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How Strattera and stimulants can be utilized in combination to extend duration of ADHD symptom relief without intolerable side effects.

Atomoxetine and Stimulants in Combination for Treatment of Attention Deficit Hyperactivity Disorder: Four Case Reports

Thomas E. Brown - Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut

Thomas E. Brown. Journal of Child and Adolescent Psychopharmacology. 2004, 14(1): 129-136. doi:10.1089/104454604773840571.


Atomoxetine and stimulants have both been demonstrated effective as single agents for treatment of attention deficit hyperactivity disorder in children, adolescents, and adults. However, attention deficit hyperactivity disorder symptoms in some patients do not respond adequately to single-agent treatment with these medications, each of which is presumed to impact dopaininergic and noradrenergic networks by alternative mechanisms in different ratios. Four cases are presented to illustrate how atomoxetine and stimulants can be utilized effectively in combination to extend duration of symptom relief without intolerable side effects or to alleviate a wider range of impairing symptoms than either agent alone. This combined pharmacotherapy appears effective for some patients who do not respond adequately to monotherapy, but because there is virtually no research to establish safety and effectiveness of such strategies, careful monitoring is needed.


Atomoxetine (ATX), a specific noradrenergic reuptake inhibitor approved by the U.S. Food and Drug Administration in November 2002, is the first new medication approved for treatment of attention deficit hyperactivity disorder (ADHD) in many years. In clinical trials including 3,264 children and 471 adults (D. Michelson, personal communication, September 15, 2003). ATX has been demonstrated to be safe and effective as a monotherapy for treatment of ADHD.

This new compound is quite different from stimulants, the long-established mainstay for treatment of ADHD. It has shown minimal risk of abuse and is not a schedule II agent; therefore, it can be prescribed with refills and distributed by physicians in samples. Unlike the stimulants that act primarily on the brain's dopamine (DA) system, ATX exerts its action primarily through the noradrenergic system of the brain.

Evidence suggests that there is an important role for both norepinephrine (NE) and DA systems in the pathophysiology of ADHD (Pliszka 2001). It appears that cognitive management systems of the brain can become dysregulated by either insufficiency of DA and/or NE in synapses or by excessive synaptic release of DA and/or NE (Arnsten 2001). There Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut. is some consensus that DA and NE are centrally important in ADHD (Biederman and Spencer 1999), but relative importance of these two catecholamines in particular ADHD subtypes or in particular cases with or without specific comorbidities has not been established.

Although the stimulants methylphenidate (MPH) and amphetamine block reuptake of both NE and DA at their respective transporters, the primary mechanism of action of these stimulant medications widely used for ADHD is via the dopaminergic system of the brain (Grace 2001; Pliszka 2001; Solanto et al. 2001). Until ATX the primary noradrenergic medications for treatment of ADHD were the tricyclic antidepressants. These agents have been shown effective for treatment of ADHD, but risks of adverse cardiovascular effects have caused many clinicians to avoid theft use. Analysis of tricyclic antidepressant response profiles suggests that these agents more consistently improve behavioural symptoms of ADHD) than cognitive function as measured in neuropsychological testing (Biederman and Spencer 1999). In contrast, ATX has not shown elevated cardiovascular risks and has been shown effective for both inattentive and hyperactive-impulsive symptoms of ADHD (Michelson et al 2001. 2002, 2003), although relative efficacy of ATX and stimulants on the two symptom sets has not yet been established.

The mechanism of action for ATX is more specific than that of the tricyclic antidepressants. It inhibits reuptake by the presynaptic NE transporter with minimal affinity for other noradrenergic transporters or receptors (Gehlert et al. 1993; Wong et al. 1982). This pattern of affinity might suggest that its therapeutic benefits derive exclusively from action on noradrenergic circuits, but the process may not be that simple. Preclinical work by Bymaster et al. (2002) and Lanau et al. (1997) suggests that noradrenergic agents such as ATX may act indirectly but potently on the DA system in addition to their recognized impact on noradrenergic receptors. It may be that both stimulants and ATX impact both dopaminergic and noradrenergic circuits in the brain, albeit in different ratios or sequences.

Given the complexity of ADHD and of the mechanisms of action in agents used to treat the disorder, it is likely that ADHD symptoms of some patients with respond to one ratio of noradrenergic versus dopaminergic intervention better than to another. For many patients, ATX or stimulants are quite effective as single agents for alleviating ADHD symptoms, yet some who suffer from ADHD impairments continue to experience significant problematic symptoms when treated with either a stimulant or ATX alone.

In cases where response obtained from a single agent is insufficient, the possibility of utilizing ATX and stimulants in combination may be considered. This combined treatment strategy is similar to the combination of MPH with fluoxetine reported by Gammon and Brown (1993), although that study focused exclusively on ADHD with comorbid symptoms. This report is concerned with treatment of core symptoms of ADHD alone as well as with the more commonly found cases of ADHD complicated by various comorbid symptoms (Brown 2000).

The following case reports describe patients carefully diagnosed with ADHD who did not respond adequately to treatment with a stimulant or ATX as a single agent. In some cases, ATX was added to an existing regimen of a stimulant; in others, a stimulant was added to a regimen of ATX. Each brief vignette describes the problematic symptoms, the regimen tried, and the patient's response. Possible indications for such combined treatment are described, and risks and benefits to such treatment strategies are discussed.