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Use of Antidepressants in the Treatment of Child and Adolescent Depression: Are They Effective?

Source: Pediatric Nursing, Nov/Dec99, Vol. 25 Issue 6, p643, 4p

Author(s): Moldenhauer, Zendi; Melnyk, Bernadette Mazurek

Abstract: Looks at the effectiveness of antidepressants in the treatment of child and adolescent unipolar, nonpsychotic, major depression. Clinical trials on the use of antidepressants in children and adolescents; Role of pediatric health care in treating children with depression; Implications for practice.

AN: 2938218 ISSN: 0097-9805

Depression is a significant cause of morbidity in childhood affecting approximately 5% of children and 10 to 20% of adolescents (Reynolds & Johnston, 1994). Despite its high incidence and negative effects on child and family functioning, depression frequently remains underdiagnosed and untreated due largely to inadequate screening by health care providers and failure to recognize the classic signs and symptoms as more than "typical adolescent mood swings" (Richardson, Keller, Selby-Harrington, & Parrish, 1996).

Studies have supported that depression is a risk factor for suicide, increased risk-taking behavior (e.g., substance abuse, early onset sexual experimentation), teen pregnancy, adult depression, conduct disorder, and delinquency (Birmaher et al., 1996). Therefore, early recognition and treatment is necessary to prevent a host of negative outcomes for children and their families.

Health professionals must be astute in their knowledge of the various presentations of depression in children and adolescents as well as diligent in routine screening for this prevalent disorder. In older children and adolescents, classic signs and symptoms include low self-esteem, guilt, loss of interest in school and work-related activities, decrease in school performance, boredom, apathy, in addition to sleep, appetite, and weight changes. Younger children also may manifest similar characteristics. However, it is common for young, school-age children to present with irritability, restlessness, and hyperactivity, which frequently leads professionals to suspect attention deficit with hyperactivity disorder (ADHD) instead of depression (Melnyk & Moldenhauer, 1999 [includes a comprehensive guide to the assessment of depression in children and adolescents]).

Screening for depression should involve sensitive interviewing as well as the use of valid and reliable clinical evaluation tools (e.g., the Children's Depression Inventory, Kovacs, 1992; the Reynolds Child Depression Scale, Reynolds, 1989; the Beck Depression Inventory-II, Beck, 1996). If depression is suspected, assessment of suicide risk is imperative, and referral to a mental health provider is indicated. A thorough examination also is necessary to rule out physical causes of depression (e.g., anemia, chronic fatigue syndrome, endocrine or eating disorders, mononucleosis, HIV infection, and substance abuse) (Melnyk & Moldenhauer, 1999).

Because 60 to 70% of depressed children and adolescents are likely to experience the persistence or reoccurrence of depression in adulthood (Rao et al., 1995), early intervention strategies are critical in order to prevent long-term negative outcomes. Although many mental health professionals continue to prescribe antidepressants to children and adolescents, studies have presented mixed findings regarding their efficacy.

Clinical Question

How effective are antidepressants in the treatment of child and adolescent unipolar, nonpsychotic, major depression?

The evidence.

Study #1. In the only double-blind, randomized, placebo-controlled trial (see Glossary of Terms) of antidepressants in children and adolescents to demonstrate effectiveness of anti-depressants over placebos, Emslie and colleagues (1997) determined that fluoxetine was superior to a placebo in the acute phase of major depressive disorder in child and adolescent outpatients with severe, persistent depression. During the course of the study, 583 patients who were self-referred or referred by practitioners to a mood-disorders program were screened per telephone, half of whom were interviewed at least once. Ninety-six willing participants meeting study criteria and completing evaluations were included in the study. Inclusion criteria were as follows: (a) aged 7-17 years; (b) fulfilling the Diagnostic and Statistical Manual, revised version III (DSM-III-R) criteria for nonpsychotic major depressive disorder (MDD); (c) in good general medical health; and (d) of normal intelligence. Exclusion criteria were as follows: (a) those with psychotic depression or bipolar disorder; (b) independent sleep-wake disorder; (c) substance abuse; (d) anorexia or bulimia; (e) previous adequate treatment with fluoxetine; and (f) a first-degree relative with bipolar disorder. After a 1-week single-blind, placebo run-in period, the 96 eligible participants were randomized to receive 20 mg of fluoxetine as a daily single dose (n=48) or a placebo (n=48), and seen on an outpatient basis weekly for 8 weeks. Groups were similar at baseline on demographic and most clinical variables, except that those assigned to the fluoxetine treatment group had a greater lifetime incidence of comorbid anxiety disorders (p=.04).

Using the Clinical Global Impressions Scale (CGIS), 56% of the patients receiving fluoxetine versus 33% receiving the placebo were rated "much" or "very much" improved at study exit (p=.02). High attrition occurred during the 8-week trial, with 14 of the fluoxetine-treated group and 22 of the placebo group leaving the trial. The most common reasons for attrition were lack of response (19 placebo patients, and 7 fluoxetine patients) and side-effects. Side-effects in the fluoxetine patients that were listed as reasons for discontinuation from the study included manic symptoms (n=3) and a severe rash (n= 1). Differential attrition may have resulted in the overall non-significant difference in the response rate between the groups in those subjects completing the entire 8-weeks of the study. Using the same CGIS, only 25 of the 34 (74%) patients receiving fluoxetine versus 15 of the 26 (58%) receiving the placebo were rated "much" or "very much" improved at the end of the 8-week trial.

Weekly ratings using the revised Children's Depression Rating Scale (CDRS-R) demonstrated significant differences at 5 through 8 weeks, with patients receiving fluoxetine having significantly lower scores than the placebo group (p=.03). There were no significant drug-by-age, or drug-by-gender interactions. Patients in both the placebo and the fluoxetine treatment groups improved over time, and there were no significant differences between the groups on measures of general psychiatric symptoms (Brief Psychiatric Rating Scale for Children), global functioning (Children's Global Assessment Scale), or self-reported depressive symptom measurements (Children's Depression Inventory or the Beck's Depression Inventory, and the Weinberg Screening Affective Scale). Complete symptom remission was rare, occurring in only 31% of the fluoxetine intervention group and 23% of the placebo-controlled group.

Study #2. In order to evaluate the effectiveness of the tricyclic antidepressant (TCA) amitriptyline, Kye and colleagues (1996) conducted a double-blind, randomized, placebo-controlled trial with 31 adolescents aged 12 through 17 years attending a psychiatric outpatient clinic for major depression. Following a 2-week single-blind, placebo-washout period, subjects meeting inclusion criteria were randomly assigned to a placebo group (n=13) or an experimental group taking a target dosage of 5 mg/kg of amitriptyline (AMI) in two divided doses, up to 300 mg/day. Inclusion criteria were as follows: (a) age 12-17 years with a tanner staging of 3 or greater; (b) fulfilling the Research and Diagnostic Criteria (RDC) for major depression; and (c) parental informed consent and adolescent assent. Exclusion criteria were as follows: (a) inpatient status; (b) psychosis; (c) comorbid psychiatric disorders; (d) substance abuse; (e) parental history of bipolar disorder; (f) psychotropic or depressogenic medication use including birth control pills with MDD remission off the medication during the placebo-washout; (g) significant medical illness; and (h) female sexual activity without contraceptive use. Twenty-two subjects completed the 8-week TCA trial, 10 in the placebo group and 12 in the AMI group. Side effects reported in the AMI group were blurry vision, poor appetite, first degree heart block, and hypomania.

Groups were similar at baseline on demographic variables, mean depressive episode duration, melancholic subtype, and suicidality. Both groups improved over time, thus, findings revealed no statistically significant differences between the placebo-controlled and AMI groups on the following measures: (a) Hamilton Depression Rating Scale (HAM-D); (b) the Schedule for Affective Disorders and Schizophrenia for School-age children clinical interview, Present episode (K-SADS-P) and Epidemiologic versions (K-SADS-E); and (c) the Clinical Global Impressions (CGI) severity of illness rating scale. The authors concluded that no definite recommendation could be made regarding the efficacy of this tricyclic antidepressant in the treatment of adolescent major mood disorder.

Critique of the evidence. A major strength of both reviewed studies is the double-blind, randomized, placebo-controlled designs. This design reduces experimenter bias and placebo effect, minimizes pre-experiment group differences, controls for confounding variables impacting the outcome variable, and allows the researcher to infer cause and effect due to the experimental condition. The other strengths of these studies include the use of multiple informant sources (adolescent, parent, and clinicians) and multiple measures of the outcome variable using both standardized questionnaires and clinical interviews. An initial single-blind placebo run-in period, and the use of criteria to reduce confounding variables by limiting participants to those with a diagnosis of nonpsychotic major depressive disorder, without a history of other major psychological, cognitive, or physical conditions, further strengthens the experimental design.

A weakness of both studies is high differential attrition and relatively small sample size, with insufficient power to detect potential differences between groups. In Emslie's study, fluoxetine was not titrated according to the subject's weight, which may have resulted in insufficient dosages to achieve the desired effect. Differences in depression exist between young children and older adolescents, thus, including a wide age range of 7-17 years is a potential confounder. Debate continues as to the optimal length of treatment, thus it is possible that treatment was of too short a duration in these studies for an appreciable improvement to become apparent. There was a high placebo-response rate in both studies despite the double-blind design, concordant with foregoing research. Kye's study findings are consistent with prior research with the use of TCAs in children and adolescents; none have demonstrated superiority of these medications over placebos. Overall, clinical trials of antidepressant medications in children and adolescents are hampered by poor design and other methodological issues, including: (a) small sample sizes; (b) lack of double-blind, placebo-controlled experimental designs; (c) standard dosages of medication not based on weight of participants; (d) medications potentially used for too short a time period; (e) lack of a second "gold standard" treatment modality against which to compare the new medication; (f) a high placebo effect; (g) the use of multiple scales not standardized across studies, making comparisons difficult; (h) wide age ranges in samples; and (j) differing inclusion and exclusion criteria, with multiple ways of defining and assessing depressive disorders. Future studies with well controlled experimental designs are still needed to further determine the efficacy of anti-depressants in children and adolescents.

Implications for Practice

From a thorough review and critique of the latest studies, it can be concluded that antidepressants alone are usually not effective in improving child and adolescent depression. Aside from one study reviewed (Emslie et al., 1997), findings from numerous clinical trials have indicated that antidepressants are no more effective than placebos in improving depressive symptoms. Numerous clinical trials of psychosocial interventions have demonstrated efficacy over placebo-controlled groups in reducing depressive symptoms and disorders in both clinical and nonclinical samples of children and adolescents (for an excellent review, see Kaslow & Thompson, 1998). Therefore, many authorities recognize that individual psychotherapy that emphasizes cognitive-behavioral training (e.g., reframing) as well as social skills development should be implemented before a trial of antidepressants is considered (Hodgeman, Kaplan, Kazdin, & van Dalen, 1993; Reynolds & Johnston, 1994). An 8- to 12-week trial of medication, the minimum length of time needed to assess therapeutic results (Kutcher, 1997) is a justified treatment option when children are not responding to psychotherapy or when they are having difficulty with school performance and daily functioning (Melnyk & Moldenhauer, 1999).

The serotonin selective reuptake inhibitors (SSRIs) (e.g., fluoxetine, sertraline, paroxetine, and fluvoxamine) are now the recommended first-line medications in depressed children and adolescents due to better tolerance and fewer side effects than the tricyclic antidepressants (e.g., amytriptyline, imipramine, desipramine) (Kutcher, 1997). Because of cardiac toxicity with overdosage, the tricyclic agents should be avoided especially with adolescents who are at risk for suicide. At least four sudden deaths have been reported in children taking Desipramine in the last decade (Abramowicz, 1990; Riddle, Geller, & Ryan, 1993), however, to date this associated finding has not been reported in adolescents. A concern has been recently raised about a potential increase in suicide associated with the use of SSRI treatment, but this has not yet been substantiated in the adult or adolescent literature (Kutcher, 1997). Before an antidepressant is initiated, it is important to assess the presence of somatic complaints (e.g., headaches, poor appetite, nausea, sleep difficulties) so that they are not mistakenly labeled as side effects of the medication. A thorough assessment for suicidal ideation and intent should always be obtained in children and adolescents with suspected depression and appropriate referrals initiated on positive findings. Pregnancy screening also should be performed on all sexually active females prior to the initiation of antidepressants', because these medications are contraindicated during pregnancy.

Fairly common side effects with the SSRIs include excitation, agitation, nausea, vomiting, diarrhea, dizziness, and chills. Less common and rare side effects include muscle twitching, fever, confusion, diaphoresis, seizures, delirium, and coma (Kutcher, 1997). Sedation and anticholinergic side effects (e.g., blurred vision, dry mouth, constipation, urinary retention) are common with the tricyclic antidepressants with cardiac toxicity (e.g., hypotension, tacchycardia, arrythmias) being a less common, but serious complication. It is important for nurses to be knowledgeable of and to educate families about these side effects so that appropriate evaluation and treatment can be obtained should they occur. Families also should be informed that antidepressants should never be abruptly discontinued, but should be slowly weaned to avoid withdrawal symptoms (e.g., anxiety, agitation, nausea, vomiting, agitation, tremors) (Kutcher, 1997).

Treating the child within the context of the family is critical, since the etiology of depression is often linked to a family member's depression, parental conflict, or environmental stressors. Therefore, parents of depressed children and adolescents should be referred and evaluated for depression if indicated because of the strong familial tendency for this condition. Individual as well as family counseling is often beneficial in improving depression as well as dysfunctional relationships or environments.

Ultimately, primary prevention is the key to decreasing the alarming incidence of childhood depression. Programs that teach parents how to build their children's self-esteem as well as social and coping skills from an early age are necessary to equip children with strengths needed to endure stressful life events and transitions. In addition, preventive interventions should specifically target children who are at highest risk for depression (e.g., those with a history of alcohol or drug usage, high family conflict, sexual or physical abuse, parents who are depressed and suicidal themselves).

In summary, depression is a prevalent mental health disorder in children and adolescents that requires a comprehensive, multidisciplinary treatment plan to prevent its persistence or reoccurrence into adulthood. Since multiple studies have indicated that antidepressants alone are usually no more effective than placebos in the treatment of depression, they should be reserved for children who are not responding to psychotherapy and who are having difficulty with school and daily functioning. If prescribed, antidepressants should always be used in combination with other treatment modalities (e.g., cognitive-behavioral therapy). Pediatric health care providers must play a key role in: (a) routinely screening for depression; (b) making appropriate referrals; (c) being part of a comprehensive plan that treats the child within the context of his or her family; (d) educating families about antidepressants, including their known efficacy and side effects; and (e) implementing primary prevention strategies for this serious condition.

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Glossary of Terms

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References

1. Abramowicz, M. (1990). Sudden death in children treated with a tricylic antidepressant. The Medical Letter on Drugs and Therapeutics, 32, 53.
2. Beck, A.T. (1996). Beck Depression Inventory-IL San Antonio, TX: The Psychological Corporation.
3. Birmaher, B., Ryan, N.D., Williamson, D.E., Brent, D.A., Kaufman, J., Dahl, R.E., Perel, J., & Nelson, B. (1996). Childhood and adolescent depression: A review of the past 10 years. Part I. Journal of the American Academy of Child and Adolescent Psychiatry, 35, 1427-1439.
4. Emslie, G.J., Rush, A.J., Weinberg, W.A., Kowatch, R.A., Hughes, C.W., Carmody, T., & Rintelman, J. (1997). A double-blind, randomized, placebo-controlled trial of Fluoxetine in children and adolescents with depression. Archives of General Psychiatry, 54, 1031-1037.
5. Hodgeman, C., Kaplan, S., Kazdin, A., & van Dalen, A. (1993, May 30). Managing depression in children. Patient Care, 51-60.
6. Kaslow, N.J. & Thompson, M.P. (1998). Applying the criteria for empirically supported treatments to studies of psychosocial interventions for child and adolescent depression. Journal of Clinical Child Psychology, 27, 146-155.
7. Kovacs, M. (1992). Children's Depression Inventory. North Towanda, NY: Multi-Health Systems.
8. Kutcher, S. (1997). Practitioner review: The pharmacology of adolescent depression. Journal of Child Psychology and Psychiatry, 38, 755-767.
9. Kye, C.H., Waterman, G.S., Ryan, N.D., Birmaher, B., Williamson, D.E., Iyengar, S., & Dachille, S. (1996). A randomized, controlled trial of Amitriptyline in the acute treatment of adolescent major depression. Journal of the American Academy of Child and Adolescent Psychiatry, 35, 1139-1144.
10. Melnyk, B.M., & Moldenhauer, Z. (1999). Current approaches to depression in children and adolescents. Advance for Nurse Practitioners, 7(2), 24-29, 97.
11. Rao, U., Ryan, N.D., Birmaher, B., Dahl, R.E., Williamson, D.E., Kaufman, J., Rao, R., & Nelson, B. (1995). Unipolar depression in adolescents: Clinical outcome in adulthood. Journal of the American Academy of Child Psychiatry, 34, 566-578.
12. Reynolds, W.M. (1989). Reynolds Child Depression Scale. Lutz, FL: Psychological Assessment Resources.
13. Reynolds, W.M., & Johnston, H.F. (1994). Handbook of depression in children and adolescents. New York: Plenum Press.
14. Richardson, L.A., Keller, A.M., Selby-Harrington, M.L., & Parrish, B. (1996). Identification and treatment of children's mental health problems by primary care providers: A critical review of research. Archives of Psychiatric Nursing, 10(5), 293-303.
15. Riddle, M.A., Geller, B., & Ryan, N. (1993). Another sudden death in a child treated with Desipramine. Journal of the American Academy of Child and Adolescent Psychiatry, 32, 792-797.

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By Zendi Moldenhauer and Bernadette Mazurek Melnyk, PhD, RN-CS, PNP

Zendi Moldenhauer, MS, RN-CS, PNP, is a Pediatric Nurse Practitioner in Private Practice; and a Doctoral Student, University of Rochester School of Nursing, Rochester, NY

Bernadette Mazurek Melnyk, PhD, RN-CS, PNP, is Associate Dean for Research and Director, Pediatric Nurse Practitioner Program, University of Rochester School of Nursing; and PNP Consultant, Children & Youth In-Patient Unit, Elmira Psychiatric Center, Elmira, NY.