AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Childhood and adolescent major depressive disorder (MDD) is a prevalent, familial, and recurrent 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.

Pathophysiology

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 are thought to contribute to depression.

Frequency

United States

Reported prevalence rates for depression in children and adolescents vary. Differences may be due to different populations sampled and variable criteria used.

In 1988, Kashani and Sherman conducted epidemiologic studies in the United States that revealed the incidence of depression to be 0.9% in preschool-aged children, 1.9% in school-aged children, and 4.7% in adolescents.¹ 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 one current or lifetime episode of unipolar depression. The percentage of male and female students with 2 or more episodes was 4.9% and 1.6%, respectively. In 1997, 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%.²

As these studies demonstrate, the occurrence of depression is not rare and is encountered regularly in pediatric and psychiatric practice.

International

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.

The Stirling County Study, which began shortly after World War II, offers a 40-year perspective of the prevalence and incidence of psychiatric disorders among an adult population in Atlantic, Canada. In 2000, Murphy et al found the overall prevalence of depression remained stable at 5% across 3 separate samples in 1952, 1970, and 1992.³ They reported a redistribution in the most recent sample that indicated prevalence had shifted from older to younger persons and that the female-to-male ratio had increased.

In 1999, a European study by Copeland et al sought to assess the prevalence of depression in 9 European nations in order to design intervention for elderly persons who were depressed.⁴ They found widely ranging prevalences in their study centers. Prevalence for females was higher than for males. They found 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 in 1981, 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.⁵

Mortality/Morbidity

As many as 15% of those with depression or bipolar disorder commit suicide each year. In 1996, the Centers for Disease Control and Prevention (CDC) listed suicide as the ninth leading cause of death in the United States, accounting for 30,862 deaths. Many believe this number is a gross underestimate. For example, children's deaths are often ruled as accidental when the intent of the deceased is not apparent. The feasibility of suicide among children is frequently unthinkable, even to health professionals. 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 mid adolescent years; the mortality rate from suicide increases steadily through the teenage years; suicide is the third leading cause of death in that age group.

Risk factors for completed suicide include the presence of a major mood disorder, occurrence of command auditory hallucinations, use of substances, and evidence of specific plans and an attempt to prevent discovery. Major depression with psychotic features, such as hallucinations, places an individual at increased risk of harm to themselves or others. Psychosis and risk of harm to self or others are indications for hospitalization.

Race

Cultural norms associated with differing racial and ethnic groups can affect the experience and reporting of symptoms of depression. For example, in some cultures, 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.

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).⁶ 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, Fourth Edition (DSM-IV) states that a symptom should not be dismissed because it is part of a cultural norm.⁷ 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.

Sex

Sex issues and depression in youths has been the subject of much research. In 1998, Hankin et al conducted a prospective, 10-year, longitudinal study of preadolescents through young adulthood and found that the most critical time for sex differences to emerge is the period when adolescents are aged 15-18 years.⁸ During this period, the increase of the overall rates of depression and 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 twice the prevalence rate for males. No sex differences are noted for depression symptom severity or recurrence.

Age

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 in adolescence and adulthood.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

The Diagnostic and Statistical Manual of Mental Disorders, Third Edition (DSM-III); the Diagnostic and Statistical Manual of Mental Disorders, Third Edition Revised (DSM-III-R); and the DSM-IV use the same basic criteria to diagnose depression in adults and children. A few small adjustments were made to the diagnostic criteria to account for the differences in age and stage of development in adults and children.

The DSM-IV diagnostic criteria for depressive disorders are the same for children and adolescents as they are for adults, with small exceptions stated as notations to the criteria.

• The DSM-IV 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
  • Sleep disturbance
  • Weight change or appetite disturbance (for children this can be 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
• At least one of the symptoms must be diminished interest/pleasure or depressed mood. The 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. Additionally, a major 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 are 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
• Depressive episodes can also be present with catatonic features that require at least 2 of the following, as illustrated in the DSM-IV:
• • Motoric immobility in the form of catalepsy or stupor
  • Motor overactivity that seems purposeless and not in response to external stimuli
  • Extreme negativism or mutism
  • Voluntary movement peculiarities such a posturing, grimacing, stereotypy, and mannerisms
  • Echolalia or echopraxia
• 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 demonstrate 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. Also, a young child might present with an apparent seasonal depressive disorder but not yet have had prior episodes.
• 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 the 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
• The DSM-IV also includes a category for depressive disorders not otherwise specified. This category includes disorders with features of depression that do not meet criteria for a specific mood disorder or adjustment disorder with depressed mood. Examples include a depressive episode superimposed on residual schizophrenia, a recurrent mild depressive disturbance that does not meet criteria for dysthymia, or non–stress-related episodes that do not meet the criteria for a major depressive episode. Consult the DSM-IV for further details as to the diagnostic criteria for depressive disorders not otherwise specified.

Physical

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

Causes

Whether ego-damaging experiences or biological processes cause depression remains the topic of some debate. The final common pathways to depression involve biochemical changes in the brain.

• Neuroimaging
• • A recently discovered abnormality in an area of the brain that helps to control emotional reactions contributes to a new understanding of why persons develop depression and other affective disturbances. By using positron emission tomographic (PET) images, researchers found an area of the prefrontal cortex with an abnormally diminished activity in patients with unipolar depression and bipolar depression. This region is related to emotional response and has widespread connections with other areas of the brain. These other areas 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 complex equipment and uses radiation.
  • MRI, magnetic resonance spectroscopy (MRS), and magnetoencephalography (MEG) are best suited to study the structural, physiological, 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. In 1996, Steingard et al observed 65 latency-aged children and adolescents who were hospitalized with depression.⁹ MRI was used to compare depressed patients with 18 hospitalized psychiatric controls who did not have a depressive disorder. 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 than controls. The researchers in this study suggest that these alterations in cerebral volumes may suggest a role for the frontal lobes in the development of early-onset depression.
  • In 1998, Tutus et al observed adolescents with MDD using single-photon emission tomography (SPET) in order to examine cerebral perfusion and any association between perfusion indices and clinical variables.¹⁰ Fourteen adolescent outpatients (aged 11-15 y) with MDD and 11 age-matched controls were studied. Significant differences were found between the perfusion index values of untreated depressed patients and those of the controls. The findings were indicative of relatively reduced perfusion in the left anterofrontal and left temporal cortical areas. They suggest that adolescents with MDD may have regional blood flow deficits in left anterofrontal and left temporal cortical regions with greater right-left perfusion asymmetry compared with healthy controls.
• Neuroendocrine abnormalities
• • In 1996, De Bellis et al studied neuroendocrine changes in prepubertal children who were depressed.¹¹ They examined nocturnal secretion of adrenocorticotropin (ACTH), cortisol, growth hormone (GH), and prolactin in the depressed groups and control groups, respectively. Prepubertal children who were depressed had lower cortisol secretion during the first 4 hours of sleep than did children in the control group. ACTH, GH, and prolactin secretion did not differ between the 2 groups.
  • Possible abnormalities of the neurotransmitter systems remain under investigation. In 1999, Nobile et al found that human platelet 5-HT (serotonin) uptake is differentially influenced in nondepressed and depressed children by a common genetic variant of the promotor region of 5-HTT.¹² In 1997, Birmaher et al found that, prior to onset of affective illness, children who were at high risk had the same pattern of neuroendocrine response to 5-hydroxy-L-tryptophan (L-5-HTP) challenge as did children with major depression.¹³ These findings could constitute the identification of a trait marker for depression in children.
• Genetic studies: Several studies of adults who are depressed, such as those reported by Akiskal and Weller in 1989¹⁴ and Weissman et al in 1984,¹⁵ suggest a genetic component in the etiology of depressive disorders.
• Parent-child relation model
• • This model conceptualizes 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. A child who is affectively ill often has a parent who is affectively ill. For children to report abuse and/or neglect by their parent(s) who is affectively ill is not uncommon.
  • In 1991, Hammen et al reported a significant temporal association between mother and child.¹⁶ They found that children with substantial stress exposure who also had symptomatic mothers were significantly more depressed than children who were exposed to comparable levels of stress only.
• Cohort effect: In 1987, 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.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Major depressive disorder is diagnosed when the required DSM-IV 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.

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. Consider 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.

Other conditions to be considered include the following:

• Medication reaction or substance abuse
• Organic disease presenting as depressive disorder

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Include a CBC count with differential in the initial laboratory evaluation to rule out infection and anemia.
• Assay electrolytes, BUN, creatinine clearance, creatinine, and urine osmolality to exclude renal disorders.
• When using tricyclic antidepressants 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

• Consider EEG evaluation for patients with a history or presentation that is suggestive of seizure disorder.
• Perform ECG prior to treatment with a tricyclic antidepressant.
• Perform liver function tests and thyroid function tests (triiodothyronine [T3], thyroxine [T4], and thyroid-stimulating hormone [TSH]) to rule out thyroid disease.
• In 1985, Weller et al report that a properly performed dexamethasone suppression test (DST) can be helpful to confirm a clinical diagnosis of depression and may be useful in monitoring treatment response during follow-up.¹⁷ The overall sensitivity of the DST is 70% in prepubertal children and 47% in adolescents.
• CDI is a simple test that may assist in detecting occurrence and degree of childhood depression.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Opinions vary about whether cognitive-behavioral psychotherapy, pharmacotherapy, or a combination of both should be offered as first-line treatment for children and adolescents with MDD. Safety is always the first concern in the evaluation of MDD in children and adolescents. 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, sertraline, and citalopram.  

Overall, the choice of the initial acute therapy depends on the severity, number of prior episodes, chronicity, subtype, age of the patient, contextual issues (eg, family conflict, academic problems, exposure to negative life events), compliance with treatment, previous response to treatment, and the motivation of the patient and family for treatment. In mild cases, psychosocial interventions are often recommended as first-line treatments, whereas, in the most 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 obsessed with thoughts of suicide or has definite plans, the patient must be hospitalized. Also, 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 to hospitalize a child or adolescent.

Psychotherapy appears to be a useful initial acute treatment for mild-to-moderate depression. Cognitive-behavioral therapy has been extensively studied, and other forms of psychotherapy, such as psychodynamic psychotherapy, interpersonal psychotherapy, and family therapy, have been found to be effective and are used clinically. More studies that compare the complementary and differential effects of these therapies are needed.

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.

Combined treatment increases the likelihood not only of mitigating depressive symptomatology but also increases the likelihood of increasing self-esteem, coping skills, and adaptive strategies and improving family and peer relationships. 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.

Many clinicians have found psychodynamic psychotherapy 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 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 focuses on problem areas of grief, interpersonal roles, disputes, role transitions, and interpersonal difficulties. In a 1996 study, Mufson and Fairbanks found that interpersonal therapy may be useful in the acute treatment of adolescents with MDD.¹⁸ They also found the rate of relapse to be relatively low after acute interpersonal therapy treatment.

Cognitive-behavioral therapy is one of the most frequently studied psychotherapy treatments. 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 counteracted with cognitive-behavioral therapy. In nonclinical samples, 4 studies have shown group cognitive-behavioral therapy to be better than no intervention for children and adolescents in the reduction of depressive symptomatology and improvement of self-esteem.

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 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 to prevent relapses of depression in adolescents.¹⁹

Several factors appear to be related to the response to psychotherapy, including age at onset of depression, severity of depression, presence of comorbid psychiatric disorders (eg, anxiety, dysthymia, substance abuse), lack of support, parental psychopathology, family conflict, exposure to stressful life events, socioeconomic status, quality of treatment, therapist's expertise, and motivation of both patient and therapist. A combination of the particular elements of cognitive-behavioral therapy, interpersonal therapy, psychodynamic psychotherapy, and other psychotherapies may be brought together in the best interests of the patient. In 1997, Brent et al reported that individual supportive treatment was found to be considerably less efficacious than cognitive-behavioral therapy in adolescents who were depressed.²⁰

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Studies on the use of medications for youths with 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), with few studies addressing SSRIs. Other antidepressants, including heterocyclics (eg, amoxapine, maprotiline), monoamine oxidase inhibitors (MAOIs), bupropion, venlafaxine, and nefazodone, have been found to be effective in the treatment of adults who are depressed.

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

The TCAs require a baseline 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.

Because of reports that SSRIs are effective for 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, the clinician may support the use of the SSRIs as first-line medications.

Open studies, such as those in 1997 by Leonard et al²¹ and Rey-Sanchez and Gutierrez-Casares,²² have reported 70-90% response to the SSRIs in the treatment of adolescents with MDD. Also in 1997, 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%).²³ Despite the significant response to fluoxetine, many patients had only partial improvement; only 31% achieved full remission.

A possible explanation for the partial response is that the effective treatment may involve variation in dose or length of treatment. Also, 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 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 contrary, if no improvement is apparent at 6 weeks, other treatment strategies should be considered.

The clinician must cautiously apply this recommendation; 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 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 GI 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.

A small number of case reports, such as those by King et al in 1994²⁴ and Teicher et al in 1993,²⁵ have described a putative association between SSRI administration and increased suicidality (perhaps linked to behavioral activation or akathisia). However, although such phenomena may have occurred 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.

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.

Physicians are advised to be aware of the following information and 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 (Prozac), 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 major depressive disorder. 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 both 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)
• 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.

This remains a controversial issue. 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.^{26, 27, 28} 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.²⁹ 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 between 1992 and 2003 by the Group Health Cooperative in Seattle found that suicide risk declines, not rises, with the use of antidepressants.³⁰ 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.

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.³¹

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 United States market]). In addition, interactions of SSRIs with other serotonergic medications, particularly 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. Also, the clinician should not prescribe SSRIs within 2 weeks after stopping the MAOIs.

Although open studies using TCAs suggest their usefulness in treating youths with MDD, several randomized controlled studies have shown 50-60% response to both 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. TCAs may also be useful for youths with comorbid ADHD, enuresis, and narcolepsy, as well as for augmentation strategies. When using TCAs, the clinician should monitor plasma levels to measure compliance and to avoid toxicity.

Drug Category: Selective serotonin reuptake inhibitor (SSRI) antidepressants

These are a relatively new group of medicines used to treat emotional and behavior 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.

Drug Category: Tricyclic antidepressants

From the 1960s to the late 1980s, 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 should be initiated at low doses to minimize adverse effects; in adolescents, TCAs are usually prescribed in once-a-day bedtime doses. Because children metabolize medications more quickly than adults, prepubertal children usually require bid dosing.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Major depression with psychotic features, such as 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 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.
• Risk factors for completed suicide include the presence of a major mood disorder, occurrence of command auditory hallucinations, use of substances, and evidence of plans 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.

Further Outpatient Care

• See Treatment.

Complications

• Because of individual variation in the pharmacokinetics of TCAs, monitoring plasma concentration is helpful to determining optimal dosage. 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.
• Perform ECG before starting TCA therapy.
• 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.
• TCAs in large doses can be lethal and should be avoided in youths who are at risk for suicidal behaviors.

Prognosis

• 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 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. Thus, a thorough family history is quite important.
• In 1999, in a 9-year 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.³³

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 from their homes to decrease the risk of suicide. Household medications also should not be accessible to depressed youths.
• For excellent patient education resources, visit eMedicine's Depression Center, Substance Abuse Center, and Antidepressants Center. Also, see eMedicine's patient education articles Depression, Substance Abuse, and Understanding Antidepressant Medications.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Risk assessment of patients who are depressed should be ongoing.
• The clinician must have a safety plan in place for patients with suicidal ideation that includes no access to medications 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.
• Do not use TCAs as a first-line treatment for patients with suicidal ideation.
• Documentation should support clinical decision-making.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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