A review of the pharmacotherapy of aggression in children and adolescents

Aggressive behavior in children and adolescents is a heterogeneous phenomenon occurring in a wide variety of illnesses. No single etiologic model seems adequate to explain this phenomenon. In many cases, pharmacotherapy may prove to be a useful adjunct to treatment. Potentially useful medications are described in reference to psychiatric diagnosis. Pharmacological treatment can be helpful in the management of the aggressive youth when judiciously applied in the context of a comprehensive treatment plan.     

Pharmacotherapy for major depression in children and adolescents

Major depression is a serious illness in children which adversely effects their social, academic, and emotional development. It is essential to identify safe and effective medication for the treatment of this disorder in youths. Only some selective serotonin reuptake inhibitors (citalopram, fluoxetine, sertraline) have demonstrated superiority to placebo on primary outcome measures in acute controlled treatment trials. This article will review acute efficacy studies as well as long-term studies of antidepressants for the treatment of childhood depression. Treatment recommendations are discussed and the issue of suicidality and antidepressants are addressed.     

The clinical picture of major depression in children and adolescents

Symptom frequency and severity were compared in two sequential clinically referred samples of 95 children and 92 adolescents, aged 6 to 18 years, all medically healthy, assessed with the Schedule for Affective Disorders and Schizophrenia for School Age Children, Present Episode, who met unmodified Research Diagnostic Criteria for major depressive disorder (MDD). There were no significant differences between the two groups in the majority of depressive symptoms. However, prepubertal children had greater depressed appearance, somatic complaints, psychomotor agitation, separation anxiety, phobias, and hallucinations, whereas adolescents had greater anhedonia, hopelessness, hypersomnia, weight change, use of alcohol and illicit drugs, and lethality of suicide attempt, but not severity of suicidal ideation or intent. Adolescents with a duration of the depressive episode of two years or greater had significantly higher rates of suicidal ideation and intent, lethality, and number of suicide attempts than youngsters with depressive episodes of shorter duration. A principal components factor analysis of psychiatric symptoms was carried out in all 296 youngsters evaluated during the same period who met DSM-III criteria for any Axis I diagnosis. The majority had an affective disorder. Factors were quite similar for both adolescents and children and included an "endogenous" and an "anxious" factor, as in many studies of adult depression. In addition, three other factors were found: negative cognitions, appetite and weight changes, and a conduct factor. Suicidal ideation was a component of both the negative cognitions factor and the conduct factor.(ABSTRACT TRUNCATED AT 250 WORDS)     

Fluoxetine versus placebo in preventing relapse of major depression in children and adolescents

OBJECTIVE: The authors compared fluoxetine and placebo in continuation treatment to prevent relapse of major depressive disorder in children and adolescents. METHOD: After a detailed evaluation, children and adolescents 7-18 years of age with major depressive disorder were treated openly with fluoxetine. Those who had an adequate response after 12 weeks, as indicated by a Clinical Global Impression improvement score of 1 or 2 and a decrease of at least 50% in Children's Depression Rating Scale-Revised score, were randomly assigned to receive fluoxetine or placebo for an additional 6 months. The primary outcome measures were relapse and time to relapse. Relapse was defined as either a score of 40 or higher on the Children's Depression Rating Scale with a history of 2 weeks of clinical deterioration, or clinical deterioration as judged by the clinician. Additional analyses were conducted with relapse defined only as a score of 40 or higher on the Children's Depression Rating Scale. RESULTS: Of 168 participants enrolled in acute fluoxetine treatment, 102 were randomly assigned to continuation treatment with fluoxetine (N=50) or placebo (N=52). Of these, 21 participants (42.0%) in the fluoxetine group relapsed, compared with 36 (69.2%) in the placebo group, a significant difference. Similarly, under the stricter definition of relapse, fewer participants in the fluoxetine group relapsed (N=11; 22.0%) than in the placebo group (N=25; 48.1%). Time to relapse was significantly shorter in the placebo group. CONCLUSIONS: Continuation treatment with fluoxetine was superior to placebo in preventing relapse and in increasing time to relapse in children and adolescents with major depression.     

Improved pharmacotherapy of major depression in psychiatric outpatient care

We studied the ability of mental health care to treat major depression in accordance with given standards. The treatment procedures for 232 patients with first-episode major depression (DSM-III-R) in 3 study years (1989, 1992, 1995) were circumstantially and retrospectively evaluated from documents in community psychiatric outpatient care in Finland. In total, two-fifths of the patients received probably inadequate pharmacotreatment. However, there was a clear improvement in pharmacotreatment of major depression during the study years. The adequacy of given antidepressant medication was associated with high basic education of the patients, accuracy of diagnosis, and new antidepressants.     

Immunity in adolescents with major depression

OBJECTIVE: The association between major depression (MD) and altered immunity appears to be age-related, with differing immune changes found in prepubertal children, young adults, and older adults. There is limited information concerning immunity in adolescents with MD. METHOD: Thirty-six otherwise healthy medication-free adolescents (aged 14-20; 23 female) from a community sample, meeting Diagnostic Interview Schedule for Children DSM-III-R criteria for unipolar MD, were compared with 36 nondepressed adolescents matched by gender, age, and racial background. A battery of quantitative and functional immune measures was obtained. RESULTS: MD adolescents had increased (p < .05) circulating lymphocytes and lymphocyte subsets; however, altered distribution of lymphocyte subsets was found only for activated T (HLA-DR+) cells (p < .004) and, possibly, natural killer (NK) (CD56+) cells (p < .06), each showing lower percentages in the MD adolescents. Concanavalin A (but not phytohemagglutinin or pokeweed mitogen) mitogen response was lower in the MD adolescents (p < .02). NK cell activity was elevated at higher effector-target ratios (p < .001), an effect not associated with the number of circulating CD56+ (NK) cells. CONCLUSIONS: Depressed adolescents showed changes in immune measures that have been found to be altered in other MD groups, although the pattern of effects differs.     

A randomized, placebo-controlled trial of citalopram for the treatment of major depression in children and adolescents

OBJECTIVE: Open-label trials with the selective serotonin reuptake inhibitor citalopram suggest that this agent is effective and safe for the treatment of depressive symptoms in children and adolescents. The current study investigated the efficacy and safety of citalopram compared with placebo in the treatment of pediatric patients with major depression. METHOD: An 8-week, randomized, double-blind, placebo-controlled study compared the safety and efficacy of citalopram with placebo in the treatment of children (ages 7-11) and adolescents (ages 12-17) with major depressive disorder. Diagnosis was established with the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version. Patients (N=174) were treated initially with placebo or 20 mg/day of citalopram, with an option to increase the dose to 40 mg/day at week 4 if clinically indicated. The primary outcome measure was score on the Children's Depression Rating Scale-Revised; the response criterion was defined as a score of < or =28. RESULTS: The overall mean citalopram dose was approximately 24 mg/day. Mean Children's Depression Rating Scale-Revised scores decreased significantly more from baseline in the citalopram treatment group than in the placebo treatment group, beginning at week 1 and continuing at every observation point to the end of the study (effect size=2.9). The difference in response rate at week 8 between placebo (24%) and citalopram (36%) also was statistically significant. Citalopram treatment was well tolerated. Rates of discontinuation due to adverse events were comparable in the placebo and citalopram groups (5.9% versus 5.6%, respectively). Rhinitis, nausea, and abdominal pain were the only adverse events to occur with a frequency exceeding 10% in either treatment group. CONCLUSIONS: In this population of children and adolescents, treatment with citalopram reduced depressive symptoms to a significantly greater extent than placebo treatment and was well tolerated.     

The pharmacotherapy of anxiety disorders in children and adolescents.

Psychopharmacologic agents may offer potentially effective treatment of child and adolescent anxiety disorders. Much further research, however, remains to be done to determine medication specificity, dosages, duration of treatment, and the optimal relationship between pharmacologic and nonpharmacologic therapies.     

Atypical depression in children and adolescents

Major depressive disorder (MDD) with atypical features has been described in adults. Furthermore, several studies have suggested that tricyclic antidepressants were less effective for MDD with atypical features than for MDD without atypical features. Thus, it may be important to determine whether atypical features are present in MDD. To date, only one study has examined the diagnosis of depression with atypical features in children and adolescents by using the DSM-IV criteria. Current knowledge suggests the DSM-IV criteria for depression with atypical features in children and adolescents may need to be reconsidered, as biological, hormonal, developmental, and psychological factors in this age group may be different from those of adults with atypical depression.     

Refractory depression in children and adolescents

Refractory or treatments resistant depression in child and adolescent populations is a difficult construct to operationalize currently. To date, only one of the small number of completed double-blind placebo-controlled treatment investigations have not demonstrated a significant effect of antidepressants in comparison to placebo. However, it has been established that child and adolescent MDD is a serious disorder that appears to have clinical continuity with adult affective disorders and is generally of long duration with high rates of recurrence and eventual progression to mania, substance abuse, or other serious psychopathology. In addition, families of children with affective disorders evidence substantial genetic loading with high rates of affective disorders contributing both genetic vulnerability and potential environmental risk as well. There have been no empirically identified treatments that alter the long-term course of the illness. Thus treatment resistance is a significant issue for this population. This review will focus on controlled treatment trials and will examine the potential relevance of psychosocial impairment, genetic-familial risk, and neuromorphometric brain differences to treatment resistance in children and adolescents with major depression. Depression and Anxiety 5:212–223, 1997. © 1997 Wiley-Liss, Inc.     

Psychotherapy for depression among children and adolescents: a systematic review

OBJECTIVE: To examine the clinical benefit, the harm and the cost-effectiveness of psychotherapies in comparison with no treatment, waiting-list controls, attention-placebos, and treatment as usual in depressed youths. METHOD: Meta-analyses were undertaken by using data from all relevant randomized-controlled trials identified by a comprehensive literature search. The primary outcome was relative risk (RR) of response. RESULTS: We identified 27 studies containing 35 comparisons and 1,744 participants. At post-treatment, psychotherapy was significantly superior (RR = 1.39, 95% CI 1.18-1.65, P = 0.0001, number-needed to treat 4.3). There was an evidence of the existence of small study effects, including a publication bias (P < 0.001). The superiority of psychotherapy was no longer statistically significant (1.18 [0.94-1.47], P = 0.15) at 6-month follow-up. None of the studies reported adverse effects or cost-effectiveness outcomes. CONCLUSION: Although the findings were biased by some small positive trials, psychotherapies appear to help depressed youths for the short term, but are no longer significantly favourable at 6-month follow-up.     

Combination pharmacotherapy in children and adolescents with bipolar disorder.

BACKGROUND: The purpose of this study was to develop prospective data on the effectiveness of combination pharmacotherapy of children and adolescents with bipolar disorder during a 6-month period of prospective, semi-naturalistic treatment. METHODS: Thirty-five subjects, with a mean age of 11 years, were treated in the extension phase of this study after having received 6-8 weeks of acute treatment with a single mood stabilizer. The extension phase of this study lasted for another 16 weeks, for a total of 24 weeks of prospective treatment. During this study phase, subjects were openly treated, and they could have their acute-phase mood stabilizer switched or augmented with another mood stabilizer, a stimulant, an antidepressant agent, or antipsychotic agent, if they were assessed to be a nonresponder to monotherapy with their initial mood stabilizer. RESULTS: During the extension phase of treatment, 20 of 35 subjects (58%) required treatment with one or two mood stabilizers and either a stimulant, an atypical antipsychotic agent, or an antidepressant agent. The response rate to combination therapy was very good, with 80% of subjects treated responding to combination therapy with two mood stabilizers after not responding to monotherapy with a mood stabilizer. CONCLUSIONS: This study suggests that children and adolescents with bipolar disorder are similar to adults with bipolar disorder, who also frequently require combination therapy.     

Polysomnographic findings in adolescents with major depression

Ten adolescents with major depression and 10 age-matched controls were studied with polysomnography for 3 consecutive nights. The sleep records were analyzed for variables pertaining to sleep continuity (total sleep time, sleep efficiency, sleep onset latency, number of awakenings, and number of stage shifts), sleep architecture (Stages 1, 2, 3, and 4), and rapid eye movement (REM) sleep (total) REM sleep time, number of REM periods, REM latency, and REM density). The experimental and control groups were compared on 14 variables with the t test for independent groups. The results indicated that none of the sleep variables differed significantly between the two groups. These results confirm earlier findings indicating that the abnormalities in REM latency and REM density that characterize adults with major depression are absent in adolescents suffering from major depression. Developmental and diagnostic variables are discussed as possible explanations for the sleep differences between adolescents and adults with depressive disorders.     

Assessment of depression in children and adolescents

Depression assessment instruments are valuable tools in the treatment of children and adolescents. Available instruments include diagnostic interviews, self-administered rating scales, and observer-rated scales. To select an appropriate instrument, the user must define the goal of the assessment and then identify instruments with the properties that match this goal. This article discusses how to choose an assessment instrument and gives an overview of currently available depression assessment instruments. Important considerations include how and by whom an instrument is administered, what kind of data are obtained by the instrument, and the validity and reliability of the instrument. Standardized instruments can greatly improve the assessment process, but the user must not overinterpret or misinterpret the results.     

Neurobiology of depression in children and adolescents

This article reviews classical and updated studies of the neurobiology of depressive disorders in children and adolescents. Most studies of childhood and adolescent depression and suicide have followed up the observations and methods used in studies in adults. These studies include neuroendocrine studies, which particularly look at the hypothalamic-pituitary-adrenal axis, the serotonergic system, peripheral blood and cerebrospinal fluid biologic markers, genetics, gene-environment interactions and sleep studies, and neuroimaging and postmortem studies, although in these areas the number of studies is limited.     

Treatment of depression in children and adolescents

Depression occurs in children and adolescents, although it may appear differently in younger patients. Research suggests juvenile depression may respond to psychotherapy and to pharmacologic agents, and that antidepressants remain a valuable treatment for juveniles with depression. Diagnostic considerations in juveniles with mood symptoms are discussed. A brief overview is provided of the evidence supporting psychotherapy for juveniles with depression. Controlled antidepressant trials in juveniles with depression provide some support for the use of some selective serotonin reuptake inhibitors and little support for atypical antidepressants, tricyclic antidepressants, or monoamine oxidase inhibitors. Evidence from suicide rates over time, autopsy findings among juvenile suicides, and impacts of antidepressant prescribing trends are related to the current controversy over suicidality and antidepressant use in juvenile patients. Based on this evidence, practical guidelines for treatment of juvenile depression are provided.