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Methylphenidate: Its Pharmacology and Uses

  • Author Footnotes
    1 Dr Challman is now at Kennedy Krieger Institute, Baltimore, Md.
    Thomas D. Challman
    Footnotes
    1 Dr Challman is now at Kennedy Krieger Institute, Baltimore, Md.
    Affiliations
    Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minn
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  • James J. Lipsky
    Correspondence
    Address reprint requests and correspondence to James J. Lipsky, MD, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, 200 First St SW, Rochester, MN 55905
    Affiliations
    Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minn
    Search for articles by this author
  • Author Footnotes
    1 Dr Challman is now at Kennedy Krieger Institute, Baltimore, Md.
      Methylphenidate is a commonly used medication in the United States. This central nervous system stimulant has a mechanism of action distinct from that of amphetamine. The Food and Drug Administration has approved methylphenidate for the treatment of attentlon-deficit/hyperactivity disorder and narcolepsy. Treatment with methylphenidate has been advocated in patients with traumatic brain injury and stroke, cancer patients, and those with human immunodeficiency virus infection. Placebo-controlled trials have documented its efficacy as an adjunctive agent in the treatment of depression and pain. This article reviews the current understanding of the mechanism of action and efficacy of methylphenidate in various clinical conditions.
      ADHD (attention-deficit/hyperactivity disorder), AIDS (acquired immunodeficiency syndrome), FDA (Food and Drug Administration), HIV (human immunodeficiency virus)
      Methylphenidate (Ritalin) is a commonly used medication in the United States. First synthesized in 1944, methylphenidate was initially used as an analeptic for reversal of barbiturate-induced coma.
      • Wax PM
      Analeptic use in clinical toxicology: a historical appraisal.
      It is now primarily used as treatment of attention-deficit/hyperactivity disorder (ADHD). Estimates are that more than 2 million Americans, mostly children, are currently being treated with methylphenidate.
      • Diller LH
      The run on Ritalin: attention deficit disorder and stimulant treatment in the 1990s.
      While concerns regarding overuse have been raised,
      • Safer DJ
      • Zilo JM
      • Fine EM
      Increased methylphenidate usage for attention deficit disorder in the 1990s.
      methylphenidate clearly has utility in several clinical situations. Recent articles have reviewed 1 or more aspects of methylphenidate use.
      • Elia J
      • Ambrosini PJ
      • Rapoport JL
      Treatment of atlention-deficit-hypcractivity disorder.
      • Zametkin AJ
      • Ernst M
      Problems in the management of attention-deficit-hyperactivity disorder.
      • Cyr M
      • Brown CS
      Current drug therapy recommendations for the treatment of attention deficit hyperactivity disorder [published correction appears in Drugs. 1999;58:597].
      • Findling RL
      • Dogin JW
      Psychopharmacology of ADHD: children and adolescents.
      • Goldman LS
      • Gcncl M
      • Bezman RJ
      • Slanctz PJ
      Council on Scientific Affairs. American Medical Association. Diagnosis and treatment of attention-deficit/hypcractivity disorder in children and adolescents.
      • Seeman P
      • Madras BK
      Anti-hypcraclivily medication: melhyl-phcnidatc and amphetamine.
      • Masand PS
      • Tesar GE
      Use of stimulante in the medically ill.
      The goals of this article are to provide a focused review for the clinician regarding what is known about the mechanism of action and pharmacology of methylphenidate and to appraise critically its therapeutic uses. Particular emphasis is given to newer uses in the adult population.

      Chemistry And Mechanism Of Action

      Methylphenidate is a piperidine-derived central nervous system stimulant. The methylphenidate molecule possesses 2 centers of chirality; thus, a total of 4 enantiomers of this drug exist (Figure 1). The earliest marketed preparations of methylphenidate contained all 4 enantiomers. Subsequent study revealed, however, that the erythro isomers were devoid of any major central nervous system stimulant effect
      • Szporny L
      • Görög P
      Investigations into the correlations hetween monoamine oxidase inhibition and other effects due to methylphcnydate and its slercoisomcrs.
      a result, currently available preparations of methylphenidate contain a racemic mixture of only d,l-threo-methylphenidate. As discussed later, the pharmacological activity is attributable to just the d-threo isomer.
      • Ding YS
      • Fowler JS
      • Volkow ND
      • et al.
      Chiral drugs: comparison of the pharmacokinctics of Cd-threo and L-three-methyl-phenidate in the human and baboon brain.
      Figure thumbnail gr1
      Figure 1The structure of d-threo (2R,2'R)-methylphenidate, the pharmacologically active enantiomer.
      The complete mechanism by which methylphenidate exerts its behavioral effect remains unknown. Early animal studies indicated that methylphenidate increased efflux of dopamine from neurons
      • Chiuch CC
      • Moore KE
      Blockade by reserpine of methylphenidate-induced release of brain dopamine.
      and inhibited dopamine reuptake from the synaptic cleft.
      • Ferris RM
      • Tang FL
      • Maxwell RA
      A comparison of the capacities of isomers of amphetamine, deoxypipradrol and methylphenidate to inhibit the uptake of tritiated catecholamines into rae cerebral cortex slices, synaptosomal preparations of rat cerebral cortex, hypothalamus and striatum and into adrencrgic nerves of rabbit aorta.
      • Taylor D
      • Ho BT
      Comparison of inhibition of monoamine uptake by cocaine, methylphenidate and amphetamine.
      • Ross SB
      The central stimulatory action of inhibitors oi the dopamine uptake.
      It was subsequently shown that methylphenidate binds to the dopamine transporter in the presynaptic cell membrane, blocking reuptake of dopamine and causing a resultant increase in extracellular dopamine levels.
      • Schweri MM
      • Skolnick P
      • Rafferty MF
      • Rice KC
      • Janowsky AJ
      • Paul SM
      [3H]Threo-)-methylphenidate binding (o 3,4-dihydroxyphenylelhylamine uptake sites in corpus striatum: correlation with the stimulant properties of ritalinic acid esters.
      • Janowsky A
      • Schweri MM
      • Berger P
      • Long R
      • Skolnick P
      • Paul SM
      The effects of surgical and chemical lesions on striatal [3H]hreo-(±)-methylphenidate binding: correlation with ['HJdopaminc uptake.
      • Hurd YL
      • Ungerstedl U
      In vivo ncurochemical profile of dopamine uptake inhibitors and releasers in rat caudate-putamen.
      • Butcher SP
      • Lipirot J
      • Aburthnott GW
      Characterisation of methylphenidate and nomifensinc induced dopamine release in rat striatum using in vivo brain microdialysis.
      • Wall SC
      • Gu H
      • Rudnick G
      Biogenic amine flux mediated by cloned transporters stably expressed in cultured cell lines: amphetamine specificity for inhibition and efflux.
      This is in contrast to the primary mode of action of amphetamine, which causes the release of newly synthesized cytosolic dopamine from the nerve terminal.
      • Hoffman BB
      • Lefkowitz RJ
      Catecholammes. sympathomimetic drugs, and adrenergic receptor antagonists.
      The dopamine transporter is thought to be a critical regulator of dopamine homeostasis.
      • Gainetdinov RR
      • Jones SR
      • Fumagalli F
      • Wightman RM
      • Caron MG
      Re-evaluation of the role of the dopamine transporter in dopamine system homeostasis.
      At oral therapeutic doses (0.3–0.6 mg/kg), methylphenidate is estimated to occupy more than half of brain dopamine transporters.
      • Volkow ND
      • Wang GJ
      • Fowler JS
      • et al.
      Dopamine transporter occupancies in the human brain induced by therapeutic doses of oral methylphenidate.
      The gene encoding this transporter has been cloned from both rats
      • Shimada S
      • Kitayama S
      • Lin CL
      • et al.
      Cloning and expression of a cocaine-sensitive dopamine transporter complementary DNA [published correction appears in Science. 1992; 255:1195].
      and humans,
      • Vandenbergh DJ
      • Pcrsico AM
      • Uhl GR
      A human dopamine transporter cDNA predicts reduced glycosylation. displays a novel repetitive element and provides racially-dimorphic Taq R FLPs.
      and in humans it is located on chromosome 5p15.3.
      • Vandenbergh DJ
      • Pcrsico AM
      • Hawkins AL
      • et al.
      Human dopamine transporter gene (DAT1) maps to chromosome 5p15.3 and displays a VNTR.
      Associations between polymorphisms of the dopamine transporter gene and various neuropsychiatric conditions, including ADHD, have been explored.
      • Cook Jr, EH
      • Stein MA
      • Krasowski MD
      • et al.
      Association of attention-deficit disorder and the dopamine transporter gene.
      • Gill M
      • Daly G
      • Heron S
      • Hawi Z
      • Fitzgerald M
      Confirmation of association between attention deficit hypcractivity disorder and a dopamine transporter polymorphism.
      In the rat, methylphenidate inhibits dopamine reuptake in the striatum, nucleus accumbens, olfactory tubercle, and prefrontal cortex.
      • Schweri MM
      • Skolnick P
      • Rafferty MF
      • Rice KC
      • Janowsky AJ
      • Paul SM
      [3H]Threo-)-methylphenidate binding (o 3,4-dihydroxyphenylelhylamine uptake sites in corpus striatum: correlation with the stimulant properties of ritalinic acid esters.
      • Unis AS
      • Dawson TM
      • Gchlert DR
      • Wamsley JK
      Autoradiographic localization of [3]methylphenidate binding sites in rat brain.
      • Izenwasser S
      • Werling LL
      • Cox BM
      Comparison of the effects of cocaine and other inhibitors of dopamine uptake in rat striatum. nucleus accumbens. olfactory tubercle, and medial prefrontal cortex.
      Microdialysis studies have confirmed the in vivo ability of methylphenidate to increase extracellular dopamine levels in the striatum and nucleus accumbens.
      • Butcher SP
      • Lipirot J
      • Aburthnott GW
      Characterisation of methylphenidate and nomifensinc induced dopamine release in rat striatum using in vivo brain microdialysis.
      • Woods SK
      • Meyer JS
      Exogenous tyrosine potentiates the methylphenidate-induced increase in extracellular dopamine in the nucleus accumbens: a microdialysis study.
      • During MJ
      • Bean AJ
      • Rolh RH
      Effects of CNS stimulants on the in vivo release of the colocalized transmitters, dopamine and neurotensin, from rat prefrontal cortex.
      • Aoyama T
      • Yamamoto K
      • Kotaki H
      • Sawada Y
      IgaT. Pharmaco-dynamic modeling for change of locomotor activity by methylphenidate in rats.
      • Kuczenski R
      • Segal DS
      Effects of methylphenidate on extracellular dopamine, serotonin, and norcpinephrine: comparison with amphetamine [published correction appears in J Neumchem. 1997;69:1332).
      The more recent application of singlephoton emission computed tomography
      • Volkow ND
      • Fowler JS
      • Ding YS
      • Wang GJ
      • Gatley SJ
      Positron emission tomography radioligands for dopamine transporters and studies in human and nonhuman primates.
      has helped to confirm that the highest area of methylphenidate uptake in humans is in the striatum.
      • Ding YS
      • Fowler JS
      • Volkow ND
      • et al.
      Chiral drugs: comparison of the pharmacokinctics of Cd-threo and L-three-methyl-phenidate in the human and baboon brain.
      • Ding YS
      • Fowler JS
      • Volkow ND
      • et al.
      Pharmacokinetics and in vivo specificity of [CJtíf-rflíeíJ-melhylphcnidatc for the presyn-aplic dopammergic neuron.
      • Volkow ND
      • Ding YS
      • Fowler JS
      • et al.
      Is methylphenidate like cocaine? studies on their pharmacokinetics and distribution in the human brain.
      Because of these observations, the prevailing theory has been that methylphenidate influences hyperactivity and behavior largely via a direct effect on key dopaminergic areas of the brain.
      • Seeman P
      • Madras BK
      Anti-hypcraclivily medication: melhyl-phcnidatc and amphetamine.
      However, methylphenidate has appreciable effects on norepinephrine reuptake
      • Ferris RM
      • Tang FL
      • Maxwell RA
      A comparison of the capacities of isomers of amphetamine, deoxypipradrol and methylphenidate to inhibit the uptake of tritiated catecholamines into rae cerebral cortex slices, synaptosomal preparations of rat cerebral cortex, hypothalamus and striatum and into adrencrgic nerves of rabbit aorta.
      • Wall SC
      • Gu H
      • Rudnick G
      Biogenic amine flux mediated by cloned transporters stably expressed in cultured cell lines: amphetamine specificity for inhibition and efflux.
      • Kuczenski R
      • Segal DS
      Effects of methylphenidate on extracellular dopamine, serotonin, and norcpinephrine: comparison with amphetamine [published correction appears in J Neumchem. 1997;69:1332).
      • Ferris RM
      • Tang F1
      Comparison of the effects of the isomers of amphetamine, methylphenidate and deoxypipradrol on the uptake of/-I'HJnorepincphrine and ['Hldopaminc by synaptic vesicles from rat whole brain, strialum and hypothalamus.
      • Ritz MC
      • Lamb RJ
      • Goldberg SR
      • Kuhar MJ
      Cocaine receptors on dopamine transporters arc related to self-administration of cocaine.
      and also binds (albeit weakly) to the serotonin transporter.
      • Wall SC
      • Gu H
      • Rudnick G
      Biogenic amine flux mediated by cloned transporters stably expressed in cultured cell lines: amphetamine specificity for inhibition and efflux.
      • Galley SJ
      • Pan D
      • Chen R
      • Chaturvcdi G
      • Ding YS
      Affinities of methylphenidate derivatives for dopamine, norepinephrinc and serotonin transporters.
      The possibility that methylphenidate causes its behavioral effects by influencing multiple neurotransmitters has been suggested.
      • Volkow ND
      • Wang GJ
      • Galley SJ
      • et al.
      Temporal relationships between the pharmacokinetics of methylphenidate in the human brain and its behavioral and cardiovascular effects.
      A mouse knockout model was recently developed in which the gene for the dopamine transporter was disrupted.
      • Giros B
      • Jaber M
      • Jones SR
      • Wightman RM
      • Caron MG
      Hypcrlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter.
      These mice exhibited significantly higher levels of baseline locomotor activity compared with wild-type mice and interestingly showed impaired learning.
      • Gaincldinov RR
      • Wetsel WC
      • Jones SR
      • Levin KD
      • Jaber M
      • Caron MG
      Role of serotonin in the paradoxical calming effect of psychostimulants on hyperactivity.
      Despite the fact that these mice do not possess any neuronal dopamine transporters, administration of methylphenidate still reduced their hyperactivity. Increasing brain serotonin levels in these mice also had a similar effect.
      • Gaincldinov RR
      • Wetsel WC
      • Jones SR
      • Levin KD
      • Jaber M
      • Caron MG
      Role of serotonin in the paradoxical calming effect of psychostimulants on hyperactivity.
      Therefore, investigators have postulated that methylphenidate may work via serotonergic neurons to. reduce hyperactivity by restoring a lost balance between certain dopaminergic and serotonergic neuronal circuits.
      • Gaincldinov RR
      • Wetsel WC
      • Jones SR
      • Levin KD
      • Jaber M
      • Caron MG
      Role of serotonin in the paradoxical calming effect of psychostimulants on hyperactivity.
      In an earlier study, however, methylphenidate had no effect on extracellular serotonin levels,
      • Kuczenski R
      • Segal DS
      Effects of methylphenidate on extracellular dopamine, serotonin, and norcpinephrine: comparison with amphetamine [published correction appears in J Neumchem. 1997;69:1332).
      and since the dose of methylphenidate used in the aforementioned dopamine transporter knockout mouse study was 50 to 100 times the usual therapeutic ADHD dose, the direct applicability of these results to humans remains uncertain.

      Pharmacokinetics And Pharmacodynamics

      After oral administration, methylphenidate is almost completely absorbed and is primarily metabolized via de-esterification to ritalinic acid.
      • Faraj BA
      • Israili ZH
      • Pcrel JM
      • et al.
      Metabolism and disposition of methylphenidate-IJC: studies in man and animals.
      Peak plasma concentrations (Cmax) occur 1 to 3 hours (Tmax) after an oral dose of stan- dard methylphenidate, with a plasma half-life (T1/2) of 1.5 to 2.5 hours.
      • Faraj BA
      • Israili ZH
      • Pcrel JM
      • et al.
      Metabolism and disposition of methylphenidate-IJC: studies in man and animals.
      • Redalieu E
      • Bartlctt MF
      • Waldes LM
      • Darrow WR
      • Egger II
      • Wagner WE
      A study of methylphenidate in man with respect to its major metabolite.
      • Shaywilz SE
      • Hunt RD
      • Jatlow P
      • et al.
      Psychophamiacology of attention deficit disorder: pharmacokinctic. ncuroendocrinc, and behavioral measures following acute and chronic treatment with methylphenidate.
      • Wargin W
      • Patrick K
      • Kilts C
      • et al.
      Pharmacokinetics of methylphenidate in man, rat and monkey.
      Absorption seems to be enhanced when methylphenidate is taken with food.
      • Chan YP
      • Swanson JM
      • Soldin SS
      • Thiessen JJ
      • Macleod SM
      • Logan W
      Methylphenidate hydrochloride given with or before breakfast, II: effects on plasma concentration of methylphenidate and ritalinic acid.
      Protein binding of methylphenidate is low
      • Winsberg BG
      • Hungund BL
      • Perel JM
      Pharmacological factors of methylphenidate metabolism in behaviorally disordered children.
      • Hungund BL
      • Percl JM
      • Hurwic MJ
      • Sverd J
      • Winsberg BG
      Pharmacokinetics of methylphenidate in hyperkinetic children.
      which may. contribute to its relatively brief T1/2. The metabolism of the enantiomers of methylphenidate is stereoselective. As previously mentioned, the currently available preparations of methylphenidate contain a racemic mixture of d,l-threo-methyl phenidate. After oral administration of methylphenidate, blood levels of the d-isomer are significantly higher.
      • Wong YN
      • King SP
      • Laughton WB
      • McCormick GC
      • Grebow PE
      Single-dose pharmacokinetics of modafinil and methylphenidate given alone or in combination in healthy male volunteers.
      • Aoyama T
      • Kotaki H
      • Sasaki T
      • Sawada Y
      • Honda Y
      • Iga T
      Nonlinear kinetics of /Areo-mcthylphcnidate cnantiomers in a patient with narcolepsy and in healthy volunteers.
      • Aoyama T
      • Kotaki H
      • Honda Y
      • Nakagawa K
      Kinetic analysis of cnantiomers of co-methylphenidate and ils metabolite in two healthy subjects after oral administration as determined by a gas chromatographic-mass spectrometric method.
      No difference is seen in the plasma levels or renal clearance of the isomers in the first 1.5 hours after intravenous administration, indicating that there is enhanced presystemic metabolism of the 1-somer after oral administration
      • Snnivas NR
      • Hubburd JW
      • Korchinski ED
      • Midha KK
      Enantioselective pharmacokinetics of rt-al-threo-methylplienidatc in humans.
      Methylphenidate is available in 5-, 10-, and 20-mg tablets, as well as a 20-mg sustained-release tablet in which the drug is embedded in a wax matrix.
      Sustained-release methylphenidate.
      • Methylphenidate revisited
      This formulation has been used for once-daily morning dosing in children with ADHD who would rather not take a noon dose of methylphenidate at school. Pharmacokinetic studies of sustained-release methylphenidate have shown a somewhat longer Tmax (3 to 4 hours) and TI/2 (4 hours).
      • Hubbard JW
      • Srinivas NR
      • Quinn D
      • Midha KK
      Enantio-selective aspects of the disposition of ííí-rftrpw-methylphenidate after the administration of a sustained-release formulation to children with attention dcficil-hypcraciivity disorder.
      • Birmaher B
      • Greenhill LL
      • Cooper TB
      • Fried J
      • Maminski B
      Sustained release methylphenidate: pharmacokinetic studies in ADDH males.
      Additionally, the Cmax of sustained-release methylphenidate is lower than that of standard methylphenidate. because of the nature of the wax-matrix tablet, halving these tablets increases the rate of dissolution.
      • Erramouspe J
      • Javi EJ
      Effect on dissolution from halving methylphenidate extended-release tablets.
      and chewed tablets behave pharmacokinetically similar to an equivalent dose of standard methylphenidate.
      • Snnivas NR
      • Hubburd JW
      • Korchinski ED
      • Midha KK
      Enantioselective pharmacokinetics of rt-al-threo-methylplienidatc in humans.
      Adverse effects have been noted in children who chew, instead of swallow whole, sustainedrelease methylphenidate tablets.
      • Rosse RB
      • Licamele WL
      Slow-release methylphenidate: problems when children chew tablets [letter].
      There is an important difference in the pharmacological activities of the 2 enantiomers of threo-methylphenidate. Studies in rats indicated that the d-isomer is more active in the induction of locomotion than is the 1-isomer.
      • Patrick KS
      • Caldwell RW
      • Ferris RM
      • Breese GR
      Pharmacology of the enantiomers of threo-methylphenidate.
      A subsequent double-blind, 4-way randomized crossover study in humans compared each individual isomer with the racemic mixture and placebo, using computer-based tests of attention.
      • Srinivas NR
      • Hubbard JW
      • Quinn D
      • Midha KK
      Enanlio-seleclive pharmacokinetics and pharmacodynamics of dl-threo-methylphenidale in children with attention deficit hyperactivity disorder.
      This study showed no difference between the activities of l-threo-methylphenidate and placebo and no difference between a 5-mg dose of d-threo-methylphenidate and a 10-mg dose of d,l-threo-methylphenidate. The clinical effect, therefore, seemed to be entirely attributable to the d-isomer. Further microdialysis studies in rats confirmed that d-threo-methylphenidate binds stereospecifically in the striaturn
      • Aoyama T
      • Kotaki H
      • Sawada Y
      • Iga T
      Stereospecific distribution of methylphenidate enantiomers in rat brain: specific binding to dopamine reuptake sites.
      and increases striatal extracellular dopamine levels substantially more than does I-threo-methylphenidate.
      • Aoyama T
      • Kotaki H
      • Sawada Y
      • Iga T
      Pharmacokinetics and pharmacodynamics of methylphenidate cnantiomers in rats.
      A more recent study using positron emission tomography in humans showed that the highest uptake of labeled d-threo-methylphenidate is in the basal ganglia, whereas l-threo-methylphenidate exhibits nonspecific uptake throughout the brain.
      • Ding YS
      • Fowler JS
      • Volkow ND
      • et al.
      Chiral drugs: comparison of the pharmacokinctics of Cd-threo and L-three-methyl-phenidate in the human and baboon brain.
      Therefore, it seems that d-threo-methylphenidate is the main pharmacologically active isomer. Differences in the plasma concentrations of these isomers in “responders” vs “nonresponders” to methylphenidate
      • Jonkman LM
      • Verbaten MN
      • de Boer D
      • et al.
      Differences in plasma concentrations of the D- and L-threo methylphenidate enantiomers in responding and non-responding children with attention-deficit hyperactivity disorder.
      indicate that the determination of variation in drug metabolism among individuals may eventually help identify those patients most likely to benefit from treatment with racemic methylphenidate. Clinical trials of a chirally pure preparation of d-threo-methylphenidate are in progress.

      Clinical Uses

      The Food and Drug Administration (FDA) has approved methylphenidate for the treatment of ADHD and narcolepsy. Its usefulness in many other conditions has been investigated, including such diverse situations as autonomic failure,
      • Jordan J
      • Shannon JR
      • Biaggioni I
      • Norman R
      • Black BK
      • Robertson D
      Contrasting actions of prcssor agents in severe autonomic failure.
      giggle incontinence,
      • Sher PK
      • Reinberg Y
      Successful treatment of giggle incontinence with methylphenidate.
      and weaning patients from mechanical ventilation.
      • Johnson CJ
      • Auger WR
      • Fedullo PF
      • Dimsdale JE
      Methylphenidate in the “hard to wean” patient.
      A larger body of literature suggests possible therapeutic uses for methylphenidate in medically ill elderly patients with depression, those with traumatic brain injury and stroke, cancer patients, and those with human immunodeficiency virus (HIV) infection.

      Attention-Deficit/Hyperactivity Disorder

      Psychostimulants were first used to treat disruptive behavior in children in 1937.
      • Bradley C
      Behavior of children receiving benzedrine.
      Since that era, further research and diagnostic refinement have led to the recognition of ADHD as a distinct clinical entity, with an estimated prevalence in children between 3% and 5%.
      • American Psychiatric Association
      Methylphenidate is the most widely used medication for the treatment of ADHD. While dilemmas remain in the accurate diagnosis of ADHD,73 a myriad of studies support the efficacy of methylphenidate and other psychostimulants in the treatment of the symptoms of ADHD in children.
      • Wilens TR
      • Biedcrman J
      The stimulants.
      • Grccnhill LL
      Pharmacologie treatment of attention deficit hypcr-aclivity disorder.
      • Swanson JM
      • McBumett K
      • Wigal T
      • et al.
      Effect of stimulant medication on children with attention deficit disorder: a “review of reviews.”.
      • Shaywiiz BA
      • Reicher JM
      • Shaywitz SE
      Attcntion-deficit/hy-pcractivity disorder.
      Methylphenidate may also have a role in the treatment of neurobehavioral symptoms in patients with other developmental disabilities. Its use for hyperactivity in patients with autism,
      • Quintana H
      • Birmaher B
      • Stedgc D
      • et al.
      Use of methy Iphenidale in the treatment of children with autistic disorder.
      Williams syndrome.
      • Bawdcn HN
      • MacDonald GW
      • Shea S
      Treatment of children with Williams syndrome with methylphenidate.
      • Power TJ
      • Blum NJ
      • Jones SM
      • Kaplan PE
      Brief report: response lo methylphenidate in two children with Williams syndrome.
      and Prader-Willi Willi syndrome
      • Martin A
      • State M
      • Koenig K
      • et al.
      Pradcr-Willi syndrome.
      has been reported, although data from large controlled studies of these conditions are lacking. Other studies have indicated that methylphenidate may be a useful part of the overall therapeutic approach in children with mental retardation and severe behavioral problems.
      • Paylon JB
      • Burkhart JE
      • Hcrscn M
      • Helsel WJ
      Treatment of ADDH in mentally retarded children: a preliminary study.
      • Handen BL
      • Breaux AM
      • Gosling A
      • Ploof DL
      • Feldman H
      Efficacy of methylphenidate among menially retarded children with attention deficit hyperaclivity disorder.
      • Aman MG
      • Marks RE
      • Turbolt SH
      • Wilshcr CP
      • Merry SN
      Clinical effects of methylphenidate and thioridazine in intellectually subaverage children.
      • Aman MG
      • Marks RE
      • Turbotl SH
      • Wilsher CP
      • Merry SN
      Methylphenidate and thioridazine in the treatment of intellectually subaverage children: effects on cognitive-motor performance.
      • Händen BL
      • Breaux AM
      • Janosky J
      • McAuliffc S
      • Feldman H
      • Gosling A
      Effects and noneffects of methylphenidate in children with mental retardation and ADHD.
      • Johnson CR
      • Händen BL
      • Lubetsky MJ
      • Sacco KA
      Efficacy of methylphenidate and behavioral intervention on classroom behavior in children with ADHD and mental retardation.
      • Handen BL
      • Janosky J
      • McAuliffe S
      • Breaux AM
      • Feldman H
      Prediction of response to methylphenidate among children with ADHD and mental retardation.
      • Blum NJ
      • Mauk JE
      • McComas JJ
      • Mace FC
      Separate and combined effects of methylphenidate and a behavioral intervention on disruptive behavior in children with mental retardation.
      • Handen BL
      • Janosky J
      • McAuliffe S
      Long-term follow-up of children with mental retardation/borderline intellectual functioning and ADHD.
      Several studies (including 2 double-blind, placebo-controlled trials) have shown comparable short efficacy between sustained-release and standard methylphenidate for the management of ADHD.
      • Whitchouse D
      • Shah U
      • Palmer FB
      Comparison of sustained release and standard methylphenidate in the treatment of minimal brain dysfunction.
      • Pelham Jr, WE
      • Greenslade K
      • Vodde-Hamilton M
      • et al.
      Relative efficacy of long-acting stimulants on children with attention deficit-hyperactivity disorder: a comparison of standard methylphenidate, sustained-release methylphenidate, sustained-release dextroamphetamine, and pemolinc.
      • Fitzpatrick PA
      • Klorman R
      • Brumaghim JT
      • Borgstedt AD
      Effects of sustained-release and standard preparations of methylphenidate on attention deficit disorder.
      One study (also doubleblind, placebo-controlled), however, has shown an apparent advantage of standard methylphenidate over the sustained-release formulation in certain behavioral measures.
      • Pelham Jr, WE
      • Sturgcs J
      • Hoza J
      • et al.
      Sustained release and standard methylphenidate effects on cognitive and social behavior in children with attention deficit disorder.
      The persistence of ADHD into adulthood is now recognized.
      • Wender PH
      Pharmacotherapy of attention-deficithyperactivity disorder in adults.
      Several studies have examined the efficacy of methylphenidate in treating the symptoms of adults with ADHD. An early double-blind, placebo-controlled trial of methylphenidate in 11 adult patients with “minimal brain dysfunction” showed significant improvement in measures such as concentration, temper, or calmness in 8 patients.
      • Wood DR
      • Rcimhcrr FW
      • Wender PH
      • Johnson GE
      Diagnosis and treatment of minimal brain dysfunction in adults: a preliminary report.
      Later studies (also double-blind, placebo-controlled) indicated therapeutic response rates to methylphenidate in 25% to 57% of adults with ADHD-like symptoms.
      • Mattes JA
      • Boswcü L
      • Oliver H
      Methylphenidate effects on symptoms or attention deficit disorder in adults.
      • Gualtieri CT
      • Ondrusck MG
      • Finley C
      Attention deficit disorders in adults.
      • Wender PH
      • Rcimherr FW
      • Wood D
      • Ward M
      A control led study of methylphenidate in the treatment of attention deficit disorder, residual type, in adults.
      This response rate is less than that typically seen in children with ADHD. Potential explanations for this disparity include clinical heterogeneity of the study populations or inadequate dosing.
      • Spencer T
      • Wilens T
      • Biedcrman J
      • Karaone SV
      • Ablon JS
      • Lapey K
      A double-bl i nd, crossover comparison of methylphenidate and placebo in adults with childhood-onset attention-deficit hyperaclivity disorder.
      A subsequent controlled trial of methylphenidate in adults with ADHD using more rigid diagnostic criteria showed a beneficial response in 78%.
      • Spencer T
      • Wilens T
      • Biedcrman J
      • Karaone SV
      • Ablon JS
      • Lapey K
      A double-bl i nd, crossover comparison of methylphenidate and placebo in adults with childhood-onset attention-deficit hyperaclivity disorder.

      Narcolepsy

      Another FDA-approved indication for methylphenidate is for the treatment of narcolepsy. An early trial of methylphenidate (dose range, 20–60 mg/d) in 106 patients with narcolepsy revealed a dose-related improvement in sleepiness and sleep attacks, as well as a beneficial effect on “psychic tension.”
      • Honda Y
      • Hishikawa Y
      • Takahashi Y
      Long-term treatment of narcolepsy with methylphenidate (Ritalin(r)).
      Later controlled trials confirmed that methylphenidate improved the patient's ability to stay awake and had beneficial subjective effects in narcoleptic patients.
      • Mitler MM
      • Shafor R
      • Ilajdukovich R
      • Timms RM
      • Browman CP
      Treatment of narcolepsy: objective studies on methylphenidate, pemolinc, and protriptyline.
      • Mitler MM
      • Hajdukovic R
      • Erman M
      • Koziol JA
      Narcolepsy.

      Medically III Elderly Patients

      Among the earliest uses of methylphenidate was as an antidepressant.
      • Robin AA
      • Wiseberg S
      A controlled trial of methyl phenidate (Ritalin) in the treatment of depressive states.
      • Kerenyi AB
      • Koranyi EK
      • Sarwer-Foner GJ
      Depressive states and drugs, 111: use of methylphenidate (Ritalin) in open psychiatric sellings and in office practice.
      As newer antidepressants were developed, the use of psychostimulants as first-line agents for depression was questioned and is now mainly of historical importance.
      • Satcl SL
      • Nelson JC
      Stimulants in the treatment of depression; a critical overview.
      Interest has persisted, however, in the use of stimulants for depression in certain clinical situationsparticularly as a supplemental agent in treatment-refractory depression
      • McGlohn SE
      • Boslwick JM
      Scrtraline with methylphenidate in an ICU patient [IcttcrJ.
      • Fawcett J
      • Kravitz MM
      • Zajecka JM
      • Schaff MR
      CNS stimulant potcntiation of monoaminc oxidase inhibitors in treatment-refractory depression.
      • Sloll AL
      • Pillay SS
      • Diamond L
      • Workum SB
      • Cole JO
      Methyl phenidate augmentation of serotonin selective reuptake inhibitors: a case series.
      • Bader GM
      • Hawley JM
      • Short DD
      Venlafaxine augmentation with methylphenidate for treatment-refractory depression: a case report [letter].
      and in medically ill elderly patients. While the usefulness of stimulants in the former situation has been questioned,
      • Schweitzer I
      • Tuckwell V
      • Johnson G
      A review of the use of augmentation therapy for the treatment of resistant depression: implications for the clinician [published correction appears in Aust N Z J Psychiatry. 1997;31:787].
      a body of evidence suggests that methylphenidate and other psychostimulants may have a role in the management of neurobehavioral symptoms in the medically ill elderly population.
      Several recent articles have reviewed the uses of stimulants in medically ill patients.
      • Masand PS
      • Tesar GE
      Use of stimulante in the medically ill.
      • Holmes VF
      Medical use of psychostimulants: an overview.
      • Emptage RE
      SemlaTP. Depression in the medically ill elderly: a focus on methylphenidate.
      • Chiuch CC
      • Moore KE
      Blockade by reserpine of methylphenidate-induced release of brain dopamine.
      Certain specific clini- cal situations (brain injury, cancer, acquired immunodeficiency syndrome [AIDS]) will be discussed subsequently in detail. The use of methylphenidate in the geriatric population dates to the 1950s. An early double-blind, placebo-controlled trial of methylphenidate indicated no positive effect on the behavior of a group of elderly, cognitively impaired institutionalized patients.
      • Darvill Jr, FT
      • Woolley S
      Double-blind evaluation of methylphenidate (Ritalin) hydrochloride: its use in the management of institutionalized geriatric patients.
      Nevertheless, stimulants were used to treat depression and apathy in geriatric patients. Uncontrolled studies of a combination medication available at the time (Ritonic) containing methylphenidate, methyltestosterone, ethinyl estradiol, and vitamins supported such use.
      • Bare WW
      A stimulant for the aged: observations on a melhylphenidate vilamin hormone combination (Ritonic).
      • Bare WW
      • Lin DY
      A stimulant for the aged, II: long-term observations with a melhylphenidale-vitamin-hormonc combination (Rilonic).
      A subsequent double-blind, placebo- controlled trial of methylphenidate in 44 withdrawn, apathetic elderly patients showed an apparent beneficial effect of the medication on cognition and functional status.
      • Kaplitz SE
      Withdrawn, apathetic geriatric patients responsive to melhylphenidate.
      A similar study, however, could not confirm a positive effect of methylphenidate on cognitive functioning in moderately impaired elderly persons.
      • Crook T
      • Ferris S
      • Sathananthan G
      • Raskin A
      • Gershon S
      The effect of melhylphenidate on lesl performance in the cognitively impaired aged.
      A senes of case repuns anu rerrospecuve stuuies nave advanced the theory that methylphenidate and other psychostimulants may be useful in particular settings, especially in alleviating depressive symptoms in patients with various medical illnesses.
      • Katon W
      • Raskind M
      Treatment of depression in the medically ill elderly with melhylphenidate.
      • Kaufmann MW
      • Cassem NH
      • Murray GB
      • Jcnike M
      Use of psychoslimulants in medically ill patients with neurological disease and major depression.
      • Kaufmann MW
      • Cassem N
      • Murray G
      • MacDonald D
      The use of melhylphenidate in depressed patients after cardiac surgery.
      • Askinazi C
      • Weintraub RJ
      • Karamouz N
      Elderly depressed females as a possible subgroup of patients responsive to melhylphenidate.
      • Masand P
      • Pickcll P
      • Murray GB
      Psychoslimulants for secondary depression in medical illness.
      • Rosenberg PB
      • Ahmed I
      • Hurwitz S
      Melhylphenidate in depressed medically ill patients.
      A double-blind, placebo-controlled trial of methylphenidate in depressed, medically ill elderly patients subsequently revealed that moderate or dramatic improvement in depressive symptoms was achieved in 10 of 13 patients without serious adverse effects.
      • Wallace AE
      • Kofoed LL
      • West AN
      Double-blind, placebo-controlled trial of melhylphenidate in older, depressed, medically ill palicnis.
      More recent uncontrolled studies suggest potential uses for methylphenidate in apathy due to various etiologies.
      • Marin RS
      • Fogel BS
      • Hawkins J
      • Duffy J
      • Krupp B
      Apathy: a treatable syndrome.
      as treatment of negative symptoms in patients with dementia.
      • Galynker I
      • leronimo C
      • Miner C
      • Rosenblum J
      • Vilkas N
      • Rosenthal R
      Melhylphenidate treatment of negative symptoms in patients with dementia.
      and for treatment of depression and cognitive symptoms in liver transplant recipients.
      • Plutchik L
      • Snyder S
      • Drooker M
      • Chodoff L
      • Shcincr P
      Melhylphenidate in post liver transplant patients.

      Brain Injury

      Psychostimulants including methylphenidate have been evaluated for use in the treatment of the sequelae of brain injuries due to both trauma and stroke.
      • Kraus MF
      Neuropsychiatrie sequelae of stroke and traumatic brain injury: the role of psychoslimulants.
      The results of studies using methylphenidate in the treatment of neurobehavioral symptoms after traumatic brain injury have been mixed. A role for psychostimulants in improving memory and attention in brain-injured patients has been proposed.
      • Evans RW
      • Gualticri CT
      • Patterson D
      Treatment of chronic closed head injury with psychostimulant drugs: a controlled case study and an appropriate evaluation procedure.
      Double-blind, placebo-controlled studies have shown both positive effects of methylphenidate on neurobehavioral symptoms
      • Gualtieri CT
      • Evans RW
      Stimulant treatment for the ncuro-behavioural sequelae of traumatic brain injury.
      • Plenger PM
      • Dixon CE
      • Castillo RM
      • Frankowski R1
      • Yablon SA
      • Levin HS
      Subacute melhylphenidate treatment for moderate to moderately severe traumatic brain injury: a preliminary double-blind placebo-controlled study.
      • Whyte J
      • Hart T
      • Schuster K
      • Fleming M
      • Polansky M
      • Coslctt HB
      Effects of melhylphenidate on attentional function after traumatic brain injury: a randomized, placebo-controlled trial.
      and no pronounced effect.
      • Speech TJ
      • Rao SM
      • Osmon DC
      • Sperry LT
      A double-blind controlled study of melhylphenidate treatment in closed head injury.
      • Williams SE
      • Ris MD
      • Ayyangar R
      • Schcfft BK
      • Berch D
      Recovery in pédiatrie brain injury: is psychostimulant medication beneficial?.
      Heterogeneity of the study populations, particularly the time elapsed since the injury, confound the interpretation of these results. The possibility of carryover effects encountered during placebo-controlled crossover trials has also been identified.
      • Gualtieri CT
      • Evans RW
      Stimulant treatment for the ncuro-behavioural sequelae of traumatic brain injury.
      Psychostimulants may have a role in alleviating certain neurobehavioral symptoms in patients immediately after a brain injury,
      • Plenger PM
      • Dixon CE
      • Castillo RM
      • Frankowski R1
      • Yablon SA
      • Levin HS
      Subacute melhylphenidate treatment for moderate to moderately severe traumatic brain injury: a preliminary double-blind placebo-controlled study.
      • Kaclin DL
      • Cifu DX
      • Matthics B
      Melhylphenidate effect on attention deficit in the acutely brain-injured adult.
      • Hornyak JE
      • Nelson VS
      • Hurvitz EA
      The use of melhylphenidate in pacdiatric traumatic brain injury.
      whereas their ef- fect may be less dramatic when administered at a later time.
      • Gualtieri CT
      • Evans RW
      Stimulant treatment for the ncuro-behavioural sequelae of traumatic brain injury.
      • Speech TJ
      • Rao SM
      • Osmon DC
      • Sperry LT
      A double-blind controlled study of melhylphenidate treatment in closed head injury.
      Case reports
      • Stiebe V
      • Kemp K
      Long-term methylphenidate use in the medically ill patient wilh organic mood syndrome.
      • Vigano A
      • Watanabe S
      • Bruera E
      Mcthylphenidate for the management of somalizalion in terminal cancer patients.
      have indicated that methylphenidate may be useful in the acceleration of recovery from coma.
      • Worzniak M
      • Fetters MD
      • Comfort M
      Melhylphenidate in the treatment of coma.
      although further controlled studies are needed to determine its efficacy for this indication. Specific use of methylphenidate in treating posttraumatic narcolepsy
      • Francisco GE
      • Ivanhoe CB
      Successful treatment of post-traumatic narcolepsy wilh melhylphenidate: a case report.
      and brain injury-related anger
      • Mooney GF
      • Haas LJ
      Effect of mcthylphenidatc on brain injury-related anger.
      has also been reported. Concerns about the possibility of increased risk of seizures in brain-injured patients who are taking methylphenidate have not been substantiated. In fact, the only study addressing this issue showed a reduction in seizure frequency in brain-injured patients with seizure disorders who were taking methylphenidate.
      • Wroblewski BA
      • Leary JM
      • Phelan AM
      • Whyle J
      • Manning K
      Methylphenidatc and seizure frequency in brain injured patients with seizure disorders.
      Case reports and retrospective analyses have pointed toward a role for psychostimulants in stroke patients with depression
      • Kaufmann MW
      • Cassem NH
      • Murray GB
      • Jcnike M
      Use of psychoslimulants in medically ill patients with neurological disease and major depression.
      • Masand P
      • Pickcll P
      • Murray GB
      Psychoslimulants for secondary depression in medical illness.
      and in treating hemineglect after stroke.
      • Hurford P
      • Stringer AY
      • Jann B
      Neuropharmaeologic treatment of hemineglect: a case report comparing bromocriptine and melhylphenidate.
      Retrospective studies have indicated response rates from 52% to 70% in depressed patients who have had a stroke and are being treated with methylphenidate.
      • Iingam VR
      • Lazarus LW
      • Groves L
      • Oh SH
      Melhylphenidate in treating poststroke depression.
      • Johnson ML
      • Roberts MD
      • Ross AR
      • Witten CM
      Methylphenidatc in stroke patients wilh depression.
      • Lazarus LW
      • Moberg PJ
      • Langslcy PR
      • Lingam VR
      Melhylphenidate and nortriptyline in the treatment of poststroke depression: a retrospective comparison.
      Improvement was generally rapid (within 48 hours). An open trial of methylphenidate for depression in patients who had a stroke resulted in full or partial response in 8 of 10 patients.
      • Lazarus LW
      • Winemillcr DR
      • Lingam VR
      • et al.
      Efficacy and side effects of mcthylphenidale for poststroke depression.
      Adverse effects occurred in half of the patients but were mild and did not interrupt therapy. A recent double-blind, placebo-controlled trial showed that methylphenidate may be helpful in the early recovery period after a stroke has occurred.
      • Grade C
      • Rcdford B
      • Chrostowski J
      • Toussaint L
      • Blackwell B
      Mcthylphenidale in early poststroke recovery: a double-blind, placebo-controlled study.
      Twenty-one patients who had a stroke were given either methylphenidate or placebo after admission to a rehabilitation unit. Significant reductions in depression rating scales and enhancements in motor and functional scores were seen in the methylphenidate-treated patients compared with the placebo controls.

      Cancer

      Cancer patients commonly experience cognitive changes, and as many as 50% will develop a depressive disorder during the course of their illness.
      • Massie MJ
      • Holland JC
      Diagnosis and treatment of depression in the cancer patient.
      • McDaniel JS
      • Musselman DL
      • Porter MR
      • Reed DA
      • Nemrroff CB
      Depression in patients with cancer: diagnosis, biology, and treatment.
      Both the disease itself (as in the case of central nervous system tumors) and the various treatments (radiation therapy, chemotherapy, opiates) can contribute to neurobehavioral changes. Methylphenidate has been evaluated as a potential therapy for improving mood, cognition, and pain control in cancer patients.
      While several case reportsl50,151 have suggested a possible role for methylphenidate in improving mood and reducing sedation in cancer patients, few controlled studies have investigated this issue in detail. A series of 5 patients with head and neck cancers were reported to have improvement in mood, appetite, and energy when treated with methylphenidate.
      • Fernandez F
      • Adams F
      Methylphenidate treatment of patients with head and neck cancer.
      These patients were thought to have depression due to their medical illnesses, and, in 1 patient, cognitive changes from radiation therapy delivered to the right hemisphere. A larger study evaluated the response to methylphenidate in 30 cancer patients with depressive symptoms.
      • Fernandez D
      • Adams F
      • Holmes VF
      • Levy JK
      • Ncidhart M
      Methylphenidatc for depressive disorders in cancer patients: an alternative to standard antidepressants.
      These patients needed a rapid response, were at high risk of adverse reactions to tricyclic antidepressants, or had a contraindication to the use of tricyclic antidepressants. Of these 30 patients, 23 had a moderate or substantial improvement in their depressive symptoms with the use of methylphenidate, with most showing a response within a few days after initiation of treatment. A retrospective study of 15 hospitalized cancer patients treated with methylphenidate for depression showed that 80% had a positive response.
      • Olin J
      • Masand P
      Psychostimulants for depression in hospitalized cancer patients.
      Five patients had an improvement in their appetite. Minor side effects were seen in 3 patients. As in the earlier studies, the depressive symptoms improved rapidly (1 to 2 days) in most patients. A less dramatic response rate was seen in a study of 26 hospice patients with advanced malignancies treated with methylphenidate for depression; 46% of these patients showed a therapeutic response.
      • Macleod AD
      Methylphenidate in terminal depression.
      Only 7% of patients in the last stages of their illness (within 6 weeks of death) showed improvement in their depressive symptoms.
      Interest has arisen in the use of methylphenidate in patients with brain tumor who routinely experience neuropsychiatric effects from both the tumor and the various treatment strategies. Improvement in neurobehavioral slowing was seen in 3 patients with brain tumors treated with low-dose methylphenidate.
      • Weitzner MA
      • Meyers CA
      • Valentine AD
      Methylphenidate in the treatment of ncurobehavioral slowing associated with cancer and cancer treatment.
      In 30 patients with malignant gliomas treated with methylphenidate, improvements in cognitive functioning and performance status were demonstrated despite ongoing neurologic injury due to disease progression or radiation therapy in half of these patients.
      • Meyers CA
      • Weitzner MA
      • Valentine AD
      • Levin VA
      Methylphenidate therapy improves cognition, mood. and function of brain tumor patients.
      In a series of 12 children with brain tumors or acute lymphocytic leukemia and consequent tumor- or therapy-induced. neurologic injury, 10 showed improvement in attention, academic performance, language skills, memory, or behavior when treated with methylphenidate.
      • Delong R
      • Friedman H
      • Friedman N
      • Gustafson K
      • Oakes J
      Mcthylphcnidate in neuropsychological sequelae of radiotherapy and chemotherapy of childhood brain tumors and leukemia [letter].
      Psychostimulants can potentiate the effects of opioid analgesics.
      • Dalai S
      • Melzack R
      Psychostiulant drugs potentiate morphine analgesia in the formalin test.
      • Dalat S
      • Melzack R
      Potentiation of opioid analgesia by psycho-stimulant drugs: a review.
      Methylphenidate has been studied as adjuvant therapy for cancer patients receiving narcotics. In a randomized, double-blind, placebo-controlled crossover trial of 32 patients with advanced cancer receiving chronic opiate therapy, statistically significant reductions in pain intensity and sedation were seen with the use of methylphenidate.
      • Bruera H
      • Chadwick S
      • Brenneis C
      • Hanson J
      • MacDonald RN
      Methylphenidate associated with narcotics for the treatment of cancer pain.
      A more recent study of methylphenidate showed no added benefit in patients taking narcotics for cancer pain but suggested some improvement in sedation.
      • Wilwerding MB
      • Loprinzi CL
      • Mailliard JA
      • et al.
      A randomized, crossover evaluation of melhylphenidate in cancer patients receiving strong narcotics.
      In a study of 50 patients with advanced cancer and opiate-induced sedation, 44 had a decrease in sedation after initiation of methylphenidate.
      • Bruera L
      • Brenneis C
      • Paterson AH
      • MacDonald RN
      Use of mcthylphcnidate as an adjuvant to narcotic analgesics in patients with advanced cancer, /.
      Tolerance to this effect was seen over a period of 1 month. Patients with incident cancer pain (mild or no pain at rest, severe pain during movements) showed better pain control, and they tolerated higher doses of narcotics when supplemented with methylphenidate.
      • Bruera E
      • Fainsinger R
      • MacEachcm T
      • Hanson J
      The use of melhylphenidate in patients with incident cancer pain receiving regular opiates: a preliminary report.
      A placebo-controlled trial demonstrated that the addition of oral methylphenidate resulted in improved cognitive function in 20 patients receiving continuous subcutaneous narcotics for cancer pain.
      • Bruera E
      • Miller MJ
      • Macmillan K
      • Kuehn N
      Neuropsycho-togical effects of methylphenidate in patients receiving a continuous infusion of narcotics for cancer pain.
      Similarly, 5 of 11 adolescent cancer patients receiving opiates exhibited improved interaction with family or decreased somnolence when methylphenidate was added to their medication regimen.
      • Yee JD
      Bcrde Cfi. Dextroamphctaminc or mcthylphcnidate as adjuvants to opioid analgesia for adolescents with cancer.

      Hiv Infection

      Cognitive impairment and neuropsychiatric symptoms are common in people infected with HIV −1. Impaired memory, decreased attention, and related neurobehavioral symptoms are typical features. These features have prompted interest in the use of psychostimulants in this group of patients.
      • Brown GR
      The use of methylphenidate for cognitive decline associated with HIV disease.
      Case reports have indicated the potential role for methylphenidate in addressing cognitive difficulties and depression in patients with AIDS.
      • Fernandez F
      • Levy JK
      • Galizzi H
      Response of HIV-related depression to psychostimulants; case reports.
      • Walling VR
      • Pfefferbaum B
      The use of methylphenidate in a depressed adolescent with AIDS.
      Uncontrolled trials of methylphenidate, amphetamine, or both in patients with HIV-related -related cognitive decline or depression have shown a positive effect of these agents on both subjective and objective neurobehavioral factors,
      • Fernandez F
      • Adams F
      • Levy JK
      • Holmes VF
      • Neidhart M
      • Mansell PW
      Cognitive impairment due to AIDS-related complex and its response to psychostimulants.
      • Holmes VF
      • Fernandez F
      • Levy JK
      Psychostimulant response in AIDS-related complex patients.
      • Angrist B
      • d'Hollosy M
      • Sanfilipo M
      • et al.
      Central nervous system stimulants as symptomatic treatments lor AIDS-related neuropsychiatrie impairment.
      although the lack of a control group in these studies limits their usefulness. A comparative trial of methylphenidate and desipramine showed similar efficacy between the 2 drugs in alleviating depressive symptoms.
      • Fernandez F
      • Levy JK
      • Samley HR
      • et al.
      Effects of methylphenidate in HIV-relaled depression: a comparative trial with desi-praminc.
      A double-blind, placebo-controlled trial of methylphenidate in a single AIDS patient demonstrated improved scores concerning depression and possibly enhanced cognitive functioning.
      • White JC
      • Christensen JF
      • Singer CM
      Methylphenidate as a treatment for depression in acquired immunodeficiency syndrome: an n-of-1 trial.
      More recently, however, a double-blind, placebo-controlled crossover trial of sustained-release methylphenidate in HIV-l-infected drug abusers failed to show that methylphenidate was superior to placebo in the treatment of cognitive impairment.
      • van Dyck CH
      • McMahon TJ
      • Rosen Ml
      • et al.
      Sustained-release methylphenidate for cognitive impairment in HIV-1-infected drug abusers: a pilot study.
      Small sample size and the effects of time, medical treatment, and drug abstinence on the results of neuropsychological testing are factors that may preclude generalization of these results. Larger, longer-term studies are needed.

      Dosing, Adverse Effects, And Risk Of Abuse

      Methylphenidate is FDA-approved for use in children older than 6 years and in adults. Typical dosing schedules for various indications are shown in Table 1. Potential adverse effects of methylphenidate are listed in Table 2. Several issues regarding possible adverse effects deserve special mention. Anorexia is a common adverse effect of stimulant use, and there have been concerns that methylphenidate may suppress growth in children being treated for ADHD. Whether growth alterations are a direct methylphenidate effect
      • Klein RG
      • Landa B
      • Mattes JA
      • Klein DF
      Methylphenidate and growth in hyperactive children: a controlled withdrawal study.
      • Klein RG
      • Mannuzza S
      Hyperactive boys almost grown up. III melhylphenidate effects on ultimate height.
      • Vincent J
      • Varlcy CK
      • Leger P
      Effects of methylphenidate on early adolescent growth.
      or related to ADHD itself,
      • Spencer TJ
      • Biederman J
      • Harding M
      • O'Donnell D
      • Faraone SV
      • Wilens TE
      Growth deficits in ADHD children revisited: evidence for disorder-associated growth delays?.
      the cause and importance of these decreases in growth velocity remain unresolved. Another lingering issue is the role of stimulants in precipitating or exacerbating tic disorders.
      • Lowe TL
      • Cohen DJ
      • Detlor J
      • Kremenitzer MW
      • Shaywiu BA
      Stimulant medications precipitate Tourelte's syndrome.
      Recent studies have indicated that methylphenidate, in usual doses, does not cause tics in most children or worsen tics in children with mild to moderate tic disorders.
      • Gadow KD
      • Sverd J
      • Sprafkin J
      • Nolan EE
      • Grossman S
      Long-term methylphenidate therapy in children with comorbid attention-deficit hyperactivity disorder and chronic multiple tic disorder.
      • Law SF
      • Schachar RJ
      Do typical clinical doses of methylphenidate cause tics in children treated for attention-deficit hyperactivity disorder?.
      Observation for the development or exacerbation of tics in patients taking methylphenidate is still recommended, however, because some patients may be susceptible.
      Table 1Dosing Regimen for Methylphenidate
      Age groupIndicationTypical initial doseUsual maximal daily dose
      Children (>6 y)Attention-deficit/hyperactivity disorderRegular release: 5 mg twice daily, with or after breakfast and lunch Sustained release: 20 mg once daily60 mg
      AdultsAttention-deficit/hyperactivity disorder, narcolepsyRegular release: 5 to 20 mg 2 to 3 times daily, with or after meals90 mg
      Sustained release: 20 mg 1 to 3 limes daily, at 8-h intervals
      Depression due to medical illnessRegular release: 5 to 10 mg 2 to 3 times daily30 mg
      Table 2Selected Methylphenidate Adverse Effects
      SystemMore frequentLess frequent
      CardiovascularHypertension, tachycardiaAngina, dysrhythmias
      Central nervous systemInsomnia, nervousnessHeadache, dizziness, dyskinesia
      GastrointestinalAnorexiaNausea, abdominal pain, weight loss
      DermatologicRash, urticaria
      The abuse potential of methylphenidate is another issue that has received considerable attention. Methylphenidate and cocaine both bind to the dopamine transporter and compete for the same binding sites in the striatum.
      • Volkow ND
      • Ding YS
      • Fowler JS
      • et al.
      Is methylphenidate like cocaine? studies on their pharmacokinetics and distribution in the human brain.
      When given intravenously, methylphenidate can induce a sensation of euphoria.
      • Volkow ND
      • Ding YS
      • Fowler JS
      • et al.
      Is methylphenidate like cocaine? studies on their pharmacokinetics and distribution in the human brain.
      Methylphenidate has been abused both intravenously
      • Parran Jr, TV
      • Jasinski DR
      Intravenous methylphenidate abuse: prototype for prescription drug abuse.
      and intranasally.
      • Massello III, W
      • Carpenter DA
      A fatality due to the intranasal abuse of methylphenidate (Ritalin).
      • Garland EJ
      Intranasal abuse of prescribed methylphenidate (Ict-erj.
      Despite these facts, methylphenidate has a much lower abuse potential than cocaine, possibly related to other pharmacological differences between the 2 drugs.
      • Volkow ND
      • Wang GJ
      • Fowler JS
      • et al.
      Methylphenidate and cocaine have a similar in vivo potency to block dopamine transporters in the human brain.
      Numerous studies in adults have shown no indication that the use of oral methylphenidate in the medically ill population leads to problems of abuse.
      • Masand PS
      • Tesar GE
      Use of stimulante in the medically ill.
      It is prudent, however, to always remember the possibility of abuse or diversion of the drug, keep careful records, and consider using nonstimulant medications in patients who have a personal or family history of current or past substance abuse problems.
      • Goldman LS
      • Gcncl M
      • Bezman RJ
      • Slanctz PJ
      Council on Scientific Affairs. American Medical Association. Diagnosis and treatment of attention-deficit/hypcractivity disorder in children and adolescents.

      Conclusions

      Methylphenidate is widely used in the United States. Its mechanism of action and pharmacology, which are distinct from those of other central nervous system stimulants such as amphetamine, illustrate the increasing importance of understanding issues of stereospecificity in drug action. While appropriate concerns have been raised regarding the possible long-term effects and abuse potential of methylphenidate, there is evidence that its utility may extend beyond solely the treatment of ADHD (Table 3). Studies support a role for methylphenidate in the treatment of depressive symptoms in medically ill elderly patients and stroke patients. Psychostimulants may be most beneficial in patients in whom a rapid response in the depressive symptoms is desired or in whom potential adverse effects of standard antidepressants would be undesirable. Depressive symptoms and cognitive functioning in cancer patients may be improved by the addition of methylphenidate, although the absence of controlled trials limits conclusive recommendations. Stronger evidence exists showing the usefulness of psychostimulants in potentiating the analgesic effects of opiates and in reducing opiate-induced sedation. Currently, there is no conclusive evidence that methylphenidate accelerates recovery in patients with traumatic brain injury or ameliorates cognitive impairment in patients with HIV infection; thus, further controlled studies are needed to help further define its usefulness in these patients.
      Table 3Some Proven and Unproven Uses of Methylphenidate
      Clinical useEfficacy supported by double-blind, placebo-controlied trialReferences
      Attention-dcficit/hyperactivity disorderYes
      • Goldman LS
      • Gcncl M
      • Bezman RJ
      • Slanctz PJ
      Council on Scientific Affairs. American Medical Association. Diagnosis and treatment of attention-deficit/hypcractivity disorder in children and adolescents.
      ,
      National Institutes of Health Consensus Development Conference Statement; diagnosis and treatment of attention-deficit/hyperactivity disorder (ADHD).
      NarcolepsyYes
      • Mitler MM
      • Shafor R
      • Ilajdukovich R
      • Timms RM
      • Browman CP
      Treatment of narcolepsy: objective studies on methylphenidate, pemolinc, and protriptyline.
      ,
      • Mitler MM
      • Hajdukovic R
      • Erman M
      • Koziol JA
      Narcolepsy.
      Depression in medically ill (including stroke) elderly personsYes
      • Wallace AE
      • Kofoed LL
      • West AN
      Double-blind, placebo-controlled trial of melhylphenidate in older, depressed, medically ill palicnis.
      ,
      • Grade C
      • Rcdford B
      • Chrostowski J
      • Toussaint L
      • Blackwell B
      Mcthylphenidale in early poststroke recovery: a double-blind, placebo-controlled study.
      Alleviation of neurobchavioral symptoms after traumatic brain injuryMixed
      • Gualtieri CT
      • Evans RW
      Stimulant treatment for the ncuro-behavioural sequelae of traumatic brain injury.
      ,
      • Plenger PM
      • Dixon CE
      • Castillo RM
      • Frankowski R1
      • Yablon SA
      • Levin HS
      Subacute melhylphenidate treatment for moderate to moderately severe traumatic brain injury: a preliminary double-blind placebo-controlled study.
      ,
      • Whyte J
      • Hart T
      • Schuster K
      • Fleming M
      • Polansky M
      • Coslctt HB
      Effects of melhylphenidate on attentional function after traumatic brain injury: a randomized, placebo-controlled trial.
      ,
      • Speech TJ
      • Rao SM
      • Osmon DC
      • Sperry LT
      A double-blind controlled study of melhylphenidate treatment in closed head injury.
      ,
      • Williams SE
      • Ris MD
      • Ayyangar R
      • Schcfft BK
      • Berch D
      Recovery in pédiatrie brain injury: is psychostimulant medication beneficial?.
      Improvement in pain control, sedation, or both in patients receiving opiatesYes
      • Dalai S
      • Melzack R
      Psychostiulant drugs potentiate morphine analgesia in the formalin test.
      ,
      • Dalat S
      • Melzack R
      Potentiation of opioid analgesia by psycho-stimulant drugs: a review.
      ,
      • Bruera H
      • Chadwick S
      • Brenneis C
      • Hanson J
      • MacDonald RN
      Methylphenidate associated with narcotics for the treatment of cancer pain.
      ,
      • Wilwerding MB
      • Loprinzi CL
      • Mailliard JA
      • et al.
      A randomized, crossover evaluation of melhylphenidate in cancer patients receiving strong narcotics.
      ,
      • Bruera L
      • Brenneis C
      • Paterson AH
      • MacDonald RN
      Use of mcthylphcnidate as an adjuvant to narcotic analgesics in patients with advanced cancer, /.
      ,
      • Bruera E
      • Fainsinger R
      • MacEachcm T
      • Hanson J
      The use of melhylphenidate in patients with incident cancer pain receiving regular opiates: a preliminary report.
      ,
      • Bruera E
      • Miller MJ
      • Macmillan K
      • Kuehn N
      Neuropsycho-togical effects of methylphenidate in patients receiving a continuous infusion of narcotics for cancer pain.
      ,
      • Yee JD
      Bcrde Cfi. Dextroamphctaminc or mcthylphcnidate as adjuvants to opioid analgesia for adolescents with cancer.
      Treatment of cognitive impairment in patients with human immunodeficiency virus infectionNo
      • van Dyck CH
      • McMahon TJ
      • Rosen Ml
      • et al.
      Sustained-release methylphenidate for cognitive impairment in HIV-1-infected drug abusers: a pilot study.

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