The treatment of adolescent depression in the era of the black box warning Tracy K. Richmond a and David S. Rosen b

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1 The treatment of adolescent depression in the era of the black box warning Tracy K. Richmond a and David S. Rosen b Purpose of review This paper reviews the epidemiology and sequelae of adolescent depression, recent studies of antidepressants and psychotherapeutic modalities for treatment of adolescent depression, and the black box warning from the United States Food and Drug Administration regarding the use of antidepressants in adolescents. Recent findings Over the past 4 years, four major randomized placebocontrolled trials of selective serotonin reuptake inhibitors in adolescents have been published. Although each of these published studies concluded that the drug under study was efficacious, the United States Food and Drug Administration and others have offered words of caution. Over the past 2 years, there has been increasing concern that antidepressants may increase suicidal thinking and behavior (not completed suicide) in depressed adolescents. The United States Food and Drug Administration has issued a black box warning asking providers to use caution when prescribing antidepressants in children under the age of 18. Summary Adolescent depression is common, socially and economically costly, and a potentially lethal disease. Recent studies of antidepressant use in adolescents have demonstrated variable efficacy and an increased risk of adverse events, including suicidality. The evidence is greatest to support the efficacy of fluoxetine, and thus it remains the only selective serotonin reuptake inhibitor approved by the United States Food and Drug Administration for the treatment of depression in children and adolescents. Psychotherapy is strongly encouraged in any patient for whom medication is prescribed. The risk of adverse events associated with antidepressant use requires caution when these medications are prescribed to adolescents. In an adolescent with depression, however, there is an inherent and greater risk to doing nothing. Keywords adolescents, children, depression Curr Opin Pediatr 17: ª 2005 Lippincott Williams & Wilkins. a Department of Medicine, Division of Adolescent Medicine, Children s Hospital Boston, Boston, Massachusetts, and b Teenage and Young Adult Program, Department of Pediatrics, University of Michigan Health Systems, Ann Arbor, Michigan, USA Funded by NICHD grant 5T32 HD and the MCHB Leadership Education in Adolescent Health Training Program grant #5T71MC , Health Resources and Services Administration, Department of Health and Human Services. Correspondence to Tracy K. Richmond, 333 Longwood Avenue, 6th floor, Boston, MA 02115, USA Tel: ; fax: ; tracy.richmond@childrens.harvard.edu Current Opinion in Pediatrics 2005, 17: Abbreviations AACAP BDI CBT CDI CDRS-R CGI-I CGI-S FDA GAF HAM-D K-SADS-L MDD RADS SIQ-Jr SSRI TADS TCA American Academy of Child and Adolescent Psychiatry Beck Depression Inventory cognitive-behavioral therapy Children s Depression Inventory Children s Depression Rating Scale-Revised Clinician s Global Impressions Improvement Scale Clinician s Global Impressions Severity Scale United States Food and Drug Administration Global Assessment of Functioning Hamilton Rating Scale for Depression Schedule for Affective Disorders and Schizophrenia for Adolescent-Lifetime version major depressive disorder Reynolds Adolescent Depression Scale Suicidal Ideation Junior High School Version selective serotonin reuptake inhibitor Treatment for Adolescents with Depression Study tricyclic antidepressant ª 2005 Lippincott Williams & Wilkins Introduction Adolescence is a time of rapid development during which youth experience dramatic physiologic, cognitive, and emotional changes. Not surprisingly, many adolescents report mood disturbance ranging from an occasional touch of the blues to persistent depressed mood interfering with normal functioning. Because of its increasing prevalence, its social and economic costs, as well as the associated morbidity and potential for mortality, adolescent depression is a disorder of major public health concern [1]. Appropriate treatment for adolescent depression has been the focus of much public discussion recently. Comorbidities and sequelae Major depressive disorder (MDD) is defined in the Diagnostic and Statistical Manual for Mental Disorders (DSM-IV) as either depressed/irritable mood or loss of pleasure along with at least three other symptoms present over the same 2-week period (Table 1) [2]. Adolescents often present atypically, describing of pervasive boredom or demonstrating behavioral problems in place of depressed mood; therefore, diagnosis relies on information from multiple sources (e.g., parents and/or teachers) [3]. By definition, MDD affects the day-to-day functioning of adolescents, but it also has potentially significant comorbidities and long-term sequelae. Adolescents with MDD often have a protracted course; a recent study found the index episode lasting 17 months [4]. They are also at risk of having multiple episodes of depression; approximately 70% of adolescents with MDD will have another depressive episode within 5 years, and they are at a fourfold increased risk of having an adult depressive episode 466

2 Adolescent depression Richmond and Rosen 467 Table 1. Major depressive disorder At least one of the following is present: Depressed or irritable mood most of the day nearly every day Diminished interest or pleasure in activities or relationships Either three or four of the following must be present for a total of five symptoms: Decreased or increased appetite, weight loss or gain, failure to achieve expected weight gain Insomnia or hypersomnia Psychomotor agitation/restlessness or retardation Low energy or fatigue Feelings of worthlessness or excessive guilt Indecision, poor concentration and memory Recurrent thoughts of death or suicide At least five symptoms, including either depressed/irritable mood or loss of pleasure, have been present during the same 2-week period and represent a significant change in functioning. These symptoms cause clinically significant distress or impairment in important areas of functioning, are not due to the direct physiologic effects of a substance or a general medical condition, do not meet criteria for a mixed episode, and are not better accounted for by bereavement. [3]. Additionally, those with early-onset depression are more likely to have treatment-resistant depressive episodes later in life, and these subsequent episodes tend to last longer and to be more likely to require hospitalization [5]. In addition to recurrence of major depressive episodes, adolescents with MDD are at increased risk for comorbid conditions and other consequences such as school failure, impaired relationships, substance abuse, teenage pregnancy, and even obesity [6 8]. Anecdotal evidence tells us that early and appropriate treatment may shorten the course of adolescent depression, minimizing the long-term consequences and providing a compelling reason for intervention. Adolescents with MDD commonly present with multiple and evolving mental health diagnoses. Approximately 20 to 40% of teenagers with diagnoses of MDD go on to experience bipolar disorder, and up to 75% have an associated anxiety disorder either at the time of diagnosis or subsequently [7]. Many also have comorbid oppositional defiant disorder and/or attention deficit disorder. Major depression is also a significant risk factor for adolescent suicide, which is currently the third leading cause of death in adolescents aged 15 through 19 [9,10]. Approximately half of adolescents with MDD will attempt suicide at some time in their lifetime, and those with MDD have a four- to fivefold increase in risk of suicide attempt compared with teens not affected by depression [1,11]. Epidemiology Depression is one of the most common mental health disorders in adolescence, with a prevalence of 4 to 8% at any one time and a lifetime prevalence of up to 25% by the end of adolescence [6,7]. Over time, researchers have identified a complex array of both environmental and genetic risk factors. Children with depressed parents have a two- to fourfold increased risk of depression, and postpubertal girls are twice as likely to experience depression than are boys [3]. Chronic illness is associated with an increased risk of depression, as is a history of abuse or being in a household of lower socioeconomic status. Interestingly, an important study by Goodman et al. [12] demonstrated that not only is the individual household income associated with adolescent depression but also the average income at the school the adolescent attends. This study also concluded that school environments could partially buffer the impact of low household income on the development of depressive symptoms in adolescents. Treatment The 1998 Practice Parameter of the American Academy of Child and Adolescent Psychiatry (AACAP) recommended that psychotherapy be the first line of treatment for adolescent and child depression and that antidepressants be reserved for children with severe depression [13]. A recent study using health service use data (the Medical Expenditure Panel Study) found that 1 in every 100 children received treatment for depression annually a rate that falls well below the estimated prevalence of depression (4 8%) in the population [14]. African-American children and adolescents were less likely than whites to receive treatment, as were those who were uninsured. In keeping with the AACAP recommendations, this study found that more than 75% of those receiving treatment for depression had at least one psychotherapy visit. More than half of those treated for depression filled a prescription for an antidepressant, and of the total treated for depression, 43% were treated with a selective serotonin reuptake inhibitor (SSRI). Psychotherapy The AACAP Practice Parameter focuses on psychotherapy as the first-line treatment for adolescents with depression. Cognitive-behavioral therapy (CBT) is one approach that has been widely studied and is described as an active, problem-oriented treatment that seeks to identify and change maladaptive beliefs, attitudes, and behaviors that contribute to emotional distress [15]. A 1997 study that compared CBTwith systemic behavior family therapy and nondirective supportive therapy found CBT to be more efficacious than either systemic behavior family therapy or nondirective supportive therapy in the treatment of adolescent depression [16]. A subsequent meta-analysis similarly demonstrated the short- and long-term efficacy of CBT in the treatment of adolescent depression. No studies to date have revealed any adverse events associated with CBT [15]. In the recent Treatment for Adolescents with Depression Study (TADS), CBT had lower efficacy in the treatment of depression than did either fluoxetine alone or fluoxetine with CBT; yet, CBTseemed to be protective against the increased risk of adverse effects associated with fluoxetine treatment [17 ].

3 468 Adolescent medicine Tricyclic antidepressants Before the advent of the SSRIs in the mid-1980s, the primary psychopharmacologic choice for treatment of adolescent depression was tricyclic antidepressants (TCAs). A 1999 study found no reproducible pattern of efficacy in the use of TCAs in children and adolescents [18]. A 2002 Cochrane Review examined the results of 13 randomized controlled trials of a TCA compared with placebo [19 ]. This review found that there was no overall improvement in those taking a TCA in comparison with those taking placebo, although there was a small but statistically significant reduction in symptoms in those taking the TCA. The side effect profile for the TCA was unfavorable; more study participants reported vertigo, dry mouth, and orthostatic hypotension while taking the TCA than did those taking placebo. When the data were stratified by age, the benefits were slightly improved for adolescents, whereas in younger children no benefit was observed. It was concluded that there could be marginal evidence to support the use of TCAs in adolescents. Keller et al. [20] compared imipramine, a TCA, and paroxetine, an SSRI, with placebo in a 2001 study and found no advantages to the use of imipramine over placebo. There was no difference in the depression markers in the imipramine-treated patients compared with the ; yet, the imipramine-treated patients had significantly higher cardiac adverse events. The continued concern over cardiotoxicity and lethality with overdose, in addition to absence of proven efficacy, has made the use of TCAs in children and adolescents difficult to justify as first-line agents. The use of TCAs has decreased dramatically since SSRIs have become an available alternative. Selective serotonin reuptake inhibitors The advent of the SSRIs dramatically increased the use of psychotropics for the treatment of depression in adolescents [14]. Fluoxetine was one of the first SSRIs to come on the market and remains the only one to be approved by the United States Food and Drug Administration (FDA) for use in child and adolescent depression. Two doubleblind placebo-controlled trials have demonstrated efficacy. The first, a single-site study of 96 adolescents, demonstrated modest but significant effects as measured by improvement in the Clinician s Global Impressions Improvement Scale (CGI-I) and Children s Depression Rating Scale-Revised (CDRS-R) scores [21]. The second, a larger (n = 219) multisite trial, also demonstrated some improvement with fluoxetine treatment, although not all the a priori efficacy measures were different from those achieved in the placebo group [22]. Although this study found significantly greater improvement in the CDRS-R scores in the fluoxetine-treated patients than in the, it demonstrated no difference in the prospectively defined response rates. Importantly, neither of these studies found an increased risk of adverse events, although neither specifically mentioned suicidality. In the TADS, fluoxetine was compared with CBT, fluoxetine with CBT, and placebo [17 ]. Fluoxetine with CBT was superior to fluoxetine alone in all measures of efficacy. Fluoxetine alone was found to be superior to placebo when CGI-I efficacy measures were considered but not when CDRS-R was considered. There was an increased risk of adverse events and psychiatric adverse events in the groups treated with fluoxetine compared with those not treated with fluoxetine; however, there was no statistically significant increase in suicide-related adverse events in those treated with fluoxetine. Studies of other SSRIs have not been able to demonstrate the same positive risk-benefit ratio as have those for fluoxetine (Table 2). A small study (n = 40) by Mandoki et al. [23] demonstrated no superiority of treatment with venlafaxine over placebo but also showed no increased risk of adverse events. Keller et al. [20] studied 275 adolescents treated with paroxetine, imipramine, or placebo. Although this study demonstrated a reduction in some markers of depression, there was no difference in paroxetine-treated patients in the prospectively defined outcomes. Additionally, there were increased rates of adverse events in the paroxetine treated patients (11 serious adverse events) compared with the (2 serious adverse events) as well as suicidal ideation (5 in paroxetinetreated patients, 0 in ). Although the authors concluded that paroxetine is generally well tolerated with good efficacy, others have concluded that the risk-benefit ratio is unfavorable [24 ]. A large (n = 376) multicenter, randomized, doubleblinded, placebo-controlled study that pooled data from two parallel studies investigated the efficacy of sertraline in comparison with placebo and found a small but statistically significant improvement in the sertraline-treated patients compared with the [1]. Their a priori primary outcome measure was the change in CDRS-R score; the sertraline-treated patients had a ÿ2.65 change in score relative to the placebo-treated patients. Additionally, the investigators demonstrated a trend toward a higher response in those treated with sertraline than in those given placebo; however, there was no information regarding the remission rates. There were higher rates of adverse events in those treated with sertraline than in those given placebo (9% of sertraline-treated patients discontinued medication because of adverse events, compared with 3% of ). Whittington et al. [24 ] in a recent review concluded that these data suggest a moderately favorable risk-benefit ratio for sertraline; however, once they included unpublished data on remission, they concluded that the riskbenefit ratio for sertraline is unfavorable. A study of 439 patients with DSM-IV defined MDD undertaken by the TADS team set out to evaluate the

4 Adolescent depression Richmond and Rosen 469 Table 2. Summary of published studies of antidepressant therapy in adolescents Drug Fluoxetine 20 mg Fluoxetine 20 mg Paroxetine (20 40 mg) and Imipramine ( mg) Venlafaxine Sertraline ( mg) Fluoxetine, CBT, fluoxetine + CBT (fluoxetine mg) Study design Randomized controlled trial (n = 219) 9 weeks Double-blind randomized placebocontrolled trial (n = 96) 8 weeks Double-blind randomized parallel design placebocontrolled (n = 275) 8 weeks Randomized controlled trial (n = 40) 6 weeks Two multicenter randomized placebocontrolled trails (n = 376) 10 weeks Randomized controlled trial (n = 439) 12 weeks Primary outcome measure Results Adverse events Primary efficacy measure was response rate ($30% change in CDRS-R score) and remission (score of,28 on CDRS-R); secondary measures were changed in CDRS-R and CGI-S from baseline to endpoint Major outcome measures were response defined as CGI-I score of 1 or 2 at endpoint and CDRS-R Primary efficacy measures were response (HAM-D score,8 or $50% reduction in HAM-D baseline) and change in baseline HAM-D; secondary measures were changed in depressed mood item in HAM-D, and/or K-SADS-L, CGI-I of 1 or 2, change in 9-item subscale of K-SADS-L, means CGI-score CDRS-R Primary efficacy measure was best description of the child from the CDRS-R; secondary outcome measures were response (40% reduction in CDRS-R score), CGI-I and CGI- S scores, proportion of CGI-I responders (those with scores of 1 or 2) CDRS-R total score and CGI-I score of 1 or 2 Fluoxetine had significantly greater improvement in mean CDRS-R score; more fluoxetine-treated patients than placebotreated patients achieved remission; no difference in response rate between fluoxetine-treated and Significantly more fluoxetinetreated patients achieved response compared with placebo-treated; small but significant difference in response (measured by CDRS-R) in fluoxetinetreated compared with More paroxetine-treated patients achieved HAM-D score,8, improved score on HAM-D depressed mood item, and CGI score of 1 or 2 than those who were placebotreated; no difference between paroxetine- and in primary outcomes of HAM-D,8 or $50% reduction in HAM-D score or change in baseline HAM-D; no difference in change in 9-item subscale of K-SADS-L or mean change in CGI score; imipramine gave no improvement compared with placebo on any of the measures No significant improvement in CDRS for venlafaxinetreated patients compared with placebotreated patients Small but statistically significant improvement in CDRS-R score in sertralinecompared with placebotreated patients (2.65 mean decrease); trend toward greater response in sertraline- compared with placebo-treated patients; no data on remission were published Fluxoetine + CBT-treated patients had improved CDRS-R compared with ; fluoxetine alone treated patients did not. Fluoxetine + CBT and fluoxetine alone treated patients were more likely to achieve CGI-I scores of 1 or 2 than were placebotreated patients Fewer adverse events were reported in fluoxetine-treated patients than in placebotreated patients, no information provided regarding suicidality No significant increase in adverse events in fluoxetine-treated compared with Imipramine resulted in higher withdrawal rates than did placebo; 14% of imipramine-treated patients withdrew because of cardiac adverse events; 11 paroxetine-treated patients, 5 imipraminetreated patients, and 2 placebo treated patients had serious adverse events; paroxetine-treated patients relative to had increased risk of suicidal ideation (5.4% compared with 0%) No serious adverse events reported 9% of sertraline-treated patients and 3% of discontinued medication because of adverse events; several adverse events were more than twice as likely to occur in sertraline-treated patients, including diarrhea, vomiting, agitation, and anorexia Statistically significant increase in adverse events in the two groups treated with fluoxetine compared with those not treated with fluoxetine; no increased risk of suicide-related adverse events associated with fluoxetine treatment K-SADS-L, Schedule for Affective Disorders and Schizophrenia for Adolescent Lifetime version; RADS, Reynolds Adolescent Depression Scale; SIQ-Jr, Suicidal Ideation Junior High School Version; HAM-D, Hamilton Rating Scale for Depression; CGI-S, Clinician s Global Impressions Severity Scale; CGI-I, Clinician s Global Impressions Improvement Scale; BDI, Beck Depression Inventory; CDI, Children s Depression Inventory; GAF, Global Assessment of Functioning; CDRS-R, Children s Depression Rating Scale Revised; CBT, cognitive behavioral therapy.

5 470 Adolescent medicine effectiveness of four treatment strategies in the treatment of adolescent depression: fluoxetine alone, fluoxetine plus CBT, CBT alone, and placebo [17 ]. The combination of fluoxetine with CBT had the greatest rates of response (71%) in comparison with any of the other treatment options (61% response for fluoxetine alone, 43% for CBT alone, 35% for placebo). All four groups had a significant decrease in suicidal thinking from baseline. Those in the fluoxetine-alone group or the fluoxetine plus CBT group were at increased risk of harm-related adverse events. The authors concluded, the effectiveness outcomes were clear and the clinical implications straightforward. The combination of fluoxetine with CBT produced the greatest improvement in symptoms of MDD. With respect to risk, suicidality decreased substantially with treatment. While fluoxetine did not seem to increase suicidal ideation, harm related adverse events may occur more frequently in fluoxetine-treated patients and CBT may protect against these events [17 ]. Food and Drug Administration black box warnings The use of SSRIs in adolescents has come under increased scrutiny over the past 2 years. On June 10, 2003, the head of the British Committee on Safety of Medicines in the United Kingdom advised that paroxetine is contraindicated for use in the treatment of depression in children younger than 18 years. This advisory statement was based on data provided by the drug manufacturing company that indicated increased risk of suicidality [25]. Although there was no increase in deaths due to suicide, there was an increase in suicidal thinking and suicide attempts. The FDA followed suit shortly thereafter, issuing a warning against prescribing paroxetine in children until safety issues had been properly investigated [26]. In late 2004, the FDA went further to issue a black box warning the most serious warning placed on the labeling of medications for all antidepressants [27]. Their warning was based on an analysis of pooled data representing more than 4400 patients involved in placebo-controlled trials of nine different antidepressants (fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram, bupropion, venlafaxine, nefazodone, mirtazapine). These were studies of MDD, obsessivecompulsive disorder, generalized anxiety disorder, social anxiety disorder, and attention deficit hyperactivity disorder. The FDA concluded that there is an increased risk of suicidal thinking and suicidal behavior in those treated with an antidepressant relative to those not so treated (an increase from 2.1% to 3.8%, or a summary risk ratio of 2.19) [28]. In addition to raising concerns about the risk of adverse events associated with antidepressant use, the FDA also questioned their efficacy in treating adolescent depression [29 ]. They concluded that only one antidepressant, fluoxetine, was effective and thus warranted FDA approval. The FDA s conclusions differed from those of the published studies in several instances. For example, whereas Keller et al. [20] reported positive effects of paroxetine on secondary measures of depression, the FDA determined no efficacy because of their failure to show benefit on their prospectively determined efficacy measures. In another example, Wagner et al. [1] concluded that sertraline is beneficial in the treatment of depression after pooling the data from two studies, whereas the FDA looked at the studies individually and determined that there is no efficacy. An FDA report notes several possible explanations for what the agency has determined to be the lack of efficacy demonstrated in these studies. First, many of the studies were done quickly in response to promised exclusivity to pharmaceutical manufacturers who conducted clinical trials of drugs in pediatric populations. This could have led to suboptimal study designs with smaller study populations and shorter length of studies. In addition, these pediatric supplemental studies were not preceded by studies establishing the most appropriate dose. The FDA also pointed out that study results of TCAs in children were uniformly negative and may indicate a greater heterogeneity in response among children and adolescents to antidepressants in general than is seen in adults [29 ]. Another potential contributor to the debatable efficacy in these studies is the high response to placebo. In most of the studies, the patients depressive symptoms improved substantially in both the treatment and placebo groups. Because efficacy is determined by improvement in those receiving active treatment relative to those receiving placebo, a greater response to placebo makes it more difficult to establish the effectiveness of the active treatment. In considering the black box warnings, we must be clear that an increased risk of completed suicide in those treated with antidepressants has never been established. Khan et al. [30] reviewed the FDA summary reports of the controlled clinical trials of nine antidepressants that provided data on a total of depressed adult patients, of whom 77 committed suicide. This analysis showed no difference in suicide risk between those randomized to the antidepressant groups and those in the placebo groups. There has never been a completed suicide in any of the pediatric trials [31]. Detecting a causal link between antidepressant use and suicide is a difficult task because suicide is rare, and establishing the link therefore requires well-controlled clinical trials with thousands of subjects. A recent study conducted in the United Kingdom demonstrated no significant difference in the risk of suicidality or completed suicides in those treated with SSRIs compared with those treated with TCAs [32 ]. Interestingly, however, this study was able to show that the risk of both suicidal behavior and completed suicide was much higher in the first 2 weeks of treatment with an SSRI compared with

6 Adolescent depression Richmond and Rosen 471 longer-term treatment. It is impossible to establish whether this result was due to selection bias (i.e., patients are being given SSRIs because of the severity of symptoms) or, what is less likely, to acute worsening of suicidality with initiation of antidepressants. The data regarding increased suicidality in depressed adolescents treated with antidepressants should be viewed with some caution. First, the studies of antidepressants were conducted largely in response to the FDA s promise of exclusivity to drug companies if trials were completed in pediatric populations. Second, the trials in pediatric populations continue to be few and to have small numbers of study participants. Third, the trials were not designed to detect a difference in suicidality, leading to heterogeneity in the manner in which adverse events data were collected. This may increase the strength of the evidence (i.e., it may be more remarkable to find an undesirable adverse effect in a study not powered to detect such a difference). Fourth, no study had any participant complete suicide, and most patients with suicidal thinking and behavior do not complete suicide [31]. Fifth, depression is a known risk factor for suicide, so leaving it untreated may further increase the risk of suicide. Additionally, in most the studies, the participants depressive symptoms improved; however, it was difficult to show greater improvement in those treated with active drug than in those treated with placebo. As Ramachandini [33] concluded, although the guidance is clear cut, the decisions have been based on relatively few studies. The dearth of research means that a high proportion of the 40,000 children and adolescents taking antidepressants. are likely to use fluoxetine in the future on the basis of randomized trials involving a few hundred people, the largest of which was funded by the company that makes the drug. Conclusion Until improved studies have been conducted, we are left with the FDA guidance. Antidepressants should be prescribed with caution in adolescents. Patients should be seen frequently in the initial phase of therapy and with any dose adjustment. The FDA advises that patients be seen once a week for 4 weeks, every 2 weeks for the next month, and then at the end of their 12th week of taking the drug. Pediatric patients being treated with antidepressants should be monitored closely for agitation, irritability, suicidality, and unusual changes in behavior [34 ]. In light of the TADS findings, psychotherapy should be considered, and perhaps even mandated, for any patient receiving antidepressants. It is important to remember that anecdotal evidence, as well as the studies themselves, has shown us that adolescents receiving treatment tend to get better. Additionally, two large-scale studies have shown decreasing rates of suicide in communities with higher rates of antidepressant prescriptions [35,36]. Although evidence and warnings have demonstrated that the prescription of antidepressants in adolescents should be approached with thoughtfulness and care, the authors argue that there is greater risk in doing nothing for the treatment of depression. References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest 1 Wagner KD, Ambrosini P, Rynn M, et al. Efficacy of sertraline in the treatment of children and adolescents with major depressive disorder. JAMA 2003; 290: American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. rev. Washington, DC: American Psychiatric Press; Brent DA, Birmaher B. Adolescent depression. N Engl J Med 2002; 347: Birmaher B, Williamson DE, Dahl RE, et al. Clinicalpresentationand course of depression in youth: does onset in childhood differ from onset in adolescence? J Am Acad Child Adolesc Psychiatry 2004; 43: Hatcher-Kay C, King CA. Depression and suicide. Pediatr Rev 2003; 24: Lewinsohn PM, Rohde P, Seeley JR, et al. Natural course of adolescent major depressive disorder in a community sample: predictors of recurrence in young adults. Am J Psychiatry 2000; 157: Kessler RC, Avenevoli S, Merikangas KR. Mood disorders in children and adolescents: an epidemiologic perspective. Biol Psychiatry 2001; 49: Goodman E, Whitaker RC. A prospective study of the role of depression in the development and persistence of adolescent obesity. Pediatrics 2002; 109: Brent DA, Baugher M, Bridge J, et al. Age- and sex-related risk factors for adolescent suicide. J Am Acad Child Adolesc Psychiatry 1999; 38: Pfeffer CR, Klerman GL, Hurt SW, et al. Suicidal children grow up: demographic and clinical risk factors for adolescent suicide attempts. J Am Acad Child Adolesc Psychiatry 1991; 30: Weissman MM, Wolk S, Goldstein RB, et al. Depressed adolescents grown up. JAMA 1999; 281: Goodman E, Huang B, Wade TJ, Kahn RS. A multilevel analysis of the relationship of socioeconomic status to adolescent depressive symptoms: does school context matter? J Pediatr 2003; 143: Birmaher B, Brent D, Brenson RS. Summary of the practice parameters for the assessment and treatment of children and adolescents with depressive disorders. J Am Acad Child Adolesc Psychiatry. 1998; 37: Olfson M, Gameroff MJ, Marcus SC, Waslick BD. Outpatient treatment of child and adolescent depression in the United States. Arch Gen Psychiatry 2003; 60: Reinecke MA, Ryan NE, Dubois DL. Cognitive-behavioral therapy of depression and depressive symptoms during adolescence: a review and metaanalysis. J Am Acad Child Adolesc Psychiatry 1998; 37: Brent DA, Holder D, Kolko D, et al. A clinical psychotherapy trial for adolescent depression comparing cognitive, family and supportive therapy. Arch Gen Psychiatry 1997; 54: Treatment for Adolescents with Depression Study (TADS) Team. Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression. JAMA 2004; 292: This study was a large multicenter randomized trial of fluoxetine plus CBT compared with fluoxetine alone, CBT alone, and placebo. The authors found greatest efficacy in treatment of depression with fluoxetine plus CBT. There was an increased risk of adverse events in the two groups treated with fluoxetine. CBT seemed to protect against adverse events. 18 Geller B, Reising D, Leonard HL, et al. Critical review of tricyclic antidepressant use in children and adolescents. J Am Acad Child Adolesc Psychiatry 1999; 38:

7 472 Adolescent medicine 19 Hazell P, O Connell D, Heathcote D, Henry D. Tricyclic drugs for depression in children and adolescents (Cochrane Review). In: The Cochrane Library, issue 1. Chichester: John Wiley and Sons, This meta-analysis evaluated studies of TCAs for treatment of depression in adolescents. They found no improvement in depression for those treated with TCAs in comparison with those treated with placebo. 20 Keller MB,Ryan ND,StroberM,et al. Efficacy of paroxetine in the treatment of adolescent major depression: a randomized controlled trial. J Am Acad Child Adolesc Psychiatry 2001; 40: Emslie GJ, Rush AJ, Weinber WA, et al. A double-blind, randomized, placebocontrolled trial of fluoxetine in children and adolescents with depression. Arch Gen Psychiatry 1997; 54: Emslie GJ, Heiligenstein JH, Wagner KD, et al. Fluoxetine for acute treatment of depression in children and adolescents: a placebo-controlled randomized clinical trial. J Am Acad Child Adolesc Psychiatry 2002; 41: Mandoki MW, Tapia MR, Tapia MA, et al. Venlafaxine in the treatment of children and adolescents with major depression. Psychopharmacol Bull 1997; 33: Whittington CJ, Kendall T,Fonagy P,et al. Selective serotonin reuptake inhibitors in childhood depression: systematic review of published versus unpub- lished data. Lancet 2004; 363: This review examined the published and unpublished data of antidepressants used to treat adolescent depression. The authors found that fluoxetine has a positive risk-benefit ratio but that sertraline, paroxetine, and venlafaxine do not. 25 Duff G. Selective serotonin reuptake inhibitors: use in children and adolescents with major depressive disorder, Available at: mhra.gov.uk/ourwork/monitorsafequalmed/safetymessages/cemssri_ pdf. Accessed March 3, US Food and Drug Administration. FDA statement regarding the anti-depressant Paxil for pediatric population. June 19, Available at: bbs/topics/answers/2003/ans01230.html. Accessed March 28, US Food and Drug Administration. FDA launches a multi-pronged strategy to strengthen safeguards for children treated with antidepressant medications. October 15, Available at: NEW01124.html. Accessed March 10, Newman TB. A black-box warning for antidepressants in children? N Engl J Med 2004; 351: US Food and Drug Administration. Background on suicidality associated with antidepressant drug treatment. January 5, Available at: Jan5.pdf Accessed March 10, This briefing from the FDA provides background information on both the efficacy of and the increased risk of adverse events associated with the use of antidepressants in adolescents. 30 Khan A, Khan S, Kolts R, Brown WA. Suicide rates in clinical trials of SSRIs, other antidepressants, and placebo: analysis of FDA reports. Am J Psychiatry 2003; 160: Vitello B, Swedo S. Antidepressant medications in children. N Engl J Med 2004; 350: Jick H, Kaye JA, Jick SS. Antidepressants and the risk of suicidal behaviors. JAMA 2004; 292: This British study compared the risk of suicide in those treated with TCAs with those treated with SSRIs and found no difference. It also examined the risk of suicidality relative to duration of treatment with antidepressants and found that the period of greatest risk for suicidality is during the first weeks of treatment. 33 Ramchandani P. Treatment of major depressive disorder in children and adolescents. BMJ 2004; 328: US Food and Drug Administration. FDA proposed medication guide: about using antidepressants in children or teenagers. November 3, Available at: March 10, This release from the FDA provides information to both providers and patients about antidepressants, their risks, and appropriate monitoring with initiation of therapy. 35 Gibbons RD, Hur K, Bhaumik DK, Mann JJ. The relationship between antidepressant medication use and rate of suicide. Arch Gen Psychiatry 2005; 62: This study examined the association between antidepressant prescriptions and suicide rates at the county level. The authors found that the rate of suicide declines with an increase in antidepressant prescriptions. 36 Olfson M, Shaffer D, Marcus SC, Greenberg T. Relationship between antidepressant medication treatment and suicide in adolescents. Arch Gen Psychiatry 2003; 60: