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Treatment of Depression and Bipolar Disorder 

Treatment of Depression and Bipolar Disorder

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Treatment of Depression and Bipolar Disorder
DOI:
10.1093/9780195173642.003.0003
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date: 23 June 2017

Although it is clear that adolescent mood disorders exist and lead to significant immediate and lifelong impairment for the child, as shown in Chapter 1, there exists limited treatment research in this special population. This has led clinicians to consult with the adult literature to provide guidance in their treatment approaches. In fact, the adult research studies have provided the template for the present interventions being explored in adolescent treatment studies. To appreciate how the adult literature informs the field of adolescent mood disorder treatments, the current status of the adult literature for both psychosocial and psychopharmacologic treatments will be reviewed. This will be followed by an appraisal of the same treatment areas for adolescents.

PSYCHOSOCIAL TREATMENTS FOR MAJOR DEPRESSIVE DISORDER

Major depressive disorder (MDD) is one of the most common adult psychiatric disorders seen in the community and in outpatient psychiatric settings (Kessler et al., 2003). There is now substantial evidence that MDD can be treated successfully with certain targeted psychotherapies. This literature is briefly reviewed below.

Psychosocial Treatment of Major Depresssion in Adults

The strongest empirical evidence exists for three manual-based psychotherapies for the treatment of MDD—behavior therapy, cognitive therapy, and interpersonal therapy—with less evidence existing for two other forms of psychotherapy—brief dynamic therapy and problem-solving therapy.

Cognitive Therapy

The most widely studied psychotherapy for MDD is cognitive therapy (Beck, Rush, Shaw, & Emery, 1979). This treatment is based on the model that the cognitions (conscious or readily accessible to consciousness) of depressed individuals are negatively biased. This negative bias is evident in negative beliefs about the self, the world, and the future. Such negative cognitions are one factor that plays a role in the initiation and maintenance of depressive symptoms. Cognitive therapy, typically consisting of 16 to 20 sessions over a period of 12 to 16 weeks, involves the application of both behavioral and cognitive techniques. The behavioral techniques serve to help patients engage in activities that give them pleasure, while cognitive techniques are used to help patients recognize negative cognitions and to evaluate the veracity of their beliefs.

Three meta-analyses of studies of cognitive therapy for MDD concluded that it is at least equal and often superior to other forms of treatment, including antidepressant medications (Dobson, 1989; Gaffan, Tsaousis, & Kemp-Wheeler, 1995; Agency for Health Care Policy Research, 1993). However, the comparison of cognitive therapy to medication continues to be controversial. While several studies have supported the finding that cognitive therapy and medication yield similar outcomes (Hollon et al., 1992; Murphy, Simons, Wetzel, & Lustman, 1984), another study (Elkin et al., 1989) failed to demonstrate that cognitive therapy is superior to pill placebo and yielded some evidence that, for more severely depressed patients, medication (imipramine) is superior to cognitive therapy (Elkin et al., 1995). Practice guidelines have recommended medication rather than psychotherapy for more severe depressions (American Psychiatric Association, 2000; Depression Guideline Panel, 1993). However, a direct examination of the comparative effects of cognitive therapy and medication across four studies revealed no evidence of a difference among those with moderate to severe depression (DeRubeis, Gelfand, Tang, & Simons, 1999).

Some further evidence on this issue has emerged from a two-site study by Hollon and DeRubeis (DeRubeis et al., in press) comparing standard cognitive therapy (N = 60), antidepressant medication (Paxil with augmentation by other agents if clinically indicated) N = 120; more patients were randomized to medication because of a subsequent continuation phase in which acute-phase medication responders were randomized to continuation medication or placebo), and placebo (N = 60) as acute treatments for moderate to severe MDD. At week 8, only 25% of placebo patients met criteria for clinical response, compared with 45% for cognitive therapy and 50% for medication (placebo treatment was ended at week 8 for ethical reasons). At week 16 (end of acute treatment), response rates for medication and cognitive therapy were identical (57%) and comparable to response rates from previous studies of cognitive therapy and medication in MDD.

Despite the lack of evidence that cognitive therapy is uniquely efficacious in the treatment of MDD, and some controversy over the comparative effects of medication and cognitive therapy in more severely depressed patients, the overall weight of the evidence is that cognitive therapy is an efficacious acute-phase treatment for MDD.

Behavior Therapy

The predominant behavioral model of MDD treatment is Lewinsohn and MacPhillamy's (1974) approach. In this model, the primary goal is to increase the frequency of pleasant activities in the patient's life. Using a group format for therapy, Shaw (1977) found that behavior therapy was superior to a wait-list control at the end of treatment. The largest study of behavior therapy for MDD found it to be significantly better than psychotherapy (an unstandardized, insight-oriented approach), relaxation therapy, and medication (amitriptyline) (McLean & Hakstian, 1979). In another study of MDD, Jacobson et al. (1996) compared three treatments: behavior therapy (behavioral activation), cognitive therapy with behavioral activation techniques plus techniques designed to address automatic negative thoughts, and cognitive therapy with behavioral activation techniques and automatic thought modification plus the addition of techniques designed to address enduring maladaptive beliefs. At the end of acute-phase treatment, remission rates (Beck Depression Inventory [BDI] score <8, no major depressive disorder) ranged from 56% for the full cognitive therapy package to 46% for behavior therapy, but no significant differences were evident on any measure.

One version of behavior therapy has been developed specifically for couples in which at least one member has MDD. The outcome of behavioral marital therapy for MDD was found to be not different from cognitive therapy when the couple was distressed, but inferior to cognitive therapy when the couple was not distressed (Jacobson, Dobson, Fruzzetti, Schmaling, & Salusky, 1991). Another study that included only distressed couples also found behavioral marital therapy to be equally effective to cognitive therapy, with both therapies being better than wait-list in the treatment of depression in the wife. The behavioral marital therapy, however, improved marital satisfaction more than cognitive therapy did.

As with cognitive therapy, there appears to be evidence that behavior therapy is an efficacious, but not uniquely effective, acute treatment for MDD.

Interpersonal Therapy for Depression

Klerman & Weissman (1989) interpersonal psychotherapy (IPT) for depression assumes that although depression is caused by a number of factors (genetic, biological, social) interacting in complex ways, it is usually triggered by problems in four interpersonal domains: role transition, grief, interpersonal deficits, and interpersonal disputes. In IPT, the interpersonal problem that triggered the current depressive episode is addressed and the person is helped to build communication and interaction skills to resolve it. The acute phase of IPT typically lasts for 16–20 sessions.

Several studies have supported the efficacy of IPT for acute treatment of MDD in adults seeking treatment in psychiatric and primary care settings. In one study, the efficacy of IPT was similar to that of amitriptyline, and both were superior to a minimal contact control in outpatients (DiMascio et al., 1979). In the National Institute of Mental Health (NIMH) Treatment of Depression Collaborative Research Program, results with IPT were not different from those with either imipramine or cognitive therapy. However, among more severely depressed patients (with a Hamilton Depression Rating scale [HAM-D] >20), imipramine and IPT were superior to placebo whereas CBT was not (Elkin et al., 1989). In a primary care setting, IPT was found to be bet-ter than usual care, and results from IPT were not different from those with nortriptyline at an 8-month assessment of depressed medical outpatients (Schulberg et al., 1996). Interpersonal therapy has also been tested with depressed HIV+ patients and was compared with imipramine, cognitive behavior therapy (CBT), and supportive psychotherapy. The IPT and imipramine showed similar efficacy and were both superior to CBT and to a lesser extent to supportive psychotherapy (Markowitz, Svartberg, & Swartz, 1998).

In the area of geriatric depression, IPT showed efficacy comparable to that of nortriptyline, but both failed to show significant difference from placebo in a 6-week trial (Schneider, Cooper, Staples, & Sloane, 1987). Interpersonal therapy has also been used to treat antepartum and postpartum depression. Treatment with IPT was superior to a parenting education program for women with antepartum depression in all measures of mood at termination (Spinelli & Endicott, 2003). Also, for symptomatic relief and social adjustment, IPT was superior to a wait-list control for women suffering from postpartum depression (O'Hara, Stuart, Gorman, & Wenzel, 2000). In a different study, IPT for postpartum depression was found to be as effective as a mother–infant therapy group and superior to a wait list control (Clark, Vittengl, Kraft, & Jarrett, 2003). Finally, in the only randomized, clinical trial of a Western psychotherapy adapted for Africa, group IPT was better than treatment as usual for depressed people in rural Uganda for depressive symptomatology and social functioning (Bolton et al., 2003).

Brief Dynamic Therapy

Psychodynamic psychotherapy comes in many forms. Brief versions of this treatment typically have a clear interpersonal or intrapsychic focus and use therapist interpretations as the key intervention designed to increase self-understanding about interpersonal or intrapsychic issues that might be contributing to or maintaining depressive symptoms. Manual-based, brief psychodynamic psychotherapy has been evaluated in the treatment of MDD in several studies. In two studies, an interpersonally oriented psychodynamic therapy (somewhat similar to IPT) was found to yield comparable outcomes to those with CBT (Barkham, Hardy, & Startup, 1994; Shapiro et al., 1994). Similarly, in an elderly sample, brief psychodynamic therapy produced equal outcomes to those with behavioral and cognitive therapies (Thompson, Gallagher, & Breckenridge, 1987), although an earlier study using inexperienced therapists showed an advantage of CBT over psychodynamic therapy for depressed elders (Gallagher & Thompson, 1982). A study of clinically depressed elderly caregivers of frail, elderly relatives also found comparable efficacy for individual brief dynamic therapy and CBT (Gallagher-Thompson & Steffen, 1994). However, the duration of caregiving was an important factor, with brief dynamic therapy showing relatively better efficacy among the depressed elders who had been caregivers for a relatively briefer time period (≤3.5 years), whereas the CBT was relatively more efficacious with those that had been caregivers for longer than 3.5 years.

Although brief dynamic therapy appears to be a promising possibility for the acute treatment of MDD, more data on comparisons to credible control groups are needed.

Problem-Solving Therapy

Problem-solving therapy for MDD (Nezu, 1986) has been examined in several controlled studies. Nezu (1986) and Nezu and Perri (1989) found problem-solving treatment to be superior to a wait-list control group, using samples that were primarily female community volunteers. In each of these studies, the full version of problem-solving therapy was found to be better than a version that had some but not all of the key elements of the treatment. Problem-solving therapy has also been found to be as efficacious as routine medication treatment by general practitioners in one study (Catalan et al., 1991) and equal to amitriptyline but better than placebo in another (Mynors-Wallis, Gath, Lloyd-Thomas, & Tomlinson, 1995). In an elderly sample, Arean and colleagues (1993) found problem-solving therapy to yield roughly equivalent results to those with reminiscence therapy, but better results than those with wait-list.

Problem-solving therapy also appears to be promising for the acute treatment of MDD. Additional larger studies are needed, as are comparisons to other standard psychotherapies for MDD, with samples recruited in psychiatric settings.

Prevention of Relapse and Recurrence

Studies that use naturalistic follow-up assessments of patients who have received a short-term course of treatment have suggested that cognitive therapy reduces relapse relative to discontinued medication (Blackburn, Eunson, & Bishop, 1986; Evans et al., 1992; Kovacs, Rush, Beck, & Hollon, 1981; Simons, Murphy, Levine, & Wetzel, 1986). In addition, for patients with residual depressive symptoms following pharmacotherapy, cognitive therapy has been found to reduce recurrence rates relative to maintenance medication only (Paykel et al., 1999) and treatment as usual (Teasdale et al., 2000). Several studies have examined continuation or maintenance psychotherapy for MDD patients who have achieved a clinical response or remission of symptoms following acute-phase treatment. In patients with recurrent MDD, continuation cognitive therapy has been found to reduce relapse relative to short-term cognitive therapy without continuation treatment (Jarrett et al., 2001). An earlier study found that both continuation-phase cognitive therapy alone or combined medication and continuation-phase cognitive therapy produced lower relapse rates than those with medication only (Blackburn et al., 1986). However, a subsequent study found that maintenance medication and maintenance cognitive therapy yielded similar prophylactic effects (Blackburn & Moore, 1997). Similarly, in patients treated to remission with fluoxetine (20 mg), Perlis et al. (2002) found that continuation treatment (28 weeks) with cognitive therapy plus fluoxetine (40 mg) yielded similar relapse rates to those with continuation treatment with fluoxetine (40 mg) alone.

Because residual symptoms of depression after successful treatment predicts the relapse or recurrence of MDD, research has examined the role of cognitive therapy in the treatment of such residual symptoms. Fava, Grandi, Zielezny, Rafanelli, and Canestrari, (1996) compared cognitive therapy targeting residual symptoms with clinical management among patients who were successfully treated with antidepressant medications (in both treatments medications were gradually tapered and discontinued). Cognitive therapy resulted in substantially lower relapse rates than those after clinical management (Fava et al., 1996) over the course of a 4-year follow-up, and there were fewer depressive episodes at a 6-year follow-up assessment (Fava, Rafanelli, Grandi, Conti, & Belluardo, 1998).

In one large study of recurrent MDD maintenance, IPT (alone) was found to be inferior to medication and to medication plus IPT, but better than placebo (Frank et al., 1990). In a geriatric sample, MDD patients treated to remission with IPT plus nortrityline fared relatively poorer in maintenance IPT plus placebo treatment compared to IPT plus nortrityline (Reynolds et al., 1999). Maintenance IPT plus placebo, however, was superior to placebo in preventing recurrences of depressive episodes (Reynolds et al., 1999). Thus, overall, the evidence is stronger for cognitive therapy than for IPT as stand-alone continuation or maintenance treatment to prevent relapse or recurrences.

Conclusion

A relatively large and growing body of literature has substantiated the efficacy of targeted psychotherapies in the treatment of MDD in adults. Research evidence from controlled clinical trials in particular supports the efficacy of cognitive therapy, IPT, and behavioral therapy for MDD. Problem-solving therapy and certain forms of brief dynamic therapy appear promising, but further research is needed. Acute-phase cognitive therapy reduces the risk of relapse or recurrence of MDD, and continuation treatment reduces such risks further. Cognitive therapy and IPT generally have been found to be equally efficacious to medications, even with more severely depressed patients. However, a recent study suggests that chronic depression might best be treated with the combination of medication and psychotherapy.

Although many of the psychotherapeutic interventions studied in adults have been adapted to the treatment of adolescents, including IPT, cognitive therapy, and behavioral therapy, the adult literature is characterized by a much broader set of studies than in the child and adolescent MDD treatment literature. Even with this relatively large number of MDD studies conducted to date, numerous questions remain about psychotherapy for MDD in adults. Despite the success of certain psychotherapies in the treatment of adult MDD, it may be risky to assume such treatments are likely to be the best psychosocial treatments for childhood and adolescent MDD. The biological, developmental, cognitive, and experiential differences between children and adolescents and adults raise the question of whether wholly different intervention strategies may be most effective with children and adolescents (Mueller & Orvaschel, 1997). For example, psychodynamic psychotherapy, especially variants that rely heavily on symbolic interpretations, may not be appropriate for younger individuals who lack the cognitive maturity to understand such interventions. Treatments that have been little studied in adults, such as family therapy, may have much greater relevance among children and adolescents. New treatments that incorporate developmental issues may be needed. Although it may be hazardous to export treatment modalities developed for adults to children and adolescents, research on children and adolescents can benefit greatly from the methodological developments in the treatment of MDD in adults, particularly the study of prevention of relapse or recurrence. Ongoing dialogue and interchange among investigators in the adult and child areas is likely to facilitate the more rapid development of literature on treatment of children with MDD.

Psychosocial Treatment of Adolescent Major Depression

In this overview of psychosocial treatments for early-onset depression, we review the randomized clinical trials in children and adolescents with depressive disorders and symptomatology. The vast majority of the intervention trials have used CBT techniques. In addition, we review the handful of studies that have used interpersonal therapy and family therapy. Finally, given the frequent interrelationship between depression and suicidal behavior, we review the published clinical trials for the treatment of adolescent suicide attempters.

Cognitive Behavior Therapy of Youth Depression

In this section, we review controlled clinical trials of treating child and adolescent depressive disorders with CBT. The cognitive-behavioral approaches for youth depression focus on identifying and modifying negative thought patterns and improving disturbed behavioral self-and social-regulation skills thought to underlie the etiology of depression. In youth depression treatment, these foci have been addressed through the application of cognitive and behavioral techniques such as (1) mood monitoring; (2) cognitive restructuring; (3) behavioral activation, pleasant activity scheduling, and goal-setting strategies; (4) relaxation and stress management; (5) social skills and conflict resolution training; and (6) training in general problem-solving skills (Kaslow & Thompson, 1998; Kazdin & Weisz, 1998). Although the total number of youth depression treatment studies is relatively small, and different investigators have used varying combinations of these CBT techniques, preliminary evidence suggests that overall, CBT packages have beneficial effects on depression symptoms in youth. In two more recent meta-analyses of treatment of adolescent depression, mean effect sizes for comparisons of CBT to controls of CBT were estimated to be quite large, 1.02 and 1.27 post-treatment, respectively (Lewinsohn & Clarke, 1999; Reinecke, Ryan & DuBois, 1998).

To date, there have been 13 randomized studies of CBT with depressed youth—three in clinically referred samples, three in diagnosed community samples, and seven in symptomatic but not diagnosed community samples. Four studies were conducted in depressed children, and the remainder in adolescents. Most studies relied on samples of depressed youth recruited from school or community settings who may have mild to moderate symptoms of depression, as assessed by dimensional screening instruments; these studies are discussed only briefly here. Within the past 5 years, however, several inves tigative teams have published controlled trials in youth who meet diagnostic criteria for depression and are often clinically referred. We will begin our discussion with these more recent and well-developed treatment programs, and then briefly review historical work with subclinical samples of community youth. A summary of studies on clinic samples is shown in Table 2.1.

Table 2.1 Results of Cognitive Behavior Therapy Conducted in Clinical Samples (% Improved)

Study

N

CBT/IPT

Family

Supportive

Rate of Relapse

Wood et al., 1996a

53

54%

50%

Vostanis et al., 1996a

63

87%

75%

46%

Brent et al., 1997a

107

60%

38%

39%

30%

Mufsont et al., 1994b

48

75%

46%

CBT, cognitive-behavioral therapy; IPT, interpersonal therapy.

a There was no major depression and a significant reduction in symptoms; CBT was an active comparator.

b Interpersonal therapy was used.

Wood, Harrington, and Moore (1996) compared the impact of a five-to eight-session CBT intervention with a comparable dose of relaxation training in the treatment of early-to middle-adolescent outpatients with depressive disorders, with 54% of the CBT group and 26% of the relaxation group remitting by the end of treatment. Similar results were obtained on self-report measures of depressive symptoms, self-esteem, and general psychosocial adjustment. Upon 6-month follow-up, the groups had converged, because of continued improvement in the relaxation group and symptomatic relapse in the CBT group. Younger age of diagnosis and higher level of functioning at intake were associated with better outcome (Jayson, Wood, Kroll, Fraser, Harrington, 1998). The addition of a median of six monthly booster CBT sessions after acute treatment resulted in a much lower relapse rate than acute treatment alone (20% vs. 50%; Kroll, Harrington, Jayson, Fraser, & Gowers, 1996).

Using a similar CBT treatment package to that of Wood et al. (1996), Vostanis, Feehan, Grattau, & Bickerton (1996) randomized depressed outpatients to either individual CBT or an attention-placebo condition termed nonfocused intervention (NFI). CBT and NFI were equivalent with regard to the proportion not meeting depressive criteria at the end of treatment (87% vs. 75%) and at 9-month follow-up (71% vs. 75%) (Vostanis et al., 1996a). However, 46% of patients across conditions reported experiencing a “depressive episode” at some point during the follow-up period (Vostanis et al., 1996). On average, patients in both the CBT and NFI conditions attended six sessions with a therapist, but the range of sessions was from two to nine, occurring over a 1-to 5-month period.

Brent and colleagues (1997) tested CBT, derived from Beck et al. (1979), against systemic behavior family therapy (SBFT) and a nondirective supportive therapy (NST), using a primarily clinically referred sample (2 3 vs. 1 3 from newspaper advertisements) of depressed adolescents. In comparison to the treatment used by Wood et al. (1996) and Vostanis et al. (1996), these treatments were much longer and more regular (12 to 16 weekly sessions).

At posttreatment assessment, significantly fewer of those subjects receiving CBT (17%) than NST (42%) continued to have diagnosable MDD. Remission, as defined by the absence of MDD and at least three consecutive BDI scores < 9, was more common in the CBT cell (60%) than in either SBFT (38%) or NST (39%). Reductions in suicidality and improvements in general psychosocial adjustment were not different across groups. Cognitive behavior therapy resulted in greater change in cognitive distortions than did either SBFT or NST, although changes in depressive symptoms were not mediated by changes in cognitive style (Kolko, Brent, Baugher, Bridge, & Birmaher, 2000). Across treatment cells, poorer response was predicted by greater cognitive distortion, more severe depression at intake, and referral to an advertisement rather than by clinical referral. Removal from the study and dropout were predicted by double depression (depression comorbid with dysthymia) and greater hopelessness, respectively (Brent et al., 1998).

In the Brent et al. trial (1998), comorbid anxiety was associated with more robust response to CBT, and maternal depressive symptoms were associated with a poorer response to CBT (Fig. 2.1). At posttreatment, CBT was superior to NST and SBFT, even in the presence of multiple adverse predictors. This suggests that CBT, in addition to being efficacious under controlled conditions, may also be efficacious for use in real-world service settings with clinically complex cases (Fig. 2.2). Lifetime suicidality was associated with a poorer response to supportive treatment, where CBT appeared robust (Barbe, Bridge, Birmaher, Kolko, & Brent, 2004b). A history of sexual abuse, however, was associated with a poorer response to CBT (Barbe, Bridge, Birmaher, Kolko, & Brent, 2004a). Subjects who entered the study via an advertisement fared much better than clinically referred subjects despite having nearly identifiable demographic, clinical, and family characteristics, and were 12 times less likely to have a recurrence of their depression on follow-up (Birmaher et al., 2000; Brent et al., 1998). The differential outcome of those who entered via an advertisement was in part mediated by hopelessness (Brent et al., 1998). At 2-year follow-up, differences between treatment groups on the presence of current MDD were not significant, although the descriptive data again favor CBT (6%) over SBFT (23%) and NST (26%). Recurrence of depression over the 2-year follow-up period was predicted by greater severity of depression symptoms at intake, higher levels of parent–child conflict, and a lifetime history of sexual abuse (Birmaher et al., 2000).

Figure 2.1 Failure to achieve remission as a function of self-reported maternal depression according to Beck Depression Inventory [data from D.A. Brent, D. Kolko, B. Birnaher, M. Bauger, J. Bridge, C. Roth, et al. (1988). Predictors of treatment efficacy in a clinical trial of three psychosocial treatments for adolescent depression. Journal of the American Academy of Child and Adolescent Psychiatry, 37, 906–914, used with permission].

Figure 2.1 Failure to achieve remission as a function of self-reported maternal depression according to Beck Depression Inventory [data from D.A. Brent, D. Kolko, B. Birnaher, M. Bauger, J. Bridge, C. Roth, et al. (1988). Predictors of treatment efficacy in a clinical trial of three psychosocial treatments for adolescent depression. Journal of the American Academy of Child and Adolescent Psychiatry, 37, 906–914, used with permission].

Figure 2.2 Depression at the end of treatment as a function of the number of adverse conditions, including comorbid anxiety, clinical source of referral, high cognitive distortion, and hopelessness [data from D.A. Brent, D. Kolko, B. Birnaher, M. Bauger, J. Bridge, C. Roth, et al. (1988). Predictors of treatment efficacy in a clinical trial of three psychosocial treatments for adolescent depression. Journal of the American Academy of Child and Adolescent Psychiatry, 37, 906–914, used with permission].

Figure 2.2 Depression at the end of treatment as a function of the number of adverse conditions, including comorbid anxiety, clinical source of referral, high cognitive distortion, and hopelessness [data from D.A. Brent, D. Kolko, B. Birnaher, M. Bauger, J. Bridge, C. Roth, et al. (1988). Predictors of treatment efficacy in a clinical trial of three psychosocial treatments for adolescent depression. Journal of the American Academy of Child and Adolescent Psychiatry, 37, 906–914, used with permission].

Table 2.2 shows a summary of the studies per formed with community samples. The following set of studies used community samples of youth with diagnostic depression recruited either from schools or via advertisements.

Table 2.2 Results of Cognitive Behavior Therapy Conducted in Diagnosed Samples (% Improved within Samples)

Study

N

CBT

IPT

WLC

Lewinsohn et al., 1990a

59

43%

5%

Clarke et al., 1999a

123

65%

48%

Rossello & Bernal, 1999b

71

59%

82%

CBT, cognitive-behavioral therapy; IPT, interpersonal therapy; WLC, wait-list control.

a There was no major depression.

b A “significant reduction in symptoms” was reported.

Lewinsohn, Clarke, Hops, and Andrews (1990) randomized 59 participants to either Coping with Depression–Adolescent version (CWD-A) alone, CWD-A plus the parent group (consisting of 7 weekly sessions), or a wait-list control. The CWD-A consisted of 14 two-hour psychoeducationally oriented group sessions delivered over 7 weeks. The focus of CWD-A is on increasing social skills, pleasant events and activities, and problem-solving and conflict resolution skills, while reducing anxious and depressive cognitions. At the conclusion of treatment, 43% of the adolescent-only group and 48% of the adolescent-plus-parent group no longer met diagnostic criteria, compared to only 5% of the wait-list control subjects. Significantly decreased scores on self-report depression measures were also obtained for both treatment groups relative to the wait-list control group. Treatment gains persisted at 1-, 6-, 12-, and 24-month follow-up. The adolescent-plus-parent group did not result in better outcomes than the adolescent-only condition. Poor outcome was associated with greater depressive symptomatology, comorbid anxiety symptoms, and greater cognitive distortions at intake (Clarke, Hops, Lewinsohn, Andrew, & Williams, 1992).

Clarke, Lewinsohn, Rohde, Hops, and Seeley (1999) replicated these results, with 65%, 69%, and 48% of subjects in the adolescent-only, adolescent-plus-parent, and wait-list control conditions, respectively, no longer meeting diagnostic criteria for MDD or dysthymia posttreatment. In this trial, there was a re-randomization to a one-to two-session booster condition that did not reduce the rate of depression recurrence for those who had remitted by the end of treatment. However, for patients who had not yet recovered from depression at the end of the acute treatment phase, booster sessions did accelerate their rate of recovery. Across both studies assessing the effects of CWD-A with diagnosed samples, a positive treatment response was predicted by a less severe initial depression, higher initial engagement in and enjoyment of pleasant activities, and fewer irrational thoughts (Clarke et al., 1992; Rohde, Clarke, Lewinsohn, Seeley, & Kaufman, 2001).

Clarke et al. (2002) examined the efficacy of group CBT for depressed adolescents whose parents were depressed. The sample was obtained through sampling the offspring of depressed parents. Subjects were assigned to either a 16-session group CBT program plus treatment as usual (N = 41) or treatment as usual alone (N = 47). Assessments were conducted at intake, after treatment, and at 12-and 24-month follow-up. According to intent-to-treat analyses, there was no advantage of group CBT over treatment as usual on rate of depressive disorders, depressive symptoms, nondepressive symptoms, or functional outcomes at the end of treatment or over the follow-up period. These findings are consistent with those of Brent et al. (1998), who also found that CBT, delivered individually, was no more effective than either family or supportive therapy in the face of significant maternal depressive symptoms.

Rohde et al. (2001) examined the impact of comorbidity on treatment outcome in an aggregated sample of depressed adolescents treated in the Lewinsohn et al. (1990) and Clarke et al. (1999) samples. Of 151 subjects enrolled in these trials, 40% had one or more comorbid diagnoses. Those with comorbid anxiety disorders showed a greater decrease in depression scores at posttreatment, similar to Brent et al. (1998). Lifetime substance abuse was associated with a slower time to recovery. Subjects with attention-deficit hyperactivity disorder (ADHD) and disruptive behavior disorders were more likely to experience a depressive recurrence. In general, the authors concluded that the effects of CBT were robust to the impact of comorbidity.

Symptomatic Community Samples

There are several community-based studies of symptomatic children and adolescents in which CBT is compared with other active treatments (e.g., relaxation treatment, self-control, modeling) as well as a wait-list control (Butler, Meizitis, & Friedman, 1980; Kahn, Kehle, Jenson, & Clark, 1990; Liddle & Spence, 1990; Reynolds & Coats, 1986; Stark, Reynolds, & Kaslow, 1987; Weisz, Thurber, Sweeney, Proffitt, & LeGagnoux, 1997). In general, all active interventions are superior to wait-list control conditions and the impact is sustained on follow-up, but with few exceptions, CBT showed no differential impact compared to the other active interventions. These studies are important because they are some of the only CBT studies of depressive symptoms in children, are usually delivered in a group format, and, therefore, may guide future efforts to prevent early-onset depression.

Prevention

Clarke and colleagues (1995) tested the efficacy of an adaptation of CWD-A, termed “coping with stress” (CWS), in preventing diagnosable depression in adolescents with subsyndromal depressive symptoms, but without a diagnos-able depressive disorder. One hundred fifty high school students who scored high on the Center for Epidemiological Studies–Depression scale (CES-D) but failed to meet diagnostic criteria for a current depressive disorder were randomly assigned to the 15-session CWS or “usual care.” At 12 months postintervention, fewer cases of depressive disorder (15%) had developed in the experimental group than in the control group (26%). Clarke et al. (2001) conducted a randomized clinical trial comparing the efficacy of group CBT plus treatment as usual versus treatment as usual alone for the adolescent offspring of depressed parents deemed to be at risk for the development of a depressive disorder (e.g., presence of subsyndromal symptoms of depression and/or a history of past mood disorder). Subjects could not meet criteria for a current mood disorder. Ninety-four adolescent subjects were randomized to the experimental treatment (N = 45) and to usual care (N = 49). At 12-month follow-up, the cumulative rate of incident major depression was much lower in the experimental condition than that with treatment as usual (9.3% vs. 28.8%). The odds of new-onset depression was nearly six times higher in the control than in the experimental group, after adjusting for gender, age, past history of depression, and intake self-reported symptoms of depression (adjusted odds ratio [OR] = 5.6, 95% confidence interval [CI] = 1.6–20.4). Significant treatment by time interactions favoring the experimental treatment were found for self-reported depression and global functioning. On average, those exposed to the experimental group experienced 33 fewer depressed days than those in the treatment-as-usual condition.

One study examined the effect of CBT “bibliotherapy,” or therapy involving pertinent reading materials, on adolescents with mild to moderate depression who were symptomatic volunteers (Ackerson, Scogin, McKendree-Smith, & Lyman, 1998). Twenty-two subjects were assigned to either reading the Feeling Good book by Burns (1980) or to a 4-week delayed-treatment condition, after which they received the bibliotherapy condition. Significant treatment by time interactions, favoring the experimental condition, were found for interview-, parent-and self-rated depression, and dysfunctional attitudes. Gains for the experimental condition were maintained at 1-month follow-up, and there was even evidence of continued improvement. Approximately 60% (59 to 64%) of subjects experienced a clinically significant improvement in their symptomatology, with evidence of sustained and even continued improvement on follow-up. Partial support was found for mediation of changes in depressive symptomatology by changes in dysfunctional thinking.

Interpersonal Psychotherapy for Adolescent Depression

Although CBT interventions have received the most attention from researchers of youth de pression, there are a number of clinical trials that focus on changing the interpersonal aspects of depression. Interpersonal psychotherapy for depressed adolescents, family therapy, and social skills training have all been investigated in at least one controlled trial (Mufson et al., 1994; Diamond et al., 2002; Fine, Forth, & Gilbert, 1991). All three treatments target behavioral and environmental processes, although the social domain targeted by the interventions differs, as do the techniques used to affect change.

Interpersonal psychotherapy for adolescents (IPT-A), an adaption of IPT, is a time-limited, focused psychotherapy that addresses common adolescent developmental issues that are closely related to depression: separation from parents, authority and autonomy issues in the parent–teen relationship, development of dyadic interpersonal relationships, peer pressure, loss, and issues related to single-parent families. Interpersonal therapy has been adapted and tested for depressed adolescents (Mufson et al., 1994; Mufson, Weissman, Moreau, & Garfinkel, 1999). In a controlled, 12-week, clinical trial of IPT-A, 48 adolescents (12–18 years old) with MDD were randomly assigned to either weekly IPT-A or biweekly to monthly 30-minute sessions of clini-cal monitoring. The sample was largely Hispanic and female. Thirty-two of the 48 patients completed the protocol (21 IPT-A-assigned patients and 11 patients in the control group). At termination, a much lower proportion of those in IPT-A still met criteria for major depression (12.5% vs. 41.6%). As measured by the Clinical Global Improvement scale, 95.5% of those treated with IPT-A were rated as significantly better than at intake, compared to 61.5% of those treated with clinical management. Moreover, only 4.5% of those treated with IPT-A were rated as significantly worse, compared to 23.1% of those assigned to clinical monitoring. Pa-tients who received IPT-A reported a significant decrease in depressive symptoms and greater improvement in overall social functioning, functioning with friends, and problem-solving skills. In the intent-to-treat sample, 18 (75%) of 24 patients who received IPT-A compared with 11 patients (46%) in the control condition met recovery criterion (HAM-D ≤6) at Week 12. These preliminary findings support the feasibility, acceptability, and efficacy of 12 weeks of IPT-A in acutely depressed adolescents in reducing depressive symptoms and improving social functioning and interpersonal problem-solving skills.

Mufson and colleagues assessed the effectiveness of IPT-A in school-based mental health clinics in New York City: they randomized 63 depressed adolescents referred for a mental health intake visit to IPT-A or treatment as usual, both performed by the clinic staff. The adolescents had either MDD, dysthymia, depressive disorder not otherwise specified (NOS), or adjustment disorder with a depressed mood. At termination, the adolescents in the IPT-A treatment experienced significantly higher symptomatic relief than the treatment-as-usual group (Mufson et al., 2004)

Rossello and Bernal (1999) compared the efficacy of a 12-week, individually administered CBT program to a similar dose of IPT and wait-list control in adolescents with diagnosed MDD and/or dysthymia referred by school personnel. Both active interventions were adapted to be culturally appropriate for use with Puerto Rican youth. Attendance problems occurred in both treatments, as only 68% of IPT cases and 52% of CBT cases completed over seven treatment sessions. To assess outcome, a clinical cutoff was selected on the Children's Depression Inventory (CDI) that was approximately 3 points lower than the mean intake CDI score for the sample. As measured by these criteria for clinically significant change (Jacobson and Truax, 1991), 59% of adolescents in the CBT condition and 82% of IPT cases achieved clinically significant improvement in depression symptoms by posttreatment; data were not provided for the wait-list control condition. Using an unspecified normative cutoff point for the CDI, the authors indicated that 56% of the IPT cases, 48% of the CBT cases, and 61% of wait-list cases were “severely depressed” at intake. At posttreatment, these percentages were 11%, 24%, and 34%, respectively, and 17% and 18% at 3-month follow-up (for IPT and CBT, respectively). Although this investigation has several methodological difficulties (e.g., substantial attrition and no intent-to-treat analyses conducted), these results provide some of the first information on the efficacy of CBT for depressed Latino youth and the only extant comparison of CBT and IPT for adolescent depression.

Attachment-Based Family Therapy

Diamond, Reis, Diamond, Siqueland, and Isaacs (2002) conducted a randomized clinical trial comparing Attachment-based family therapy (ABFT) with a wait-list control in 32 clinical referred adolescents meeting DSM-III-R criteria for major depression in a largely (69%) African-American, poor, inner-city sample. On average, subjects received eight sessions of ABFT, which focuses on strengthening family bonds, reduc-ing conflict, improving trust, improving cross-generational empathy, and, subsequently, improving affect regulation, communication, and promotion of competence. Those in the wait-list condition received 15 minutes of weekly telephone monitoring of their clinical condition as well as a face-to-face assessment at Week 6, at which point those still meeting criteria for major depression were offered ABFT. The treatment data from these latter cases were not included in the primary outcome analyses. At posttreatment, 81% of those treated with ABFT no longer met criteria for depression, compared to 47% in the wait-list control group. A significantly greater number of those assigned to ABFT reported a BDI <9 (62% vs. 19%). A significant treatment-by-time interaction favoring ABFT was found for interview-rated depression, self-reported anxiety, and child-reported parent–child conflict, with nonsignificant trends favor-ing ABFT for attachment to mother, suicidal ideation, and hopelessness.

One limitation of the study was that ABFT was 12 weeks in duration whereas the control treatment lasted 6 weeks, so that it is hard to differentiate time versus treatment effects. Therefore, analyses were conducted focusing on the first 6 weeks. While most of these analyses were not statistically significant, a significantly greater proportion of those treated with ABFT showed a BDI <9 by 6 weeks (56% vs. 19%). Fifteen of those treated with ABFT were followed up for 6 months after the end of treatment and only 13% had a depressive relapse. These results suggest that ABFT may be a promising treatment for adolescent major depression, and that it is efficacious in a poor, African-American population. It is important to note, however, that in the one clinical trial comparing CBT with family therapy for depressed adolescents (Brent et al., 1997), family therapy produced significantly worse outcomes than CBT. The model of family therapy in the Brent et al. (1997) study focused on problem solving and communication, but it did not address attachment issues as in the study of Diamond et al. (2002).

Social Skills Training

Fine, Forth, Gilbert, and Haley (1991) compared two forms of short-term group therapy, either social skills training or therapeutic support, for depressed adolescents in a randomized clinical trial. Subjects in the therapeutic support group showed significantly greater reductions in clinical depression and significant increases in self-concept, although there were no group differences by 9-month follow-up. Subjects in the support group maintained their gains, and those who attended the social skills group caught up.

Suicide Attempters

A high proportion of adolescent suicide attempters have mood disorders, and suicide attempts are a serious complication of mood disorder (Lewinsohn, Rohde, & Seeley, 1996). Therefore, we examine the three randomized clinical trials of adolescent suicide attempters that have been conducted thus far.

Rotheram-Borus et al. (1996) compared the efficacy of a cognitive behavior family therapy plus an emergency room intervention with that of family CBT alone. The family CBT plus emergency room intervention resulted in greater compliance with treatment. No baseline characteristics were reported, but end point analyses on maternal depression and general psychopathology, patient ideation, and parent-reported family interaction favored the combined intervention.

Harrington et al. (1998) compared a four-session, home-based family problem-solving intervention with treatment as usual for 162 adolescents who had taken an overdose. Subjects were assessed at intake and at 2 and 6 months after intake. There were no differences between the two groups with respect to suicidal ideation, hopelessness, or family variables. A post-hoc subgroup analysis showed that nondepressed subjects who received the family intervention (vs. treatment as usual) reported lower suicidal ideation. However, the authors note that the depressed subgroup had much more severe ideation, so that the intervention was not effective in the more severely suicidal group.

Wood, Trainor, Rothwell, Moore, and Harrington (2001) randomized 63 adolescents who, prior to randomization, had made at least two suicide attempts within a year to either a six-session group intervention or to treatment as usual. The group treatment consisted of a combination of interpersonal skills training, anger management, problem solving, addressing of depression and hopelessness, and conflict resolution. In intent-to-treat analyses, those who received the experimental treatment were 6.3 times less likely to have made two or more attempts over an average of 29 weeks of follow-up (6% vs. 31%). Subjects in the experimental treatment were 60% less likely to make at least one attempt, although this effect was not statistically significant. They were also less likely to use routine care, had better school attendance, and had a lower rate of disruptive disorders than those who received treatment as usual. However, the two treatments did not differ in their effects on depression or global outcome.

Conclusion

Cognitive behavior therapy for youth depression appears to be more efficacious than no treatment, wait-list control, or attention placebo controls. There is also evidence in clinically referred samples that CBT can produce better results than alternate active treatments (Brent et al., 1997; Wood et al., 1996). Cognitive behavior therapy may also be “robust” in the face of many of the adverse clinical predictors of poor outcome (e.g., comorbidity) (Brent et al., 1998; Rohde et al., 2001). A recently completed benchmarking study has also suggested that much of the advantage of CBT found in clinical trials can be sustained in outpatient clinic settings (Weersing, Iyengar, & Birmaher, submitted). Efficacy also appears to be robust to format (group vs. individual), emphasis (behavioral vs. cognitive), and dose (5 to 16 sessions).

While these results are promising, many patients continue to have clinically significant levels of depression following CBT, and near majorities of patients experience at least one recurrence of depression within 2 years of treatment termination. It is perhaps not surprising that many patients (estimates range from 29% to 48%) seek additional services following acute CBT (Brent, Kolko, Birmaher, Baugher, & Bridge, 1999).

These studies provide some clues about the improvement of depression when CBT is used. Treatment with CBT fared more poorly in the face of maternal depressive symptoms, greater severity, and double depression; family discord also retarded recovery and predicted recurrence. Therefore, additional interventions that target maternal depression and family discord may well augment outcome. Moreover, particularly refractory and chronic conditions, such as double depression, may respond better to combinations of medication and CBT than to either as monotherapy alone, as suggested by comparable data in adults with chronic depression (Keller et al., 2000). Further work on improving outcome in patients with these poor prognostic risk factors needs to be conducted. There is little in the extant literature about the transportability of CBT to community settings. We do have evidence from benchmarking studies that CBT appears to be superior to community treatment and that it can yield similar results in clinical trials and in open treatment, under less controlled conditions (Weersing et al., 2003; Weisz & Weersing, 2002). We currently have very little information on the treatment of serious depression in preadolescents, and it is unclear how CBT may need to be adapted to take into account the more concrete cognitive style and greater dependence on parents seen in most preadolescent (as compared to adolescent) patients (Weisz & Weersing, 1999).

Much less is known about the efficacy of other forms of psychotherapy, such as interpersonal or family therapy. Interpersonal therapy for adolescents appears to be a promising treat ment for adolescent depression and has been well accepted and efficacious in Latino populations. The one direct comparison of CBT and IPT is difficult to interpret, but IPT appeared at least as efficacious as CBT and with respect to some measures, more so (Rossello & Bernal, 1999). With additional studies of IPT it will be important to understand which factors predict good and poor response.

Despite numerous studies implicating family factors in adolescent depression, there have only been two studies that examine the efficacy of family therapy in child or adolescent depression. A skills-based family treatment did not appear to be as efficacious as CBT, whereas ABFT that focused on repairing and strengthening emotional bonds achieved results that were as good as those either with CBT or IPT-A (Brent et al., 1997; Diamond et al., 2002). This treatment mode clearly requires further study.

Relatively few studies have examined the impact of psychosocial intervention on the prevention of recurrent suicidal behavior, in part because those teens at higher risk for recurrence of suicide attempt are usually excluded from treatment trials for adolescent depression. The few studies that have been conducted are not definitive but suggest some utility for family cognitive behavior approaches and skills training. This vulnerable population deserves further scrutiny and study.

PSYCHOPHARMACOLOGICAL TREATMENT OF MAJOR DEPRESSION

In adults, effective antidepressants for the treatment of adult major depression include monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs) and dual-action agents. Through these treatments at least partial symptomatic response is achieved, but often complete remission is difficult to obtain. The existence of residual symptoms may be the best predictor for a relapse or reoccurrence, which may have very significant implications if the first episode occurs in adolescence (Keller, 2003). Therefore, determination of the psychopharmacological approaches, both monotherapies or combinations, that have the best outcome in adults may be significant for the treatment of adolescent depression.

Pharmacological Treatment of Adult Major Depression

Monotherapy

At this time the first line medication treatment for adult MDD is the SSRIs, which include fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), fluvoxamine (Luvox), citalopram (Celexa), and escitalopram (Lexapro). They have a greater affinity for the serotonin transporter than for the noradrenergic transporter, and each compound selectively inhibits 5-hydroxytryp-tamine (5-HT) reuptake and has unique secondary binding properties. This class of drug is rarely associated with fatalities and given its safety profile provides an easy treatment option for the clinician (Farvolden, Kennedy, & Lam, 2003).

The latest generation of antidepressants is the selective serotonin and noradrenaline reuptake inhibitors (SNRIs), such as venlafaxine (Effexor), duloxetine (Cymbalta), and milnacipran. It appears that venlafaxine possesses a selective high affinity for the noradrenergic and sertonergic reuptake sites; however, it is only at higher doses (150 to 225 mg) that its noradrenergic reuptake becomes activated. This dual reuptake inhibition may contribute to the high rates of remission of depressive symptoms compared to those with SSRIs (Thase, Entsuah, & Rudolph, 2001). Although venlafaxine's side effect profile is similar to that of SSRIs, at higher doses >200 mg there is a 5.5% clinically significant elevation of blood pressure and at higher doses >300 mg the incidence of hypertension reaches 13%. Duloxetine is a newer SNRI with reportedly dual reuptake inhibition that is equal at clinical doses. Reboxetine is a selective norepinephrine reuptake inhibitor not approved in the United States for the treatment of major depression. Mirtazapine, which belongs to the piperazine-azepine group of compounds, has not been investigated in the treatment of pediatric depression.

Another novel compound used for the treatment of adult depression is bupropion, which has it effects by blocking noradrenergic and do pamine reuptake (Dong & Blier, 2001). It has the side effects of insomnia, nausea, increased anxiety, and restlessness. Another potential side effect is an increased incidence of seizures, which occur at a rate of 0.4% with daily doses below 450 mg and 2.4% with daily doses between 450 and 600 mg (Johnston et al., 1991). However, one important advantage of this compound in treating adults is that it has been found to cause no weight gain or sexual dysfunction.

Nefazodone and trazodone inhibit the 5-HT2A receptors. This class of compounds is effective for the symptom of insomnia; however, sedation is a common problematic side effect along with orthostatic hypotension. A common clinical practice is to use low doses of trazodone for insomnia while simultaneously starting an SSRI. Trazodone is associated with a rare side effect of priaprism. In addition, hepatic toxicity and liver failure have been found to be associated with these compounds.

Older classes of antidepressants efficacious in treating adult MDD, such as the tricyclic and heterocyclic antidepressants (amitriptyline, amoxapine, clomipramine, desipramine, doxepin, imipramine, maprotiline, nortriptyline, and protriptyline) inhibit different combinations of serotonin, noradrenergic, and dopamine receptors. Their antagonism at other receptor types causes difficult side effects such as dry mouth, confusion, orthostatic hypotension, tachycardia, weight gain, urinary retention, and constipation. In addition, doses outside of the therapeutic range may be lethal because of conduction abnormalities. The MAOIs (phenelzine and tranylcypromine) irreversibly inhibit the monoamine oxidase isozymes A and B. It is thought that the blockade of the isozyme A lends these compounds their clinical efficacy (Mann et al., 1989). One major issue with this class of antidepressants is the required tyramine-restricted diet, which if not adhered to can prove to be fatal with dangerous elevation of the patient's blood pressure. Also, drugs that increase synaptic monoamines must be avoided, such as over-the-counter cold medications, TCAs, SSRIs, stimulants, and cocaine. There is also a risk of lethal, rare hyperthermic reactions that occur with meperidine and other opiates. Given these issues of tolerability and potential serious adverse events, TCAs and MAOIs have been more often reserved as second-and third-line agents for patients who have failed treatment with one of the newer antidepressant classes.

Pharmacological Combination and Augmentation Therapy

The definition of treatment-resistant depression is the failure to clinically respond to one or two antidepressant trials with an adequate amount of time and dosage. There are several strategies for treating adults with this clinical problem: maximize the dose and duration of treatment; switch to another antidepressant within a class or another class; use a combination of antidepressants; and augment with other compounds. Response rates when switching to another type of antidepressant have ranged from 40% to 60% (Thase, Trivedi, & Rush, 1995). There is evidence that supports the use of lithium and triodothyronine as augmentation treatment for patients who are TCA nonresponders (Aronson, Offman, Joffee, & Naylor, 1996; Freemantle, Anderson, & Young, 2000). There are limited data available on the efficacy of lithium and triodothryonine augmentation with SSRIs (one study with citalpram and one with fluoxetine) and newer antidepressant nonresponders (Baumann, 1996; Katona et al., 1993). Open studies of combinations of antidepressants from different classes suggest possible usefulness for the strategy, but more controlled research is required (Seth, Jennings, Bindman, Phillips, & Bergman, 1992). In addition, there is some evidence for the usefulness of novel antipsychotic agents in combination with antidepressants for treatment-refractory depression, such as the combination of fluoxetine and olanzapine (Shelton et al., 2001).

Pharmacologial Treatment of Adolescent Major Depression

The FDA has issued an advisory to physicians that the use of antidepressants may lead to suicidal thinking or attempts in depressed youths (see Part VI: Youth Suicide, Chapter 4). The FDA has requested that a warning be added to the product label of these antidepressants, with information highlighting the need for close obser vation for worsening of depression and the emergence of suicidality in adults and children treated with these medications. This advisory is based on the available evidence from pediatric major depression trials that seem to suggest modest efficacy of antidepressants for this illness and a small increased risk for suicidal thinking in some of these studies. This is a complex issue, and the available pediatric data do not clearly support or refute these treatment concerns for pediatric depression. However, these issues highlight the need for continued research to examine the efficacy and safety of both acute and long-term use of these medications in the pediatric population.

To date, the only medications that have demonstrated safety and efficacy in double-blind, placebo-controlled trials for children and adolescents with major depression are the SSRIs. Fluoxetine was the first SSRI shown to be efficacious in the treatment of children and adolescents with major depression. In a single-site 8-week trial, fluoxetine 20 mg was significantly superior to placebo. Fifty percent of the fluoxetine group compared to 33% of the placebo group were much or very much clinically improved (Emslie et al., 1997). In a subsequent multicenter study of 219 outpatient youths with major depression, significantly greater improvement in depression as assessed by the Children's Depression Rating Scale–Revised (CDRS-R) scores was found for the fluoxetine group compared to the placebo group. Fifty-two percent of the fluoxetine group was much or very much clinically improved compared to 37% of the placebo group (Emslie et al., 2002). On the basis of the positive findings of this study, fluoxetine received FDA approval for the treatment of major depression in children and adolescents.

The efficacy of paroxetine has been assessed in two pediatric studies, one with adolescents only and one with children and adolescents. In a multicenter study of 275 adolescent outpatients with major depression, patients were randomized to paroxetine (up to 40 mg), imipramine (up to 300 mg), or placebo for an 8-week trial. Sixty-six percent of the paroxetine group was much or very much clinically improved, compared to 52% of the imipramine group and 48% of the placebo group. However, on the primary efficacy measure of the HAM-D total score, there was no statistically significant difference among the groups (Keller et al., 2001). Adverse events most commonly reported for paroxetine were headache, nausea, dizziness, dry mouth, and somnolence, which occurred at rates similar to those in the placebo group except for somnolence. The most common adverse events in the imipramine group were dizziness, dry mouth, headache, nausea, and tachycardia. In a multicenter double-blind, placebo-controlled trial of paroxetine treatment of children and adolescents with major depression, there was no statistically significant difference in the response rates between the paroxetine and placebo groups (GlaxoSmith Kline, data on file).

Citalopram treatment for major depression in children and adolescents was assessed in 174 youths, ages 7 to 17 years. In this double-blind, placebo-controlled, 8-week trial, patients were randomized to citalopram (mean 23 mg/day) or placebo. Significantly greater improvement in depression, based on change in CDRS-R scores from baseline to end point, was found for the citalopram group compared to the placebo group. Remission rates, defined as a CDRS-R score # 28, were 36% in the citalopram group and 24% in the placebo group. Headache, nausea, rhinitis, abdominal pain, and influenza-like symptoms were the most frequent side effects in the citalopram group (Wagner et al., 2001).

The efficacy and safety of sertraline were assessed in two identical multicenter studies of 376 children and adolescents ages 6 to 17 years with major depression. Patients were randomized to sertraline (mean 131 mg/day) or placebo during this 10-week, double-blind, placebo-controlled trial. On the basis of change in CDRS-R scores from baseline to end point, the sertraline group showed significantly greater improvement in depression than the placebo group. Response rates, defined as a decrease of >40% in the CDRS-R score, were 69% in the sertraline group and 59% in the placebo group. Headache, nausea, insomnia, upper respiratory tract infection, abdominal pain, and diarrhea were the most common side effects in the sertraline-treated group (Wagner et al., 2003).

With regard to other antidepressant classes, nefazadone was evaluated in a double-blind, 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).

Table 2.3 Selected Monotherapy Studies in Treatment of Adolescent Depression

Study

Agent(s) Used

Study Design

Study Length (weeks)

Sample Size

Comments

Esmlie et al., 1997

Fluoxetine

Double-blind, placebo-controlled

8

64

Fluoxetine 20 mg superior to placebo

Esmlie et al., 2002

Fluoxetine

Double-blind, placebo-controlled

8

219

Fluoxetine effective 52% vs. 37% placebo; FDA approval in pediatric MDD on the basis of this study

Keller et al., 2001

Paroxetine, imipramine

Double-blind, placebo-controlled

8

275

Overall response rates were as follows:

Paroxetine = 66%

Imipramine = 52%

Placebo = 48%

GlaxoSmithKline (data on file)

Paroxetine

Double-blind, placebo-controlled

10

Not statistically significant between paroxetine and placebo

Wagner et al., 2001

Citalopram

Double-blind, placebo-controlled

8

174

On the basis of CDRS-R scores, citalopram showed significant improvement over placebo

Wagner et al., 2003

Sertraline

Double-blind, placebo-controlled

10

376

Sertraline showed significant improvement over placebo

Rynn et al., 2002

Nefazadone

Double-blind, placebo-controlled

8

195

Nefazadone not superior to placebo on primary outcome (CDRS-R), but significant on secondary outcome (HAM-D)

Ryan, 2003

Tricyclic antidepressants

Aggregate studies

500

Tricyclics not superior to placebo

CDRS-R, Children's Depression Rating Scale–Revised; FDA, Food and Drug Association; HAM-D, Hamilton Depression Rating Scale; MDD, major depressive disorder.

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.

Conclusion

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 response 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.

COMBINED PSYCHOTHERAPY AND MEDICATION

Adult 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.

Adolescent Major Depression

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.

BIPOLAR DISORDER

Mood disorders by definition disrupt functioning in several areas of an individual's life, including school, family, and peer relationships. Practice guidelines for the treatment of bipolar disorder in adults recognize both pharmacotherapy and psychotherapy as essential components of optimal treatment (American Psychiatric Association, 1994). From a developmental standpoint, research supports the notion that early psychosocial impairment tends to promote later impairment, as the individual arrives at each progressive stage of development with inadequate resources available to meet the challenges unique to the ensuing developmental period (Cicchetti, Rogosch, & Toth, 1998). Thus, it is crucial that treatment be provided promptly and effectively to maintain a normal developmental trajectory as much as possible, and minimize the effects that symptoms have on functioning.

Given the more recent recognition of bipolar disorder in childhood, it is not surprising that little is known about treatment strategies, both pharmacologic and psychotherapeutic, for this population. To date, no randomized, controlled trials of psychosocial intervention with a pediatric bipolar disorder population have been completed; however, several are currently under way. Potentially promising treatment approaches for pediatric bipolar disorder rely on the literature for treatment of adult bipolar disorder. In the next section we review the literature on the psychosocial treatment of adult bipolar disorder. This is followed by suggestions for adaptation of adult psychosocial treatments for use with children and adolescents.

Psychosocial Treatment of Adult Bipolar Disorder

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).

Cognitive Behavior Therapy

Cognitive behavior therapy conceptualizes mood swings as a function of negative thought and behavioral patterns. These maladaptive patterns are then targeted in the therapy. Three randomized, controlled clinical trials with bipolar adults (for a review see Craighead, Miklowitz, Frank, & Vajk, 2002) suggest that adjunctive CBT leads to increased medication compliance, fewer hospitalizations, and improved social and occupational functioning.

Interpersonal Therapy and Social Rhythm Therapy

Interpersonal therapy, as discussed earlier, is a short-term, present-oriented, problem-focused individual therapy developed and supported for the alleviation of symptoms of major depression (Klerman et al., 1987). In IPT, the onset of the depressive episode is placed in the context of interpersonal relationships, and current interpersonal difficulties are addressed. With the knowledge that circadian rhythm disturbances are linked to bipolar disorder (Ehlers, Frank, & Kupfer, 1988), Frank and colleagues supplemented IPT with social rhythm therapy (SRT) to create IPSRT for bipolar disorder. The focus of IPSRT is on the regularization of both social and circadian rhythms to control mood cycling. Results of a controlled trial with bipolar adults indicate that IPSRT is most effective in controlling the depressive symptoms of bipolar disorder, and also affects greater stabilization of sleep–wake cycles than case management treatment (Frank et al., 1997).

Family-Based Therapies

Several randomized, controlled trials of family-based treatments have been documented in the literature. Inpatient family intervention (IFI; Clarkin et al., 1990), a nine-session intervention focused on psychoeducation, aims to modify negative family patterns and increase coping skills. Results indicate that female patients had better global and symptomatic functioning than those receiving standard hospital treatment (Clarkin et al., 1990).

Miklowitz and Goldstein (1990) developed family-focused therapy (FFT), a 9-month treatment incorporating psychoeducation, communication skills training, and problem-solving skills training. In a randomized trial, patients receiving FFT experienced fewer depressive symptoms, increased compliance with medication regimens, had fewer hospitalizations, and experienced a longer period to mood relapse than patients in a case management condition (Miklowitz et al., 2000).

At present, a multisite, randomized, controlled trial of family-focused therapy for adolescents (FFT-A; Miklowitz & George, 2000), a modified version of Miklowitz and Goldstein's (1990) FFT, is under way. We know that familial climate is related to relapse in bipolar adults (Miklowitz, Goldstein, Neuchterlein, Snyder, & Mintz, 1988). Therefore, family-based interventions among the families of bipolar children and adolescents may shed light on the role of family involvement in intervention with a pediatric bipolar population.

Group Psychotherapy

Among adults with bipolar disorder, several different group approaches have been successful. For example, Colom and colleagues (2003) demonstrated increased time to relapse of mood symptoms, as well as lower rates of rehospitalization among remitted bipolar adults attending a psychoeducational group, compared with those receiving standard treatment (medications alone). Another structured group approach, The Life Goals Program (Bauer, McBride, Chase, Sachs, & Shea, 1998), consists of psychoeducation, behavioral skills, and individually tailored goals; at present, no data are available on outcome.

Psychosocial Treatment of Adolescent Bipolar Disorder

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 conflict, teasing, and academic concerns, that may not be relevant in an adult population. Finally, because bipolar disorder is highly familial, it is likely that at least one of the parents of a child with pediatric bipolar disorder has either unipolar or bipolar mood disorder (Geller, Fox, & Clark, 1994). The course of a parent's mood disorder is likely to be intimately related to the child's presentation, compliance, and management. Given that parental depression may interfere with a mood-disordered child's response to treatment (Brent et al., 1998), it is particularly important that the parent's own affective illness be addressed when treating a bipolar child or adolescent.

Conclusion

The empirical literature on psychosocial treatment of adult bipolar disorder suggests that several forms of therapy, including CBT, IPT supplemented with SRT, family-based treatments, and group therapy, are useful adjunctive treatments. These treatments have been found to produce better medication compliance, fewer hospitalizations, and improved social and occupational functioning.

PHARMACOTHERAPY FOR BIPOLAR DISORDERS

Pharmacological Treatment for Adult Bipolar Disorder

Mood Stabilizers

Lithium has been shown through placebo-controlled trials to significantly reduce episodes of new manic and/or depressive episodes in adults. However, approximately 42% to 64% of patients do not respond to lithium (Solomon et al., 1995). To obtain maximum benefit and prevention of relapses, it appears that the blood level of lithium needs to be titrated to and maintained at a blood level range of 0.8 to 1.2 mmol/L (Gelenberg et al., 1989). At this higher blood level the patient may experience an increase in side effects, such as tremor, diarrhea, weight gain, increased urinary frequency, and gastrointestinal distress. Long-term treatment with lithium may lead to hypothyroidism, renal compromise, and cardiovascular side effects. Patients who are diagnosed with mixed states, rapid cycling, and mania due to medical disorders may be less responsive to lithium treatment (Bowden et al., 1997).

Divaloproex and carbamazepine are anticonvulsants used to treat acute symptoms of bipolar disorder as well as for long-term maintenance treatment. Bowden and colleagues (1994) published a double-blind, randomized, parallel-group trial in which patients hospitalized with acute mania (N = 179) were randomly assigned to 3 weeks of treatment with lithium, divaloproex, or placebo. Both lithium and divaloproex significantly reduced patients' symptoms of mania compared to placebo. Bowden and colleagues (2000) completed a double-blind, randomized maintenance treatment trial of lithium vs. divaloproex vs. placebo for patients diagnosed with bipolar I. The study's primary end point was the time to develop any mood episode and there was no difference found between the three groups. However, divaloproex was shown to significantly reduce the number of patients who dropped from the study because of relapse and it also showed a significantly improved outcome of secondary mood measurements.

Lamotrigine has been shown to be an effective treatment for bipolar I depression (Hirschfeld et al., 2002) and for long-term treatment of in patients with bipolar II disorder and rapid cycling (Bowden et al., 1999). Treatment with lamotrigine is associated with a 5% incidence of a skin rash. Most of these rashes appear in the first 8 weeks of treatment and resolve with cessation of drug treatment. However, these skin rashes can evolve to a more serious form of a skin reaction such as Stevens-Johnson syndrome (Wong, Kennedy, & Lee, 1999). At this time, there are limited data to support the use of gabapentin or topiramate as mood stabilizers.

Atypical Antipsychotics

Olanzapine is presently the most studied atypical antipsychotic medication for the treatment of bipolar disorder and was approved by the FDA for treatment of acute mania (Tohen et al., 1999). The most concerning side effect with this medication is weight gain. Segal, Berk, and Brook (1998) showed in a randomized study that risperidone, compared to lithium and haloperidol, produces similar improvement in manic symptoms. It has also been shown in combination as an add-on therapy with a mood stabilizer to have superior efficacy to that of monotherapy, as found in a study using quetiapine (Sachs, Grossman, Ghaemi, Okamoto, & Bowden, 2002).

Antidepressants

There are conflicting views on the use of antidepressants for the treatment of bipolar depression. However, there is agreement that antidepressants should only be used in combination with a mood stabilizer for the treatment of bipolar depression (Thase, Bhargave, & Sachs, 2003). For patients who are suffering from a severe depressive episode it is recommended that lithium or lamotrigine be used as first-line therapy. If the patient is nonresponsive, then a combination is recommended, such as the addition of lamotrigine, bupropion, or paroxetine. Another option would be to add an SSRI, venlafaxine, or an MAOI. It appears that SSRIs have a lower risk of inducing mania than that with TCAs (Moller & Nasarallah, 2003). For bipolar depression, there are limited data available that compare the treatment outcome of treating only with a mood stabilizer versus the combination of a mood stabilizer with an antidepressant.

Pharmacological Treatment of Adolescent Bipolar Disorder

Compared with what is known about the pharmacotherapy of bipolar disorder in adults, relatively little is known about the medication management of bipolar disorder in young people. This is unfortunate, as there has been an increased appreciation over the past few years that bipolar disorder is a chronic, debilitating condition when it occurs in children and adolescents. Most prospective pharmacotherapy studies in pediatric bipolar disorder are uncontrolled, focused on the manic phase of the illness, and of brief duration. Therefore, definitive conclusions about the best way of treating mania or depressive symptomatology both acutely and over the long term cannot be made.

Fortunately, there has been a substantial increase in the number of medication studies within this patient population over the past few years. These data can provide practicing clinicians practical information on rational treatment approaches to the pharmacotherapy of this illness.

Monotherapy

Several agents have been examined within the context of acute prospective monotherapy treatment trials (Table 2.4). More research has been done to examine the use of lithium for the treatment of mania than any other compound. Although several open-label studies have been conducted, at present there has only been one published, methodologically rigorous study that has examined the acute efficacy of lithium in the treatment of mania in young people (Kowatch & DelBello, 2003). In that study, 25 adolescents with bipolar-spectrum disorders with secondary substance abuse dependence were randomized to receive either lithium monotherapy or placebo for 6 weeks. The average age of the subjects was 16 years. The authors found that subjects treated with lithium had superior global functioning and fewer positive urine drug assays than those who were treated with placebo (Geller et al., 1998).

Table 2.4 Selected Monotherapy Studies in Treatment of Pediatric Bipolarity

Study

Agent(s) Used

Study Design

Study Length (weeks)

Sample Size

Comments

Geller et al., 1998

Lithium

Double-blind, placebo-controlled

6

25

Lithium superior to placebo

Wagner et al., 2002

Divalproex sodium

Open-label, prospective

8

40

Divalproex effective with 61% response rate

Kowatch et al., 2000

Lithium, carbamazepine, divalproex sodium

Prospective, open-label, random assignment to one of the 3 agents

6

41 (13 to CBZ, 13 to Li, 15 to DVPX)

Overall response rates were as follows:

CBZ = 34%,

Li = 42%,

DVPX = 46%

Frazier et al., 2001

Olanzapine

Open-label, prospective

8

23

Treatment was noted to be effective in 61%. Mean weight gain = 5.0 kg

CBZ, carbamazepine; DVPX, divalproex sodium; Li, lithium.

A review of the available treatment studies suggest that lithium carbonate may often be useful in ameliorating symptoms of bipolar disorder in young people and is generally well tolerated. The available data also suggest that approximately half of patients treated with this agent will respond to acute treatment with lithium (Chang & Ketter, 2001; Kowatch et al., 2000). The implication of this observation is that a substantial number of patients will not experience a meaningful response to lithium treatment alone. Moreover, many patients treated with lithium monotherapy who benefit from substantial symptom reduction will not experience syn dromal remission when treated with lithium alone.

At present, there are no published placebo-controlled studies that have examined the efficacy of divalproex sodium (Depakote) in the treatment of pediatric mania. There are several open trials that have examined the acute effectiveness of divalproex sodium (Depakote) in young patients with mania or mixed states. In the largest of these trials, 40 youths between the ages of 7 and 19 who were suffering from either a manic, hypomanic, or mixed episode were treated with open-label divalproex sodium for up to 8 weeks (Wagner, 2002; Wagner et al., 2002). Overall, the authors reported that divalproex sodium was an effective and reasonably well-tolerated intervention in the study subjects. Approximately 60% of the subjects were considered to be treatment responders.

On the basis of results of this trial and other published reports, the available data suggest that, similar to lithium, divalproex sodium may be an effective treatment for young patients with mania and related mood states (Wagner, 2002; Wagner et al., 2002). Like lithium, it appears that a substantial number of youths will not respond to monotherapy and only a small number of patients will experience syndromal remission with divalproex sodium monotherapy.

Carbamazepine has historically been given as a treatment to young people with a variety of neuropsychiatric conditions. Most reports describing the use of this drug in young people with neuropsychiatric conditions lack methodological rigor. At present, there is only one prospective study that has examined this agent's utility in young people with bipolar disorder. In that trial, Kowatch and colleagues treated 42 youths with an average age of 11 years, 20 of whom met diagnostic symptom criteria for bipolar 1 disorder and 22 of whom met diagnostic symptom criteria for bipolar II disorder (Kowatch et al., 2000). In order to be enrolled in this trial, the subjects had to have moderate symptoms of mania. Upon enrollment, subjects were randomized to open treatment with carbamazepine, divalproex sodium, or lithium. Of the 41 youths who completed at least 1 week of medication therapy, 13 were treated with carbamazepine. Treatment with carbamazepine was associated with an effect size of 1.00 with an overall response rate of 34 percent. Although these numbers were more modest than those seen with lithium or divalproex sodium, no statistically significant differences in effectiveness were noted between the three different study drugs.

At present there is one prospective open-label trial that has examined the use of olanzapine in youths suffering from a manic, mixed, or hypomanic episode (Frazier et al., 2001). In that trial, the 23 patients (mean age, 10.3 years) were treated with olanzapine in doses that could range between 2.5 and 20 mg/day. The authors noted that treatment was associated with reductions in symptoms of mania and that the agent was generally well tolerated, with the most common reported adverse events being increased appetite and sedation. The average weight gain over the course of the study was 5 kg.

There are several other agents that have been noted to have possible roles in the treatment of bipolar disorder in adults. These include lamotrigine, gabapentin, omega-3 fatty acids, verapamil, and topiramate. At present, none of these agents have been examined in a methodologically sound prospective treatment study in pediatric patients with bipolar disorder. Therefore, definitive statements about these agents' possible utility cannot be made.

Psychopharmacological Combinations

Since a substantial number of patients do not appear to derive optimal clinical response from acute treatment with a single drug, investigators have begun to explore whether treatment with more than one agent may be useful in the acute therapy of young people who present with symptoms of mania. The majority of these studies have explored treatment with an atypical antipsychotic combined with a traditional mood stabilizer.

In a retrospective chart review, Kowatch and colleagues (1995) described five youths with bipolar disorder and mixed presentations between the ages of 8 and 15 years who were treated with clozapine. In four of these five cases, clozapine was an adjunct to other psychotropic agents (most commonly lithium). At clozapine doses ranging from 75 to 150 mg/day, the authors noted that all five patients had a “marked” response to clozapine. The authors also observed that clozapine therapy was generally well tolerated. The authors concluded that clozapine might be an effective treatment for treatment-refractory patients.

The response of 35 adolescent inpatients treated predominantly with lithium plus haloperidol or lithium plus risperidone for up to 4 consecutive weeks has been described (Kafantaris, Coletti, Dicker, Padula, & Kane, 2001). These youths, who were between the ages of 12 and 18, had prominent symptoms of psychosis as well as moderate symptoms of mania at the time of treatment initiation. At the end of the trial, almost all of the subjects had their psychotic symptoms fully resolved, with most subjects experiencing significant amelioration of mood symptoms. The authors then took some of the subjects who responded to combination treatment and discontinued their antipsychotic. The authors found that most patients experienced clinical deterioration during lithium monotherapy. This response suggests that they would have benefited from continued combination treatment.

In a chart review study, Frazier and colleagues (1999) examined the use of risperidone in a group of 28 young people with bipolar-spectrum disorders. All but one patient was being treated with one or more concomitant medications during risperidone administration. These concomitant agents most commonly included mood stabilizers and ADHD medications (stimulants and α2-agonists). At an average total daily dose of 1.7 mg, the authors noted that risperidone appeared to be effective in symptom reduction and that the risperidone appeared to be generally well tolerated.

There is one published study that has rigorously examined quetiapine treatment as an adjunct in young people ages 12 to 18 suffering from bipolar I disorder (DelBello, Schwiers, Rosenberg, & Strakowski, 2002). In that 6-week trial, 30 hospitalized adolescents with mania or mixed presentations were treated with divalproex sodium at an initial dose of 20 mg/kg/day. Half of the subjects were randomized to receive adjunctive quetiapine and half were randomized to receive adjunctive placebo. The quetiapine was titrated to a total daily dose of 450 mg. Results from this trial noted greater reductions in manic symptomatology in the cohort of youths randomized to receive combination therapy. However, sedation was also more common in these youths.

The largest prospective trial that has examined combination pharmacotherapy in pediatric bipolar disorder described the response of 90 outpatients with a mean age of about 11 years who were treated with combination lithium and divalproex sodium therapy for up to 20 weeks (Findling et al., 2003). In that trial, the authors observed that the response rates were larger than those seen in other prospective trials in this patient population. The authors also found that response rates were higher than those described in adults using a similar combination treatment paradigm. In addition, it was noted that combination treatment was well tolerated. Of particular interest was the observation that residual depressive symptomatology was not manifest after combination lithium plus divalproex treatment in this patient population. This is in direct contrast to adults, in whom depression was often seen as a problematic residual mood state.

Conclusion

On the basis of available evidence, it appears that combination pharmacotherapy with more than one mood stabilizing agent may be a rational approach for some youth who have manic, hypomanic, or mixed states. Whether treatment should begin with drug monotherapy or combination pharmacotherapy should be a topic of further study.

Maintenance Trials

At present, there are no published prospective trials that have examined the maintenance pharmacotherapy of pediatric bipolar disorder. The first data to suggest that lithium maintenance therapy might be useful in the treatment of adolescents with bipolar disorder were published in 1990. That report described the results of a naturalistic, prospective, 18-month follow-up study of 37 youth with bipolar I disorder who had responded to lithium treatment (Strober, Morrell, Lampert, & Burroughs, 1990). In that trial, the authors found that in the 13 youth who discontinued lithium maintenance therapy, the relapse rate was 2.5 times greater than that in those who continued lithium treatment. Despite methodological limitations inherent in this study design, these data suggest that maintenance lithium treatment in young people who respond to administration of this compound may be beneficial.

There is one unpublished prospective trial of maintenance pharmacotherapy in pediatric bipolarity. In that trial, 60 youths who had responded to acute treatment with combination therapy using both lithium and divalproex sodium were randomized to receive monotherapy treatment with either lithium or divalproex for up to 76 weeks in a double-blind fashion (Findling, Gracious, McNamara, & Calabrese, 2000). The authors found that the overall median survival time in the study was approximately 100 days. It was also noted that lithium and divalproex sodium had similar effectiveness as monotherapy.

Conclusions

There are only limited data from methodologically rigorous trials in pediatric bipolarity. Evidence, predominantly from open-label trials, suggests that monotherapy with lithium, carbamazepine, divalproex sodium, and olanzapine may be useful in the treatment of young patients with mania and related mood states. A consistent theme from the extant literature is that a substantial number of patients do not respond to monotherapy with these agents. For this reason, investigators have begun to explore combination pharmacotherapy. It seems that simultaneous treatment with more than one agent may be a rational form of intervention for some patients. What has yet to be identified are those circumstances in which combination drug therapy might be most rationally employed. Because pediatric bipolarity is a chronic condition, it appears that young people suffering from this illness will need long-term treatment. Although maintenance pharmacotherapy data are lacking, patients who respond to a given acute pharmacotherapy regimen may continue to benefit from ongoing treatment with the drug(s) that led to successful symptom amelioration.

In summary, pediatric bipolarity is a chronic condition associated with substantial dysfunction and human suffering. There is a paucity of methodologically sound pharmacological treatment studies, thus more research on this topic is sorely needed.