NEWER ANTIDEPRESSANTS: Beyond Selective Serotonin Reuptake Inhibitor Antidepressants

Major depressive disorder in children and adolescents is a significant problem and is also a predictive indicator of severe long-term difficulties. 22,43 Although the phenomenology of child and adolescent depression versus adult depression is held to be similar, 51 child and adolescent depression has not been shown to clearly respond to treatment with tricyclic antidepressants (TCAs) in double-blind studies. More evidence may be available for children than for adolescents. 1a,19,42 These generally negative findings have been reviewed, 20 and the sudden unexplained deaths in children receiving desipramine 29,32,33,39 have caused widespread concern about use of TCAs in children and adolescents. Citing the lack of rigorous scientific evidence supporting the superiority of TCAs in child and adolescent depression compared with placebo, along with these sudden unexplained deaths, Geller 17 and Werry 52 have expressed concern about the routine use of TCAs in children and adolescents. As noted in the article by Labellarte and colleagues elsewhere in this issue, the emergence of selective serotonin reuptake inhibitors (SSRIs) has allowed for further psychopharmacologic methods for treating child and adolescent depression. Fluoxetine, fluvoxamine, sertraline, and paroxetine have been found in open studies to provide effective antidepressant activity without the sedating, anticholinergic, or cardiotoxic reactions observed with TCAs, although the incidence of insomnia, nervousness, restlessness, and anxiety are higher. 4,21,50 McConville and colleagues 25 found positive effects for sertraline in treating major depressive disorder in adolescents and also noted that scale ratings of depression frequently varied, being worsened by adverse events and improved by positive life circumstances. There may also be an emergence of an endogenous component in early childhood and adolescence, either as a pure syndrome or following repeated stressors. 34 If repeated stressors can be shown to lead to a nonreactive pattern, a strong argument can be made for early psychopharmacologic and psychotherapeutic intervention in children and adolescents with major depressive disorders and double depressions (e.g., dysthymia and major depressive disorder). Follow-up of child and adolescent depressives suggests that these disorders can become long-term, causing debilitating problems, including not only depression but also impairment in psychosocial and educational functioning. 23,37 A few double-blind studies on SSRIs in child and adolescent depression have been conducted. Simeon and colleagues 45a did not find statistically significant differences between fluoxetine versus placebo for depression; however, in an important study by Emslie and colleagues, 12 in which 96 children and adolescents were treated with either fluoxetine or placebo, a significant difference was found among treated and untreated groups on the Children's Depression Rating Scale Revised 36 and the Clinical Global Impression Scale for depression. 28 In this study, placebo effect was similar to drug effect in the first week of outpatient treatment; however, over the 8-week period of the trial, significant differences emerged in the criteria noted earlier. 3 Therefore, a significant difference in efficacy may exist among drug versus placebo studies for both TCAs and SSRIs in depressed children and adolescents provided that a sufficiently large sample is used in studies to indicate differences between placebo and drug response. In addition, careful measurements must be taken both within single centers and between centers to ensure inter-rater reliability. Although the current clinical preference is to use SSRIs rather than TCAs in the treatment of child and adolescent depression, the hard evidence for efficacy from controlled studies is minimal. Moreover, a connection between the clinical effectiveness of these medications and their degree of serotonin reuptake inhibition seems to be lacking. Further studies of the "traditional" TCAs and SSRIs are needed, including multidose studies of SSRIs in children and adolescents with depressive disorders; however, also needed is more exploration of newer or alternate antidepressive agents. The following section begins with an overview of these compounds and leads into a discussion of the most common alternate antidepressants used by practitioners, as well as some newer developments.