abre los ojos
02-10-05, 08:14 PM
Here's a good article to show a Dr. who thinks all stimulants are the same.
Algorithm for the Psychopharmacological
Treatment of ADHD
Steven R. Pliszka, M.D.
Associate Professor and Chief
Division of Child and Adolescent Psychiatry
The University of Texas Health Science Center at San Antonio
Review of treatment literature in ADHD
ADHD is one of most effectively treated child disorders. A quarter-century of published treatment studies and clinical experience attest to the short-term effectiveness of pharmacological strategies (Richters et al., 1995). It has been estimated that between 2 and 2 1/2% of all school-aged children in North America receive some pharmacological intervention for hyperactivity (Bosco& Robin, 1980), with more than 90% being treated with the psychostimulant methylphenidate (MPH) (Greenhill, 1995; Wilens& Biederman, 1992).
Stimulants
Psychostimulants have consistently shown robust behavioral efficacy in over 100 randomized controlled trials (RCTs) of school age children; the level of support for these drugs in ADHD is more than adequate to inform practice. Studies comparing stimulants to placebo began in the early 1960s, with small-numbered, single-site, short-duration trials. By 1993, Swanson’s "Review of reviews" reported over 3,000 citations and 250 reviews of stimulant treatment (Swanson et al., 1993). Robust short-term stimulant-related improvements in ADHD symptoms were found in 161 studies encompassing 5 preschool, 140 school age, 7 adolescent and 9 adult RCTs (Spencer et al., 1996). Improvement was noted for 65-75% of the 5,899 patients assigned to stimulant treatment versus only 4-30% of those assigned to placebo for MPH (n=133 trials), dextroamphetamine (DEX) (n=22 trials), and pemoline (PEM) (n=6 trials). Compared to placebo in short-term, double-blind trials, the stimulants demonstrate robust efficacy in improving the two prominent symptom clusters found in ADHD (inattentiveness and hyperactivity-impulsivity) assessed on the basis of parent and teacher rating scales, direct observations in natural settings, and laboratory tests (Greenhill, 1998; Jacobvitz et al., 1990; Spencer et al., 1996; Swanson et al., 1993). Three meta-analyses, conducted in the early 1980's, separately concluded that the efficacy for stimulants - in placebo-controlled, double-blind trials - was very strong, with effect sizes in the range of 0.8-1.0 (Kavale, 1982; Ottenbacher& Cooper, 1983; Thurber& Walker, 1983).
Recently, three studies found mixed amphetamine salts (Adderallâ ) superior to placebo (Pelham et al., 1999; Pliszka et al., 1999; Swanson et al., 1998), with the first two studies suggesting the mixed amphetamine salts to have some advantages over immediate-release methylphenidate. Pliszka et al (1999) found that Adderall was superior to methylphenidate in improving teacher ratings of inattention and oppositional behavior; clinician ratings also found the Adderall superior to the methylphenidate. Seventy per cent of the subject’s on Adderall were managed on once a day dosing, compared to only 15% of the children on methylphenidate who were managed on once a day dosing. Pelham et al (1999) conducted a double blind placebo controlled crossover study of low and high doses of methylphenidate and Adderall, and while both drugs were superior to placebo, clinicians recommended that 52% of the subjects be placed on Adderall for their long term medication management. <DIR><DIR><DIR>https://labs-sec.uhs-sa.com/clinical_ext/RefDocs/Image20.gif
</DIR></DIR></DIR>As noted in the figure 1, when methylphenidate and dextroamphetamine are compared head to head, only about 38% of children with ADHD respond equally well to both classes of stimulant medication (Greenhill et al., 1996) with the other subjects being selective responders. Thus having only one stimulant medication on the subsidized formulary is not sufficient- up to 30% of children with ADHD will be non-responders to it. Since mixed salts amphetamine contains levo amphetamine as well as dextroamphetamine, there may be children who respond to it rather than dextroamphetamine (Arnold et al., 1976). Thus all three stimulants should be tried before moving on to non-stimulant treatment. If 90% or more of ADHD can be managed on stimulants, the clinician can avoid moving to non-stimulants which are not only less effective, but as in the case of imipramine and clonidine, require monitoring of EKG’s and, in the case of imipramine, serum levels. The expense of this far outweighs the low cost of the imipramine.
Two reviews indicate that tricyclic antidepressant (TCA) drugs are effective in ADHD. The first, an omnibus review of pharmacotherapy of ADHD across the lifetime, identified 29 studies of tricylics involving 1016 patients (Spencer et al., 1996). A more conservative evidence-based report (Jadad& Atkins, 1998) identified 5 randomized controlled trials involving 170 children and adults, who showed robust responses to desipramine, with effect sizes approaching that reported for MPH. However, these studies reported a high rate of adverse events. Controversy over the use of desipramine (DMI) for children with ADHD was further heightened after the report of several sudden deaths in this age group with DMI treatment (Biederman et al., 1989; Popper& Ziminitzky, 1995b). Imipramine has been shown to superior to placebo, but less efficacious than methylphendiate in a number of controlled trials (Pliszka, 1987). Antidepressants should only be tried after simulants have failed.
Clonidine has been shown to be superior to placebo in reducing ADHD symptoms in a number of controlled trials (Gunning, 1992; Hunt, 1987; Hunt et al., 1985; Leckman et al., 1991; Singer et al., 1995; Hunt, 1987), though these trials were not as methodologically sound as those for stimulants or antidepressants. Controversy continues over the degree to which clonidine is associated with cardiovascular side effects (Cantwell et al., 1997; Popper, 1995a; Swanson et al., 1995). The effect size for clonidine appears to be about equal to that of tricyclic antidepressants, but far less than that of stimulants. Clonidine should be used for children who have failed stimulants and antidepressants for treatment of their ADHD. It may be used in ADHD children with comorbid Tic disorder and severe aggressive outbursts.
The algorithm illustrated in the figure shows the five medications recommended in the management of ADHD: mixed salts amphetamine (Adderall) methylphenidate, dextro-amphetamine and, bupropion, imipramine, and clonidine.
Stage 1: Stimulant Treatment
Since effectiveness of stimulants in the treatment of ADHD is without dispute, the first stage of medication intervention inevitably involves their use. No clinical predictors exist as to which child will respond to which stimulant, thus the choice of methylphenidate vs. dextroamphetamine vs mixed salts amphetamine is left to the physician and the parent. Due to economic considerations, unless contraindicated, it is recommended to start with the mixed salts amphetamine (Adderall). Prescribing, subsidy and dosing guidelines of the stimulants are shown in table 1.
Stage 2: Alternative Stimulant-1
If a child fails to respond to Adderall, or has side effects which make its long-term use inappropriate, the child should be switched to methylphenidate.
Stage 3: Alternative Stimulant –2
If a child fails both Adderall and methylphenidate, dextroamphetamine should be given a trial in stage 3.
Stage 4: Antidepressant Treatment
A number of controlled trials have shown imipramine (Pliszka, 1987) and bupropion (Conners et al., 1996) to be superior to placebo in the treatment of ADHD. It should be emphasized that since the effect size of the antidepressants is so much less than that of the stimulants; antidepressants should never be viewed as drugs of first choice in the treatment of ADHD, hence their position further down the algorithm. Bupropion may have an advantage over imipramine as the first antidepressant tried, as it does not require electrocardiogram (EKG) or serum level monitoring, though it is contraindicated in children with a seizure disorder. It only comes in 75, 100, and 150 mg pills and since the starting dose is 3 mg/kg/day it difficult to prescribe it in doses small enough for young children. The starting dose of imipramine is 1 mg/kg/day in divided doses, with increases every 2-3 weeks up to a maximum of 4 mg/kg/day. EKG and serum level should be obtained when the dose is stable and annually thereafter. Buproprion is available for CareLink patients through a medication-assistance program. Initial enrollment is made over the phone by calling the CareLink authorization line at 358-3224. The patient can receive an initial 30-day supply on the same day. The MD & the patient must sign & return the enrollment forms before refills are authorized. The patient may fill the prescription at a Health System Pharmacy for no-co-pay or at any retail pharmacy for a $5 co-pay. Unless contraindicated, or patient is too young to dose appropriately, buproprion should be tried before imipramine (which is subsidized).
Stage 5: Alternative Antidepressant
If the child’s ADHD symptoms do not respond or significant side effects are encountered with the antidepressant used in Stage 4, the physician should switch to the alternate antidepressant.
Stage 6: Clonidine
Clonidine would be the final step in the algorithm. Double asterisks (**) are added to indicate unresolved questions regarding its efficacy, safety, and the need for close monitoring of cardiovascular function. Dosing of clonidine and laboratory tests are noted in table 2.
Table 1 Dosing of Stimulants
Special Note on Prescription writing:
All of these stimulants are Class II controlled substances and require special triplicate prescription forms. To maximize cost-effectiveness, the University Health System Pharmacies will carry only certain strengths of these drugs. To avoid verbal changes and rewritten prescriptions, prescribe the doses as listed in parentheses in the following tables. For example : 10mg tablets, take ¼ tab q am ; or 10mg tablets, take 2 tabs in the am & 1 tab at noon. Do not write "take 2.5mg q am" or "20mg in am and 10mg at noon".
Special Note on Subsidy:
All three of these stimulants will be subsidized for CareLink pediatric patients (through high school or age 18). Adult CareLink patients with methylphenidate prescriptions written by Dr. James Dickson will also be subsidized. All other adult CareLink patients with prescriptions for these stimulants must have prior authorization.
Algorithm for the Psychopharmacological
Treatment of ADHD
Steven R. Pliszka, M.D.
Associate Professor and Chief
Division of Child and Adolescent Psychiatry
The University of Texas Health Science Center at San Antonio
Review of treatment literature in ADHD
ADHD is one of most effectively treated child disorders. A quarter-century of published treatment studies and clinical experience attest to the short-term effectiveness of pharmacological strategies (Richters et al., 1995). It has been estimated that between 2 and 2 1/2% of all school-aged children in North America receive some pharmacological intervention for hyperactivity (Bosco& Robin, 1980), with more than 90% being treated with the psychostimulant methylphenidate (MPH) (Greenhill, 1995; Wilens& Biederman, 1992).
Stimulants
Psychostimulants have consistently shown robust behavioral efficacy in over 100 randomized controlled trials (RCTs) of school age children; the level of support for these drugs in ADHD is more than adequate to inform practice. Studies comparing stimulants to placebo began in the early 1960s, with small-numbered, single-site, short-duration trials. By 1993, Swanson’s "Review of reviews" reported over 3,000 citations and 250 reviews of stimulant treatment (Swanson et al., 1993). Robust short-term stimulant-related improvements in ADHD symptoms were found in 161 studies encompassing 5 preschool, 140 school age, 7 adolescent and 9 adult RCTs (Spencer et al., 1996). Improvement was noted for 65-75% of the 5,899 patients assigned to stimulant treatment versus only 4-30% of those assigned to placebo for MPH (n=133 trials), dextroamphetamine (DEX) (n=22 trials), and pemoline (PEM) (n=6 trials). Compared to placebo in short-term, double-blind trials, the stimulants demonstrate robust efficacy in improving the two prominent symptom clusters found in ADHD (inattentiveness and hyperactivity-impulsivity) assessed on the basis of parent and teacher rating scales, direct observations in natural settings, and laboratory tests (Greenhill, 1998; Jacobvitz et al., 1990; Spencer et al., 1996; Swanson et al., 1993). Three meta-analyses, conducted in the early 1980's, separately concluded that the efficacy for stimulants - in placebo-controlled, double-blind trials - was very strong, with effect sizes in the range of 0.8-1.0 (Kavale, 1982; Ottenbacher& Cooper, 1983; Thurber& Walker, 1983).
Recently, three studies found mixed amphetamine salts (Adderallâ ) superior to placebo (Pelham et al., 1999; Pliszka et al., 1999; Swanson et al., 1998), with the first two studies suggesting the mixed amphetamine salts to have some advantages over immediate-release methylphenidate. Pliszka et al (1999) found that Adderall was superior to methylphenidate in improving teacher ratings of inattention and oppositional behavior; clinician ratings also found the Adderall superior to the methylphenidate. Seventy per cent of the subject’s on Adderall were managed on once a day dosing, compared to only 15% of the children on methylphenidate who were managed on once a day dosing. Pelham et al (1999) conducted a double blind placebo controlled crossover study of low and high doses of methylphenidate and Adderall, and while both drugs were superior to placebo, clinicians recommended that 52% of the subjects be placed on Adderall for their long term medication management. <DIR><DIR><DIR>https://labs-sec.uhs-sa.com/clinical_ext/RefDocs/Image20.gif
</DIR></DIR></DIR>As noted in the figure 1, when methylphenidate and dextroamphetamine are compared head to head, only about 38% of children with ADHD respond equally well to both classes of stimulant medication (Greenhill et al., 1996) with the other subjects being selective responders. Thus having only one stimulant medication on the subsidized formulary is not sufficient- up to 30% of children with ADHD will be non-responders to it. Since mixed salts amphetamine contains levo amphetamine as well as dextroamphetamine, there may be children who respond to it rather than dextroamphetamine (Arnold et al., 1976). Thus all three stimulants should be tried before moving on to non-stimulant treatment. If 90% or more of ADHD can be managed on stimulants, the clinician can avoid moving to non-stimulants which are not only less effective, but as in the case of imipramine and clonidine, require monitoring of EKG’s and, in the case of imipramine, serum levels. The expense of this far outweighs the low cost of the imipramine.
Two reviews indicate that tricyclic antidepressant (TCA) drugs are effective in ADHD. The first, an omnibus review of pharmacotherapy of ADHD across the lifetime, identified 29 studies of tricylics involving 1016 patients (Spencer et al., 1996). A more conservative evidence-based report (Jadad& Atkins, 1998) identified 5 randomized controlled trials involving 170 children and adults, who showed robust responses to desipramine, with effect sizes approaching that reported for MPH. However, these studies reported a high rate of adverse events. Controversy over the use of desipramine (DMI) for children with ADHD was further heightened after the report of several sudden deaths in this age group with DMI treatment (Biederman et al., 1989; Popper& Ziminitzky, 1995b). Imipramine has been shown to superior to placebo, but less efficacious than methylphendiate in a number of controlled trials (Pliszka, 1987). Antidepressants should only be tried after simulants have failed.
Clonidine has been shown to be superior to placebo in reducing ADHD symptoms in a number of controlled trials (Gunning, 1992; Hunt, 1987; Hunt et al., 1985; Leckman et al., 1991; Singer et al., 1995; Hunt, 1987), though these trials were not as methodologically sound as those for stimulants or antidepressants. Controversy continues over the degree to which clonidine is associated with cardiovascular side effects (Cantwell et al., 1997; Popper, 1995a; Swanson et al., 1995). The effect size for clonidine appears to be about equal to that of tricyclic antidepressants, but far less than that of stimulants. Clonidine should be used for children who have failed stimulants and antidepressants for treatment of their ADHD. It may be used in ADHD children with comorbid Tic disorder and severe aggressive outbursts.
The algorithm illustrated in the figure shows the five medications recommended in the management of ADHD: mixed salts amphetamine (Adderall) methylphenidate, dextro-amphetamine and, bupropion, imipramine, and clonidine.
Stage 1: Stimulant Treatment
Since effectiveness of stimulants in the treatment of ADHD is without dispute, the first stage of medication intervention inevitably involves their use. No clinical predictors exist as to which child will respond to which stimulant, thus the choice of methylphenidate vs. dextroamphetamine vs mixed salts amphetamine is left to the physician and the parent. Due to economic considerations, unless contraindicated, it is recommended to start with the mixed salts amphetamine (Adderall). Prescribing, subsidy and dosing guidelines of the stimulants are shown in table 1.
Stage 2: Alternative Stimulant-1
If a child fails to respond to Adderall, or has side effects which make its long-term use inappropriate, the child should be switched to methylphenidate.
Stage 3: Alternative Stimulant –2
If a child fails both Adderall and methylphenidate, dextroamphetamine should be given a trial in stage 3.
Stage 4: Antidepressant Treatment
A number of controlled trials have shown imipramine (Pliszka, 1987) and bupropion (Conners et al., 1996) to be superior to placebo in the treatment of ADHD. It should be emphasized that since the effect size of the antidepressants is so much less than that of the stimulants; antidepressants should never be viewed as drugs of first choice in the treatment of ADHD, hence their position further down the algorithm. Bupropion may have an advantage over imipramine as the first antidepressant tried, as it does not require electrocardiogram (EKG) or serum level monitoring, though it is contraindicated in children with a seizure disorder. It only comes in 75, 100, and 150 mg pills and since the starting dose is 3 mg/kg/day it difficult to prescribe it in doses small enough for young children. The starting dose of imipramine is 1 mg/kg/day in divided doses, with increases every 2-3 weeks up to a maximum of 4 mg/kg/day. EKG and serum level should be obtained when the dose is stable and annually thereafter. Buproprion is available for CareLink patients through a medication-assistance program. Initial enrollment is made over the phone by calling the CareLink authorization line at 358-3224. The patient can receive an initial 30-day supply on the same day. The MD & the patient must sign & return the enrollment forms before refills are authorized. The patient may fill the prescription at a Health System Pharmacy for no-co-pay or at any retail pharmacy for a $5 co-pay. Unless contraindicated, or patient is too young to dose appropriately, buproprion should be tried before imipramine (which is subsidized).
Stage 5: Alternative Antidepressant
If the child’s ADHD symptoms do not respond or significant side effects are encountered with the antidepressant used in Stage 4, the physician should switch to the alternate antidepressant.
Stage 6: Clonidine
Clonidine would be the final step in the algorithm. Double asterisks (**) are added to indicate unresolved questions regarding its efficacy, safety, and the need for close monitoring of cardiovascular function. Dosing of clonidine and laboratory tests are noted in table 2.
Table 1 Dosing of Stimulants
Special Note on Prescription writing:
All of these stimulants are Class II controlled substances and require special triplicate prescription forms. To maximize cost-effectiveness, the University Health System Pharmacies will carry only certain strengths of these drugs. To avoid verbal changes and rewritten prescriptions, prescribe the doses as listed in parentheses in the following tables. For example : 10mg tablets, take ¼ tab q am ; or 10mg tablets, take 2 tabs in the am & 1 tab at noon. Do not write "take 2.5mg q am" or "20mg in am and 10mg at noon".
Special Note on Subsidy:
All three of these stimulants will be subsidized for CareLink pediatric patients (through high school or age 18). Adult CareLink patients with methylphenidate prescriptions written by Dr. James Dickson will also be subsidized. All other adult CareLink patients with prescriptions for these stimulants must have prior authorization.