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Historically, the first nonstimulant treatments for ADHD that were extensively evaluated were the TCAs (see Table 4–2). Out of 33 studies (21 controlled, 12 open) evaluating TCAs in children, adolescents (n = 1,139), and adults (n = 78), 91% reported positive effects on ADHD symptoms (Spencer et al. 1997). Imipramine and desipramine are the most studied TCAs, followed by a handful of studies on other TCAs. Although most TCA studies (73%) were relatively brief, lasting a few weeks to several months, nine studies (27%) reported enduring effects for up to 2 years. Outcomes in both short- and long-term studies were equally positive. Although one study (Quinn and Rapoport 1975) reported a 50% dropout rate after 1 year, it is noteworthy that among participants who remained on imipramine, improvement was sustained. Other studies using aggressive doses of TCAs have reported sustained improvement for up to 1 year with desipramine (>4 mg/kg) (Biederman et al. 1986; Gastfriend et al. 1985) and nortriptyline (2.0 mg/kg) (Wilens et al. 1993). Although response was equally positive at all dosage ranges, it was more sustained in those studies that used higher doses. A high interindividual variability in TCA serum levels has been consistently reported for imipramine and desipramine, with little relationship between serum level and daily dosage, response, or side effects. By contrast, nortriptyline appears to have a positive association between dosage and serum level (Wilens et al. 1993).

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