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Atlantic-counseling.netW H AT W E K N O W
Managing Medication for
Adults with AD/HD
AD/HD is recognized as a neurobiological disorder
that often persists from childhood into adulthood, resulting in about 4-5% of adults having AD/HD.1-5 Medication, which is an integral part of the multimodal treatment of AD/HD in children, is the cornerstone of treatment for adults.6-8 Although there is a significant amount of research in children, there is much less controlled research data on medication therapy in adults.4,9 Regarding the use of medication in the treatment of AD/HD, it has been said that "pills do not substitute for skills."45 This means that medication alone is not sufficient to help a person improve his or her problems in areas such as organization, time management, prioritizing, and using cognitive aids. However, medication levels the neurobiologic playing field, and allows adults with AD/HD to learn and develop the skills they need to succeed.
• provide a basic understanding of how stimulants can be used safely and effectively to treat AD/HD in adults • discuss nonstimulant medications for AD/HD in adults, including those approved by the Food and Drug Administration for the treatment of AD/HD in adults • discuss the effect of co-existing psychiatric disorders on the medical treatment of adults with AD/HD HOW MEDicATiON WOrKs
• Blood levels. The level of medication in the blood
Medications that most effectively improve the core varies from person to person, and blood levels symptoms of AD/HD seem to primarily and directly alone do not seem to directly correlate with clinical affect certain neurotransmitters (brain molecules that facilitate the transmission of messages from one • changes in Blood levels. There is some evidence to
neuron [brain cell] to another). The neurotransmitters indicate that the clinical response is, in part, related involved are dopamine and norepinephrine. Both to the rate of increase or decrease of the blood levels neurotransmitters appear to play a role in the attentional of the medicine. As the blood levels of the stimulants and behavioral symptoms of AD/HD. However, the exact contribution of each neurotransmitter to each type of symptom is not known. Similarly, one cannot predict " … medication levels the
which medication, with its own specific actions on the individual neurotransmitters, will result in the best neurobiologic playing field, and
clinical response for a particular person.9-11 allows adults with AD/HD to learn
and develop the skills they need to
Psychostimulants continue to be first line medications
for the treatment of AD/HD in adults as well as children and adolescents.9 To date, none of the psychostimulants are approved by the Food and Drug Administration (FDA) for the treatment of AD/HD in adults and so fall, a rebound or recurrence of the original AD/HD are routinely prescribed off label. The two stimulants symptoms may take place. In some cases, the rebound most commonly used, methylphenidate (MPH) and may involve even more intense symptoms including amphetamines (AMP), are regulated as Schedule II drugs significant irritability.9,14,15 by the Drug Enforcement Administration because they Studies have demonstrated the short-term safety of have a potential for abuse when not used as prescribed stimulants. Preliminary results from a long-term by a medical professional. controlled study of adults taking MPH demonstrated Several factors contribute to an adult's response to continued efficacy and safety over six months.18,19 As stimulant medication: with all medication therapy, the doctor (or other medical professional) and the individual must work together to • dose. Recent controlled studies indicate that the
find a medication with characteristics that fit the needs clinical response of adults with AD/HD to MPH12 of the individual.
and mixed amphetamine salts (Adderall)13 is dose-related. So, within the therapeutic range, higher doses may produce a better individual response as long as FrEquENTly AsKED quEsTiONs AbOuT
the medication is tolerated. Lower and inconsistent response rates seen in early controlled studies were due to low doses of medication, inconsistent Q. When an adult has been diagnosed with AD/HD and
diagnostic criteria, and a lack of control for co- decides to seek medical treatment, should the person
existing psychiatric conditions.9 Recent short-term try MPH or AMP first?
controlled studies using relatively high doses of a. At this stage of our knowledge, there is no scientific
stimulants have demonstrated the efficacy of the basis for choosing one type of stimulant over the stimulants (MPH,12 Adderall,13 and Adderall XR16,17) other for a given individual who has not yet tried in about 70% of adults. Underdosing stimulant either. Because MPH and AMP affect dopamine and medication in adults can result in decreased norepinephrine somewhat differently, it is reasonable to assume that they would also affect people differently.
Both MPH and AMP block the reuptake of dopamine and norepinephrine and increase their levels in the What We KnoW 10 managing medication for adults with ad/hd
synapse (space where the brain cells connect). AMP also of appetite, weight loss (but less weight loss than is increases the level of dopamine and norepinephrine in seen in children), and some cardiovascular effects.12 the synapse through another mechanism in the pre- The cardiovascular effects in those with normal blood synaptic (pre-connection) brain cell.20,21 pressure include increases in blood pressure (systolic and diastolic increases of about 4 mm Hg) and increases After an unsuccessful treatment attempt with one family in heart rate (less than 10 beats per minute).6,7 No of stimulants (MPH or AMP), an attempt with the other long-term controlled studies of cardiovascular effects is warranted.9 Because MPH and AMP have different have yet been published. Likewise, there are no studies mechanisms of action, combining MPH and AMP may on the effects of stimulants in people with borderline be useful in a person who does not respond to either hypertension (high blood pressure) or with hypertension that is controlled by medication. Regular monitoring of Q. Are adults who take psychostimulant medications
blood pressure is generally recommended in adults with more likely to have substance abuse problems?
or without AD/HD.
a. No. Generally, the stimulants are well tolerated
in therapeutic doses without any abuse. There is no
evidence to substantiate the fear that stimulant use leads
to substance abuse or dependence. On the contrary, In a controlled MPH study of adults with AD/HD, 78 studies indicate that successful treatment of AD/HD with percent experienced a therapeutic response with an stimulants lowers the chances of substance use disorders, average dose of 0.92mg/kg/day split into three daily compared to adults with untreated AD/HD.23-25 doses. The most common side effects were loss of Adults with AD/HD who have a co-existing substance appetite, insomnia and anxiety.12,26 Preliminary results of use disorder and are actively using sometimes abuse a recent unpublished long-term (six-month), controlled psychostimulants. Generally, the active substance use study demonstrated MPH's efficacy in almost 75 percent disorder needs to be treated before the co-existing of adults with AD/HD.18,19 AD/HD can be treated. In this case, it may be advisable not to use a psychostimulant for the treatment of AD/HD. For people with a recent history of substance iMMEDiATE rElEAsE MPH
use but no current use, deciding to use stimulant The immediate release preparations of MPH are a medication needs to be dealt with on a case-by-case mixture of the mirror-image molecules (d and l isomers) basis. Certain extended release preparations are less in a 1 to 1 ratio. They are available as Ritalin, Metadate, likely to be abused, like Concerta (a recent extended Methylin, and generic MPH. The formulations are short-acting and last up to three or four hours. The d isomer, which is the active MPH isomer, has been isolated and "Psychostimulants continue to
released as Focalin. It lasts about as long as or possibly slightly longer than the others.27,28 be first line medications for the
treatment of AD/HD in adults…"
ExTENDED Or susTAiNED rElEAsE MPH
Older first generation sustained release preparations,
release preparation of MPH with an osmotic delivery which contain a wax matrix, do not have an immediate system that cannot be crushed and used other than as release portion and the release of the sustained portion prescribed orally).
is somewhat irregular. These medications include Ritalin SR, Metadate ER and Methylin ER.9,22 Q. What are the possible side effects of stimulant use in
adults with AD/HD?
The new second generation extended release MPH a. Side effects of stimulant use in adults are generally
preparations include Concerta, Metadate CD and Ritalin not severe. For MPH, one controlled study showed LA. So far, there are no controlled efficacy studies of side effects such as insomnia, headaches, anxiety, loss these three products in adults, and none is yet approved by the FDA for the treatment of AD/HD in adults.29-31 What We KnoW 10 managing medication for adults with ad/hd
These newer extended release MPH preparations (as Since both of the mirror-image isomers of AMP are well as the newer extended release AMP preparation active but have different effects,9-11,20 Dexedrine and mentioned below) differ from each other in several ways: Dextrostat (the d-AMP preparations) will likely have a different therapeutic effect than Adderall or mixed • The way MPH is released and how it works in the amphetamine salts (3 to 1 mixture of both d and l AMP isomers).10,11 However, there are no controlled studies • The amount of stimulant that is released immediately comparing the two types of amphetamine medication in and the amount that is in the extended release extended or sustained release amP
• Whether the extended release portion is released all There are no controlled data on the use of older first at once (for example, four hours after the immediate generation sustained release preparations of the release portion) or gradually and continuously over a d-amphetamine isomer in adults. This preparation is certain period of time.
available as Dexedrine Spansules and dextroamphetamine sulfate sustained release capsules (generic).
• Under some circumstances, premature release of the extended release portion. For example, for a given The newer second generation extended release AMP total dose, one extended release stimulant preparation mixed salt preparation has d and l isomers in a 3 to 1 could have a more gradual onset and last longer than ratio (Adderall XR).34 Preliminary unpublished results the others; another could have a bigger initial effect of a multi-center controlled adult study of once daily but not last as long. Adderall XR indicate efficacy in about 70% of adults with There are no published controlled data in adults symptom improvement that was dose dependent. The that use accurate and frequent measures of most commonly reported side effects were dry mouth, medication efficacy over time.9,22,29-32 The reader is decreased appetite, insomnia, and headache.18,19 During referred to Table 1 for a detailed comparison. the first 10 months of a 24-month, open label (non-controlled) study of Adderall XR, adults in the study tolerated the medication and experienced improvement in symptoms.35,36 The reader is referred to Table 2 for details of the AMP preparations.
immediate release Preparations of amP
One of the immediate release preparations is
d-amphetamine (Dexedrine and Dextrostat), which
OTHEr sTiMulANT TrEATMENT
contains the d isomer and lasts about 4 hours clinically. A recent short-term, controlled study showed the Matching the characteristics of the various extended efficacy of d-amphetamine in adults with AD/HD, with release stimulants with the needs of the adult requires weight loss being the only significant side effect.33 both a knowledge of these medications as well as an There is also an immediate release preparation of mixed understanding of the specific needs of the adult with amphetamine salts that contains both the d and l mirror- AD/HD and how these needs change over time. It is image molecules of amphetamine in a 3 to 1 ratio. The often useful for the prescribing professional and adult preparation has been released as Adderall and mixed to chart the adult's needs and individual response to amphetamine salts (generic), and lasts about 4-6 hours. the medication. Fine tuning may require changing In a recent controlled study, Adderall was efficacious in the amount and/or timing of the dosing, changing about 70% of adults with AD/HD who had an average the extended release stimulant to one with different total dose of 54 mg with twice daily dosing. Adderall characteristics, or adding an immediate release was well tolerated with only two significant side effects: preparation at the beginning, middle or end of the loss of appetite and agitation. Adults also experienced extended release preparation's action. For example, if an adult has a business meeting later in the day or after dinner, he or she could take the extended release medication later than usual or add an immediate release dose or two late in the day. What We KnoW 10 managing medication for adults with ad/hd
Methylphenidate Medications used for the Treatment of AD/HD in Adults
category of release
of er or sr
of action (hours)
• d & l isomers, 1/1 • Ritalin, Metadate, Methylin, generics D-Methylphenidate or sustained release
• d & l isomers, 1/1 • Ritalin SR, Metadate but erratic after 4-5 continuous release extended release
• d & l isomers, 1/1
• oRoS: osmotic • Pulsatile release • If low acidity, premature release possible note: two references, referred to as "ref. 4" and "ref. 22", are mentioned in tables 1 and 2. the structures of tables 1 and 2 are adapted from reference 22. the references from which information was adapted include 4, 22, 27, 28, 29, 30, 31, and 34. What We KnoW 10 managing medication for adults with ad/hd
Amphetamine Medications used for the Treatment of AD/HD in Adults
category of release
of er or sr
of action (hours)
• Dexedrine, Dextrostat D, L-amphetamine • adderall, generic mixed amphetamine salts sustained release
Spansules, generic dextroamphetamine sulfate sustained release capsules extended release
D, L-amphetamine • Pulsatile release 4 • If low acidity, premature release possible note: two references, referred to as "ref. 4" and "ref. 22", are mentioned in tables 1 and 2. the structures of tables 1 and 2 are adapted from reference 22. the references from which information was adapted include 4, 22, 27, 28, 29, 30, 31, and 34. What We KnoW 10 managing medication for adults with ad/hd
Further consideration needs to be given to the effect of stimulants.42 It may be useful in adults with AD/HD of a high fat meal on blood levels of the medication. and co-existing depression and/or anxiety, but controlled Generally, such a meal tends to delay the onset of data is not yet available for atomoxetine's efficacy in this the medication's clinical effects.27-31,34 In addition, a recent study indicated that after a high fat breakfast, It is not clear what atomoxetine's role in the treatment the blood levels of AMP associated with Adderall of adult AD/HD will eventually be. It certainly looks XR were significantly reduced over the first eight very promising and will likely either be another first line hours, in contrast to the MPH levels associated with medication, like psychostimulants, or a first second line Concerta, which were not reduced. However, the clinical medication after stimulants.
significance of these findings is not yet known.37 In controlled studies of adults, atomoxetine was associated with cardiovascular side effects including increased heart rate of five beats per minute and an Pemoline (Cylert) is another psychostimulant that increase in blood pressure of 3 mm Hg for systolic and has been used over the years with good to moderate 1 mm Hg for diastolic blood pressure. No controlled clinical responses. However, because of infrequent studies comparing the cardiovascular effects of but potentially severe and even life threatening liver atomoxetine and of stimulants have yet been published. damage, the use of pemoline in both adults and children Atomoxetine use has not been seen with the cardiac side has decreased significantly. It is not considered a effects associated with tricyclic antidepressants. Other first line treatment, as its use continues to be highly side effects can include dry mouth, insomnia, nausea, constipation, decreased appetite, dizziness, decreased libido, erectile disturbance, and urinary retention, hesitation or difficulty.41 Atomoxetine may lead, in rare cases, to severe liver injury resulting in liver failure if not stopped immediately on finding any liver effects With the exception of atomoxetine (Strattera), which (itching, dark urine, right upper quadrant tenderness or will be discussed below, non-stimulant medications unexplained "flu-like" symptoms). have generally been considered second line medications. They have been used in people who have an incomplete In a long-term, open label study of atomoxetine, two- response or no response to stimulants, cannot tolerate thirds of adults with AD/HD continued to have a positive stimulants, or have certain co-existing psychiatric therapeutic response through an average of 34 weeks.44-46 atomoxetine with other medications
Atomoxetine is metabolized (broken down) in the liver Atomoxetine (Strattera) was recently approved by by the CYP2D6 enzyme. Drugs that inhibit this enzyme, the FDA for the treatment of AD/HD in children, such as fluoxetine, paroxetine and quinidine, can inhibit adolescents and adults. It is a potent selective this enzyme and slow the metabolism of atomoxetine. norepinephrine reuptake inhibitor. It is the first Decreasing the dosage of atomoxetine may be nonstimulant medication to be approved by the FDA for necessary when the person is taking these medications. the treatment of AD/HD and the first medication of any Atomoxetine (as with the stimulants and TCAs) should kind specifically approved for the treatment of AD/HD not be taken with a mono-amine oxidase inhibitor in adults.41 It lacks the abuse potential of stimulants, and (MAOI) or within two weeks of discontinuing a MAOI. since it is not a controlled Schedule II drug, atomoxetine Likewise, treatment with a MAOI should not be initiated can be prescribed with refills and on the phone. within two weeks of discontinuing atomoxetine.41 Atomoxetine was approved for once or twice daily dosing, but so far there is only published controlled data in adults on twice a day dosing.44 While the effects of stimulants are almost immediate, atomoxetine Antidepressants that have a direct effect of increasing takes longer to produce a response. In terms of its the neurotransmitter norepinephrine (but not serotonin effectiveness, a preliminary open label study in children as in the selective serotonin reuptake inhibitors [SSRIs] indicated that its effectiveness might be similar to that like fluoxetine) appear to have a positive effect on the What We KnoW 10 managing medication for adults with ad/hd
core symptoms of AD/HD. None of the antidepressants venlafaxine may include increases in blood pressure, so has been approved by the FDA for the treatment of AD/ blood pressure monitoring is recommended.6-8,52-53 HD in children, adolescents or adults; such treatment is
tricyclic antidepressants (tcas)
Desipramine (Norpramine) and nortriptyline both Clonidine (Catapres) and guanfacine (Tenex) are alpha- inhibit norepinephrine reuptake significantly. Both 2 and alpha-2a noradrenergic agents, respectively, moderately reduce the core symptoms of AD/HD that may indirectly affect dopamine by first affecting in adults. The TCAs show negligible risk of abuse, norepinephrine. Although they have been used to have once daily dosing with 24 hour coverage, and help children who have AD/HD with hyperactive and are efficacious in those with co-existing anxiety and aggressive symptoms, their use in adults has been depression. However, it takes several weeks before a generally minimal. A recent preliminary controlled study positive clinical effect, which is generally less robust showed some efficacy of guanfacine in adults with than that of the stimulants, is seen. They are associated AD/HD. However, sedation and hypotensive effects with potentially serious side effects including cardiac as well as potential hypertensive rebound are issues of problems and possible death by overdose.6-8,48 mono-amine oxidase inhibitors (maoi)
MAOIs help AD/HD by blocking the metabolism
(breakdown) of norepinephrine and dopamine. There are no controlled studies on the treatment of AD/HD Modafinil (Provigil) is approved by the FDA for the in adults with MAOIs. The use of MAOIs requires strict treatment of narcolepsy. Its main effect appears to be adherence to a special diet to prevent a hypertensive indirect activation of the frontal cortex rather than direct crisis (massive, acute rise in blood pressure). The MAOIs, involvement in central dopamine and norepinephrine therefore, may have only limited usefulness in treating pathways. In a recent two week, controlled study of adults with treatment-resistant, non-impulsive AD/HD modafinil, 48% of adults responded favorably to the symptoms with co-existing depression and anxiety.6-8 medication. Longer, controlled studies in adults are clearly needed. At this time, modafinil's utility may be limited to adults with AD/HD who do not respond to Bupropion is an atypical antidepressant that increases first line medications.6-8,55 dopamine and norepinephrine levels. It has a "moderate" response in adults with AD/HD, but the effect is not considered as large as the effect of stimulants and may cHOOsiNg A MEDicATiON
take several weeks to develop. When co-existing bipolar disorder is present, buproprion may result in less mood With or without a co-existing psychiatric disorder, the instability than TCAs. Presently, it must be dosed twice importance of matching the needs of the individual daily, but there is a once daily dose set to appear soon. with the characteristics of the AD/HD medication It may be associated with a higher than average rate of cannot be overemphasized. To date, the stimulants have drug-induced seizures if given in excessively high doses been considered first line medications for AD/HD. or to those with a history of seizures or bulimia.
The process of choosing a medication should involve recognizing the negative side effects of a medication so Venlafaxine (effexor) that the risks and benefits can be adequately weighed Venlafaxine blocks the reuptake of both norepinephrine in the decision. It is often useful to construct a daily and serotonin. Although there are no controlled studies timeline of the needs (both attentional and behavioral) of of venlafaxine use in adults with AD/HD, several non- controlled studies show some encouraging results. It may have a role in treating AD/HD with co-existing depression and/or anxiety. Side effects of higher doses of What We KnoW 10 managing medication for adults with ad/hd
For example, an adult who has severe AD/HD symptoms disorders
that threaten his/her job may also have difficulty Approximately two-thirds to three-quarters of adults controlling his/her hypertension. In this case, choosing a with AD/HD will have at least one other psychiatric treatment for AD/HD that has a significant effect during disorder during their lifetime.56 These other disorders the most crucial hours of the work day but does not include antisocial personality disorder, anxiety disorders, destabilize the tentatively controlled hypertension will depressive disorders, bipolar disorder, and substance use require knowledge of the medications' actions over time disorders (SUD). After diagnoses have been made, the as well as their cardiovascular side effects. clinician and adult should decide which diagnoses need to be treated and in what order.
MONiTOriNg THE EFFEcTs OF
There is no controlled research on medication therapy in adults with AD/HD and co-existing conditions. The treatment decisions of the medical professional and the Monitoring the effectiveness of medication over time is individual will be guided by their previous therapeutic important and may require substantial effort. However, and clinical experience, extrapolations from others' fine tuning of the timing and dosing of the medication clinical experiences, and a rational, empirical approach can often improve the time-related clinical response. to the individual's clinical response. Sometimes the prescribing professional alone may fulfill these functions; sometimes an experienced therapist who Significant co-existing conditions are usually treated is familiar with the adult can provide additional input first, before AD/HD, especially if they cause more to help maximize the effectiveness of the medicine.57 significant clinical and functional impairment and Clinical adjustment may include adding other disturbance. This is particularly true with substance medications or adding or changing the psychosocial use disorders, severe depression and bipolar disorder, interventions, such as behavioral, cognitive or supportive psychoses, and homicidal or suicidal ideation. It is psychotherapy, coaching, and tutoring. important to consider how the AD/HD may be affected by medication for a co-existing disorder—both positive and negative, both helpful and harmful. For example, iMPrOviNg FuNcTiONiNg AND
treating depression with bupropion may also help AD/ quAliTy OF liFE
HD. On the other hand, some medications for major While improvement of the core symptoms of AD/HD depression and bipolar disorder may actually worsen is important and crucial, it is often not the only goal AD/HD symptoms. In an apparent middle case, the of treatment. Rather, improved functioning in the real SSRIs (selective serotonin reuptake inhibitors), which world (being self-sufficient, having a better quality of by themselves do not appear to effectively treat AD/ life and being able to cope with the demands of daily HD symptoms directly, appear to be successful in the life) may be the most important outcome for an adult treatment of individuals who have co-existing depression with AD/HD. Recent controlled medication studies in and who are taking stimulants at the same time for adults with AD/HD have begun to track and measure these functional improvements including psychosocial It is also important to note that medications for and quality of life functioning.16-19,43 Preliminary results AD/HD may affect co-existing disorders. For example, of recent longer-term, open label studies with Adderall psychostimulants may worsen an untreated anxiety XR35,36 and Strattera44-46 have also become available. or bipolar disorder. The risk of stimulant abuse is also Future controlled, long-term medication studies in greater in an adults with substance use disorder and adults with AD/HD are needed to accurately measure are actively using. However, as previously mentioned, the effect of medication on functioning in the workplace, successful treatment of AD/HD tends to decrease the college and interpersonal relationships. chances of a person with AD/HD eventually developing a SUD.23-25 medication theraPy in adults with
ad/hd and co-existing Psychiatric
What We KnoW 10 managing medication for adults with ad/hd
Some nonstimulant treatments of AD/HD may 7. Prince, J., & Wilens, T. (2002). Medications used in the simultaneously and adequately treat the co-existing treatment of AD/HD in women. In P. Quinn & K. Nadeau disorder along with the AD/HD. For example, an (Eds.), Gender issues and AD/HD. Silver Spring: Advantage antidepressant (TCA, bupropion, venlafaxine) may effectively treat co-existing depression and AD/HD, and 8. Wilens, T., Spencer, T., & Biederman, J. (2002). A review of the pharmacotherapy of adults with attention-deficit/ similarly, a TCA or venlafaxine may successfully treat co- hyperactivity disorder. Journal of Attention Disorders, 5, 189- existing anxiety and AD/HD. The use of atomoxetine in treating a co-existing depression and/or anxiety disorder 9. American Academy of Child and Adolescent Psychiatry. is promising, but there are no data from controlled adult (2002). Practice parameter for the use of stimulant medications in the treatment of children, adolescents, and adults. Journal of the American Academy of Child and Adolescent Psychiatry, 41(Suppl. 2), 26-49.
10. Solanto, M.V. (1998). Neuropsychopharmacological mechanisms of stimulant drug action in attention-deficit As awareness of AD/HD's persistence and consequences hyperactivity disorder: a review and integration. Behavioral throughout the lifespan has increased, so has the desire Brain Research, 94, 127-152.
for successful treatment in adulthood. Medication 11. Solanto, M.V., Arnsten, A.F.T., & Castellanos, F.X. (2002). continues to be a mainstay of treatment for AD/ The neuroscience of stimulant drug action in ADHD. In M.V. HD. Psychostimulants continue to be the first line Solanto, A.F.T. Arnsten, & F.K. Castellanos (Eds.), Stimulant medications. The newest addition is atomoxetine, the drugs and ADHD: basic and clinical neuroscience (pp. 355-379). first nonstimulant to be approved by the FDA for the New York: Oxford University Press.
treatment of AD/HD and the first to be approved for 12. Spencer, T., Wilens, T., Biederman, J., Faraone, S.V., Ablon, treatment in adults with AD/HD. Atomoxetine also J.S., & Lapey, K. (1995). A double-blind, crossover comparison of methylphenidate and placebo in adults with childhood-onset shows promise to be a first line medication. Many other attention-deficit hyperactivity disorder. Archives of General nonstimulant treatments are available and their roles in Psychiatry, 52, 434-443.
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14. Swanson, J., Gupta, S., Guinta, D., Flynn, D., Agler, D., Lerner, M., et al (1999). Acute tolerance to methylphenidate in the treatment of attention deficit hyperactivity disorder in children. Clinical Pharmacology and Therapeutics, 66, 295-305.
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BEWARE OF OVERCLAIMING, FEDERAL COURT OF CANADA WARNS Alexandra Steele* LEGER ROBIC RICHARD, Lawyers ROBIC, Patent & Trademark Agents Centre CDP Capital 1001 Square-Victoria – Bloc E – 8th Floor Montréal, Québec, Canada H2Z 2B7 Tel.: (514) 987-6242 - Fax (514) 845-7874 email@example.com –www.robic.ca INTRODUCTION The Applicant's application for a writ of prohibition preventing the Canadian Minister of National Health and Welfare from issuing a Notice of Compliance to the Respondent in respect of anti-depression medication was denied, the Court having ruled that the Respondent's al egations that the proposed drug would not infringe the Applicant's patents were sufficient. [Biovail Pharmaceuticals Inc. et al v. Minister of National Health and Welfare at al,  F.C.J. No. 7, Harrington J., January 6, 2005] BACKGROUND
Journal of Colloid and Interface Science 316 (2007) 762–770 Structure and size of spontaneously formed aggregates in Aerosol OT/PEG mixtures: Effects of polymer size and composition M. Mercedes Velázquez Margarita Valero Francisco Ortega J. Benito Rodríguez González a Departamento de Química Física, Universidad de Salamanca, E-37008 Salamanca, Spain b Departamento de Química Física I., Facultad de Ciencias Químicas, Universidad Complutense de Madrid, E-28040 Madrid, Spain