Antidepressant use in children and adolescents: Practice touch points to guide paediatricians

Abstract

Depression in children and youth is common, and requires an understanding of its developmental character and associated comorbid conditions. Initial treatment of mild depression involves active supportive measures with a focus on symptom reduction and improved daily function. Where pharmacotherapy is warranted, evidence supports the use of selective serotonin reuptake inhibitor (SSRI) antidepressants, particularly fluoxetine, to manage moderate/severe depression. SSRI treatment should include a comprehensive management plan in the context of interdisciplinary care, an understanding of its pharmacology and clearly articulated goals for symptom reduction, functional status tracking (school, home and peers) and monitoring for the emergence of suicidal ideation/behaviour. For children with more severe symptoms or complicating factors (comorbid conditions), referral to mental health clinicians should be considered. Use of an SSRI should be associated with family/patient education about medication effects, specific social and health goals that promote self-esteem, improved function and close monitoring for adverse effects.

Depressive disorders affect one in five children before 18 years of age, and may have a significant impact on psychosocial function and academic achievement, as well as increased risks for suicide and health across the child’s lifespan (1). Identifying and managing depression may be challenging in paediatric practices. Young people may not present with classic symptoms; there are different ways of understanding the nature of depression, and there has been considerable concern about the role of antidepressant medications, especially regarding the effectiveness and safety of the most commonly prescribed antidepressants – selective serotonin reuptake inhibitors (SSRIs). Variations in knowledge, medical specialty and community context affect how comfortable paediatricians feel prescribing SSRIs for their patients. Rather than developing a ‘one size fits all’ approach, decision-making principles are needed that optimize the benefits of SSRI therapy and reduce the risks for adverse effects. Based on an overview of key review articles and practice guidelines, the present article discusses recent evidence regarding the use of SSRIs to treat depression in children and youth, and risks regarding safety, as well as presents practice touch points to guide management. We refer to SSRIs and nonselective serotonergic inhibitors collectively under the rubric of SSRIs. Readers seeking a comprehensive account of the prevention, assessment and management of depression in children and youth may refer to more detailed sources (2–4). The use of SSRIs for other childhood mental health conditions, such as anxiety and obsessive compulsive disorder, is beyond the scope of the present article.

In considering the use of SSRIs to manage major depressive disorders (MDD) in children, three key features need to be considered. First, MDD in children and adolescents is a common disorder that has implications for mental and physical well being across the child’s lifespan; as such, it may be considered a childhood developmental disorder. Second, SSRI antidepressants are frequently prescribed, but with the exception of fluoxetine, sertraline and citalopram (5), evidence supporting their effectiveness in this setting is limited. Third, given concerns about the association between SSRIs and suicide risk (with a causal link not yet established), and recent evidence of recurrence or relapse following medication and short-course psychological therapies (6), careful, close and long-term follow-up is essential.

MDD in childhood

Depression typically encompasses both MDD and dysthymic disorder, and impairs function in one or more major areas of daily living, and family and peer relations. While altered mood may be a leading symptom, depression may present as a range of emotional disturbances; clinicians need to be sensitive to the changing or ‘evanescent’ character of childhood emotional disturbances that often contribute to diagnostic uncertainty. Such symptoms may include insomnia and weight loss, attentional difficulties, irritability, aggression, and social or academic impairment.

MDD affects 2% of children and 8% of adolescents, and increases the risk of substance abuse, attempted and completed suicide, and depression later in adulthood (7). Early onset in adolescence appears to predict a more chronic and recurrent course than depression that starts in adulthood (8,9). Approximately 50% of children and adolescents remain clinically depressed at 12 months, and 20% to 40% at 24 months (8), with many developing episodes into adult life (1). In childhood, boys experience MDD at the same rate as girls, while in adolescence, females are twice as likely to be depressed (10). Moreover, children of depressed parents carry a 15% to 45% lifetime risk for MDD; first-degree relatives of depressed children and adolescents have an MDD prevalence rate of 20% to 46% (11), highlighting long-term implications of childhood mental illness across the lifespan (1). Comorbid conditions (anxiety, aggressive disorders and substance abuse) are found in 40% to 70% of children and youth with MDD.

Trends in SSRI prescription use

The move from tricyclic antidepressants to SSRIs in the 1990s was accompanied by substantial increased use of SSRIs (12), as well as critical questions about their safety and effectiveness (2,13). Antidepressant prescriptions to children increased threefold to 10-fold in the United States (US) from 1987 to 1996 (14); in Canada, prescription prevalence among children increased by 75% to 80% between 1997 and 2003 (12). This was followed by a sharp decline in antidepressant use in 2003, most likely reflecting a response to Health Canada’s warnings related to reports of suicidal ideation/attempts associated with paroxetine use (12). In a 2000 US study, an estimated 25% of paediatricians and more than 40% of family physicians prescribed SSRIs for children younger than 18 years of age (15). In 2003, it was estimated that just under 2% of the Canadian paediatric population were prescribed anti-depressants (16).

Questions regarding SSRI effectiveness

The evidence for antidepressant efficacy among children and teenagers treated for depression is limited and somewhat inconsistent (5,17,18). A high rate of placebo response rates in children and youth (40% to 60%) (8), and substantial research methodological issues, have together contributed to the uncertainty regarding how SSRIs can and should be used for the management of depression in children and youth (19). To date, the body of evidence for the efficacy of fluoxetine is more consistent than for other SSRIs (5,17,20), although there is some evidence for the efficacy of sertraline and citalopram (18). Available evidence suggesting that one SSRI is better than another may be largely attributable to study methodological considerations (for example, how patients are selected, endpoints used, etc), as well as wide variations in placebo responses observed across trials (18). A failure to account for concurrent stressful life events (parental support, poor school functions and chronic illness), to stratify the data according to age (ie, grouping younger and older children together into one cohort) and to account for the high rates of concurrent maternal depression (11) are other methodological inconsistencies that potentially influence the ability to detect antidepressant efficacy. For years, fluoxetine was the only SSRI approved for the treatment of depression among children and youth in the US, although recently escitalopram has been approved. To date, no SSRIs have been approved in Canada for persons younger than 18 years of age. Consistent data reporting on the effectiveness of other newer generation antidepressants remain lacking (11). Although fluoxetine (with or without short-course psychotherapy) is associated with recovery in the majority of treated adolescents, follow-up studies show that almost 50% may experience depression recurrence within the first five years (6), illustrating the complexities and challenges of managing depression among youth. Importantly, no SSRI has consistently demonstrated positive results for depressive disorders in prepubertal children (5).

Questions regarding SSRI safety and suicide risk

With increasing rates of prescriptions and concerns about safety and efficacy of antidepressants, the past decade has been an unsettling time for the management of depression in children and adolescents (13). The possibility of increased suicide risk or suicidality has been a particular concern, leading to warnings placed by regulatory agencies (21).

In the early 2000s, reports appeared associating SSRIs with a higher risk of suicidal behaviour in children and adolescents (22). Shortly after the 2003 US Food and Drug Administration approval of fluoxetine for MDD in children seven to 17 years of age, a public warning followed in 2004 highlighting an increased risk for suicidal ideation and behaviour in children and youth treated with these antidepressants. The 2004 report cited a significant increased risk of “possible suicidal ideation and suicidal behavior” by 80%, and of agitation/hostility and aggression by 130% (23). While this was confirmed by Hammad et al’s (23) meta-analysis, other reports have been inconclusive (15), and yet others have failed to identify an increased risk (24). Higher rates of SSRI prescriptions are associated with lower rates of suicide in children, although because this is correlational evidence, the true nature of the relationship remains unclear (25). To date, the best evidence shows that SSRI treatment decreases suicidal ideation and attempts (18,26,27) because findings do not support a strong relationship between suicide risk in youth and SSRI treatment (27). Troublesome psychiatric or behavioural side effects associated with SSRIs may resemble depression itself and require close ongoing monitoring (5).

Decisions regarding the management of MDD must be made by weighing the possible risks of SSRI treatment against the risks associated with the disorder itself. The consequences of untreated disorders can be devastating to children and parents alike. Nontreatment is never an option, and untreated or undertreated MDD may adversely affect the development of emotional, cognitive, academic and social achievements, and interfere with family relationships (8). Suicide is the most significant and devastating outcome – with approximately 60% reporting having considered suicide and 30% actually attempting suicide (7). Suicide is the sixth leading cause of death in five- to 14-year-old children, and the third leading cause of death in the 15- to 24-year-old age group (18). However, ‘treatment’ for depressive disorders is not necessarily synonymous with medical treatment, as discussed below.

Establishing decision-making practice points to guide use of SSRIs (Table 1)

TABLE 1.

Factors to consider when initiating selective serotonin reuptake inhibitor (SSRI) use in children and youth

1. Evaluate for depression in children and youth who present with mood disturbances, emotional problems	Assessments guided by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) criteria using standardized tools including direct interviews with patients, families, caregivers, assessment of functional impairment (home, school and peer settings) and other comorbid conditions
2. Confirm diagnosis and severity of the condition	The diagnostic criteria should be clearly met, and functional impairment should be clearly documented. Check for other potential causes of the depressive presentation (eg, substance abuse, prodromal psychotic state)
3. Assessment of parental/family mental health	Who else is depressed at home or is there a family history? History of suicide?
4. Suicidal risk at baseline?	While measuring symptoms of depression at the initial assessment, special attention to suicidality needs to be documented
5. Open discussion	Provide comprehensive information about the illness and various treatment options to the patient and family. Appropriate literature should be available in your office and you should have a list of reputable websites to which you can direct their attention.
6. Where to start therapy	After an initial diagnosis for mild depression, start with a period of active support and monitoring symptoms – follow-up visit in seven to 10 days
7. When to start an SSRI?	Medications should be reserved for the treatment of moderate to severe conditions
8. Where to get started with an SSRI: Do no harm	Do a proper risk-benefit relationship analysis of the situation. Complete history/family history and assessment of risk factors. Fully discuss the risks and benefits of medication with your patient/family
9. Acknowledge risks for antidepressant	Check for signs and symptoms that may imply an increased risk of adverse effects (ie, risk for switch to mania). For example, anxiety symptoms (especially panic), impulsivity/restlessness, agitation and history of mania/hypomania
10. Review what other drugs are currently being used and the risk for adverse drug effects	Drug-drug interactions? Potential for therapeutic failure or toxicity? (Consider role of hepatic cytochrome 450 factors in risks for side effects or therapeutic failure). History of previous adverse reactions to psychotropic drugs, and concurrent use of psychotropic medications that might increase risk for drug-drug interactions
11. Starting an antidepressant	Provide the patient and family with a detailed account of the possible adverse effects (both behavioural and somatic), and the expected timelines to improvement. Document your discussion
12. Start low/go slow	Consider a low-test dose and ask for contact from the youth or caregiver if there is a problem in the first few days. Since starting an antidepressant is rarely emergent and the time it takes to see a response is several weeks, you only need to increase the dose slowly (eg, once a week until the expected minimally effective dose is reached). Where possible, wait the required six to eight weeks to determine efficacy
13. Tracking goals and outcomes	Goals should include improved functional status (school, home and peers) and lessening of depressive symptoms. Use the World Health Organization’s International Classification of Functioning, Disability and Health framework to guide treatment outcomes (ie, symptoms and function)
14. Monitor for emergence of adverse events/follow-up/ongoing management	Observe closely for clinical worsening, suicidality and changes in behaviour during the initial few months of treatment or at times when dose changes. See the patient weekly (where possible) for the first few weeks and allow for telephone follow-up whenever the dose is changed. Always ask about and document any adverse effects (use a monitoring form). Monitoring on a monthly basis should extend for six to 12 months after the resolution of symptoms and, with a recurrence of symptoms, monitoring should be extended to two years
15. When to refer?	If no improvement in six to eight weeks, diagnosis and initial treatment should be reassessed. For children or youth with persisting moderate or severe depression (ie, therapeutic failure) or complicating factors (substance abuse or psychosis, suicidal or homicidal ideation, or new or worsening comorbid conditions), consultation with a psychiatrist is needed
16. Taking advantage of the placebo effect	Take advantage of the placebo response (found to be high in most adolescent depression trials). That is, invoke a similar approach to patient care as in studies, including frequent face-to-face contact early in the course of therapy, the development of a trusting and supportive relationship, efforts to measure response objectively and subjectively, and careful elicitation of side effects, overall tolerance, ongoing concerns and satisfaction with treatment
17. Pharmacotherapeutic failure	Consider what else is going on: Consider drug-drug interactions, pharmacogenetic or dietary influences (ie, grapefruit)
18. Avoid therapeutic failure: Develop collaborative care network	What to do when you get ‘stuck’ with therapeutic failure? Where are you in your community – do you have a shared care plan? Shared care between paediatricians, family physicians and psychiatrics should be sought when possible. Appropriate roles and responsibilities regarding the coordination of care should be communicated on a regular basis

Adapted from references 3, 5, 27 and 30

Current expert opinion suggests that nonpharmacological approaches are essential first-line treatments (5,28,29). The initiation of antidepressants in childhood must be based on a thorough understanding of the child, family and social/school context (3,30). A key part of any initial assessment is consideration of individual developmental differences and emerging capacities for self-regulation that underlie psychological and physiological development inherent to childhood and adolescence. This should include risks for substance abuse, presence of stressful life events, possible effects of prenatal substance/alcohol exposure, physical illness, family dysfunction and academic failure. Both genetic and nongenetic factors have an influence, thus highlighting the importance of a family history for MDD (31). However, even in high-risk adoption and twin settings, MDD is a familial disorder that is critically interwoven with environmental and early life experiential factors (32).

Use of depression screening instruments may be helpful in establishing a diagnosis; however, these should not take the place of sound clinical judgment based on direct interview. Combined self-report and parent report using depression checklists and clinical interviews may increase the awareness of underlying family, peer and comorbid conditions. The 2001 World Health Organization’s International Classification of Functioning, Disability and Health presents a useful model to help ensure comprehensiveness in depression assessment and management. It reminds clinicians that it is the combined effect of a health condition (such as MDD), along with personal factors (the individual patient’s unique attributes and resources) and environmental factors (family, friends and school), that result in the impact on relevant health outcomes such as psychological functioning, performing daily tasks and participating in social activities (33). For paediatricians, flexibility in office/time organization, staff training and links with community professions can contribute to effective management of children and youth at risk in an office setting.

Where symptoms are mild or the diagnosis is unclear, an initial period of careful observation and active supportive therapy is warranted. This should include a focus on management of comorbid anxiety, functional needs, availability of self-help material and addressing psychoeducational needs, as well as establishing regular sleep, nutrition, coping patterns, family interventions and exercise including a course of psychotherapy (30) or cognitive behavioural therapy (26,28,34). Enlisting school-based supports should also help set realistic academic, social and activity expectations.

Where symptoms are severe or persist with comorbid disorders, the use of SSRIs may be indicated (30). Best practice (2,3,5,27,30) suggests the deployment of combined treatment with both medication and psychotherapy, with careful monitoring of benefits and safety risks (35). The decision to initiate SSRI use should be made within a broad and comprehensive therapeutic context of continuing to promote social, emotional and physical health that supports self-esteem, improves the quality of family and peer relationships, and healthy lifestyles, and identifies the potential onset of worsening of suicidality (11). As covered above, the best evidence supports the use of fluoxetine for depression (18,36), although this drug has not been approved for use in Canada in children younger than 18 years of age (5,27).

SSRI treatment needs to begin with a realistic discussion of the expectations (child, parents and clinicians) about the risks and potential benefits, identification of target symptoms and adverse effects (behavioural and emotional). Importantly, because the benefits of SSRI treatment may be delayed and placebo response rates may be high, the initiation of antidepressant therapy could be delayed beyond the first visit. Following the initial consultation, a follow-up appointment for the re-evaluation of symptoms, level of self-harm and reconsideration of the diagnosis within seven to 10 days is essential. Both patients and caregivers need to be properly informed about the potential for medication benefits and risks, with close monitoring of suicide risk and efforts to ensure there is no acute cessation of SSRI treatment (5).

Understanding key features of SSRI pharmacology is essential. Because SSRIs primarily act by blocking the serotonin transporter, consequently increasing extracellular serotonin levels, they may lead to pathological increases in serotonin, and potential serotonin syndrome, when used in combination with other serotonergic medications (antidepressants, opioids and central nervous system stimulants). SSRI effects may be mediated by genetic factors that influence the availability of serotonin at the presynaptic membrane (ie, serotonin transporter polymorphisms that regulate the levels of the transporter protein), and the presence of concurrent psychotropic drugs, leading to adverse side effects and hepatic CYP450-dependent metabolism (37).

Ongoing monitoring is essential for the emergence of adverse events, suicidality and behavioural changes, particularly during the initial few months of treatment. This should include seeing the patient weekly for the first few weeks, and subsequently allowing for telephone follow-up when doses change. Systematic and ongoing documentation of findings is recommended. Monthly monitoring should extend from six to 12 months after the resolution of symptoms; with recurrence of symptoms, patients should be monitored for a two-year period.

If no improvement is observed in the first six to eight weeks, diagnosis and initial treatment should be reassessed and the low starting dose should be optimized (ie, fluoxetine dose increased to 30 mg or 40 mg if tolerated). However, even when a systematic comprehensive approach has been pursued, therapy can still fail; recurrences are not infrequent (6). Consultation with a psychiatrist should be sought where moderate or severe depression persists (ie, therapeutic failure) or coexisting substance abuse, psychosis, suicidal or homicidal ideation, or worsening comorbid conditions emerge.

Ideally, management of child and youth depression requires a shared care plan between paediatricians, family physicians, psychiatrists, and associated health and education professionals. The need for collaborative health care has been recently highlighted by a study of paediatricians in British Columbia who overwhelmingly reported that children with mental health problems need comprehensive team approaches with timely access to community resources (38). As we continue to face a paucity of child psychiatrists, especially in communities outside of tertiary care centres, developing models such as ‘shared care’ or collaborative mental health networks are necessary (39,40). Such models can offer coordination of complex care, interprofessional communication and facilitation of case-by-case support, which may avoid ‘therapeutic failure’. Emerging evidence suggests that shared care models may be beneficial for the management of depression in children (30). Such community-based teams can promote professional education, strengthening mental health services for the child, family and professionals.

CONCLUSIONS

Phenotypic variations and frequent comorbidities often lead to diagnostic uncertainty, making the management of depression in children and adolescents challenging. The lifelong implications of early poor mental health (1) warrant the use of a chronic illness perspective to promote improved outcomes well into adulthood. Although many uncertainties persist in approaching and managing childhood depression, paediatricians can play a critical role.