Sections

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,^[40]sertraline,^{[41, 42]}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.^[43]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.^[44]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.^{[45, 46]}

Cognitive-behavioral therapy

Cognitive-behavioral therapy (CBT) is one of the most frequently studied psychotherapy treatments.^[47]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.^[48]

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.^[49]

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.^[50]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.^[50]

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.^[51]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.^{[52, 53]}

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.^[54]

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.^{[55, 56, 57]}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^[58]and Rey-Sanchez and Gutierrez-Casares,^[59]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%).^[60]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.^[61]

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^[62]and Teicher et al,^[63]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)^[64]
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.^[65]It has also been noted that monitoring of these patients did not increase following the warnings.^{[66, 67]}

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.^{[68, 69]}

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.^[70]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.^{[71, 72, 73]}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

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