Depressive disorders are common in children and adolescents, impair psychosocial functioning, and are often accompanied by comorbid psychopathology. Despite its detrimental effects, pediatric depression is often undertreated. The clinical manifestations of depression include symptoms, functional impairment, and comorbid psychopathology.
Symptoms: Symptoms of pediatric depressive disorders include:
●Depressed or irritable mood – Depressed mood, such as feeling low, down, sad, or blue much of the time, is a cardinal symptom of depressive disorders. Patients may manifest a depressed mood by perceiving others as antagonistic or uncaring, brooding about real or potentially unpleasant circumstances, maintaining a gloomy or hopeless outlook, believing that everything is “unfair”, or feeling helpless or that they disappoint others. However, pediatric patients may lack the emotional and cognitive ability to correctly identify and organize their emotional experiences, and depressive disorders may express themselves with an irritable mood. Irritability can manifest as feeling “annoyed,” “grouchy,” or “bothered” by everything and everyone. Rather than expressing sadness, patients with depressive disorders may be negative and argumentative, and pick fights as a means to convey their emotional distress. Patients may be unable to tolerate frustration and respond to minor provocations with angry outbursts. Mood reactivity (the capacity to be cheered up in response to positive events) may be more common in children. Mood reactivity can cause adolescents to seek activities and experiences to temporarily lift their moods. Examples of these activities include affiliation with peers, thrill-seeking, promiscuity, and drug use. Diminished interest or pleasure – Loss of interest or pleasure (anhedonia) in formerly pleasurable activities may be expressed by describing experiences as “boring,” “stupid,” or “uninteresting.”
Change in appetite or weight – Appetite and weight may decrease or increase in depression.
Sleep disturbance – Sleep disturbance manifests as insomnia, hypersomnia, or significant shifts of sleep pattern over the diurnal cycle:
- Initial insomnia (difficulty getting to sleep)
- Middle insomnia (waking in the middle of the night, with difficulty returning to sleep)
- Terminal insomnia (waking too early and being unable to return to sleep)
- Hypersomnia (extended nighttime sleep or daytime sleeping)
- Circadian reversal (daytime sleeping and nighttime arousal)
Many depressed patients describe their sleep as nonrestorative and report difficulty getting out of bed in the morning.
Psychomotor agitation or retardation – Psychomotor agitation refers to handwringing; the inability to sit still; pacing; or pulling or rubbing clothes, the skin, or other objects. Alternatively, depressed patients with psychomotor retardation talk or move more slowly than is typical for them; in addition, speech volume or inflection may be decreased, and the amount of speech may be diminished. Psychomotor agitation or retardation is regarded as a depressive symptom only if it is noticeable to others, in contrast to subjective feelings of restlessness or feeling slowed down.
Fatigue or loss of energy – Lack of energy (anergia) manifests with feeling tired, exhausted, listless, and unmotivated. Patients may feel the need to rest during the day, experience heaviness in their limbs, or feel like it is hard to initiate activities.
Feelings of worthlessness or guilt – The self-perceptions of depressed children and adolescents may be marked by feelings of inadequacy, inferiority, failure, worthlessness, and guilt. Evaluation of this symptom is challenging because many youth do not directly acknowledge such negative self-perceptions. In addition, guilt about struggling with depression and its associated functional impairment is not considered a symptom of depression unless the guilt is of delusional proportions.
Feelings of worthlessness or guilt may manifest as:
- Excessively self-critical assessment of accomplishments
- Difficulty identifying positive self-attributes
- Strong dissatisfaction with several aspects of themselves
- Compulsive lying about success or skills to bolster self-esteem
- Envy or preoccupation with the success of others, especially in comparison with self-evaluation
- Marked self-reproach or guilt for events that are not their fault
- The belief that they deserve to be punished for things that are not their fault
- Reluctance to try to do things because patients fear they will fail, and decide “what’s the use?”
Impaired concentration and decision making – Depressed youth can have problems with attention, concentration, and memory that were not present to the same degree before the depressive episode. It can take longer to complete homework and class work than before the depressive episode; school performance may thus decline.
Recurring thoughts of death or suicide – Depressed patients can experience recurrent thoughts of death (not just fear of death) or suicide, or attempt suicide. Morbid thoughts are common in depressed teens and can manifest as preoccupation with music and literature that has morbid themes, or as passive suicidal ideation (eg, thoughts that life is not worth living or that others would be better off if the patient was dead). In addition, there may be active suicidal ideation of wanting to die or killing oneself, suicide plans, suicide pacts, and suicide attempts. Thoughts that contribute to suicidality include pervasive hopelessness (eg, negative expectations for the future) and a view of suicide as the only option to escape emotional pain.
Functional impairment — Functional impairment in depressed children and adolescents includes disturbances in school functioning, relationships with parents and peers, and daily activities and responsibilities In addition, depressed adolescents are at increased risk for engaging in health risk behaviors such as promiscuity
The academic and social sequelae of depression during childhood and adolescence reinforce depression once an episode begins, and increase the risk for future depressive episodes. Examples of sequelae that perpetuate or trigger new episodes of depression include:
- Academic failure and school avoidance
- Interpersonal dysfunction with family, peers, and teachers
- Social withdrawal
- Negative attributions about the perceptions or intent of others
- Seeking reassurance excessively
Diagnosis
Diagnosis should be based upon a formal clinical interview with the child or adolescent that is supplemented by information from parents and teachers. Standardized instruments are available as screening tools and to monitor outcomes, but they should not be used as the basis for diagnosis. Examples include the self-report Patient Health Questionnaire – Nine Item (PHQ-9): Modified for Teens, Mood and Feelings Questionnaire, Patient Reported Outcome Measurement Information System, Beck Depression Inventory, the Child Depression Inventory, or the Reynolds Adolescent Depression Scale.
Treatment
Psychotherapy
Psychosocial treatments include, but are not limited to, cognitive-behavioral therapy (CBT), interpersonal therapy for adolescents (IPT-A), family therapy, dynamic therapy, group therapy, and supportive therapy. Among these, only CBT and IPT-A have been shown to be efficacious in controlled research within a delineated population.
CBT: CBT monotherapy is more effective than other psychosocial interventions in reducing symptoms and inducing remission. The rates of remission range from 50 to 65 percent. CBT also appears to be beneficial in preventing relapse. The cognitive-focused tradition of CBT is based on the premise that individuals who are depressed have a distorted view of themselves, the world, and the future. Both the cognitive-focused and the behavior-focused approaches have empirical support for efficacy in treatment of depressed adolescents. Regardless of emphasis, the efficacious forms of CBT for depression in adolescents share the following methods or treatment components:
- Increasing involvement in pleasurable, mood-enhancing activities
- Increasing quantity and improving the quality of social interactions
- Improving conflict resolution and social problem-solving skills
- Reducing physiological tension
- Modifying or restructuring depressogenic thoughts
Interpersonal psychotherapy for adolescents (IPT-A): According to this treatment model, there are many possible pathways into depression, but independent of the cause, depression is associated with relationship disruptions. Thus, IPT-A focuses on current relationship problems associated with the adolescent’s depression.
The initial phase of treatment includes exploring the adolescent’s relationships by conducting a relationship inventory to identify problem areas that will be the focus of treatment. Typical foci of treatment include grief reactions, interpersonal conflicts (such as parent-child disputes or peer conflicts), role disputes, adjustments and transitions, interpersonal deficits, and adjustments related to single parent families in the context of divorce, separation, incarceration, death, etc.
The IPT-A approach takes into account developmentally relevant issues for adolescents such as establishing autonomy, negotiating romantic relationships, sexual orientation, managing parent-adolescent tensions, and coping with peer pressures. Through weekly individual intervention, the therapist helps the adolescent identify specific strategies to successfully manage interpersonal difficulties related to his or her depression. Typical IPT-A techniques include promoting effective expression of affect, clarifying and reframing expectations for relationships, communication analysis, social problem solving, and role playing of effective methods of interaction.
Medications:
First Line: For children and adolescents with acute depressive disorders, first line pharmacotherapy is fluoxetine. There is more consistent, high quality evidence for the efficacy of fluoxetine than other antidepressants.
Choosing an antidepressant other than fluoxetine as first line treatment may be reasonable for reasons that include:
- Desire to avoid specific adverse effects
- Response to a different antidepressant during a prior depressive episode
- Response to a different antidepressant by parent or sibling
- Known hypersensitivity to fluoxetine in the patient or family
- Patient and/or family preference
- Potential drug-drug interactions
Second line: Acute pediatric depressive episodes do not remit with fluoxetine in approximately 30 percent of patients. For these treatment resistant patients, we suggest sertraline; however, escitalopram or citalopram are reasonable choices, based upon their efficacy in randomized trials. Another reasonable alternative is venlafaxine, which appears to be comparable to SSRIs in treatment resistant patients. We typically do not use paroxetine for pediatric depression because of its lack of demonstrated efficacy
Third line: For children and adolescents with acute depressive disorders who do not respond to fluoxetine as well as a second trial with a different SSRI and a third trial with venlafaxine, we suggest bupropion or duloxetine, based upon randomized trials in adults and low quality studies in youth.
Dose — For adolescents, SSRIs are generally started at approximately one-half the usual adult dose for the first week of treatment. For children, lower doses are used when prescribing fluoxetine. By contrast, doses of citalopram, escitalopram, and sertraline are similar for children and adolescents because younger children metabolize these drugs more quickly than fluoxetine. For both children and adolescents, doses are titrated up, depending upon response and tolerability:
●Fluoxetine – For adolescents, fluoxetine is started at 10 mg per day for one week and then increased to a target dose of 20 mg per day. After three weeks, if response is insufficient and the drug is tolerated, the dose is increased to 40 mg per day for the remainder of the drug trial. However, if a partial response occurs within four weeks of prescribing 40 mg per day, the dose is increased to 60 mg per day. For children, we start at 5 mg per day for one week and then titrate up to a target dose of 10 mg per day. After three weeks, if response is inadequate, we increase the dose to 20 mg per day for the remainder of the drug trial.
●Citalopram – Citalopram is started at 10 mg per day for one week and then increased to a target dose of 20 mg per day. After three weeks, if response is insufficient and the drug is tolerated, the dose is increased to 40 mg per day for the remainder of the drug trial. However, if a partial response occurs within four weeks of prescribing 40 mg per day, we discuss with the patient and family both the possibility of raising the dose further, as well as concerns that doses above 40 mg per day can cause QT interval prolongation. If the patient and family wish to continue citalopram, we obtain an electrocardiogram (ECG) at 40 mg per day, prior to increasing the dose, and if the ECG is normal, we increase the dose to 60 mg per day. One week after increasing the dose to 60 mg, we obtain a second ECG.
●Escitalopram – Escitalopram is started at 5 mg per day for one week and then increased to a target dose of 10 mg per day. After three weeks, if response is insufficient and the drug is tolerated, the dose is increased to 20 mg per day for the remainder of the drug trial. However, if a partial response occurs within four weeks of prescribing 20 mg per day, we discuss with the patient and family both the possibility of raising the dose further, as well as concerns that doses above 20 mg per day can cause QT interval prolongation. If the patient and family wish to continue escitalopram, we obtain an ECG at 20 mg per day, prior to increasing the dose, and if the ECG is normal, we increase the dose to 30 mg per day. One week after increasing the dose to 30 mg per day, we obtain a second ECG.
●Sertraline – Sertraline is started at 25 mg per day for one week and then increased to a target dose of 50 mg per day. After three weeks, if response is insufficient and the drug is tolerated, the dose is increased to 100 mg per day for the remainder of the drug trial. However, if a partial response occurs within four weeks of prescribing 100 mg per day, the dose may be increased by 25 to 50 mg per day every several (eg, three) weeks to a maximum dose of 200 mg per day
We typically do not use paroxetine for pediatric depression because of its lack of demonstrated efficacy
Symptoms typically begin to improve within two to four weeks after the target dose is achieved.
Duration of an adequate trial — An adequate antidepressant trial in children and adolescents lasts 6 to 12 weeks, which includes the time to titrate from the starting dose to the minimum therapeutic dose, as well as 4 to 6 weeks at the minimum therapeutic dose. For depressed patients who improve but do not remit at the minimum therapeutic dose, a dose increase within the therapeutic range is indicated, provided the drug is tolerated. If improvement is insufficient after 4 weeks at the maximum therapeutic dose, switching medications is indicated. Evidence supporting this approach includes a meta-analysis of 13 randomized trials that compared SSRIs with placebo in pediatric unipolar major depression (n >3000). Approximately 70 percent of the benefit occurred within the first two weeks of treatment, and minimal treatment gains were observed after four weeks of treatment.
Monitoring — Clinicians prescribing pharmacotherapy for depressed patients should assess symptoms, side effects, functioning, adherence, and satisfaction with treatment.
Pediatric patients with depressive disorders who are treated with antidepressants must be monitored by clinicians and families for the following adverse responses, particularly during the initial few months of therapy and when doses are increased or decreased:
- Worsening depressive symptoms (eg, suicidal ideation and behavior, anxiety and panic attacks, or insomnia)
- Agitation
- Irritability or hostility
- Impulsivity
- Akathisia (ie, restlessness and inability to sit down)
- Hypomania or mania.
Dose dependent QT interval prolongation with citalopram and escitalopram.
Frequency — For outpatients who are treated with antidepressants, we typically contact families weekly for the first four weeks at the onset of pharmacotherapy and when medications are switched. Contact can be in person or by phone but should include several in-person appointments within the first eight weeks of starting medication and as clinically necessary.
The frequency of follow-up at other times is individualized, and can range from once every two weeks to once every three months. The schedule is based upon the severity of the depressive syndrome, level of social support, and the presence of comorbidity, adverse effects, and stressors (eg, break-up with girlfriend, death of a close relative, or poor school performance).
Based upon randomized trials, children and adolescents with unipolar major depression who remit with pharmacotherapy should continue the same regimen for at least another 6 to 12 months. Relapse frequently occurs in pediatric patients who stop their antidepressants soon after their depressive syndromes improve
Discontinuing Medications: Antidepressants should generally be tapered before discontinuation. A taper of approximately 25 to 50 percent per week provides a gradual decrease that allows the body time to adjust to the lower dose. As an example, sertraline 200 mg per day can be decreased to 150 mg per day for week one, 100 mg per day for week two, 50 mg per day for week three, and 25 mg per day for week four, after which the medication is stopped.
Abrupt discontinuation of SSRIs can cause a discontinuation (withdrawal) syndrome marked by Anxiety, Chills, Dizziness, Fatigue, Myalgias, Nausea. Discontinuation symptoms may occur after just six to eight weeks of therapy. However, the half-life of fluoxetine is long enough such that abrupt discontinuation generally does not cause problems
BLACK BOX WARNING
There is concern that selective serotonin reuptake inhibitors (SSRIs) and other antidepressants may increase the risk of suicidal ideation and behavior in children, adolescents, and adults younger than 25 years. In early 2004, the US Food and Drug Administration (FDA) in the United States asked manufacturers of a number of antidepressants to make labeling changes to include a warning about a possible increased risk of suicidal ideation or behavior, particularly at the initiation of therapy or at the time of dose changes. After further analysis, in October 2004, the FDA directed manufacturers of all antidepressants (including tricyclic antidepressants and monoamine oxidase inhibitors) to include a warning stating that antidepressants may increase the risk of suicidal ideation and behavior in children and adolescents.
The US FDA convened an advisory panel to reexamine analyses regarding suicidal thoughts and behaviors and antidepressants in children and adolescents. The advisory panel’s combined analysis of 24 short-term (4 to 16 weeks), placebo-controlled trials of nine antidepressant medications in more than 4400 children and adolescents being treated for unipolar major depression and other psychiatric disorders yielded the following results:
- 78 patients (2 percent) experienced adverse events representing suicidal ideation or behavior, collectively termed suicidality; adverse events were reports made by the research clinician if a patient or parent spontaneously shared thoughts about suicidality.
- Among the adverse events that were reported, patients on antidepressant medication had an increased risk of suicidality during the first few months of treatment compared with those on placebo (4 versus 2 percent).
- In 17 trials, standardized forms were used to ask each patient about suicidality at each visit. The data revealed that medication neither increased the suicidality that was present before treatment, nor induced suicidality in patients who were not thinking about suicide at the start of the study. Over the course of treatment, all studies combined showed a slight reduction in suicidality.
- No completed suicides occurred during any of the trials.
The FDA advisory panel concluded that there was a small increased risk of suicidal thoughts or behavior in children taking antidepressants compared with placebo (risk ratio 2.0, 95% CI 1.3-3.0). The risk appeared to be greatest in the first few weeks after initiating therapy.
Establishing the causal association is difficult because of the clear associations between severe depression and suicide and between severe depression and the need for antidepressant therapy. Because suicide is uncommon, it also is difficult to demonstrate the negative, which is that antidepressants do not cause suicide.
Evidence for and against an association between antidepressant therapy and suicidal thoughts and/or behaviors in children, adolescents, and young adults comes from randomized trials, observational studies, and population-based studies comparing the rates of suicide and antidepressant use over time. Each of these study designs has limitations in demonstrating a causal association:
Suicide is rare in randomized, controlled trials of antidepressants. Thus, individual trials typically lack the power to detect a relationship between antidepressants and suicidal ideation or behavior.
Observational studies can more easily detect rare events such as suicide. However, causality is difficult to establish because of the association between severe depression and the use of antidepressants.
Population-based studies have examined rates of antidepressant use and suicide over time. These studies have generally found lower rates of suicide with increasing rates of antidepressant use. Accordingly, the consensus has been that increases in prescribing likely yield lower rates of suicide. However, rare antidepressant-induced suicides could be masked by secular trends.
Randomized trials: Randomized trials of antidepressants in children and adolescents were not designed primarily to determine whether these antidepressants increase suicidal behavior. Most of the trials excluded subjects with suicidal ideation and did not have enough power to detect rare adverse events such as suicide deaths. Suicidal ideation and behavior were not methodically assessed as prespecified outcomes in earlier studies; rather, suicidal ideation and behavior were spontaneously reported as adverse events and were not uniformly defined. More recent studies have systematically evaluated suicidal ideation and behavior in pediatric antidepressant trials, prompted partly by the US Food and Drug Administration’s (FDA) concern of a lack of standardized language to define, monitor, and clinically assess suicidal behavior. One study (n = 334 patients) found that suicidal ideation and behavior were detected less often by spontaneous reporting, compared with systematic assessment (9 versus 21 percent of patients).
In addition, patients in randomized trials who are assigned to treatment with active drug often have more side effects, which may have led to increased contact with study personnel and a greater opportunity to report suicidal ideation and behavior (ascertainment bias). Most of the reported suicidal events were suicidal thoughts, rather than suicidal behavior.
Systematic reviews of randomized trials, subject to the limitations described above, have yielded different conclusions about the association between antidepressants and increased risk of suicidal ideation and behavior, as illustrated in the two subsections below. In many instances, the reviews conducted meta-analyses that pooled results from trials in patients with different disorders, such as unipolar major depression, anxiety disorders, and obsessive-compulsive disorder.