Efficacy From Published Trials

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Chapter: Pharmacovigilance: The Efficacy and Safety of Selective Serotonin Reuptake Inhibitors for the Treatment of Depression in Children and Adolescents

The studies used many outcome measures including (1) symptom rating scale score change from baseline (intent to treat model); (2) symptom rating scale score change at final endpoint (completers model); (3) percent improved and (4) clinical global impression (CGI) rating score change.


EFFICACY FROM PUBLISHED TRIALS

Table 45.1 describes the major published SSRI efficacy studies conducted in US youth. The studies used many outcome measures including (1) symptom rating scale score change from baseline (intent to treat model); (2) symptom rating scale score change at final endpoint (completers model); (3) percent improved and (4) clinical global impression (CGI) rating score change. Two of the fluoxetine studies did not meet the a priori primary endpoint of symp-tom score reduction from baseline (Emslie, Rush and Weinberg, 1997; Emslie et al., 2002) causing a FDA statistical expert to reject the efficacy claim (Shen, 2003). For the studies including both children and adolescents, Wagner (sertraline) and Emslie (fluoxe-tine), significant improvement resided entirely in the adolescent group. Moreover, even in the age group most likely to benefit, symptom reduction was not different between active drug- and placebo-treated youth in the paroxetine study of adolescent depression by Keller et al. (2001). The authors therefore based the conclusion of paroxetine efficacy on a relatively modest difference in the percent improved (63 vs. 46). The NIMH-funded treatment of adolescent depression study (TADS) was added to the list of registra-tion trials for the FDA safety analysis (see below ‘SAFETY FROM CLINICAL TRIAL DATA’). The TADS study is listed here among the major efficacy studies, but it should be noted that it was primar-ily conducted to assess the efficacy of fluoxetine relative to a psychotherapy intervention of proven efficacy [cognitive behaviour therapy (CBT)] and may better qualify as a management trial because of the limited use of blinded observations. The TADS authors concluded that for the treatment of adoles-cent depression fluoxetine in combination with CBT gave better results than fluoxetine alone, CBT alone or placebo. In summary, published US studies on SSRIs show modest but statistically significant effects over placebo in adolescents. The data do not support effi-cacy in children although published clinical interpreta-tions suggest moderate overall effectiveness (Vitiello and Swedo, 2004), are silent on this important distinc-tion (Cheung, Emslie and Mayes, 2005) and focus on the weak safety evidence in the face of the seri-ous risks of the failure to treat depression irrespective of efficacy in children compared with adolescents (Brent, 2004; Cheung, Emslie and Mayes, 2005; Mann et al., 2006).

 

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