Fadi T. Maalouf1'2, David A. Brent1 1Western Psychiatric Institute and Clinic, university of Pittsburgh School of Medicine, Pittsburgh, PA, USA 2Department of Psychiatry, American university of Beirut, Beirut, Lebanon
Depressive disorders in children and adolescents include major depressive disorder (MDD), depressive disorder not otherwise specified (► depressive disorder nos) and ► dysthymic disorder. Discussion in this essay will be limited to major depressive disorder because there are no controlled trials for the treatment of dysthymic disorder or depressive disorder nos. However, in clinical practice, treatment recommendations for MDD are successfully used in the management of dysthymic disorder and depressive disorder nos.
MDD in children and adolescents is characterized by one or more major depressive episodes, defined as at least 2 weeks of persistent change in mood manifested by either depressed or irritable mood or loss of interest or pleasure and at least four additional symptoms of depression, including changes in appetite or weight, sleep, psychomo-tor activity, decreased energy, feelings of worthlessness or guilt, difficulty thinking or concentrating, or recurrent thoughts of death or suicidal ideation, plans, or attempts. The symptoms must persist for most of the day nearly every day, must be associated with an impairment in functioning (social, academic or other), must not represent the direct physiologic effect of a substance or a general medical condition and must not be better accounted for by bereavement (American Psychiatric Association 1994).
Depressive disorders in children are common, recurrent, and impairing. Depression is prevalent in 1-2% of children and 3-8% of adolescents. By the end of adolescence, approximately 1 in 5 adolescents will have experienced at least one depressive episode. After the onset of puberty, girls have twice the risk of developing depression that boys do, and risk is closely correlated with levels of testosterone, estradiol, and follicular stimulating hormone (Lewinsohn et al. 1998). Depression is a recurrent condition in children and adolescents, with 40% of patients experiencing a second episode within 2 years, and nearly 75% within 5 years. Almost all will experience another episode in their adult life. Untreated depression is associated with substantial impairment both during and after the episode, with difficulties in school, interpersonal relationships, and occupational adjustment, tobacco and ► substance abuse, suicide attempts, and a 30-fold increased risk of completed suicide.
When depression presents with psychotic symptoms, especially in adolescents with family history of bipolar disorder, it is usually resistant to treatment and is associated with increased risk for bipolar disorder. Atypical depression presents with atypical symptoms such as lethargy (► leaden Paralysis), increased appetite, ► hypersomnia and increased sensitivity to rejection. While the major symptoms of depression persist across all ages, manifestations of depression may vary with age. Preschoolers may exhibit irritability, withdrawal, or regression as symptoms of depression (Luby et al. 2003). School-age children may display irritable or depressed mood, crying spells, or somatic complaints such as headaches and stomachaches. Adolescents often present with extreme irritability or atypical depressive symptoms such as increased appetite, hypersomnia, and excessive fatigue.
Clinical guidelines for the acute management of child and adolescent depression recommend the prescribing of antidepressant medications, psychotherapy, or both, with the best-studied psychotherapy being cognitive behavioral therapy (CBT) (Birmaher et al. 2007).
It is important to personalize the selection of a specific medication to each patient by taking into consideration the relative safety for the particular patient, comorbid psychiatric diagnoses, side-effect profiles, and the patient's other medical conditions. Physicians need to discuss risks and benefits of the medication and available alternative treatments, and obtain informed consent prior to starting treatment.
The ► selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed class of antidepres-sants. They work by inhibiting reuptake of serotonin by presynaptic neurons, with at least 70% reuptake inhibition required to result in clinical improvement. They include ► fluoxetine (Prozac), ► sertraline (Zoloft), ► paroxetine (Paxil), ► fluvoxamine (Luvox), ► citalo-pram (Celexa), and ► escitalopram (Lexapro). Currently, fluoxetine and escitalopram are the only antidepressants approved by the U.S. Food and Drug Administration for the treatment of depression in patients under the age of 18, although other SSRIs are often prescribed based on factors such as side-effect profile or personal or family history of response to a specific medication. Depressed patients treated with SSRIs have a relatively good response rate (40-70%), but placebo response rate in ► randomized controlled trials of pediatric depression is also high (30-60%), resulting in an overall ► number needed to treat (► NNT) of 10 (Bridge et al. 2009). Baseline depression severity was an inverse predictor of treatment response in these studies (i.e., less severely ill children were more likely to respond) (Curry et al. 2006).
Antidepressants are more efficacious in adolescents than in children (NNT of 7 vs. 15), except for studies of fluoxe-tine, in which the effects are equal in children and in adolescents and are stronger than in most other studies of pediatric depression (NNT=5). The half-lives of paroxe-tine, sertraline, citalopram, and ► venlafaxine are shorter in children and adolescents than in adults, which may explain the superior efficacy of fluoxetine vs. these other agents in prepubertal youth. While response and sustained improvement occurs in well over half of treatment-naive depressed adolescents, complete symptomatic ► remission rates are considerably lower, on the order of 20-37% after 12 weeks of treatment.
To date, no non-SSRI medication - except for venlafax-ine in treating resistant depression - has demonstrated clear efficacy in treating pediatric depression, but a number of newer non-SSRI antidepressants are available (Brent et al. 2008). These agents preferentially affect a variety of different receptor sites, and they include ► bupropion (Wellbutrin, Zyban), a primarily noradrenergic agent with some dopaminergic effect; ► trazodone (Desyrel) and nefazodone (serzone), serotonin receptor blockers; ► mirtazapine (Remeron), a serotonergic and adrenergic receptor blocker; venlafaxine (Effexor) and ► duloxetine (Cymbalta), serotonin and norepinephrine reuptake inhibitors; and
► atomoxetine (Strattera), a selective norepinephrine reuptake inhibitor (which is marketed for ► attention deficit hyperactivity disorder [ADHD], but not as an antidepressant). These are in addition to the older
► tricyclic antidepressants (TCAs), mixed serotonergic and noradrenergic agents that include ► amitriptyline (Elavil), ► clomipramine (Anafranil), desipramine (Norpramin), ► imipramine (Tofranil), ► nortriptyline (Pamelor, Aventyl), and protriptyline (Vivactil).
► Randomized control trials (RCTs) conducted with nefazodone are contradictory, with one trial demonstrating positive efficacy on some measures while the other was negative. Trials conducted with mirtazapine were negative. Conversely, in a study comparing response to an alternative SSRI or venlafaxine in adolescents who had failed to respond to an adequate trial of an SSRI, both classes of antidepressants were equally effective in reducing depressive symptoms, although venlafaxine has resulted in more side effects. Small open-label studies have suggested bupropion's efficacy in treating adolescent MDD with and without ADHD but no RCTs have been conducted. In a study of adolescents with ADHD and comorbid MDD, atomoxetine was shown to improve ADHD symptoms but not depression compared to placebo. RCTs, as well as a ► meta-analysis, have shown that TCAs are no more efficacious than placebo for the treatment of child and adolescent depression and should not be used as a first-line medication. Moreover, they are associated with more side effects than the SSRIs and are potentially lethal in overdose.
Antidepressants increase the risk of spontaneously reported suicidal adverse events by about twofold, with estimates of the risk difference ranging between 9 to 2% (Bridge et al. 2007). Most of these suicidal adverse events were increases in suicidal ideation, with relatively few attempts and no completions. Twelve times more depressed youths show a clinical response than experience a suicidal event. Those depressed youth with high suicidal ideation, irritability or anger, family conflict, and drug and alcohol use have been reported to be at higher risk for a suicidal adverse event. While disinhibition, switch to ► mania, onset of ► akathisia, increased irritability, and non-adherence followed by withdrawal from medication have all been posited to be related to suicidal adverse events, none of these hypotheses have been tested in pedi-atric samples. The ability to identify those who are most likely to respond and least likely to have adverse events is critical given the current level of concern about the associated risk of suicidality (Brent and Maalouf 2009).
SSRIs and other newer antidepressants are associated with side effects that are dose dependent and that may subside with time. The most common side effects include gastrointestinal symptoms, sleep changes (e.g., insomnia, somnolence or nightmares), restlessness, headaches, changes in appetite, and ► sexual dysfunction. Approximately 5% of youths, mainly young children, may have behavioral activation characterized by increased agitation and irritability or silliness. It is clinically important to differentiate these symptoms from mania or hypomania that may be induced by the antidepressant in children and adolescents with bipolar disorder or a family history of bipolar disorder. Other rare side effects include ► serotonin syndrome, ► extrapyramidal syndrome and increased bleeding time.
Side effects that are specific to some newer antidepres-sants include elevated blood pressure and tachycardia with venlafaxine; increased appetite, weight gain and somnolence with mirtazapine; risk of priapism in males taking trazodone; risk of fulminant hepatitis with nefazo-done (which has led to its removal from some markets as a result); and risk of seizure with immediate-release formulations of bupropion, especially in doses higher than 400 mg/day and in patients with a history of eating disorders.
Issues to consider in treating a child or adolescent who is not responding to treatment include misdiagnosis, undetected bipolar disorder, untreated comorbid medical or psychiatric disorder and non-adherence to treatment. Evidence shows that for the treatment of depressed adolescents who have not responded to an initial adequate trial with an SSRI, a switch to another SSRI is just as efficacious as a switch to venlafaxine, with fewer side effects (Brent et al. 2008). Small studies using ► lithium augmentation in resistant depression in adolescents have shown contradictory results. Studies in adult depression suggest that augmentation with atypical antipsychotics (such as ► aripiprazole), lithium, or thyroid hormone (T3) is efficacious and well-tolerated, but such studies have not been conducted in younger populations. Finally, some reports have suggested that ► electroconvulsive therapy (ECT) may be efficacious in treating resistant depression in adolescents, especially those with bipolar depression, although further research in this area is needed.
► Adolescence and Responses to Drugs
► Antidepressants: Recent Developments
► Bipolar Disorder in Children
► Dysthymic Mood Disorder
► NARI Antidepressants
► SNRI Antidepressants
► SSRIs and Related Compounds
American Psychiatric Association (1994) Diagnostic and statistical manual of mental disorders (DSM-IV), First, M. B. 4th edn. American Psychiatric Association, Washington Birmaher B, Brent D, Work Group on Quality Issues (2007) Practice parameters for the assessment and treatment of children and adolescents with depressive disorders. J Am Acad Child Adolesc Psychiatry 46:1503-1526 Brent DA, Maalouf FT (2009) Pediatric depression: is there evidence to improve evidence-based treatment? J Child Psychol Psychiatry 50(1-2):143-152
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Bridge JA, Birmaher B, Iyengar S, Barbe RP, Brent DA (2009) Placebo response in randomized controlled trials of antidepressants for pe-diatric major depressive disorder. Am J Psychiatry 166:42-49 Curry J, Rohde P, Simons A, Silva S, Vitiello B, Kratochvil C, Reinecke M, Feeny N, Wells K, Pathak S, Weller E, Rosenberg D, Kennard B, Robins M, Ginsburg G, March J, TADS Team (2006) Predictors and moderators of acute outcome in the Treatment for Adolescents with Depression Study (TADS). J Am Acad Child Adolesc Psychiatry 45(12):1427-1439
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