New Agents and Second-line Therapies for Attention-Deficit/Hyperactivity Disorder

Marcia L. Buck, Pharm.D., FCCP


Pediatr Pharm. 2002;8(4) 

In This Article

Tricyclic Antidepressants and SSRIs

Over two dozen studies have documented the benefits of the tricyclic antidepressants and their successors, the selective serotonin reuptake inhibitors (SSRIs) in patients with ADHD. While they may not be as effective as stimulants, these agents are often beneficial in refractory cases, as combination therapy in patients failing single-agent therapy, or in patients with psychiatric comorbidities. Traditionally, imipramine and desipramine have been chosen for this patient population. The recommended starting dose for both agents in children with ADHD is 2 mg/kg/day (divided into two doses) titrated weekly up to 5 mg/kg/day. While these low doses have been effective for controlling ADHD symptoms, they are usually too low to treat comorbid depression or anxiety.[12] However, they may improve other comorbidities, such as tic disorders.

Patients receiving tricyclic antidepressants should be monitored for adverse cardiovascular effects. Five cases of sudden cardiac death in children receiving tricyclic antidepressants were reported in the 1980's and 1990's, although causality could not be clearly established. Prior to starting therapy and periodically during treatment, a history and physical examination should be obtained to identify any changes in heart rate or rhythm. Other disadvantages to their use include tolerance with long-term use, the need for multiple daily dosing, and the risk for severe toxicity in the event of an overdose.

Because of their selectivity for serotonin, the SSRIs offer several advantages over the tricyclics, primarily fewer adverse effects and reduced toxicity with overdose. Their selectivity, however, may limit their usefulness in ADHD, where inhibition of norepinephrine reuptake may also be needed. In 1991, Barrickman and colleagues reported the results of an open-label trial of fluoxetine in 19 children (ages 7-15 years) with ADHD.[13] All were considered resistant to standard treatment. The average dose after titration was 27 mg/day (range 20-60 mg). Eleven patients (58%) showed at least moderate improvement over six weeks. Adverse effects were minimal. Based on their results, the authors recommended fluoxetine as an alternative for refractory ADHD.

In 1993, Gammon and Brown conducted a second open-label trial of fluoxetine.[14] In their study, 32 patients (9-17 years of age), were given doses up to 20 mg/day over 12 weeks, in addition to their baseline methylphenidate regimen. Thirty patients (94%) showed significant improvement in ADHD symptoms. As in the earlier trial, fluoxetine was well tolerated. With a lack of comparison trials, the role of the SSRIs in ADHD remains undefined. Further research is needed to explore the potential utility of this therapeutic class.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.