Pediatric Depression

Pediatric depression in the form of childhood and adolescent major depressive disorder (MDD) is a relatively common psychiatric condition that can continue 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.) 

The degree to which adverse childhood events, biologic processes, and genetic predispositions trigger depressive episodes remains the topic of some debate. However, the final common pathways to depression involve neurochemical changes in the brain. (See Pathophysiology and Etiology.) 

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR) 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 – 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 moderate to severe cases, medication in addition to psychotherapeutic intervention is often recommended. (See Treatment.) 

Cognitive-behavioral therapy (CBT) as well as interpersonal therapy (IPT) have both been shown in multiple randomized clinical trials to be effective in the treatment of MDD in children and adolescents. For moderate-to-severe depression, both psychotherapy 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] (See Treatment and Medication.) 

Go to the Medscape article on depression for complete information on this topic.

The pathophysiology of depression is complex, multifactorial, and incompletely understood. Differences in clinical presentation, etiological factors, subjective diagnostic criteria, and the methodological challenges inherent in studying behavior have made research in this area difficult. However, as available evidence grows, it seems increasingly evident that there is not a single pathophysiologic pathway to exhibiting the signs and symptoms of depression. Indeed, there is enough diversity in genetic, psychosocial, anatomical, neurochemical, and developmental factors in individuals presenting with clinical depression that it has been suggested that major depressive disorder (MDD) is the final common pathway of a variety of physiologic anomalies rather than a discrete disorder of its own.[2, 3]   

Stress response 

The hypothalamic–pituitary–adrenal axis is activated in response to perceived stress, including psychological stress. Dysregulation of this axis, with abnormalities in negative feedback and CRH production, have been noted in pediatric depression.[4] In contrast, this finding has not been commonly observed in adult depression, except in those with significant trauma exposures.[3] This may be explained in part by the greater contribution from childhood adversity noted in pediatric-age depressive disorders.[2]  

Brain changes 

A variety of neuroimaging and post-mortem studies of depression agree that there are subtle yet significant anatomical and functional differences in the brains of depressed individuals. Unfortunately, there has been little consensus between studies on what exactly these changes are. Differences in the prefrontal cortex,[5]  total cerebral volume, lateral ventricle size,[6] reduced hippocampal volume, altered anterofrontal perfusion,[7]  and other changes have been inconsistently observed in youth with depression. 

These inconsistencies between studies reflect the difficulty of detecting subtle brain changes and correlating these changes between different imaging techniques. This is made even more difficult given the heterogeneity in what is currently categorized as major depression. Further complicating interpretation of these results is understanding how an observed neuroimaging difference correlates to a specific functional outcome and determining the correct etiology of observed changes. Determining the etiology of neuroimaging changes can be especially difficult given the comorbidities, such as trauma and anxiety, often present in depressed individuals.[8]  

Despite these difficulties, decreased volume and abnormal function of the left subgenual cingulate cortex has been identified in a variety of functional, structural, and post-mortum studies in depressed patients.[3] This has further been verified by more recent meta-analyses of neuroimaging data, including an analysis by Gray et al in 2020[9] that found decreased size and increased activity of the subgenual cingulate to be a convergent finding between studies. This analysis also identified decreased size and increased activity in the left hippocampus and right amygdala, and decreased activity in the right putamen as weakly convergent abnormalities.  

Monoamine abnormalities 

The monoaminergic system includes serotonergic, noradrenergic, and dopaminergic neurons projecting from the midbrain and brainstem to significant portions of the entire brain. This system is involved in the regulation of a variety of brain functions that are altered in depression including mood, attention, sleep, appetite, cognition, and reward processing. This system has long been implicated in the pathophysiology of depression and remains the primary target of known pharmacologic interventions.[8]  

Monoamine deficiency as part of the pathophysiology of depression is supported by numerous studies over the years. These studies have observed that tryptophan deficiency in individuals with a family history of depression can induce symptoms of depression,[3]  that individuals with depression have lower monoamine oxidase (MAO) B activity,[10]  that these individuals exhibit decreases in certain serotonergic and dopaminergic receptors,[11] and that pharmacologic compounds that block reuptake of monoamines or inhibit MAO generally have antidepressant effects.  

Deficiency in monoamines, however, has not been sufficient to explain the entirety of the pathophysiology of depression. For example, other studies have shown that tryptophan deficiency does not cause depression in individuals without a family history of depression and that reserpine, which depletes around 95% of the brain’s monoamine supply, only causes depressive symptoms in around 5% of patients. In addition, SSRI medication leads to an almost immediate increase in synaptic serotonin activity, however, improvement in depressive symptoms typically does not occur for 3–5 weeks after starting an SSRI. For these reasons, monoamine deficiency is considered only part of the complex pathophysiology of depression.[8]  

Circuit dysfunction 

Integration of neuroimaging and neurochemical findings remains an ongoing area of research, however, there has been a shift in regarding depression as strictly a neurochemical or a neuroanatomical abnormality. Rather, an integrated model where a pathway of brain areas becomes dysregulated and eventually leads to persistent affective changes is increasingly adopted. In this circuit model, areas of the limbic system involved in affect regulation, such as the prefrontal and orbitofrontal cortices, anterior cingulate, basal ganglia, and thalamus, make up a neurologic circuit. Many of the brain areas involved in this circuit are either connected by or regulated by monoamine tracts. The circuit as a whole is affected by developmental experiences that exploit potential genetic vulnerabilities and lead to epigenetic, functional, and anatomic changes to the circuit. These changes result in affect deregulation and persistent depressive symptoms.[12]  

Biologic versus nonbiologic causes 

Both family history and psychosocial stressors, especially childhood adversity, are identified risk factors for the development of depression. While the relative contributions of these factors to the development of depression in a specific individual may vary, the final common pathways to depression involve neurochemical changes in the brain. (See Pathophysiology.)  

Genetic predispositions 

Major depression has been shown to be a familial disorder across a variety of family, twin, and adoption studies.[3]  Keeping in mind that depression is a multifactorial illness, genetic factors have been suggested to account for about 30–40% of this risk[13] with the remaining risk attributed predominantly to psychosocial stress. In pediatrics, around 40–60% of children and adolescents with a depressed parent will develop the disorder, most commonly initially presenting in adolescence.[2]  

Early life adversity 

Psychosocial stress is a well-established risk factor for the development of depressive disorders and can take a variety of forms. From interpersonal traumas and family relationship issues to societal issues such as poverty, discrimination, and acculturation stress, these events and circumstances can contribute to depression risk in all ages. In particular, early childhood adversity occurring prior to age 13 is an inciting factor in the majority (around 57%) of individuals with early onset (prepubertal) depression and remains a strong contributor in about 30% of those with later-onset depression.[14] While these associations are strongest with severe forms of child maltreatment such as abuse and neglect, less malignant stressors like interpersonal loss, household dysfunction, and economic hardship can add to the cumulative risk of depression. Several studies have noted that depression risk and severity correlate with the number and severity of adverse events in a dose response fashion.[15]  

Temperament and parent–child relationship effects 

In addition to childhood adversity, child temperament and parenting style can have potentially depressogenic potential. Child traits that increase risk for depression include underdeveloped self-understanding, underdeveloped mentalization, negative affectivity, and negative attributional style. Features of parent–child interaction and attachment can also contribute to depression risk. These features may include obvious issues such as emotional abuse, unsupportive parenting, and insecure attachment, or may be subtle such as diminished reward effort, dysfunctional interpersonal processes, impaired self-regulation, learned helplessness, or passive parenting styles.[2]  

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.[16] 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.[17] 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.[18]  

Electronic media and screen time 

Increased time spent using electronic devices (eg, 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.[19]  

 A study by Boers et al in 2019 found an increase in 4-year depressive symptom severity for every hour increase in screen time. This correlation was strongest for social media screen time, but also was found with computer use and watching television.[20]  

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. 

According to the Centers for Disease Control and Prevention (CDC), 4.4% (approximately 2.7 million) of children aged 3–17 years in 2016–2019 received a diagnosis for depression.[21, 22]  

The 2022 American Academy of Child and Adolescent Psychiatry (AACAP) Clinical Practice Guideline[2] reported lifetime prevalence of major depressive disorder in adolescents to be 11% with a past-year prevalence of 7.5%. Major depressive disorder (MDD) prevalence increased across adolescence with greater increases in female youth compared to male youth. Rates of depression in prepubertal children are lower, with a prevalence of preschool-age depression less than 2% 

International occurrence 

A meta-analysis completed by Polanczyk et al in 2015 estimated the worldwide prevalence of depressive disorders in children and adolescents to be 2.6%.[23]  

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.[24]  

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.[25, 26, 27, 28]  

Gender-related demographics 

A 2012 report by the Substance Abuse and Mental Health Services Administration (SAMHSA) indicates that gender 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.[29]  

During adolescence, 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. 

Race- and culture-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.[30]  

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).[31] This study also found significant effects of social class on depression. As income decreased, the average level of depression increased. 

Studies have shown that both Black and Hispanic adolescents receive fewer mental health services in general and are less likely to receive minimally adequate pharmacotherapy for depression compared to Whites. This finding remained significant regardless of socioeconomic status. Hispanic children are 50% more likely to be admitted to the hospital for mental health reasons compared to White children.[32]  

More extensive studies of ethnic subpopulations of adolescents who are depressed are needed. The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR) 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. 

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.[33, 34] 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. 

Episode duration 

The median duration of a major depressive disorder (MDD) episode has been estimated at 1 to 2 months in community samples and 8 months in clinical samples. The average duration of persistent depressive disorder is estimated to be 3–4 years in both community and clinical samples.[2]  

Risk of future depression 

According to the American Academy of Child and Adolescent Psychiatry 2022 practice guideline for depressive disorders in childhood and adolescence, MDD is highly recurrent. An estimated 20% to 60% of cases will reoccur within 1–2 years after remission and 70% will reoccur within 5 years. Cases with higher comorbidity, prior reoccurrence, persistent subsyndromal symptoms, negative cognitive style, family dysfunction, and ongoing adversity are more likely to reoccur. Around 10% of cases become chronic.[2]  

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.[35]  

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, 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. 

Around 30% of adolescents with MDD report suicidality of some form in the past year. Roughly 10% of adolescents with MDD report attempting suicide.[2]  

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.[36]  

Another study noted a significant NSSI rate (3000 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.[37]  

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. Clinicians should help youth and families develop working safety plans for worsening symptoms.[38, 39]

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR) uses the same basic criteria to diagnose depression in adults and children.[1]  

The DSM-5-TR 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 symptoms 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. Depressive episodes may occur independent from and 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 (SAD) 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.[40] Thus, a thorough family history is also quite important. 

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: 

• Infections 

• Medications 

• Endocrine disorders 

• Tumors 

• Neurologic disorders 

• Rheumatologic disorders 

Depression is highly comorbid with anxiety and attention disorders and may lead to behavioral problems, substance use, and impaired functioning in adulthood.[2]  

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, creatinine clearance, and thyroid function 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 or Patient Health Questionnaire 9 for Adolescents - Simple self-report surveys that may assist in determining the severity of childhood depression 

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 in pediatrics using 3 selective serotonin reuptake inhibitors (SSRIs): fluoxetine,[42] sertraline,[43, 44]  and escitalopram.[45]  

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 and immediate 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.  

In some areas more intensive treatment options are available for youth with worsening symptoms who do not yet meet criteria for inpatient hospitalization. These programs include partial hospitalization, day treatment, and intensive outpatient programs and are designed to help mitigate acute safety risks and the need for inpatient psychiatric hospitalization. These programs require that the patient is not at acute risk and is still safe to reside at home.  

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 (IPT), cognitive-behavioral therapy (CBT), behavior therapy, family therapy, supportive psychotherapy, and group psychotherapy have all been used for the treatment of youths with MDD.[46] 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 CBT in adolescents who were depressed.[47] 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.[48, 49]  

Cognitive-behavioral therapy 

CBT is one of the most frequently studied psychotherapy treatments.[50] 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 CBT. 

In a well-done review of 16 methodologically rigorous meta-analyses, CBT was found to be effective for a wide range of diagnoses in the adult and pediatric populations.[51]

In most clinical samples, CBT was found to be superior to other manualized treatments, including relaxation training and family and supportive therapy; however, all clinical studies of CBT 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. A continuation study in depressed youths suggests that monthly CBT sessions may be effective in preventing relapses of depression in adolescents.[52]  

A study by Garber et al also suggested that CBT 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.[53] 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.[53]  

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 

IPT 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.[54] They also found the rate of relapse to be relatively low after acute interpersonal therapy treatment. 

Studies on pharmacotherapy for youths with major depressive disorder (MDD) are few compared to adult studies, and some have methodologic problems. Additionally, very few pharmacokinetics studies have been performed in children. A 2020 Agency for Healthcare Research and Quality (AHRQ) review[55] concluded that of SSRIs used for depression management in children and adolescents, only fluoxetine and escitalopram had sufficient evidence to recommend treatment over placebo. A 2021 Cochrane Review also reported that duloxetine, a serotonin and norepinephrine reuptake inhibitor (SNRI), showed modest benefit in children and adolescents.[56] Other antidepressants, including other SSRIs and SNRIs, monoamine oxidase inhibitors (MAOIs), bupropion, mirtazapine, and vilazodone, have been found to be effective in treating depressed adults, but evidence remains mixed or insufficient on efficacy in pediatric populations. 

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. Given the psychosocial context in which depression occurs, pharmacotherapy is insufficient as the only treatment. 

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.[57]  

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. These medications should be reserved only for refractory cases. 

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.[58, 59, 60] In individuals aged 25 years or older, however, the antidepressant dose had essentially no effect on the frequency of deliberate self-harming behavior. 

Because of reports that selective serotonin reuptake inhibitors (SSRIs) are effective in the treatment of youths with major depressive disorder (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. 

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%).[61] Despite the significant response to fluoxetine, however, many patients had only partial improvement; only 31% achieved full remission. Many subsequent studies, including meta-analyses and literature reviews, have reported similar response rates in depressed youth on fluoxetine. While single drug studies on other SSRIs remain mixed, pooled SSRI studies in youth continue to show statistically significant improvement in depressive symptoms.[2]  

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.[62]  

The clinician should treat patients with adequate and tolerable doses for at least 4–6 weeks. At 4 weeks, if the patient has not shown even minimal improvement, the clinician should consider increasing the dose. If there is no response after 8 weeks, then a different SSRI should be trialed. If a patient shows improvement, the medication dose should be titrated as tolerated until symptoms are manageable. Once remission is achieved, medication should be continued for at least 6–12 months to help prevent depression relapse.[2]  

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 should 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 behavioral activation causing patients to 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. Rare (< 2%) reports of medication-induced mania have been reported, however, these are difficult to distinguish from medication-induced behavioral activation or agitation.[2] Of note, a medication-induced episode of mania is not sufficient for a diagnosis of bipolar disorder and does not preclude trial of other SSRI medication. 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[63] and Teicher et al,[64] 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)[65]  

• 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.[66] It has also been noted that monitoring of these patients did not increase following the warnings.[67, 68]  

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.[69, 70]  

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.[71] 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. 

Of note, paroxetine has been associated with increased risk of suicidal thinking or behavior compared to other SSRIs.[55]  

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 discontinuation syndrome 

Abrupt discontinuation of SSRIs with shorter half-lives, such as paroxetine, fluvoxamine, and sertraline, may induce discontinuation symptoms, some of which may mimic a relapse or recurrence of a depressive episode (eg, tiredness, irritability, severe somatic symptoms). Discontinuation 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. 

Serotonin and norepinephrine reuptake inhibitors (SNRIs), such as duloxetine, venlafaxine, and desvenlafaxine, are just beginning to be studied in pediatric depression. Similar to other antidepressant classes, literature is mixed on the efficacy of these medications. SNRIs are generally recommended in youth as second-line therapies after failing at least 2 SSRI medications. A 2021 Cochrane review[56] suggested that duloxetine is associated with a small but statistically significant improvement in pediatric depression, while results for other medications remain mixed.  

SNRIs dually inhibit uptake of both serotonin and norepinephrine, similar to tricyclic antidepressants (TCAs), but with less serious side effects. Side effects can be similar to SSRIs and include insomnia, restlessness, sexual dysfunction, headaches, and initial increases in anxiety. However, compared to SSRIs, SNRIs may cause more nausea, insomnia, dry mouth, and elevated blood pressure.[72] In pediatrics, these medications may be associated with slightly more suicidal ideation and behaviors compared to SSRIs.[56]  

Although several randomized, controlled studies have shown 50–60% response to tricyclic antidepressants (TCAs) (nortriptyline, desipramine, amitriptyline) in depressed youth vs placebo, these results should be considered 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.[73, 74, 75] 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. 

Mirtazapine is an alpha-2 norepinephrine autoreceptor inhibitor and serotonin antagonist at 5-HT2A/2C receptors. Side effects include sedation, increased appetite, and orthostatic hypotension, but it has a lower rate of sexual dysfunction than SSRIs. It shows faster[72] onset of antidepressant effect than SSRI medication; however, after 8 weeks, the antidepressant effect size is similar to SSRIs in adults. Because of its alternative mechanism of action, this medication can be safely used in combination with SSRI or SNRI medication. There are few studies on mirtazapine in pediatrics and results of studies that do exist show mixed results. Mirtazapine does seem to have lower odds of suicide-related outcomes in pediatric populations compared with most SSRIs.[56] Anecdotally, mirtazapine’s side effect profile makes it a good medication for use in depressed patients with comorbid insomnia or avoidant-restrictive eating disorders.   

Bupropion is a norepinephrine and dopamine reuptake inhibitor used for depression in adults. In adult studies, efficacy is similar to that of SSRIs,[72] however, there is very little evidence for use or efficacy in pediatrics. Bupropion has a different side effect profile from most other antidepressants, the most prominent of which is its potential to induce seizures at higher doses. For this reason, this medication is contraindicated in any individual with a seizure disorder. Bupropion is also an appetite suppressant and is contraindicated in patients with comorbid eating disorders. Other side effects include headache, insomnia, increased energy, and anxiety. It does not cause any weight gain or sexual dysfunction. Bupropion is thought to be more dangerous in overdose compared to SSRIs and careful consideration should be given to suicidality in patients before prescribing.  

Ketamine is an NMDA antagonist used as a dissociative anesthetic that has recently shown promise in the short-term treatment of depression. Studies in adolescents are new and ongoing, but initial results show similar efficacy as in adults with rapid but short-term remission of depressive symptoms.[76] Initial studies in adolescent populations have also shown ketamine treatment to have a good safety profile,[77]  but additional studies are needed to assess long-term safety and efficacy in both pediatric and adult populations. 

Electroconvulsive therapy (ECT) has been a longstanding treatment for refractory depression. Despite controversy, stigma, and misapplication in the past, ECT, conducted under general anesthesia, is a highly effective, evidence-based treatment commonly used for refractory depression in adults. Use in child and adolescent depression is much less common. Available research suggests that ECT in pediatric populations is both safe and highly effective with a 70–92% response rate in depressed adolescents,[78]  which is significantly higher than most antidepressant medications. Most side effects, including nausea, headache, fatigue, confusion, and memory loss, are minor and transient.   

Transcranial magnetic stimulation (TMS) is an emerging treatment for depressive disorders that involves use of a magnetic field to activate targeted electrical activity in the brain. Research is ongoing for both adult and adolescent populations to better characterize the efficacy and safety profile of this intervention.[79]  

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. 

Several classes of antidepressants, including selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), bupropion, mirtazapine, and vilazodone, 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.  

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 neurotransmitter that exists naturally in the brain. The SSRIs increase serotonin signaling in certain brain circuits eventually inducing a change in neurochemical receptors that may help mediate an antidepressant effect. SSRIs include, but are not limited to, the following medications: fluoxetine, paroxetine, sertraline, citalopram, and fluvoxamine. In youth, paroxetine has been associated with increased suicidal thinking and behavior compared to other SSRIs.[55]  

Escitalopram and fluoxetine have been approved by the FDA for treatment of pediatric depression. Fluoxetine has been the most studied agent for pediatric depression, and, in the 2022 AACAP clinical practice guidelines, fluoxetine is preferred over other SSRIs for the treatment of pediatric depression.[2]  

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. It is one of two FDA approved medications for pediatric depression and, in the 2022 AACAP clinical practice guidelines, fluoxetine is preferred over other SSRIs for the treatment of pediatric depression.  

Escitalopram (Lexapro)

Escitalopram is an isolated enantiomer of citalopram and shares a similar clinical profile, including risk of QT prolongation at higher doses. It has better evidence for efficacy in child and adolescent depression than other SSRIs except for fluoxetine. It is one of two medications approved by the FDA for the treatment of pediatric depression. 

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). However, fluvoxamine has greater potential for drug-drug interactions than other SSRIs and generally requires twice daily dosing due to its short half-life. Fluvoxamine is approved for treatment of obsessions and compulsions in adults and children aged 8 years and older with OCD.  

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. Citalopram may cause more QT prolongation than other SSRIs in a dose-dependent fashion and has been associated with Torsade de Pointes, ventricular tachycardia, and sudden death at daily doses exceeding 40 mg per day. Citalopram should be avoided in patients with long QT syndrome.  

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. In youth, paroxetine has been associated with increased suicidal thinking and behavior compared to other SSRIs. 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. This medication should not be stopped abruptly due to risk of discontinuation symptoms.

Class Summary

Serotonin and norepinephrine reuptake inhibitors (SNRIs) are generally considered second-line therapies for depressive disorders, after patient’s have not tolerated or not responded to two SSRI trials. These medications generally have more side effects than SSRIs, but less serious side effects than TCAs. Blood pressure should be monitored while initiating and continuing on SNRI therapy due to rare, but significant increases in blood pressure. In pediatrics, these medications are thought to be associated with a slightly higher risk of suicidal ideation and behaviors compared to SSRIs.  

SNRIs have been noted to have significant discontinuation syndromes including mood fluctuations, headache, nausea, imbalance, irritability, general malaise, and flu-like symptoms. For this reason, these medications should be weaned off over a matter of weeks and not abruptly discontinued.  

Venlafaxine (Effexor (DSC), Effexor XR, Venbysi XR)

Inhibits serotonin and norepinephrine reuptake to exert an antidepressant effect. May rarely cause significant increases in blood pressure. Efficacy in adults has been shown to be similar to SSRIs, however results in child and adolescent studies remain mixed.  

Desvenlafaxine (Khedezla (DSC), Pristiq)

Desvenlafaxine is the primary active metabolite of venlafaxine, this drug was designed to be a more potent and refined form of venlafaxine. In adult studies, desvenlafaxine has been shown to be as effective as venlafaxine and SSRIs. Pediatric data for this medication, however, has been largely equivocal in placebo-controlled trials.  

Duloxetine (Cymbalta, Irenka)

Duloxetine inhibits serotonin and norepinephrine reuptake at presynaptic membranes. It is commonly used not only as an antidepressant, but also for neuropathic pain and in chronic pain syndromes. Studies done in pediatrics show a small, but significant efficacy in treating depressive symptoms, comparable to fluoxetine, sertraline, and escitalopram.  

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, but may be indicated for other disorders including migraine disorders or obsessive-compulsive disorder. TCAs commonly used in children and adolescents are imipramine (Tofranil), nortriptyline (Pamelor), clomipramine, 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.