placebo-controlled trial of 195 adolescents with major depression. Adolescents were randomized to nefazadone in targeted daily doses of 300–400 mg/week or placebo over 8 weeks. Although greater improvement was found with nefazadone than with placebo, this was not statistically significant. In a second multicenter trial for children and adolescents ages 7–17 years, nefazadone did not differentiate from placebo (Rynn et al. 2002).

Double-blind, placebo-controlled trials of TCAs in the treatment of depressed youths have not demonstrated superiority of TCAs over placebo. Approximately 500 children and adolescents have been included in aggregate in these studies (Ryan, 2003) (Table 2.3).

The efficacy of venlafaxine, mirtazapine, and bupropion have not been established in children and adolescents with depression. Dietary restrictions markedly limit the utility of MAOIs for pediatric patients.

Therefore, for medication treatment of major depression in children and adolescents, only the SSRIs have demonstrated efficacy and tolerability in acute, short-term treatment studies. The SSRIs are currently first-line pharmacological treatment for children and adolescents who are suffering from depression, although care must be taken to monitor the possible emergence of suicidal ideation.

Controlled, large-scale studies demonstrating the efficacy of antidepressants in the treatment

of youths with major depression are limited to acute SSRI trials. Moreover, it remains to be determined whether children and adolescents respond similarly, since these trials were not adequately powered to determine the relative efficacy of treatment between these age groups.

There are a number of limitations to these acute SSRI treatment trials that limit their generalizability to the pediatric population. Commonly occurring comorbid disorders were often exclusion criteria in these studies. For example, in the study of citalopram treatment for major depression, ADHD was an exclusion criterion. Comorbidity has been shown to affect response rates of SSRI treatment. In a subset analysis of the study by Keller and colleagues (2001), the presence of comorbid ADHD significantly reduced response rates in all of the treatment groups. On the basis of Clinical Global Improvement ratings of very much improved or much improved, the response rates among patients without ADHD were as follows: paroxetine, 71%; imipramine, 64%; and placebo, 59%. For patients with ADHD, response rates were as follows: paroxetine, 25%; imipramine, 31%; and placebo, 13% (Birmaher, McCafferty, Bellew, & Beebe, 2001). Substance abuse was an exclusion criterion in all of the SSRI treatment trials. There was minimal ethnic diversity in the patients included in these trials—i.e., the majority of patients were Caucasian.

Other than the SSRIs, there are no data available to support the efficacy of other classes of antidepressants in treating children and adolescents with major depression. Because children have been shown to have high placebo response rates in depression studies, open studies with other antidepressants provide little information about the efficacy of these agents in youths.

Very little information is known about the optimal treatment duration for a child with major depression. The only controlled data available for children and adolescents are from a study by Emslie et al. (2001), which showed that extending treatment 19 weeks after the end of acute treatment with fluoxetine decreased the relapse rate to 34%, compared to 60% in the placebo group.

There is a paucity of data about augmentation strategies for youths who have an inadequate re sponse to an antidepressant. Lithium augmentation (Ryan, Myer, et al., 1988; Strober, Freeman, Rigali, Schmidt, & Diamond, 1992) and MAOI augmentation (Ryan, Puig-Antich, et al., 1988) to TCAs for depressed adolescents have been reported. However, since TCAs are now rarely used to treat depression in youths, these earlier augmentation studies are less clinically relevant.

There is little known about the long-term safety of antidepressant use in children. The longest duration of safety data available is from a 52-week open-extension study of sertraline following an acute 10-week trial for the treatment of obsessive-compulsive disorder in children and adolescents (Cook et al., 2001).

There is a pressing need to identify effective medication alternatives to the SSRIs for treating depression in youth. It is important that future studies be powered sufficiently to determine efficacy and safety of antidepressants in both child and adolescent populations. Ethnic diversity should be an aim of subject inclusion. Long-term studies of antidepressants are required to evaluate their safety profile in children. This information will enable a risk-benefit analysis of extended antidepressant use.

Maintenance studies are needed to guide optimal medication treatment duration. Strategies for relapse prevention need to be developed. Studies of antidepressants should focus on remission of symptoms rather than treatment response. The role of antidepressant medications in improving cognitive functioning, peer relationships, family harmony, and overall quality of life needs to be assessed.

Predictors of treatment response and remission should be evaluated in pediatric pharmacological studies. Some factors that may influence outcome are age of onset of illness, severity and duration of illness, comorbid disorders, family history of major depression, and current episode of parental major depression.

Medication augmentation strategies and the role of psychotherapy to enhance treatment response require further investigation. The order of treatment selection—i.e., medication, psychotherapy, or combined medication and psychotherapy—should be established, particularly as it relates to depression severity.

Information is needed as to whether early treatment interventions affect the course of the illness or prevents its later occurrence in adulthood. A new area of investigation is treatment for youths at risk for the development of major depression. Clark et al. (2003) found that adolescent offspring of depressed parents who had subsyndromal depressive symptoms benefited more from a group cognitive therapy prevention program than from the usual health maintenance organization care. At 12 months follow-up, cumulative major depression incidence was 9% in the cognitive treatment group and 29% in the usual-care group. It remains to be determined whether pharmacological treatment of youths at risk for depression will reduce the likelihood or prevent the occurrence of major depression.

In summary, a medication treatment algorithm based on empirically derived information in pediatric populations is necessary to provide optimal care to children and adolescents suffering from major depression.

Reviews of controlled studies have historically concluded that the combination of medication and psychotherapy does not yield appreciable benefits above the effects of either medication or psychotherapy alone (Conte, Plutchik, Wild, & Karasu, 1986; Depression Guideline Panel, 1993; Robinson, Powers, Cleveland, & Thyer, 1990). However, the combination of medication and psychotherapy may be especially beneficial for certain subtypes of MDD. Along these lines, Thase et al. (1997) combined the data from six trials involving cognitive therapy, IPT, and/or combined medication and cognitive therapy or IPT for acute-phase treatment of MDD. The results revealed that combined treatment and psychotherapy alone were equally effective for nonsevere, nonrecurrent MDD, but combined treatment was more effective than psychotherapy alone for recurrent or severe MDD.

Particularly striking results for the value of combined treatment were evident in a recent trial examining nefazodone, cognitive-behavioral analysis system of psychotherapy (CBASP), and the combination, as treatments for chronic forms of MDD (Keller et al., 2000). The CBASP is a new psychotherapy, developed specifically for chronic forms of depression, that draws elements from cognitive, behavioral, and interpersonal therapies. Using a problem-solving approach, the treatment teaches patients to examine the consequences of their interpersonal behavior as a means of resolving interpersonal conflicts. In the Keller et al. (2000) study, combined nefazodone and CBASP resulted in significantly greater acute depression–phase treatment response rates (73%) than those with nefazodone alone (48%) and CBASP alone (48%). Although these results for combined CBASP and nefazodone deserve attention, the lack of a placebo control or alternate form of psychotherapy prevents any inferences about whether CBASP is uniquely effective in combination with nefazodone, or whether any other form of psychotherapy would have achieved similar results.

The comparative efficacy of medication, psychotherapy, and the combination of medication and psychotherapy remains to be determined. A NIMH-funded multicenter, randomized trial has just been completed to determine the efficacy of fluoxetine vs. CBT vs. fluoxetine plus CBT vs. placebo in the treatment of adolescents with major depression (Treatment for Adolescents with Depression Study Team, 2003). The preliminary results from the first 12 weeks (N = 378) showed that 71% responded well to combination treatment, compared to 61% who received fluoxetine alone, 43% who received CBT alone, and 35% of those treated with placebo (March et al., 2004). The study also reported that patients became significantly less suicidal regardless of the treatment that they received. For suicide attempts, 4 occurred in the combination treatment group, 2 in the fluoxetine alone, and 1 in CBT alone. There were no completed suicides. It is hoped that with subsequent analyses of this study there will be a better understanding

of the treatments that work best for particular adolescents.

There are no data available about treatment strategies for depressed youth who fail to respond to usual treatment with an SSRI. An NIMH-funded multicenter trial is under way to assess the efficacy of treatments for SSRI-resistant depression in adolescents. In this study, adolescents are randomized to an alternative SSRI, alternative SSRI plus CBT, venlafaxine, or venlafaxine plus CBT.

Several different manualized psychosocial treatments have been applied to the treatment of bipolar disorder in adults; although they are based on different theoretical orientations, they share the goal of diminishing relapse to ultimately improve quality of life. Common areas of treatment focus include increasing treatment compliance, enhancing protective factors (e.g., support, self-care routines), and decreasing risk factors associated with relapse (e.g., stress, substance use).

In adapting existing psychosocial treatments used with bipolar adults for children and adolescents, several considerations should be made. For example, modifications should take into account the developmental level of the patient. Thus, information provided within an age-appropriate context may be more understandable and more widely accepted by the patient and family members; this may include the use of age-appropriate language rather than medical terminology. Psychoeducation conducted against the backdrop of a normal developmental trajectory may help distinguish normal childhood tantrums and adolescent moodiness from bipolar disorder. Given the high rate of comorbidity in pediatric bipolar disorder (Papolos & Papolos, 2002), information about comorbidly existing conditions may be included as part of psychoeducation. Comparative risks and benefits of psychotropic medications used with this population should be included, given that medications commonly used for the treatment of pediatric bipolar disorder have been understudied in randomized, controlled trials and are often used off-label (Ryan, 2002). Psychoeducation may focus on the manner in which early-onset bipolar disorder differs from adult bipolar disorder—childhood bipolar disorder often manifests in less discrete episodes and more frequent mood swings (Papolos & Papolos, 1999). Additionally, the manner in which symptoms manifest themselves may need to be considered within a developmental framework, as children exhibit several affective symptoms differently than adults (Geller et al., 2002). Similarly, the literature has indicated that there may be symptoms of bipolar disorder that are unique to this population (e.g., gory dreams; Papolos & Papolos, 1999). Furthermore, age-specific issues may be targeted, including substance use, suicide prevention, family