Major depressive disorder (MDD)
Unipolar Depression

A major depressive episode is diagnosed when a child or adolescent has a distinct change in mood, becomes persistently depressed or irritable, and/or experiences a loss of interest or pleasure (anhedonia) for at least 2 weeks. The shift in mood adversely affects social, school, and/or occupational functioning. The diagnosis of major depression outlined in the DSM-5-TR requires 5 total symptoms; 1 of the symptoms must be either depressed/irritable mood or anhedonia. [American: 2022] Additional symptoms include sleep disturbance, appetite or weight disturbance, low energy, psychomotor disturbance, poor concentration, feelings of guilt or shame, and suicidal thoughts or behavior.

The diagnosis is clinical and based on a variety of factors and clinical presentations. See Screening & Diagnostic Testing below.

The history should address symptoms of depression that overlap with those of medical illness (e.g., insomnia, hypersomnia, low energy, appetite changes, and weight changes) and signs that might indicate an underlying cause for depression. In youth with chronic illnesses that may have overlapping physical and mood symptoms, it also is important to assess for cognitive and psychological changes that may be indicative of a diagnosis of depression (e.g. anhedonia, excessive guilt, worthlessness, etc).

When assessing youth with depressive symptoms, it is essential to interview the patient separately from the parents or caregivers for at least a portion of the visit. The time spent alone with the patient may depend on age, developmental level, and patient comfort level. Often, it is uncomfortable for the patient to discuss the symptoms or related life stressors in the presence of caregivers. That said, it is also essential to speak to caregivers and other sources of collateral information about signs, symptoms, current level of functioning, and history to obtain a well-rounded assessment. It is important that the evaluation of children and adolescents and their families should be in the language they are proficient in to avoid misdiagnosis and miscommunication. [Walter: 2023] Not only is the interview essential in making an initial diagnosis, but it can be helpful during treatment monitoring. See Interim History below.

Family history is also helpful to assess as depressive disorders have a well-demonstrated genetic component. A complete psychiatric family history should include a family history of depression, suicide attempts, completed suicide, psychiatric hospitalizations, bipolar disorder, anxiety disorders, substance use disorders, ADHD, learning disorders, and schizophrenia.

Clinically significant distress or impairment in social, occupational, or other important areas of functioning is one of the criteria for a major depressive episode diagnosis. It is common for children and adolescents with depression to be more withdrawn from family or friends, irritable, or less interested in usual activities.

In the past, it was assumed that infants and children could not experience depression, and if they exhibited depressive symptoms, they would “grow out of” it. Research demonstrates that depression may manifest as early as infancy and that early depression may recur or persist into later developmental stages. For children with developmental delays or intellectual disability, always consider the child's developmental level when looking for behaviors and changes in mood that might signal a depressive disorder.

Infants
Depressive symptoms in infants may include sadness, inactivity, withdrawn behavior, agitation, sleep problems, feeding problems, and failure to thrive. A major controversy is whether symptoms may occur endogenously or are always associated with environmental stress (separation from caregivers, maternal depression, neglect, abuse, severe illness). Such symptoms should prompt a search for environmental causes or physical conditions. Diagnostic criteria for depression in infancy are available in the Classification of Mental and Developmental Disorders (Zero to Three). The proper diagnosis and treatment of such cases warrant referral to a specialist. There is no data on treatment in this age group, but providers and families should consider environmental interventions as appropriate.

Preschoolers
The prevalence of depression in preschoolers is approximately 2%, based on available studies. [Whalen: 2017] Depressive symptoms may include those listed above for infants, as well as the child’s stated emotions (e.g., “I’m sad”) or observation of depressive themes in the child’s play (e.g., themes of sadness, loss, guilt, aggression, death, or suicide). Somatic symptoms (e.g., headaches, stomachaches) may be present but are less frequent than more typical depressive symptoms. [Luby: 2003] Endogenous depression is less controversial in this age group, but environmental factors are still important. As with infant depression, diagnostic criteria are available that have been modified to reflect developmental stage and include decreased number and duration of symptoms. [Luby: 2003]

The Preschool Feelings Checklist (PFC) ( 22 KB) has been used as a quick way to screen for depression in preschoolers. The most commonly used tool with a more structured interview is the Preschool Age Psychiatric Assessment (PAPA)

School-Age Children
The prevalence of endogenous depression in school-age children is thought to be 1-2% with a 1:1 male-to-female ratio. [Costello: 2003] Diagnosis is based on DSM-5-TR criteria. [American: 2013] The criteria for depression in children are the same as adult criteria except for the inclusion of irritable mood in addition to depressed or sad mood. School-age children are more able than younger children to report their symptoms and commonly present with temper tantrums, increased frustration and irritability, and somatic symptoms. [Walter: 2023] Often, symptoms reported by the child may be combined with those reported by caregivers to arrive at a diagnosis. School dysfunction may be a strong indicator of the need for evaluation.

Adolescents
The prevalence of depression in adolescence is 11.0% in the United States. [Miller: 2021] The sex ratio changes as the prevalence in girls increases relative to boys resulting in a 2:1 female-to-male ratio that persists until late middle age. Pubertal hormonal and physiologic changes undoubtedly play a role, but research has not yet defined causal factors. [Angold: 2006] Diagnosis is by DSM-5-TR criteria and often can be made by an interview with the adolescent alone. It is strongly recommended to interview the adolescent and their caregivers; school dysfunction, social withdrawal, changes in friends, and new onset of arguing or defiant behavior at home may be clues to underlying depression.

The following criteria are based on the Diagnostic and Statistical Manual of Mental Disorders 5th Ed. [American: 2013]; permission to quote the criteria directly was denied. Symptoms in children and adolescents include depressed mood, loss of interest or pleasure, sleep disturbance, appetite or weight disturbance, low energy, psychomotor disturbance, poor concentration, guilt or shame, and suicidal thoughts or behavior; symptoms also must impair social or school/occupational functioning.

Major depressive disorder (MDD) consists of 1 or more major depressive episodes (2 weeks or more of 5 or more of the symptoms described above). If mania or hypomania is present or has been present in the past, MDD cannot be diagnosed (thus, bipolar disorder excludes MDD). Persistent depressive disorder consists of depressed or irritable mood on most days for at least 1 year in children (2 years in adults).

Persistent depressive disorder may be less severe than MDD in the overall number of symptoms. Still, its chronicity can result in significant social and school/occupational areas.

Premenstrual dysphoric disorder (PMDD) consists of symptoms presenting in the week before the onset of menses, including one or more of the following: depressed mood, anxiety, irritability, or mood swings combined with one or more of the following (for a total of 5 symptoms): loss of interest, poor concentration, low energy, appetite change, sleep disturbance, feeling overwhelmed, or physical symptoms.

Disruptive mood dysregulation disorder (DMDD) is a diagnosis introduced in DSM-5 meant to address the youth experiencing severe, chronic, non-episodic irritability with outbursts. DMDD consists of severe, frequent (>3 times weekly), and recurrent outbursts inconsistent with the child’s or adolescent’s developmental level. This disorder also commonly presents with persistent irritable or angry mood between outbursts over at least 12 months. If mania or hypomania has been present in the past, DMDD cannot be diagnosed (bipolar disorder excludes DMDD). The diagnosis should not be applied to children before the developmental age of 6 years or after 18 years.

Other specified depressive disorder or unspecified depressive disorder may be diagnosed when a patient has a depressed mood but does not meet complete symptom or duration criteria for MDD or persistent depressive disorder. “Sub-syndromal” or “sub-threshold” symptoms of depression (i.e., symptoms that do not meet the threshold for diagnosis of MDD) are associated with a 4-5 fold increased risk for subsequent onset of a depressive disorder. [Fergusson: 2005] Certain symptoms (e.g., sad mood, irritability, low motivation) are of a more significant concern than others (e.g., appetite or weight disturbance, poor concentration).

Depressive disorder due to another medical condition consists of features of a depressive disorder due to an underlying identifiable medical condition. Once the medical illness is treated, the depressive symptoms tend to improve.

Substance/medication-induced depressive disorder consists of features of a depressive disorder due to medication side effects, substance use, or withdrawal. Once the offending agent is stopped, the depressive symptoms tend to improve..

The United States Preventive Services Task Force (USPSTF) recommends universal screening for depression in adolescents 12-18 years old.[Walter: 2023] Insufficient evidence exists to recommend universal screening for children 11 years old and younger. [Siu: 2016]

The following validated tools may be used for screening. Providers may also use these tools in at-risk populations to follow and quantify changes in depression severity over time and in response to treatment.

• Beck Depression Inventory-II - ages 13 and older (available for a fee)
• Patient Health Questionnaire Modified for Adolescents (PHQ-A) ( 228 KB) - ages 11 to 17 (free)
• Center for Epidemiological Studies Depression Scale for Children (CES-DC) ( 37 KB) - ages 12 to 18 (free)
• Center for Epidemiologic Studies Depression Scale Revised (CESD-R-20) ( 262 KB) - ages 14 and older (free)
• Pediatric Symptom Checklist - ages 4-17 (free)
• Mood and Feelings Questionnaire – ages 6-19 (free)
• Strengths and Difficulties Questionnaire (SDQ) – ages 2-17 (free) - Useful to assess problematic behaviors that can be indicative of a diagnosis such as depression. [Mieloo: 2012]

The diagnosis of depression is mostly clinical. A semi-structured interview guide, such as KSADS-PL ( 699 KB), is a useful tool for diagnosis. Level 1 Cross-Cutting Symptom Measures (APA) can be a valuable tool for assessing comorbidities. [Walter: 2023]

A normal physical exam can help to rule out medical illness as a cause for depressive symptoms. An examination is also helpful to assess and address the multiple physical complaints (e.g., abdominal pain, fatigue) that may accompany depression. Injuries or scars from self-harm may be found on a thorough physical exam that may also warrant questioning about depressive symptoms, even if depression isn’t the patient’s original chief complaint. If a patient presents with concerns of depression, has had a recent physical exam (within the past 6-12 months), and has no new physical complaints or illnesses upon a review of systems, the physical exam may be deferred at the clinician's discretion to allow more time for interviewing.

Screening Family Members

Parental depression increases the risk of mood and behavior problems in children. The USPSTF recommends screening for depression in the general adult population, including pregnant and postpartum people. [Siu: 2016] It may be appropriate for referral to the parents’ primary care clinician for screening or utilization of the Edinburgh Postnatal Depression Scale (Spanish) ( 54 KB). The American Academy of Pediatrics (AAP) recommends screening all mothers for maternal depression at well-child visits until the child is 6 months of age. Postpartum Depression Screening provides free screens.

Although no formal diagnostic criteria for paternal postpartum depression exist, providers should be aware that paternal depression also adversely affects a child’s mental health and family functioning and consider asking fathers about depression during well-child visits. [Walsh: 2020] There is currently no specific screening tool for paternal postpartum depression. Whereas women may present more frequently with sadness as a cardinal symptom of depression, men may be more likely to present with irritability and/or alcohol or substance use. [Kim: 2007] Screen siblings in the pediatric setting using the Center for Epidemiological Studies Depression Scale for Children (CES-DC) ( 37 KB) or other depression screens if appropriate.

Labs

A thorough history with a complete review of systems (ROS) and a physical exam may indicate the need for further laboratory testing. Studies in adults have shown little to no value in routine screening laboratory tests for psychiatric admission without indications of abnormal physical exam or history. [Zwank: 2020] In evaluating a depressive disorder, consider including tests such as TSH to screen for hypothyroidism, vitamin D to test for vitamin D deficiency, and urine drug screen to screen for substance use, which may complicate or cause depression. A urine pregnancy test should be performed for anyone with a uterus to consider pregnancy in treatment decisions.

Other

Although depression has a genetic component, no genetic tests are available to aid in diagnosing depression. Microarray analysis of cytochrome P450 enzyme gene subtypes, which can identify differences in the metabolism of antidepressants, is available, but studies to guide clinical use in youth are lacking. Routine use of imaging or EEG in the clinical evaluation of depressive disorders is not recommended. [Luby: 2016]

The risk of depression in first-degree relatives of a person with depression is about 2 to 4 times higher than in the general population. [Lohoff: 2010] Though multiple studies support a genetic component to depression, candidate genes are not well defined, and a multifactorial etiology, which may include environmental factors, is hypothesized. [Flint: 2014] [Kupfer: 2012]

Depression is common. By the end of high school, an estimated 1:5 youth will have experienced at least 1 episode of depression. In prepubertal children, males and females are equally affected; after puberty, rates of depression are twice as high in females. [Merikangas: 2009] [Bitsko: 2018] [Birmaher: 2007] Exposure to adverse childhood experiences increases the risk of depression and anxiety in children and adolescents. [Elmore: 2020] Transgender or gender non-conforming (TGN) adolescents experience higher rates of depression and suicidality than cisgender adolescents. [Connolly: 2016] [Tordoff: 2022] Additional risk factors for adolescent depression include minority sexual orientation, female sex, chronic medical illness, family conflict, and family history of depression. [Miller: 2021] Prospective studies of childhood depression show stable prevalence over time. [Merikangas: 2009]

Many psychiatric disorders share symptoms with depressive disorders.

Bipolar disorder may present with depressive symptoms. All of the symptoms of depression can be present in patients with bipolar disorder, in which patients alternate between depression and elevated mood states known as mania or hypomania. Diagnostic criteria for bipolar disorder in adults are well established, but there is controversy over its application in children and adolescents. Estimates show that at least 60% of patients with bipolar disorder are misdiagnosed with MDD. Many aspects of treating bipolar disorder are distinct from those of other depressive disorders; therefore, it is crucial to rule out bipolar disorder if diagnosing a child or adolescent with depression. Referral to a child and adolescent psychiatrist for diagnostic confirmation is appropriate.

Anxiety disorders may present with low self-esteem, worthlessness, apparent lack of motivation (often anxiety-based avoidance rather than true low motivation), sleep disturbance (insomnia is common as the patient lies awake worrying), eating problems (decreased appetite or eating rituals), and/or poor concentration. The incidence of depression in children and youth with anxiety is 4-fold that of other children. Eliciting specific mood symptoms (sadness, irritability) is vital in differentiating these diagnoses. Anxiety generally precedes the onset of depression, so carefully assess youth with anxiety for symptoms of depression. See Anxiety Disorders, Initial Diagnosis for assessment information.

Attention-Deficit/Hyperactivity Disorder (ADHD) & Disruptive Behaviors may present with poor concentration, low self-esteem, and feelings of worthlessness due to social and academic difficulties.

Eating disorders often present with depressed or irritable mood, low motivation, low energy, and changes in food intake and weight fluctuations. Disordered eating habits are more prominent eating disorders and should be carefully evaluated. Fear of weight gain is a hallmark feature of several eating disorders. See Screening for Eating Disorders.

Adjustment disorder with depressed mood consists of depressed mood and impaired function within three months of a clearly defined stressful life event. To be diagnosed with an adjustment disorder, the patient cannot meet the full criteria for a major depressive episode.

Disruptive mood dysregulation disorder (DMDD) is characterized by at least 12 months of predominantly irritable mood superimposed by severe, episodic behavioral outbursts that are developmentally inappropriate. The neurovegetative symptoms of MDD are generally not present, and anhedonia is not a prominent feature of DMDD. Its onset is in children aged 6-10, and symptoms are present for at least a year (episodes of MDD in children are generally shorter). Children with an initial diagnosis of DMDD have higher rates of anxiety and depression later in life.

Gender dysphoric disorder is an incongruence between assigned gender and gender identity and expression. Individuals with this condition often experience increased social or school impairments or significant distress. Stigmatization of and discrimination against individuals with gender dysphoria leads to increased rates of depression and Suicidality & Self-Harm. It is important to note that gender nonconformity is not a mental disorder, and not all people who identify as transgender suffer from gender dysphoria. [American: 2022] More about gender can be found at Caring for Transgender & Gender-Diverse Youth.

It is estimated that 40%-90% of children and adolescents with depression have at least 1 other psychiatric disorder. [Walter: 2023] The most common psychiatric comorbidities in youth with depression include anxiety disorders, ADHD, oppositional defiant disorder (ODD), and substance use disorders. Other common comorbidities include insomnia, disordered eating, obesity, and weight changes. Comorbidity is more prevalent among children and adolescents with severe MDD. [Avenevoli: 2015] A careful history and psychiatric review of systems can help delineate diagnoses.

Anxiety Disorders are a common comorbid condition in children with depression. The incidence of depression in children and youth with anxiety is 4-fold that of other children. [Avenevoli: 2015] Anxiety generally precedes the onset of depression and is a risk factor for developing depression. Therefore, it is also essential to evaluate for anxiety when evaluating depression.

About 1:5 children with Anxiety Disorders & Attention Deficit Hyperactivity Disorder (ADHD) have comorbid depression. [Mitchison: 2019] MDD with comorbid ADHD is associated with increased impairments, psychosocial difficulties, and stress compared to children with either disorder alone. In patients with a dual diagnosis of MDD and ADHD, the internalizing disorder, MDD, should be treated first, given the risk of suicidality. [Coutinho: 2021] See Attention-Deficit/Hyperactivity Disorder (ADHD) & Mood Disorders.

In a recent study, at least half of children and adolescents with oppositional defiant disorder (ODD) had comorbid anxiety or depression. Those with angry and irritable ODD symptoms are at a higher risk of comorbid mood disorders such as anxiety and depression. The presence of argumentative and defiant behavior in ODD can help differentiate between ODD and mood disorders because these behaviors do not typically occur in mood disorders without some primary mood disturbance (depression, anhedonia, or irritability). [Riley: 2016] Also see Attention-Deficit/Hyperactivity Disorder (ADHD) & Disruptive Behaviors.

Substance Use Disorders are twice as likely in adolescents with MDD compared to the general population. [Hinckley: 2019] It is essential to screen adolescents for substance use to diagnose MDD appropriately. [Hinckley: 2019] Some individuals may use substances to self-medicate mood symptoms and then develop a substance use disorder with more habitual use.

Interim History

When assessing youth with depressive symptoms, it is essential to interview the patient separately from the parents or caregivers for at least a portion of the visit. The time spent alone with the patient depends on factors such as age, developmental level, and patient comfort level. Often, it is uncomfortable for the patient to discuss the symptoms or related life stressors in the presence of caregivers. That said, it is also essential to speak to caregivers and other sources of collateral information about signs, symptoms, current level of functioning, and history to obtain a well-rounded assessment.

Asking about depressive symptoms is the first step in ongoing assessment. A stepwise approach may help save time:

• Ask if the patient has, over the past month, frequently felt depressed, hopeless, sad, or irritable or has felt less interest in or enjoyment of usual activities. Depression and diminished interest (aka anhedonia) are cardinal symptoms of depression – one or the other must be present for diagnosis.
• Positive replies should prompt further questioning. The diagnosis of major depression in children and adolescents outlined in the DSM-5-TR [American: 2022] requires 5 total symptoms; one of the symptoms must be either depressed or irritable mood, or anhedonia. Additional symptoms include:
  • Changes in sleep
  • Feelings of guilt or worthlessness
  • Low energy
  • Poor concentration
  • Appetite or weight change
  • Psychomotor slowing or agitation
  • Suicidal thoughts or behaviors

• See the SIGECAPS mnemonic for depressive symptoms in Key Points above. Gather information from both the child/adolescent and a guardian. Most child/adolescent mental health professionals agree that combining symptoms from these separate reports is sufficient for a clinical diagnosis of depression. Symptoms must cause significant distress or dysfunction to meet criteria – ask about the impact on school, home, and social areas/activities. Because children may not report symptoms clearly, assessment of changes in behavior or function may provide the best clues.

The use of a validated screening tool is up to the clinician; see Screening above. A screening tool may be administered before a visit to eliminate or reduce the need for the questions outlined in 1 and 2. If depression concerns are uncovered during the routine visit, consider scheduling another visit within a week to more thoroughly address depression if it is safe to do so, and after providing information about available crisis resources to the patient and family. A screening tool could be administered in the interim. If a patient expresses Suicidality & Self-Harm, clinicians must take measures immediately to ensure the child’s or adolescent’s safety.

Treatment Approaches

Treatment approaches vary based on age:

• Infants - Medication and psychotherapy have not been studied in this age group. A nurturing home environment and treatment of depression in affected caregivers may help reduce rates of depression in infants at high familial risk. [American: 2020]
• Preschoolers - Psychotherapeutic and parenting/behavioral interventions are the treatment options most commonly used. Medication is not recommended as first-line treatment in this age group and should be referred to a psychiatrist if medication is considered due to the severity of the case; please see Monitoring treatment efficacy below for more information about referrals.
• School-Age Children - There are positive research findings for using medications and cognitive behavioral therapy (CBT) in this age group.
• Adolescents - There are positive research findings in this age group for the use of medications, cognitive behavioral therapy (CBT), interpersonal psychotherapy (IPT), and electroconvulsive therapy (ECT).

Treatment should be individualized with the priorities of the patient and family considered. Treatment plans should be discussed with patients and their parents/guardians with adequate information to enable them to make an informed decision. Specific details of informed consent for treatment vary among states. The informed consent process includes four important elements agreed upon by many experts. This includes decision-making capacity, adequate disclosure of information for the decision-maker to make an informed decision, confirming the decision-maker’s understanding of information, and understanding that their decision for treatment should be freely authorized. [Walter: 2023] Treatment with psychotherapy and medication is generally advised for moderate to severe depression. Some of the best evidence has pointed to an advantage of medication over therapy alone. [March: 2004] However, treatment with medication may not be the first choice for all, and psychotherapy alone may be considered for patients with mild to moderate depression.

Patients expressing active suicidal ideation or who have recently made a suicide attempt should be referred for inpatient psychiatric hospitalization.

Monitoring treatment efficacy

Most of the screening tools listed in this module can also be used to monitor treatment efficacy. A psychiatric referral is necessary for patients with suspected bipolar disorder or depression with psychotic features. Due to chronic shortages in the US, psychiatrists often only see those patients with severe mental illness or complicating biological, psychological, or social factors. The intervention of a child and adolescent psychiatrist should be considered based on provider experience and comfort level and for patients who:

• Require more than 2 psychotropic medications to control symptoms or has had only partial response to medication
• Have no improvement after 6-8 weeks of medication or therapy
• Require psychiatric hospitalization
• Have parents with significant emotional impairment or substance use issues
• Have complex psychosocial issues (e.g., history of abuse/neglect, legal problems, poor parental support/supervision, family conflict)
• Have a family history suggesting adverse reactions to therapy (e.g., planned antidepressant treatment in a patient with a family history of bipolar disorder)
• Are young (<5 years old) with emotional and behavioral disturbances that are severe or prolonged
• Have chronic medical illness with behaviors that interfere with the treatment of that illness

This section details the use of medications to treat depression and discusses antidepressants and suicidal adverse events. Medications can be effective and serve as the mainstay of treatment for many children with depression, but the variability of response to different medications is substantial. An up-to-date history of medication use and current medications, including herbal medicines (particularly St. John's Wort and saffron), dietary supplements (such as S -Adenosylmethionine (SAMe), hydroxytryptophan (5-HTP), eicosapentaenoic acid (EPA), zinc, and folate) and OTC medications, is essential, especially if medication therapy for depression is a consideration as risk of side effects increases with polypharmacy.

Antidepressant medications include selective serotonin reuptake inhibitors (SSRI), serotonin and norepinephrine reuptake inhibitors (SNRI), atypical antidepressants (such as bupropion and mirtazapine), tricyclic antidepressants (TCAs), and monoamine oxidase inhibitors (MAOIs). Only the SSRIs fluoxetine, sertraline, escitalopram are FDA approved for use under 18 years of age; the use of all other antidepressants is considered “off-label” for MDD in children and adolescents. When obtaining a report of prior treatment “failures,” assess whether adequate duration (at least 4 weeks to full effect), appropriate dosage titration and adherence were achieved. Primary care clinicians may do best by developing experience with a few selected medications and referring patients who don’t respond for more expert care.

General considerations for treatment with any antidepressant include: [Boylan: 2007]

• Start at low doses and titrate up as tolerated. A trial at an adequate dose should last 2-4 weeks before any further dose increase because it may take that long to see any benefit. If there is no beneficial effect after 2-4 weeks, and the patient is tolerating the medication, the dose may be increased.
• Total trial time should be at least 6-8 weeks. A medication trial should not be considered a failure until the maximum tolerated dose has been used for this long without improvement.
• Patients should have frequent follow-ups, preferably weekly, until a dose is stable and medication is tolerated.
• Antidepressants work best when taken at the same time daily, which helps adherence and minimizes the risk of discontinuation syndrome (especially agents with a shorter half-life).
• Most antidepressants with once-a-day dosing can be taken in the morning or evening based on patient preference and observed side effects. • Family history of response to a particular medication may be an approximate guide for medication selection.
• The FDA approval of fluoxetine and escitalopram may make those medications appealing choices for clinicians; however, clinical judgment may lead to the “off-label” use of other medications.

The following is not an exhaustive review and should not be substituted for clinician training and judgment. For complete prescribing information, please refer to the manufacturer’s package insert. The medication classes are presented in the order in which they are generally prescribed, based on the side effect profile.

Selective Serotonin Reuptake Inhibitors (SSRIs)

SSRIs are the best-studied antidepressant medications for children and adolescents. They also have significant benefits for anxiety disorders, including generalized anxiety disorder, panic disorder, and OCD. The effects of SSRIs on anxiety reduction are important, given that anxiety disorders are commonly comorbid with depression.

SSRIs increase levels of serotonin activity by decreasing the presynaptic reuptake of serotonin. SSRIs have a minimal effect on other neurotransmitters, such as dopamine and norepinephrine. SSRI side effects are usually mild and often self-resolve in 1-2 weeks. Common side effects include headaches, GI upset, somnolence, agitation, and sexual side effects (e.g., decreased libido, anorgasmia).

SSRIs are considered first-line pharmacological treatment.

Fluoxetine has the most positive data from controlled trials in children and adolescents, with three trials demonstrating significant differences from placebo. [March: 2004] [Emslie: 2002] It has a longer half-life than most other SSRIs (1-4 days), and an active metabolite, norfluoxetine, which has an even longer half-life (7-15 days). The half-life can be a useful pharmacokinetic feature since it is more forgiving than other SSRIs when patients miss doses. However, if a patient has a negative response to fluoxetine, the long half-life can extend the duration of the adverse reaction.

• FDA approved for use in children eight years and older with MDD and those seven years and older with obsessive-compulsive disorder.
• Available as brand name (e.g., Prozac) and generic in several formulations, including 10 mg, 20 mg, 40 mg, and 60 mg tablets; 10 mg, 20 mg, and 40 mg capsules; 90 mg delayed release (weekly) capsules; 20 mg/5 ml solution
• Starting dose for adolescents: 10 to 20mg once daily, initial target dose 20mg once daily, dose range 10mg-60mg once daily

Escitalopram is the S-isomer of citalopram. Escitalopram has had 3 controlled trials. One controlled trial in adolescents aged 12 to 17 years had positive results. [Emslie: 2009] Two other controlled trials [Wagner: 2006] and unpublished data (Forest Laboratories) did not significantly differ from placebo. Of note, a post-hoc analysis of the data from the published negative study showed a significant difference from placebo for the adolescent age group.

• FDA-approved treatment of depression in adolescents aged 12 to 17 years (based on the strength of the positive study and data from a study of citalopram)
• Available as brand name (e.g., Lexapro) and generic in 5 mg, 10 mg, 20 mg tablets and 5 mg/5 ml oral solution.
• Starting dose for adolescents: 5mg to 10mg once daily, initial target dose 10mg once daily, dose range 10mg to 30mg once daily.

Sertraline has 1 positive trial (2 studies, which were combined by study design); however, the significance of the trial results was lessened by a very high placebo response rate (53%). [Wagner: 2003] High placebo response rates are characteristic of all existing trials of antidepressants in children and adolescents.

• FDA approved for use in children 6 years and older with MDD.
• Available as brand name (e.g., Zoloft) and generic in several formulations, including 25 mg, 50 mg, 100 mg tablets, and 20 mg/ml oral concentrate.
• Starting dose for adolescents: 12.5mg to 25mg once daily, initial target dose 50mg once daily, dose range 25mg to 200mg once daily.

Paroxetine has 1 trial with mixed results [Keller: 2001] and 1 negative trial [Emslie: 2006], so the evidence for efficacy is equivocal. Paroxetine also appears to be less well tolerated in children and adolescents and has significant discontinuation symptoms (possibly due to the short half-life of 20 hours). Paroxetine had worse suicidal ideation and treatment withdrawal in children and adolescents with MDD when compared to placebo. [Walter: 2023]

• Not FDA approved for use in children; other SSRIs may be better for children and adolescents who may be more prone to missing doses and therefore be at higher risk of discontinuation syndrome.

Citalopram has had 2 controlled trials. One had positive results [Wagner: 2006]; the other did not show a significant difference from the placebo (unpublished). The non-significant study included inpatients and a high dropout rate, which may have made the results difficult to interpret. Citalopram has also been studied in pediatric patients with functional abdominal pain, with a trend toward efficacy. [Roohafza: 2014]

• Not FDA-approved for use in children. In August 2011, the FDA issued a Drug Safety Communication warning of the potential for QT prolongation and Torsades de Pointes in patients taking citalopram at doses higher than 40mg daily, and that citalopram should no longer be used at such doses. The FDA also discouraged citalopram in patients with cardiac conditions predisposing to arrhythmia, including congenital long QT syndrome.
• Available as brand name (e.g., Celexa) and generic in 10 mg, 20 mg, and 40 mg tablets and 10 mg/5 ml oral solution
• Starting dose for adolescents: 10mg once daily; initial target dose 10mg to 20mg once daily; dose range 10mg to 40mg once daily.

Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs)

SNRIs increase levels of serotonin and norepinephrine activity by decreasing the presynaptic reuptake of serotonin and norepinephrine. SNRI side effects are usually mild and often self-resolve in 1-2 weeks. Common side effects include headaches, dry mouth, GI upset, somnolence, insomnia, and sexual side effects (e.g., decreased libido, anorgasmia).

Venlafaxine (Effexor) has effects similar to SSRIs. In fact, at lower doses (<225 mg daily), the norepinephrine reuptake action is not present, effectively making venlafaxine an SSRI at these doses. There have been few studies on its use in children and adolescents. Venlafaxine was studied in a large RCT involving patients who continued to have depression despite adequate treatment with one SSRI and was not significantly better in that context than a second SSRI; there was no placebo arm. [Brent: 2008] One unpublished study and 1 small, randomized controlled trial did not show significant benefits. [Boylan: 2007] Pooled results of these 2 studies showed only a small benefit for adolescents. A high rate of placebo response may have hampered studies. Venlafaxine also has significant discontinuation symptoms that may begin within a few hours of a missed dose.

• Not FDA approved for use in children and adolescents
• Available as brand name (e.g., Effexor or Effexor XR) and generic in 25 mg, 37.5 mg, 50 mg, 75 mg, and 100 mg tablets.
• “Off label” starting dose for adolescents: 37.5-75 mg/day with maintenance dose of 150-300 mg/day

Desvenlafaxine SR (Pristiq) is a form of the active metabolite of venlafaxine. Desvenlafaxine SR has had 1 controlled trial. [Weihs: 2018] This trial compared desvenlafaxine SR weight-based dosing to fluoxetine and placebo and was non-significant due to improvement in all study arms.

• Not FDA approved for use in children and adolescents
• Starting dose in adults: 50 mg/day

Duloxetine (Cymbalta) has had 2 controlled trials. [Emslie: 2014] [Atkinson: 2014] Both studies compared duloxetine to fluoxetine (as a standard treatment) and placebo. Both studies showed no significant differences between treatments due to improvement in depression in all study arms (duloxetine at fixed and flexible doses of up to 120 mg daily, fluoxetine up to 40 mg daily, and placebo).

• Not FDA approved for depression in children and adolescents, but is FDA-approved for Generalized Anxiety Disorder (GAD) in ages 7-17
• Starting dose for GAD in children and adolescents : 30 mg/day

Levomilnacipran (Fetzima) is the newest SNRI on the market, approved by the FDA for treating depression in adults in July 2013. A controlled study was completed in 2020 for treatment with levomilnacipran in adolescents with MDD, and interpretation of the results is in progress.

• Not FDA approved for use in children and adolescents
• Starting dose in adults: 20 mg/day

Atypical Antidepressants

Atypical antidepressants are antidepressants that act differently than any of the other four classes of antidepressants. The mechanism of action of each of these is unique to the specific medications. Common side effects include dry mouth, dizziness, or lightheadedness. Other possible side effects differ between the atypical antidepressants.

Bupropion has no controlled studies for depression in children and adolescents. One open study of bupropion in children with depression and comorbid ADHD has positive results. [Daviss: 2001] Bupropion is used in adults for depression and smoking cessation. Unlike SSRIs, bupropion has little positive effect on anxiety (and can cause anxiety in some). It may be useful in patients with bipolar disorder and depression as it is less likely than other antidepressants to induce mania. There is a small risk of generalized seizures with bupropion, higher at doses >300 mg daily. Due to the increased risk of seizures, bupropion is contraindicated in patients with an active eating disorder.

• Not FDA-approved for use in children.
• Available as brand names (Wellbutrin, Wellbutrin SR, Wellbutrin XL, Zyban) and generic in 75 mg and 100 mg tablets; 100 mg, 150 mg, and 200 mg extended release (12-hour) tablets; 174 mg, 348 mg, and 522 mg extended release (24 hours) tablets (as hydrobromide); and 150 mg, 300 mg, and 450 mg extended release (24 hours) tablets (as hydrochloride)
• Starting doses in adolescents: bupropion SR 75 mg twice daily, initial target dose 100 mg twice daily, dose range 75 mg to 150 mg twice daily; bupropion XL (Wellbutrin XL) starting dose 150 mg once daily, initial target dose 150 mg to 300 mg once daily, dose range 150 mg to 450 mg once daily.

Mirtazapine (Remeron) has multiple actions at the CNS receptor level that may contribute to the antidepressant effect. There have been 2 unpublished trials of mirtazapine for depression in children and adolescents. Neither trial demonstrated a significant difference from the placebo. As with venlafaxine, this lack of apparent effect may be due to high placebo response rates. Mirtazapine has a sedating effect that paradoxically occurs at lower doses and is sometimes used at night to treat comorbid insomnia.

• Not FDA approved for use in children and adolescents
• “Off label” use starting dose: 7.5 mg up to 30 mg daily. Lower doses preferred when additionally targeting insomnia.

Vortioxetine (Trintellix) was approved by FDA for treating depression in adults in September 2013. It increases circulating serotonin levels. A controlled study on adolescent MDD was published in 2022 with negative results showing no difference between combined doses of vortioxetine and placebo. Vortioxetine used in adolescents showed a safety profile similar to that in adults. [Findling: 2022]

• Not FDA approved for use in children and adolescents
• Starting dose in adults: 10 mg/day

Vilazodone (Viibryd) was approved by FDA for treating depression in adults in January 2011. A controlled study in pediatric MDD focused on adverse effects was completed in Clinical Trials Vilazodone in Adolescents (clinicaltrials.com).

• Not FDA approved for use in children and adolescents
• Starting dose in adults: 10 mg/day with food

Tricyclic Antidepressants (TCAs)

TCAs have been available for many years but have been eclipsed by SSRIs, SNRIs, and other antidepressants for primary treatment of depression, primarily due to other agents having fewer side effects and less toxicity. TCAs inhibit the reuptake of serotonin and norepinephrine, leading to increased concentration of these neurotransmitters. In addition, TCAs also block postsynaptic histamine, alpha-adrenergic, and muscarinic-acetylcholine receptors. TCAs have several adverse side effects, including common side effects of constipation, dizziness, and dry mouth. Toxicity and overdose can result in cardiac arrhythmias, seizures, coma, and death. [Moraczewski: 2022] Pediatric clinicians need to know that multiple trials of TCAs have failed to show significant benefits compared to placebo for treating depression in children and adolescents. A Cochrane review from 2013 supported the same conclusion. [Hazell: 2013]

Monoamine oxidase inhibitors (MAOIs) function by inhibiting the monoamine oxidase enzyme resulting in accumulation of serotonin, norepinephrine, and dopamine in synaptic clefts. MAOIs' side effect profile is severe. MAOI cross-reacts with tyramine, resulting in hypertensive crisis, and dietary restrictions are recommended for doses used to treat depression. A frequent adverse side effect of MAOIs includes dizziness in almost half of users. [Sabri: 2022]

Over-the-Counter and Herbal

St. John’s Wort (hypericum), an herbal remedy sometimes recommended for depression, induces cytochrome P450 3A4, which can result in lowered blood levels of other drugs that are metabolized by that enzyme (e.g., macrolide antibiotics, azole antifungals, benzodiazepines, calcium channel blockers, and calcineurin inhibitors, like cyclosporin and tacrolimus). St. John’s Wort also interacts with other antidepressants, such as SSRIs (e.g., fluoxetine, sertraline), SNRIs (e.g., venlafaxine), and MAOIs (e.g., selegiline). If taken along with these antidepressants, it may increase the risk of serotonin syndrome, a severe and potentially fatal drug reaction.

Saffron is another herbal remedy being used for treatment of depression. Further studies are required to determine if any interactions exist with other antidepressants.

Nutritional supplements used to treat depression include S-adenosylmethionine (SAMe), 5-hydroxytryptophan (5-HTP), eicosapentaenoic acid (EPA), zinc, and folate. 5-HTP is the only serotonergic agent of these and may increase the risk of serotonin syndrome. [Sarris: 2019]

Light therapy is a nonpharmacological treatment that exposes individuals to artificial light, typically at a “dose” of 10,000 lux for 30-60 minutes in the morning. [Campbell: 2017] [Nussbaumer-Streit: 2019]The evidence for light therapy as preventive treatment for Seasonal affective disorder (SAD) is limited. Ultimately the decision for or against treatment should be based on patient preferences. is identified as major depressive disorder with a seasonal pattern. Symptoms commonly occur during the fall or winter months and usually improve in the spring.

Safety Considerations

Psychotherapy

The other primary treatment modality is psychotherapy, which refers to any psychology-based treatment directed by a trained mental health professional and delivered by means of communication or behavioral techniques. Psychotherapy is often referred to as ”counseling“ or “talk therapy.” Several types of psychotherapy exist, but the only two with significant research evidence for efficacy in treating depressive disorders in children and adolescents recommended by the American Psychological Association for initial treatment are cognitive behavior therapy (CBT) and interpersonal therapy (IPT).

Children and adolescents with depression may experience sleep disturbances associated with increased severity of depressive symptoms, suicidality, more significant fatigue, and decreased concentration. [Molendijk: 2018] Insomnia and sleep deprivation have been shown to increase the risk of major depression. [Roberts: 2014]

Antidepressants may have side effects, including insomnia which further complicates sleep disturbances. Improving sleep hygiene is one of the most important aspects to prevent the detrimental effects of insufficient sleep. See Behavioral Techniques to Improve Sleep and Sleep Medications for further guidance.

Research on the effect of diet on child and adolescent depression is in its early stages. In adults, there is evidence that diet quality is associated with a lower risk of depressive symptoms. Recent studies have also shown the association between vitamin D deficiency and depression. There is evidence that supplementation with vitamin D in those with depression and vitamin D deficiency is beneficial. [Parker: 2017] Refer to Calcium and Vitamin D for dosing in children and adolescents.

Associations have been found between physical activity and lower rates of depression in adolescents. [Rodriguez-Ayllon: 2019] [Korczak: 2017] Clinical guidance for exercise in this population includes group-based and supervised light-to-moderate-intensity activities 3 times a week for 6-12 weeks. Studies showed that exercise is effective in both inpatient and outpatient settings for children and adolescents with moderate and severe depression. [Carter: 2016]