Stimulant Medications

Methylphenidate hydrochloride, a piperidine derivative structurally similar to amphetamine, is a commonly prescribed stimulant for the treatment of ADHD in children age 6 years and older. It is a racemic mixture of d,l methyl a-phenyl-2-piperidineacetate hydrochloride. The drug is available in immediate-release, extended-release, and controlled-release formulations. It is hepatically metabolized to an inactive metabolite and excreted by the kidneys. 

In school-age children and adolescents with ADHD, treatment with immediate-release methylphenidate typically consists of administration once a day in the morning or in divided morning and noon doses. Doses can then be titrated upward on a weekly basis until improvement of target symptoms is achieved. Some patients take a third dose (typically 50% of other doses) in the late afternoon to manage symptoms in the early evening hours or to minimize rebound symptoms. Extended-release and controlled-release formulations have longer durations of action and are often preferred because less frequent dosing is needed. 

Ritalin-SR, ADHD May be given once every morning in place of total daily dose of Methylin ER, immediate-release methylphenidate to achieve an estimated 8-hour duration of Metadate ER action. 

Ritalin LA ADHD Children 6 years old Start at 20 mg once daily (or lower at clinician s discretion) increase by 10 mg weekly. 

Switching from immediate-release methylphenidate or methylphenidate-SR  

---

The main indication for certain psychostimulants is ADHD in children and adults [4]. Recent research shows that the clinical effect and benefit are dramatic even in adults. About 60% of adult patients receiving stimulant medication showed moderate-to-marked improvement, as compared with 10% of those receiving placebo. The core symptoms of hyperactivity,... 

The proposed mechanism of ADHD pharmacotherapy is to modulate neurotransmitters in order to improve academic and social functioning. Pharmacologic therapy can be divided into two categories stimulants and non-stimulants. Stimulant medications include methylphenidate, dexmethylphenidate, amphetamine salts, and dextroamphetamine, whereas non-stimulant medications include atomoxetine, tricyclic antidepressants (e.g., imipramine), clonidine, guanfacine, and bupropion. 

Psychostimulants (e.g., methylphenidate and dextroamphetamine with or without amphetamine) are the most effective agents in treating ADHD. Once the diagnosis of ADHD has been made, a stimulant medication should be used first line in treating ADHD (Fig. 39-1). Stimulants are safe and effective, with a response rate of 70% to 90% in patients with ADHD.3,13,14 Generally, a trial of at least 3 months on a stimulant is appropriate, and this includes dose titration to response... 

Stimulants Medications that increase physiologic activity in the body by augmenting dopamine and/or norepinephrine. 

Dopamine-Stimulating Medications. A variety of drugs that increase the availability of dopamine have been studied in cocaine addicts including L-DOPA, bupropion, amantadine, and methylphenidate. In small uncontrolled trials, these have shown some benefit, but definitive studies have yet to be performed. In addition, some dopamine-stimulating medications (in particular, the stimulants like methylphenidate or the amphetamines) are themselves subject to abuse, though, of note, this is typically not a problem when they are prescribed to patients who do not have a history of substance abuse such as, for example, in the treatment of attention deficit-hyperactivity disorder. 

Tricyclic Antidepressants (TCAs). The TCAs have been nsed to treat ADHD for 30 or more years. Most often used are imipramine (Tofranil) and desipramine (Norpramin), mainly becanse they are the TCAs that most specihcally increase norepinephrine activity. Remember, boosting norepinephrine activity in the brain shonld improve attention. Other TCAs, namely, amitriptyline (Elavil, Endep) and nortriptyline (Pamelor), have been used, though they also increase norepinephrine activity. TCAs do offer a modest benefit for both the inattention and the hyperactivity of ADHD. In addition, they are often effective at doses mnch lower than those required to treat depression. However, their effectiveness nsnally falls short of the stimulant medications. In addition, TCAs have considerable side effects including dry mouth, constipation, drowsiness, weight gain, and adverse cardiac effects. 

Bupropion (Wellbutrin, Zyban). Bupropion is a newer atypical antidepressant that was initially suggested to increase both norepinephrine and dopamine activity in the brain, though controversy surrounds this hypothesis. Although bupropion has not been studied extensively in ADHD, early evidence does indeed indicate that it may be effective for both inattention and hyperactivity/impulsivity. Its effectiveness for ADHD does not appear to rival the stimulant medications, though a recent controlled study for adult ADHD showed that bupropiou outperformed placebo. 

For example, stimnlants can cause irritability. However, irritability can also resnlt from depression. So it is always important to rule out comorbid depression in the patient with ADHD before discontinuing the stimulant medication. If the irritability does resnlt from depression, then the obvious solution is to add an antidepressant to the stimnlant. Conversely, irritability can also be a symptom of emerging hypomania or mania. 

Straterra is the first new chemical entity approved to treat ADHD in over 30 years, and it has major advantages over the stimulant medications in that it has been clinically demonstrated to have no abuse liability. The nonstimulant mechanism of action also appears to come with some caveats in terms of efficacy versus the stimulants. Synthetically, the main challenge within this molecule is installing the chiral center, which is... 

The most common treatments for ADHD are the stimulant medications methylphenidate and amphetamines. Secondary medications include dopaminergic or noradrenergic reuptake blockers (e.g., a tamoxetine) and ttj-adrenergic agonists. These treatments are reviewed in this volume (see Chapters 20, 21, 24, and 35). Thus, only brief reference will be made here to the possible effects these compounds may have vis-a-vis modulation of attentional circuits. These ideas are summarized in Figure 8.2. 

Although these long-duration versions of stimulant medications have been available for more than a decade, their clinical use has been limited. Expert raters reviewing behavioral and continuous performance test (CPT) data first reported that MPH-SR20 was less effective than the standard MPH at 10 mg two times a day, when both were used to treat 13 children with ADHD in a summer program (Pelham et ah, 1989). This reduced effect may be related to delayed onset of action and its lower plasma level peak (Birmaher et ah, 1989). 

Once the child has been stabilized on a stimulant medication, the child should come in for regular medication management. This may be as frequent as once a month for children with adverse events or unstable symptoms, or once every other month for those who are stable. 

The effects of stimulant medication generally cease upon discontinuation of the treatment. One double-blind study, however, did not find this to be necessarily true for DEX (Gillberg et ah, 1997). Many patients favor a period off the medication, a drug holiday, to deal with the partial suppression of weight gain, worries about long-term effects, or to assess the need for staying on medication. This type of trial is best done when the child is not scheduled for important school tests or social activities (e.g., summer camp). 

Matochik, J., Nordahl, T., Gross, M., Semple, M., King, A., and Cohen, R., Zametkin, A. (1993) Effects of acute stimulant medication on cerebral metabolism in adults with hyperactivity. Neuropsychopharmacology 8 377—386. 

Schmidt, K., Solanto, M.V., and Sanchez, M. (1984) The effect of stimulant medication of academic performance, in the context of multimodal treatment, in attention deficit disorders with hyperactivity. / Clin Psychopharm 4 100—103. 

Swanson, J. (1993) Effect of stimulant medication on hyperactive children a review of reviews. Exceptional Child 60 154-162. 

The Multimodal Treatment of ADHD (MTA) Study, a large, multisite study of ADHD treatment (MTA Cooperative Group, 1999), highlights the importance of this therapeutic alliance. When outcome was measured only in terms of the child s inattention, stimulant medication alone did as well as medication plus psychosocial treatment. However, the combination of medication and psychotherapy had the best outcome in parent satisfaction and in reducing disruptive behaviors (Hinshaw et ah, 2000), which are important factors in longer-term compliance with treatment and outcome. 

A bright 10-year-old boy had had a life-changing response to combined cognitive behavioral therapy and stimulant medication that allowed him to transfer to a better school, make new friends, and return to his beloved music classes. Still, his father, who had suffered similarly, but gone untreated as a child, was concerned that all we had done was a naughty-ectomy, not real therapy. His son, somehow aware of his father s concerns, would occasionally taunt him Just call me Speedo [aware he was on a stimulant]—I am what I takeV ... 

First, exclusive treatment with stimulant medication is effective, but may not be maximally effective for core ADHD outcomes in some children. That is, many children will experience reductions in symptoms that nevertheless continue to occur at clinically significant levels. Stated differently, while many children improve substantially with pharmacotherapy, most do not reach full normalization on symptoms with stimulant treatments alone, even at very high doses. Conversely, a greater percentage of children achieve normalization with combination treatment. 

Swanson, J., Kinsbourne, M., Roberts, W, and Zucker, K. (1978) Time-response analysis of the effect of stimulant medication on... 

Taylor, E., Schachar, R., Thorley, G., Wieselberg, H.M. Everitt, B., and Rutter, M. (1987) Which boys respond to stimulant medication A controlled trial of methylphenidate in boys with dis-tuptive behaviour. Psychol Med 17 121-143. 

Whalen, C. (1989). Does stimulant medication improve the peet status of hyperactive children J Consult Clin Psychol 57 545-549. 

Case reports have suggested that adding stimulant medications or combining a SSRI and a TCA or bupropion may also be effective (APA, 2000), but these combinations need to be done with caution, given the possibility of drug interactions (e.g., SSRIs cytochrome inhibition leading to toxic TCA levels). Additionally, in adults, the combination of antidepressants and psychotherapy (CBT, IPT) for patients with severe or treatment-resistant depression has been found useful (APA, 2000 Keller et al., 2000). 

Varley, C.K., Vincent, J., Varley, R, and Calderon, R. (2001) Emergence of tics in children with attention deficit hyperactivity disorder treated with stimulant medications. Compr Psychiatry 42 228-233. 

Another major safety concern in the treatment of youth with SUD is abuse of prescribed medications. Particular controversy has arisen around the use of stimulant medication in youth with SUD and ADHD. In one controlled study of adults, the use of methyl-phenidate (Ritalin) did not increase cocaine use or craving for cocaine (Grabowski et ah, 1997), suggesting that the abuse potential of stimulants may be overestimated. Riggs et al. (1996) did not report any difficulties with abuse when administering pemoline (Cylert) to a group of adolescents with SUD and ADHD. While Riggs and associates have observed that... 

Firestone, P., Monteiro-Musten, L., Pisterman, S., Mercer, J., and Bennett, S. (1998) Short-term side effects of stimulant medication are increased in preschool children with attention-deficit/hyper-activity disorder a double-blind placebo-controlled study. / Child Adolesc Psychopharmacol 8 13—25. 

---