New Advances in the Psychopharmacological Treatment of Mood Disorders
Graham J. Emslie, M.D.
Taryn L. Mayes, M.S.
Depressive disorders are leading causes of morbidity and mortality in the pediatric age group, with a prevalence rate of up to 8.3%. Unfortunately, depression in children and adolescents continues to go frequently undetected. It is associated with increased family problems and school failure and, particularly in adolescents, suicide, substance abuse, and truancy. Generally speaking, the phenomenology and biology of depression in children and adolescents are similar to adult depression. However, accurate diagnosis requires experience in the diagnostic assessment of children, given that the evaluation process requires the use of multiple informants (child, parent, and teachers or school counselors) and synthesis of the information collected.
General Treatment Approach
The primary aim of treatment is to shorten the episode of depression (remission), to prevent recurrence, and to decrease the negative consequences of episodes of depression. To achieve these goals, intervention can occur at multiple levels, including individual psychotherapy, family therapy/ education, and pharmacologic treatment. Treatment should be individualized and based on need, resources, and assessment of stressors involved in a particular case. Supportive psychotherapy is an essential component of an individualized treatment plan, independent of whether specific psychotherapies or medication are used.
Assuming that the symptoms of depression are persistent in the depressed child in spite of preliminary psychosocial interventions, then an initial decision is which medication is the first line of medication treatment. Selective Serotonin Reuptake Inhibitors (SSRIs) are the initial medication choice in this age group. Several well-designed trials of tricyclic antidepressants (TCAs) in children and adolescents have failed to demonstrate effectiveness compared to placebo.1 However, two recent trials in children and adolescents have shown the effectiveness of fluoxetine2 and paroxetine3 (in adolescents). Additionally, side effects are substantially less with SSRIs compared to TCAs, and of particular relevance in adolescents, they are safer in overdose.
For patients who do not respond to acute treatment, the question of switching medications versus augmentation often plagues clinicians. However, prior to making any changes, it is important to reassess the following based on the accuracy of the initial diagnosis and on the presence of previously unrecognized conditions: 1) Are there previously unrecognized comorbid diagnoses [e.g. attention-deficit/ hyperactivity disorder (ADHD), anxiety disorders, bipolar, substance abuse, eating disorder, etc.]? 2) Are there unrecognized medical conditions? 3) Has the patient been compliant with treatment? 4) Are there new or additional psychosocial factors impacting treatment? and 5) Is there family dysfunction or psychopathology in family members that require more intensive treatment?
The benefits of switching to a different medication over augmentation of the current medication include: 1) lower chance of medication interaction, 2) possibly fewer side effects, 3) possibly less expensive, 4) possible different mechanism of action of the new medication, and 5) possible increased adherence to the medication.
In children and adolescents, data exist to support efficacy of lithium as an augmenting agent4. Augmentation is typically used when there is a partial response in prior treatment, or the possibility of drug-drug synergy. The advantages of augmentation versus switching to an alternative treatment are 1) no need for discontinuation of initial antidepressant; 2) no lag of response; 3) partial responders continue to get treatment without interruption; and 4) no loss of drug-drug synergy. By definition, augmentation is with an agent not normally used as an antidepressant monotherapy.
Failure of treatment can also result from side effects. It is important to separate the use of additional medications to treat side effects from the use of additional medication to augment the initial treatment response. Adverse events seen in SSRIs include insomnia and behavioral activation. Insomnia is a common symptom of depression and also a side effect of SSRIs, so many clinicians prescribe SSRIs in combination with trazadone or another sedating antidepressant. However, frequently the insomnia improves with continued treatment of the SSRI alone, and often combined treatment is unnecessary
A proportion of children treated with antidepressants will evidence a worsening of their behavior. Some of these are due to development of manic symptoms. Approximately 3-6% of children with severe depression can switch to develop manic symptoms on antidepressant treatment.
Course of Illness
Recovery from an episode of major depression in children and adolescents is remarkably consistent across samples, with over 85% of depressed children and adolescents having recovered within one to two years. However, substantial information exists that relapse and recurrence (new episode) of depression occur naturalistically in children and adolescents equally or surpassing the relapse rates in adults. Once recovered, depressed children and adolescents have a high rate of recurrence (new episode) of their depression. Follow-up studies show rates of recurrence of 54-72% in depressed children and adolescents followed for 3-8 years. These rates are similar in inpatients5,6 and outpatients.7,8,9,10
Unfortunately, no controlled data is available specific to children and adolescents to provide a guideline for how long to treat an episode of depression to prevent relapse. Most suggests it is the same as adults, i.e. 4 to 6 months. Also, it is not possible at this time to determine who requires maintenance treatment, i.e. treatment to prevent new episodes of depression. Patients with severe depression and a history of previous episodes are likely to be treated for a longer period of time than 4-6 months, but unlike adults it is premature to assume that a certain number of previous episodes would necessarily necessitate lifelong treatment.
Diagnosing depressive disorders requires substantial clinical acumen. Failure to identify these problems will often lead to under-treatment or less than adequate treatment of a potentially very curable condition. While it is possible that preliminary indication for efficacy can be extrapolated from adults, there is sufficient difference between adult mood disorders and mood disorders in children and adolescents to require that all treatments be evaluated in children and adolescents. There appears to be a consensus that the first line of medication treatment for major depressive disorders (MDD) in an adolescent would be an SSRI, primarily based on preliminary effectiveness trials, limited side effect profile, and safety in overdose. However, continued research is needed about the effectiveness and safety of medication in children and adolescents. Also, research on how long to continue treatment once it has been shown to be effective is needed. Finally, research is needed on the combination of effective psychotherapies with psychopharmacology. While research in mood disorders in children and adolescents poses many methodological challenges, it is an exciting and important area of study.
- Hazell P, O'Connell D, Heathcote D, et al (1995), Efficacy of tricyclic drugs in treating child and adolescent depression: A meta-analysis. BMJ 310:987-901
- Emslie GJ, Weinberg WA, Kowatch RA, Hughes CW, Carmodv T, Rintelmann JW (1997a), A double-blind, randomized, placebo-controlled study of fluoxetine in depressed children and adolescents. Archives of General Psychiatry, 54:1031-1037
- Wagner KD, Birmaher B, Carlson G, et al. (1998), Safety of paroxetine and imipramine in the treatment of adolescent depression. Presented at the New Clinical Drug Evaluation Unit Program (NCDEU), 39th Annual Meeting, Boca Raton, FL
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