. Serotonin is a chemical that exists naturally in the brain. The SSRIs increase brain serotonin to reference range levels. SSRIs include, but are not limited to, the following medications: fluoxetine, paroxetine, sertraline, citalopram, and fluvoxamine.

Fluoxetine (Prozac)

Fluoxetine is an antidepressant agent that is chemically unrelated to the tricyclic, tetracyclic, or other available antidepressants. It selectively inhibits presynaptic serotonin reuptake with minimal or no effect on the reuptake of norepinephrine or dopamine and has been the best studied agent for pediatric depression.

Paroxetine (Paxil, Paxil CR, Pexeva)

Paroxetine is a potent selective inhibitor of neuronal serotonin reuptake. It has a weak effect on norepinephrine and dopamine neuronal reuptake. For maintenance therapy, make dosage adjustments to maintain the patient on the lowest effective dosage, and reassess the patient periodically to determine the need for continued treatment.

Sertraline (Zoloft)

Sertraline selectively inhibits presynaptic serotonin reuptake. Sertraline is approved by the US Food and Drug Administration (FDA) to treat obsessive-compulsive disorder (OCD) in children. It has also been used off label to treat depression in children.

Fluvoxamine (Luvox CR)

Fluvoxamine is a potent selective inhibitor of neuronal serotonin reuptake. It does not significantly bind to alpha-adrenergic, histamine, or cholinergic receptors and, thus, has fewer adverse effects than tricyclic antidepressants (TCAs).

Citalopram (Celexa)

Citalopram enhances serotonin activity owing to selective reuptake inhibition at the neuronal membrane. Although citalopram is not FDA approved for use in children, various clinical trials have shown efficacy in the treatment of moderate-to-severe major depressive disorder (MDD) in children and adolescents.

Antidepressants, TCAs

Class Summary

From the 1960s to the late 1980s, tricyclic antidepressants (TCAs) represented the primary pharmacologic treatment for depression in the United States. Therapeutic effects of TCAs are thought to be caused by their ability to block the reuptake of the neurotransmitters serotonin and norepinephrine in nerve terminals, which results in alterations in the sensitivity of various neuroreceptors.

TCAs are not currently recommended as a first-line treatment for depression in children and adolescents. TCAs commonly used in children and adolescents are imipramine (Tofranil), nortriptyline (Pamelor), and amitriptyline.

TCAs should be initiated at low doses to minimize adverse effects; in adolescents, TCAs are usually prescribed in once-daily bedtime doses. Because children metabolize medications more quickly than adults, prepubertal children usually require twice-daily dosing.

Imipramine (Tofranil)

Imipramine inhibits the reuptake of norepinephrine or serotonin (5-hydroxytryptamine, 5-HT) at the presynaptic neuron. Use parenteral administration for starting therapy only in patients unable or unwilling to use oral medication.

Nortriptyline (Pamelor)

Nortriptyline works by inhibiting the reuptake of serotonin and/or norepinephrine by the presynaptic neuronal membrane, thus increasing the synaptic concentration of these neurotransmitters in the central nervous system (CNS). Pharmacodynamic effects such as the desensitization of adenyl cyclase and down-regulation of beta-adrenergic receptors and serotonin receptors also appear to play a role in its mechanisms of action.

Desipramine (Norpramin)

Desipramine may increase the synaptic concentration of norepinephrine in the central nervous system (CNS) by inhibiting reuptake by the presynaptic neuronal membrane. It may have effects in the desensitization of adenyl cyclase, down-regulation of beta-adrenergic receptors, and down-regulation of serotonin receptors. Extreme caution should be used when desipramine is prescribed to patients with a family history of sudden death, conduction abnormalities, or cardiac dysrhythmias. In addition, in certain patients, seizures may precede dysrhythmias and death.

Amitriptyline

Amitriptyline inhibits the reuptake of serotonin and/or norepinephrine at the presynaptic neuronal membrane, thus increasing the concentration of these neurotransmitters in the CNS.