Psychopharmacology Grand Rounds

A source of clinically focused, concise information about psychopharmacotherapy

Katharine P. Bailey, MSN Column Editor Vice President of Clinical Affairs High Watch Farm Kent, Connecticut

Depression in Children & Adolescents

The Latest Evidence-Based Psychopharmacological Treatments

his article reviews the epidemiology and comorbidity of childhood depression, as well as the unique developmental and clinical presentation observed in this population. Assessment approaches, including child and adolescent depression rating scales, are discussed, and evidence-based psychopharmacological treatments that have been evaluated in children are presented. BACKGROUND Several decades ago, the diagnosis of major depressive disorder (MDD) in children and adolescents was controversial because psychoanalytic theory precluded the possibility of the development of depression until the superego was formed. It is now well accepted that MDD is a common psychiatric condition in children and adolescents, which has been increasing in prevalence in each generation since the 1940s and is developing in successively younger children (Oesterheld, Shader, Parmelee, & Sood, 2003). In the United States, up to 2.5% of children and up to 8.3% of adolescents suffer from depression, and the lifetime prevalence rate of major depression in adolescents has been estimated to range from 15% to 20%, comparable to the lifetime rate in the adult population (Birmaher et al., 1996; Kessler, McGonagle, Zhao, et al., 1994). Early onset depression often persists, recurs, continues into adulthood, and may also predict more severe illness in adult life (Weissman et al., 1999). Rates of depression are

VANYA HAMRIN, RN, MS, APRN, BC, AND MARYELLEN C. PACHLER, RN, MSN
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similar between boys and girls, but in adolescents, the female-to-male ratio is approximately 2 to 1, paralleling the ratio reported in adults with MDD (Kessler, McGonagle, Nelson et al., 1994). Forty percent to 70% of children and adolescents with depression have comorbid psychiatric disorders, most frequently, anxiety disorder, disruptive behavior disorder, attention-deficit/hyperactivity disorder (ADHD), or substance abuse (Angold, Costello, & Erkanli, 1999). In addition, in a follow-up study, Geller, Fox, and Clark (1994) found that 20% to 40% of adolescents with MDD develop bipolar I disorder within 5 years after the onset of depression. Depression in children and adolescents is also associated with an increased risk for suicidal behaviors (Weissman et al., 1999), and the risk may increase, particularly among male adolescents, if the depression is accompanied by conduct disorder and alcohol or other substance abuse (Shaffer & Craft, 1999). As many as 7% of adolescents who develop MDD may commit suicide in the young adult years (Weissman et al., 1999). In 1997, suicide was the third leading cause of death in individuals ages 10 to 24 (Hoyert, Kochanek, & Murphy, 1999). Children and adolescents with MDD are more likely to have a family member with the disorder, often a parent. Other risk factors include stress; cigarette smoking; loss of a parent or loved one; break up of a romantic relationship; and having attentional, conduct, or learning disorders (Lewinsohn, Rohde, & Seeley, 1998). Given the relative frequency, high rates of recurrence, and associated risk factors, prompt identification and treatment of depression in children and adolescents can reduce its duration, severity, and associated functional impairment.

CLINICAL CHARACTERISTICS Diagnostic criteria and key defining features of MDD in children and adolescents are the same as for adults (American Psychiatric Association, 2000), but recognition and diagnosis may be more difficult in this population, in part because symptoms vary with developmental stage. Children are more likely to exhibit symptoms of anxiety or irritability, frustration, somatic complaints, auditory hallucinations, temper tantrums, and behavioral problems. Adolescents show more irritability, sleep and appetite disturbances, delusions, and suicidal ideation and attempts (Oesterheld et al., 2003). The single most useful tool for diagnosis of depressive disorders in children is a comprehensive, psychiatric diagnostic evaluation. This includes interviews with the child and caregivers, both separately and together, and other collateral informants, such as teachers, child care providers, and social service personnel. Parents and teachers may disagree in their views of the child because of bias or because the child may behave differently in different settings (e.g., mild oppositional behavior may be evident at home, while bullying other children may be evident on the playground). In addition, rating scales such as the Childrens Depression Inventory (CDI) (Kovacs, 1992), Hamilton Rating Scale for Depression (HAM-D) (Hamilton, 1967), Childrens Depression Rating Scale-Revised (CDRS-R) (Poznanski, Freeman, & Mokros, 1985), and the Childrens Schedule for Affective Disorders and Schizophrenia (K-SADS) (Chambers et al., 1985) can be valid and reliable instruments for screening symptoms. These measures are also important in assessing the severity of symptoms and monitoring clinical improve-

ment, and should be used when evaluating a patients global functioning (Practice Parameters, 1998). Assessment should also include: Family history of psychiatric illnesses. Identification of comorbid conditions, especially substance use. Review of medical conditions that may accompany depression in this age group. Determination of suicide risk. Clinicians must integrate all data and place the information into a developmental, familial, and cultural perspective to generate a diagnosis (or diagnoses) and to generate a comprehensive treatment plan. PHARMACOLOGICAL TREATMENT Using medication to treat mental illness in children and adolescents has caused, and continues to cause, controversy. For example, there have been recent warnings that paroxetine (Paxil) may increase suicide ideation in children younger than age 18 (U.S. Food and Drug Administration [FDA], 2003) and that venlafaxine (Effexor) may cause increased suicidal thoughts, hostility, and self-harm in adolescents (Alliance for Human Research Protection, 2003). Although numerous case studies and open trials have been conducted, there is a relative paucity of scientifically rigorous, controlled clinical trials to guide clinicians in the safe and effective treatment of MDD in children and adolescents. Pharmaceutical companies have had little incentive to undertake the perceived excessive potential liability associated with testing drugs in children. Therefore, due to increasing concern about the lack of evidence base, the National Institute of

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Mental Health (NIMH) and the U.S. FDA have supported and required more research in pediatric psychopharmacology since 1995, and the number of studies and publications has increased since that time. The NIMH has funded almost all of the studies of antidepressant efficacy in children and adolescents (Ryan, 2003). Almost all psychotropic agents and indications lack pediatric labeling and are unapproved or offlabel for children (Unapproved Uses of Approved Drugs, 1996). Consequently, clinicians are forced to extrapolate from adult data or to rely on clinical lore and the limit-

ed information from open trials and case studies.

Tricyclic Antidepressant Agents

Tricyclic antidepressant agents (TCAs) have been studied extensively in children and adolescents (Birmaher et al., 1996). In aggregate, approximately 500 children and adolescents have been included in studies of TCA agents versus placebo. The methods of several of these studies were solid, with adequate diagnostic and assessment measures, adequate treatment duration and dosage, and adequate numbers of participants. However, no double-blind studies show the efficacy of TCA agents over placebo (Birmaher et al., 1996). Despite the lack of proven efficacy, amitriptyline (Elavil) has an indi-

To date, nine double-blind, placebo-controlled trials of selective serotonin reuptake inhibitors (SSRIs) have been conducted with children and adolescents. The first reported study of an SSRI (Simeon, The single most useful tool Dinicola, Ferguson, for diagnosis of depressive & Copping, 1990) compared fluoxetine disorders in children is a (Prozac) with placecomprehensive, psychiatric bo. The findings did diagnostic evaluation. not show statistically significant superiority of the active treatment. However, a high placebo response rate effecAnother possible explanation is related to the pharmacokinetics tively eliminated the possibility for TCAs, which are different in of showing medication efficacy. Two other controlled, positive children than adolescents or studies of fluoxetine in children adults. Most children do not have the buffer of a relatively large vol- and adolescents with depression have been conducted, both by ume of fat in which the drug can be stored. Children have larger Emslie et al. (1997, 2002). The livers, relative to body size, lead- first study (Emslie et al., 1997), ing to faster metabolism, more funded by the NIMH, included rapid absorption, and lower pro- 96 children and adolescents, ages tein binding than adults. These 7 to 17. Participants taking fluoxfactors all contribute to shorter etine showed a 56% improvehalf-lives of these agents and a ment rate on the Clinical Global tendency for rapid, dramatic Impression Scale. In the second swings in blood levels from toxic study (Emslie et al., 2002), 219 to ineffective (Dulcan, Bregman, children and adolescents with Weller, & Weller, 2001). major depression were assigned either to placebo or fluoxetine Monoamine Oxidase (20 mg). The CDI-Revised was Inhibitors the primary measure. Sixty-five In 1988, Ryan et al. published percent of the participants taking results of an open series studying fluoxetine met response criteria, adolescents treated with compared to 53% of participants

cation for individuals age 18 and older (Physicians Desk Reference: Drug Guide for Mental Health Professionals, 2002). Many explanations have been offered for the lack of demonstrated response to TCAs in children, compared to the relatively high response rate in adults. These include the possibility that rating scales may not be as sensitive to childhood depression and a higher rate of nonadherence, compared to adults. However, there are no particular data suggesting there is, in fact, more nonadherence in children (Ryan, 2003).

monoamine oxidase inhibitors (MAOIs), either alone or as an augmentation strategy with TCAs, and some adolescents seemed to respond well. However, the potential for morbidity and mortality due to dietary or drug indiscretions with this agent has made MAOIs a rarely used treatment for depression in children and adolescents.
Serotonin Reuptake Inhibitors

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taking placebo. This high response rate to placebo by children and adolescents is a consistent finding in the research. In the largest controlled trial with this population to date, Wagner et al. (2003) studied 367 children and adolescents with MDD ages 6 to 17 to evaluate the effectiveness of sertraline (Zoloft). The dosage ranged from 50 mg to 200 mg. The primary outcome measure was the CDRS-R. Sixtynine percent of participants taking sertraline were considered responders, compared to 59% of participants taking placebo. Nine per-

ty of paroxetine to placebo in adolescents with depression, based on several measures including depression severity and response (Findling et al., 1999; Keller et al., 2001). One trial of citalopram (Celexa) showed positive results, compared to placebo (Wagner, Robb, Findling, & Tiseo, 2001).
Other Agents

To date, there have been no controlled trials using any of the newer antidepressant agents for the treatment of MDD in children or adolescents, but an open

efficacy of SSRIs, compared to placebo, for treatment of MDD in children and adolescents, and SSRIs are the first-line medication treatment. The use of other antidepressant agents requires further research. Ongoing, NIMH-funded, multicenter studies aimed at determining the sequence of treatment for adolescents with depression who fail to respond to an SSRI, and at examining the efficacy of combined medication and psychotherapy are reasons for optimism regarding the care of this population (Wagner, 2003). REFERENCES
Alliance for Human Research Protection. (2003). Wyeth Pharma warns doctors against rx Effexor to kids. Retrieved March 4, 2004, from http://www. researchprotection.org/infomail/03/ 09/02.html Ambrosini, P.J., Wagner, D., Biederman, J., Glick, I., Tan, C., Elia, J., et al. (1999). Multicenter open-label sertraline study in adolescent outpatients with major depression. Journal of the American Academy of Child and Adolescent Psychiatry, 38, 566-572. American Psychiatric Association. (2000). Diagnostic and statistical manual of mental disorders (4th ed., Text Rev.).Washington, DC: Author. Angold. A., Costello, E.J., & Erkanli, A. (1999). Comorbidity. Journal of Child Psychology and Psychiatry, 40, 57-87. Arredondo, D.E., Docherty, J.P., & Streeter, B.A. (1993, May). Bupropion treatment of adolescent depression. Paper presented at the 146th annual meeting of the American Psychiatric Association, San Francisco, CA. Birmaher, B., Brent, D.A., & Benson, R.S. (1998). Summary of the practice parameters for the assessment and treatment of children and adolescents with depressive disorders. Journal of the American Academy of Child and Adolescent Psychiatry, 37, 1234-1238. Birmaher, B., Ryan, N.D., Williamson, D., Brent, D., Kaufman, J., Dahl, R., et al. (1996). Childhood and adolescent depression: A review of the past 10 years. Part II. Journal of the American Academy of Child and Adolescent Psychiatry, 35, 1497-1439. Chambers, W., Puig-Antich, J., Hirsch, M., Paez, P., Ambrosini, P., Tabrizi, M., et al. (1985). The assessment of

Medication should be considered a first-line course of treatment for children and adolescents who have severe symptoms that would prevent psychotherapy,...have psychosis, or have chronic or recurrent episodes.
cent of participants taking sertraline and 5% of participants taking placebo prematurely discontinued the study because of adverse events, which were diarrhea, vomiting, anorexia, and agitation. A preplanned aggregation of two coordinated studies involving more than 1,000 children who were divided almost equally between taking sertraline and placebo indicated sertraline probably works as well in children as it does in adolescents (both male and female) (Donnelly, Winokur, & Wohlberg, 2001). However, not all of the data from these two studies are available yet. Open-label and single-blind, placebo-controlled studies have also shown positive results in children and adolescents with MDD (Ambrosini et al., 1999; Nixon, Milin, & Simeon, 2001). Two positive, controlled trials of paroxetine found the superioritrial of bupropion (Wellbutrin) in adolescents with MDD showed promising results (Arredondo, Docherty, & Streeter, 1993). CONCLUSION Depression in children and adolescents is a serious mental health problem that requires immediate assessment and intervention to treat symptoms, restore optimal functioning, and prevent relapse. Treatment often involves psychotherapy, medication, or a combination, and targeted interventions at home or school. Medication should be considered a first-line course of treatment for children and adolescents who have severe symptoms that would prevent effective psychotherapy, are unable to undergo psychotherapy, have psychosis, or have chronic or recurrent episodes (Birmaher, Brent, & Benson, 1998). Studies have demonstrated the

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affective disorders in children and adolescents by semi-structured interview. Archives of General Psychiatry, 42, 696-702. Donnelly, C.L., Winokur, A., & Wohlberg, C.J. (2001, December). Efficacy and safety of sertraline in the treatment of pediatric major depressive disorder. Paper presented at the annual meeting of the American College of Neuropsychopharmacology, Waikaloa, HI. Dulcan, M.K., Bregman, J., Weller, E.B., & Weller, R. (2001). Treatment of childhood and adolescent disorders. In A.F. Schatzberg & C.B. Nemeroff (Eds.), Essentials of clinical pharmacology (pp. 459-517). Washington, DC: American Psychiatric Association. Emslie, G.J., Heiligenstein, J.H., Wagner, K.D., Hoog, S.L., Ernest, D.E., Brown, E., et al. (2002). Fluoxetine for acute treatment of depression in children and adolescents: a placebo-controlled, randomized clinical trial. Journal of the American Academy of Child and Adolescent Psychiatry, 41, 1205-1215. Emslie, G.J., Rush, J., Weinberg, W., Kowatch, R.A., Hughs, C.W., Carmody, T., et al. (1997). A doubleblind, randomized, placebo-controlled trial of fluoxetine in children and adolescents with depression. Archives of General Psychiatry, 54, 1031-1037. Findling, R.L., Reed, M.D., Myers, C., Riordan, M.A., Fiala, S., Branicy, L., et al. (1999). Paroxetine pharmacokinetics in depressed children and adolescents. Journal of the American Academy of Child and Adolescent Psychiatry, 38, 952-959. Geller, B., Fox, L.W., & Clark, K.A. (1994). Rate and predictors of prepubertal bipolarity during follow-up of 6to 12-year-old depressed children. Journal of the American Academy of Child and Adolescent Psychiatry, 33, 461-468. Hamilton, M. (1967). Development of a rating scale for primary depressive illness. British Journal of Social and Clinical Psychology, 6, 278-296. Hoyert, D.L., Kochanek, K.D., & Murphy, S.L. (1999). Deaths: Final data for 1997. National Vital Statistics Report (DHHS Publication No. PHS 991120). Hyattsville, MD: National Center for Health Statistics. Keller, M.B., Ryan, N.D., Strober, M., Klein, R.G., Kutchner, S.P., Birmaher, B., et al. (2001). Efficacy of paroxetine in the treatment of adolescent major depression: a randomized, controlled trail. Journal of the American Academy of Child and Adolescent Psychiatry, 40, 762-772.

Kessler, R.C., McGonagle, K.A., Nelson, C.B., Hughes, M., Swartz, M., & Blazer, D.G. (1994). Sex and depression in the National Comorbidity Survey. II: Cohort effects. Journal of Affective Disorders, 30, 15-26. Kessler, R.C., McGonagle, K.A., Zhao, S., Nelson, C.B., Hughes, M., Eshleman, S., et al. (1994). Lifetime and 12month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey. Archives of General Psychiatry, 51, 8-19. Kovacs, M. (1992). Childrens depression inventory manual. North Tonowanda, NY: Multi-Health Systems. Lewinsohn, P.M., Rohde, P., & Seeley, J.R. (1998). Major depressive disorder in older adolescents: Prevalence, risk factors, and clinical implications. Clinical Psychology Review, 18, 765794. Nixon, M., Milin, R., & Simeon, J.G. (2001). Sertraline effects in adolescent major depression and dysthymia: A sixmonth open trial. Journal of Child and Adolescent Psychopharmacology, 11, 131142. Oesterheld, J.R., Shader, R.I., Parmelee, D.X., & Sood, A.B. (2003). Approaches to the psychopharmacologic treatment of children and youth. In R.I. Shader (Ed.), Manual of psychiatric therapeutics (3rd ed., 346364). Philadelphia: Lippincott Williams and Wilkins. Physicians desk reference: Drug guide for mental health professionals (1st ed.). (2002). Montdale, NJ: Medical Economics Company. Poznanski, E.O., Freeman, L.N., & Mokros, H.B. (1985). Childrens depression rating scale-revised. Psychopharmacology Bulletin, 21, 979989. Practice parameters for the assessment and treatment of children and adolescents with depressive disorders. (1998). Journal of the American Academy of Child and Adolescent Psychiatry, 37(10 Suppl.), 63S-83S. Ryan, N.D. (2003). Medication treatment for depression in children and adolescents. CNS Spectrum, 8, 283-287. Ryan, N.D., Puig-Antich, J., Rabinovich, H., Fried, J., Ambrosini, P., Meyer, V., et al. (1988). MAOIs in adolescent major depression unresponsive to tricyclic antidepressants. Journal of the American Academy of Child and Adolescent Psychiatry, 27, 755-758. Shaffer, D., & Craft, L. (1999). Methods of adolescent suicide prevention. Journal of Clinical Psychiatry,

60(Suppl. 2), 70-74, discussion, 7576, 113-116. Simeon, J.G., Dinicola, V.F., Ferguson, H.B., & Copping, W. (1990). Adolescent depression: A placebocontrolled fluoxetine treatment study and follow-up. Progress in Neuropsychopharmacological and Biological Psychiatry, 14, 791-795. Unapproved uses of approved drugs: The physician, the package insert, and the Food and Drug Administration: Subject review. American Academy of Pediatrics Committee on Drugs. (1996). Pediatrics, 98, 143-145. U.S. Food and Drug Administration. (2003). FDA public health advisory: Reports of suicidality in pediatric patients being treated with antidepressant medications for major depressive disorder. Retrieved February 17, 2004, from http://www.fda.gov/cder/drug/advisory/mdd.htm Wagner, K.D. (2003). The psychopharmacologic armamentarium in the pediatric population. CNS Spectrum, 8, 252. Wagner, K.D., Ambrosini, P., Rynn, M., Wohlberg, C., Yang, R., Greenbaum, M., et al. (2003). Efficacy of sertraline in treatment of children and adolescents with major depressive disorder: Two randomized controlled trials. Journal of the American Medical Association, 290, 1033-1041. Wagner, K.D., Robb, A.S., Findling, R., & Tiseo, P.J. (2001, December). Citalopram is effective in the treatment of major depressive disorder in children and adolescents: results of a placebo-controlled trial. Paper presented at the annual meeting of the American College of Neuropsychopharmacology, Waikaloa, HI. Weissman, M.M., Wolk, S., Goldstein, R.B., Moreau, D., Adams, P., Greenwald, S., et al. (1999). Depressed adolescents grown up. Journal of the American Medical Association, 281, 1701-1713. Ms. Hamrin is Assistant Professor, and Ms. Pachler is a post-masters candidate, Yale University School of Nursing, New Haven, Connecticut. Address correspondence to Vanya Hamrin, RN, MS, APRN, BC, Assistant Professor, Yale University School of Nursing, 100 Church Street North, PO Box 9740, New Haven, CT 065360740; e-mail: vanya.hamrin@yale.edu.

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