Recent attention has focused on recognition of childhood depression and identification of effective treatments. This article reviews prevalence, diagnosis, suicidai risk, familial association, comorbidity, and treatment strategies for depression in children and adolescents.
PREVALENCE AND DIAGNOSIS
The prevalence of major depression in school children, ages 6 to 8 years old, is 4.6%,' which is similar to rates previously reported for adolescents. The criteria for diagnosing depression in children and adolescents are the same criteria as for adults.2 However, youths often display irritable mood rather than dysphoria. Parents of a depressed child frequently state that nothing seems to please their child. Sometimes parents view their child's mood as intentionally cantankerous or as a passing stage. For those teenagers who have insight into their irritability, they often state that they feel as if they have a short fuse and everything makes them angry whether it is important or not. Children with depression lose interest in activities and spend increasingly less time with their peers.
Sleep disturbance is common, especially difficulty falling asleep. Although many children with depression lose weight, some gain significant amounts, such as 30 pounds in 1 year. Children with depression often are fatigued and nap after school. Diminished concentration may be manifested by declining school grades. Feelings of worthlessness can be striking in a depressed child who states unequivocally that no one could ever love him or her.
Parents often do not recognize that their child is depressed, although they recognize there is something troubling their child. It is not uncommon for parents of a depressed child to state that the child's constant complaining and lack of interest in family activities is disruptive to family functioning. Often a decline in school grades is a reason parents seek evaluation for their child.
Assessment of suicidality is critical in the evaluation of a depressed child. In a long-term followup study of adolescents diagnosed with major depression, 7.7% of these adolescents committed suicide by early adulthood.3 This is an extremely high mortality rate for a disorder of youth.
Prior suicide attempt, mood disorder, and substance abuse are among the top risk factors for suicide in children and adolescents. Questions about access to firearms should be routine in a psychiatric evaluation, since firearms are associated with an increased rate of suicide in adolescents. Parents should be strongly encouraged to remove any weapons from their home, it tney refuse, then they should be encouraged to lock firearms in a secure location. However, this is less than optimal because there have been tragic cases of depressed adolescents who committed suicide with their parents' firearms that presumably were locked in a secure location.
There is increasing evidence of a familial association with depression. In a study of 91 families with 181 children, the children of parents with major depression had eight times the risk of major depression, three times the risk of anxiety disorders, five times the risk of conduct disorder, and five times the risk of early adult-onset major depression than youths who did not have a depressed parent. Moreover, the risk of major depression in children increased substantially if the parent had an early onset of major depression in adulthood. For those parents whose major depression occurred prior to age 30, there was a 1 3-fold risk of childhood-onset depression and a 7-fold risk of adult-onset depression in their children compared to the children of nondepressed parents.4 In addition, the greater the number of maternal depressive episodes, the longer an adolescent's episode of major depression.5
Neuroimaging studies of children with depression have been conducted recently. Although sample sizes are small, children and adolescents with major depression who had a family history of major depression had significantly larger leftsided prefrontal cortex volumes than depressed children with nonfamilial major depression.6 Amygdala responses in depressed children to fearful faces were assessed with structural and functional magnetic resonance imaging scans. When exposed to fearful and neutral faces, children with depression had blunted amygdala responses to fearful faces, which contrasted with children with anxiety disorders who had exaggerated amygdala responses to fearful faces compared to controls.7
It is important for clinicians to identify comorbid disorders that are associated with major depression in children and adolescents. These comorbid conditions may affect the course of major depression and impact on treatment outcomes. For example, depressed adolescents who had attention-deficit/hyperactivity disorder (ADHD) showed a significantly lower response rate to paroxetine for treatment of depression than did those depressed adolescents without ADHD. The response rate to paroxetine was 71% in adolescents without ADHD and 25% in adolescents with ADHD.8
Common comorbid disorders with major depression in children include anxiety disorders, ADHD, substance abuse, conduct disorder, and eating disorders. The relationship between depression and smoking was examined in a prospective 1-year study of adolescents. At baseline, there were 8704 nondepressed adolescents and 6947 nonsmoking adolescents. At 1-year follow-up, cigarette smoking was the strongest predictor of developing high depressive symptoms; however, depressive symptoms did not predict smoking.9 This study may provide a mental health reason for adolescents to avoid smoking.
The mean length of an episode of major depression in children and adolescents is 9 months, with relapse rates of approximately 54%. 10 In the first longitudinal study of the outcome of prepubertal major depression,11 72 children (mean age 10 years) with prepubertal major depression who had participated in a nortriptyline study and 28 healthy controls were followed into adulthood (mean age 20 years). The rates of psychiatric disorders in those adults who had prepubertal major depression compared to normal controls were: bipolar I disorder, 33% versus 0%; any bipolar disorder, 48% versus 7%; major depression, 36% versus 14%; substance use disorder, 3 1 % versus 11%; and suicidality, 22% versus 4%. The adults who had prepubertal major depression also had significant impairments in familial and social relationships, school and work, and quality of Ufe. The impairment was worse if there was a recurrence of a mood disorder or substance use disorder in late adolescence.12
The course of adolescent depression was assessed in 274 community adolescents diagnosed with major depression. These adolescents were reassessed during young adulthood at age 24. Importantly, only 20% of these adolescents received treatment despite having been diagnosed with depression. During the age period of 19 to 23 years, 46% of these previously depressed adolescents had a recurrence of major depression and 23% developed an anxiety disorder or substance abuse; only 31% had no psychiatric disorder.13
These follow-up studies support the continuity between major depression in children and adolescents and its occurrence in adulthood.
Given the severity, chronicity, and extension of childhood-onset depression in adulthood, it is essential to identify effective treatments for this disorder. Research in the area of psychotherapy for adolescent depression and pharmacologic treatments of depression for both children and adolescents recently has increased.
With regard to psychotherapy, interpersonal and cognitive behavioral therapy - shown to be effective for treating depression in adults - have been modified and assessed for the treatment of depression in adolescents. Interpersonal psychotherapy for depressed adolescents focuses on developmental issues such as separation from parents, authority conflicts, peer pressures, and dyadic relationships.14
In a study of 48 adolescent outpatients ages 12 to 18 years with major depression, 12-week interpersonal psychotherapy was compared to clinical monitoring. Interpersonal psychotherapy led to greater decrease in depressive symptoms, improvement in social functioning, and improved problem solving compared to the clinical monitoring condition.15
Cognitive behavioral therapy has been assessed in a large psychotherapy trial for depressed adolescents. In this study, 107 adolescent outpatients with major depression were randomized to 12 to 16 treatment sessions of either individual cognitive behavioral therapy, individual nondirective supportive therapy, or systemic behavior family therapy. Cognitive behavioral therapy resulted in greater reduction in depression, more rapid symptom relief, and higher remission rates than the other therapies. All treatments reduced suicidality and reduced functional impairment.16 However, in a 2-year follow-up study there were no significant differences in outcome among the psychotherapies. Eighty percent of the adolescents had recovered from depression, but 30% had a recurrence of depression.17 These results provide compelling support for some maintenance treatment following short-term psychotherapy.
An area of new interest is treatment of adolescents at high risk for developing depression. Clarke and colleagues identified 94 adolescent children of depressed adults who had subsyndromal depressive symptoms.18 These adolescents did not fulfill diagnostic criteria for depression at the time of study participation. They were randomized to usual health maintenance organization (HMO) care or a 16session group cognitive therapy prevention program. The focus of the therapy was on cognitive restructuring of beliefs related to having a depressed parent, eg, the adolescents believed they were destined to become depressed because their parents were depressed. The risk for depression was significantly reduced in the group therapy prevention program compared to the HMO group. At 12-month follow-up the cumulative major depression incidence was 9% in the group cognitive therapy program and 29% in the usual care group.
In a similarly designed study, depressed aolescent children of depressed parents were randomized to 16-session group cognitive behavior therapy or usual HMO care.19 In this study, there was no significant advantage of group cognitive behavior therapy over usual HMO care. The discrepancy between the outcomes of these two studies may argue for earlier treatment of adolescents who are at high risk for depression rather than waiting until the adolescent has a fullblown depressive episode.
With regard to pharmacotherapy, significant advances have been made within the past few years in the identification of efficacious treatments for depressed children and adolescents. Although in the past tricyclic antidepressants had been used frequently for the treatment of depression in youth, no controlled studies demonstrated the superiority of tricyclic antidepressants to placebo in depressed youths. Moreover, tricyclic antidepressants have significant side effects including the potential for adverse cardiovascular effects in children.
There is a growing body of evidence to support the use of selective serotonin reuptake inhibitors (SSRIs) for the treatment of depression in children and adolescents. In the original single-site controlled study that demonstrated the efficacy of antidepressant medication in children and adolescents, 20 mg of fluoxetine was significantly superior to placebo in an 8- week trial. Fifty percent of the fluoxetine group compared to 33% of the placebo group were much more or very much improved.20
In a multi-center study of fluoxetine treatment for depressed youths, 219 outpatients with major depression, aged 8 to 17 years, were randomized to 20 mg of fluoxetine or placebo in a double-blind, placebo-controlled, 8-week trial. The fluoxetine group showed significantly greater improvement in depression as assessed by changes in the Children's Depression Rating Scale-Revised (CDRS-R) scores than placebo.21 In this study, 52% of the fluoxetine group was much or very much improved compared to 37% of the placebo group.22
The efficacy and safety of paroxetine was assessed in 275 adolescent outpatients with major depression who were randomized to up to 40 mg of paroxetine, up to 300 mg of inupramine, or placebo for an 8-week trial. In approximately 80% of patients, this was a first depressive episode. The average duration of the current episode of major depression for these adolescents was 14 months. The paroxetine group showed significantly greater improvement than the other groups. Sixty-six percent of the paroxetine group were much or very much improved compared to 52% of the Imipramine group and 48% of the placebo group. There was no statistically significant difference between the Imipramine and placebo groups. The most common side effects of the paroxetine group were gastrointestinal symptoms, insomnia, somnolence, headache, dizziness, and tremor. For the imipramine group, the most common side effects were cardiovascular (eg, tachycardia, orthostatic hypotension and electrocardiogram changes), gastrointestinal symptoms, headache, dizziness, and tremor.23
The efficacy and safety of Citalopram were assessed in 174 child and adolescent outpatients with major depression, ages 7 to 17 years. In this double-blind, placebo-controlled, 8-week trial patients were randomized to either 20 to 40 mg of Citalopram (mean 23 mg/d) or placebo. The Citalopram group showed significantly greater improvement in depression based on CDRS-R scores than the placebo group. Remission rates, defined as a CDRS-R score less than or equal to 28, were 36% in the Citalopram group and 25% in the placebo group. The most frequent side effects in the Citalopram group were headache, nausea, rhinitis, abdominal pain, and influenza-like symptoms.24
Sertraline treatment for major depression in children and adolescents was assessed in two identical multi-center studies of 376 children and adolescents with major depression, ages 6 to 17 years. In this 10- week, double-blind, placebo-controlled trial patients were randomized to 50 to 200 mg/d of sertraline (mean 131 mg/d) or placebo. The sertraline group, based on CDRS-R scores, showed significantly greater improvement in depression than the placebo group. Response rates, defined as a decrease of greater than 40% in the CDRS-R score, were 69% in the sertraline group and 59% in the placebo group. The most common side effects in the sertraline group were headache, nausea, insomnia, upper respiratory tract infection, abdominal pain, and diarrhea.25
With regard to other antidepressants, nefazodone was shown in a double-blind, placebo-controlled trial with adolescents to be significantly superior to placebo.26 However, in another multi-center trial that included both children and adolescents, there was no statistically significant difference between the nefazodone and placebo groups. The efficacy of venlafaxine, mirtazapine, and bupropion have not been determined in children and adolescents with depression.
Therefore, the SSRIs (Citalopram, fluoxetine, paroxetine, and sertraline) are first-line pharmacologic treatment for children and adolescents who are suffering from depression. Since these medications take time to be effective in children and adolescents, it is reasonable to initiate a 10- week SSRI trial. Common SSRI doses for children range from 5 to 40 mg of Citalopram, paroxetine, and fluoxetine or 25 to 200 mg for sertraline. Dose increases of 10 mg every 2 to 3 weeks for Citalopram, paroxetine, and fluoxetine or 50 mg for sertraline are appropriate for children and adolescents. Rapid dose escalation or high doses of SSRIs can lead to symptoms of akathisia, restlessness, and motoric hyperactivity that will adversely affect compliance with medication.
If a child fails to respond to one SSRI it is reasonable to try another, since failure to respond to one SSRI does not necessarily predict failure to respond to another. If a child fails to respond to two trials of a SSRI, then alternative monotherapy or augmentation strategies can be attempted. Other monotherapy options are bupropion, mirtazapine, nefazodone, and venlafaxine. Some augmentation agents to SSRIs are lithium, buspirone, or another antidepressant.
Although monoamine oxidase inhibitors have been efficacious in the treatment of depression in adults, the dietary restrictions required for the use of these agents limit their use in children. Electroconvulsive therapy has been effective, in some cases, in treating severe depression with psychotic features in children.
When an effective antidepressant is identified for a child, continue the medication for at least 9 months after symptom resolution. It is prudent to taper the medication for a 2-month period if the effective dose is high enough to allow for a taper of medication. Given the possibility of a relapse in depression, inform parents to contact their child's psychiatrist if symptoms of depression recur.
More treatment research is needed in the area of childhood depression. Whether combination treatment with psychotherapy and medication is more effective than either medication or psychotherapy alone for depressed children remains to be determined. Similarly, empirically derived medication algorithms for treatment-resistant depression in children and adolescents require further investigation.
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